Category Archives: Human Genetics

Today, sea cows are only found in tropical waters. Credit: Colourbox

Giants of the Ice Age: International research team on molecular trail.

The giant sea cow from the Ice Age was discovered in 1741 by Georg Wilhelm Steller and later named after him. The 18th-century naturalist was interested not only in the enormous size of this animal species but also in its unusual, bark-like skin. He described it as a skin so thick that it is more like the bark of old oaks than the skin of an animal.

Such a bark-like structure of the epidermis is not found in related sirenians, which today live exclusively in tropical waters. In scientific circles, it was previously assumed that the bark-like epidermis was the result of parasite feeding, but also insulated heat and thus protected the sea cow well from the cold during the Ice Age and from injuries in the polar seas.

In the current study, the scientists led by Dr. Diana Le Duc and Professor Torsten Schneberg from Leipzig University, Professor Michael Hofreiter from the University of Potsdam, and Professor Beth Shapiro from the University of California, show that the paleogenomes of Stellers sea cow reveal functional changes. These changes were responsible for the bark-like skin and the adaptation to cold.

To find this out, an international research team from Germany and the US reconstructed the genome of this extinct species from fossil bone remains of a total of twelve different individuals. The most spectacular result of our investigations is that we have clarified why this giant of the sea had bark-like skin, said Diana Le Duc from the Institute of Human Genetics at Leipzig University Hospital. The scientists found inactivations of genes in the sea cow genome that are necessary for the normal structure of the outermost layer of the epidermis. These genes are also used in human skin.

Hereditary defects in these so-called lipoxygenase genes lead to what is known as ichthyosis in humans. This is characterized by a thickening and hardening of the top layer of skin with large scales, and is sometimes also known as fish scale disease, said Schneberg from the Rudolph Schnheimer Institute of Biochemistry. The results of our research thus also sharpen our view of this clinical picture, explained the biochemist, adding: Here may lie the key to new therapeutic approaches.

The scientists pinpointed the genetic defect by comparing the genome with that of the closest relative, the dugong. The researchers received support with their investigations from the Max Planck Institute for Evolutionary Anthropology in Leipzig, which contributed its bioinformatics expertise in the analysis of ancient DNA. As a result, they identified important evidence of genetic changes that may have contributed to adaptation to the cool North Pacific habitat.

This is an impressive example of how gene defects can not only cause disease, but also have advantages depending on the habitat, said Hofreiter from the University of Potsdam. Furthermore, the genome data revealed a dramatic reduction in population size. This began 500,000 years before the species was discovered and may have contributed to its extinction. Hofreiter summed it up as follows: With todays molecular genetic clarification, our study closes the circle of an exact observation by a German naturalist in the early 18th century.

Background

Georg Wilhelm Steller (17091746) studied medicine and the natural sciences in Leipzig, Jena and Halle and took part in the legendary expedition by Danish captain Vitus Bering to Alaska in 1741. Bering, after whom todays Bering Strait was named, and many of the ships crew died during this expedition. Steller survived and was the first and only explorer ever to see and scientifically describe one of these gigantic sea cows alive. The related sea cows (sirenians) that exist today manatees and dugongs are found exclusively in tropical waters. They grow to a maximum length of three meters, less than half the body length of their ice-age ancestors. Of the former population of Stellers sea cow of around 100,000 animals in the 18th century, only bones can be found today on the coasts of Bering Strait islands. Georg Steller first described the sea cow from the Ice Age in 1741. His landmark work was completed by his secretary on the basis of his manuscript and academic tributes. It was published in 1753, a few years after Stellers death. He died on his return journey from eastern Siberia to St Petersburg.

Reference: Genomic basis for skin phenotype and cold adaptation in the extinct Stellers sea cow by Diana Le Duc, Akhil Velluva, Molly Cassatt-Johnstone, Remi-Andre Olsen, Sina Baleka, Chen-Ching Lin, Johannes R. Lemke, John R. Southon, Alexander Burdin, Ming-Shan Wang, Sonja Grunewald, Wilfried Rosendahl, Ulrich Joger, Sereina Rutschmann, Thomas B. Hildebrandt, Guido Fritsch, James A. Estes, Janet Kelso, Love Daln, Michael Hofreiter, Beth Shapiro and Torsten Schneberg, 4 February 2022, Science Advances.DOI: 10.1126/sciadv.abl6496

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Giants of the Ice Age: Genome of Stellers Sea Cow Decoded - SciTechDaily

CAMBRIDGE, Mass., Feb. 14, 2022 /PRNewswire/ --InsideTracker, the leading truly personalized performance and nutrition system, today announced the addition of Dr. Ali Torkamani, who currently serves as director of genome informatics for Scripps Research Translational Institute's Department of Integrative Structural and Computational Biology, to its scientific advisory board.

