Genetics

Clemson researchers pave the way for precision medicine with AI – Clemson News

April 12, 2024April 12, 2024

Two people are prescribed the same drug to treat similar ailments. One patient quickly recovers, while the other realizes no real benefit from the course of treatment.

Why the same drug does not always produce the same result for different patients is part of what Clemson University researchers are trying to discoverin the realm of precision medicine.

Zhana Duren, an assistant professor in the Department of Genetics and Biochemistry, is delving into the genetic makeup of people to unlock the answer to this and other questions. He has co-authored a paper on the topic withpostdoctoral fellow Qiuyue Yuan. Both Duren and Yuan are at theClemson University Center for Human Genetics in Greenwood, South Carolina.

The researchers are using a novel approach by applying two relatively new tools big data and artificial intelligence to better understand the workings of gene-regulatory networks (GRNs), which are like roadmaps that show how genes, proteins and other substances interact uniquely from person to person.

GRNs map the complex interactions between genes, regulatory elements and proteins, holding the key to understanding how genetic variations influence phenotype like drug response, Duren explained. Each individual possesses a unique GRN shaped by their specific genotype, explaining why the same drug can elicit different responses in different people.

To interpret individual genetic variants within the context of unique GRNs, we aim to answer critical questions, (such as) how and why do genetic variants influence individual phenotypes through intricate GRN interactions, Duren said. By elucidating these mechanisms, we pave the way for predicting drug response based on personal genetics, enabling the development of more-targeted therapies and minimizing ineffective treatments.

The problem facing the researchers, according to Duren, is that most genetic variants linked to diseases are hidden in areas of our DNA that dont directly code for proteins. This makes it tricky to understand how they impact our health.

To help solve the riddle, Duren and Yuan turned to AI and big data analytics. Theydeveloped LINGER Lifelong Neural Network for Gene Regulation a novel deep learning-based method to infer GRNs from other cellular-level data.

With the help of the new tools, Duren and Yuan made discoveries that promise to more accurately predict how GRNs work.

There are many methods developed for gene regulatory network inference in the past two decades, Duren noted. However, our systematic benchmarking based on experimental data shows that the accuracies of these existing methods are about 17% to 29% higher than the random predictor. The new method increases it to 125% higher than the random predictor, showing four- to seven-fold relative increase.

Since this is a significant improvement in fundamental research, it will have the potential to lead discovery in broad biomedical research fields, he added.

The gains the two reported did not come without a variety of challenges. Chief among those was data sparsity.

Because it is single-cell data, the number of observations we get at each cell is so limited, Duren said. The gene regulatory network is such a complex problem that it requires large amounts of data to learn. But the available independent data we have data from many single cells, but they are not independent is not enough for this task.

The research has potential applications in a number of fields, according to Duren, including molecular biology, developmental biology and medical health research. Duren also noted the researchs potential for adding to the understanding of drug addiction, which could make it possible to develop more effective treatments.

Currently, we are applying this method in the field of drug addiction, he noted. I have three collaborations working on that; one is applying this to cocaine addiction.

The teams research was made possible in part through two National Institutes of Health grants for $2.2 million, which were awarded in 2023 and 2024, respectively.

The paper, Inferring gene regulatory networks from single-cell multiome data usingAtlas-Scale External Data, was published by the peer-reviewed top journal Nature Biotechnology.

Or email us at news@clemson.edu

Original post:
Clemson researchers pave the way for precision medicine with AI - Clemson News

Genetics

The genomic architecture of inherited DNA variants – Baylor College of Medicine | BCM

Image courtesy of the National Human Genome Research Institute

You have your mothers eyes and your fathers smile, but genetics is much more than just whats on the surface. In a study that spans more than a decade, researchers at Baylor College of Medicine have looked at generations of families in a specific population to reveal the role newly inherited DNA variants play on recessive disease traits, and in the process, they have created a population specific database revealing unique DNA information unseen in larger cohorts.

The findings, now published inGenetics in Medicine OPEN, revealed a correlation between occurrences of complex genetic disorders in those families with increased levels of consanguinity when compared to unaffected populations. Consanguinity is when both parents contribute similar genetic markers to an offspring, such as by sharing a common ancestor, and the genetic information from both the genome inherited from the father and that from the mother are identical.

We observed that the areas on the chromosome known as ROH, regions of homozygosity, were longer in those individuals in which there was a higher degree of parental consanguinity when compared to those with less, saidDr. Zeynep Coban-Akdemir, postdoctoral associate in molecular and human genetics at Baylor and currently assistant professor at UTHealth School of Public Health as well as co-lead author on the study. We can see what is happening when consanguinity is at play and also when new genetic variations are introduced into the family unit of the clan or tribe representing more distant ancestors.

Dr. Xiaofei Song, a former Baylor graduate student now working as an assistant professor at Moffitt Cancer Center, said, We further applied a statistical method to systematically assess the impact of these genetic variations on disease. Our results indicate that the newly introduced genetic variations can better explain the clinical features observed in our patients. Song also is co-lead author on the study.

