Category Archives: Transhuman News

In the United States, cardiovascular disease (CVD) is a major health problem accounting for nearly 40 percent of all deaths each year, according to the US National Library of Medicine. Now, scientists from University of Utah Health have confirmed that artificial intelligence (AI) can better predict cardiovascular disease, including risk factors, onset, and course.

Fortunately, several risk factors for heart diseasesuch as tobacco use, hypertension, obesity, elevated low-density lipoprotein cholesterol (LDL-C), and hypercoagulable states can be modified. Much like detecting cancer early, therapeutic lifestyle changes and drug treatment can be highly effective at reducing a patients risk of heart attack and stroke if risk factors can be identified in patients early. But AI technology could improve this process, with the potential of saving lives before adverse events occur.

The Centers for Disease Control and Prevention (CDC) lists heart disease as the #1 leading cause of death in the US, followed by cancer and Covid. Cardiovascular disease is a grave concern in the field of medicine. Here in Utah, University of Utah Health researchers have been working closely with physicians at Intermountain Primary Childrens Hospital to develop computational tools that accurately measure the combined effects of existing medical conditions on a patients heart and blood vessels.

While the initial research is limited to cardiovascular disease, its only the beginning. Researchers see the vast potential of AI technology and how it can essentially help identify and pinpoint risk factors in a broad range of medical diagnoses.

We can turn to AI to help refine the risk for virtually every medical diagnosis, [including] the risk of cancer, the risk of thyroid surgery, the risk of diabetesany medical term you can imagine, says Martin Tristani-Firouzi, the studys corresponding author, a pediatric cardiologist at U of U Health and Intermountain Primary Childrens Hospital, and scientist at the Nora Eccles Harrison Cardiovascular Research and Training Institute.

The current methods for calculating various risk factors on cardiovascular diseasessuch as medical history and demographicsare subjective and imprecise, says Mark Yandell, senior author of the study, professor of human genetics, and co-founder of Backdrop Health. Since these methods fall short, they fail to identify those interactions that can profoundly affect the health of a persons heart and blood vessels.

Instead, the researchers focused on measuring comorbidities and how they influence patient health. Yandell, Tristani-Firouzi, and their colleagues from Intermountain Primary Childrens Hospital and U of U Health sorted through more than 1.6 million anonymous electronic health records (EHRs) utilizing AI. These EHRs included detailed information about patients, including lab tests, diagnoses, medication prescribed, and medical procedures, which helped researchers identify which comorbidities were most likely to aggravate cardiovascular disease.

The important thing is that we can now calculate any outcome given multiple combinations of prior events in the patients medical record, Yandell says. This allows us to refine a patients risk for a medical diagnosis and understand how prior events influence future ones.

The researchers found that patients with a previous diagnosis of cardiomyopathy, a disease of the heart muscle, had an 86 times higher risk of needing a heart transplant than those without cardiomyopathy. Individuals with viral myocarditis had about a 60 times higher chance of needing a heart transplant. Transplant risk for those who used the drug milrinone (used to treat heart failure) rose by 175 timesthe strongest predictor of a heart transplant.

In certain cases, the combined risk was significantly higher. When individuals took milrinone and had cardiomyopathy, for instance, their risk of needing a heart transplant jumped to 405 times higher than individuals with healthier hearts.

This novel technology demonstrates that we can estimate the risk of medical complications with precision and even determine better medicines for individual patients, Josh Bonkowsky, director of the Primary Childrens Center for Personalized Medicine, told U of U Health.

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This AI device is changing heart attack prevention - Utah Business - Utah Business

When talking about caribou, most people probably think of some version of Santa Clauss reindeer. Although real-life reindeer sadly do not exhibit any of the fantastical traits associated with helping Santa deliver gifts all over the world, caribou their North American counterpart of the same species (Rangifer tarandus) are in fact known to perform epic long-distance migrations.

