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In a groundbreaking study, a team of UC Davis discount coupon cialis researchers has discovered a special type of stem cell that can reduce the amount of the cialis causing AIDS, boosting the body’s antiviral immunity and repairing and restoring the gut’s lymphoid follicles damaged by the simian immunodeficiency cialis (SIV), the equivalent of the human immunodeficiency cialis (HIV) in non-human primates. HIV disrupts the lymphoid immune battlegroundThe study, published June 22 in JCI Insight, showed the mechanism through which mesenchymal stem/stromal discount coupon cialis cells (MSCs) enhance the body’s immune response to the cialis. It also provides a roadmap for developing multi-pronged HIV eradication strategies.“Impaired immune functions in HIV and incomplete immune recovery pose obstacles for eradicating HIV,” said Satya Dandekar, senior author of this paper. €œOur objective was to develop strategies to boost immunity against the cialis and empower the host immune discount coupon cialis system to eradicate the cialis.

We sought to repair, regenerate and restore the lymphoid follicles that are damaged by the viral .”The lymphoid tissue in the gut is an early site for viral replication and the establishment of viral reservoirs. Dandekar’s group has previously shown that an HIV causes severe loss of gut mucosal T immune cells and disrupts the gut epithelial barrier lining, leading to a leaky gut.“The lymphoid follicles are organized structures discount coupon cialis where the long-term immune attack is launched against pathogens by generating antibody response targeting the cialis. These important regions are functionally impaired very early following HIV ,” Dandekar said.While antiretroviral drugs effectively suppress viral replication, they do not repair the damage caused by the cialis to the immune system. On their own, these drugs cannot restore the functionality of the lymphoid discount coupon cialis follicles damaged by HIV .Can stem cells counteract the gut damage caused by HIV?.

The researchers administered bone marrow-derived MSC in a rhesus macaque model of AIDS that had impaired immunity and disrupted gut functions due to the viral .“We are starting to recognize the great potential of these stem cells in the context of infectious diseases. We have yet to discover how these stem cells can impact chronic viral s such as AIDS,” discount coupon cialis Dandekar said. She is a professor at and the chairperson of the Department of Medical Microbiology and Immunology at UC Davis and affiliated with the California National Primate Research Center.The study found that the MSCs can modulate, alter and remodel the damaged mucosal site. There were immediate benefits, with a rapid rise in antibodies and discount coupon cialis T-immune cells targeting the cialis.

The stem cells were instrumental in the recovery and restoration of these lymphoid follicles.MSCs also offer an opportunity for an innovative, multi-pronged HIV cure strategy by complementing current HIV treatments.“Stem cells are good synergistic partner components with drugs. The antiretroviral drugs can stop the fire of the viral but cannot restore the discount coupon cialis forest of the lymphoid tissue compartment. The MSCs would rejuvenate the field and bring back immune vitality,” Dandekar said.Even without the use of antiviral drugs, MSCs were able to increase the host’s antiviral response by repairing the lymphoid follicles, restoring the mucosal immunity and reviving what has been targeted by the cialis very early on.MSC treatmentsMSC treatments require well defined cell quality controls and specific delivery mechanisms. The UC Davis Stem Cell Program, a center for excellence for stem cell research, is leading multiple clinical trials on MSC discount coupon cialis use in treating diseases such as spina bifida and Huntington’s disease.

Findings from this study provide a scientific basis for investigating MSC in treating HIV and other infectious diseases in the clinical setting.###Co-authors on this study are Mariana G. Weber, Chara discount coupon cialis J. Walters-Laird, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Juan Arredondo, discount coupon cialis Amir Kol, Sonny R.

Elizaldi, Smita S. Iyer and Alice Tarantal at UC Davis, and Bipin Balan at Università di Palermo, Italy.This work was supported by National Institutes of Health grants (R01AI discount coupon cialis 153025, R21 AI 116415, R21AI34368, and OD P51 OD011107) and from the National Council for Scientific and Technological Development (CNPq), Brazil.Article. Weber et al. (2021) Gut germinal center regeneration and enhanced antiviral discount coupon cialis immunity by mesenchymal stem/stromal cells in SIV .

JCI Insight. 6(12), Doi:10.1172/jci discount coupon cialis. Insight.149033.The secret to healthier skin and joints may reside in gut microorganisms. A study led by UC Davis Health researchers has found that a diet rich in sugar discount coupon cialis and fat leads to an imbalance in the gut’s microbial culture and may contribute to inflammatory skin diseases such as psoriasis.

Changing from a Western diet to a balanced diet may reduce skin and joint inflammation.The study, published in the Journal of Investigative Dermatology, suggests that switching to a more balanced diet restores the gut’s health and suppresses skin inflammation.“Earlier studies have shown that Western diet, characterized by its high sugar and fat content, can lead to significant skin inflammation and psoriasis flares,” said Sam T. Hwang, professor and chair of dermatology at UC Davis discount coupon cialis and senior author on the study. €œDespite having powerful anti-inflammatory drugs for the skin condition, our study indicates that simple changes in diet may also have significant effects on psoriasis.”What is psoriasis?. Psoriasis is a stubborn skin condition linked to the discount coupon cialis body’s immune system.

When immune cells mistakenly attack healthy skin cells, they cause skin inflammation and the formation of scales and itchy red patches.Up to 30% of patients with psoriasis also have psoriatic arthritis with symptoms such as morning stiffness and fatigue, swollen fingers and toes, pain in joints and changes to nails.Diet affects the microbial balance in the intestines and skin inflammationFood is one of the major modifiable factors regulating the gut microbiota, the community of microorganisms living in the intestines. Eating a Western diet can cause rapid change to discount coupon cialis the gut’s microbial community and its functions. This disruption in microbial balance – known as dysbiosis- contributes to gut inflammation.Since bacteria in the gut may play key roles in shaping inflammation, the researchers wanted to test whether intestinal dysbiosis affects skin and joint inflammation. They used a mouse model discount coupon cialis to study the effect of diet on psoriasis and psoriatic arthritis.

They injected mice with Interleukin-23 (IL-23) minicircle DNA to induce a response mimicking psoriasis-like skin and joint diseases.IL-23 is a protein generated by the immune cells responsible for many inflammatory autoimmune reactions, including psoriasis and inflammatory bowel disease (IBD).Hwang and his colleagues found that a short-term Western diet appears sufficient to cause microbial imbalance and to enhance susceptibility to IL-23‒mediated psoriasis-like skin inflammation.“There is a clear link between skin inflammation and changes in the gut microbiome due to food intake,” Hwang said. €œThe bacterial balance in the gut disrupted shortly after starting a discount coupon cialis Western diet, and worsened psoriatic skin and joint inflammation.”One critical finding of their work was identifying the intestinal microbiota as a pathogenic link between diet and the displays of psoriatic inflammation. The study also found that antibiotics block the effects of the Western diet, reducing skin and joint inflammation.Is the damage caused by an unhealthy diet reversible?. The researchers wanted to test if switching to a balanced diet can restore discount coupon cialis the gut microbiota, despite the presence of IL-23 inflammatory proteins.

They fed mice a Western diet for six weeks before giving them an IL-23-inducing agent to trigger psoriasis and psoriatic arthritis features. Then, they discount coupon cialis randomly divided the mice into two groups. A group that continued the Western diet for another four weeks and a group that switched to a balanced diet for the same duration.Their study showed that eating a diet high in sugar and fat for 10 weeks predisposed mice to skin and joint inflammation. Mice that discount coupon cialis were switched to a balanced diet had less scaling of the skin and reduced ear thickness than mice on a Western diet.

The improvement in skin inflammation for mice taken off the Western diet indicates a short-term impact of the Western diet on skin inflammation.This suggests that changes in diet could partially reverse the proinflammatory effects and alteration of gut microbiota caused by the Western diet.“It was quite surprising that a simple diet modification of less sugar and fat may have significant effects on psoriasis,” said Zhenrui Shi, visiting assistant researcher in the UC Davis Department of Dermatology and lead author on the study. €œThese findings reveal that patients with psoriatic skin and joint disease should consider changing to a healthier dietary discount coupon cialis pattern.”“This work reflects a successful collaboration among researchers, especially with Professor Satya Dandekar and her team at the Department of Medical Microbiology and Immunology and Professor Yu-Jui Yvonne Wan at the Department of Medical Pathology and Laboratory Medicine,” Hwang said.### Co-authors on this study are Xuesong Wu, Mindy Huynh, Mimi Nguyen, Timothy Law, Daisuke Yamada, Clarissa Santos Rocha and Matthew Rolston at the University of California, Davis. Zhenrui Shi at the University of California, Davis and the Sun Yat-sen University, China. Emma Garcia-Melchor and Neal discount coupon cialis L.

Millar at the University of Glasgow, United Kingdom. And Kelly discount coupon cialis N. Haas at University of Massachusetts Amherst.This study was supported by the National Psoriasis Foundation Discovery and Translational Grants, a National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant (1R01AR063091-01A1), and a National Cancer Institute/National Institutes of Health grant (1R01CA222490).Article. Shi et al discount coupon cialis.

(2021). Short-Term Western Diet Intake discount coupon cialis Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice. Journal of Investigative Dermatology, doi:10.1016/j.jid.2020.11.032.

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Customers return year active ingredient in cialis and viagra after year to obtain the new pin design. All proceeds from angel pin sales are used to support new technology and patient services at the Medical Center.For 25 years, the Psychiatric Partial Hospitalization Program (PHP) at MidMichigan Medical Center – Gratiot has provided an intensive therapeutic outpatient day program for patients. Since opening its doors in November 1995, the program staff have helped more than 2,500 individuals and continues to serve the Central Michigan area and beyond, having served 17 counties throughout the state of Michigan active ingredient in cialis and viagra. The Medical Center’s PHP program is one of only 25 in Michigan, and Gratiot is home to one of only three north of Lansing.The program offers daily treatment for those who need something more than a weekly appointment yet do not require an inpatient stay.

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Chuck Sherwin, president, MidMichigan Medical Center – Alpena with volunteer Barb Nye.Barb Nye, dedicated volunteer discount coupon cialis at http://www.rsflowerdesign.co.uk/product/romeo-juliet/ MidMichigan Medical Center – Alpena, has pinned the 2020 angel pin on the lapel of Chuck Sherwin, president. Barb has been an involved volunteer at the Medical Center since early 2019. She has served in a wide variety of roles including Fundraising, Lobby Greeter, Surgical Lounge, Cancer Center and as a clerk in the volunteers’ gift shop, The Gift Corner discount coupon cialis.

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Those interested in referral information or details on insurance coverage may call the Psychiatric Partial Hospitalization program at (989) 466-3253. Those interested in more information on MidMichigan’s comprehensive behavioral health programs may visit www.midmichigan.org/mentalhealth..

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The Medicare Savings Program cialis generico en colombia includes the Qualified Medicare Beneficiary (QMB) http://karenlkaplan.com/kiwanis-event-june-27-hackneys-glenview-illinois/ program, which covers beneficiaries up to 100% FPL. Specified Low-Income Medicare Beneficiary (SLIMB), for those between 100-120%. And the Qualified Individual (QI-1) program, for individuals between 120-135% FPL. There are no resource tests in New York's Medicare Savings Program.) The New York State Department of Health posts the Medicare Savings Program income guidelines on their website cialis generico en colombia. Just like Medicaid, Medicare Savings Program recipients are deemed into LIS and don't need to apply through SSA.

For more information see this article. 3) by applying for Extra Help cialis generico en colombia through the Social Security Administration. The Extra Help income limits are 150% FPL and there is an asset test. SSA lists the income and resource limits for Extra Help on their website, where you can also file an application online and get more information about the program. You can cialis generico en colombia also find out information about Extra Help in many different languages.

See Medicare Rights Center chart on Extra Help Income and Asset Limits - updated annually You can apply for Extra Help and MSP at the same time through SSA. SSA will forward your Extra Help application data to the New York State Department of Health, who will use that data to assess your eligibility for MSP. Individuals who apply for LIS through SSA and those who are deemed into LIS should receive written confirmation of their Extra cialis generico en colombia Help status through SSA. Of course, individuals who apply for LIS through SSA and are found ineligible are also entitled to a written notice and have appeal rights. Benefits of Extra Help 1) Assistance with Part D cost-sharing The Extra Help program provides a subsidy which covers most (but not all) of beneficiary’s cost sharing obligations.

Extra Help beneficiaries do not have to worry about hitting the “donut hole” – the LIS subsidy continues to cover cialis generico en colombia them through the donut hole and into catastrophic coverage. Full Extra Help. LIS beneficiaries with incomes up to 135% FPL are generally eligible for "full" Extra Help -- meaning they pay no Part D deductible, no charge for monthly premiums up to the benchmark amount, and fixed, relatively low co-pays (between $1.30 and $8.95 for 2020 depending on the person's income level and the tier category of the drug. Medicaid beneficiaries in nursing homes, waiver programs, cialis generico en colombia or managed long term care have $0 co-pays). Full Extra Help beneficiaries who hit the catastrophic coverage limit have $0 co-pays.

See current co-pay levels here. Partial Extra cialis generico en colombia Help. Beneficiaries between 135%-150% FPL receive "partial" Extra Help, which limits the Part D deductible to $89 (2020 figure - click here for updated chart). Sets sliding scale fees for monthly premiums. And limits co-pays to 15%, until the beneficiary reaches the catastrophic coverage limit, at which point co-pays are limited to a $8.95 maximum (2020 or see current amount here) or 5% of cialis generico en colombia the drug cost, whichever is greater.

2) Facilitated enrollment into a Part D plan Extra Help recipients who aren’t already enrolled in a Part D plan and don’t want to choose one on their own will be automatically enrolled into a benchmark plan by CMS. This facilitated enrollment ensures that Extra Help recipients have Part D coverage. However, the downside to facilitated enrollment is that the plan may not be the best “fit” for the beneficiary, if it doesn’t cover all his/her cialis generico en colombia drugs, assesses a higher tier level for covered drugs than other comparable plans, and/or requires the beneficiary to go through administrative hoops like prior authorization, quantity limits and/or step therapy. Fortunately, Extra Help recipients can always enroll in a new plan … see #3 below. 3) Continuous special enrollment period Extra Help recipients have a continuous special enrollment period, meaning that they can switch plans at any time.

They are not “locked into” the annual cialis generico en colombia open enrollment period (October 15-December 7). NOTE. This changed in 2019. Starting in 2019, those with Extra Help will cialis generico en colombia no longer have a continuous enrollment period. Instead, Extra Help recipients will be eligible to enroll no more than once per quarter for each of the first three quarters of the year.

4) No late enrollment penalty Non LIS beneficiaries generally face a premium penalty (higher monthly premium) if they delayed their enrollment into Part D, meaning that they didn’t enroll when they were initially eligible and didn’t have “creditable coverage.” Extra Help recipients do not have to worry about this problem – the late enrollment penalty provision does not apply to LIS beneficiaries. 1) For “deemed” beneficiaries (Medicaid/Medicare cialis generico en colombia Savings Program recipients). Extra Help status lasts at least until the end of the current calendar year, even if the individual loses their Medicaid or Medicare Savings Program coverage during that year. Individuals who receive Medicaid or a Medicare Savings Program any month between July and December keep their LIS status for the remainder of that calendar year and the following year. Getting Medicaid coverage for even just a short period of time (ie, meeting a spenddown for just one month) can help ensure that the individual obtains Extra cialis generico en colombia Help coverage for at least 6 months, and possibly as long as 18 months.