The published study contributes to the field of both rare disease and population genomics. From a trainee perspective, the article provides a valuable resource for comprehending fundamental concepts of human genetics and applying diverse computational methods to elucidate these concepts, said Ph.D candidate Tugce Bozkurt-Yozgatli, with the Acibadem University in Istanbul, Turkey.

Coban-Akdemir, who worked in the Lupski Lab at Baylor where the research was conducted, says this is an important part of the findings because it reveals how genes act within different populations and clans to contribute to different recessive genetic disorders.

The population studied was a cohort of individuals originating from Turkey that is known to have different variations in genetic markers when compared to other populations from greater Europe. Researchers created and analyzed a database of variants derived from exome sequencing, a genomics assay providing a glimpse into genetic variation genomewide, of 773 unrelated volunteers who were affected with various suspected rare Mendelian disease traits, which are diseases caused by a mutation in a single gene and clearly passed down from one generation to the next in accordance with Gregor Mendel expectations. They were compared to another database created by the same researchers of 643 unaffected relatives.

Roughly half of the genetic variants in this Turkish group are not present in greater European control populations that are found in shared databases commonly used by genetic researchers.

This group of Turkish individuals and families gives us insight into genetics that the average population doesnt provide. What we found in this Turkish population is very unique. Not only is this group underrepresented in larger databases, but it shows us that they have an enriched genetic variation that is only seen within this population when compared to European populations, Coban-Akdemir said.

Dr. Davut Pehlivan, assistant professor of pediatrics neurology at Baylor, said on a single individual there are around 40 million Watson-Crick base pair variations within our DNA.

The Human Genome Project opened the doors for researchers to investigate entire genomic DNA complement using next-generation sequencing technology. However, more struggles appeared with these advancements. For example, it is hard to pinpoint which variant is causing disease among 40 million variations of our DNA. Studying healthy populations helps us to eliminate many of these common variations from consideration. Thus, we studied both patients and their healthy relatives in the Turkish population, Pehlivan said. There are a lot of changes in the genome, and we dont fully understand the meaning of all of those details, but the data from this population study will help all investigators around the world who are trying to interpret the results of other variants in the human genome DNA.

Pehlivan described gathering the information and families wanting to participate in genomics research beginning in 2010, traveling long distances to rural areas where the patients were mostly located, a human interest story itself, to make sure the database and clinical information would show an accurate representation for these families.

We discovered more than 200 genes that contributed to the existing body of disease gene associations. This will help us get closer to understanding, in this population and in others, what is causing these diseases and the human biological perturbation underlying a broad scope of diseases. Our studies will open new avenues of research in human biology and genome biology and eventually help to potentially bring nucleic acid treatments, something used to develop the COVID vaccine, to the patients and families Pehlivan said.

This team of researchers is not just helping the population that they studied, but their findings also can be applied to many populations. We all are very different individuals on this planet, yet our genes act very similarly, and we all share a common humanity. So, understanding how genetic disorders work helps us to support affected families across the globe, saidDr. James R. Lupski, the Cullen Foundation Endowed Chair in Genetics and Genomics at Baylor.

In the past, Coban-Akdemir and Dr. Claudia M.B Carvalho, previously with Baylor and currently in her own laboratory at the Pacific Northwest Research Institute (PNRI) in Seattle who also contributed to this study, have worked on studying variants of genes to identify causes of diseases through production of truncated or altered proteins that take on a new or different function. Their work also focused on databases of populations with and without genetic disease. Their current work reflects the importance of diversity and inclusion as work continues to reveal causes of genetic diseases.

This work was supported in part by the U.S. National Human Genome Research Institute /National Heart Lung and Blood Institute grant number UM1HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG), the U.S. National Human Genome Research Institute U01HG011758 to the Baylor College of Medicine for the Genomics Research to Elucidate the Genetics of Rare Disease consortium (BCM-GREGoR), the National Institute of Neurological Disorders and Stroke Q22 (NINDS) R35NS105078, and the National Human Genome Research Institute U54-HG003273. J.E.P. was supported by NHGRI K08 HG008986.

Other authors who contributed to the study include: Francisco C. Ceballos, Ender Karaca, Yavuz Bayram, Tadahiro Mitani, Tomasz Gambin, Tugce Bozkurt-Yozgatli, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Lewis, Pengfei Liu, Eric Boerwinkle, Ada Hamosh, Richard A. Gibbs, V. Reid Sutton, Nara Sobreira, Claudia M.B. Carvalho, Chad A. Shaw, Jennifer E. Posey, David Valle. They are affiliated with the Department of Molecular and Human Genetics, Baylor College of Medicine; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute; Instituto de Salud Carlos III, National Center of Microbiology, Madrid, Spain; Section of Neurology, Department of Pediatrics, Baylor College of Medicine; Sanford Medical Genetics Laboratory, Sanford Imagenetics; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Childrens Hospital of Philadelphia; Perelman School of Medicine, University of Pennsylvania; Institute of Computer Science, Warsaw University of Technology; Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; Human Genome Sequencing Center, Baylor College of Medicine; Department of Pediatrics, Baylor College of Medicine; Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine; Texas Childrens Hospital; Pacific Northwest Research Institute; Baylor Genetics. To view list, along with author contributions, conflicts of interest and ethics declarations, clickhere.