Torkamani's research career has covered a broad range of areas centered on the use of genomic technologies to uncover the genetic causes and underlying mechanisms of disease and identify precision therapies. His major focus areas include human genome interpretation and genetic dissection of novel rare diseases, predictive genomic signatures of response to therapy and novel sequencing-based assays as biomarkers of disease.

In his role on the InsideTracker scientific advisory board, he will advise the company on new genetic approaches, developing advanced genetics scores and utilizing Mendelian randomization techniques on InsideTracker's growing database of biometric data from well people thought to be the largest in the world.

"Ali brings a wealth of expertise in genomics and bioinformatics to our scientific advisory board, which is vital to the research and development of our personalized health and wellness product," said Dr. Gil Blander, chief scientific officer and co-founder, InsideTracker. "As InsideTracker pursues our mission of creating the ultimate human optimization platform, we look forward to his guidance on further predicting which interventions will have maximum value on an individual level."

"The human body offers an incredibly complex network of genomic, physiological and biological data that can be applied not just to reverse disease, but to improve healthspan," said Torkamani. "InsideTracker unites this information, decodes it and offers everyday people unprecedented insight into their inner health, and I'm excited to apply my expertise in making personalized analysis and effective interventions more broadly available."

As a member of the InsideTracker scientific advisory board, Torkamani joins notable academics and subject-matter experts that include Dr. David Sinclair, Dr. David Katz, Dr. Jeffrey Blumberg, Dr. Lenny Guarante and Dr. Roger Fielding.

About InsideTrackerFounded in 2009 by top scientists from acclaimed universities in the fields of aging, genetics and biology, InsideTracker is a truly personalized nutrition and performance system. InsideTracker's mission is to help people add years to their lives and life to their years by optimizing their bodies from the inside out. By analyzing the body's data from blood, DNA and fitness trackers, InsideTracker gives a crystal clear picture of what's going on inside, along with a science-backed action plan for improving your health and becoming your best self. Read our peer-reviewed papers inScientific Reportsand Current Developments in Nutrition.

Follow InsideTracker on Instagram, Twitterand Facebook.

Media Contact:Heather Hawkins [emailprotected] (415) 598-8662

SOURCE InsideTracker

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InsideTracker Grows Genomics, Bioinformatics Expertise on Scientific Advisory Board with Appointment of Ali Torkamani, PhD - PRNewswire

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With its generally high-quality online content, Khan Academy exercises a remarkable influence on what students and teachers alike learn about science and other subjects. Thats why I have devoted four posts to analyzing the outdated junk science in their video on Evidence for Evolution. After going through supposed lines of evidence fromembryos,homology, andfossil horses, the video ends by looking at biochemical similarities between organisms, presented as a suite of arguments for common ancestry.

Khan claims that How the DNA gets replicated and translated and transcribed is very similar from one life-form to another. Yet a2020 papernoted that the Origin of DNA replication is an enigma because the replicative DNA polymerases (DNAPs) are not homologous among the three domains of life, Bacteria, Archaea, and Eukarya. These differences are so great that one paper asked Did DNA replication evolve twice independently? The paper proposes that the modern-type system for double-stranded DNA replication likely evolved independently in the bacterial and archaeal / eukaryotic lineages. And while were discussing fundamental biomolecular similarities, anotherpapercompared the genomes of 1,000 different prokaryotic organisms and found that of the 1,000 genomes available, not a single protein is conserved across all genomes.

It is of course true that all life uses DNA and proteins. The video argues that this universal similarity across life hints at a common ancestry. True, universal common ancestry is one possible explanation for such biochemical similarities but are there others that go unmentioned by Khan? As we saw withhomology in vertebrate limbs, its key to appreciate functional requirements. Last year Emily Reevesexplainedthat many properties of the amino acids used in life appear optimal for our biochemical needs. So, there are good functional reasons why all life should use these same molecules.

Moreover, because all life-forms use DNA (which contains nucleotides) and proteins (made of amino acids), we are able to gain nutrients we need amino acids and nucleotide bases from the plants, animals, and other organisms that we eat. The fact that all life uses the same basic building blocks is precisely what makes the food web possible! These universally shared similarities might indicate the design of the ecosystem, not common ancestry.

Once we appreciate that there are good functional reasons for life re-using the same basic molecules (e.g., DNA, proteins), common design becomes an alternative explanation. Intelligent agents frequently re-use the same types of parts in different designs to meet functional requirements. Think of how both cars and airplanes use wheels, or how different versions of Microsoft Windows re-use key computer codes. As Paul Nelson and Jonathan Wells observe in the bookDarwinism, Design, and Public Education:

An intelligent cause may reuse or redeploy the same module in different systems, without there necessarily being any material or physical connection between those systems. Even more simply, intelligent causes can generate identical patterns independently. If we suppose that an intelligent designer constructed organisms using a common set of polyfunctional genetic modules just as human designers, for instance, may employ the same transistor or capacitor in a car radio or a computer, devices that are not homologous as artifacts then we can explain why we find the same genes expressed in the development of what are very different organisms.