TIP. People with a high spend-down who want to receive Medicaid for just one month in order to get Extra Help for 6-18 months can use past medical bills to meet their spend-down for that one month. There are different rules for using past paid medical bills verses past cialis generico en colombia unpaid medical bills. For information see Spend down training materials. Individuals who are losing their deemed status at the end of a calendar year because they are no longer receiving Medicaid or the Medicare Savings Program should be notified in advance by SSA, and given an opportunity to file an Extra Help application through SSA.

2) For “non-deemed” beneficiaries (those who filed their LIS applications through cialis generico en colombia SSA) Non-deemed beneficiaries retain their LIS status until/unless SSA does a redetermination and finds the individual ineligible for Extra Help. There are no reporting requirements per se in the Extra Help program, but beneficiaries must respond to SSA’s redetermination request. What to do if the Part D plan doesn't know that someone has Extra Help Sometimes there are lengthy delays between the date that someone is approved for Medicaid or a Medicare Savings Program and when that information is formally conveyed to the Part D plan by CMS. As a practical cialis generico en colombia matter, this often results in beneficiaries being charged co-pays, premiums and/or deductibles that they can't afford and shouldn't have to pay. To protect LIS beneficiaries, CMS has a "Best Available Evidence" policy which requires plans to accept alternative forms of proof of someone's LIS status and adjust the person's cost-sharing obligation accordingly.

LIS beneficiaries who are being charged improperly should be sure to contact their plan and provide proof of their LIS status. If the plan still won't recognize their LIS cialis generico en colombia status, the person or their advocate should file a complaint with the CMS regional office. The federal regulations governing the Low Income Subsidy program can be found at 42 CFR Subpart P (sections 423.771 through 423.800). Also, CMS provides detailed guidance on the LIS provisions in chapter 13 of its Medicare Prescription Drug Benefit Manual. This article was authored by the Empire Justice Center.Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for cialis generico en colombia low-income Medicare beneficiaries and qualify enrollees for the "Extra Help" subsidy for Part D prescription drugs.

There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below. Those in QMB receive additional subsidies for Medicare costs. See 2019 Fact Sheet on MSP in NYS by Medicare cialis generico en colombia Rights Center ENGLISH SPANISH State law. N.Y. Soc.

Serv. L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1. No Asset Limit 1A.

Summary Chart of MSP Programs 2. Income Limits &. Rules and Household Size 3. The Three MSP Programs - What are they and how are they Different?. 4.

FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5. Enrolling in an MSP - Automatic Enrollment &. Applications for People who Have Medicare What is Application Process?. 6.

Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7. What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A.

SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &. Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?.

Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No retro for January application). See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?.

YES YES NO!. Must choose between QI-1 and Medicaid. Cannot have both, not even Medicaid with a spend-down. 2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits.

The income limits are tied to the Federal Poverty Level (FPL). 2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below. NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment).

Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y. Soc. Serv.

L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded. The most common income disregards, also known as deductions, include. (a) The first $20 of your &.

Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS. * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind.

(c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO.

18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE. Bob's Social Security is $1300/month.

He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit. In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO. DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010.

This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP. When is One Better than Two?. Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a).

(Link is to NYC HRA form, can be adapted for other counties). 3. The Three Medicare Savings Programs - what are they and how are they different?. 1. Qualified Medicare Beneficiary (QMB).

The QMB program provides the most comprehensive benefits. Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive. The program’s benefits will begin the month after the month in which your client is found eligible.

** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB). For those with http://www.mstopjobandfriends.net/?p=1008 incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months.

3. Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year.

(GIS 07 MA 027) So if you apply in January, you get no retroactive coverage. Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice. DOH MRG p.

19. In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST). Benefit 1.

Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year. The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL. However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit.

People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy. Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients.

In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application. The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability.

An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center. If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties... For life..

Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer. Benefit 3. No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55.

Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits. Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses.

Benefit 4. SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections.

Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?. And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification. New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods.

Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit. It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits.

See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below.

Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP. See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B.

Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing. Strategy TIP.

Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive. Note. The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application.

As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program. Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare.

If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev. 8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &.

Back), and proof of residency/address. See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time. If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1.

Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare. To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district.

The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification. NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district.

See 2014 LCM-02. Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit.

Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down. If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility. EXAMPLE.

Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016. Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund.

This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p.

19). Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6.

Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013. In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment.

The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program. Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums. In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period.

(The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st). 7. What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check. SSA also refunds any amounts owed to the recipient.

Just like Medicaid, Medicare Savings Program recipients discount coupon cialis are deemed into LIS and don't need to apply through SSA click here for more info. For more information see this article. 3) by applying for Extra Help through the Social Security Administration. The discount coupon cialis Extra Help income limits are 150% FPL and there is an asset test.

SSA lists the income and resource limits for Extra Help on their website, where you can also file an application online and get more information about the program. You can also find out information about Extra Help in many different languages. See Medicare Rights discount coupon cialis Center chart on Extra Help Income and Asset Limits - updated annually You can apply for Extra Help and MSP at the same time through SSA. SSA will forward your Extra Help application data to the New York State Department of Health, who will use that data to assess your eligibility for MSP.

Individuals who apply for LIS through SSA and those who are deemed into LIS should receive written confirmation of their Extra Help status through SSA. Of course, individuals who apply for LIS through SSA and are found ineligible are also entitled to a written notice and have appeal discount coupon cialis rights. Benefits of Extra Help 1) Assistance with Part D cost-sharing The Extra Help program provides a subsidy which covers most (but not all) of beneficiary’s cost sharing obligations. Extra Help beneficiaries do not have to worry about hitting the “donut hole” – the LIS subsidy continues to cover them through the donut hole and into catastrophic coverage.

Full Extra discount coupon cialis Help. LIS beneficiaries with incomes up to 135% FPL are generally eligible for "full" Extra Help -- meaning they pay no Part D deductible, no charge for monthly premiums up to the benchmark amount, and fixed, relatively low co-pays (between $1.30 and $8.95 for 2020 depending on the person's income level and the tier category of the drug. Medicaid beneficiaries in nursing homes, waiver programs, or managed long term care have $0 co-pays). Full Extra Help beneficiaries who discount coupon cialis hit the catastrophic coverage limit have $0 co-pays.

See current co-pay levels here. Partial Extra Help. Beneficiaries between discount coupon cialis 135%-150% FPL receive "partial" Extra Help, which limits the Part D deductible to $89 (2020 figure - click here for updated chart). Sets sliding scale fees for monthly premiums.

And limits co-pays to 15%, until the beneficiary reaches the catastrophic coverage limit, at which point co-pays are limited to a $8.95 maximum (2020 or see current amount here) or 5% of the drug cost, whichever is greater. 2) Facilitated enrollment into a Part D plan Extra Help discount coupon cialis recipients who aren’t already enrolled in a Part D plan and don’t want to choose one on their own will be automatically enrolled into a benchmark plan by CMS. This facilitated enrollment ensures that Extra Help recipients have Part D coverage. However, the downside to facilitated enrollment is that the plan may not be the best “fit” for the beneficiary, if it doesn’t cover all his/her drugs, assesses a higher tier level for covered drugs than other comparable plans, and/or requires the beneficiary to go through administrative hoops like prior authorization, quantity limits and/or step therapy.

Fortunately, Extra Help recipients can always enroll in a new plan discount coupon cialis … see #3 below. 3) Continuous special enrollment period Extra Help recipients have a continuous special enrollment period, meaning that they can switch plans at any time. They are not “locked into” the annual open enrollment period (October 15-December 7). NOTE discount coupon cialis.

This changed in 2019. Starting in 2019, those with Extra Help will no longer have a continuous enrollment period. Instead, Extra Help recipients will be eligible to enroll no more than once per quarter for each of the first three quarters of the discount coupon cialis year. 4) No late enrollment penalty Non LIS beneficiaries generally face a premium penalty (higher monthly premium) if they delayed their enrollment into Part D, meaning that they didn’t enroll when they were initially eligible and didn’t have “creditable coverage.” Extra Help recipients do not have to worry about this problem – the late enrollment penalty provision does not apply to LIS beneficiaries.

1) For “deemed” beneficiaries (Medicaid/Medicare Savings Program recipients). Extra Help status lasts at least until the end of the current calendar discount coupon cialis year, even if the individual loses their Medicaid or Medicare Savings Program coverage during that year. Individuals who receive Medicaid or a Medicare Savings Program any month between July and December keep their LIS status for the remainder of that calendar year and the following year. Getting Medicaid coverage for even just a short period of time (ie, meeting a spenddown for just one month) can help ensure that the individual obtains Extra Help coverage for at least 6 months, and possibly as long as 18 months.

TIP discount coupon cialis. People with a high spend-down who want to receive Medicaid for just one month in order to get Extra Help for 6-18 months can use past medical bills to meet their spend-down for that one month. There are different rules for using past paid medical bills verses past unpaid medical bills. For information see Spend discount coupon cialis down training materials.

Individuals who are losing their deemed status at the end of a calendar year because they are no longer receiving Medicaid or the Medicare Savings Program should be notified in advance by SSA, and given an opportunity to file an Extra Help application through SSA. 2) For “non-deemed” beneficiaries (those who filed their LIS applications through SSA) Non-deemed beneficiaries retain their LIS status until/unless SSA does a redetermination and finds the individual ineligible for Extra Help. There are no reporting requirements per se in the Extra Help program, but beneficiaries must discount coupon cialis respond to SSA’s redetermination request. What to do if the Part D plan doesn't know that someone has Extra Help Sometimes there are lengthy delays between the date that someone is approved for Medicaid or a Medicare Savings Program and when that information is formally conveyed to the Part D plan by CMS.

As a practical matter, this often results in beneficiaries being charged co-pays, premiums and/or deductibles that they can't afford and shouldn't have to pay. To protect discount coupon cialis LIS beneficiaries, CMS has a "Best Available Evidence" policy which requires plans to accept alternative forms of proof of someone's LIS status and adjust the person's cost-sharing obligation accordingly. LIS beneficiaries who are being charged improperly should be sure to contact their plan and provide proof of their LIS status. If the plan still won't recognize their LIS status, the person or their advocate should file a complaint with the CMS regional office.

The federal regulations governing the Low Income Subsidy program can be found at 42 CFR Subpart P (sections 423.771 through 423.800) discount coupon cialis. Also, CMS provides detailed guidance on the LIS provisions in chapter 13 of its Medicare Prescription Drug Benefit Manual. This article was authored by the Empire Justice Center.Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for low-income Medicare beneficiaries and qualify enrollees for the "Extra Help" subsidy for Part D prescription drugs. There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below discount coupon cialis.

Those in QMB receive additional subsidies for Medicare costs. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH State law. N.Y discount coupon cialis. Soc.

Serv. L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1.

No Asset Limit 1A. Summary Chart of MSP Programs 2. Income Limits &. Rules and Household Size 3.

The Three MSP Programs - What are they and how are they Different?. 4. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5.

Enrolling in an MSP - Automatic Enrollment &. Applications for People who Have Medicare What is Application Process?. 6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7.

What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A.

SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &.

Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?. Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No retro for January application).

See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?. YES YES NO!. Must choose between QI-1 and Medicaid.

Cannot have both, not even Medicaid with a spend-down. 2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL).

2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below. NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment).

Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y. Soc.

Serv. L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded.

The most common income disregards, also known as deductions, include. (a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS.

* The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted.

You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO.

18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE.

Bob's Social Security is $1300/month. He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit.

In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO. DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP.

When is One Better than Two?. Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties).

3. The Three Medicare Savings Programs - what are they and how are they different?. 1. Qualified Medicare Beneficiary (QMB).

The QMB program provides the most comprehensive benefits. Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive.

The program’s benefits will begin the month after the month in which your client is found eligible. ** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB).

For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3. Qualified Individual (QI-1).

For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage.

Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice. DOH MRG p.

19. In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST).

Benefit 1. Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year.

The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL. However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy.

Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application.

The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability.

An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center. If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties...

For life.. Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer.

Benefit 3. No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits.

Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4.

SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections.

Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?. And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification.

New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods. Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit.

It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare.

Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP.

See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B.

Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing.

Strategy TIP. Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive.

Note. The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program.

Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev.

8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &.

Back), and proof of residency/address. See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time.

If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan.

GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare. To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification.

NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02.

Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit.

Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down. If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility.

EXAMPLE. Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016.

Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan.

See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p. 19).

Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6.

Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013.

In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment. The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program.

Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums. In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st). 7.

What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check. SSA also refunds any amounts owed to the recipient. (Note.

This process can take awhile!. !. !. ) CMS “deems” the MSP recipient eligible for Part D Extra Help/ Low Income Subsidy (LIS).

​Can the MSP be retroactive like Medicaid, back to 3 months before the application?.

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Late on a Friday night get cialis in April 2020, Lexi Walls was alone in her laboratory at the University of Washington, waiting nervously for the results of the most important experiment of her life. Walls, a young structural biologist with expertise in erectile dysfunctiones, had spent the past three months working day and night to develop a new kind of treatment against the pathogen ravaging the world. She hoped that her approach, if successful, might not only tame erectile dysfunction treatment but also revolutionize the field of vaccinology, putting get cialis us on a path to defeat infectious diseases from flu to HIV. Unlike any treatment used before, the treatment Walls was developing was not derived from components found in nature.

It consisted of artificial microscopic proteins drawn up on a computer, and their creation marked the beginning of an extraordinary leap in our ability to redesign biology. Proteins are intricate nanomachines that perform most tasks in living things by constantly interacting with one get cialis another. They digest food, fight invaders, repair damage, sense their surroundings, carry signals, exert force, help create thoughts, and replicate. They are made of long strings of simpler molecules called amino acids, and they twist and fold into enormously complex 3-D structures.

Their origamilike shapes are governed by the order and number of the different aminos used to build them, which have distinct attractive get cialis and repellent forces. The complexity of those interactions is so great and the scale so small (the average cell contains 42 million proteins) that we have never been able to figure out the rules governing how they spontaneously and dependably contort from strings to things. Many experts assumed we never would. But new insights and breakthroughs in artificial intelligence are get cialis coaxing, or forcing, proteins to give up their secrets.

Scientists are now forging biochemical tools that could transform our world. With these tools, we can use proteins to build nanobots that can engage infectious diseases in single-particle combat, or send signals throughout the body, or dismantle toxic molecules like tiny repo units, or harvest light. We can get cialis create biology with purpose. Walls is at the forefront of this research.

She completed her doctorate in erectile dysfunction structure in December 2019, making her a member of what was at the time a very small club. €œFor five years I'd been trying to convince people that erectile dysfunctiones were important,” get cialis she says. €œAt my Ph.D. Defense, I began by saying, ‘I'm about to tell you why this family of cialises has the get cialis potential to cause a cialis, and we are not prepared for that cialis.' Unfortunately, that ended up coming true.” As soon as word of a mysterious new pneumonia trickled out of Wuhan, China, in late December 2019, Walls suspected a erectile dysfunction.

On January 10, 2020, the genetic sequence for erectile dysfunction was released to the world. Walls and biochemist David Veesler, the head of her lab at the University of Washington, stayed up all night analyzing it. Walls says get cialis she felt an overwhelming sense of focus. €œIt was like, ‘Okay, we know what to do,'” she says.