Despite this, not everyone knows that not all caribou migrate caribou that live in boreal forests are indeed mainly sedentary. Things can get even trickier when we consider populations in which only some caribou migrate, a phenomenon called partial migration.

Why these behavioral differences exist is a fascinating research question, the answer to which is strategically important for the conservation of migratory animals, which are globally imperiled.

In a recently published study, we examined these two types of behaviors in western Canadian endangered caribou and linked a caribous tendency to migrate with its genetic heritage.

The main purpose of our study was to investigate whether caribou migratory behaviour is associated with genetics. To do this, we examined single nucleotide polymorphisms (SNPs), which are fragments of DNA increasingly used by researchers in genetic studies. SNPs are highly abundant and found in genes all across an organisms entire genetic makeup. This means that they are particularly suitable for studies aimed at determining the association between genetic, ecological and behavioural characteristics.

At first, these kinds of markers were used only for model species such as humans and mice, but thanks to recent technologies, they can now be obtained and analyzed in the context of wild species at a reasonable cost.

Our research group, based at the University of Calgary, studied migratory behaviour in 139 radio-collared caribou across western Canada. These caribou belonged to populations located in different environments, ranging from tundra to forests and mountains. We examined GPS locations for each animal using several approaches, including looking at an individual animals movement and seasonal ranges (the winter and summer areas where the animals live).

As a result, we were able to tell which animals were migratory and which were not, and determined that caribou in the tundra tend to be more migratory than others, performing the longest migration (up to 500 kilometres one way). These findings also supported previous studies.

Our first step was to examine SNPs and determine groups of individuals with similar genetic characteristics. For each of the 139 caribou we tracked, we obtained around 30,000 SNPs. Our caribou mainly belonged to either a northern or southern group, which is consistent with previous studies.

Historically, two caribou genetic lineages evolved in separated glacial refugia (areas without ice, where flora and fauna survived) located north and south of the ice sheet during the ice ages. The historical northern refugia was predominantly composed of tundra habitat, where caribou migrated to follow seasonally available food.

In contrast, the southern portion of the species range was dominated by forested environments, where caribou were sedentary as a consequence of reduced seasonality of resources. Our findings showed that that caribou belonging to the northern group were more likely to migrate, indicating that migration may be associated with the genetic ancestry of caribou.

We then wanted to know whether there were specific genetic mutations associated with migratory behaviour, and consequently identified 57 SNPs associated with migration. Many of these SNPs were found in genes that may influence migration in other species. These genes included those regulating including circadian rhythms, sleep, fat metabolism and hormone production.

Overall, our findings provide initial evidence of a package of ancestral genes common across migratory groups that affects the inclination to migrate.

Migratory animals are known to positively affect biodiversity and ecosystem functioning. Upon arrival at a destination site, migrants deposit nutrients and other substances into resident communities and ecosystems. This is being affected by human activities, and there have been resultant dramatic declines in the populations of migratory ungulates. The disappearance of migratory behaviour is now recognized as a global conservation challenge, with alarming new findings for threatened caribou in particular.

Human-caused habitat alterations and climate change have both contributed to caribou decline. This, alongside the local extinction of some populations of mountain caribou, could mean the disappearance of other ecological and genetic behaviours.

If, as we report, migratory behaviour is genetically influenced, caribou could be further impacted by the permanent loss of migratory behaviour. Migratory behaviour, as well as the set of mutations contributing to it, may not be easily re-established once lost.

Genetic mutations, especially those that are beneficial, occur in evolutionary timeframes that are incompatible with the fast decline of caribou. In the face of rapid declines, novel mutations, including those influencing migration, are unlikely to emerge.

This loss could perhaps be averted with the maintenance of seasonal habitats for caribou a strategy that would facilitate migration and give caribou a better fighting chance at population persistence.

