StemCell Therapy

Research coming out of the University of Pennsylvania School of Medicine last month demonstrated how artificial intelligence (AI) can be utilized to fight against opioid abuse. It focused on a chatbot which sent reminders to patients who underwent surgery to fix major bone fractures.

The research was published in the Journal of Medical Internet Research.

Christopher Anthony, MD, is the studys lead author and the associate director of Hip Preservation at Penn Medicine. He is also an assistant professor of Orthopaedic Surgery.

We showed that opioid medication utilization could be decreased by more than a third in an at-risk patient population by delivering psychotherapy via a chatbot, he said. While it must be tested with future investigations, we believe our findings are likely transferable to other patient populations.

Opioids are an effective treatment for pain following a severe injury, such as a broken arm or leg, but the large prescription of the drugs can lead to addiction and dependence for many users. This is what has caused the major opioid epidemic throughout the United States.

The team of researchers believe that a patient-centered approach with the use of the AI chatbot can help reduce the number of opioids taken after such surgerys, which can be a tool used against the epidemic.

Those researchers also included Edward Octavio Rojas, MD, who is a resident in Orthopaedic Surgery at the University of Iowa Hospitals & Clinics. The co-authors included: Valerie Keffala, PhD; Natalie Ann Glass, PhD; Benjamin J. Miller, MD; Mathew Hogue, MD; Michael Wiley, MD; Matthew Karam, MD; John Lawrence Marsh, MD, and Apurva Shah, MD.

The research involved 76 patients who visited a Level 1 Trauma Center at the University of Iowa Hospitals & Clinics. They were there to receive treatment for fractures that required surgery, and those patients were separated into two groups. Both groups received the same prescription for opioids to treat pain, but only one of the groups received daily text messages from the automated chatbot.

The group that received text messages could expect two per day for a period of two weeks following their procedure. The automated chatbot relied on artificial intelligence to send the messages, which went out the day after surgery. The text messages were constructed in a way to help patients focus on coping better with the medication.

The text messages, which were created by a pain psychologist specialized in pain and commitment therapy (ACT), did not directly go against the use of the medication, but they attempted to help the patients think of something other than taking a pill.

The text messages could be broken down into six core principles, : Values, Acceptance, Present Moment Awareness, Self-As-Context, Committed Action, and Diffusion.

One message under the Acceptance principle was: feelings of pain and feelings about your experience of pain are normal after surgery. Acknowledge and accept these feelings as part of the recovery process. Remember how you feel now is temporary and your healing process will continue. Call to mind pleasant feelings or thoughts you experienced today.

The results showed that the patients who did not receive the automated messages took, on average, 41 opioid pills following the surgeries, while the group who did receive the messages averaged 26. The 37 percent difference was impressive, and those who received messages also reported less overall pain two weeks after the surgery.

The automated messages were not personalized for each individual, which demonstrates success without over-personalization.

A realistic goal for this type of work is to decrease opioid utilization to as few tablets as possible, with the ultimate goal to eliminate the need for opioid medication in the setting of fracture care, Anthony said.

The study received funding by a grant from the Orthopaedic Trauma Association.

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AI Algorithms Can Enhance the Creation of Bioscaffold Materials and Help Heal Wounds - Unite.AI

SAN DIEGO, Sept. 14, 2020 /PRNewswire/ -- Locanabio, Inc., a leader in RNA-targeted gene therapy, today announced that results from a preclinical study of the company's therapeutic systems for the potential treatment of myotonic dystrophy type 1 (DM1) were published in Nature Biomedical Engineering. For the full article, titled "The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy," please visit: https://www.nature.com/articles/s41551-020-00607-7

Scientists at Locanabio, working with academic collaborators at UC San Diego School of Medicine and the University of Florida, assessed whether an RNA-targeting CRISPR Cas9 system (RCas9) could provide molecular and functional rescue of dysfunctional RNA processing in a DM1 mouse model. The RCas9 system was administered with one dose of an AAV gene therapy vector. Results in both adult and neonatal mice and using both intramuscular and systemic delivery showed prolonged RCas9 expression even at three months post-injection with efficient reversal of molecular (elimination of toxic RNA foci, MBNL1 redistribution, reversal of splicing biomarkers) and physiological (myotonia) features of DM1.Importantly, there were no significant adverse responses to the treatment.

"These results are consistent with earlier findings from several in vitro studies in muscle cells derived from DM1 patients published by Locanabio's scientific co-founder Dr. Gene Yeo of UC San Diego and further indicate the significant potential of our RNA-targeting gene therapy as a DM1 treatment," said Jim Burns, Ph.D., Chief Executive Officer at Locanabio. "Data show that our RNA-targeting system is able to destroy the toxic RNA at the core of this devastating genetic disease and thereby correct the downstream molecular and biochemical changes that result in myotonia, which is a hallmark symptom of DM1. We are pleased that Nature Biomedical Engineering recognizes the value of these preclinical data and we look forward to further advancing this developmental program to the benefit of DM1 patients."

"Currently available treatments for DM1 can improve specific symptoms but do not target the underlying biology and cause of the disease. These data demonstrate that RNA-targeting systems may efficiently and specifically eliminate toxic RNA repeats that cause DM1 and potentially lead to a more effective treatment option for patients," said Dr. Yeo. "The results also indicate that RNA-targeting gene therapy has potential applications in the treatment of other diseases, such as Huntington's disease and certain genetic forms of ALS, which are also caused by a buildup of toxic RNA repeats."

These studies were funded in part by the Muscular Dystrophy Association (MDA). "We are delighted to support Locanabio's recent work in myotonic dystrophy. These preclinical results represent a promising advance and a novel scientific approach for a group of patients who represent a major unmet medical need," said Sharon Hesterlee, Ph.D., Chief Research Officer, MDA.

About Locanabio, Inc.

Locanabio is the global leader in developing a new class of genetic medicines. Our unique and multi-dimensional approach uses gene therapy to deliver RNA binding protein-based systems to correct the message of disease-causing RNA and thereby change the lives of patients with devastating genetic diseases. These broad capabilities delivered via gene therapy enable Locanabio to potentially address a wide range of severe diseases with a single administration. The company is currently advancing programs in neuromuscular, neurodegenerative and retinal diseases. For more information, visit http://www.locanabio.com.

About Myotonic Dystrophy

Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disorder affecting skeletal muscle, cardiac muscle, the gastrointestinal tract, and the central nervous system. DM1 is caused by a mutation in the myotonic dystrophy protein kinase (DMPK) gene. This mutation leads to a repeat expansion of the CTG (cytosine-thymine-guanine) trinucleotide. The expanded CTG is transcribed into toxic CUG (cytosine-uracil-guanine) repeats in the DMPK messenger RNA (mRNA). These toxic mRNA repeats lead to disease symptoms including progressive muscle wasting, weakness and myotonia (delayed relaxation of skeletal muscle), a hallmark of DM1. The incidence of myotonic dystrophy has historically been estimated at one in 8,000 individuals worldwide or approximately 40,000 people in the United States.

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Treatment with RNA-Targeting Gene Therapy Reverses Molecular and Functional Features of Myotonic Dystrophy Type 1 in Mice - PRNewswire

-- Webcast conference call to be held on Monday, Sept. 28, 2020 at 8:30 a.m. Eastern Time --

-- Additional poster presentations at WMS will highlight data from Sareptas RNA and gene therapy programs --

CAMBRIDGE, Mass., Sept. 14, 2020 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that new data from its most advanced gene therapy programs will be presented at the WMS25 Virtual Congress, the 25th International Annual Congress of the World Muscle Society, being held Sept. 28 Oct. 2.

Sarepta will host a webcast and conference call on Monday, Sept. 28, 2020 at 8:30 a.m. ET, to discuss the results, which include two-year functional data from Study 101 of SRP-9001 for Duchenne muscular dystrophy and 18-month functional results from Cohort 1 in the study of SRP-9003 for Limb-girdle muscular dystrophy Type 2E.

This will be webcast live under the investor relations section of Sarepta's website at https://investorrelations.sarepta.com/events-presentationsand will be archived there following the call for one year. Please connect to Sarepta's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary. The conference call may be accessed by dialing (844) 534-7313 for domestic callers and (574) 990-1451 for international callers. The passcode for the call is 6793650. Please specify to the operator that you would like to join the "Long-term Functional Data from Sareptas Gene Therapy Programs call.

In total, Sarepta will present 16 abstracts at this years meeting. All posters will be available on-demand throughout the Congress beginning on Monday, Sept. 28 at 7:00 a.m. EST. The full WMS25 Virtual Congress program is available here: https://www.wms2020.com/programme/.

Gene Therapy:

RNA Platform:

Natural history and other presentations:

Presentations will be archived under the events and presentations section of the Sarepta Therapeutics website at http://www.sarepta.comforone year following their presentation at WMS25.

AboutSarepta TherapeuticsAt Sarepta, we are leading a revolution in precision genetic medicine and every day is an opportunity to change the lives of people living with rare disease. The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visitwww.sarepta.com or follow us on Twitter, LinkedIn, Instagram and Facebook.

Internet Posting of Information

We routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Source: Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.

Investors: Ian Estepan, 617-274-4052, iestepan@sarepta.com

Media: Tracy Sorrentino, 617-301-8566, tsorrentino@sarepta.com

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Long-term functional data from Sarepta Therapeutics' Most Advanced Gene Therapy Programs to be Presented at Upcoming Annual Congress of the World...

JAPAN

Japans official medical research funding agency Japan Agency for Medical Research and Development (AMED), reports that public financial support for university-based research in collaboration with industry into COVID-19 vaccines and treatments has ballooned since March.

Almost JPY113 billion (US$1.07 billion) in funds was allocated this fiscal year against a backdrop of increasing global competition for successful breakthroughs as second and third waves of the COVID-19 pandemic affect the economy, society and education, as well as being a serious health problem. Japan has enacted large supplementary budgets of trillions of yen to help the economy cope since the outbreak hit the country in March.

The global pandemic, which is very contagious and life-threatening, represents an emergency situation. Investment towards a cure is critical for public safety, said Atsuko Oshima, who is in charge of public relations at AMED.

Oshima explained that the government views COVID-19 and new infections as a new global challenge and has turned its attention towards strengthening research funds for pandemics.

For example, it is funding a university-led task force for joint COVID-19 research projects established by prominent Japanese universities, including the University of Tokyo, Keio University, Tokyo Institute of Technology, Kitasato University and Osaka University, with experts from diverse fields, including infectious diseases, virology, molecular genetics, genomic medicine and computational science.

In an initial project, the task force will use state-of-the-art genomic analysis technology to reveal the genetic basis for the mechanism that causes exacerbation of COVID-19 and will work to develop an effective mucosal vaccine to protect against the virus.

Academics view the COVID-19 crisis as a landmark event for multidisciplinary university research. With the novel coronavirus affecting millions of people around the world, scientists and medical communities face intense pressure to develop potential solutions, noted Takafumi Ueno, biomolecular research specialist at the leading Tokyo Institute of Technology.

The university, famous for technology development, is participating in collaborative research with the private sector and other universities, including participating in the task force.

Ueno referred to pressure to respond to the large amount of public funds poured into coronavirus-related research. With taxpayer funds available, researchers are intensely mindful that results must provide for the betterment of society, he said.

Joint research between academia and the private sector is not a new development. But COVID-19 has provided a boost against a backdrop of rising funding and pressure for swift results.

Shinzo Abe, who stepped down as prime minister on 28 August, pledged to make a vaccine available for every Japanese person.

Push for locally developed vaccine

The government is pushing for a home-grown vaccine. A special measure aimed at securing vaccines as quickly as possible was enacted in late August to exempt Japanese and foreign pharmaceutical companies and other concerned parties from liability against compensating people whose health is damaged due to vaccination against COVID-19. Instead, the government will be responsible for any redress.

Japans Kyodo News service reported in late August that the government plans to submit related bills for this measure in the Diet, the Japanese parliament, in October.

Among the slew of ongoing domestic projects to prevent COVID-19 infections, Osaka City University Hospital reported in June that it conducted the first clinical trials on humans of a DNA vaccine.