€œâ€˜Let's go do it.'” Like other erectile dysfunctiones, erectile dysfunction resembles a ball covered in protein “spikes.” Each spike ends in a cluster of amino acids—a section of the protein known as the receptor-binding domain, or RBD—whose alignment and atomic charges pair perfectly with a protein on the surface of human cells. The viral protein docks at the get cialis receptor like a spacecraft, and the cialis uses this connection to slip inside the cell and replicate. Because of its dangerous role, the RBD is the primary target of the immune system's antibodies. They, too, are proteins, created by the body to bind to the RBD and take it out of commission.

But it takes a while for specialized cells to get cialis manufacture enough effective antibodies, and by that time the cialis has often done considerable damage. The first-generation erectile dysfunction treatments, including the mRNA treatments that have been such lifesavers, work by introducing the cialis's spike into the body, without a functional erectile dysfunction attached, so the immune system can learn to recognize the RBD and rally its troops. But the RBD is periodically hidden by other parts of the spike protein, shielding the domain from antibodies looking to bind to it. This blunts get cialis the immune response.

In addition, a free-floating spike protein does not resemble a natural cialis and does not always trigger a strong reaction unless a large dose of treatment is used. That big dose increases costs and can trigger strong side effects. treatment developers Lexi Walls (left) and Brooke Fiala (right) used custom-crafted proteins to get cialis create a promising new erectile dysfunction treatment inoculation. It waves a vulnerable part of the erectile dysfunction cialis in front of immune system cells, provoking a strong neutralizing response.

Credit. Timothy Archibald As successful as the erectile dysfunction treatments have been, many experts see inoculations based on natural proteins as an interim technology. €œIt's becoming clear that just delivering natural or stabilized proteins is not sufficient,” says Rino Rappuoli, chief scientist and head of treatment development at U.K.-based pharmaceutical giant GlaxoSmithKline. Most current treatments, from childhood inoculations to adult flu shots, involve such natural proteins, which vaccinologists call immunogens.

GSK makes a lot of them. €œWe need to design immunogens that are better than natural molecules,” Rappuoli says. Walls and Veesler had an idea. What if, instead of a whole spike, the immune system were presented with just the RBD tip, which would not have any shield to hide behind?.

“We wanted to put the key component on display,” Walls says, “to say, ‘Hey, immune system, this is where you want to react!. ' The immediate trouble with that notion was that biology does not make isolated RBDs, and the segment on its own would be too small and unfamiliar to get the immune system's attention. But Walls and Veesler knew some people who could help them solve that problem. Just up the street from them was the Bell Labs of protein invention, the University of Washington's Institute for Protein Design (IPD).

The institute had learned enough about protein folding to design and build a few hundred very simple, small proteins—unlike any that have ever been found in a living organism—that would fold into consistent shapes with predictable functions. In 2019 a group in the IPD led by biochemist Neil King had designed two tiny proteins with complementary interfaces that, when mixed together in solution, would snap together and self-assemble into nanoparticles. These balls were about the size of a cialis and were completely customizable through a simple change to their genetic code. When the scientists festooned the particles with 20 protein spikes from the respiratory syncytial cialis, the second-leading cause of infant mortality worldwide, they triggered an impressive immune response in early tests.

Why not try a similar nanoparticle core for a erectile dysfunction treatment, Walls and Veesler thought, using just the RBD instead of an entire spike?. As a bonus, the protein-based nanoparticle would be cheap and fast to produce compared with treatments that use killed or weakened cialis. It would also be stable at room temperature and easy to deliver to people, unlike fragile mRNA treatments that must be kept in a deep freeze. Walls reached out to the IPD and collaborated with nanoparticle specialist Brooke Fiala, who worked with King, on a prototype—a nanoparticle sphere displaying 60 copies of the RBD.

The scientists also tried something radical. Instead of fusing the RBDs directly to the surface of the nanoparticle, they tethered them with short strings of amino acids, like kites. Giving the RBDs a little bit of play could allow the immune system to get a better look at every angle and produce antibodies that would attack many different spots. But nobody knew whether that would really happen.

So on that April Friday last year, as Walls waited for results, she had her fingers crossed. Three weeks earlier she and her colleagues had injected some mice with the nanoparticle treatment. Other mice got the plain spike that other treatments were using. Now the researchers had drawn blood from the mice and mixed it with a erectile dysfunction pseudocialis, an artificial, nonreplicating version of the cialis that is safer to use in labs.

The idea was to see whether any vaccinated mice had developed antibodies that would home in on and neutralize the pseudocialis. It takes a while for antibodies to do their thing, which is why Walls had to wait until late that Friday night. No way was she going home to be kept in suspense all weekend. Her colleagues had wished her good luck as they headed out the door.

Before Veesler cut out, he asked her to contact him as soon as she had results. Now it was dark outside, and the lab was ghostly quiet. It was finally time to look. Walls fired up a lab instrument that could detect and count antibodies attached to cialis particles, took a deep breath and peeked at the numbers.

Some mice had been given a low dose of the plain spike, and that was a total failure. Zero effect on the pseudocialises. Mice given a high dose of the spike showed antibodies with a moderate neutralizing effect, similar to what some other treatments had produced. But in mice that got the nanoparticle treatment, the pseudocialis was completely outmatched.

Antibodies smothered it and had 10 times the neutralizing effect of the large-dose spike preparation. That magnitude held even when only a minuscule dose was used. Walls was looking at something that could be a low-cost, shelf-stable, uapotent treatment. Walls fired off an all-caps text message to Veesler.

€œTHEY'RE NEUTRALIZING!. € Veesler wrote right back. €œThe next generation of erectile dysfunction treatments is in your hands!. € That was only the first of several tests the treatment had to pass.

From there they would have to prove the treatment could offer protection from the live cialis in mice, nonhuman primates and, finally, people. The nanoparticles entered that last testing phase early in 2021. But at that moment, as an emblem of the power of protein design, it was already a success—the clearest sign yet that a technology long beyond our grasp had suddenly arrived. We were learning to sculpt the living clay from which we are all made.

Credit. Falconieri Visuals As transformational as the genetics revolution of the past decades has been, at its heart has always been a mystery. Proteins. A gene is simply the code for making a single protein.

In that gene, a set of three DNA nucleotides, represented by letters, yields one amino acid, and another triplet codes for a different amino acid. There are 20 amino acids that a cell can use as protein-building blocks, and each one has a unique shape and function. Some are more flexible than others. Some are positively charged, some negative.

Some are attracted to water. Others are repelled by it. All day long our cells churn out new proteins in the exact order of amino acids dictated by our genetic code, and the proteins spontaneously snap into shape. That shape, along with the charges of the atoms on the exposed bits, determines the function.

What they respond to, what they attach to, what they can do. When we say, “He has the gene for red hair,” it means he has the blueprint for proteins that lead to a particular kind of pigment. When we say, “She has a gene that causes breast cancer,” it means she has a mutation in a gene that causes its protein to be made with an incorrect amino acid, which screws up its function in a way that can lead to cancer. Understanding the mechanics of protein folding would allow us to design new classes of drugs that could hobble or replace proteins gone wrong and to probe the etiology of diseases such as Alzheimer's, Parkinson's, Huntington's and cystic fibrosis, which are linked to misshapen proteins.

Unfortunately, because proteins are so small, it is almost impossible to tell what is happening in this nanoworld, even with powerful microscopes. We do not know precisely how all of these proteins fold correctly, much less what goes wrong when they misfold. It can take a year and $120,000 to produce a high-resolution image of one protein on specialized equipment. We currently know the structures of just 0.1 percent of them.

For the rest, we guess. That is why there is a mystery at the center of the genetics revolution. Certain genetic sequences are associated with physical and mental effects, but often we cannot tell why. We have lacked the Rosetta stone of protein structure to translate between the starting point of genes and the end point of bodily functions.

In theory, it should be possible to predict the final structure of a protein from its genetic sequence—a task so essential to our understanding that in 2005 Science magazine included it in its 125th-anniversary issue's list of the most important unanswered questions in science. But in reality, it has been possible for only a very few extremely simple proteins. For example, scientists know that if they want to build a straight helix (a common Slinky-like structure in proteins that provides stability), they can use amino acids such as leucine, alanine and glutamate, which have the right curve and complementarity to form regular spirals and bond tightly to the amino acids on the coil above or below them. If scientists want a kink in their Slinky, they can add a proline, which does not form a bond and allows the rest of the helix to bend away from it.

Structural biologists such as David Baker, who founded the IPD—where Walls and Veesler went to get their nanoparticles—have been able to deduce a few of these basic rules. Baker's group has incorporated these rubrics into a structure-predicting computer program called Rosetta and used them to make a number of small proteins, typically a few dozen amino acids in size. Some of their successes have shown the great potential of the field. Microscopic “nanocages” that could be used to package drugs and transport them into the body and molecular detectors that go off when they encounter cells with specific combinations of amino acids on their surface, indicating such cells are cancerous.

But most important proteins in living things are much bigger than these examples and contain thousands of amino acids, each of which interacts with up to a dozen neighbors, some forming bonds as strong as those in a diamond, some pushing others away. All those relationships morph depending on proximity. So the possibilities quickly become astronomical, and the formulas for figuring out the final structures have long eluded our best minds and supercomputers. Frustrated by this problem back in 1994, a group of computational biologists decided that a little friendly competition might spur some progress.

Led by John Moult of the University of Maryland, they launched CASP, the Critical Assessment of Structure Prediction contest. Moult obtained detailed specs of proteins whose structure had been recently identified but not released. He sent the genetic sequence for the proteins to various teams from different research labs, which then submitted their best ideas about what the finished protein looked like. Those predictions were scored on their similarity to the actual structure based on the percentage of molecules in the right place.

Getting the basic architecture right might score a 50, getting the angles and links between the main parts might be good for a 70, and nailing the tiny molecular threads that sprout off proteins like hairs would merit a 90-plus. Moult has been running the contest every two years since then. For a long time not even the best teams could do much better than guesswork. In 2012, the year Baker's protein design institute started up, the very best CASP teams were averaging scores in the low 20s, and there had been no improvement for a decade.

€œThere were moments after some CASPs where I'd see the results and despair,” Moult says. €œI'd think, ‘This is all a joke. Why are we even doing this?. '” Some new insights led to a rise at CASP11, with the best scores averaging nearly 30, and another slight bump to around 40 at CASP12.

Then came CASP13 in 2018. The best teams, led by Baker's institute, improved again, averaging nearly 50, but they were bested by a surprise entrant. Google's DeepMind, whose artificial-intelligence system had trounced the world's best Go player in 2017. The AI averaged a score of about 57 per protein.

That result rocked the world's protein-engineering labs, but it turned out to be just a dress rehearsal for 2020. In that year DeepMind's predictions were spot-on. €œI thought, ‘This can't be right. Let's wait for the next one,'” Moult says.

€œAnd they just kept coming.” DeepMind averaged a 92 for all proteins. On the easier ones, it had virtually every atom in the right place. But its most impressive results were on some exceedingly difficult proteins that completely stymied most teams. On one molecule, no group scored higher than the 20s—DeepMind scored in the high 80s.

Moult was stunned by the results. €œI spent a lot of my career on this,” he says. €œI never thought we'd get this level of atomic accuracy.” Most impressive, he says, is the indication that DeepMind has picked up on previously unknown fundamentals. €œIt's not just pattern recognition.

In some alien way, the machine ‘understands' the physics and can calculate how the atoms in a unique arrangement of amino acids are going to arrange themselves.” “It was shocking,” agrees structural biologist and CASP competitor Mohammed AlQuraishi of Columbia University. €œNever in my life had I expected to see a scientific advance so rapid.” AlQuraishi expects the breakthrough to transform the biological sciences. The DeepMind team is expected to publish its methods paper, with details about how it worked, later this year. Some aspects may remain inscrutable—the AI picks up on faint relationships that cannot easily be explained with rules—but at the moment, scientists do have the general outlines.

To predict amino acids' effects on one another, the machine's programmers invoked a technique called attention that has been responsible for recent leaps forward in accurate language translation by AIs. Like proteins, language is a seemingly linear string of information that folds back on itself to produce meaning. A word such as “it” might draw its significance from a word used in an entirely different sentence. (“For the longest time, AI made no sense to me.

And then, after much reading, I finally understood it.”) When we communicate, we are constantly moving backward and forward along this linear string, paying attention to one local cluster of words to understand what a different word means in context. Once we have that meaning resolved, we can move to another, related passage and understand those words in light of the new information. DeepMind does something like this for proteins, focusing its attention on one local cluster of amino acids, understanding as much as it can about their relation to one another. Some pairs of aminos, for example, appear to have coevolved, indicating a bond between them and limiting their possible positions in the protein.

DeepMind uses this information to leap to a different part of the protein and analyze that section in light of what it knows about the first cluster. It carries out multiple iterations across all parts of the protein string and eventually uses this information to build a 3-D cloud of points that represents the relations among all the atomic constituents of every amino. It basically treats protein folding like a new, alien language to be deciphered. As other labs incorporate DeepMind's techniques and on-point protein prediction becomes ubiquitous, AlQuraishi says, the lengthy trial-and-error period of getting a real-world protein to fold like you thought it would will become much faster.

€œIt will percolate everywhere,” he says. €œIt's going to make protein design much more effective.” To block a cialis, Longxing Cao of the Institute for Protein Design developed small synthetic proteins called mini binders. They glom on to the part of a erectile dysfunction that attaches to cells, stopping it. Mini binders could be sprayed up the nose to prevent s.

Credit. Timothy Archibald But the DeepMind team is not in the business of applied science, so the AI will not spend its time churning out blueprints for complicated protein construction on demand. Its big contribution will be indirect. €œTheir work shines light on the power of proteins and the bright future of engineering new ones,” says California Institute of Technology biochemist Frances Arnold, who won the Nobel Prize in Chemistry in 2018 for improving the performance of natural proteins through a method called directed evolution.

€œBut they have not solved the problem of designing or engineering proteins to solve problems for people.” That work will fall to the Arnolds and Bakers of the world, who are trying to use DeepMind's techniques to supercharge their labs' abilities to sculpt proteins. €œIt's a big breakthrough,” says Baker, whose team again finished a distant second in the competition. €œI think it will make what's already working well work even better.” Right now there is an enormous problem for people, to use Arnold's phrase, that is wracking the world. That problem is erectile dysfunction treatment.

When it hit, Baker and others in his lab looked to proteins for solutions. They plugged the genetic sequence for the erectile dysfunction into Rosetta, their protein-structure-prediction computer program, to produce a 3-D model, then pored over it for weaknesses like Rebel pilots plotting an assault on the Death Star. As Walls did, they zeroed in on the spike's RBD. But instead of making a treatment to trigger antibody production, Baker wanted to build a better antibody.

He wanted a protein whose sole purpose was to ensnare the RBD like microscopic Velcro. Amazing as they are, antibodies are not perfect. The body cannot custom-design an antibody in advance for a pathogen it has never seen, so it makes a lot of different versions. When a new invader shows up, immune system cells make many copies of whatever antibody binds best, but the fit is not always tight enough to stop the pathogen.

Natural antibodies are also relatively big proteins that are not always able to get their business end snug against a cialis's RBD. Enter the “mini binders,” as Baker calls them. These are small synthetic proteins that can be designed amino acid by amino acid to fit precisely against a cialis's RBD. With no extraneous bits, they bind more tightly.