The Khan Academy video never considers this possibility, but again, common design the intentional re-use of a common blueprint or components is a viable explanation for the widespread functional similarities among the biomolecules found in different types of organisms.

The video then compares humans and chimps, saying that the latters behaviors and facial expressions are eerily human. I could say the same thing about the behavior of my family cat, Bonsai who is very intelligent and often seems able to read my mind and anticipate my behaviors. This doesnt necessarily mean were genetically related it means we were built with minds and mental outlooks that have important overlap. And the fact that our minds and behaviors have important overlap means that we can relate to one another quite well. In fact there are numerous examples of animals within species or across species being able to relate to one another. Just Google animal friend videos and make sure youve got an hour to kill! Heres my point: if the designer is a being that is into relationships, then designing species with mental and emotional similarities that foster inter- or intra-species deep emotional connections and friendships should not come as a surprise. No common ancestry needed.

But that overlap has significant limits. Just like chimpanzees, my cat doesnt use complex language, build complex tools, use fire, wear clothing, engage in abstract reasoning, do math, compose music, write poetry, ponder the mysteries of the universe, practice religion, or engage in any number of advanced cognitive or spiritual activities. (I would say that he doesnt engage in moral reasoning. However, I am pretty sure that he knows there are things I dont want him to do and he deliberately does those things, apparently for that very reason, like when he recently woke me up from a badly-needed nap by crying at my bedroom door. In any case, my cat definitely lacks an appreciation for morality as found in humans.) So, while some basic behaviors link all mammals, there are numerous higher behaviors found only in humans. Somehow these points get left out of the Khan Academy video.

The video then claims that humans and chimps are 98 percent genetically similar, saying their genes show just how close to human beings they actually are. That statistic is false: it overstates human-chimp genetic similarity, as I explained here last year; see, Human-Chimp Similarity: What Is It and What Does It Mean? At that post, I further explained that any given percent genetic similarity between two species does not necessarily imply an ancestral relationship since that similarity could be present for functional reasonsreflecting their common design.

The video closes by saying that the fact that we can measure how far things are away allows us to create a very accurate tree of life. This sounds like the claim I responded to from Richard Dawkins last year that genetics data allow us to create a perfect hierarchy a perfect family tree. Except when you dig into the technical literature you find out this isnt true at all. I also reviewed this evidence last year in response to Dawkins at Phylogenetic Conflict Is Common and the Hierarchy Is Far from Perfect. A very nice treatment of problems with the tree of life is given in Jonathan Wellss sequel to his bookIcons of Evolution,titledZombie Science: More Icons of Evolution. He summarizes there the many problems facing the tree-of-life hypothesis, including:

Perhaps Wellss most relevant point in rebuttal to Khan Academy comes when the video claims that we can easily determine percent genetic similarity between organisms. And then out pops a tree. Heres what Wells writes inZombie Science:

Since the rise of molecular biology in the mid-twentieth century, biologists have increasingly used comparisons of sequences in DNA, RNA and protein to construct phylogenetic trees. For example, a particular DNA sequence might be present in different species, though with minor variations. Comparing the sequence differences in species A, B, and C could lead to an inference that species A is more closely related (that is, more similar) to species B than it is to species C. The similarity between two sequences (often called homology) can be expressed as a percentage, representing how many subunits at corresponding positions are identical between them.

Similarity may be assumed to imply genealogy, but this is only an assumption. Any inference to genealogy based on sequence similarity is hypothetical. And since molecular sequences (with rare exceptions) are available only from living organisms, any inference about the evolutionary past of those organisms-including their ancestors-is even more hypothetical.

This is exactly right. As I haveexplained in the past, the basic logic behind building molecular trees is relatively simple. First, investigators choose a gene, or a suite of genes, found across multiple organisms. Next, those genes are analyzed to determine their nucleotide or amino acid sequences, so the gene sequences of various organisms can then be compared. Finally, an evolutionary tree is constructed based upon the principle that the more similar the nucleotide sequence, the more closely related the species.But the whole process is based upon theassumptionthat genetic similarities between different species necessarily result from common ancestry.But theres no need for that assumption. If the similarities being compared are functional similarities which is always the case when you are comparing gene sequences between organisms then those functional similarities could reflect common design rather than common descent.

The Khan Academy video opens by quoting Theodosius Dobzhansky who famously stated, Nothing in biology makes sense except in the light of evolution. Khan further says that the modern theory of evolution is about as strong as theories get. But when, to make the case for the theory, you have to resort to all these old, long-refuted icons of evolution, how strong is the evidence really? Its worth recalling Jonathan Wellss remarks at the end ofIcons of Evolution:

[T]he claim that nothing in biology makes sense except in the light of evolution is demonstrably false. The icons of evolution are a logical consequence of the dogma that nothing in biology makes sense except in the light of evolution. All the misleading claims we have examined in this book follow from the sort of thinking represented by Dobzhanskys profoundly anti-scientific starting-point. [S]cience at its best pursues the truth. Dobzhansky was dead wrong, and so are those who continue to chant his antiscientific mantra. To a true scientist, nothing in biology makes sense except in the light of evidence.