According a June news release from AnGes, this type of vaccine will inject genetically engineered circular DNA (plasmid) that produces spike proteins, which are characteristic of coronavirus. When the pathogen proteins are made, the bodys immune system is stimulated to make antibodies against the virus.

DNA vaccines are produced using an inactivated virus which only uses the genetic information of the virus rather than the virus itself, and can be manufactured faster than protein-based vaccines, according to the company statement.

However, globally to date no DNA vaccine has yet been approved for use in humans, requiring more time to determine safety and efficacy before it can be rolled out for general use.

The project is owned by AnGes Inc, a medical start-up venture by Osaka University in partnership with Japanese biotech company Takara Bio Inc. Takara Bio has production facilities and manufacturing experience with plasmid DNA products and will be responsible for vaccine production.

Special cooperation model

Yasufumi Kaneda, vice-president of Osaka University and an expert on DNA therapy, leads the industry-academia Co-creation group at the university that oversees the collaborative project. He explained to University World News that AnGess venture a separate entity affiliated with the university represents a rare set up in collaborative research.

The venture acts as a bridge between academic research and the final deployment of the product with a drug maker. By collecting and analysing information, its role is to ensure the safety of the vaccine before large-scale manufacturing for public use. The venture eases the risk faced when defining the final product, he said.

Kaneda explained that the basic research sector collaboration with cross-industry vaccine and treatment is spearheaded by universities with the private sector leading mass manufacturing and dissemination.

The success of the final product demands a high element of risk taking. While COVID-19 research is the exception, it is common practice in Japan for big companies to shun investment in projects that do not indicate clear results, he said, adding that the university-industry venture system can narrow the gap.

The role of providing concrete and appropriate data and scientific facts of the project to companies strengthens understanding and investment for the final product, he said.

The AnGes vaccine trial is now concentrating on the antibody reaction observed in patients. A separate clinical trial is planned at the Osaka hospital as another critical step to obtain government approval in 2021.

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Vaccine research deepens university-industry collaboration - University World News

Myotonic dystrophy type I (DM1) is the most common type of adult-onset muscular dystrophy. DM1 is caused by mutations in the DMPK gene. A normal DMPK gene has 3 to 37 repetitions of the CTG sequence, while in DM1, there are hundreds to thousands of repetitions of this sequence. When a DMPK gene with too many CTG repeats is transcribed, the resulting RNA is too long. This abnormally long RNA is toxic to cells, and those affected experience progressive muscle wasting and weakness.

CRISPR-Cas9 is a technique increasingly used in efforts to correct the genetic defects that cause a variety of diseases. Now a research team from the University of California, San Diego (UCSD), School of Medicine, reports they redirected the technique to modify RNA in a method they call RNA-targeting Cas9 (RCas9), to eliminate the toxic RNA and almost fully reverse symptoms in a mouse model of myotonic dystrophy.

Their findings, The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1, was published in Nature Biomedical Engineering and led by Gene Yeo, PhD, professor of cellular and molecular medicine at UCSD School of Medicine.

Myotonic dystrophy is part of a group of inherited disorders called muscular dystrophies. There are two major types of myotonic dystrophy: type 1 and type 2. The muscle weakness associated with type 1 particularly affects muscles farthest from the center of the body, such as those of the lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves muscles close to the center of the body, such as those of the neck, shoulders, elbows, and hips. The two types of myotonic dystrophy are caused by mutations in different genes.

Many other severe neuromuscular diseases, such as Huntingtons and ALS, are also caused by similar RNA buildup, explained Yeo. There are no cures for these diseases. Yeo led the study with collaborators at Locanabio and the University of Florida.

CRISPR-Cas9 works by directing Cas9 to cut a specific target gene, allowing researchers to inactivate or replace the gene. However, the Cas9 in the RCas9 method is guided to an RNA molecule instead of DNA. In a previous study, Yeo and his team established RCas9 as a means to track RNA in living cells in a programmable manner without genetically encoded tags. In a 2017 study, in lab models and patient-derived cells, the researchers used RCas9 to eliminate 95% of the abnormal RNA linked to myotonic dystrophy type 1 and type 2, one type of ALS and Huntingtons disease.

In the current study, the method goes further, by reversing myotonic dystrophy type 1 in a mouse model of the disease. Toxic RNAs expressed from such repetitive sequences can be eliminated using CRISPR-mediated RNA targeting, yet evidence of its in vivo efficacy and durability is lacking, noted the researchers. Here, using adult and neonatal mouse models of DM1, we show that intramuscular or systemic injections of adeno-associated virus (AAV) vectors encoding nuclease-dead Cas9 and a single-guide RNA targeting CUG repeats results in the expression of the RNA-targeting Cas9 for up to three months, redistribution of the RNA-splicing protein muscleblind-like splicing regulator 1, elimination of foci of toxic RNA, reversal of splicing biomarkers and amelioration of myotonia.

The researchers packaged RCas9 in a non-infectious virus. They then gave the mice a single dose of the therapy or a placebo. RCas9 reduced the abnormal RNA repeats by more than 50%, varying a bit depending on the tissue, and the treated myotonic dystrophy mice became indistinguishable from healthy mice.

To prevent the potential of the RCas9 proteins, developing an immune reaction in the mice, the researchers tried suppressing the mices immune systems briefly during treatment. As a result, they were surprised to see that they successfully prevented immune reaction and clearance. The researchers did not see signs of muscle damage, but found an increase in the activity of genes involved in new muscle formation.

Yeo believes the findings will open a new avenue of understanding and lead the way for treating other genetic diseases. This opens up the floodgates to start testing RNA-targeting CRISPR-Cas9 as a potential approach to treat other human genetic diseasesthere are at least 20 caused by buildup of repetitive RNAs, Yeo added.

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Muscular Dystrophy Condition in Mice Reversed by RNA-Targeting Cas9 - Genetic Engineering & Biotechnology News

Precision medicine has been changing the game for the healthcare industry.

FREMONT, CA: Precision medicine, as the name suggests, is a technique to ensure the highest level of accuracy. The modern healthcare industry has been increasingly adopting the conceptualizations of precision medicine to level up their results and elevate their milestones. The pandemic that has been caused due to the outbreak of the novel COVID virus has raised the possibilities of opportunities for the healthcare researchers and technologists lately. The modern developments in precision medicine are today enabling the healthcare experts to personalize treatment by examining the genetic makeup of the patient individually.

Modern learned professionals and specialists in the healthcare industry believe that everybody is unique, and their physiological makeup is different. In the wake of making medicine personalized, precision medicine technology is offering new features and uses cases that help in crafting therapies and treatments by analyzing the genetic makeup and other unique characteristics to determine the condition of the health of an individual.

Precision medicine has proved to be beneficial in handling diseases such as cancer and other diseases that involve mutations and even infectious diseases. This technique also helps in dealing with inherited diseases as well. With the help of data, precision medicine would actually become one of the most significant aspects in not only treating the diseases according to individual vitals and characteristics but ensuring accuracy as well. Doctors and healthcare specialists believe in the fact that most of the diseases involve a range of multiple genes, and hence, a clear and complete analysis of the genetic data would be the key in the making the precision approach a success.

Data analytics and even AI and other deep learning technologies are coupled with precision medicine to help double the potential of this technique. The future of healthcare is precision medicine, and the essence and potentiality of data is the key and crucial input for the success of the precision approach. This could be the way for expert personalization of treatments as well.

See Also:Top Data Analytics Consulting/Service Companies

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How Precision Medicine Helps in Personalizing Medicine Based on the... - Healthcare Tech Outlook

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SALINAS, Calif. (KSBW) The Borofka family celebrated their son JTs second birthday by throwing him a drive-by birthday parade Sunday. JT Borofka has already achieved more obstacles than most kids his age. Suffering with Triosephosphate Isomerase Deficiency, or TPI, this rare genetic disease has been challenging to say the least.

Hes weaker, but at the moment hes stable, explained JTs mom, Tara Borofka. We still work with physical therapy. Hes got a little bit better head control. JT is extremely strong and doesnt give up. If theres a toy that is a little too far, he will reach for it even if he has to fall over.

And just like JT, his doctors in Pittsburgh arent giving up either.

The next step is to go through all the compounds they have found that could possibly be a cure, explained Jason Borofka, JTs dad.

Michael Palladino, Professor of Pharmacology and Chemical Biology at the University of Pittsburgh School of Medicine said those compounds will need to be tested.

We can test them first in a mouse model, explained Palladino. If you can show that not only did it work in JTs cell. We have JTs cells to test these drugs in, but when we put it in an animal model with his same mutations, that that animal model improves as well.

The process can take anywhere from 8 months to 3 years, but while the Borofkas wait for the cure, theyre focusing on celebrating another year with their son.

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Family celebrates another year with son who has a rare genetic disease - KESQ

By UW Medicine | Newsroom

The immune system usually mounts a strong immune response to infection by SARS-CoV-2, the virus that causes COVID-19. That defensive response, however, appears to be weaker in men and people over the age of 60, a study led by researchers at the University of Washington School of Medicine in Seattle has found.

There were some early studies that suggested that there was a fairly weak antiviral response shortly after infection, but we found a very robust immune response in patients at the time of symptom onset, said lead author Nicole Lieberman. But differences in the immune response in older individuals and men may contribute to the greater severity and higher mortality we see in these groups.

Lieberman is a research scientist in the laboratory of Alex Greninger. He is an assistant professor in the department of Laboratory Medicine and Pathology at the University of Washington School of Medicine and head of the project. The results of the study appear in the open-access journal PLOS Biology. Click here for the paper.

In the study, the researchers compared samples swabbed from the noses and throats of 430 people who were infected with SARS-CoV-2 and 54 people who were not. They also worked with colleagues at Columbia University Medical Center in New York City and University of Texas Medical Branch, Galveston, Texas. These groups have developed techniques to infect cells in culture to track changes in the immune response over time.

To assess immune responses the researchers analyzed the RNA in the samples. Because the SARS-CoV-2 stores its genetic instructions in RNA, levels of viral RNA in the samples revealed the amount of virus, or viral load, an indicator of the severity of infection. In human cells. On the other hand, RNA reveals which proteins the cells are producing in response to the infection. Thats because, for the instructions for synthesizing proteins encoded in the DNA of genes to be read by the cells, the code must first be copied, into RNA. As a result, analyzing the RNA transcriptsin a sample can show which genes are being dialed up in response to the infection and which are being dialed down. This sort of analysis can reveal what sort of immune counterattack the cells are mounting against the virus.

The researchers found that the viral load in these patients was high, but also that SARS-CoV-2 triggers a strong antiviral response. This includes up-regulation of genes for a number of antiviral factors that activate the cells defenses against viral invaders. It also includes chemical signals that summon immune cells to fight the infection, such as interferons and chemokines.

The viral load with SARS-CoV-2 infection is one of the highest seen, Greninger said. But the immune response is very strong, and the higher the viral load, the stronger the response.

However, in older individuals over age 60, infection did not activate genes to summon virus-fighting cells called cytotoxic T cells and natural killer cells that are some of the bodys the most effective antiviral weapons.

The older patients activate a weaker immune response like a singer that just cant hit the high notes anymore, Greninger said.

The researchers also found that men mounted a less vigorous response compared to women. The males produced lower levels of transcripts of some anti-viral proteins, and pumped out some proteins that put a damper on the immune response.

In men were seeing an up-regulation of signals that turn off the immune system, Lieberman said. Its speculation, but it appears as though some men may throttle back their immune system too soon before mounting an effective response to infection.

This work was supported by National Institutes of Health (AI146980, AI121349, and NS091263) and the Department of Laboratory Medicine and Pathology at the UW School of Medicine.