By Graciela Gutierrez

Follow From the Labs on X @BCMFromtheLabs and Instagram!

See more here:
The genomic architecture of inherited DNA variants - Baylor College of Medicine | BCM

Genetics

Genetic Analysis Guides Conservation of Endangered Bumble Bee – Entomology Today

The rusty patched bumble bee (Bombus affinis), shown here in Cherokee Regional Park in St. Paul, Minnesota, is one of nine bee species listed as endangered by the U.S. Fish and Wildlife Service, and the species only remains in a small proportion of its original range. A research team led by John Mola, Ph.D., at Colorado State University sampled rusty patched bumble bees throughout their range and examined the allele frequencies in their genomes. They found that the species occurs in three distinct clusters in the midwestern U.S., that these clusters are genetically differentiated, and that they have small population sizes. They conclude that the remaining colonies are fragile and that entomologists should be cautious about management procedures that could be disruptive to colony health. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

By John P. Roche, Ph.D.

Numerous bee species are declining in the U.S. due to pesticides, pathogens, habitat loss, and climate change. Bees are important because they pollinate 80 percent of flowering plants, including $15 billion worth of agricultural products in the U.S. each year. Genetic factors have strong effects on the viability of bee populations, so bee conservation can be strengthened by data on population genetics.

John Mola, Ph.D., assistant professor of forest and rangeland stewardship at Colorado State University, and colleagues have studied the population genetics of rusty patched bumble bees (Bombus affinis) with the goal of informing management efforts for this endangered species. They report their findings in a study published last week in the Journal of Insect Science.

Rusty patched bumble bees used to be widespread in the northeastern and midwestern U.S., but they are now gone from 7090 percent of their historical range. They are one of nine bee species classified as endangered by the U.S. Fish and Wildlife Service (USFWS).

Mola and colleagues pursued two main questions in their study: One, what is the broad population structure of rusty patched bumble bees? And, two, what are patterns of population genetic diversity and differentiation across the range of the species? The team included researchers from Colorado State University, the University of Minnesota, the University of Wisconsin, the Minnesota Zoo, the USFWS, Ohio State University, the Wisconsin Department of Natural Resources, and the USDA Agricultural Research Service, as well as two independent ecological research consultants. (For more about the project, see Rusty-patched bumblebees struggle for survival found in its genes, from the CSU Warner College of Natural Resources.)

To examine the genetic makeup of the rusty patched bumble bee populations, in 2020 and 2021 the team collected samples from the final leg segment (or tarsus) of sampled bees. They collected a total of 498 bee samples, of which, after selecting for samples that met certain screening criteria, they had 470 samples to use in the study. They extracted DNA from the samples and amplified the DNA using polymerase chain reaction (PCR). They focused on sections of DNA with repeating sequences of base pairs called microsatellite markers to examine genetic differentiation across the species range. With these genetic data, the team calculated, for each population, the genetic diversity of the samples, the degree to which individuals in populations had different alleles at the same locus (called heterozygosity), the degree of inbreeding, and the proportion of males that were diploid (males that carried two sets of DNA instead of one). Bees have a haplodiploid reproduction system in which females queens and workers are diploid (having two sets of chromosomes) and reproductive drone males are normally haploid (having one set of chromosomes).

The rusty patched bumble bee (Bombus affinis), one of nine endangered bee species in the U.S., occurs in three genetically distinct clusters in the Midwest and Appalachia, a new study shows. But low levels of genetic diversity between colonies and other underlying genetic factors suggest their populations remain fragile, researchers say. Here, study coauthor Michelle Boone, Ph.D., a graduate student at the University of Minnesota during the study and now a project manager for the U.S. National Park Service Inventory and Monitoring Division, takes genetic samples from a rusty patched bumble bee. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

The rusty patched bumble bee (Bombus affinis), one of nine endangered bee species in the U.S., occurs in three genetically distinct clusters in the Midwest and Appalachia, a new study shows. But low levels of genetic diversity between colonies and other underlying genetic factors suggest their populations remain fragile, researchers say. Here, study coauthor Michelle Boone, Ph.D., a graduate student at the University of Minnesota during the study and now a project manager for the U.S. National Park Service Inventory and Monitoring Division, takes genetic samples from a rusty patched bumble bee. (Photo courtesy of Tamara Smith, U.S. Fish and Wildlife Service)

Mola and colleagues found support for the presence of three distinct genetic clusters of rusty patched bumble bees in the U.S.: a northwestern cluster in Minnesota; a large central cluster in Wisconsin, Illinois, and Iowa; and an Appalachian cluster in West Virginia and Virginia. The clusters were isolated geographically and had small population sizes. The investigators found differences in allelic richness and in the degree of inbreeding among clusters. These clusters were found to be genetically differentiated, but it is not yet known if this differentiation was caused by the decrease in numbers in these populations or if it existed prior to the population decline.