Wells is correct that when you start with Dobzhanskys dogmatic statement, you get bad science. You also get bad science education. Its very unfortunate that Khan Academy which is so good on so many other subjects is misinforming students about the evidence, or lack of it, for evolution.

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Khan Academy Video Misleads on Common Ancestry - Discovery Institute

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It has long been believed that dogs age seven times faster than humans, but a new study has busted the myth and wants to shed light on how our canine friends actually age.

The old adage would mean that a one-year-old dog is seven in human years. However, different breeds age at different rates, with large breeds ageing ten times quicker than humans and some small dogs can be half of that.

A major study called The Dog Ageing Project aims to examine the genomes of 10,000 dogs to see why super centenarian dogs that can live till the age of 20 survive for so long.

The researchers want to identify specific biomarkers of canine ageing and translate to apply their findings to human ageing.

Professor Joshua Akey, at Princeton University, said: This is a very large, ambitious, wildly interdisciplinary project that has the potential to be a powerful resource for the broader scientific community.

Personally, I find this project exciting because I think it will improve dog, and ultimately, human health.

Prof Akey said that that the study , believed to be the first of its kind, will produce one of the largest genetics data sets ever produced for dogs, which will help scientists understand how genetics impact ageing.

The research will also help answer more fundamental questions about the evolutionary history and domestication of dogs, he added.

The super-centenarian part of the study will compare the DNA of dogs that live for an exceptionally long time to those that live to the average age for their breed.

Dogs are one of the most genetically diverse species in the world and have been bred into a huge array of difference sizes, colours, and body types.

According to the RSPCA, the average lifespan of certain popular dog breeds can vary from 5.5 years for a Dogue de Bordeaux (also known as a French Mastiff) to 14.2 years for a miniature poodle.

The researchers from The Dog Ageing Project anticipate their findings will apply to human ageing because dogs experience almost the same functional decline and diseases of ageing that humans do.

Story continues

Veterinary care also has many parallels with human healthcare, and dogs share much of the same lived environment as humans, which is a major determinant of ageing and one that cannot be recreated in any lab setting.

Professor Daniel Promislow, from the University of Washington and the principal investigator of the study, said: Given that dogs share the human environment and have a sophisticated health care system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan.

The project has been outlined in the journal Nature.

Additional reporting by SWNS

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Researchers bust the seven-year dog myth - Yahoo! Voices

Some people don't get COVID despite being exposed to the virus a mystery researchers are trying to unravel.

Why it matters: Understanding the small cohort of "never COVID" people could lead to new vaccine targets or other protections as the world enters the third year of the pandemic.

Driving the news: Using a highly debated method called a human challenge study, a British trial deliberately exposed people who were unvaccinated and had no evidence of prior infection by placing a droplet of SARS-CoV-2 in their nose. They found 16 out of 34 participants did not get infected, according to the pre-print paper posted recently.

The latest: Researchers are now trying to zero in on that question.

1. Cross-immunity from the four endemic human coronaviruses is one hypothesis. Those other coronaviruses cause many of the colds people catch and could prime B-cell and T-cell response to this new coronavirus in some people.

2. Multiple genetic variations may make someone's immune system more or less susceptible to the virus.

3. Mucosal immunity may play an underrecognized role in mounting a defense.

4. Where the virus settled on the human body, how large the particle was, the amount and length of exposure, how good the ventilation was and other environmental circumstances may also play a role, Openshaw says.

The bottom line: Vaccination and boosters, wearing masks, washing hands and good ventilation remain our most important tools in preventing infection or mitigating symptoms, Brooks says.

Editor's note: This story originally published on Feb. 10.

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Unlocking the mystery of the "never COVID" cohort - Axios

What caused the 1918 Spanish flu to cease?

I get it Miranda. Sitting, as we are, in throes of a pandemic, our interest in outbreaks of bygone eras is naturally piqued. Everythings crazy; everything changes theres no pandemic handbook, right?

Or is there?

The swings and roundabouts of the COVID pandemic feel new and strange, but its not the first time humanity has stared down a deadly viral disease. Can past pandemics offer a blueprint as to how our current mess will play out?

The US Centre for Disease Control (CDC) certainly believes theres merit to this idea.

In 2005, the CDC recreated the Spanish flu virus safely contained within tightly controlled laboratories, of course. They hoped to sequence its genome and study its secrets in order to be better prepared for future pandemics.

The Spanish flu of 1918-19 has long stood out to virologists and epidemiologists as a stark warning that devastating viruses can spring seemingly from nowhere and wreak havoc across the globe. The Spanish flu killed as many as 50 million people worldwide over a period of approximately 18 months, with an unusually high death rate among otherwise healthy young people (1535-year-olds). Around 500 million people were infected almost a third of the global population at the time.