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Why is COVID-19 more severe in men and elders? | UW... - Covington-Maple Valley Reporter

Abstract

Large-scale genomic and transcriptomic initiatives offer unprecedented insight into complex traits, but clinical translation remains limited by variant-level associations without biological context and lack of analytic resources. Our resource, PhenomeXcan, synthesizes 8.87 million variants from genome-wide association study summary statistics on 4091 traits with transcriptomic data from 49 tissues in Genotype-Tissue Expression v8 into a gene-based, queryable platform including 22,515 genes. We developed a novel Bayesian colocalization method, fast enrichment estimation aided colocalization analysis (fastENLOC), to prioritize likely causal gene-trait associations. We successfully replicate associations from the phenome-wide association studies (PheWAS) catalog Online Mendelian Inheritance in Man, and an evidence-based curated gene list. Using PhenomeXcan results, we provide examples of novel and underreported genome-to-phenome associations, complex gene-trait clusters, shared causal genes between common and rare diseases via further integration of PhenomeXcan with ClinVar, and potential therapeutic targets. PhenomeXcan (phenomexcan.org) provides broad, user-friendly access to complex data for translational researchers.

Unprecedented advances in genetic technologies over the past decade have identified over tens of thousands of variants associated with complex traits (1). Translating these variants into actionable targets for precision medicine or drug development, however, remains slow and difficult (2). Existing catalogs largely organize associations between genetic variants and complex traits at the variant level rather than by genes and often are confined to a narrow set of genes or traits (3). This has greatly limited development and application of large-scale assessments that account for spurious associations between variants and traits. As a result, only 10% of genes are under active translational research, with a strong bias toward monogenic traits (4, 5).

Complex diseases are generally polygenic, with many genes contributing to their variation. Concurrently, many genes are pleiotropic, affecting multiple independent traits (6). Phenome-wide association studies (PheWAS) aim to complement genome-wide association studies (GWAS) by studying pleiotropic effects of a genetic variant on a broad range of traits. Many PheWAS databases aggregate individual associations between a genetic variant and a trait, including GeneATLAS [778 traits from the UK Biobank (http://geneatlas.roslin.ed.ac.uk/trait/)] (7), GWAS Atlas [4155 GWAS examined over 2965 traits (https://atlas.ctglab.nl/)] (8), and PhenoScanner [more than 5000 datasets examined over 100 traits (www.phenoscanner.medschl.cam.ac.uk/)] (9). Other PheWAS databases are constructed on the basis of polygenic scores estimated from multiple variants per GWAS locus (10), latent factors underlying groups of variants (11), or variants overlapping between GWAS and PheWAS catalogs (12). By building associations directly from variants (most of which are noncoding), most PheWAS results lack mechanistic insight that can support proposals for translational experiments. Genes are primarily assigned to PheWAS results by genomic proximity to significant variants, which can be misleading (13). Some studies have attempted to improve translation of PheWAS results using gene sets and pathways (14) or networks of PheWAS variants and diseases (15, 16). However, these studies rely on the same variant-trait associations on which PheWAS are built and fall short of prioritizing likely actionable targets.

Integration of genomic, transcriptomic, and other regulatory and functional information offers crucial justification for therapeutic target identification efforts, such as drug development (17). Translational researchers also need access to this integrated information in a comprehensive platform that allows convenient investigation of complex relationships across multiple genes and traits.

To meet this need, we present PhenomeXcan, a massive integrated resource of gene-trait associations to facilitate and support translational hypotheses. Predicted transcriptome association methods test the mediating role of gene expression variation in complex traits and organize variant-trait associations into gene-trait associations supported by functional information (1820). These methods can describe direction of gene effects on traits, supporting how up- or down-regulation may link to clinical presentations or therapeutic effects. We trained transcriptome-wide gene expression models for 49 tissues using the latest Genotype-Tissue Expression (GTEx; v8) data (21) and tested the predicted effects of 8.87 million variants across 22,515 genes and 4091 traits using an adaptation of the PrediXcan method (18), Summary-MultiXcan (S-MultiXcan), that uses summary statistics and aggregates results across tissues (22). We then prioritized genes with likely causal contributions to traits using colocalization analysis (23). To make computation feasible given the large scale of data in this study, we developed fastENLOC (fast enrichment estimation aided colocalization analysis), a novel Bayesian hierarchical colocalization method. We showed separately that this approach of combining an association and a colocalization method performs better than each method individually at prioritizing causal genes and is comparable to baselines such as the nearest gene while incorporating greater biological context (24). We demonstrate results from integrating this tool with a deeply annotated gene-trait dataset to identify associations; this integration can be performed in any deeply annotated database of genes and traits, including molecular or biological traits rather than disease traits. PhenomeXcan is the first massive gene-based (rather than variant-based) trait association resource. Our approach not only uses state-of-the-art techniques available to biologically prioritize genes with possible contributions to traits but also presents information regarding pleiotropy and polygenicity across all human genes in an accessible way for researchers. Below, we provide several examples that showcase the translational relevance and discovery potential that PhenomeXcan offers.

We built a massive gene-to-phenome association resource that integrates GWAS results with gene expression and regulation data. We ran a version of PrediXcan (18), S-MultiXcan, designed to use summary statistics and aggregate effects across tissues (22) on publicly available GWAS. In total, we tested the predicted effects of 8.87 million variants across 22,515 genes and 4091 traits from publicly available GWAS summary statistics (see Supplementary Materials). Traits incorporate binary, categorical, or continuous data types and range from basic anthropometric measurements to clinical traits and biochemical markers. We inferred association statistics (P values and Z scores) between predicted gene-expression variation and traits using optimal prediction models trained using 49 tissues from GTEx v8 (21, 25). LD (linkage disequilibrium) contamination due to proximity between expression quantitative trait loci (eQTLs) and causal variants can produce noncausal, spurious gene-trait associations (21, 24). We therefore first performed Bayesian fine mapping using the DAP-1/fgwas algorithm in TORUS (26, 27). We then calculated the posterior probability of colocalization between GWAS loci and cis-eQTLs to prioritize possible causal genes via fastENLOC, a newly developed Bayesian hierarchical method that uses precomputed signal clusters constructed from fine mapping of eQTL and GWAS data to speed up colocalization calculations (see Supplementary Materials). The result is a matrix of 4091 traits and 22,515 genes in which each intersection contains a PrediXcan P value aggregated across 49 tissues and refined by a locus regional colocalization probability (locus RCP) (Fig. 1). While a given colocalization threshold may be arbitrary, to minimize false negatives given the conservative nature of colocalization approaches (24), we defined putative causal gene contributors as those genes with locus RCP >0.1.

Blue areas highlight methods that we performed for this project, with fastENLOC being a novel colocalization method developed in the context of PhenomeXcan development. We developed PhenomeXcan by integrating GWAS summary statistics with GTEx v8 using PrediXcan methodology and then performing fine mapping and colocalization to identify the most likely causal genes for a given trait. PhenomeXcan is a massive resource containing PrediXcan P values across 4091 traits and 22,515 genes, aggregated across 49 tissues and refined by locus RCP. SNP, single-nucleotide polymorphism; b, effect size; snpn refers to the nth SNP in the list, after SNP 1, SNP 2, ..., SNP N.

We found 72,994 significant associations (Bonferroni-corrected P value of <5.49 1010) across the entire genome/phenome space, where 22,219 (30.5%) had locus RCP >0.1 (table S1). We constructed a quantile-quantile plot of all associations, which did not show evidence of systematic inflation (fig. S1). These associations represent numerous potential targets for translational studies with biological support.

We evaluated PhenomeXcans performance using three different independent validation approaches. For the first validation, we compared significant results from PhenomeXcan to significant results from the PheWAS catalog, which combines the NHGRI-EBI (National Human Genome Research Institute - European Bioinformatics Institute) GWAS catalog (as of 4/17/2012) and Vanderbilt Universitys electronic health record to establish unique associations between 3144 variants and 1358 traits (https://phewascatalog.org/phewas) (12, 28). These gene-trait pairs, mapped to GWAS loci mostly by proximity, are likely enriched in but do not necessarily represent causal genes. We mapped traits from PhenomeXcan to those in the PheWAS catalog using the Human Phenotype Ontology (HPO) (29). After filtering for genes included in both PhenomeXcan and the PheWAS catalog, we tested 2202 gene-trait associations. At a nominal threshold (P < 0.01), 1005 PhenomeXcan gene-trait associations replicated with matched traits in the PheWAS catalog [area under the curve (AUC) = 0.62; Fig. 2A]. Considering different methods of gene assignments for each GWAS locus (PheWAS: proximity, PhenomeXcan: PrediXcan and Bayesian colocalization), we further evaluated our replication rate using random classifiers in a precision-recall (PR) curve (Fig. 2B) and found significant replicability between PhenomeXcan and PheWAS results (empirical P value of <0.01).

MultiXcan refers to the version of PrediXcan designed to take GWAS summary statistics and aggregate results across tissues (22). (A and B) Receiver operating curve (ROC) and PR curve of PrediXcan significance scores (blue) and fastENLOC (orange) to predict PheWAS catalog gene-trait associations. (C and D) ROC and PR curve of PrediXcan significance scores (blue) and fastENLOC (orange) to predict OMIM catalog gene-trait associations. AP, average precision. The predictive ability of both PrediXcan and fastENLOC demonstrate the statistical validity of PhenomeXcan associations. The maximum fastENLOC colocalization probability across tissues was used for all figures.

For the second validation, we identified a set of high-confidence gene-trait associations using the Online Mendelian Inheritance in Man (OMIM) catalog (30). We previously demonstrated that integrated analysis using PrediXcan (18) and colocalization (23) successfully predicts OMIM genes for matched traits (24). We mapped 107 traits from PhenomeXcan to those in OMIM using the HPO (29) and curated a list of 7809 gene-trait associations with support for causality. We compared gene-trait associations from this standard near GWAS loci (table S2) and found that both PrediXcan and fastENLOC in PhenomeXcan successfully predict OMIM genes (AUC = 0.64; Fig. 2C). The combination of PrediXcan and fastENLOC improves precision in this dataset (fig. S2). The limited precision seen here is expected in the setting of genes, such as those in OMIM, with large effects and rare variants (Fig. 2D). The conservative nature of colocalization analysis can lead to increased false negatives (24), which may contribute to decreased performance of fastENLOC.

For the third validation approach, we applied a medium-throughput approach to examine a disease trait with multiple functionally established gene-trait associations. The Accelerating Medicines Partnership: Type 2 Diabetes (AMP T2D) Knowledge Portal curates a list of genes with causal, strong, moderate, possible, and weak associations to type 2 diabetes based on functional data (table S3) (31). We tested the ability of both PrediXcan and fastENLOC in PhenomeXcan to successfully predict the causal, strong, and moderate genes curated by AMP T2D Knowledge Portal paired with seven UK Biobank traits: type 2 diabetes, type 2 diabetes without complications, type 2 diabetes with ophthalmic complications, type 2 diabetes with peripheral circulatory complications, Self-reported type 2 diabetes, Non-insulin dependent diabetes mellitus, and Unspecified diabetes mellitus. PhenomeXcan successfully predicted the causal gene list for type 2 diabetes (AUC = 0.67; Fig. 3, A and B).

MultiXcan refers to the version of PrediXcan designed to take GWAS summary statistics and aggregate results across tissues (22). (A and B) ROC and PR curve of PrediXcan significance scores (blue) and fastENLOC (orange) to predict significant associations between a curated gene list from the AMP T2D Knowledge Portal and type 2 diabetes traits. PrediXcan and fastENLOC, particularly PrediXcan, demonstrate predictive ability in the setting of a disease trait with 20 genes with causal, strong, and moderate evidence and present in LD blocks with GWAS signal. The maximum fastENLOC colocalization probability across tissues was used for all figures.

PhenomeXcan provides a resource for hypothesis generation using gene-trait associations, with more than 22,000 potentially causal associations (P < 5.49 1010, locus RCP > 0.1; table S1). As case studies, we discuss associations identified on the basis of trait [Morning/evening person (chronotype)] and gene (TPO).