The researchers also observed that, of 115 males sampled, 18 (~15 percent) were diploid. The presence of diploid males in bumble bee colonies suggests inbreeding. The presence of diploid males is unhealthy for bee colonies because bee populations depend on haploid males for reproduction.

The amount of genetic differentiation among the three clusters, as determined by a measure of genetic variation called the pairwise fixation index, was fairly low. This suggests that there may still be considerable gene flow among the subpopulations.

Population problems in Bombus affinis observed in the study include the presence of inbreeding and low levels of heterozygosity. Also, rusty patched bumble bee populations are so small that random environmental or genetic fluctuations could lead to local extinction of remaining colonies.

The results of this study advance our knowledge of the population genetics of rusty patched bumble bee populations. But determining the degree and significance of population size and genetic variability in a bumble bee population is complex.

One cannot just simply count the number of individuals and be confident that means there is a large and robust population, Mola says. Instead, we can use the term genetic health to suggest that the underlying genetics of the population are either in line, or not, with a population that is resilient to processes causing random perturbations. In our study, we find that the low number of genetically distinct colonies we observeas opposed to counts of individual workersand the levels of male diploidy we observei.e., inbreedingsuggest that even though counts of individual workers at a site may be high, the underlying genetics suggest those populations may be at risk.

Genetic information can help wildlife managers identify genetics-based management units in nature, help them evaluate the risk/benefit ratios of performing introductions of bees to endangered populations, and help them design optimal interventions within the limits of their budgets. Management activities aimed at bolstering declining bee populations include reintroducing individuals of a species to locales where the species formerly lived and introducing captive-reared males or females to threatened populations.

Mola and colleagues suggest that the three separate clusters of Bombus affinis may have different management needs and that entomologists should be careful about activities that could disrupt the fragile remaining colonies, including moving males or females among populations. One potential management measure they do suggest is increasing the connectivity of habitats to increase gene flow among populations.

There are limitations in being able to compare across different bumble bee studies. Different studies can collect samples in different manners, can select different genetic loci for comparison, and can score alleles in different ways, all of which make comparisons difficult. But advances in the field depend on cooperation across multiple research groups and organizations. Doing this type of work inherently requires collaboration among a large team, Mola says. The species is not necessarily easy to find, and not everyone has the appropriate training and permits to take genetic material, so no one team can do a large-scale study on their own. So, continuing the culture of data sharing, generosity, and collegiality that currently characterizes the bee-conservation community is extremely important for the success of future research and conservation efforts.

Next research steps that the team suggests include collecting comparative data on the proportion of diploid males in populations that are declining versus populations that are stable. They also suggest collecting data on similar bumble bee species that live in similar habitats.

Summing up their findings, Mola says, The results suggest that even in some of the locations that we might think of as current-day strongholds for the species, it still has a much lower number of genetically distinct colonies compared to other stable species. So, we cannot rest easy, even in these areas where we see the species year-to-year with reliability.

The decline of the rusty patched bumble bee has been precipitous. But some signs are encouraging, including considerable apparent gene flow among populations. With ongoing research and carefully planned management, we can hope that populations of the species can become more genetically robustand eventually more abundant.

John P. Roche, Ph.D., is an author, biologist, and science writer with a Ph.D. and postdoctoral fellowship in the biological sciences and a dedication to making rigorous science clear and accessible. He authors books and articles, and prepares materials for universities, scientific societies, and publishers. Professional experience includes serving as a scientist and scientific writer at Indiana University, Boston College, and the UMass Chan Medical School; serving as a visiting professor at four tier-one schools; and developing concept-based science curricula for universities and publishers.

Continue reading here:
Genetic Analysis Guides Conservation of Endangered Bumble Bee - Entomology Today

Genetics

Otago University Discovers Cause of Rare Genetic Condition – Mirage News

An international team of researchers has discovered what causes an unusual and incredibly rare genetic condition, giving hope to the families with it and others with related disorders.

Led by the University of Otago, with academics from across the USA, South Africa, UK and Europe, the study focused on the role of glutamine in brain development.

By analysing the effects genetic variants had on brain cells, they found the cause of a new rare condition Glutamine Synthetase Stabilization Disorder which causes seizures and delayed development. They have just published their findings in prestigious international journal The American Journal of Human Genetics.

Amy Jones

Lead author Amy Jones, PhD candidate in Otago's Dunedin School of Medicine, says the work started with one child with the condition.

"From there eight other individuals from around the world with disrupted brain development and severe epilepsy had their DNA sequenced and causative genetic variants were found. These variants were all positioned at the start of the same gene, prompting us to ask why," she says.