And they are small and lightweight enough to be administered through a spritz up the nose rather than an injection into the arm. No needles!. Baker's dream was to create a medication rather than a treatment. A nasal spray that could be used at the first sign of —or beforehand as daily prevention—to flood the nose with a mist of mini binders that would coat the RBDs of cialis particles before they could attach to anything.

It would have the long shelf life of a bag of dried lentils, and it could be quickly reformulated for any new pathogen and rushed into the hands of health-care workers, teachers and anyone else on the front lines—a kind of designer-driven immune system for civilization. To engineer the mini binder, Longxing Cao, a postdoc in Baker's lab who headed the project, scouted the cialis RBD's structure, comparing it with the library of tiny proteins the institute had previously designed and looking for complementary shapes. Like a rock climber on a challenging face, the mini binder needed to be small enough to wriggle into the cleft where the RBD lay, and it needed to be shaped so that it could get firm handholds and toeholds in the right places. Cao cataloged where the RBD's amino acids made patches of positive electrical charges, patches of negative charges and hydrophobic (water-hating) patches, then tailored mini binders to have as many complementary patches as possible.

He tested millions of possibilities on Rosetta. The best designs were made of three helixes connected like sausage links by short strings of amino acids. Each mini binder was about 60 amino acids long in total—less than a tenth the size of an antibody and a twentieth the size of a erectile dysfunction spike. Then, of course, Cao had to take his protein from Rosetta to the real world.

Amazingly, that process has become trivially easy. DNA—the As, Cs, Gs and Ts of the genetic code—can be printed for pennies on devices that resemble inkjet printers. Cao printed DNA strands with the sequence for his mini binder and inserted them into yeast, which, like programmable livestock, pumped out those tiny proteins along with their normal ones. He then harvested the proteins and tested them.

The top mini binder bound the cialis six times more effectively than the best antibodies known—better than any molecule on the planet, in fact, forming dozens of strong bonds with the RBD. It was extraordinarily stable, and it sprayed easily out of a nozzle. Hamsters given a snootful became immune to erectile dysfunction treatment. €œI was definitely excited,” Cao says, “but not totally surprised.” Researchers expect clinical trials for mini binders to start later in 2021, and a number of labs around the world are now exploring other ways that mini proteins might help the body function or ward off illness.

Although there is great optimism about the technology, some biosecurity researchers have expressed concerns about proteins that could be designed for nefarious purposes. Prions, for example, which are responsible for “mad cow” and other neurodegenerative diseases, are misfolded proteins that cause other proteins to misfold in turn, triggering deadly chain reactions that are transmissible. They could be delivered by aerosol. The Biological Weapons Convention, which virtually all nations have signed, effectively bans the development or use of pathogen-based bioweapons, but no one ever thought to extend it to address proteins that were never part of an organism.

€œThis is a real concern,” says biosecurity expert Filippa Lentzos of King's College London, “because potential future biological weapons won't necessarily make us sick using pathogens.” Synthetic mini proteins may or may not fall under the control of the convention, she says, “so legal status is an important issue.” But engineered mini proteins are also an extremely unlikely threat, Lentzos says, and quite low on her list of worries. €œIf you want to cause harm, why would you turn to something as sophisticated and complicated as protein design?. There are plenty of more accessible things in nature you could use.” Naturally occurring toxins and pathogens are ready-made and all over the place. If you really want to hurt people, there are easier ways.

At this moment, the helpful types of de novo proteins are attracting an increasing amount of scientific energy and expertise, and the molecules may be coming to a clinic near you. As most of the world's nearly eight billion people await a erectile dysfunction treatment, Walls's nanoparticle is looking like a promising candidate. After successfully neutralizing the pseudocialis in mouse cells, the treatment's next big test was against the real erectile dysfunction. For that, Walls had to ship her mice to the University of North Carolina lab of Ralph S.

Baric, one of the world's foremost erectile dysfunction researchers. The facility has the biosecurity level required to work with the live cialis. Baric and his colleagues see many treatment candidates, so in June 2020 Walls was pleased to get an encouraging e-mail from them. The neutralizing power of the nanoparticle treatment was off the charts—higher than anything they had tested.

€œEverything worked better than we'd hoped!. € Walls says. When exposed to the real cialis, the mice did well. €œCompletely protected.

No sign of illness.” (Later Walls found that she could reduce the already low dose an additional ninefold, add a booster and get equally good results.) In January of this year the treatment began early clinical trials in Washington State and South Korea. Yet even as those trials were progressing, the cialis was spawning a new wave of variants with the ability to evade some of the antibodies triggered by the first generation of treatments. So Walls went back to work, designing a new and improved nanoparticle. Instead of copies of just the erectile dysfunction RBD, this version had a mosaic of four different RBDs.

Some from erectile dysfunction, some from the original SARS cialis from the early 2000s and some from two other erectile dysfunctiones. This broad spectrum of RBDs elicited a robust antibody response against all erectile dysfunctiones tested, including the most elusive of the variants. A treatment that is effective in tiny doses, that is easy and inexpensive to produce, that does not require refrigeration and that protects against a bunch of mutant cialises, including ones that may emerge in the future, could be exactly the solution the world needs. These advantages have drawn the attention of the world's treatment heavyweights, including GSK's Rappuoli.

€œThere is no question that our immune system likes nanoparticles,” he says. €œThese represent the best option we have.” In a recent commentary in the journal Cell, Rappuoli predicted that such designer molecules will usher in a new era of treatments. €œFrom here, the sky is the limit.” And the capability will not end with treatments. In this new Amino Age, the ability to intelligently design nanomachines at an atomic scale could turn fighting every disease into an engineering exercise.

€œWhen we tackle problems involving any sort of protein, we need to have this in mind,” Walls says. €œWe need to look at the protein and know that we can engineer solutions. Every day there are new successes coming.” Some of those successes will come in areas other than medicine, such as materials science. The IPD has invented proteins that self-assemble into microscopic honeycomb grids that attract mineral deposition, a new way to produce efficient superconductors and batteries.

Another project is crafting proteins that harvest light, as do photosynthetic proteins in plants, and convert that energy into electricity and fuel. As the Amino Age tool kit grows, the natural proteins we now use for help—insulin for people with diabetes, for instance—may come to seem as archaic as the sharpened rocks our Stone Age ancestors once used. By the same token, our current designer proteins, as exciting as they are, are just sundials and wagon wheels. The features of a future landscape filled with bespoke molecules are beyond conception.

But like the new proteins themselves, those features will, eventually and elegantly, fold into shape.Most U.S. Cities have tree-planting programs, but not all urban tree canopies are created equal, according to a new analysis from American Forests.The conservation organization said today that the United States needs to plant more than a half-billion new trees to achieve an equitable urban canopy across nearly 500 metropolitan areas and 150,000 local communities.The findings are based on a new "Tree Equity Score" data tool that allows users to see where urban trees exist, and where they don't. American Forests also identified 20 large U.S. Cities that are lagging in urban forest canopies that would protect their most vulnerable populations from hotter temperatures."The findings confirm a disturbing pattern of inequitable distribution of trees that has deprived many communities of color of the health and other benefits that sufficient tree cover can deliver," American Forests said.For example, communities of color have 33% less tree canopy on average than majority white communities, the analysis revealed.

And neighborhoods with 90% or more of their residents living in poverty have 41% less tree canopy than communities with only 10% or less of the population in poverty. (Greenwire, Sept. 16, 2020)."The scale and pace at which trees are planted or naturally regenerate must significantly increase if trees are to continue to make people healthier or slow effects of climate change," Ian Leahy, American Forests' vice president for urban forestry, said in a statement.Achieving "tree equity" nationally would require planting 522 million trees in places with populations of 50,000 or greater, American Forests said. As those trees mature, they would mitigate 56,613 tons of particulate pollution and absorb 9.3 million tons of carbon dioxide — the equivalent of taking 92 million cars off the roads, American Forests said.The report identified several cities that would benefit from more equitable tree cover.

Those include the five most populated cities in the United States — New York, Los Angeles, Chicago, Houston and Phoenix — and a handful of smaller cities such as Fresno, Calif.. Jacksonville, Fla.. And Oklahoma City.Tree canopies are particularly good at reducing health stress associated with urban heat islands. These areas often are much hotter than surrounding neighborhoods — a condition caused by a lack of trees and the absorption of heat by buildings, streets and parking lots.Scientists say urban heat islands can cause temperatures to be 5 to 7 degrees warmer during the day and as much as 22 degrees warmer at night.This creates a dangerous health risk.

Under current climate warming trajectories, heat-related deaths from 2031 to 2050 could be 57% higher than from 1971 to 2000, American Forests said."We need to make sure the trees go where the people are," said Jad Daley, American Forests president and CEO. "And more than 70% of the people live in cities or suburbs, so it's a place-based problem with a place-based solution."He also stressed the need for local, state and federal lawmakers and nonprofits to fund the protection of existing trees and plant new ones.Reprinted from E&E News with permission from POLITICO, LLC. Copyright 2021. E&E News provides essential news for energy and environment professionals.Two treatments made using messenger RNA (mRNA) have proved spectacularly successful at warding off erectile dysfunction treatment, but a third mRNA-based candidate has flopped in a final-stage trial, according to an initial report released this week.

Researchers are now asking why — and some think that choices about the type of mRNA chemistry used might be to blame. Any insight could help to guide the future design of mRNA treatments against erectile dysfunction treatment or other diseases. The company behind the beleaguered trial, CureVac, based in Tübingen, Germany, announced preliminary data on 16 June from a 40,000-person trial, which showed that its two-dose treatment was just 47% effective at preventing disease. CureVac’s mRNA treatment was expected to be cheaper and to last longer in refrigerated storage than the earlier mRNA treatments made by Pfizer–BioNTech and Moderna.

Many had hoped that it could help to expand the reach of mRNA-based treatments in lower-income countries, and European countries were expecting to order hundreds of millions of doses. €œI’m definitely surprised — and also disappointed,” says Philip Santangelo, a biomedical engineer at the Georgia Institute of Technology in Atlanta who has worked with many mRNA-focused companies, including CureVac. He and others suspect that CureVac’s decision not to tweak the biochemical make-up of its mRNA, as Pfizer–BioNTech and Moderna did, might be behind its poor performance — although it is too early to know for sure. Variant problem CureVac executives put the poor results down to the high number of erectile dysfunction variants — including emerging ones such as the Lambda variant first detected in Peru — circulating in the ten countries across Europe and Latin America where the company is running its trial.

Of 124 erectile dysfunction treatment cases for which scientists obtained a genetic sequence, only one was caused by the original version of erectile dysfunction. But the other mRNA treatments have fared much better in the face of variants. Researchers in the United Kingdom have reported, for instance, that the Pfizer–BioNTech shot offered 92% protection against symptomatic cases of erectile dysfunction treatment caused by the Alpha variant (first identified in the United Kingdom) and 83% protection against the Delta variant (initially reported in India). A study in Qatar similarly found the treatment to be around 90% effective against the Alpha strain and 75% effective against the Beta variant that emerged in South Africa.

Those differences in efficacy have led trial investigators and other scientists to suggest that the problem is with the treatment itself. Dose of reality “My best take is that the dose is the culprit,” says Peter Kremsner, an infectious-disease specialist at Tübingen University Hospital who is leading CureVac’s clinical studies. In phase I testing, Kremsner and his colleagues evaluated doses ranging from 2 to 20 micrograms of mRNA per injection. At the higher dose levels, the treatment caused too many side effects, with trial participants frequently complaining of problems such as severe headaches, fatigue, chills and injection-site pain.

At 12 micrograms, the treatment proved more tolerable, and all recipients developed antibodies that blocked the cialis from entering cells. But the levels of those ‘neutralizing’ antibodies were relatively low — on a par with the amounts found in people who have recovered from erectile dysfunction s, but well below the levels seen in recipients of the Moderna and Pfizer–BioNTech treatments, which are both given at higher doses. Perhaps it’s no surprise, then, that CureVac’s shot came up short, says Nathaniel Wang, the chief executive of Replicate Bioscience, an RNA-focused biotech start-up based in San Diego, California. Those low antibody titres in early testing were “already a red flag”, he says.

Some researchers wonder why the treatment couldn’t be administered at higher doses without inducing side effects. The tiny bubbles made of lipids that mRNA treatments are encapsulated in — to help deliver their genetic payloads into cells — can trigger side effects such as those documented by the CureVac trial. But Santangelo says that the CureVac and the Pfizer–BioNTech treatments use practically indistiguishable, if not identical, lipid bubbles. He and others think that the problem might lie in the mRNA sequence.

Modified RNA All three mRNA treatments encode a form of the erectile dysfunction spike protein, which helps cialis particles to penetrate human cells. But the Moderna and Pfizer–BioNTech treatments use modified RNA, incorporating an mRNA nucleotide called pseudouridine — which is similar to uridine but contains a natural modification — in place of uridine itself. This is thought to circumvent the body’s inflammatory reactions to foreign mRNA. CureVac’s treatment uses normal uridine and relies on altering the sequence of RNA letters in a way that does not affect the protein it codes for, but helps the treatment to evade immune detection.

Proponents of modified mRNA have long argued that the chemical adjustment is integral to the success of the treatment technology. Drew Weissman, an immunologist at the University of Pennsylvania in Philadelphia who co-discovered the importance of pseudouridine in this context in the mid-2000s4, describes it as the “best platform for antibody and neutralization levels”. In light of the new CureVac data, many scientists who spoke to Nature agree. €œModified mRNA has won this game,” says Rein Verbeke, an mRNA-treatment researcher at Ghent University in Belgium.

There are a few other possible explanations for CureVac’s tolerability problems. Structural differences in the non-coding regions of the CureVac sequence could play a part. Alternatively, the higher storage temperature of CureVac’s jab might have accelerated the breakdown of mRNA in the vial, yielding pieces of genetic code that would raise immune hackles. And if any impurities were introduced during the company’s manufacturing process, these would, in principle, have the same effect.

So for some scientists it remains too early to draw conclusions. €œThe jury is still out on which of these is a better technology,” says Jeffrey Ulmer, a former pharmaceutical executive who now consults on treatment research issues. He predicts that both modified and unmodified mRNA will be useful in different contexts. €œIt could be that there’s not a one-size-fits-all solution to everything.” CureVac hopes that its treatment — or at least its unmodified mRNA technology — might yet deliver.

The company is continuing its trial and expects a final analysis in the next few weeks. On a public health level, even if the treatment fails, “I don’t think it’s going to set the world back much”, says Jacob Kirkegaard, a treatment-supply expert at the Peterson Institute for International Economics, a think-tank in Washington DC. He points out that another second-generation treatment that offers many of the same logistical selling points as CureVac’s, such as long-term refrigerator storage, has stood up to the variant challenge well. Earlier this week, Novavax in Gaithersburg, Maryland, reported that its protein-based treatment was more than 90% effective at preventing erectile dysfunction treatment in a large US trial, run at a time that the Alpha variant was prevalent.

The scale of production of other treatments more than makes up for the lack of CureVac’s product, Kirkegaard says. CureVac, in collaboration with London-based GlaxoSmithKline, also has a second-generation erectile dysfunction treatment in the works that, like its predecessor, uses unmodified mRNA, but has been fine-tuned so that it elicits levels of neutralizing antibodies that are around ten times higher, according to data from rat and monkey studies. €œOur optimization has never stopped,” says CureVac’s chief technology officer Mariola Fotin-Mleczek. €œIt’s too early to say unmodified, natural messenger RNA is not an option.” Human trials are due to launch later this year.