We reviewed the 15 most significant genes associated with Morning/evening person (chronotype) (a UK Biobank trait) based on PrediXcan P values across the 49 tissues and locus RCP >0.1 (table S4). Three of 15 genes had not been previously reported in any GWAS involving UK Biobank participants related to sleep or chronotype: VIP, RP11-220I1.5, and RASL10B. Notably, a variant associated with VIP (P = 1.812 1017, locus RCP = 0.26) is discussed in a GWAS of 89,283 individuals from the 23andMe cohort who self-report as a morning person (rs9479402 near VIP, 23andMe GWAS P = 3.9 1011) (32). VIP produces vasoactive intestinal peptide, a neurotransmitter in the suprachiasmatic nucleus associated with synchronization of circadian rhythms to light cycles (33). The long noncoding RNA RP11-220I1.5 (P = 6.427 1011, locus RCP = 0.20) and the gene RASL10B (P = 1.098 1010, locus RCP = 0.15) have not been previously reported in any GWAS or functional/clinical studies associated with this trait. RASL10B produces a 23-kDa guanosine triphosphatase protein that demonstrates overexpression in the basal ganglia in GTEx (21), potentially representing a novel association. Besides VIP, three other genes in this set had clinical/functional studies associated with sleep or chronotype in PubMed: RAS4B, CLN5, and FBXL3. RAS4B (P = 1.660 1019, locus RCP = 0.63) was linked to a transcriptional network regulated by LHX1 involved in circadian control (34). CLN5 (P = 5.248 1018, locus RCP = 0.34) mutations are associated with neuronal ceroid lipofuscinosis, which can manifest with sleep-specific dysfunction (35). FBXL3 (P = 1.54 1016, locus RCP = 0.35) assists with turnover of the CRY protein through direct interaction to regulate circadian rhythms (36). Our results were also significant for the overlapping genes PER3 (P = 1.65 1017, locus RCP = 0.08) and VAMP3 (P = 7.317 1018, locus RCP = 0.63). PER3 is one of the Period genes characterized as part of the circadian clock and described in numerous functional studies, animal models, and human polymorphism association studies (37), whereas VAMP3 has little research in chronotype or sleep. VAMP3, in this instance, is likely to be a false positive in the setting of the overlapping gene structure and coregulation.

We also reviewed PhenomeXcans performance in associating chronotype traits with well-established circadian rhythm genes that have been identified through functional approaches. In mammals, the transcription factors CLOCK and BMAL1 influence the expression of the Period genes (PER1 and PER2) and the Cryptochrome genes (CRY1 and CRY2). PER3 stabilizes PER1 and PER2 (38). NPAS2 acts as a paralog to CLOCK. All genes demonstrated nominal significance (P < 0.01) with at least one chronotype trait in PhenomeXcan except CRY2 (strongest association P = 0.11) and CLOCK (strongest association P = 0.08). Except for PER1 (locus RCP = 0.24) and NPAS2 (locus RCP = 0.12), all genes showed locus RCP <0.1.

PhenomeXcan, to our knowledge, is one of the first hypothesis-generating tools to provide unbiased links between a trait and associated genes for the researchers evaluation. In conjunction with rich knowledge obtained from functional studies, PhenomeXcan can be used to generate or support subsequent translational efforts.

We next evaluate PhenomeXcan as a platform to study novel and underreported gene-trait associations. Thyroid peroxidase (TPO) encodes a membrane-bound glycoprotein that plays a crucial role in thyroid gland function (39). The strongest associations in PhenomeXcan support the known role of TPO in thyroid hormone production: Self-reported hypothyroidism or myxedema (P = 1.40 1014, locus RCP = 0.99) and Treatment with levothyroxine (P = 1.54 1010, locus RCP = 0.99). Hypothyroidism has been clinically linked to increased respiratory symptoms. Although the mechanism for this is not well understood (40), our results suggest that these could be explained by common genetic factors; Treatment with salmeterol (a medication used to treat lung disease such as asthma or chronic obstructive pulmonary disease) showed moderate associations with TPO in PhenomeXcan (P = 7.45 105, locus RCP < 0.1). TPO is also contained in the National Institutes of Health (NIH) Biosystems Pathways for the development of pulmonary dendritic cells (41). Time to complete round (drawing as a measure of cognitive function) showed another moderate association in PhenomeXcan (P = 1.19 104, locus RCP < 0.1). Thyroid function has been clinically linked to time to draw a clock as a form of cognitive measurement (42). Other trait associations identified in PhenomeXcan with TPO include Single major depression episode (P = 2.48 104, locus RCP < 0.1) and Treatment with doxazosin (a medication used in the United Kingdom for hypertension) (P = 8.80 104, locus RCP < 0.1), both of which have demonstrated clinical association with thyroid abnormalities (43, 44). When reviewing thyroid dysfunction traits in PhenomeXcan, TPO is among the 35 most significantly associated genes, with the others primarily involved in immune regulation or the hypothalamic-pituitary-thyroid axis. To our knowledge, depression and doxazosin use have not been deeply investigated with TPO previously, highlighting how PhenomeXcan may be useful in expanding gene-trait association studies and functional studies through consideration of independent traits associated with a given gene.

PhenomeXcan allows more complex investigation of associated genes and traits beyond individual queries. As an example, to study genes associated with white blood cell count, we can cluster related genes and traits. Starting from the trait Lymphocyte percentage, the top associated genes include PSMD3, CD69, KLF2, CXCL2, CREB5, CXCL3, ZFP36L2, JAZF1, NCOR1, and TET2. These genes represent pathways associated with chemokine and interleukin signaling as well as peptide ligand binding but are not specific to one particular pathway or genomic location (45). We can assess these genes associations with white blood cell traits (neutrophil count/percentage, lymphocyte count/percentage, eosinophil count/percentage, and monocyte and basophil percentages) and infer some understanding of their causal mechanism. PSMD3, for instance, demonstrates stronger associations with neutrophil and lymphocyte traits (mean P < 1 1030, mean locus RCP = 0.50), whereas ZFP36L2 demonstrates consistent associations across white blood cell, platelets, and red blood cell traits (mean P < 1.54 1024, mean locus RCP = 0.36) (Fig. 4). Disruption of ZFP36L2 results in defective hematopoiesis in mice (46), whereas PSMD3 has been identified in GWAS related to white blood cell count and inflammatory states (47). Clusters of associated genes and traits can support more robust translational hypotheses through similarities in associations and generate more nuanced experimental designs through differences between associations.

Z scores are derived from PrediXcan P values, with the ceiling of association (dark blue) 7. In this heatmap, we demonstrate the associations between the genes PSMD3, CD69, KLF2, CXCL2, CREB5, CXCL3, ZFP36L2, JAZF1, NCOR1, and TET2 and the white blood cell traits neutrophil count and neutrophil percentage, lymphocyte count and lymphocyte percentage, eosinophil count and eosinophil percentage, monocyte percentage and basophil percentage. Platelet count and mean corpuscular volume (for red blood cells) serve as alternate blood traits. ZFP36L2 has consistent associations across platelets and red blood cells relative to other genes. Accordingly, functional studies demonstrate that ZFP36L2 plays a role in hematopoiesis, whereas studies support the other genes involvement in inflammation-related pathways or diseases. These types of clusters can support hypotheses and experimental designs regarding the mechanisms through which genes contribute to traits.

PhenomeXcan can also be integrated with any gene-trait databases to study pleiotropically linked traits and shared associated genes. We integrated PhenomeXcan with ClinVar, a publicly available archive of rare human diseases and associated genes (including OMIM) and one of the most widely used gene-trait databases in the clinical setting (48). We examined the associations between the 4091 GWAS-derived traits in PhenomeXcan and 5094 ClinVar diseases by (i) calculating PrediXcan Z scores for every gene-trait association in PhenomeXcan and (ii) for each PhenomeXcan/ClinVar trait pair, we computed the average squared PrediXcan Z score considering the genes reported in the ClinVar trait (see Materials and Methods). We then created a matrix of PhenomeXcan traits by ClinVar traits with mean squared Z scores (Fig. 5, A and B), where peaks represent shared genes. We defined significant associations between traits as those with Z score >6; this represents the equivalent of a Bonferroni-adjusted P value of 0.05 based on our map of the distribution of Z scores (fig. S3).

(A) Schematic depicting the development of PhenomeXcan ClinVar. For each PhenomeXcan/ClinVar trait pair, we computed the average squared PrediXcan Z score considering the genes reported in the ClinVar trait. (B) Heatmap visualizing the overall structure of associations in PhenomeXcan ClinVar. Darker blue represents stronger association. Again, complex clusters of intertrait associations can be identified to link common traits and rare diseases. Queries for traits or genes of interest can be submitted through a web application at phenomexcan.org. (C) Heatmap demonstrating an example linked traits in PhenomeXcan (rows) and ClinVar (columns) using the association between Parkinsons disease and red blood cell traits. We see the strongest associations between mean corpuscular volume, mean reticulocyte volume, and mean spherical red cell volume and Parkinson disease 15. In ClinVar, each variant of Parkinsons disease linked to a different gene is listed under a different number, making it expected that associations to other forms of Parkinsons disease are not as strong.

As an example, we found links between the ClinVar trait Parkinson disease 15 and the following traits: mean corpuscular volume, mean reticulocyte volume, and mean spherical red cell volume (Fig. 5C). The gene linked to Parkinson disease 15 in ClinVar is FBXO7. The mean Z score across eight red blood cell traits was 21.14; the mean locus RCP was 0.84 with P values all <1 1030. FBXO7 plays a role in the ubiquitin system; its entry in ClinVar is associated with an autosomal recessive, juvenile-onset form of Parkinsons disease (49). Three GWAS [the HaemGen consortium, eMERGE (Electronic Medical Records and Genomics), and van der Harst et al.] link FBXO7 with red blood cell attributes including mean corpuscular volume and mean cell hemoglobin (5052). At least one mouse model describes defective erythropoiesis and red blood cell changes due to induced mutations in FBXO7 (53). Through PhenomeXcan, we found a pleiotropic relationship between Parkinsons disease and red blood cell traits mediated through FBXO7 that has not been studied in humans. The nearest adjacent genes, SYN3 and BPIFC, are unlikely to be separately affecting red blood cells; they have no published association to red blood cells and demonstrate mean locus RCPs with red blood cell traits in PhenomeXcan of 0.55 and 0, respectively. Validating this finding, one mouse model specifically studies the pleiotropy of FBXO7 on both parkinsonism and red blood cell traits (54). This case study demonstrates how this powerful variation on PhenomeXcan can substantially improve translational hypothesis generation by supporting genetic links between associated rare diseases and common traits across research platforms.

PhenomeXcan offers direct translational applicability, providing genomic evidence to support therapeutic targets and associated side effects. As an example, PCSK9 is a genetically supported, clinically validated target for cardiac prevention through inhibition of its binding to the low-density lipoprotein (LDL) receptor and reduction of blood LDL cholesterol levels (55). We can study the cluster of genes and traits produced by PCSK9 in PhenomeXcan for relevant information about this target. Most of the traits with strongest associations to PCSK9 relate to diagnosis and treatment of elevated cholesterol or atherosclerosis, including familial heart disease. Because inherited PCSK9 variation is associated with increased likelihood of type 2 diabetes, there was concern that PCSK9 therapies could elevate risk to type 2 diabetes. The inhibiting drugs therefore required large substudies from clinical trials to confirm no association with worse diabetes (56, 57). While not at genome-wide significance, PCSK9 has a negative association with type 1 diabetes in PhenomeXcan (P = 8.2 104, locus RCP < 0.1), consistent with the clinical concern that down-regulation of the gene could lead to increased diabetes risk. We recognize that type 1 and type 2 diabetes have different clinical etiologies. For the purpose of drug development, though, assessing PCSK9 in PhenomeXcan produces both its primary target (blood cholesterol levels as related to atherosclerosis) and, through independently identified traits, potential adverse effects via diabetes. The most commonly represented genes associated with the strongest traits for PCSK9 include APOE, LDLR, APOB, PSRC1, CELSR2, SORT1, ABCG8, ABCG5, and HMGCOR. Unsurprisingly, all of these genes have all been implicated in genetic susceptibility to hypercholesterolemia (some, such as SORT1, may be the primary causative gene in their pathway) (58). Examining potential targets in PhenomeXcan could not only help anticipate side effects via independent traits but also identify related gene networks or alternative targets with therapeutic relevance.