Molecular experiments revealed the genetic variants had the effect of producing a stabilised enzyme that produces the small molecule glutamine in an unregulated fashion.

"Typically, genetic disorders result from genetic variants that disable a gene, so it was surprising that in this case there was an increase in stability of the enzyme. In some ways these variants can be thought to be taking the handbrake off the enzyme and letting it free wheel in an unregulated fashion.

"This tells us that the production of glutamine needs to be maintained within a very tight specific range during brain development both too much and too little damages the developing brain," she says.

Senior author Professor Stephen Roberston, Cure Kids Professor of Paediatric Genetics, describes the study as "an excellent example of finely tuned precision medicine".

"All of these children were previously treated according to their symptoms rather than from an understanding of the cause of their condition.

"There are thousands of similar rare disorders, collectively affecting eight per cent of the general population and many of them are genetic. Defining their causes is the first logical step to formulating treatments specific to them to enable more effective management of the disorders," he says.

Ms Jones says it is important new disorders are discovered and understood.

"Not only does such research provide answers for the individuals and families who participated in this work but also enables the recognition and diagnosis of the same condition in the future.

"This work on a rare disorder also contributes to the collective knowledge of critical components of healthy brain development."

She hopes the findings will enable other individuals who fit the clinical profile, but don't have a diagnosis, to be tested for this disorder.

"It is very likely there are individuals with this disorder that aren't yet diagnosed."

Publication:

Clustered de novo Start-Loss Variants in GLUL Result in a Developmental and Epileptic Encephalopathy via Stabilization of Glutamine Synthetase

Amy G Jones, Matilde Aquilino, Rory J Tinker, Laura Duncan, Zandra Jenkins, Gemma L Carvill, Stephanie J DeWard, Dorothy K Grange, MJ Hajianpour,Benjamin J Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I Esterhuizen, Tilman Polster, Alice Spano, Ins Gmez-Lozano, Abhishek Kumar, Gemma Poke, John A Phillips III, Hunter R Underhill, Gregory Gimenez, Takashi Namba, and Stephen P Robertson

American Journal of Human Genetics

Read the original here:
Otago University Discovers Cause of Rare Genetic Condition - Mirage News

Genetics

First insights into the genetic bottleneck characterizing early sheep husbandry in the Neolithic period – EurekAlert

image:

Excavation section in the settlement mound of Akl Hyk (Central Anatolia, Turkey). The numerous layers that formed during the millennia of settlement at the site are clearly visible.

Credit: Nadja Pllath (SNSB-SPM)

Modern Eurasian sheep predominantly belong to only two so-called genetic matrilineages inherited through the ewes. Previous research thereby assumed that genetic diversity must already have decreased rapidly in the early stages of domestication of wild sheep. Our study of a series of complete mitogenomes from the early domestication site Askl Hyk in central Anatolia, which was inhabited between 10,300 and 9,300 years ago, disproves this assumption: despite a millennium of human interference with the keeping and breeding of sheep, mitogenomic diversity remained invariably high, with five matrilineages being evidenced including one previously unknown lineage. The persistently high diversity of matrilineages observed during the 1,000 years of sheep farming was unexpected for the researchers.

"In Akl Hyk, there were both sheep raised in captivity and wild sheep hunted by the inhabitants of the site. We assume that occasionally managed flocks were supplemented by native wild sheep when necessary, e.g. to compensate for losses due to disease or stress in captivity. One should also consider that people exchanged sheep over wider areas. A possible parallel to such practice can be found in the import of cereal crops to Central Anatolia, which are native to Southeast Anatolia," says Prof. Peters, interpreting the results of the study.

The different matrilineages or haplogroups are similar to the branches of a family tree. Individuals belonging to a particular lineage show comparably little variation in their mitochondrial genomes, because descending from a common female ancestor. Today, haplogroup B predominates among sheep in Europe and haplogroup A in East Asia. Consequently, mitogenomic diversity decreased later in the domestication process or at the time when sheep farming spread beyond the original domestication region during the Neolithic, a question that had so far remained unanswered.

To address this question, the international team of researchers led by Prof. Joris Peters, State Collection of Palaeoanatomy Munich (SNSB-SPM), Prof. Ivica Medugorac, Population Genomics of Animals, LMU Munich, and Prof. Dan Bradley, Smurfit Institute for Genetics, Trinity College Dublin, investigated matrilineal affiliation and phylogenetic relationships of 629 modern and ancient sheep across Eurasia.

Comparison of Akl Hyk's results with ancient DNA signatures in archaeological sheep bones from later settlements in Anatolia and surrounding regions as well as in Europe and Middle Asia clearly illustrates that mitogenomic diversity decreased significantly in the ninth millennium before present. One result of this is the aforementioned dominance of matrilineage B in Europe. "We can now assume that this development is due to a so-called "bottleneck" that took place later in the Neolithic period, when sheep farming spread beyond the natural distribution of wild sheep following the early domestication of the species. This bottleneck likely relates to so-called founder effects, in which smaller flocks were consecutively removed from an already greatly reduced sheep population in the course of the spread of small animal husbandry on the way to Europe," Peters continued.