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Whether caribou migrate or stay put is determined by genes that evolved in the last ice age - The Conversation Indonesia

NEW YORK--(BUSINESS WIRE)--Kallyope, Inc., a leading biotechnology company focused on identifying and developing therapeutics involving the gut-brain axis, today announced the appointments of George Shiebler as General Counsel and Anita Kawatra as Executive Vice President, Corporate Affairs, to help steer the company as it advances a pioneering drug discovery platform, clinical trials, and pipeline of multiple programs mediated by gut-brain axis signaling across a broad range of therapeutic areas.

With novel compounds in two lead programs now in clinical development, this is an inflection point for Kallyope. As we embark upon our next phase of growth to bring forth powerful new therapeutics driven by our unique drug discovery platform, we are continuing to build a world-class team to help take our work from the lab to the real world, said Jay Galeota, president and CEO, Kallyope. George and Anita are recognized industry leaders with extraordinary track records. George brings to Kallyope comprehensive knowledge of pharmaceutical industry regulations and unmatched expertise in negotiating a wide variety of sophisticated corporate transactions. Anita has an extensive background in the life sciences, global public health, and public policy, with a strong history of success advising management and boards of startup and growing biotech companies. We look forward to benefiting from their experience and perspectives as we move forward.

George Shiebler has more than 30 years of experience as an attorney in the pharmaceutical and biotech industries. Most recently, he was Senior Vice President and General Counsel of nference, an AI-driven health technology company. Previously, he was a founding executive and General Counsel at Inheris Biopharma, and General Counsel and Chief of Staff for G&W Laboratories. Mr. Shiebler spent 23 years at Merck & Co., leading the worldwide transaction and licensing practice and overseeing multibillion-dollar public and private mergers and acquisitions, multinational joint ventures, and venture investments in startups. He holds a JD from the University of Georgia School of Law, where he was a member of the Law Review, and a bachelors degree from the University of Virginia.

Anita Kawatra has held numerous senior management positions in the life sciences over the past 20 years, following a decade in government and policy. Most recently, she was Chief Corporate Affairs Officer at nference. Previously, she was a founding executive of Inheris Biopharma and held global roles at Elan Pharmaceuticals, Prothena Biosciences, Merck & Co., and the International AIDS Vaccine Initiative. Prior to her work in biopharmaceuticals, she served in the administrations of New York City Mayor David Dinkins and New York Governor Mario Cuomo. Ms. Kawatra is a board member of the New York City Health and Hospitals Corporation, the largest public health system in the United States. In 2020, she was named among the 100 most influential Asian Americans in New York politics and policy. She holds a masters degree from Columbia University and a bachelors degree from Yale University.

About Kallyope

Kallyope, headquartered at the Alexandria Center for Life Science in New York City, is a biotechnology company dedicated to unlocking the therapeutic potential of the gut-brain axis. The companys cross-disciplinary team integrates advanced technologies in sequencing, bioinformatics, neural imaging, cellular and molecular biology, and human genetics to provide an understanding of gut-brain biology that leads to transformational therapeutics to improve human health. The companys founders are Charles Zuker, Ph.D., Lasker Award winner Tom Maniatis, Ph.D., and Nobel laureate Richard Axel, M.D. For more information visit http://www.kallyope.com.

Excerpt from:
Kallyope, Pioneers in Drug Discovery via the Gut-Brain Axis, Strengthens Senior Leadership Team with Key Appointments - Business Wire

Cyprium Therapeutics, a subsidiry of Fortress Biotech, is developing CUTX-101 for the treatment of Menkes disease

CUTX-101 has potential to be first FDA-approved treatment for Menkes disease; rolling submission of New Drug Application to FDA is ongoing and expected to be completed in mid-year 2022

MIAMI and SOLANA BEACH, Calif., March 21, 2022 (GLOBE NEWSWIRE) -- Cyprium Therapeutics, Inc. (Cyprium), a Fortress Biotech, Inc. (Nasdaq: FBIO) (Fortress) subsidiary, with support from its licensing partner Sentynl Therapeutics, Inc. (Sentynl), a wholly owned subsidiary of Zydus Lifesciences Ltd. (formerly known as Cadila Healthcare Ltd.), today announced positive data on CUTX-101, copper histidinate (CuHis), in patients with Menkes disease. The data will be presented as a Top-Rated Abstract and Poster at the 2022 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting taking place March 22-26, 2022, virtually and at Music City Center in Nashville, TN. The previously reported results are from an efficacy and safety analysis of data integrated from two completed pivotal studies in patients with Menkes disease treated with CUTX-101.