Its easy to see the merit in trying to understand the trajectory of a virus that hit hard a century ago but no longer poses any threat. perhaps well see our own path out of the dark COVID woods. What was it that made the 1918 virus so deadly? Where did it come from? And where did it go?

Todays pandemic is mapped and documented in minute detail. We track its waves across the globe in real time, and our understanding of its internal machinery is developing rapidly. But in 1918, the study of infectious pathogens was a new field. In the wake of Spanish flu, generations of researchers and public health experts had little more than estimated death tolls and social histories with which to build a picture of the pandemic.

How could scientists understand what happened when the biggest puzzle piece, the pathogen itself, was missing?

That conundrum was initially tackled by Swedish researcher Johan Hultin in 1951. Hed heard of a mass burial site in an Alaskan village called Brevig Mission. There, the interred bodies of at least 72 Spanish flu victims lay untouched in the permafrost. Hultin with permission from village elders set to work excavating frozen corpses, hoping to find tissue harbouring traces of the 1918 virus.

Hutins efforts failed, although not for want of trying on his flight from Alaska to research facilities at the University of Iowa he tried to keep lung samples frozen using carbon dioxide from a fire extinguisher. But the technology of the time didnt allow him to properly prepare and analyse the samples.

In 1997, nearly a half century after his first attempt, Hultin returned to Brevig Mission to give it another shot. Armed with his wifes garden shears and a handful of local assistants, Hultin dug the frozen burial grounds once more.

Tech advancements had allowed other researchers to partially sequence the viral genome of a lung sample from a US serviceman who died in 1918. Hultin reset his sights on obtaining the best possible tissue samples for these scientists to work with and this time his efforts paid off.

He unearthed and preserved the perfectly frozen lungs of an Inuit woman whod died of Spanish flu complications. Just days after the lungs reached the researchers, Hultin had the news: positive genetic material had been obtained from the frozen samples.

By 1999, and largely thanks to Hultins samples, the entire code of the 1918 flu was sequenced, laying the foundations for the ultimate goal reconstructing a live version of the lost virus.

The effort began in earnest in 2005.

Using a pioneering technique called reverse genetics, CDC researchers took small, circular strands of DNA called plasmids for each of the 1918 viruss eight gene segments and inserted them into human kidney cells. The plasmids then instructed the cells to reconstruct the RNA of the complete 1918 virus. This zombie-like reanimation of the Spanish flu was then tested on mice, allowing researchers to document for the first time the mechanisms of its virulence and spread.

The results were terrifying. Four days after infection, the amount of Spanish flu virus found in the lung tissue of infected mice was 39,000 times higher than that produced by similar strains in the flu family.

By watching the virus in action, researchers were finally able to link its genetic structure with the patterns of disease it produced. Experiments showed that it was not any single component of the 1918 virus but instead, as researchers wrote at the time, the constellation of all eight genes together that made the Spanish flu an exceptionally virulent virus.

The CDC team also tested theories on the viruss origins. After much experimentation, it was ultimately a chicken egg that held the answer. When 10-day-old fertilised eggs were inoculated with the virus, the results were lethal for the nascent chicken embryos. Paired with gene sequencing evidence suggesting a close link between the Spanish flu virus and other avian influenza viruses, this insight was enough for researchers to declare that the 1918 virus first arose in birds before making the leap to humans.

So that covers off the first two big questions about the Spanish flu where it came from, and why it was so deadly.

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But what about the biggest how did the pandemic end?

This first requires a little clarification.

The Spanish flu pandemic certainly ended, but the virus that kicked it off did not.

Instead, it gradually grew milder, morphing from its lethal beginnings into a much more placid sniffle.

This is a common natural progression for viruses, partly because the best evolutionary pathway optimises spread but leaves virulence primarily to random chance. This means that while theres active selection for increased transmissibility, theres a good chance that lethality will fade. But there is no concrete rule that dictates diminishing virulence, and there can certainly be surprising spikes along the way.

This was true of the Spanish flu, which ebbed and flowed in waves much like COVIDs peaks and troughs. While the general trajectory was towards becoming milder, the path wasnt linear some waves were significantly deadlier than their predecessors, just as in the current crisis, the Delta and Omicron variants have posed challenges that the first viral waves did not.

But if the Spanish flus overarching pattern is followed by SARS-CoV-2, as many experts believe it will be, we can expect that while well never eradicate the virus, it wont always be a major public health threat.

The scarily virulent 1918 form of Spanish flu that researchers reanimated is long gone, but its descendants still circulate as part of our seasonal flus. Some genetic aspects of the virus have been implicated in the lesser pandemics of 1957 and 1968; its likely that people who lived through the Spanish flu years had a degree of protection from these genetic cousins.

Here again is a lesson for current times: immunity is key. Each wave of the Spanish flu added layers of immunity to the surviving global population, until gradually the threat abated. With COVID, we know that whilst our immunity fades over a period of months following vaccination or infection, we retain an increasing ability to ward off severe disease with each exposure.