"Particularly fascinating are the insights gained through the integration of genetic and archaeological datasets. Together with the numerous other mosaic pieces that zooarchaeologists, archaeologists and geneticists have collected over decades, an increasingly coherent picture of human cultural adaptations since the last Ice Age now emerges. Studies like these show that animal domestication is not to be understood in terms of a cross-generational plan, but rather as a process of chance and necessity that has significantly shaped our recent cultural history and accompanies us to this day," adds Prof. Ivica Medugorac.

Animals

Ancient mitogenomes from Pre-Pottery Neolithic Central Anatolia and the effects of a Late Neo-lithic bottleneck in sheep (Ovis aries).

12-Apr-2024

The authors declare that they have no competing interests.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Here is the original post:
First insights into the genetic bottleneck characterizing early sheep husbandry in the Neolithic period - EurekAlert

Cardiology

Impact of Interatrial Shunt May Vary by Heart Failure Type – Diagnostic and Interventional Cardiology

April 6, 2024 Patients with heart failure who had a small shunt inserted between the hearts left and right atria did not see any significant benefits overall compared with those who received a placebo procedure after a median of 22 months follow-up, in a study presented at the American College of Cardiologys Annual Scientific Session.

The trial, called RELIEVE-HF, is the first randomized placebo-procedure controlled trial of interatrial shunting that included patients with both major types of heart failure: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). While the trial did not meet its primary endpoint, it moves the field forward by offering signals that the benefits and risks of interatrial shunts may vary by heart failure type, according to researchers.

Gregg Stone, MD

When you examine the outcomes in patients with heart failure across a broad range of left ventricular ejection fraction, the Ventura interatrial shunt was extremely safe but did not improve outcomes compared with no treatment. However, in a prespecified analysis, data suggest that the shunt may be beneficial in patients with HFrEF and worsen outcomes in patients with HFpEF, said Gregg Stone, MD, professor of cardiology and population health sciences at Icahn School of Medicine at Mount Sinai in New York and the studys first author. We believe further studies are warranted to confirm the benefits we observed in patients with reduced ejection fraction.

Heart failure is a condition in which the heart becomes too weak or stiff to effectively pump blood, leading to fatigue, organ damage, shortness of breath and an increased risk of life-threatening cardiovascular events. In HFrEF, the heart muscle becomes weak and does not squeeze as hard as it should. In HFpEF, the left ventricle becomes stiff and does not properly fill with blood.

The Ventura shunt is one of several interatrial devices being tested to aid in the treatment of heart failure. It is designed to form a small connection or passage between the left and right atria to allow blood to leave the left atriumespecially as left atrial pressure risesthus reducing the pressure in the left atrium and the lungs. High left atrial pressure is a primary cause of shortness of breath and hospitalizations related to heart failure.

The trial randomized 508 patients at 94 sites in North America, Europe, Israel, Australia and New Zealand. All participants had symptomatic heart failure despite taking medications at maximally tolerated doses. About 40% of participants had HFrEF and 60% had HFpEF.

Participants were randomly assigned to undergo a procedure to insert the Ventura shunt or a placebo procedure in which a script was followed with all the same protocols to mask patients as to whether the shunt was inserted. Operators were aware of which procedure each patient received but patients, their families and the rest of the medical teams taking care of the patient after the procedure were not. Researchers tracked outcomes in each participant for at least one year and up to two years.

The results showed no significant difference between groups in terms of the trials primary endpoint, a hierarchical composite ranking of death from any cause; heart transplant or left ventricular assist device; heart failure hospitalizations; worsening of outpatient heart failure events; and change in quality of life, as measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ). This hierarchical composite approach for assessing efficacy allows diverse types of outcomes to be incorporated in ranked fashion into an overall win ratio reflecting the overall outcome of a drug or device.

In a pre-planned analysis focused on heart failure type, patients with HFrEF who received the shunt were found to have improvements across all outcomes assessed (especially fewer hospitalizations for heart failure), while those with HFpEF who received the shunt were found to have increased rates of death and heart failure hospitalizations. This difference could be attributed to the greater compliance or flexibility of the heart muscle with HFrEF, potentially allowing it to more easily accommodate the extra blood flowing into the right atrium, Stone said.

There were no device-related or procedure-related major adverse cardiovascular or neurologic events in either group during the duration of the trial.

Surprisingly, a marked improvement in quality of life as measured with KCCQ was observed across all groupsincluding those who received a placebo procedure, both with HFrEF and HFpEFsuggesting that the metric may not be a reliable indicator for quality-of-life outcomes in this context, Stone said.

There was a tremendous placebo effect, he said. These observations, especially the fact that quality of life improved in HFpEF patients who were more likely to be hospitalized for heart failure and had reduced survival after shunt treatment, raise questions about the interpretation of this quality-of-life measure in these kinds of trials.