Here, we introduce PhenomeXcan, an innovative, powerful resource that makes comprehensive gene-trait associations easily accessible for hypothesis generation. Using PrediXcan allows us to derive gene-based associations with traits in context by integrating GWAS summary statistics with transcriptome-wide predicted expression and regulatory or functional information. We previously demonstrated that integrated analysis using PrediXcan and colocalization improves precision and power for target gene identification (24). To build PhenomeXcan, we also develop a novel, rapid colocalization method, fastENLOC, that could handle data at this scale (4091 traits 22,515 genes 49 tissues) (see Materials and Methods). PhenomeXcan implements the best practices derived from applying GTEx v8 (21, 59) to biologically prioritize genes with possible causal contribution to a given trait.

PhenomeXcans flexible structure and adaptability allow translational researchers to easily explore clinically relevant questions. The resource can be queried by gene or trait and allows identification of novel and underrepresented associations. It offers exploration of polygenicity and pleiotropy dimensions by allowing for queries across multiple genes and traits. It can also be integrated with other gene-trait datasets to explore linked traits and report common associated genes. We offer ClinVar as an example, but any deeply annotated database of genes and traits, including molecular or biological traits, may be integrated in this manner. Other possible translational uses of PhenomeXcan include biomarker exploration, identification of clinically relevant disease modifiers, and polygenic score building (using genes associated with queried traits), as well as novel directions for basic science collaborations and clinical study of linked traits (using traits associated with queried genes).

We note some caveats. Diseases with variability not related to changes in gene expression (e.g., epigenetic regulation or traits with important environmental contributions) are not expected to be captured well by this method. With just expression levels, this resource is a starting point, and additional molecular traits, such as microRNA levels, protein levels, and alternative splicing structures, are a priority for us to incorporate as data become available in sufficiently large sample sizes. Our model also better captures common overall genetic contributors rather than genes identified from rare variants. We do note that our validation standards tend to favor larger-effect genes with monogenic etiology, while the PhenomeXcan association method itself is less biased. Regulatory pleiotropy is widespread across the genome (21). In our chronotype example, VAMP3 and PER3 demonstrate regulatory pleiotropy. VAMP3, from our findings associated with chronotype, is likely to be a false positive because of coregulation of both genes by causal variants. With that degree of proximity, large-scale tools are not able to well distinguish causal genes, exemplifying the need for additional functional data to determine the causality of the gene (21). We discuss this finding to acknowledge how PhenomeXcan encounters this phenomenon and show the benefit of performing these associations across all human genes. We offer colocalization as a possible means of prioritizing causal variants, but significance of association, colocalization, and coregulatory sites must be taken into account in our results. Work from large-scale statistical genetics tools, such as PhenomeXcan, and Mendelian genetics and functional studies must then be combined to best understand the breadth of genetic contributors to complex traits. We have favored a locus RCP threshold of 0.1 to limit false negatives related to colocalization. Poor RCP (locus RCP ~ 0) may reflect a lack of sufficient evidence with available data, particularly for understudied genes, rather than true lack of causality. We therefore reported traits in this paper that had a locus RCP <0.1 but had functional support for potential association. Similarly, the genome-wide threshold of significance is conservative, and we discuss associations with functional support even with less significant P values. GWAS summary statistics used in this project were for participants and patients of European ancestry. Improving the applicability of this type of work to global populations remains of paramount importance throughout genetic medicine, and we will continue to integrate more GWAS summary statistics from broader consortia.

Resources that translate biologically relevant genomic and transcriptomic information into gene-trait associations are already critical for hypothesis generation and clinically relevant research (60). We offer PhenomeXcan, an integrated mapping for the function of every human gene, as a publicly available resource to advance the investigation of complex human diseases by improving the accessibility of relevant links between the entire genome and the phenome.

S-MultiXcan is a method in the PrediXcan family (18) that associates genes and traits by testing the mediating role of gene expression variation in complex traits but (i) requires only GWAS summary statistics and (ii) uses multivariate regression to combine expression information across tissues (22). First, linear prediction models of genotype in the vicinity of the gene to expression are trained in reference transcriptome datasets such as the GTEx project (21). Second, predicted expression based on actual genetic variation is correlated to the trait of interest to produce a gene-level association result for each tissue. In S-MultiXcan, the predicted expression is a multivariate regression of expression across multiple tissues. To avoid collinearity issues and numerical instability, the model decomposes the predicted expression matrix into principal components and keeps only the eigenvectors of non-negligible variance. We considered a principal components analysis regularization threshold of 30 to be a conservative choice. This approach improves detection of associations relative to use of one tissue type alone and offers a reduced false-negative rate relative to a Bonferroni correction. We used optimal prediction models based on the number and proportion of colocalized gene-level associations (24). These models select features based on fine mapping (25) and weights using eQTL effect sizes smoothed across tissues using mashr (59). The result of this approach is a genome-wide gene-trait association list for a given trait and GWAS summary statistic set.

Bayesian fine mapping was performed using TORUS (27). We estimated probabilities of colocalization between GWAS and cis-eQTL signals using Bayesian RCP, as described in the ENLOC (enrichment estimation aided colocalization analysis) methodology (23). For this particular study, given the large scale of the data, we developed a novel implementation, entitled fastENLOC. fastENLOC was applied for all trait-tissue pairs, and the maximum colocalization probability across all tissues was used, thus obtaining a single RCP value for each gene-trait pair. This aggregation of RCP values across tissues allowed us to combine results from fastENLOC and S-MultiXcan.

We evaluated the accuracy of gene-trait associations in PhenomeXcan by using two different gene-trait association datasets (PheWAS catalog and OMIM) as well as genes linked with functional evidence with type 2 diabetes (T2D) according to the AMP T2D. We then derived the receiver operating characteristic curve (ROC) and PR curves for PrediXcan and fastENLOC independently and a combination of both.

We mapped traits from PhenomeXcan to those in either PheWAS catalog (28) or OMIM (30) by using the HPO (29) and the GWAS catalog as intermediates. For traits in the PheWAS catalog, we tested 2202 gene-trait associations that could be mapped in both PhenomeXcan and the PheWAS catalog, from a total 19,119 gene-traits associations consisting of all genes present in an LD block with GWAS signal. For the OMIM traits, we developed a standard (table S2) of 7809 high-confidence gene-trait associations that could be used to measure the performance of PhenomeXcan, of which 125 presented in the LD block of GWAS signal so those were included in the analysis. This standard, as described in our recent work (24), was obtained from a curated set of trait-gene pairs from the OMIM database by mapping traits in PhenomeXcan to those in OMIM. Briefly, traits in PhenomeXcan were mapped to the closest phecode using the GWAS catalogtophecode map proposed in (28). As disease description in OMIM has been mapped to the HPO (29), we created a map from phecodes to terms in HPO, which allowed us to link our GWAS traits to OMIM disease description by using phecodes and HPO terms as intermediate steps. For each gene-trait pair considered causal in this standard, we determined whether PhenomeXcan identified that association as significant on the basis of the resulting P value. The OMIM-based standard is publicly available through R package (https://github.com/hakyimlab/silver-standard-performance).

For T2D, we obtained a list of predicted effector transcripts identified by AMP T2D and used 76 genes categorized as causal, strong, or moderate as our gold standard for evaluation (table S3). As we did for OMIM and PheWAS catalogs, 20 of these causal genes could be mapped in PhenomeXcan, from a total of 5036 genes present in an LD block with GWAS signal. We used seven traits highly related to T2D: International Classification of Diseases 10 codes E11 and E14, Self-reported type 2 diabetes (data-field 20002 in UK Biobank with code 1223), and four phenotypes manually curated by the FinnGen Consortium (type 2 diabetes without complications, type 2 diabetes with ophthalmic complications, type 2 diabetes, and type 2 diabetes with peripheral circulatory complications); then, we took the maximum Z score obtained (for MultiXcan) and the maximum RCP (for fastENLOC) across the seven T2D traits for each gene evaluated. The results are shown in Fig. 3 and fig. S2. Notice that multiple testing is not an issue, since for the performance curves, we are not using a significance threshold, but all levels are assessed in terms of the false-positive and true-positive rates.

PhenomeXcan results for case studies were included on the basis of their P values and locus RCP. We defined putative causal gene contributors as those genes with P values less than 5.49 1010 and locus RCP >0.1. Given these conservative measures, however, we did discuss associations that were less significant or had a lower locus RCP with functional evidence. We used the NHGRI-EBI GWAS catalog (21 October 2019) to identify GWAS results both using the UK Biobank (given the predominance of this dataset in PhenomeXcan) and other datasets. We performed systematic literature searches on PubMed using the gene name alone, with the specific trait category and trait name to identify functional studies relevant to a trait of interest.

We examined links between 4091 PhenomeXcan traits and 5094 ClinVar traits and associated genes. ClinVar traits were excluded if they did not have known associated genes in PhenomeXcan. To compare a PhenomeXcan trait t and a ClinVar trait d, we calculated the mean squared Z scoreavg(t,d2)=1ki=1kZt,i2where k is the number of genes reported in ClinVar for trait d and Z is the Z score of gene i obtained with S-MultiXcan for trait t. We then created a matrix of PhenomeXcan traits by ClinVar traits with mean squared Z scores. We defined significant associations between traits as those with Z score >6; this represents the equivalent of a Bonferroni-adjusted P value of 0.05 based on our map of the distribution of Z scores (fig. S3).

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PhenomeXcan: Mapping the genome to the phenome through the transcriptome - Science Advances

We seek a new postdoc who will work within the Center of Public Health Sciences, Faculty of Medicine, University of Iceland, on the ERC funded project StressGene led by Prof Unnur Valdimarsdttir.

The main goal of the StressGene program is to study health sequels after significant life stressors or trauma and uncover sequence variants associated with stress-related psychiatric disorders and somatic conditions (e.g. cardiovascular disease) following such adversities. This research is conducted in collaboration between an extended network of researchers at (but not limited to) the University of Iceland, deCODE Genetics, and Karolinska Institutet in Sweden. The postdoc will work in close collaboration with senior colleagues at these institutions and leverage population-based register and biobank resources with the overarching goal of understanding how genes and environment act and interact to modify risk of ill health after significant life stressors or trauma. Prof Valdimarsdttirs team has long-standing experience in using Nordic health and population registers as well as longitudinal cohort studies (e.g. the SAGA cohort, Swedish Tsunami Cohort, and COVID-19 National Resilience Cohort) in research of mental disorders, especially stress-related disorders and unravelling their associations to various somatic conditions.This project builds on recent findings and prospective work aims at identifying common molecular mechanisms to stress-related disorders and various somatic diseases.

Your mission

We seek an outstanding and innovative postdoc to join our team for one year with a possible extension to two years. We are data-rich, and need a professional-level data scientist, with a solid background in biostatistics or genetic epidemiology, to maximize our understanding of the data we have. This individual should be passionately committed to furthering knowledge of psychiatric disorders and somatic conditions associated with trauma in order to improve the lives of these vulnerable populations. The successful applicant will join our

team and conduct research on the genomics of psychiatric disorders and somatic conditions associated with trauma leveraging multi-omic approaches and approaches used for complex register data.

Your profile

PhD degree in medical science such as epidemiology, biostatistics, computer science, statistics, genetics, etc. is required. Applicants who have not completed a doctorate at the end of the application period may also apply, provided that all requirements for a completed degree are met before the (intended) date of employment. This must be substantiated by the applicants main supervisor, director or equivalent. Those with PhDs in other areas but who have advanced/relevant data science skills will also be considered.

Experience in professional analysis of multiple types of modern genomic datasets, including GWAS, exome sequencing, or register-based studies are a plus.

Skills in programming (e.g., R, Python, SQL, Unix/Linux), use of standard software packages (e.g., PLINK, GATK), flexibly manipulating large datasets, bioinformatic integration, and pathway analysis.

Knowledge of complex trait genomics.

Good skills in teamwork in scientific work as well as independent, organized and solution-oriented work methods.

Excellent oral and written communication skills in English are required, along with experience with scientific writing.

What do we offer?

We are a friendly, creative, international and inspiring environment full of expertise and curiosity.