This article is reproduced with permission and was first published on June 18 2021.CRISPR is the basis of a revolutionary gene editing system. One day, it could make it possible to do everything from resurrect extinct species to develop cures for chronic disease.It’s built on a natural adaptation found in the DNA of bacteria and single-celled organisms. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. They’re really just bits of genetic code with a specific, recognizable format.

They contain a sequence that shows up over and over again, though it’s often reversed each time. That’s what makes it "Palindromic:” palindromes are words that can be read the same backwards as forwards. Palindromes are common in DNA. Some serve as backups for damage to our genetic code, while others are common in cancer mutations.

With CRISPR, a group of enzymes recognize certain repeats, and break the DNA there to insert important information in the middle. These insertions are called “spacers,” and they contain the genetic code of different cialises that have invaded in the past. Such previous invasions served a very important evolutionary purpose. Immunizing against foreign threats.

Researchers first discovered CRISPR in E. Coli in the 1980s. When E. Coli survives viral attacks, it incorporates some of the cialis DNA into its own genetic code.

E. Coli isn’t unique in using this strategy. Between the 1980s and 2000, scientists found that lots of bacteria and single-celled organisms incorporate viral DNA this way. Cells use these sequences as templates for transcribing complementary strands of RNA.

When cialises matching the template sequence enter the cell, the complementary RNA binds to them, and directs a series of CRISPR-associated enzymes, or “Cas” enzymes, to attack—cutting invader DNA at the binding site. That neutralizes the viral threat. The CRISPR-Cas system is incredibly effective. It’s also easy to manipulate, letting us alter a cell’s genetic code however we want.

In 2012, French microbiologist Emmanuelle Charpentier and American biochemist Jennifer Doudna discovered that Cas enzymes—specifically Cas9—can be reprogrammed to cut nearly any part of the genome, using RNA sequences made in a lab. Those “guide RNA” molecules tell Cas9 where to cut DNA in a cell. For their discovery, Charpentier and Doudna won the Nobel Prize in Chemistry in 2020. And the use of CRISPR has taken off in science since their breakthrough.

But scientists are still far from realizing CRISPR’s potential. Cas9 is great at suppressing or knocking out unwanted genes. But for most medical purposes, it’s not enough to cut unwanted DNA out. Scientists need to control how the DNA repairs itself.

Left to their own devices, cells tend to repair broken DNA using a method that introduces lots of random errors. Researchers can provide cells with templates to guide the repair process, but they’re still working on making that more reliable. Researchers have found lots of applications for CRISPR in animals, like making disease-resistant chickens and pigs, and mosquitos that can’t bite or lay eggs. But they’ve got many projects underway, like making disease-resistant crops—including wine grapes.

More ambitiously, they’re working to genetically alter pigs so their organs could be transplanted into humans. And bring extinct species such as the passenger pigeon back to life, by tweaking the genomes of similar birds. When it comes to the human genome, though, scientists have been more hesitant. Editing our own DNA could easily end up causing more problems than it solves.

While Cas9 reliably cuts DNA where we want it to, recent experiments have shown it can also affect genes far off-target. And even if we could get it to work reliably, many experts have flagged ethical concerns about using the technology for eugenics and “designer babies.” If parents can one day pay scientists to edit their babies’ DNA, making them stronger and smarter, CRISPR could make the world even more unequal and prejudiced. In 2018, Chinese researcher HEH JEE'-an-qway claimed he’d used CRISPR to make HIV-resistant children. Whether or not he succeeded, his work violated China’s National Health Commission rules, and he was sentenced to three years in prison.

Using CRISPR on babies is widely illegal. But there are some cases where using CRISPR on humans may be worth the risk. In 2020, American researchers began the first clinical trials injecting CRISPR directly into living humans, aiming to repair a genetic mutation that causes blindness. Many researchers hope CRISPR-based therapies could eventually cure hereditary diseases.

They’ve already seen promising results in various animal studies. Though given the risks of editing the human genome, we’re still a ways off from widespread use of CRISPR in medicine. CRISPR has given science a tool to reliably tinker with the code of life. But the question remains.

Can we do so safely and ethically, while avoiding the unintended consequences of such power?. Three years ago, Laura Gaither and her family spent their summer vacation in Panama City Beach, Florida. One afternoon, while rinsing sand off her feet, the 35-year-old Alabama resident felt something biting her legs and noticed tiny black bugs on her skin. Gaither brushed them away, and later, when she described the bites to local residents, they told her that she had likely been bitten by sand flies.

Three of Gaither’s five kids had been bitten, too, but she didn’t worry. The marks on their legs and arms looked like ant or mosquito bites, which can cause burning and itching, but usually subside within a week. But about two weeks later, back at home, Gaither noticed that the bites had morphed into small open wounds. They worsened over the next couple of weeks, but when she took her children to their pediatrician, “he just chalked it up to eczema,” Gaither said.

Eventually Gaither took her young daughter, whose condition was the most concerning, to the emergency room at Children’s of Alabama, where she was tested for fungal and bacterial s. The results came back negative, and the anti-fungal and steroid topical creams the doctors prescribed proved ineffective. Meanwhile, the ulcers kept growing larger and more painful. Gaither started doing her own research and learned about a flesh-eating disease called cutaneous leishmaniasis (pronounced leash-ma-NYE-a-sis).

This skin disease is caused by more than 20 species of Leishmania parasites. It can be transmitted to humans through the bite of some sand flies after the flies themselves have been infected by animals—usually rodents in the United States—whose blood the insects feed on. Sand flies thrive in hot sandy beaches and in rural areas, and they had been particularly abundant in Florida in 2018, Gaither was told during her visit. Leishmaniasis, Gaither learned, is common in tropical and subtropical countries like Brazil, Mexico, and India.

Looking through peer-reviewed papers, she saw pictures of leishmaniasis wounds that looked a lot like her own. Crater-like ulcers coated with a thick, yellowish pus. During the visits with her children’s pediatrician and in the ER, Gaither asked her doctors about the parasite. They dismissed the possibility that the family might have contracted a tropical disease without traveling abroad, she said.

"Nobody would even entertain what I was saying." That is, until the wound on Gaither’s knee worsened and, armed with research papers, she convinced her own physician to test a biopsy for leishmaniasis. The results were inconclusive. Fortunately, by this time the children’s wounds had begun to heal. Three months after they appeared, the ulcers completely cleared up, leaving Gaither to wonder what really caused them.

While her family’s ordeal has ended, scientists say the story of leishmaniasis in the U.S. Is just beginning. Americans, it turns out, can be exposed to Leishmania parasites without leaving the country. The parasites are currently endemic in Texas and Oklahoma, and new studies suggest that they might be present in other states, including Florida.

While reported cases of leishmaniasis contracted in the U.S. Are currently negligible, they may soon be on the rise. As climate change pushes rodent and sand fly habitat northward, scientists caution that in the future, an increasing number of U.S. Residents could be exposed to different varieties of the flesh-eating parasite.

Some strains of Leishmania parasites can be life-threatening. The one currently present in the U.S., Leishmania mexicana, induces milder symptoms and over time, can heal on its own. But if doctors fail to recognize it, or overreact to it, damages caused by wrong therapies and unnecessary toxic systemic medication can cause more harm than the disease itself. Bridget McIlwee, an Illinois-based dermatologist, has treated patients who contracted leishmaniasis in Texas.

She wants her colleagues to be more aware of the parasite’s expansion into the U.S. €œIt's a pretty striking difference for a disease that we used to think of as limited to South America now extending as far north as Canada,” she said, “potentially within the next several decades.” Every year, between 1.5 to 2 million people worldwide contract leishmaniasis, and around 70,000 die from it, mostly in poor rural areas. The most dangerous Leishmania strains, such as infantum and donovani, don’t just eat a person’s skin, they also infect the liver, spleen, and bone marrow, leading to death if not treated. Drugs like miltefosine and amphotericin B, used to cure these strains of Leishmaniasis, are expensive or toxic, and not much funding goes into researching and developing better treatments.

In 2007, the World Health Organization added leishmaniasis to the list of neglected tropical diseases, which mainly affect the word’s poor and do not receive much attention. While Leishmania parasites are present in about 90 countries, the symptoms of an vary by strain. The mexicana strain, typically found in Mexico and Central America, causes skin sores that can sometimes take years to heal and leave ugly scars. Others, like panamensis, mostly found in Panama and Colombia, attack the mucous membranes that line the inside of the nose and mouth, disfiguring people permanently.

Most leishmaniasis cases treated in the U.S. Are linked to international travel. But there is evidence that an increasing number of people are infected in the U.S., likely by Leishmania mexicana. Between 1903 and 1996, only 27 cases of locally-acquired leishmaniasis were reported in the U.S.

Then, in just 10 years between 2007 and 2017, 41 new local cases were reported. But those numbers might not reflect extent of the problem, said McIlwee. Currently, Texas is the only state that requires health professionals to report leishmaniasis cases to the state’s health department. Without a federal reporting requirement, she said, it is “a little bit tough to say exactly” how many cases occur across the country each year.

While the true U.S. Case count is certainly lower than in tropical regions, a 2010 study sounded an alarm. Scientists from the University of Texas at Austin and the National Autonomous University of Mexico spent hours doing fieldwork, catching sand flies and rodents in Texas and northern Mexico to pinpoint the species’ range. They then incorporated this data into computer models that map ecological niches—the highly specific environmental conditions in which these sand flies can sustain a population—and also took into account how temperatures across North America will be affected by climate change.

This allowed the international team to predict the geographical expansion of sand flies and Leishmania-infected rodents. According to the models, by 2020, the rodent-fly-parasite habitat was expected to extend to Oklahoma, Kansas, Arkansas, and Missouri. By 2080, the results showed the habitat stretching as far north as southern Canada, exposing nearly 27 million North Americans to the disease. "Climate change has a strong link with the emergence of zoonotic disease," said Víctor Sánchez-Cordero, a study author and an ecology professor at the National Autonomous University of Mexico.

"There is the possibility that there will soon be cases of human leishmaniasis in the U.S. Where before [they] did not exist." In fact, at least one case has already been reported as far north as North Dakota. Sahotra Sarkar, another author on the study and professor of integrative biology at the University of Texas at Austin, said that the team needs a few more years to gather the data that would confirm the accuracy of their modeling. But based on unpublished field data and citizen science reports, he believes the study’s predictions for 2020 were correct.

Climate change is probably not the only factor driving the species’ habitat expansion, said Sarkar. Human development can also play a role. When wild areas, like forests or savannas, are eliminated, the species living there will migrate. This can bring the migrating species into closer contact with people, increasing the risk for diseases to spill over into human populations.

Climate change is expanding the range of animals that carry Leishmania parasites in other countries, too. "The real spread of the disease is underestimated," said Camila González Rosas, a biology professor at the University of the Andes in Colombia. Her own research has demonstrated that a warming climate is pushing these vector species to higher altitudes in Colombia. Rojelio Mejia, an infectious disease physician at Baylor College of Medicine, in Houston, said that a couple of years ago he treated a patient who had traveled to Mexico’s Yucatan Peninsula.

While there, the patient contracted leishmaniasis, not the familiar local strain, but braziliensis, which is dominant farther south. According to Mejia, that strain, which is even more aggressive and disfiguring than mexicana, was not supposed to be in Mexico. "So you can just start saying, if we continue climate change, will braziliensis continue to climb up?. " Mejia wonders.

If the Brazilian strain does head north, it will create a more significant public health problem than the one the U.S. Is currently dealing with. In 2018, McIlwee co-authored a study that found 41 human cases of leishmaniasis contracted in the U.S. Since 2007, most of them occurring in Texas.

Most physicians, the paper contended, are not aware that the disease can be contracted within the country and that they only consider it as a diagnosis if a patient has traveled abroad. "They're not thinking about it when they're looking at a skin lesion," McIlwee said. Physicians have been known to mistake the wounds for symptoms of a bacterial . This misdiagnosis can lead to inappropriate treatments, such as a prescription for antibiotics, which may inhibit the body's immune system, leaving the parasite to reproduce unchecked.

Over-treatment can also be a problem. "When most medical students are learning about leishmaniasis in medical textbooks, they're seeing really impressive, ulcerated, deforming lesions," McIlwee said. These cases sometimes require treatments that can cause significant side-effects, but Leishmania mexicana, if caught on time, can be defeated with a gentler approach. "The cases that I saw were all very subtle.

They weren't very advanced, they didn't have a lot of damage to the surrounding skin or anything like that. And all of them could be treated locally," McIlwee said, recalling her days as a dermatology resident at the University of North Texas Health Science Center. There, she successfully cured a patient with an ear lesion by applying liquid nitrogen. And she’s not the only one.

Dustin Wilkes, a dermatologist in Weatherford, Texas, recently used the same approach to successfully treat a patient with three leishmaniasis lesions on his left shoulder. Prior to seeing Wilkes, the 65-year-old had declined a prescription for a harsh medication from a different doctor. For those in other countries battling more aggressive Leishmania strains, there is hope for both ancient and modern approaches. Mexican Mayan healers, who have been dealing with the illness—known locally as úlcera de los chicleros—for millennia, may have found an even less invasive way to treat the disease.

An herb paste applied to the ulcer for one to two weeks. In a study published in 2018 in the Journal of Ethnopharmacology, researchers found that the plant, known as Cleoserrata serrata, mostly found in southern Mexico, significantly inhibits parasite growth. Additionally, Abhay Satoskar, a pathology professor at the Ohio State University is working on a treatment, which he says looks “very promising." The treatment is slated to begin clinical trials next year, and plans are being laid by manufacturers in India for its commercial production, Satoskar said. While physicians and researchers grapple with the flesh-eating parasite, scientists say additional challenges are on the horizon.

As climate change pushes disease-vector species north, said McIlwee, “leishmaniasis is just one of a number of different diseases that we're going to see more of.” This story is part of the Pulitzer Center’s Connected Coastlines reporting initiative. This article was originally published on Undark. Read the original article..

Late on discount coupon cialis a Friday night in April 2020, Lexi Walls was alone in her laboratory at the University of Washington, waiting nervously for the results of the our website most important experiment of her life. Walls, a young structural biologist with expertise in erectile dysfunctiones, had spent the past three months working day and night to develop a new kind of treatment against the pathogen ravaging the world. She hoped that her approach, if successful, might not only tame erectile dysfunction treatment but also revolutionize discount coupon cialis the field of vaccinology, putting us on a path to defeat infectious diseases from flu to HIV. Unlike any treatment used before, the treatment Walls was developing was not derived from components found in nature. It consisted of artificial microscopic proteins drawn up on a computer, and their creation marked the beginning of an extraordinary leap in our ability to redesign biology.

Proteins are discount coupon cialis intricate nanomachines that perform most tasks in living things by constantly interacting with one another. They digest food, fight invaders, repair damage, sense their surroundings, carry signals, exert force, help create thoughts, and replicate. They are made of long strings of simpler molecules called amino acids, and they twist and fold into enormously complex 3-D structures. Their origamilike shapes are governed by the order and number of the different aminos used to build them, which have distinct attractive discount coupon cialis and repellent forces. The complexity of those interactions is so great and the scale so small (the average cell contains 42 million proteins) that we have never been able to figure out the rules governing how they spontaneously and dependably contort from strings to things.