Although the observed differences in outcomes among people with different types of heart failure may inform future research and development for interatrial devices, the researchers said that the trial was not powered to show differences in the two types of heart failure. As such, these results should be considered exploratory. They also said that the results may not be applicable to other interatrial shunts beyond the Ventura shunt.

The study was funded by V-Wave Medical.

For more information: http://www.acc.org

Find more ACC24 conference coverage here

Visit link:

Impact of Interatrial Shunt May Vary by Heart Failure Type - Diagnostic and Interventional Cardiology

Cardiology

Association of Black Cardiologists’ "We Are The Faces" Campaign Unveils New Videos for Black Maternal Health Week – PR Newswire

WASHINGTON, April 6, 2024 /PRNewswire/ -- In celebration of Black Maternal Health Week (April 11-17, 2024) and April's Minority Health Month, the Association of Black Cardiologists (ABC) is proud to unveil a new slate of videos as part of its third year of the "We Are The Faces of Black Maternal Health" awareness and advocacy campaign.

This new collection of videos features excerpts from powerful patient narratives interwoven with insights from leading ABC member clinicians across diverse specialties. This series amplifies the intergenerational impact of the Black maternal health crisis and underscores the critical role of healthcare professionals in addressing racial disparities in maternal health outcomes.

Recent findings continue to show that Black women are disproportionately impacted by maternal morbidity and mortality. These disparities extend to other women of color as well, highlighting the need for comprehensive action to ensure equitable access to quality care for all.

"Decades of headlines emphasize the urgent need for a multi-faceted approach that addresses the systemic and institutional factors exacerbating the disparity gap in Black maternal and cardiovascular health," states ABC President Dr. Anekwe Onwuanyi. "ABC remains committed to raising awareness, fostering collaboration and finding solutions to advance the health and wellbeing of Black women and their families."

ABC members are uniquely positioned to address the maternal health crisis, given the intersection of maternal health and cardiovascular well-being. Standing at the "crossroads" of being patients, relatives of patients, healthcare professionals treating these patients, or all of the aforementioned, gives them a distinct perspective and opportunity to drive meaningful change on this issue.

"It is so important to recognize that we all have a role to play in mitigating this epidemic that negatively affects the Black family," said Rachel M. Bond, MD, Co-chair of the Cardiovascular Disease in Women and Children Committee for ABC. "An essential aspect of the campaign draws attention to the vital role Black men play - whether as spouses or relatives - in their support of Black women by advocating to ensure the mother's concerns are heard and addressed, but this support also includes prioritizing their own cardiovascular health before, during, and after the pregnancy."

"As a pediatric cardiologist, I recognize the profound impact of maternal health on the well-being of families, especially Black families" states Annette K. Ansong, MD, Co-Chair of the Cardiovascular Disease in Women and Children Committee for ABC. "We must work collaboratively with our colleagues in primary care, obstetrics, and cardiology to advocate for integrated strategies that prioritize the health of mothers and babies. After all, Black women are first Black girlsTM, and by promoting heart-healthy habits from childhood, we can help pave the way for healthier pregnancies."

Individuals are invited to visit WeAreTheFaces.ABCardio.org to watch the videos, download patient and clinician infographic resources, share their stories, and learn more about maternal health disparities. Together, we can effect tangible change and rewrite the narrative on Black maternal health.

About ABC

Founded in 1974, the Association of Black Cardiologists, Inc. (ABC) is a nonprofit with a global membership exceeding 2,000 individuals, including health professionals, community health advocates, and corporate and institutional members. The ABC remains dedicated to its mission of promoting heart health and wellness in minority communities. Today, by fostering public and private partnerships and advocating for equitable access to care, ABC continues to make strides in improving cardiovascular outcomes for all. Connect with us atwww.abcardio.org and join our efforts on Twitter,Facebook,Instagram, andLinkedIn.

SOURCE Association of Black Cardiologists, Inc.

View original post here:

Association of Black Cardiologists' "We Are The Faces" Campaign Unveils New Videos for Black Maternal Health Week - PR Newswire

Cardiology

No Reduction in 90-Day Deaths, Heart Attacks With Human Apo/A1, A Building Block of HDL Cholesterol – Diagnostic and Interventional Cardiology

April 6, 2024 The first trial of a novel strategy for removing cholesterol from patients arteries did not reduce the risk of death, heart attack or stroke within three months of a prior heart attack, according to research presented at the American College of Cardiologys Annual Scientific Session. However, the findings suggest that the strategy may be beneficial with longer follow-up.

C. Michael Gibson, MD

We did not see a statistically significant reduction in the primary endpoint of risk for death, a heart attack or a stroke at 90 days, or a reduction in risk for stroke at any time, said C. Michael Gibson, MD, a professor of medicine at Harvard Medical School and the studys lead author. However, in an exploratory analysis of outcomes, treated patients had fewer heart attacks and heart-attack deaths than patients in the control group at six months, he said.