The University of Iceland is a progressive educational and scientific institution in the heart of Reykjavk, the capital of Iceland. A modern, diversified and rapidly developing institution, it is by far the largest teaching and research institution in Iceland ranked in the top 300 in clinical medicine and public health on the Times Higher Education Ranking for the past 5 years. Located in the deCODE Genetics Building, Sturlugata 8 Reykjavik, Center of Public Health Sciences (CPHS) is the Universitys research institution in population sciences and organizes interdisciplinary academic graduate programs in public health sciences, including in epidemiology and biostatistics. CPHS includes five professors, two associated professors and 5 research fellows on a post-doctoral level, 2-3 research administrators and 12 doctoral students.CPHS research activity is funded by multiple national and international grants including the ERC consolidator-grant (awarded to Prof. Valdimarsdttir): The genetics of morbidity and survival in response to significant life stressors (StressGene).

Please check out our latest cohort initiatives:

THE SAGA COHORT

ABOUT

Application

Please apply through the University of Iceland website, vacancies

Deadline for application is 21st of September 2020 and the starting date is according to an agreement.

An employment application must contain the following documents in English or Icelandic:

i. A complete resum, including date of the thesis defense, title of the thesis, previous academic

positions, academic title, current position, academic distinctions, and committee work

ii. Certified copy of diplomas

iii.Letter of recommendation

iv. A statement in which the interest in the project is described and discusses what the applicant can contribute to it.

Applicants will be asked to describe past examples of having developed structured approaches to solving unanticipated and complex problems.

Salary is according to official agreement between collective wage and salary agreement between the Minister of Finance and the relevant union.

All applications will be answered and applicants will be notified of the employment decision when a decision has been made. Applications will be valid for six months from the end of the application deadline.

Further information

For further information, please contact Unnur Anna Valdimarsdttir (unnurav@hi.is) or Dra R. lafsdttir (dro@hi.is).

Appointments to positions at the University of Iceland are made in consideration of the Equal Rights Policy of the University of Iceland.

Read more:
Postdoctoral Researcher in Psychiatric- and Genetic Epidemiology, - Nature.com

PLEASANTON, Calif., Sept. 15, 2020 (GLOBE NEWSWIRE) -- 10x Genomics (Nasdaq: TXG) today announced it has begun shipping its Chromium Single Cell Multiome ATAC + Gene Expression solution to customers, marking the first commercial release of a product capable of simultaneously profiling the epigenome and transcriptome from the same single cell. This multi-omic approach provides customers with the ability to link a cells epigenetic program to its transcriptional output, enabling a better understanding of cell functionality and bypassing the need to infer relationships through computer simulations.

This is one of our most ambitious undertakings at the company, said Ben Hindson, co-founder and Chief Scientific Officer of 10x Genomics. By introducing the first solution that captures ATAC and gene expression simultaneously, researchers can gain even more clarity by combining two already powerful methods to profile biological systems at single cell resolution simultaneously for the first time.

The new solution builds on an array of new products launched by the company this year for both its Chromium platform for single cell analysis as well as its Visium platform for spatial genomics. Early customers already working with Chromium Single Cell Multiome ATAC + Gene Expression include Stanford University School of Medicine, Icahn School of Medicine at Mt. Sinai and Spains Centro Nacional de Anlisis Genmico.

My lab is interested in understanding why some immune cell types fail to fight the cancer, said Dr. Ansuman Satpathy, Assistant Professor of Pathology, Stanford University School of Medicine. We plan to use 10x Genomics' new assay to understand the epigenetic and transcriptional regulation of immune cell dysfunction directly in patient samples, and to use this information to precisely engineer more effective immunotherapies in the future.

Until now, we have relied on computational prediction to match a cell's epigenome to a single-cell gene expression profile, said Dr. Holger Heyn, leader of the single cell genomics team at Spains Centro Nacional de Anlisis Genmico that is working on delineating the dynamics underlying B-cell differentiation and activation. 10x Genomics new multiome assay will allow us to directly measure what before could only be predicted, and offers a new gold standard that will confirm how accurate these predictions had been.

"With this new technology, we can better understand the mechanisms affected by the non-coding risk genetic variation across a wide range of neuropsychiatric diseases, including Alzheimers, Parkinsons, Schizophrenia, bipolar disorder and major depression, along with different severity of neuropathology and clinical symptomatology," added Dr. Panagiotis Roussos, Associate Professor of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai.

By using Chromium Single Cell Multiome ATAC + Gene Expression, researchers can:

Chromium Single Cell Multiome ATAC + Gene Expression is shipping to customers. To learn more, visit https://www.10xgenomics.com/products/single-cell-multiome-atac-plus-gene-expression.

About 10x Genomics10x Genomics is a life science technology company building products to interrogate, understand and master biology to advance human health. The companys integrated solutions include instruments, consumables and software for analyzing biological systems at a resolution and scale that matches the complexity of biology. 10x Genomics products have been adopted by researchers around the world including 97 of the top 100 global research institutions and 19 of the top 20 global pharmaceutical companies, and have been cited in over 1,500 research papers on discoveries ranging from oncology to immunology and neuroscience. The companys patent portfolio comprises more than 775 issued patents and patent applications.

Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements generally can be identified by the use of forward-looking terminology such as may, will, should, expect, plan, anticipate, could, intend, target, project contemplate, believe, estimate, predict, potential or continue or the negatives of these terms or variations of them or similar terminology. These forward-looking statements include statements regarding 10x Genomics, Inc.s partnership activities, which involve risks and uncertainties that could cause 10x Genomics, Inc.s actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on managements current expectations, forecasts, beliefs, assumptions and information currently available to management, and actual outcomes and results could differ materially from these statements due to a number of factors. These and additional risks and uncertainties that could affect 10x Genomics, Inc.s financial and operating results and cause actual results to differ materially from those indicated by the forward-looking statements made in this press release include those discussed under the captions "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" and elsewhere in the documents 10x Genomics, Inc. files with the Securities and Exchange Commission from time to time. The forward-looking statements in this press release are based on information available to 10x Genomics, Inc. as of the date hereof, and 10x Genomics, Inc. disclaims any obligation to update any forward-looking statements provided to reflect any change in its expectations or any change in events, conditions, or circumstances on which any such statement is based, except as required by law. These forward-looking statements should not be relied upon as representing 10x Genomics, Inc.s views as of any date subsequent to the date of this press release.

Disclosure Information10x Genomics uses filings with the Securities and Exchange Commission, its website (www.10xgenomics.com), press releases, public conference calls, public webcasts and its social media accounts as means of disclosing material non-public information and for complying with its disclosure obligations under Regulation FD.

ContactsMedia:media@10xgenomics.comInvestors:investors@10xgenomics.com

More:
10x Genomics First to Market With Product to Simultaneously Capture Epigenome and Transcriptome - GlobeNewswire

DENVER, Sept. 15, 2020 (GLOBE NEWSWIRE) -- Mydecine Innovations Group Inc. (CSE:MYCO) (OTC:MYCOF) (FSE:0NFA) ("Mydecine" or the "Company"), today announced the Company has formed a special committee to evaluate a number of options to increase shareholders value.

Topics that the special committee will discuss include, but limited to, a potential spin out of certain company assets. Currently, the company owns and operates a number of growing US assets in the THC-cannabis and hemp-CBD space, along with distribution, that are being evaluated and assessed as potential spin out options with respect to the Mydecine's non-fungi related assets. Current shareholders would receive automatic shares of the SpinCo.

We are constantly looking at ways to increase our shareholder value. Our company has grown at an incredible rate and is quickly establishing itself as a leader in the functional mushroom and psychedelic medicine space, said Mydecine Chief Executive Officer, Joshua Bartch. With that said, the company has a number of highly valuable assets that could potentially create larger shareholder value if they were spun out into a more focused stand-alone vehicle. We are currently evaluating a number of potential options and partners to accomplish this goal."

Further information will be provided as this opportunity develops.

About Mydecine Innovations Group Inc.Mydecine Innovations Group is a publicly traded life sciences parent company dedicated to the development and production of adaptive pathway medicine, natural health products and digital health solutions stemming from fungi. Mydecines experienced cross functional teams have the dynamic capabilities to oversee all areas of medicine development including synthesis, genetic research, import/export, delivery system development, clinical trial execution, through to product commercialization and distribution. By leveraging strategic partnerships with scientific, medical, military, and clinical organizations, Mydecine is positioned at the forefront of psychedelic medicine naturally derived from fungi, therapeutic solutions, and fungtional mushroom vitality products. Our portfolio of unified companies, including Mydecine Health Sciences, Mindleap Health, and NeuroPharm focus on providing innovative and effective options that can provide millions of people with a healthier quality of life.

For further information about Mydecine Innovations Group Inc., please visit the Companys profile on SEDAR at http://www.sedar.comor visit the Companys website at http://www.mydecine.com.

On behalf of the Board of Directors:Joshua Bartch, Chief Executive Officercontact@mydecineinc.com

Corp Communication:Charles Lee, Investor Relationscorp@mydecineinc.com+1 (250) 488-6728

Public Relations:Cynthia Salarizadeh, PRpr@mydecineinc.com

The Canadian Securities Exchange has neither approved nor disapproved the contents of this news release and accepts no responsibility for the adequacy or accuracy hereof. This news release contains forward-looking statements, which relate to future events or future performance and reflect managements current expectations and assumptions. Such forward-looking statements reflect managements current beliefs and are based on assumptions made by and information currently available to the Company. Readers are cautioned that these forward-looking statements are neither promises nor guarantees, and are subject to risks and uncertainties that may cause future results to differ materially from those expected including, without limitation, the availability and continuity of financing, the ability of the Company to adequately protect and enforce its intellectual property, the Company's ability to bring its products to commercial production, continued growth of the global adaptive pathway medicine, natural health products and digital health industries, and the risks presented by the highly regulated and competitive market concerning the development, production, sale and use of the Company's products. Although the Company has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. There can be no assurance that such information will prove to be accurate, as actual results and future events could differ materially from those anticipated in such information. These forward-looking statements are made as of the date hereof and the Company does not assume any obligation to update or revise them to reflect new events or circumstances save as required under applicable securities legislation. This news release does not constitute an offer to sell securities and the Company is not soliciting an offer to buy securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such jurisdiction. This news release does not constitute an offer of securities for sale in the United States. These securities have not and will not be registered under United States Securities Act of 1933, as amended, or any state securities laws and may not be offered or sold in the United States or to a U.S. Person unless so registered, or an exemption from registration is relied upon.

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Mydecine Innovations Group, Inc. to Create Special Committee for the Spin Out of US Related Assets - GlobeNewswire

Research coming out of the University of Pennsylvania School of Medicine last month demonstrated how artificial intelligence (AI) can be utilized to fight against opioid abuse. It focused on a chatbot which sent reminders to patients who underwent surgery to fix major bone fractures.

The research was published in the Journal of Medical Internet Research.

Christopher Anthony, MD, is the studys lead author and the associate director of Hip Preservation at Penn Medicine. He is also an assistant professor of Orthopaedic Surgery.

We showed that opioid medication utilization could be decreased by more than a third in an at-risk patient population by delivering psychotherapy via a chatbot, he said. While it must be tested with future investigations, we believe our findings are likely transferable to other patient populations.

Opioids are an effective treatment for pain following a severe injury, such as a broken arm or leg, but the large prescription of the drugs can lead to addiction and dependence for many users. This is what has caused the major opioid epidemic throughout the United States.

The team of researchers believe that a patient-centered approach with the use of the AI chatbot can help reduce the number of opioids taken after such surgerys, which can be a tool used against the epidemic.

Those researchers also included Edward Octavio Rojas, MD, who is a resident in Orthopaedic Surgery at the University of Iowa Hospitals & Clinics. The co-authors included: Valerie Keffala, PhD; Natalie Ann Glass, PhD; Benjamin J. Miller, MD; Mathew Hogue, MD; Michael Wiley, MD; Matthew Karam, MD; John Lawrence Marsh, MD, and Apurva Shah, MD.

The research involved 76 patients who visited a Level 1 Trauma Center at the University of Iowa Hospitals & Clinics. They were there to receive treatment for fractures that required surgery, and those patients were separated into two groups. Both groups received the same prescription for opioids to treat pain, but only one of the groups received daily text messages from the automated chatbot.

The group that received text messages could expect two per day for a period of two weeks following their procedure. The automated chatbot relied on artificial intelligence to send the messages, which went out the day after surgery. The text messages were constructed in a way to help patients focus on coping better with the medication.