But as we wait for global immunity to build, our key public health measures remain vital in protecting us from the worst effects of the virus.

The importance of these measures was laid bare in the 1918-19 pandemic. As the flu raged a century ago, people were asked to wear masks and adopt social distancing measures, just as we are today. And, just as today, a number of anti-mask advocates opposed these impositions. But experts agree that these measures significantly dampened the death toll while immunity grew, and that they remain vital for us in the current pandemic as we wait for its severity to diminish.

When CDC researchers resurrected and characterised the Spanish Flu, they felt theyd taken significant steps towards safeguarding humanity against future outbreaks. They described how the 1918 virus was special a uniquely deadly product of nature, evolution and the intermingling of people and animals. Sound familiar?

At the time, they believed their work would serve as a portent of natures ability to produce future pandemics and help us to begin building our defences and public health capabilities.

But were we paying enough attention?

In a summary of their work on the virus, CDC researchers noted that despite advances in medicine and public health, a severe pandemic could still be devastating to populations globally.

Amongst other things, they identified a global deficiency in surveillance capacity, infrastructure, and pandemic planning, and noted insufficient critical and clinical care capacity, especially in low-income countries. They bemoaned the fact that milestones established in 2005 in revised International Health Regulations (IHR) for countries to improve their response capacity for public health emergencies had only been met by a third of countries by 2016.

In a sense, the blueprint for our current pandemic was laid out for us in CDCs study of the Spanish flu. Though the two viruses are genetically dissimilar, the lessons regarding their management were made clear years before COVID emerged.

We will inevitably make it through this pandemic, though the length of the road ahead remains unclear. But when the next outbreak occurs, will we be any better prepared than we were this time?

This much is clear: if we fail to heed the lessons of pandemics past, COVID-19 will fade from our collective memory the way that the Spanish flu did over the course of a mere century.

Why is the sky blue? What actually is carbon capture and storage? Why does my vacuum cleaner make that noise? How does bitcoin work? And could Yodareallyforce push Palpatine?

Theres no such thing as a stupid science question, but sometimes the answers can be tricky to find.

This summer weve partnered with ACM for the Summer of science: Ask us anything!Sendus your curliest chemistry conundrum, perplexing physics problem or any science question at alland well get our journalists onto the case.

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COVID isn't humanity's first pandemic rodeo. How did we make it through the Spanish flu? - Cosmos

An initiative of the University of Cape Towns (UCT) Institute of Infectious Disease and Molecular Medicines (IDM) Transformation Committee, the Postgraduate Student Publication Competition recognises student publications. It was designed to foster a culture of research publication among postgraduate students based in IDM member groups, while lauding students who have made the intellectual and practical contributions that earn them a place as first authors in published journal articles.

In her welcome at the online celebration, IDM director, Professor Valerie Mizrahi, said that getting ones work out there is a critical part of being a scientist.

The selection panel consisted of world-famous Emeritus Professors Siamon Gordon and Wieland Gevers. Emeritus Professor Gordon is an immunologist and clinician from the University of Oxford and a UCT alumnus.

Professor Mizrahi said of Gordon: [He] has been the chair of the International Scientific Advisory Committee for the Institute, I believe, since its inception certainly for as long as Ive been the director of the institute.

Emeritus Professor Gevers, the second judge, conceptualised the IDM over a decade ago. He also created the facultys Department of Medical Biochemistry. [He] has held huge positions in building the science-research ecosystem of South Africa through the Academy of Science amongst many other contributions, said Mizrahi.

The 14 submissions received from students illustrated the quality of research underway at the IDM, highlighting the depth of talent of the institutes next-generation researchers.

Theres a range of publications in a range of different journals. They were of a very high standard ... Im proud to be part of the IDM family, said Gordon.

Gevers added: This gives me an opportunity to see the diverse, excellent, purposeful, advanced work that is going on [at the IDM].

2021 IDM Postgraduate Student Publication competition winners

Arash Iranzadeh, Division of Computational Biology, Department of Integrative Biomedical Sciences

The Original Research category win was shared by Arash Iranzadeh and Ryan Dinkele. Iranzadeh is based at the HIV Diversity Group.

His paper, Detection of a SARS-CoV-2 variant of concern in South Africa, published in Nature reported on and characterised a newly identified SARS-CoV-2 lineage after the first wave of the epidemic in South Africa. This Beta variant or B.1.351 has eight mutations in the spike protein which likely increase virus transmissibility.

The finding highlighted the importance of coordinated molecular surveillance systems in all parts of the world in enabling the early detection and characterisation of new lineages, as well as in informing the global response to the COVID-19 pandemic, said Iranzadeh.

It is a great honour and privilege for me to attain the prize from UCT. Im grateful to everyone who contributed to this work, he said.

Ryan Dinkele, Division of Medical Microbiology, Department of Pathology

The second recipient of the first prize for Original Research category was Ryan Dinkele, based at the Molecular Mycobacteriology Research Unit (MMRU) and the Centre of Excellence for Biomedical TB Research (CBTBR). His paper, Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols, was published in PLOS Pathogens.