Details of the poster are as follows:

Poster Title: Safety and Efficacy of Copper Histidinate (CUTX-101) Treatment for Menkes Disease Caused by Severe Loss-of-Function Variants in ATP7APoster Number: eP195Authors:Stephen G. Kaler, M.D., M.P.H., Shama Munim, M.S., Michael Chen, Ph.D., Robert Niecestro, Ph.D., Lung S. Yam, M.D., Ph.D.Dates / Times: Posters will be available for viewing on Wednesday, March 23, 5:00 p.m. 7:00 p.m., Thursday, March 24, 9:30 a.m. - 4:30 p.m. and Friday, March 25, 10:00 a.m. 1:00 p.m. in the Exhibit Hall. Dr. Kaler will formally present the poster on Thursday, March 24 from 10:00 a.m. 11:30 a.m. CT.

The abstract can be viewed here.

The positive data that will be presented at the 2022 ACMG Annual Clinical Genetics Meeting demonstrate the efficacy and safety of CUTX-101 and its potential to be the first treatment approved by the U.S. Food and Drug Administration (FDA) for patients with Menkes disease. We continue to make progress with our rolling submission of a new drug application (NDA) for CUTX-101 which we anticipate to be completed in the middle of this year, said Lung S. Yam, M.D., Ph.D., President and Chief Executive Officer of Cyprium. We welcome the opportunity to present the positive efficacy and safety data of CUTX-101 to medical geneticists who are often involved in the diagnosis and treatment of Menkes disease, a rare, fatal pediatric disease.

In 2021, Cyprium partnered with Sentynl Therapeutics, Inc., a U.S.-based specialty pharmaceutical company owned by the Zydus Group, to bring CUTX-101 to market. Cyprium will retain development responsibility of CUTX-101 through approval of the NDA by the FDA, and Sentynl will be responsible for commercialization of CUTX-101 as well as progressing newborn screening activities.

About Menkes Disease Menkes disease is a rare X-linked recessive pediatric disease caused by gene mutations of copper transporter ATP7A. The minimum birth prevalence for Menkes disease is believed to be 1 in 34,810 live male births, and potentially as high as 1 in 8,664 live male births, based on recent genome-based ascertainment (Kaler SG, Ferreira CR, Yam LS. Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD). Molecular Genetics and Metabolism Reports 2020 June 5;24:100602). The condition is characterized by distinctive clinical features, including sparse and depigmented hair (kinky hair), connective tissue problems, and severe neurological symptoms such as seizures, hypotonia, failure to thrive, and neurodevelopmental delays. Mortality is high in untreated Menkes disease, with many patients dying before the age of three years old. Milder versions of ATP7A mutations are associated with other conditions, including Occipital Horn Syndrome and ATP7A-related Distal Motor Neuropathy. Currently, there is no FDA-approved treatment for Menkes disease and its variants.

About CUTX-101 (Copper Histidinate)CUTX-101 is in clinical development to treat patients with Menkes disease. CUTX-101 is a subcutaneous injectable formulation of Copper Histidinate manufactured under current good manufacturing practice (cGMP) and physiological pH. In a Phase 1/2 clinical trial conducted by Stephen G. Kaler, M.D., M.P.H., at the National Institutes of Health (NIH), early treatment of patients with Menkes disease with CUTX-101 led to an improvement in neurodevelopmental outcomes and survival. In August 2020, Cyprium reported positive topline clinical efficacy results for CUTX-101, demonstrating statistically significant improvement in overall survival for Menkes disease subjects who received early treatment (ET) with CUTX-101, compared to an untreated historical control cohort, with a nearly 80% reduction in the risk of death. CUTX-101 has been granted FDA Breakthrough Therapy, Fast Track, Rare Pediatric Disease and FDA Orphan Drug Designations. Additionally, the European Medicines Agency granted Orphan Drug Designation for CUTX-101. A Cyprium-sponsored expanded access protocol for patients with Menkes disease is ongoing at multiple U.S. medical centers.