The text messages, which were created by a pain psychologist specialized in pain and commitment therapy (ACT), did not directly go against the use of the medication, but they attempted to help the patients think of something other than taking a pill.

The text messages could be broken down into six core principles, : Values, Acceptance, Present Moment Awareness, Self-As-Context, Committed Action, and Diffusion.

One message under the Acceptance principle was: feelings of pain and feelings about your experience of pain are normal after surgery. Acknowledge and accept these feelings as part of the recovery process. Remember how you feel now is temporary and your healing process will continue. Call to mind pleasant feelings or thoughts you experienced today.

The results showed that the patients who did not receive the automated messages took, on average, 41 opioid pills following the surgeries, while the group who did receive the messages averaged 26. The 37 percent difference was impressive, and those who received messages also reported less overall pain two weeks after the surgery.

The automated messages were not personalized for each individual, which demonstrates success without over-personalization.

A realistic goal for this type of work is to decrease opioid utilization to as few tablets as possible, with the ultimate goal to eliminate the need for opioid medication in the setting of fracture care, Anthony said.

The study received funding by a grant from the Orthopaedic Trauma Association.

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AI Used To Identify Gene Activation Sequences and Find Disease-Causing Genes - Unite.AI

MEDIA ADVISORY

FOR IMMEDIATE RELEASE: Nature Communications: Published Monday, September 14, 2020

Newswise Corresponding Author:Yasmin Hurd, PhD, Director of The Addiction Institute of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, and other coauthors.

Bottom Line:Herion-addicted individuals have alterations in the expression a gene called FYN - a gene known to regulate the production of Tau, a protein that is highly elevated and implicated in neurocognitive disorders like Alzheimers disease. The study emphasizes that opioid use can affect the brain in a way that might increase vulnerability of neural systems that trigger neurodegeneration later in life; however, since these changes are epigenetic (alterations in gene function that are influenced by environmental factors and not alterations of the DNA itself), they are reversible and medications that have already been developed to target FYN for neurodegenerative disorders may be studied as a novel treatment for opioid addiction.

Results:Interestingly, findings were consistent across human, animal and cell models. Through post-mortem analysis of the brains of human heroin users, the team found that, specifically in neurons, the most significantly impaired epigenetic region is related to a gene called FYN. Essentially, heroin opened up the DNA at the FYN gene, which encodes a protein called tyrosine kinase FYN, that is strongly linked to synaptic plasticity and which directly results in production of Tau. Too much Tau in the brain is associated with neurodegenerative diseases. They observed that expression and activity of tyrosine kinase FYN was also induced in rats trained to self-administer heroin and also in primary striatal neurons treated with chronic morphine in vitro. Additionally, they demonstrated that inhibition of the FYN kinase (either via pharmacological means or through genetic manipulation) reduces heroin-seeking and heroin-taking behaviors.

Why the Research Is Interesting:The findings will increase awareness about the potential impact of heroin to alter neural systems related to neurodegenerative disorders. The findings also identify FYN inhibitors as a novel therapeutic treatment for heroin use disorders.

Who: Human brains from a cohort of subjects who succumbed to heroin overdose and normal controls, translational animal model of rats trained to self-administer heroin, and primary striatal neurons treated with chronic morphine in vitro.

When: Adult animals were exposed to heroin and their brains studied.

What:They performed unbiased, cell-type-specific, genome-wide profiling of chromatin accessibility, providing insights into epigenetic regulation directly in the brains of heroin-addicted individuals. To assess the causal relationship between heroin use and FYN pathology, they studied the brains of rats trained to self-administer heroin and they hit primary striatal neurons with chronic morphine in petri dishes to examine the effect at the individual cellular level.

Study Conclusions:By scanning the entire genome of heroin users to identify whether disturbances in how genes are turned on or off exist, Mount Sinai researchers found that heroin opened up the DNA at the FYN gene. The FYN gene is known to regulate the production of Tau, a protein implicated in neurodegenerative disorder like Alzheimers disease, meaning that heroin may put users at an increased risk of neurodegenerative disease later in life. Importantly, these novel findings suggest that FYN inhibitors (which have already been developed and are being assessed for use in Alzheimers disease) may be promising therapeutic tools for heroin-use disorder.

Paper Title: Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

Said Mount Sinai's Dr. Yasmin Hurd of the research: Drug overdoses due to opioid abuse remain at epidemic levels and continue to rise precipitously during the current pandemic, with novel treatments desperately needed. Direct molecular insights into the heroin-addicted human brain are critical to guide future therapies. Our new study findings clearly open up new lines of treatment opportunities for opioid use disorder, which could benefit and potentially save the lives of so many.

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People with Heroin Addiction Have Unique Molecular Alterations to The Brain That Resemble Brain Disturbances Seen in Neurodegenerative Disorders Like...

Image credit: NASA

Duke researchers team up with NASA to explore gene-environment interactions in astronauts

By Alexis Kessenich

Astronauts on long-duration spaceflights (LDSF) face a number of risks to their health some more obvious that others like during dynamic events such as launch and landing. But there are also lesser-known dangers, such as spaceflight-associated neuro-ocular syndrome (SANS), a spectrum of physiologic and pathologic neuro-ophthalmic changes that include swelling of the optic disc, nerve damage and vision impairment.

An astronauts susceptibility of developing SANS remains largely unknown, but a team of researchers in the Center for Applied Genomics and Precision Medicine (CAGPM) is on a mission to discover what causes the predisposition.

The Nutritional Biochemistry Laboratory at NASAs Johnson Space Center, led byScott M. Smith, completed preliminary studies and found metabolomics and geneticdifferencesin astronauts who developed SANS. This ledto a broader evaluation of genetics, so the team at CAGPM engaged to help.

Rachel MyersandRicardo Henaowill lead the studys data science efforts.

Were exploring over 80 genes associated with these metabolic pathways and around 500 different genetic variants within those genes, says Rachel Myers, lead analyst for the study. Our team will test each to see if one or groups of these variants are associated with SANS.

The study is comprised of three different cohorts: one pre- and post-spaceflight cohort and two cohorts mimicking SANS and spaceflight environments on Earth.

For the first cohort, data, such as eye measurements, were collected from astronauts before and after an LDSF. For the second cohort, data will be collected from patients at the Mayo Clinic with polycystic ovary syndrome, which shares some characteristics with SANS. The third cohort is a 30-day head-down tilt bedrest study, which mimics spaceflight environments and has been shown to inflict similar ocular changes.

Because the sample size is so small, and the number of astronauts available to participate is limited, the team will look at ways to combine different variants together and test association with the phenotypes provided by NASAs preliminary study to see if they can find what causes the predisposition.

No one has ever looked at the genetic aspect of SANS before. Its going to be really interesting to explore non-traditional approaches for genetic associations, adds Myers.

At the end of the study, the team hopes to have both an understanding of what the genetic landscape of SANS is and a sense of what approaches are going to work for further investigation.

With a small cohort, we run the risk of finding something thats completely random, says Myers, so well do additional validation after our initial findings before making recommendations.

Ultimately, were exploring gene-environment interactions, addsGeoff Ginsburg, principal investigator on the study. The astronauts exposures in space from ionizing radiation and microgravity to extreme social isolation presents an exciting scientific opportunity to understand how this intense and hostile environment interacts with our genomes.

Myers says after the study the team also hopes to have a new pipeline in the Center for processing sequencing data to get genetic variants, which will help with future studies.

A solution for these astronauts is hopefully on the horizon. But, for now, the project is one small leap for CAGPM, one giant leap for genetic research!

Association of Genetics and B Vitamin Status With the Magnitude of Optic Disc Edema During 30-Day Strict Head-Down Tilt Bed RestAstronaut ophthalmic syndromeGenotype, Bvitamin status, and androgens affect spaceflightinduced ophthalmic changesSpaceflight-related ocular changes:the potential role of genetics, and the potential ofB vitaminsas a countermeasure

Originally posted here:
Houston, We Have an Eye Problem - Duke Today

SAN FRANCISCO, CA / ACCESSWIRE / August 24, 2020 / Tribe Public announced today that Dietrich Stephan, Chief Executive Officer of NeuBase Therapeutics, Inc. (NASDAQ:NBSE), a biotechnology company developing next-generation antisense oligonucleotide (ASO) therapies using its scalable PATrOL platform to address genetic diseases, will present at Tribe Public's Presentation and Q&A Webinar Event at 8 am pacific/11 am eastern on Wednesday, August 26th, 2020. During this complimentary, 30-minute event, Dr. Stephan will introduce the NeuBase's next-generation gene silencing technology and discuss the company's progress with treatment candidates in Huntington's Disease (HD) and Myotonic Dystrophy (DM1). A question and answer session will follow the presentation. To register to join the complimentary event, please visit the Tribe Public LLC website: http://www.tribepublic.com, or send a message to Tribe's management at research@tribepublic.com to request your seat for this limited capacity Zoom-based event.

Dietrich A. Stephan, Ph.D. is an industry veteran who is considered one of the fathers of the field of precision medicine, having trained with the leadership of the Human Genome Project at the NIH and then going on to lead discovery research at the Translational Genomics Research Institute and serve as professor and chairman of the Department of Human Genetics at the University of Pittsburgh. Dr. Stephan has identified the molecular basis of dozens of genetic diseases and published extensively in journals such as Science, the New England Journal of Medicine, Nature Genetics, PNAS, and Cell. In parallel, Dr. Stephan has founded or co-founded more than ten biotechnology companies and has advised numerous other companies. These companies are backed by top-tier investors such as Sequoia Capital, KPCB, Thiel Capital, and Khosla Ventures as well as corporate partners such as Life Technologies, Pfizer, and Mayo Clinic. Notably, Dr. Stephan founded NeuBase Therapeutics in August 2018, took it public in 2019, and has since grown the company to market capitalization to the tune of hundreds of millions of dollars. Dr. Stephan received his Ph.D. from the University of Pittsburgh and his B.S. from Carnegie Mellon University.

ABOUT TRIBE PUBLIC LLCTribe Public LLC is a San Francisco, CA-based organization that hosts complimentary worldwide webinar & meeting events in the U.S. Tribe's events focus on issues that the Tribe members care about with an emphasis on hosting management teams from publicly traded companies from all sectors & financial organizations that are seeking to increase awareness of their products, progress, and plans. Tribe members primarily include Institutions, Family Offices, Portfolio Managers, Registered Investment Advisors, & Accredited Investors. Website: http://www.tribepublic.com.

ABOUT NEUBASE THERAPEUTICSNeuBase Therapeutics, Inc. is developing the next generation of gene silencing therapies with its flexible, highly specific synthetic antisense oligonucleotides. The proprietary NeuBase peptide-nucleic acid (PNA) antisense oligonucleotide (PATrOL) platform allows for the rapid development of targeted drugs, increasing the treatment opportunities for the hundreds of millions of people affected by rare genetic diseases, including those that can only be treated through accessing of secondary RNA structures. Using PATrOL technology, NeuBase aims to first tackle rare, genetic neurological disorders. NeuBase is continuing its progress towards developing treatment candidates in Huntington's Disease (HD) and Myotonic Dystrophy (DM1.)

CONTACT:

Tribe Public, LLC.John F. Heerdink, Jr.Managing Partnerjohn@tribepublic.com

SOURCE: NeuBase Therapeutics, Inc.

View source version on accesswire.com:https://www.accesswire.com/603092/NeuBase-Therapeutics-CEO-Dietrich-A-Stephan-PhD-to-Present-at-Tribe-Publics-Presentation-and-QA-Webinar-Event-on-August-26-2020

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NeuBase Therapeutic's CEO, Dietrich A. Stephan, Ph.D., to Present at Tribe Public's Presentation and Q&A Webinar Event on August 26, 2020 - BioSpace

A woman spits into a tube so that her saliva can be tested for the presence of the novel coronavirus.