The aim of the research was to develop a new system to detect M. tb, the bacteria that causes tuberculosis (TB), in aerosols produced by TB patients during normal breathing and coughing. This microscopy-based system provided a rapid and sensitive readout for aerosolized M. tb within 24 hours in about 90% of TB patients.

Consequently, we have a unique approach for studying TB transmission within a South African context, said Dinkele.

Referring to the accolade, he said, The recognition of this work by such distinguished scientists has provided the inspiration required to persevere in the challenging field of TB transmission.

Cheleka Mpande, Division of Immunology, Department of Pathology

Cheleka Mpande received second prize for Original Research with her paper: Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection, which was published in EBioMedicine. Mpande is part of the South African Tuberculosis Vaccine Initiative.

The risk of developing TB is not uniform among individuals infected with M. tb. The risk is said to be very high in people who have recently been infected with M. tb. Current TB diagnostic tools are good at identifying people with TB disease but cannot identify people who have recently become infected with M. tb.

This formed the foundation for the studys aim: to find immunological markers that are only present during recent M. tb infection that can be used to design immune-based diagnostics. These can then be used to identify recent M. tb infection and by extension potentially infer risk of TB progression.

Referencing the research, Mpande said: This is a culmination of more than six years of work including results from some of my first successful experiments as an MSc student. It is an amazing achievement for everyone involved in the project.

Arinao Ndadza, Division of Human Genetics, Department of Pathology

Based at the Pharmacogenomics and Drug Metabolism Research Group, Arinao Ndadza was awarded third prize under the Original Research, jointly with Terry Kipkorir. Her paper, Profiling of warfarin pharmacokinetics-associated genetic variants: Black Africans portray unique genetic markers important for an African specific warfarin pharmacogenetics-dosing algorithm, was published in the Journal of Thrombosis and Haemostasis.

The papers aim was to profile and identify genetic variants that contribute to warfarin dose variability among Southern African populations. The research focused on genes with a pharmacokinetic effect meaning those involved in the disposition of the drug in terms of its absorption, transport, metabolism and excretion. This work contributes to the ongoing efforts of developing an African-specific pharmacogenetics-based warfarin dosing algorithm that can assist clinically in predicting a precise warfarin starting dose that is suitable for individuals with African ancestry.

For Ndadza this recognition validates that the research shes a part of is impactful and has the potential of being translated in the healthcare system.

This acknowledgment further proves that there is space for me to occupy and further contribute [to] pharmacogenomics and genomics research, she said.

Terry Kipkorir, Division of Medical Microbiology, Department of Pathology

Terry Kipkorir, who was also awarded third prize, had his paper, De novo cobalamin biosynthesis, transport and assimilation and cobalamin-mediated regulation of methionine biosynthesis in Mycobacterium smegmatis, published in the Journal of Bacteriology.

The papers objective is to describe the production, acquisition and utilisation of cobalamin a near-identical form of vitamin B12, in Mycobacterium smegmatis, a soil-dwelling model for M. tb. It also aimed to investigate how cobalamin-sensing via an RNA switch controls gene expression and bacterial growth.

Our findings provide key insights into the roles of cobalamin in mycobacterial physiology and pathogenicity, said Kipkorir whose study is based at the MMRU. He added that the prize affirmed the scientific rigour of the groups work and the impact of their findings in TB research.

Liam Devenish, Division of Chemical, Systems, and Synthetic Biology; Department of Integrative Biomedical Sciences

Liam Devenish, based at the Gene Expression and Biophysics Group, won first prize for his review article: Immune Regulation in Time and Space: The Role of Local- and Long-Range Genomic Interactions in Regulating Immune Responses. It was published in Frontiers in Immunology.

The review explores and frames new discoveries surrounding the phenomenon of immune priming. Immune priming is a central element of the immune system in almost all multi-cellular living organisms. It remembers previous immune challenges and becomes able to respond more appropriately and robustly in future. The paper explores this in the context of the burgeoning field of chromatin topology.

Immune priming is about discovering why we're so good at responding quickly to a staggering array of insults from the environment and from within our own bodies. Its about our immune systems learning and remembering how to be better equipped with each assault, said Devenish.

This memory spills over to various systems including resistance to developing cancers, responses to vaccines, and resilience to new organisms. The understanding that the physical shape and organisation of the genome within the nucleus informs gene regulation is one which is growing and has recently been well-applied to the field of immunology.

These genomic interactions happen at remarkable speed and with incredible accuracy to create a synchronised, powerful defence to almost any challenge we encounter, said Devenish.

He added: Sharing my thoughts and understanding has been challenging and exceptionally rewarding.

Sherazaan Ismail, Division of Medical Virology, Department of Pathology

Sherazaan Ismail straddles two groups at the IDM: the HIV/TB Immunology research group and the HIV Diversity Group. Her paper, Addressing an HIV cure in LMIC, published in Retrovirology, earned her the second prize under the Review category.