About Cyprium TherapeuticsCyprium Therapeutics, Inc. (Cyprium) is focused on the development of novel therapies for the treatment of Menkes disease and related copper metabolism disorders. In March 2017, Cyprium entered into a Cooperative Research and Development Agreement (CRADA) with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the NIH, to advance the clinical development of CUTX-101 (Copper Histidinate injection) for the treatment of Menkes disease. In addition, Cyprium and NICHD entered into a worldwide, exclusive license agreement to develop and commercialize adeno-associated virus (AAV)-based gene therapy, called AAV-ATP7A, to deliver working copies of the copper transporter that is defective in patients with Menkes disease, and to be used in combination with CUTX-101. CUTX-101 was granted FDA Breakthrough Therapy, Fast Track and Rare Pediatric Disease Designations, and both CUTX-101 and AAV-ATP7A have received FDA Orphan Drug Designation previously. Additionally, the European Medicines Agency previously granted Orphan Drug Designation to CUTX-101. Cyprium was founded by Fortress Biotech, Inc. (Nasdaq: FBIO) and is based in New York City. For more information, visit http://www.cypriumtx.com.

About Fortress BiotechFortress Biotech, Inc. (Fortress) is an innovative biopharmaceutical company focused on acquiring, developing and commercializing high-potential marketed and development-stage drugs and drug candidates. The company has nine marketed prescription pharmaceutical products and over 30 programs in development at Fortress, at its majority-owned and majority-controlled partners and at partners it founded and in which it holds significant minority ownership positions. Such product candidates span six large-market areas, including oncology, rare diseases and gene therapy, which allow it to create value for shareholders. Fortress advances its diversified pipeline through a streamlined operating structure that fosters efficient drug development. The Fortress model is driven by a world-class business development team that is focused on leveraging its significant biopharmaceutical industry expertise to further expand the companys portfolio of product opportunities. Fortress has established partnerships with some of the worlds leading academic research institutions and biopharmaceutical companies to maximize each opportunity to its full potential, including AstraZeneca plc, City of Hope, Fred Hutchinson Cancer Research Center, St. Jude Childrens Research Hospital, Nationwide Childrens Hospital and Sentynl Therapeutics, Inc. For more information, visitwww.fortressbiotech.com.

About Sentynl TherapeuticsSentynl Therapeutics is a U.S.-based biopharmaceutical focused on bringing innovative therapies to patients living with rare diseases.The company was acquired by the Zydus Group in 2017. Sentynls highly experienced management team has previously built multiple successful pharmaceutical companies. With a focus on commercialization, Sentynl looks to source effective and well differentiated products across a broad spectrum of therapeutic areas to address unmet needs. Sentynl is committed to the highest ethical standards and compliance with all applicable laws, regulations, and industry guidelines. For more information, visit http://www.sentynl.com.

About Zydus The Zydus Group, with an overarching purpose of empowering people with freedom to live healthier and more fulfilled lives, is an innovative, global pharmaceutical company that discovers, develops, manufactures, and markets a broad range of healthcare therapies. The group employs over 23000 people worldwide and is driven by its mission to unlock new possibilities in life-sciences through quality healthcare solutions that impact lives. The group aspires to become a global life-sciences company transforming lives through pathbreaking discoveries. For more information, visit https://www.zyduslife.com/zyduslife/