Many experts assumed we never would. But new insights and breakthroughs in discount coupon cialis artificial intelligence are coaxing, or forcing, proteins to give up their secrets. Scientists are now forging biochemical tools that could transform our world. With these tools, we can use proteins to build nanobots that can engage infectious diseases in single-particle combat, or send signals throughout the body, or dismantle toxic molecules like tiny repo units, or harvest light. We can discount coupon cialis create biology with purpose.

Walls is at the forefront of this research. She completed her doctorate in erectile dysfunction structure in December 2019, making her a member of what was at the time a very small club. €œFor five years I'd been trying to convince people that erectile dysfunctiones were important,” discount coupon cialis she says. €œAt my Ph.D. Defense, I began by saying, ‘I'm about to tell you why this family of cialises has the potential to cause a cialis, and we are discount coupon cialis not prepared for that cialis.' Unfortunately, that ended up coming true.” As soon as word of a mysterious new pneumonia trickled out of Wuhan, China, in late December 2019, Walls suspected a erectile dysfunction.

On January 10, 2020, the genetic sequence for erectile dysfunction was released to the world. Walls and biochemist David Veesler, the head of her lab at the University of Washington, stayed up all night analyzing it. Walls says she felt an overwhelming sense of focus discount coupon cialis. €œIt was like, ‘Okay, we know what to do,'” she says. €œâ€˜Let's go do it.'” Like other erectile dysfunctiones, erectile dysfunction resembles a ball covered in protein “spikes.” Each spike ends in a cluster of amino acids—a section of the protein known as the receptor-binding domain, or RBD—whose alignment and atomic charges pair perfectly with a protein on the surface of human cells.

The viral protein docks at the receptor like a spacecraft, and the cialis uses this connection to slip discount coupon cialis inside the cell and replicate. Because of its dangerous role, the RBD is the primary target of the immune system's antibodies. They, too, are proteins, created by the body to bind to the RBD and take it out of commission. But it takes a while for specialized cells discount coupon cialis to manufacture enough effective antibodies, and by that time the cialis has often done considerable damage. The first-generation erectile dysfunction treatments, including the mRNA treatments that have been such lifesavers, work by introducing the cialis's spike into the body, without a functional erectile dysfunction attached, so the immune system can learn to recognize the RBD and rally its troops.

But the RBD is periodically hidden by other parts of the spike protein, shielding the domain from antibodies looking to bind to it. This blunts the immune discount coupon cialis response. In addition, a free-floating spike protein does not resemble a natural cialis and does not always trigger a strong reaction unless a large dose of treatment is used. That big dose increases costs and can trigger strong side effects. treatment developers Lexi Walls (left) and Brooke discount coupon cialis Fiala (right) used custom-crafted proteins to create a promising new erectile dysfunction treatment inoculation.

It waves a vulnerable part of the erectile dysfunction cialis in front of immune system cells, provoking a strong neutralizing response. Credit. Timothy Archibald As successful as the erectile dysfunction treatments have been, many experts see inoculations based on natural proteins as an interim technology. €œIt's becoming clear that just delivering natural or stabilized proteins is not sufficient,” says Rino Rappuoli, chief scientist and head of treatment development at U.K.-based pharmaceutical giant GlaxoSmithKline. Most current treatments, from childhood inoculations to adult flu shots, involve such natural proteins, which vaccinologists call immunogens.

GSK makes a lot of them. €œWe need to design immunogens that are better than natural molecules,” Rappuoli says. Walls and Veesler had an idea. What if, instead of a whole spike, the immune system were presented with just the RBD tip, which would not have any shield to hide behind?. “We wanted to put the key component on display,” Walls says, “to say, ‘Hey, immune system, this is where you want to react!.

' The immediate trouble with that notion was that biology does not make isolated RBDs, and the segment on its own would be too small and unfamiliar to get the immune system's attention. But Walls and Veesler knew some people who could help them solve that problem. Just up the street from them was the Bell Labs of protein invention, the University of Washington's Institute for Protein Design (IPD). The institute had learned enough about protein folding to design and build a few hundred very simple, small proteins—unlike any that have ever been found in a living organism—that would fold into consistent shapes with predictable functions. In 2019 a group in the IPD led by biochemist Neil King had designed two tiny proteins with complementary interfaces that, when mixed together in solution, would snap together and self-assemble into nanoparticles.

These balls were about the size of a cialis and were completely customizable through a simple change to their genetic code. When the scientists festooned the particles with 20 protein spikes from the respiratory syncytial cialis, the second-leading cause of infant mortality worldwide, they triggered an impressive immune response in early tests. Why not try a similar nanoparticle core for a erectile dysfunction treatment, Walls and Veesler thought, using just the RBD instead of an entire spike?. As a bonus, the protein-based nanoparticle would be cheap and fast to produce compared with treatments that use killed or weakened cialis. It would also be stable at room temperature and easy to deliver to people, unlike fragile mRNA treatments that must be kept in a deep freeze.

Walls reached out to the IPD and collaborated with nanoparticle specialist Brooke Fiala, who worked with King, on a prototype—a nanoparticle sphere displaying 60 copies of the RBD. The scientists also tried something radical. Instead of fusing the RBDs directly to the surface of the nanoparticle, they tethered them with short strings of amino acids, like kites. Giving the RBDs a little bit of play could allow the immune system to get a better look at every angle and produce antibodies that would attack many different spots. But nobody knew whether that would really happen.

So on that April Friday last year, as Walls waited for results, she had her fingers crossed. Three weeks earlier she and her colleagues had injected some mice with the nanoparticle treatment. Other mice got the plain spike that other treatments were using. Now the researchers had drawn blood from the mice and mixed it with a erectile dysfunction pseudocialis, an artificial, nonreplicating version of the cialis that is safer to use in labs. The idea was to see whether any vaccinated mice had developed antibodies that would home in on and neutralize the pseudocialis.

It takes a while for antibodies to do their thing, which is why Walls had to wait until late that Friday night. No way was she going home to be kept in suspense all weekend. Her colleagues had wished her good luck as they headed out the door. Before Veesler cut out, he asked her to contact him as soon as she had results. Now it was dark outside, and the lab was ghostly quiet.

It was finally time to look. Walls fired up a lab instrument that could detect and count antibodies attached to cialis particles, took a deep breath and peeked at the numbers. Some mice had been given a low dose of the plain spike, and that was a total failure. Zero effect on the pseudocialises. Mice given a high dose of the spike showed antibodies with a moderate neutralizing effect, similar to what some other treatments had produced.

But in mice that got the nanoparticle treatment, the pseudocialis was completely outmatched. Antibodies smothered it and had 10 times the neutralizing effect of the large-dose spike preparation. That magnitude held even when only a minuscule dose was used. Walls was looking at something that could be a low-cost, shelf-stable, uapotent treatment. Walls fired off an all-caps text message to Veesler.

€œTHEY'RE NEUTRALIZING!. € Veesler wrote right back. €œThe next generation of erectile dysfunction treatments is in your hands!. € That was only the first of several tests the treatment had to pass. From there they would have to prove the treatment could offer protection from the live cialis in mice, nonhuman primates and, finally, people.

The nanoparticles entered that last testing phase early in 2021. But at that moment, as an emblem of the power of protein design, it was already a success—the clearest sign yet that a technology long beyond our grasp had suddenly arrived. We were learning to sculpt the living clay from which we are all made. Credit. Falconieri Visuals As transformational as the genetics revolution of the past decades has been, at its heart has always been a mystery.

Proteins. A gene is simply the code for making a single protein. In that gene, a set of three DNA nucleotides, represented by letters, yields one amino acid, and another triplet codes for a different amino acid. There are 20 amino acids that a cell can use as protein-building blocks, and each one has a unique shape and function. Some are more flexible than others.

Some are positively charged, some negative. Some are attracted to water. Others are repelled by it. All day long our cells churn out new proteins in the exact order of amino acids dictated by our genetic code, and the proteins spontaneously snap into shape. That shape, along with the charges of the atoms on the exposed bits, determines the function.

What they respond to, what they attach to, what they can do. When we say, “He has the gene for red hair,” it means he has the blueprint for proteins that lead to a particular kind of pigment. When we say, “She has a gene that causes breast cancer,” it means she has a mutation in a gene that causes its protein to be made with an incorrect amino acid, which screws up its function in a way that can lead to cancer. Understanding the mechanics of protein folding would allow us to design new classes of drugs that could hobble or replace proteins gone wrong and to probe the etiology of diseases such as Alzheimer's, Parkinson's, Huntington's and cystic fibrosis, which are linked to misshapen proteins. Unfortunately, because proteins are so small, it is almost impossible to tell what is happening in this nanoworld, even with powerful microscopes.

We do not know precisely how all of these proteins fold correctly, much less what goes wrong when they misfold. It can take a year and $120,000 to produce a high-resolution image of one protein on specialized equipment. We currently know the structures of just 0.1 percent of them. For the rest, we guess. That is why there is a mystery at the center of the genetics revolution.

Certain genetic sequences are associated with physical and mental effects, but often we cannot tell why. We have lacked the Rosetta stone of protein structure to translate between the starting point of genes and the end point of bodily functions. In theory, it should be possible to predict the final structure of a protein from its genetic sequence—a task so essential to our understanding that in 2005 Science magazine included it in its 125th-anniversary issue's list of the most important unanswered questions in science. But in reality, it has been possible for only a very few extremely simple proteins. For example, scientists know that if they want to build a straight helix (a common Slinky-like structure in proteins that provides stability), they can use amino acids such as leucine, alanine and glutamate, which have the right curve and complementarity to form regular spirals and bond tightly to the amino acids on the coil above or below them.

If scientists want a kink in their Slinky, they can add a proline, which does not form a bond and allows the rest of the helix to bend away from it. Structural biologists such as David Baker, who founded the IPD—where Walls and Veesler went to get their nanoparticles—have been able to deduce a few of these basic rules. Baker's group has incorporated these rubrics into a structure-predicting computer program called Rosetta and used them to make a number of small proteins, typically a few dozen amino acids in size. Some of their successes have shown the great potential of the field. Microscopic “nanocages” that could be used to package drugs and transport them into the body and molecular detectors that go off when they encounter cells with specific combinations of amino acids on their surface, indicating such cells are cancerous.

But most important proteins in living things are much bigger than these examples and contain thousands of amino acids, each of which interacts with up to a dozen neighbors, some forming bonds as strong as those in a diamond, some pushing others away. All those relationships morph depending on proximity. So the possibilities quickly become astronomical, and the formulas for figuring out the final structures have long eluded our best minds and supercomputers. Frustrated by this problem back in 1994, a group of computational biologists decided that a little friendly competition might spur some progress. Led by John Moult of the University of Maryland, they launched CASP, the Critical Assessment of Structure Prediction contest.

Moult obtained detailed specs of proteins whose structure had been recently identified but not released. He sent the genetic sequence for the proteins to various teams from different research labs, which then submitted their best ideas about what the finished protein looked like. Those predictions were scored on their similarity to the actual structure based on the percentage of molecules in the right place. Getting the basic architecture right might score a 50, getting the angles and links between the main parts might be good for a 70, and nailing the tiny molecular threads that sprout off proteins like hairs would merit a 90-plus. Moult has been running the contest every two years since then.

For a long time not even the best teams could do much better than guesswork. In 2012, the year Baker's protein design institute started up, the very best CASP teams were averaging scores in the low 20s, and there had been no improvement for a decade. €œThere were moments after some CASPs where I'd see the results and despair,” Moult says. €œI'd think, ‘This is all a joke. Why are we even doing this?.

'” Some new insights led to a rise at CASP11, with the best scores averaging nearly 30, and another slight bump to around 40 at CASP12. Then came CASP13 in 2018. The best teams, led by Baker's institute, improved again, averaging nearly 50, but they were bested by a surprise entrant. Google's DeepMind, whose artificial-intelligence system had trounced the world's best Go player in 2017. The AI averaged a score of about 57 per protein.

That result rocked the world's protein-engineering labs, but it turned out to be just a dress rehearsal for 2020. In that year DeepMind's predictions were spot-on. €œI thought, ‘This can't be right. Let's wait for the next one,'” Moult says. €œAnd they just kept coming.” DeepMind averaged a 92 for all proteins.

On the easier ones, it had virtually every atom in the right place. But its most impressive results were on some exceedingly difficult proteins that completely stymied most teams. On one molecule, no group scored higher than the 20s—DeepMind scored in the high 80s. Moult was stunned by the results. €œI spent a lot of my career on this,” he says.

€œI never thought we'd get this level of atomic accuracy.” Most impressive, he says, is the indication that DeepMind has picked up on previously unknown fundamentals. €œIt's not just pattern recognition. In some alien way, the machine ‘understands' the physics and can calculate how the atoms in a unique arrangement of amino acids are going to arrange themselves.” “It was shocking,” agrees structural biologist and CASP competitor Mohammed AlQuraishi of Columbia University. €œNever in my life had I expected to see a scientific advance so rapid.” AlQuraishi expects the breakthrough to transform the biological sciences. The DeepMind team is expected to publish its methods paper, with details about how it worked, later this year.

Some aspects may remain inscrutable—the AI picks up on faint relationships that cannot easily be explained with rules—but at the moment, scientists do have the general outlines. To predict amino acids' effects on one another, the machine's programmers invoked a technique called attention that has been responsible for recent leaps forward in accurate language translation by AIs. Like proteins, language is a seemingly linear string of information that folds back on itself to produce meaning. A word such as “it” might draw its significance from a word used in an entirely different sentence. (“For the longest time, AI made no sense to me.

And then, after much reading, I finally understood it.”) When we communicate, we are constantly moving backward and forward along this linear string, paying attention to one local cluster of words to understand what a different word means in context. Once we have that meaning resolved, we can move to another, related passage and understand those words in light of the new information. DeepMind does something like this for proteins, focusing its attention on one local cluster of amino acids, understanding as much as it can about their relation to one another. Some pairs of aminos, for example, appear to have coevolved, indicating a bond between them and limiting their possible positions in the protein. DeepMind uses this information to leap to a different part of the protein and analyze that section in light of what it knows about the first cluster.

It carries out multiple iterations across all parts of the protein string and eventually uses this information to build a 3-D cloud of points that represents the relations among all the atomic constituents of every amino. It basically treats protein folding like a new, alien language to be deciphered. As other labs incorporate DeepMind's techniques and on-point protein prediction becomes ubiquitous, AlQuraishi says, the lengthy trial-and-error period of getting a real-world protein to fold like you thought it would will become much faster. €œIt will percolate everywhere,” he says. €œIt's going to make protein design much more effective.” To block a cialis, Longxing Cao of the Institute for Protein Design developed small synthetic proteins called mini binders.

They glom on to the part of a erectile dysfunction that attaches to cells, stopping it. Mini binders could be sprayed up the nose to prevent s. Credit. Timothy Archibald But the DeepMind team is not in the business of applied science, so the AI will not spend its time churning out blueprints for complicated protein construction on demand. Its big contribution will be indirect.

€œTheir work shines light on the power of proteins and the bright future of engineering new ones,” says California Institute of Technology biochemist Frances Arnold, who won the Nobel Prize in Chemistry in 2018 for improving the performance of natural proteins through a method called directed evolution. €œBut they have not solved the problem of designing or engineering proteins to solve problems for people.” That work will fall to the Arnolds and Bakers of the world, who are trying to use DeepMind's techniques to supercharge their labs' abilities to sculpt proteins. €œIt's a big breakthrough,” says Baker, whose team again finished a distant second in the competition. €œI think it will make what's already working well work even better.” Right now there is an enormous problem for people, to use Arnold's phrase, that is wracking the world. That problem is erectile dysfunction treatment.