By Robert F. ServiceAug. 24, 2020 , 5:00 PM

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

First, a technician pushes a pencil-length swab to the very back of your nasal passages. Then you pay $100 or more, and wait days for an answer. But faster, cheaper, more pleasant ways to test for the novel coronavirus are coming online. This month, the U.S. Food and Drug Administration granted emergency use authorization for two tests that sample saliva instead of nasal fluid, and more innovations are likely after FDA relaxed rules to allow new tests to be adopted more quickly. One candidate was announced last week: an experimental test, potentially faster and cheaper, that analyzes saliva in a new way.

There is real promise here, says Anne Wyllie, a microbiologist at Yale University who helped develop one of the new tests authorized this month. Takanori Teshima, chief of laboratory medicine at Hokkaido University, who also reported successful results testing saliva, agrees. It will have a big impact worldwide.

When SARS-CoV-2, the respiratory virus that causes COVID-19, emerged in December 2019, researchers scrambled to develop tests to detect the virus. Initially, they turned to a long-trusted technique for diagnosing respiratory infections: looking for viral genetic material in mucosal fluid, thought to be the best hunting ground for a respiratory virus, collected from deep in a patients nasal passages. Thats where the 15-centimeter swab comes in. The swab goes into a plastic tube with a chemical mixture that stabilizes the virus during transport to a diagnostics lab. There, technicians extract its genetic material and load it into a machine to carry out the polymerase chain reaction (PCR), which amplifies snippets of genetic material unique to the virus.

The procedure accurately identifies infections about 95% of the time. But the test is uncomfortable and, because collecting the swab requires close contact with patients, it puts medical personnel at risk of contracting the virus. Nobody wants to do that job, Teshima says.

Testing saliva for SARS-CoV-2 was no sure thing. Studies with other respiratory diseases showed saliva tests identified only about 90% of people for whom swab tests indicated an infection. But the appeal of an easier and safer test for the new coronavirus led researchers to try. People being tested simply drool into a bar-coded plastic tube, seal it, and drop it in a pouch thats shipped to a lab for PCR analysis. Because the procedure directly tests the fluid responsible for transmitting the virus between people, it may give a better indication of who is most contagious, says Paul Hergenrother, a chemist at the University of Illinois, Urbana-Champaign (UIUC), who led his universitys saliva test development.

As early as 12 February, researchers in Hong Kong and China reported inClinical Infectious Diseasesthat they couldidentify SARS-CoV-2 from salivain 11 of 12 patients whose swabs showed virus. Since then, groups in the United States, Singapore, and Japan have confirmed and further simplified the procedures, cutting out costly steps such as adding specialized reagents to stabilize the virus during transport and extract the genetic material.

In May, Wyllie and Yale colleagues teamed up with the National Basketball Association, which provided $500,000 to develop Yales saliva test; the test is now used for frequently testing players. On 4 August, the Yale team posted a preprint on medRxiv that said its saliva testagreed with swab results 94% of the time, at a cost of as little as $1.29 per sample, roughly 1/100 as much as commercial swab-based tests. On 15 August, FDA granted emergency approval for the SalivaDirect test, so that other FDA-approved labs can use the protocol. Last week, the agency extended approval to the UIUC test given its similarity to the Yale test. UIUC is now using its saliva test to test all 60,000 students, faculty, and staff twice a week, so they can isolate infected individuals as quickly as possible. Testing saliva makes sense scientifically, and it makes sense logistically, Hergenrother says.

Anew saliva test for RNA viruses, such as Zika and SARS-CoV-2, was reported last week inScience Advancesby researchers at the University at Albany. It could be even faster and cheaper because it does not need expensive lab equipment such as PCR machines. Rather than amplifying RNA to identify the virus, the approach uses snippets of DNA that bind to short, unique sections of RNA and change them from linear strands to loops. That alters how the RNA behaves in a common lab procedure known as gel electrophoresis, making it easy to detect. This is innovative, Wyllie says.

A relaxation of FDA rules announced last week could lead to still more variants. The new rules allow approved clinical labs to use tests they have developed without any additional approval step. In a tweet, Michael Mina, an epidemiologist at Harvard Universitys T.H. Chan School of Public Health, called FDAs decision Huge news!! because it would encourage labs to develop novel tests. It may also help speed development ofrapid tests that look for viral proteinsrather than genetic materialan efficient way to screen large numbers of asymptomatic people.

We dont need one test to be the end all and be all, Wyllie says. We just want options.

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New drool-based tests are replacing the dreaded coronavirus nasal swab - Science Magazine

A man in Hong Kong who recovered from COVID-19 was reinfected with the virus four-and-a half months later in the first recorded instance of a second infection, researchers at the University of Hong Kong said on Monday.

The findings suggest the disease can infect multiple times despite herd immunity.

According to the researchers, a genetic analysis showed that these two successive infections of the same patient had been caused by two different strains of the SARS-CoV-2 virus, responsible for COVID-19.

The 33-year-old man was first diagnosed with COVID-19 in late March but tested positive again while being tested after he returned to Hong Kong from Spain via Britain on August 15.

But he was found to be infected with a different coronavirus strain the second time around and was asymptomatic.

The two viral signatures were said to be "completely different", and belonged to different coronavirus lineages, or clades.

The first closely resembled strains collected in March and April, and the second strain matched the virus found in Europe -- where the patient had just been visiting -- in July and August.

"Our study proves that immunity for COVID infection is not lifelong -- in fact, reinfection can occur quite quickly," said Kelvin Kai-Wang To, a microbiologist at Hong Kong University's Faculty of Medicine and lead author of a forthcoming study that details the findings.

"COVID-19 patients should not assume after they recover that they won't get infected again," he told AFP.

To also said those who have overcome the virus should still practice social distancing, wear masks and practise hand washing.

Experts have voiced different opinions on how alarmed people should be at the new findings, which will be published in the peer-reviewed medical journal Clinical Infectious Diseases.

"This is a worrying finding for two reasons," said David Strain, a clinical senior lecturer at the University of Exeter Medical School.

"It suggests that previous infections are not protective. It also raises the possibility that vaccinations may not provide the hope that we have been waiting for."

If antibodies don't provide lasting protection, "we will need to revert to a strategy of viral near-elimination in order to return to a normal life", he said.

But others say the new case is likely to be rare. .

"It is to be expected that the virus will naturally mutate over time," said microbiologist Brendan Wren of the London School of Hygiene & Tropical Medicine.

"This is a very rare example of re-infection and it should not negate the global drive to develop COVID-19 vaccines."

The virus has killed over 800,000 people worldwide and there has been an uptick of new infections after many countries lifted lockdown measures.

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Hong Kong man becomes first patient reinfected with COVID-19, say researchers - Euronews

(Reuters) - The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

Hong Kong man has first documented COVID-19 reinfection

A 33-year-old man who had recovered from a severe case of COVID-19 in April was infected again four months later in the first documented instance of human reinfection, University of Hong Kong researchers said on Monday. In August, after returning from a trip to Europe, he was diagnosed again - but with a different strain of the virus. While the first infection landed him in the hospital, the second produced no symptoms. Genetically, the first virus was closely related to strains collected in March/April while the second was closely related to strains collected in July/August, the researchers wrote in a report seen by Reuters. "Our findings suggest that SARS-CoV-2 may persist in the global human population as is the case for other common-cold associated human coronaviruses," they said in a statement. "Since the immunity can be short lasting after natural infection, vaccination should also be considered for those with one episode of infection," researchers said. "Patients with previous COVID-19 infection should also comply with epidemiological control measures such as universal masking and social distancing," they added. The report has been accepted for publication in Clinical Infectious Diseases. (bit.ly/34v5Lii; reut.rs/3l823Rv)

Low oxygen in COVID-19 pneumonia linked to vascular widening

Widened small blood vessels in the lungs appear to be linked with the low oxygen levels seen in COVID-19 respiratory failure, a small study suggests. Researchers made the discovery by injecting saline with tiny microbubbles into the veins of 18 critically ill COVID-19 patients and tracked the bubbles using ultrasound. Normally, the bubbles would travel through the heart and enter the lungs, but would not get through the lungs because they would not fit through the capillaries. In more than 80% of these patients, however, the bubbles passed through the lungs and reached the blood vessels of the brain, which means the lung's capillaries were abnormally dilated, researchers reported earlier this month in the American Journal of Respiratory and Critical Care Medicine. The more bubbles that made their way beyond patients' lungs, the lower their oxygen levels, researchers said. This "may explain the disproportionate low oxygen levels seen in many patients with COVID-19 pneumonia," coauthor Dr. Hooman Poor of the Mount Sinai - National Jewish Health Respiratory Institute in New York City told Reuters. Researchers should consider testing drugs that would cause these patients' pulmonary blood vessels to constrict, he suggested. An editorial published in the journal on Friday points out that with dilated pulmonary blood vessels, a higher-than-usual volume of blood flows into the brain, which "raises the question of whether increased neurologic complications of COVID-19 could be related" to the dilation observed by the researchers. (bit.ly/32jSLsZ; bit.ly/3jeHtwL)

Genetic barcodes may help monitor coronavirus mutations

"Genetic barcodes" can help track how the new coronavirus spreads and mutates, researchers said on Saturday in the International Journal of Infectious Diseases. Based on the organization, or sequence, of the genetic code of the virus, the researchers identified 11 distinct SARS-CoV-2 "barcodes" that represent different clades, or lineages, descended from a common viral ancestor. "We were able to assign approximately 94% of the global sequenced genomes to one of the clades," Arnab Pain of King Abdullah University of Science and Technology in Saudi Arabia told Reuters. Different continents have different variations, his team found. The subtle differences in the genetic sequences represented by the barcodes may affect virus infectivity or illness severity, he noted. Most of the genetic profiles available for the study were from North America and Europe, with COVID-19 cases from other regions under-represented. The researchers plan to regularly update the barcodes. "This is a dynamic process, and some virus clades/subclades may eventually die-off in the future, and new clades may form," Pain said. "We will continue to monitor the viral mutations in the global scenario and share our observations with the scientific community." (bit.ly/31mZVNK)

Open tmsnrt.rs/3a5EyDh in an external browser for a Reuters graphic on vaccines and treatments in development.

Reporting by Nancy Lapid; Editing by Bill Berkrot

Original post:
First COVID-19 reinfection case reported; low oxygen levels linked to widening blood vessels in lungs - Reuters

By The Canadian Press on August 24, 2020.

CALGARY Alberta has become the third province in Canada to offer a promising treatment for individuals with specific types of leukemia and lymphoma.

The provincial government, in partnership with the Alberta Cancer Foundation, has earmarked $15 million for the program, commonly known as CAR T-cell therapy.

CAR T-cell therapy genetically reprograms a persons immune cells to attack cancer cells in the body and then after the genetic mutations happen in the laboratory infuse back into the patient, Alberta Health Minister Tyler Shandro said at a news conference in Calgary.

Its provided when conventional treatments are ineffective and the cancer reoccurs.

Alberta will be the third province to offer CAR T-cell therapy, which is also available in Ontario and Quebec.

Shandro said the therapy will be available to about 60 patients a year and the cost is about $400,000 per individual.

He said the funding will be used to conduct a clinical trial with CAR T-cells manufactured in Alberta at three sites: the Cross Cancer Institute, Tom Baker Cancer Clinic and Alberta Childrens Hospital.

The money will also pay for nursing staff, training and education for health-care workers, patient education and psychosocial support, lab and diagnostic imaging, and followup care.

Shandro said the results of the treatment have been positive.

CAR T-cell therapy trials have demonstrated durable remissions and potential cures in about 50 per cent of adults and 80 per cent of children and young adults. We want to provide Albertans with the same recovery opportunities, he said.

Treatment using cells manufactured in the U.S. is expected to begin by wintertime at the Tom Baker Cancer Centre, with the Alberta Childrens Hospital and Cross Cancer Institute to follow.

CAR T-cell therapy is a game-changing treatment that offers some patients their only chance to survive cancer, said Alicia Talarico, president of the Leukemia and Lymphoma Society of Canada.

Martha Kandt, from Lacombe, Alta., said she was given three months to live and sought the treatment in the U.S.

As a family, we decided the risk was worth it, to see if the treatment would work. I recently had a PET scan and I am in remission. Im so pleased this treatment is going to be available to Albertans who need it.

This report by The Canadian Press was first published on Aug. 24, 2020.

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