Forward-Looking StatementsThis press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, as amended. As used below and throughout this press release, the words we, us and our may refer to Fortress individually or together with one or more partner companies, as dictated by context. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; uncertainties relating to preclinical and clinical testing; risks relating to the timing of starting and completing clinical trials, including the possible disruption of trials due to the hostilities in Europe; our dependence on third-party suppliers; risks relating to the COVID-19 outbreak and its potential impact on our employees and consultants ability to complete work in a timely manner and on our ability to obtain additional financing on favorable terms or at all; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our Securities and Exchange Commission filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as may be required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. The information contained herein is intended to be reviewed in its totality, and any stipulations, conditions or provisos that apply to a given piece of information in one part of this press release should be read as applying mutatis mutandis to every other instance of such information appearing herein.

Company Contacts:Jaclyn Jaffe and William BegienFortress Biotech, Inc.(781) 652-4500ir@fortressbiotech.com

Lung Yam, M.D., Ph.D.Cyprium Therapeutics, Inc. ir@cypriumtx.com

Michael HerczSentynl Therapeutics, Inc. ir@sentynl.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Fortress Biotech, Cyprium Therapeutics and Sentynl - GlobeNewswire

image:Ana Victoria Lechuga-Vieco, Raquel Justo, Jos Antonio Enrquez, Jess Vzquez y Enrique Calvo. view more

Credit: CNIC

Research carried out at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) has demonstrated that mixing mitochondrial DNAs (mtDNAs) of different origins can have damaging effects over the medium and long term. mtDNA is a component of the genetic material that is transmitted exclusively from mothers to their children.

The study, published in Circulation, provides invaluable information about how to identify and avoid possible risks associated with mitochondrial therapeutic interventions. The most popular of these methods include the injection of mitochondria from a donor egg into the egg of a woman with fertility problems and mitochondrial replacement therapy aimed at preventing the transmission of disease-causing mutations to descendents, popularly known as "three-parent children". Mitochondrial replacement therapy has already been approved in the United Kingdom.

The new study shows that, while most cells do not tolerate the presence of two mitochondrial genetic variants and progressively eliminate one of the two mtDNAs, some major organs are unable to do this, including the heart, lungs, and skeletal muscle.

For lead researcher Dr. Jos Antonio Enrquez, who heads the Functional Genetics of the Oxidative Phosphorylation System (GENOXPHOS) group at the CNIC, the findings have major implications for treatments involving the transfer of donor mitochondria because they show that animals generated through these procedures appear healthy early in life but go on to suffer in later life from heart failure, pulmonary hypertension, loss of muscle mass, frailty, and premature death.

In the body, most of the DNA is contained in the cell nuclei. In humans, this is where approximately 20 000 genes of the genome are located. However, another 37 genes are located outside the nucleus. These genes are located in cellular compartments called mitochondria and constitute the mitochondrial DNA, explained Dr. Enrquez.

Nuclear DNA is transmitted from parents to their offspring, with the mother and father contributing 50% shares that mix when an egg is fertilized by a sperm.

In contrast, mtDNA is inherited only from the mother because the sperm mitochondria are destroyed in the interior of the fertilized egg. Uniparental transmission of mtDNA is found in almost all organisms. In addition, mtDNA is present in multiple copies per cell, and these copies are all essentially identical, a phenomenon known as homoplasmy.

The presence of more than one mtDNA genetic variant in the cell is called heteroplasmy. Although very rare, heteroplasmy sometimes occurs naturally as a result of mtDNA mutations and can cause several diseases. New therapeutic approaches proposed in recent years and aimed at preventing disease or treating infertility can generate a new form of heteroplasmy in people.

This new form of heteroplasmy, involving distinct non-mutated mtDNA variants, is produced when an individuals cells contain both the original recipient mtDNA and the donor mtDNA transferred during the intervention. In the GENOXPHOS group at the CNIC, we have been investigating whether this breaching of a natural biological barrier has detectable physiological effects, said Dr. Enrquez.

The researchers show that the selection between mtDNA variants coexisting in the same cell depends on their impact on cell metabolism and can be modulated by variations in gene function, drug actions, and dietary changes. All of these factors help to determine the preference for one type of mitochondrial genome over another, they write.