When it hit, Baker and others in his lab looked to proteins for solutions. They plugged the genetic sequence for the erectile dysfunction into Rosetta, their protein-structure-prediction computer program, to produce a 3-D model, then pored over it for weaknesses like Rebel pilots plotting an assault on the Death Star. As Walls did, they zeroed in on the spike's RBD. But instead of making a treatment to trigger antibody production, Baker wanted to build a better antibody. He wanted a protein whose sole purpose was to ensnare the RBD like microscopic Velcro.

Amazing as they are, antibodies are not perfect. The body cannot custom-design an antibody in advance for a pathogen it has never seen, so it makes a lot of different versions. When a new invader shows up, immune system cells make many copies of whatever antibody binds best, but the fit is not always tight enough to stop the pathogen. Natural antibodies are also relatively big proteins that are not always able to get their business end snug against a cialis's RBD. Enter the “mini binders,” as Baker calls them.

These are small synthetic proteins that can be designed amino acid by amino acid to fit precisely against a cialis's RBD. With no extraneous bits, they bind more tightly. And they are small and lightweight enough to be administered through a spritz up the nose rather than an injection into the arm. No needles!. Baker's dream was to create a medication rather than a treatment.

A nasal spray that could be used at the first sign of —or beforehand as daily prevention—to flood the nose with a mist of mini binders that would coat the RBDs of cialis particles before they could attach to anything. It would have the long shelf life of a bag of dried lentils, and it could be quickly reformulated for any new pathogen and rushed into the hands of health-care workers, teachers and anyone else on the front lines—a kind of designer-driven immune system for civilization. To engineer the mini binder, Longxing Cao, a postdoc in Baker's lab who headed the project, scouted the cialis RBD's structure, comparing it with the library of tiny proteins the institute had previously designed and looking for complementary shapes. Like a rock climber on a challenging face, the mini binder needed to be small enough to wriggle into the cleft where the RBD lay, and it needed to be shaped so that it could get firm handholds and toeholds in the right places. Cao cataloged where the RBD's amino acids made patches of positive electrical charges, patches of negative charges and hydrophobic (water-hating) patches, then tailored mini binders to have as many complementary patches as possible.

He tested millions of possibilities on Rosetta. The best designs were made of three helixes connected like sausage links by short strings of amino acids. Each mini binder was about 60 amino acids long in total—less than a tenth the size of an antibody and a twentieth the size of a erectile dysfunction spike. Then, of course, Cao had to take his protein from Rosetta to the real world. Amazingly, that process has become trivially easy.

DNA—the As, Cs, Gs and Ts of the genetic code—can be printed for pennies on devices that resemble inkjet printers. Cao printed DNA strands with the sequence for his mini binder and inserted them into yeast, which, like programmable livestock, pumped out those tiny proteins along with their normal ones. He then harvested the proteins and tested them. The top mini binder bound the cialis six times more effectively than the best antibodies known—better than any molecule on the planet, in fact, forming dozens of strong bonds with the RBD. It was extraordinarily stable, and it sprayed easily out of a nozzle.

Hamsters given a snootful became immune to erectile dysfunction treatment. €œI was definitely excited,” Cao says, “but not totally surprised.” Researchers expect clinical trials for mini binders to start later in 2021, and a number of labs around the world are now exploring other ways that mini proteins might help the body function or ward off illness. Although there is great optimism about the technology, some biosecurity researchers have expressed concerns about proteins that could be designed for nefarious purposes. Prions, for example, which are responsible for “mad cow” and other neurodegenerative diseases, are misfolded proteins that cause other proteins to misfold in turn, triggering deadly chain reactions that are transmissible. They could be delivered by aerosol.

The Biological Weapons Convention, which virtually all nations have signed, effectively bans the development or use of pathogen-based bioweapons, but no one ever thought to extend it to address proteins that were never part of an organism. €œThis is a real concern,” says biosecurity expert Filippa Lentzos of King's College London, “because potential future biological weapons won't necessarily make us sick using pathogens.” Synthetic mini proteins may or may not fall under the control of the convention, she says, “so legal status is an important issue.” But engineered mini proteins are also an extremely unlikely threat, Lentzos says, and quite low on her list of worries. €œIf you want to cause harm, why would you turn to something as sophisticated and complicated as protein design?. There are plenty of more accessible things in nature you could use.” Naturally occurring toxins and pathogens are ready-made and all over the place. If you really want to hurt people, there are easier ways.

At this moment, the helpful types of de novo proteins are attracting an increasing amount of scientific energy and expertise, and the molecules may be coming to a clinic near you. As most of the world's nearly eight billion people await a erectile dysfunction treatment, Walls's nanoparticle is looking like a promising candidate. After successfully neutralizing the pseudocialis in mouse cells, the treatment's next big test was against the real erectile dysfunction. For that, Walls had to ship her mice to the University of North Carolina lab of Ralph S. Baric, one of the world's foremost erectile dysfunction researchers.

The facility has the biosecurity level required to work with the live cialis. Baric and his colleagues see many treatment candidates, so in June 2020 Walls was pleased to get an encouraging e-mail from them. The neutralizing power of the nanoparticle treatment was off the charts—higher than anything they had tested. €œEverything worked better than we'd hoped!. € Walls says.

When exposed to the real cialis, the mice did well. €œCompletely protected. No sign of illness.” (Later Walls found that she could reduce the already low dose an additional ninefold, add a booster and get equally good results.) In January of this year the treatment began early clinical trials in Washington State and South Korea. Yet even as those trials were progressing, the cialis was spawning a new wave of variants with the ability to evade some of the antibodies triggered by the first generation of treatments. So Walls went back to work, designing a new and improved nanoparticle.

Instead of copies of just the erectile dysfunction RBD, this version had a mosaic of four different RBDs. Some from erectile dysfunction, some from the original SARS cialis from the early 2000s and some from two other erectile dysfunctiones. This broad spectrum of RBDs elicited a robust antibody response against all erectile dysfunctiones tested, including the most elusive of the variants. A treatment that is effective in tiny doses, that is easy and inexpensive to produce, that does not require refrigeration and that protects against a bunch of mutant cialises, including ones that may emerge in the future, could be exactly the solution the world needs. These advantages have drawn the attention of the world's treatment heavyweights, including GSK's Rappuoli.

€œThere is no question that our immune system likes nanoparticles,” he says. €œThese represent the best option we have.” In a recent commentary in the journal Cell, Rappuoli predicted that such designer molecules will usher in a new era of treatments. €œFrom here, the sky is the limit.” And the capability will not end with treatments. In this new Amino Age, the ability to intelligently design nanomachines at an atomic scale could turn fighting every disease into an engineering exercise. €œWhen we tackle problems involving any sort of protein, we need to have this in mind,” Walls says.

€œWe need to look at the protein and know that we can engineer solutions. Every day there are new successes coming.” Some of those successes will come in areas other than medicine, such as materials science. The IPD has invented proteins that self-assemble into microscopic honeycomb grids that attract mineral deposition, a new way to produce efficient superconductors and batteries. Another project is crafting proteins that harvest light, as do photosynthetic proteins in plants, and convert that energy into electricity and fuel. As the Amino Age tool kit grows, the natural proteins we now use for help—insulin for people with diabetes, for instance—may come to seem as archaic as the sharpened rocks our Stone Age ancestors once used.

By the same token, our current designer proteins, as exciting as they are, are just sundials and wagon wheels. The features of a future landscape filled with bespoke molecules are beyond conception. But like the new proteins themselves, those features will, eventually and elegantly, fold into shape.Most U.S. Cities have tree-planting programs, but not all urban tree canopies are created equal, according to a new analysis from American Forests.The conservation organization said today that the United States needs to plant more than a half-billion new trees to achieve an equitable urban canopy across nearly 500 metropolitan areas and 150,000 local communities.The findings are based on a new "Tree Equity Score" data tool that allows users to see where urban trees exist, and where they don't. American Forests also identified 20 large U.S.

Cities that are lagging in urban forest canopies that would protect their most vulnerable populations from hotter temperatures."The findings confirm a disturbing pattern of inequitable distribution of trees that has deprived many communities of color of the health and other benefits that sufficient tree cover can deliver," American Forests said.For example, communities of color have 33% less tree canopy on average than majority white communities, the analysis revealed. And neighborhoods with 90% or more of their residents living in poverty have 41% less tree canopy than communities with only 10% or less of the population in poverty. (Greenwire, Sept. 16, 2020)."The scale and pace at which trees are planted or naturally regenerate must significantly increase if trees are to continue to make people healthier or slow effects of climate change," Ian Leahy, American Forests' vice president for urban forestry, said in a statement.Achieving "tree equity" nationally would require planting 522 million trees in places with populations of 50,000 or greater, American Forests said. As those trees mature, they would mitigate 56,613 tons of particulate pollution and absorb 9.3 million tons of carbon dioxide — the equivalent of taking 92 million cars off the roads, American Forests said.The report identified several cities that would benefit from more equitable tree cover.

Those include the five most populated cities in the United States — New York, Los Angeles, Chicago, Houston and Phoenix — and a handful of smaller cities such as Fresno, Calif.. Jacksonville, Fla.. And Oklahoma City.Tree canopies are particularly good at reducing health stress associated with urban heat islands. These areas often are much hotter than surrounding neighborhoods — a condition caused by a lack of trees and the absorption of heat by buildings, streets and parking lots.Scientists say urban heat islands can cause temperatures to be 5 to 7 degrees warmer during the day and as much as 22 degrees warmer at night.This creates a dangerous health risk. Under current climate warming trajectories, heat-related deaths from 2031 to 2050 could be 57% higher than from 1971 to 2000, American Forests said."We need to make sure the trees go where the people are," said Jad Daley, American Forests president and CEO.

"And more than 70% of the people live in cities or suburbs, so it's a place-based problem with a place-based solution."He also stressed the need for local, state and federal lawmakers and nonprofits to fund the protection of existing trees and plant new ones.Reprinted from E&E News with permission from POLITICO, LLC. Copyright 2021. E&E News provides essential news for energy and environment professionals.Two treatments made using messenger RNA (mRNA) have proved spectacularly successful at warding off erectile dysfunction treatment, but a third mRNA-based candidate has flopped in a final-stage trial, according to an initial report released this week. Researchers are now asking why — and some think that choices about the type of mRNA chemistry used might be to blame. Any insight could help to guide the future design of mRNA treatments against erectile dysfunction treatment or other diseases.

The company behind the beleaguered trial, CureVac, based in Tübingen, Germany, announced preliminary data on 16 June from a 40,000-person trial, which showed that its two-dose treatment was just 47% effective at preventing disease. CureVac’s mRNA treatment was expected to be cheaper and to last longer in refrigerated storage than the earlier mRNA treatments made by Pfizer–BioNTech and Moderna. Many had hoped that it could help to expand the reach of mRNA-based treatments in lower-income countries, and European countries were expecting to order hundreds of millions of doses. €œI’m definitely surprised — and also disappointed,” says Philip Santangelo, a biomedical engineer at the Georgia Institute of Technology in Atlanta who has worked with many mRNA-focused companies, including CureVac. He and others suspect that CureVac’s decision not to tweak the biochemical make-up of its mRNA, as Pfizer–BioNTech and Moderna did, might be behind its poor performance — although it is too early to know for sure.

Variant problem CureVac executives put the poor results down to the high number of erectile dysfunction variants — including emerging ones such as the Lambda variant first detected in Peru — circulating in the ten countries across Europe and Latin America where the company is running its trial. Of 124 erectile dysfunction treatment cases for which scientists obtained a genetic sequence, only one was caused by the original version of erectile dysfunction. But the other mRNA treatments have fared much better in the face of variants. Researchers in the United Kingdom have reported, for instance, that the Pfizer–BioNTech shot offered 92% protection against symptomatic cases of erectile dysfunction treatment caused by the Alpha variant (first identified in the United Kingdom) and 83% protection against the Delta variant (initially reported in India). A study in Qatar similarly found the treatment to be around 90% effective against the Alpha strain and 75% effective against the Beta variant that emerged in South Africa.

Those differences in efficacy have led trial investigators and other scientists to suggest that the problem is with the treatment itself. Dose of reality “My best take is that the dose is the culprit,” says Peter Kremsner, an infectious-disease specialist at Tübingen University Hospital who is leading CureVac’s clinical studies. In phase I testing, Kremsner and his colleagues evaluated doses ranging from 2 to 20 micrograms of mRNA per injection. At the higher dose levels, the treatment caused too many side effects, with trial participants frequently complaining of problems such as severe headaches, fatigue, chills and injection-site pain. At 12 micrograms, the treatment proved more tolerable, and all recipients developed antibodies that blocked the cialis from entering cells.

But the levels of those ‘neutralizing’ antibodies were relatively low — on a par with the amounts found in people who have recovered from erectile dysfunction s, but well below the levels seen in recipients of the Moderna and Pfizer–BioNTech treatments, which are both given at higher doses. Perhaps it’s no surprise, then, that CureVac’s shot came up short, says Nathaniel Wang, the chief executive of Replicate Bioscience, an RNA-focused biotech start-up based in San Diego, California. Those low antibody titres in early testing were “already a red flag”, he says. Some researchers wonder why the treatment couldn’t be administered at higher doses without inducing side effects. The tiny bubbles made of lipids that mRNA treatments are encapsulated in — to help deliver their genetic payloads into cells — can trigger side effects such as those documented by the CureVac trial.

But Santangelo says that the CureVac and the Pfizer–BioNTech treatments use practically indistiguishable, if not identical, lipid bubbles. He and others think that the problem might lie in the mRNA sequence. Modified RNA All three mRNA treatments encode a form of the erectile dysfunction spike protein, which helps cialis particles to penetrate human cells. But the Moderna and Pfizer–BioNTech treatments use modified RNA, incorporating an mRNA nucleotide called pseudouridine — which is similar to uridine but contains a natural modification — in place of uridine itself. This is thought to circumvent the body’s inflammatory reactions to foreign mRNA.

CureVac’s treatment uses normal uridine and relies on altering the sequence of RNA letters in a way that does not affect the protein it codes for, but helps the treatment to evade immune detection. Proponents of modified mRNA have long argued that the chemical adjustment is integral to the success of the treatment technology. Drew Weissman, an immunologist at the University of Pennsylvania in Philadelphia who co-discovered the importance of pseudouridine in this context in the mid-2000s4, describes it as the “best platform for antibody and neutralization levels”. In light of the new CureVac data, many scientists who spoke to Nature agree. €œModified mRNA has won this game,” says Rein Verbeke, an mRNA-treatment researcher at Ghent University in Belgium.

There are a few other possible explanations for CureVac’s tolerability problems. Structural differences in the non-coding regions of the CureVac sequence could play a part. Alternatively, the higher storage temperature of CureVac’s jab might have accelerated the breakdown of mRNA in the vial, yielding pieces of genetic code that would raise immune hackles. And if any impurities were introduced during the company’s manufacturing process, these would, in principle, have the same effect. So for some scientists it remains too early to draw conclusions.