Although we missed our primary endpoint, our data support the hypothesis that HDL cholesterol plays a role in reducing subsequent coronary plaque disruption events like heart attack via enhanced cholesterol efflux attacks, Gibson said.

People who have had a heart attack are at high risk for another one, especially during the next 90 days, Gibson said. This study was the first in which patients received an infusion of ApoA-I, a component of HDL (good) cholesterol, shortly after a heart attack, with the aim of stabilizing coronary plaque and reducing adverse cardiovascular events. The investigational drug CSL112 used in the study is a form of ApoA-I thats extracted from human plasma, the liquid component of blood.

High levels of LDL cholesterol create a build-up of plaque in the arteries that carry blood to the heart, increasing risk for an arterial blockage that causes a heart attack. HDL cholesterol removes cholesterol from the arteries and carries it to the liver, which then excretes it. ApoA-I, the main component of HDL cholesterol, helps initiate the process of removing cholesterol from the body. A previous study showed that a single infusion of CSL112 reduced the amount of LDL cholesterol in arterial plaque by as much as 50%.

Other studies have shown that high levels of HDL cholesterol are associated with reduced heart attack risk. Recent research, however, suggests that the level of HDL cholesterol number may be less important for reducing heart attack risk than how well it performs at removing cholesterol, Gibson said.

We know that in the setting of a heart attack, when the HDL cholesterol is good at getting a lot of cholesterol out of the arteries, that results in better outcomes for patients, he said.

Gibson and his colleagues hypothesized that infusions of CSL112 given shortly after a heart attack mightby boosting the bodys ability to dispose of cholesterolreduce patients risk for a repeat heart attack during the next crucial 90 days. The international AEGIS-II trial, conducted in 49 countries, was designed to test this hypothesis.

The study enrolled 18,219 patients (median age 65.5 years, 74% men and 84.5% White) who had been hospitalized for a heart attack and had multiple blockages in arteries carrying blood to the heart that elevated their risk for another heart attack. They also had other risk factors, including having had a previous heart attack, receiving drug treatment for diabetes or being 65 or older. Patients were randomly assigned to receive infusions of either CSL112 or a placebo for four weeks, with the first infusion given within five days of hospitalization.

The studys primary endpoint was the time to the first occurrence of a major adverse cardiovascular event (MACE; i.e., heart attack, stroke or death due to heart disease or a stroke) at 90 days. Secondary endpoints included the time to the first occurrence of a MACE within six months and one year and of each specific event within 90 days, six months and one year.

At 90 days, patients treated with CSL112 had a 4.8% reduction in risk for death, heart attack or stroke compared with 5.2% for those treated with a placebo, a difference that was not statistically significant. In an exploratory analysis, however, patients treated with CSL112 were 14% less likely to have or die from a heart attack at 180 days. In addition, patients treated with CSL112 were 32% less likely to have a heart attack caused by a blood clot in a stent (a tiny mesh tube inserted into an artery to prevent it from becoming blocked) at 90 days and 29% less likely at 180 days.

Another potentially important finding, Gibson said, is that patients whose LDL cholesterol level was 100 mg/dL or higher at study entry experienced a 30% decrease in the primary endpoint, a statistically significant finding, whereas patients whose LDL cholesterol at study entry was less than 100 mg/dL saw no decrease in the primary endpoint.

Baseline LDL modulated the treatment effect, Gibson said.

Overall, our findings are consistent with ApoA-I having a role in stabilizing heart blockages and reducing the risk of a blockage that ruptures and causing a heart attack further out than 90 days, Gibson said. Its plausible that by giving ApoA-1 to clear the cholesterol out of the body and then treating the patient with cholesterol-lowering medications to keep LDL cholesterol levels low, we could see reductions in deaths and heart attacks that continue over time.

Future research will focus on identifying high-risk patients who might benefit from this approach, he said. An antiplatelet effect of CSL112 or a reduction of cholesterol in the arteries resulting from treatment with CSL112 could also explain the significant reduction in the number of heart attacks caused by a blood clot in a stent, he said. The reason strokes were not reduced may be that strokes can be caused by mechanisms other than the rupture of arterial blockages, he said.

A limitation of the study is that women, Black people and people of Asian heritage were underrepresented, which could reduce the findings generalizability, Gibson said.

The study was funded by CSL Behring, the manufacturer of CSL112

This study was simultaneously published online in the New England Journal of Medicine at the time of presentation. The findings of the exploratory analysis were/will be published in the Journal of the American College of Cardiology, JACC.

Gibson presented the study, Patients With Acute Myocardial Infarction (ApoA-I Event Reducing In Ischemic Syndromes II (AEGIS-II) Trial): Primary Trial Results, on Saturday, April 6, the first day of the ACC Scientific Session being held thru April 8 in Atlanta, GA.

For more information: http://www.acc.org

Find more ACC24 conference coverage here

See the rest here:

No Reduction in 90-Day Deaths, Heart Attacks With Human Apo/A1, A Building Block of HDL Cholesterol - Diagnostic and Interventional Cardiology