The question as to why mtDNA is transmitted to descendents from only one parent has yet to be answered, but until now the issue had no health implications, said first author Dr. Ana Victoria Lechuga-Vieco. The new medical therapies that breach this biological barrier can generate, intentionally or non-intentionally, mixtures of mtDNA from more than one individual in the same cell.

Before the publication of the new study, we did not know what impact this mtDNA mixing had for the individual, said Dr. Enrquez.

To address this question, the GENOXPHOS group generated mice with a single nuclear genome but with all their cells simultaneously containing two distinct mtDNA variants. This mouse strain was fertile, and young animals showed no related disease, explained Dr. Lechuga-Vieco.

But long-term analysis over the full lifetime of these mice showed that the coexistence of two mtDNA variants in the same cell compromised mitochondrial function.

We observed that cells rejected the presence of two mitochondrial genomes, and most of them progressively eliminated one of the mtDNA variants. Surprisingly, however, major organs like the heart, lungs, and skeletal muscle were unable to do this, explained Dr. Lechuga-Vieco.

Organs that could eliminate one of the mtDNA variants, like the liver, recovered their mitochondrial metabolism and cellular health, but those that could not progressively deteriorated as the animals aged, continued Dr. Enrquez.

Thus the animals, which appeared healthy in their youth, in later life suffered from heart failure, pulmonary hypertension, loss of muscle mass, frailty, and premature death.

The researchers conclude that the dangerous effects of mitochondrial therapeutic interventions identified in the new study show the need for caution in the selection of the donor mtDNA genotype.

As the authors state in their article, the results of the Circulation study also imply that Even the most promising method, for the replacement of oocyte mitochondria carrying known pathological mtDNA mutations, may fail to achieve 100% replacement.

The study shows that recipient cells have a high capacity to select and amplify the original, pre-existing mtDNA variant, which may have been undetectable before transfer of the donor mtDNA. The procedure thus has the potential to result in a mix of mtDNA from two individuals in descendent cells. The same problem arises with oocyte rejuvenation by microinjection of donor cytoplasm, pointed out Dr. Enrquez.

Similarly, added Dr. Enrquez, A similar risk can arise when purified donor mitochondria are used to treat damaged cells implicated in cardiopulmonary or neurlogical diseases.

Dr. Enrquez stressed that these risks do not mean that mitochondrial replacement therapy should be abandoned. In the same way as blood transfusions and organ transplants require careful control of compatibility between recipient and donor, Dr. Enrquez recommends that any therapeutic strategy that risks the mixing of healthy mtDNA variants from two individuals should ensure full compatibility between the donor and recipient mitochondrial genomes.

The study was supported by the following funding bodies: Ministerio de Asuntos Econmicos y Transformacin Digital (MINECO); Ministerio de Economa, Industria y Competitividad (MEIC); Human Frontier Science Program; European Molecular Biology Organization; Programa Red Guipuzcoana de Ciencia, Tecnologa e Informacin del Gobierno Vasco; and the ELKARTEK Program Department of Industry, Innovation, Commerce, and Tourism.

About the CNIC

The Centro Nacional de Investigaciones Cardiovasculares (CNIC), directed by Dr. Valentn Fuster, is dedicated to cardiovascular research and the translation of knowledge gained into real benefits for patients. The CNIC, recognized by the Spanish government as a Severo Ochoa center of excellence, is financed through a pioneering public-private partnership between the government (through the Carlos III Institute of Health) and the Pro-CNIC Foundation, which brings together 12 of the most important Spanish private companies.

Experimental study

Animals

Heteroplasmy of Wild Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty

3-Mar-2022

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A CNIC study highlights the risks of mitochondrial therapeutic interventions - EurekAlert

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Genetic and morphological variation of Vespa velutina nigrithorax which is an invasive species in a mountainous area | Scientific Reports - Nature.com