€œThe jury is still out on which of these is a better technology,” says Jeffrey Ulmer, a former pharmaceutical executive who now consults on treatment research issues. He predicts that both modified and unmodified mRNA will be useful in different contexts. €œIt could be that there’s not a one-size-fits-all solution to everything.” CureVac hopes that its treatment — or at least its unmodified mRNA technology — might yet deliver. The company is continuing its trial and expects a final analysis in the next few weeks. On a public health level, even if the treatment fails, “I don’t think it’s going to set the world back much”, says Jacob Kirkegaard, a treatment-supply expert at the Peterson Institute for International Economics, a think-tank in Washington DC.

He points out that another second-generation treatment that offers many of the same logistical selling points as CureVac’s, such as long-term refrigerator storage, has stood up to the variant challenge well. Earlier this week, Novavax in Gaithersburg, Maryland, reported that its protein-based treatment was more than 90% effective at preventing erectile dysfunction treatment in a large US trial, run at a time that the Alpha variant was prevalent. The scale of production of other treatments more than makes up for the lack of CureVac’s product, Kirkegaard says. CureVac, in collaboration with London-based GlaxoSmithKline, also has a second-generation erectile dysfunction treatment in the works that, like its predecessor, uses unmodified mRNA, but has been fine-tuned so that it elicits levels of neutralizing antibodies that are around ten times higher, according to data from rat and monkey studies. €œOur optimization has never stopped,” says CureVac’s chief technology officer Mariola Fotin-Mleczek.

€œIt’s too early to say unmodified, natural messenger RNA is not an option.” Human trials are due to launch later this year. This article is reproduced with permission and was first published on June 18 2021.CRISPR is the basis of a revolutionary gene editing system. One day, it could make it possible to do everything from resurrect extinct species to develop cures for chronic disease.It’s built on a natural adaptation found in the DNA of bacteria and single-celled organisms. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. They’re really just bits of genetic code with a specific, recognizable format.

They contain a sequence that shows up over and over again, though it’s often reversed each time. That’s what makes it "Palindromic:” palindromes are words that can be read the same backwards as forwards. Palindromes are common in DNA. Some serve as backups for damage to our genetic code, while others are common in cancer mutations. With CRISPR, a group of enzymes recognize certain repeats, and break the DNA there to insert important information in the middle.

These insertions are called “spacers,” and they contain the genetic code of different cialises that have invaded in the past. Such previous invasions served a very important evolutionary purpose. Immunizing against foreign threats. Researchers first discovered CRISPR in E. Coli in the 1980s.

When E. Coli survives viral attacks, it incorporates some of the cialis DNA into its own genetic code. E. Coli isn’t unique in using this strategy. Between the 1980s and 2000, scientists found that lots of bacteria and single-celled organisms incorporate viral DNA this way.

Cells use these sequences as templates for transcribing complementary strands of RNA. When cialises matching the template sequence enter the cell, the complementary RNA binds to them, and directs a series of CRISPR-associated enzymes, or “Cas” enzymes, to attack—cutting invader DNA at the binding site. That neutralizes the viral threat. The CRISPR-Cas system is incredibly effective. It’s also easy to manipulate, letting us alter a cell’s genetic code however we want.

In 2012, French microbiologist Emmanuelle Charpentier and American biochemist Jennifer Doudna discovered that Cas enzymes—specifically Cas9—can be reprogrammed to cut nearly any part of the genome, using RNA sequences made in a lab. Those “guide RNA” molecules tell Cas9 where to cut DNA in a cell. For their discovery, Charpentier and Doudna won the Nobel Prize in Chemistry in 2020. And the use of CRISPR has taken off in science since their breakthrough. But scientists are still far from realizing CRISPR’s potential.

Cas9 is great at suppressing or knocking out unwanted genes. But for most medical purposes, it’s not enough to cut unwanted DNA out. Scientists need to control how the DNA repairs itself. Left to their own devices, cells tend to repair broken DNA using a method that introduces lots of random errors. Researchers can provide cells with templates to guide the repair process, but they’re still working on making that more reliable.

Researchers have found lots of applications for CRISPR in animals, like making disease-resistant chickens and pigs, and mosquitos that can’t bite or lay eggs. But they’ve got many projects underway, like making disease-resistant crops—including wine grapes. More ambitiously, they’re working to genetically alter pigs so their organs could be transplanted into humans. And bring extinct species such as the passenger pigeon back to life, by tweaking the genomes of similar birds. When it comes to the human genome, though, scientists have been more hesitant.

Editing our own DNA could easily end up causing more problems than it solves. While Cas9 reliably cuts DNA where we want it to, recent experiments have shown it can also affect genes far off-target. And even if we could get it to work reliably, many experts have flagged ethical concerns about using the technology for eugenics and “designer babies.” If parents can one day pay scientists to edit their babies’ DNA, making them stronger and smarter, CRISPR could make the world even more unequal and prejudiced. In 2018, Chinese researcher HEH JEE'-an-qway claimed he’d used CRISPR to make HIV-resistant children. Whether or not he succeeded, his work violated China’s National Health Commission rules, and he was sentenced to three years in prison.

Using CRISPR on babies is widely illegal. But there are some cases where using CRISPR on humans may be worth the risk. In 2020, American researchers began the first clinical trials injecting CRISPR directly into living humans, aiming to repair a genetic mutation that causes blindness. Many researchers hope CRISPR-based therapies could eventually cure hereditary diseases. They’ve already seen promising results in various animal studies.

Though given the risks of editing the human genome, we’re still a ways off from widespread use of CRISPR in medicine. CRISPR has given science a tool to reliably tinker with the code of life. But the question remains. Can we do so safely and ethically, while avoiding the unintended consequences of such power?. Three years ago, Laura Gaither and her family spent their summer vacation in Panama City Beach, Florida.

One afternoon, while rinsing sand off her feet, the 35-year-old Alabama resident felt something biting her legs and noticed tiny black bugs on her skin. Gaither brushed them away, and later, when she described the bites to local residents, they told her that she had likely been bitten by sand flies. Three of Gaither’s five kids had been bitten, too, but she didn’t worry. The marks on their legs and arms looked like ant or mosquito bites, which can cause burning and itching, but usually subside within a week. But about two weeks later, back at home, Gaither noticed that the bites had morphed into small open wounds.

They worsened over the next couple of weeks, but when she took her children to their pediatrician, “he just chalked it up to eczema,” Gaither said. Eventually Gaither took her young daughter, whose condition was the most concerning, to the emergency room at Children’s of Alabama, where she was tested for fungal and bacterial s. The results came back negative, and the anti-fungal and steroid topical creams the doctors prescribed proved ineffective. Meanwhile, the ulcers kept growing larger and more painful. Gaither started doing her own research and learned about a flesh-eating disease called cutaneous leishmaniasis (pronounced leash-ma-NYE-a-sis).

This skin disease is caused by more than 20 species of Leishmania parasites. It can be transmitted to humans through the bite of some sand flies after the flies themselves have been infected by animals—usually rodents in the United States—whose blood the insects feed on. Sand flies thrive in hot sandy beaches and in rural areas, and they had been particularly abundant in Florida in 2018, Gaither was told during her visit. Leishmaniasis, Gaither learned, is common in tropical and subtropical countries like Brazil, Mexico, and India. Looking through peer-reviewed papers, she saw pictures of leishmaniasis wounds that looked a lot like her own.

Crater-like ulcers coated with a thick, yellowish pus. During the visits with her children’s pediatrician and in the ER, Gaither asked her doctors about the parasite. They dismissed the possibility that the family might have contracted a tropical disease without traveling abroad, she said. "Nobody would even entertain what I was saying." That is, until the wound on Gaither’s knee worsened and, armed with research papers, she convinced her own physician to test a biopsy for leishmaniasis. The results were inconclusive.

Fortunately, by this time the children’s wounds had begun to heal. Three months after they appeared, the ulcers completely cleared up, leaving Gaither to wonder what really caused them. While her family’s ordeal has ended, scientists say the story of leishmaniasis in the U.S. Is just beginning. Americans, it turns out, can be exposed to Leishmania parasites without leaving the country.

The parasites are currently endemic in Texas and Oklahoma, and new studies suggest that they might be present in other states, including Florida. While reported cases of leishmaniasis contracted in the U.S. Are currently negligible, they may soon be on the rise. As climate change pushes rodent and sand fly habitat northward, scientists caution that in the future, an increasing number of U.S. Residents could be exposed to different varieties of the flesh-eating parasite.

Some strains of Leishmania parasites can be life-threatening. The one currently present in the U.S., Leishmania mexicana, induces milder symptoms and over time, can heal on its own. But if doctors fail to recognize it, or overreact to it, damages caused by wrong therapies and unnecessary toxic systemic medication can cause more harm than the disease itself. Bridget McIlwee, an Illinois-based dermatologist, has treated patients who contracted leishmaniasis in Texas. She wants her colleagues to be more aware of the parasite’s expansion into the U.S.

€œIt's a pretty striking difference for a disease that we used to think of as limited to South America now extending as far north as Canada,” she said, “potentially within the next several decades.” Every year, between 1.5 to 2 million people worldwide contract leishmaniasis, and around 70,000 die from it, mostly in poor rural areas. The most dangerous Leishmania strains, such as infantum and donovani, don’t just eat a person’s skin, they also infect the liver, spleen, and bone marrow, leading to death if not treated. Drugs like miltefosine and amphotericin B, used to cure these strains of Leishmaniasis, are expensive or toxic, and not much funding goes into researching and developing better treatments. In 2007, the World Health Organization added leishmaniasis to the list of neglected tropical diseases, which mainly affect the word’s poor and do not receive much attention. While Leishmania parasites are present in about 90 countries, the symptoms of an vary by strain.

The mexicana strain, typically found in Mexico and Central America, causes skin sores that can sometimes take years to heal and leave ugly scars. Others, like panamensis, mostly found in Panama and Colombia, attack the mucous membranes that line the inside of the nose and mouth, disfiguring people permanently. Most leishmaniasis cases treated in the U.S. Are linked to international travel. But there is evidence that an increasing number of people are infected in the U.S., likely by Leishmania mexicana.

Between 1903 and 1996, only 27 cases of locally-acquired leishmaniasis were reported in the U.S. Then, in just 10 years between 2007 and 2017, 41 new local cases were reported. But those numbers might not reflect extent of the problem, said McIlwee. Currently, Texas is the only state that requires health professionals to report leishmaniasis cases to the state’s health department. Without a federal reporting requirement, she said, it is “a little bit tough to say exactly” how many cases occur across the country each year.

While the true U.S. Case count is certainly lower than in tropical regions, a 2010 study sounded an alarm. Scientists from the University of Texas at Austin and the National Autonomous University of Mexico spent hours doing fieldwork, catching sand flies and rodents in Texas and northern Mexico to pinpoint the species’ range. They then incorporated this data into computer models that map ecological niches—the highly specific environmental conditions in which these sand flies can sustain a population—and also took into account how temperatures across North America will be affected by climate change. This allowed the international team to predict the geographical expansion of sand flies and Leishmania-infected rodents.

According to the models, by 2020, the rodent-fly-parasite habitat was expected to extend to Oklahoma, Kansas, Arkansas, and Missouri. By 2080, the results showed the habitat stretching as far north as southern Canada, exposing nearly 27 million North Americans to the disease. "Climate change has a strong link with the emergence of zoonotic disease," said Víctor Sánchez-Cordero, a study author and an ecology professor at the National Autonomous University of Mexico. "There is the possibility that there will soon be cases of human leishmaniasis in the U.S. Where before [they] did not exist." In fact, at least one case has already been reported as far north as North Dakota.

Sahotra Sarkar, another author on the study and professor of integrative biology at the University of Texas at Austin, said that the team needs a few more years to gather the data that would confirm the accuracy of their modeling. But based on unpublished field data and citizen science reports, he believes the study’s predictions for 2020 were correct. Climate change is probably not the only factor driving the species’ habitat expansion, said Sarkar. Human development can also play a role. When wild areas, like forests or savannas, are eliminated, the species living there will migrate.

This can bring the migrating species into closer contact with people, increasing the risk for diseases to spill over into human populations. Climate change is expanding the range of animals that carry Leishmania parasites in other countries, too. "The real spread of the disease is underestimated," said Camila González Rosas, a biology professor at the University of the Andes in Colombia. Her own research has demonstrated that a warming climate is pushing these vector species to higher altitudes in Colombia. Rojelio Mejia, an infectious disease physician at Baylor College of Medicine, in Houston, said that a couple of years ago he treated a patient who had traveled to Mexico’s Yucatan Peninsula.

While there, the patient contracted leishmaniasis, not the familiar local strain, but braziliensis, which is dominant farther south. According to Mejia, that strain, which is even more aggressive and disfiguring than mexicana, was not supposed to be in Mexico. "So you can just start saying, if we continue climate change, will braziliensis continue to climb up?. " Mejia wonders. If the Brazilian strain does head north, it will create a more significant public health problem than the one the U.S.

Is currently dealing with. In 2018, McIlwee co-authored a study that found 41 human cases of leishmaniasis contracted in the U.S. Since 2007, most of them occurring in Texas. Most physicians, the paper contended, are not aware that the disease can be contracted within the country and that they only consider it as a diagnosis if a patient has traveled abroad. "They're not thinking about it when they're looking at a skin lesion," McIlwee said.

Physicians have been known to mistake the wounds for symptoms of a bacterial . This misdiagnosis can lead to inappropriate treatments, such as a prescription for antibiotics, which may inhibit the body's immune system, leaving the parasite to reproduce unchecked. Over-treatment can also be a problem. "When most medical students are learning about leishmaniasis in medical textbooks, they're seeing really impressive, ulcerated, deforming lesions," McIlwee said. These cases sometimes require treatments that can cause significant side-effects, but Leishmania mexicana, if caught on time, can be defeated with a gentler approach.

"The cases that I saw were all very subtle. They weren't very advanced, they didn't have a lot of damage to the surrounding skin or anything like that. And all of them could be treated locally," McIlwee said, recalling her days as a dermatology resident at the University of North Texas Health Science Center. There, she successfully cured a patient with an ear lesion by applying liquid nitrogen. And she’s not the only one.

Dustin Wilkes, a dermatologist in Weatherford, Texas, recently used the same approach to successfully treat a patient with three leishmaniasis lesions on his left shoulder. Prior to seeing Wilkes, the 65-year-old had declined a prescription for a harsh medication from a different doctor. For those in other countries battling more aggressive Leishmania strains, there is hope for both ancient and modern approaches. Mexican Mayan healers, who have been dealing with the illness—known locally as úlcera de los chicleros—for millennia, may have found an even less invasive way to treat the disease. An herb paste applied to the ulcer for one to two weeks.

In a study published in 2018 in the Journal of Ethnopharmacology, researchers found that the plant, known as Cleoserrata serrata, mostly found in southern Mexico, significantly inhibits parasite growth. Additionally, Abhay Satoskar, a pathology professor at the Ohio State University is working on a treatment, which he says looks “very promising." The treatment is slated to begin clinical trials next year, and plans are being laid by manufacturers in India for its commercial production, Satoskar said. While physicians and researchers grapple with the flesh-eating parasite, scientists say additional challenges are on the horizon. As climate change pushes disease-vector species north, said McIlwee, “leishmaniasis is just one of a number of different diseases that we're going to see more of.” This story is part of the Pulitzer Center’s Connected Coastlines reporting initiative. This article was originally published on Undark.