People living with HIV require lifelong antiretroviral therapy (ART) due to the persistence of HIV in a latent reservoir in infected cells. To achieve a global HIV cure it is important to understand the reservoir in different contexts, especially because viral subtypes, disease progression, and the timing of ART differs around the world.

Ismails paper discussed the latest findings in HIV cure research as well as the considerations for implementing a cure in low- and middle-income countries.

This win reaffirms that, as PhD students, we are experts in our field, and we shouldnt let impostor syndrome get in the way of fostering collaborations and making our important contributions known, she said.

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Student publications prove to be purposeful and advanced - University of Cape Town News

DetailsCategory: Small MoleculesPublished on Tuesday, 15 February 2022 11:02Hits: 34

Centrally Confirmed Objective Response Rate of 21% and Disease Control Rate of 84%

Largest Dataset and Only Global Clinical Trial to Date to Evaluate the Efficacy and Safety of a KRAS G12C Inhibitor in Advanced Pancreatic Cancer

THOUSAND OAKS, CA, USA I February 14, 2022 I Amgen (NASDAQ: AMGN) today announced the presentation of efficacy and safety data from the CodeBreaK 100 Phase 1/2 trial in patients with KRAS G12C-mutated advanced pancreatic cancer who received LUMAKRAS (sotorasib)*. The data will be presented at the monthly American Society of Clinical Oncology (ASCO) Plenary Series on Feb. 15, 2022. Data show encouraging and clinically meaningful anticancer activity and a positive benefit:risk profile.

"Based on these exciting data, we are expanding CodeBreaK 100 to enroll more patients with pancreatic and other tumor types to better understand the efficacy and safety of LUMAKRAS in tumors outside of non-small cell lung and colorectal cancers," said David M. Reese, M.D., executive vice president of Research and Development atAmgen. "CodeBreaK is the largest and broadest global clinical trial program to date with one of the most robust, centrally reviewed datasets. As we learn more from the extensive data that we collect, we'll continue to invest in the program by expanding cohorts and exploring new combinations so that we can help as many patients as possible."

LUMAKRAS demonstrated a centrally confirmed objective response rate (ORR) of 21% and disease control rate (DCR) of 84% across 38 heavily pre-treated advanced pancreatic cancer patients. Nearly 80% of patients received LUMAKRAS as a third-line or later therapy. Eight of the 38 patients achieved a confirmed partial response (PR) performed by a blinded independent central review (BICR). Two of the eight patients with PR have ongoing responses. Median duration of response was 5.7 months with a median follow-up of 16.8 months as of the data cutoff date of Nov. 1, 2021. The results also show a median progression free survival (PFS) of 4 months and a median overall survival (OS) of almost 7 months. No new safety signals were identified with this study of patients with advanced pancreatic cancers. Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42%) patients with diarrhea (5%) and fatigue (5%) as the most common grade 3 TRAEs. No TRAEs were fatal or resulted in treatment discontinuation.

"After decades of research, current treatments for patients with pancreatic cancer provide limited survival benefit, illustrating the critical need for novel, safe and effective treatment options," said John Strickler, M.D. associate professor of medicine, Duke University School of Medicine and gastrointestinal oncologist. "In the largest dataset evaluating the efficacy and safety of a KRASG12C inhibitor in heavily pretreated advanced pancreatic cancer, sotorasib achieved a centrally confirmed response rate of 21% and a disease control rate of 84%. This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third-line of treatment."

Cancer of the pancreas is a highly lethal malignancy. Itis the fourth leading cause of cancer-related deaths in both men and women in the U.S. with a 5-year survival rate of approximately 10%.1 There is a high unmet need for patients with advanced pancreatic cancer that has progressed after first-line treatment, where FDA-approved second-line therapy has provided survival of about six months and a response rate of 16%.2 After progression on first- and second-line chemotherapy, there are no therapies with a demonstrated survival benefit.2,3 Despite advances in treatment, few improvements have been made to improve diagnosis and treatment of pancreatic cancer.

It is estimated that approximately 90% of patients with pancreatic cancer harbor a KRAS mutation with KRAS G12C accounting for approximately 1-2% of these mutations.4-5

ASCO Plenary Series SessionASCO will host a livestream event on Tuesday, Feb. 15 at 3 p.m. ET featuring presentation of the abstract "First data for sotorasib in patients with pancreatic cancer withKRASp.G12C mutation: A phase I/II study evaluating efficacy and safety"by Dr. John Strickler from Duke University. To participate in the free and open session, participants may register and login at https://www.asco.org/meetings-education/monthly-plenary-series/program.

*LUMAKRAS is marketed as LUMYKRAS (sotorasib) in the European Union and the United Kingdom.

About LUMAKRAS/LUMYKRAS(sotorasib)Amgentook on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12Cinhibitor.6 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring theKRASG12Cmutation with a once daily oral formulation.7

Amgenis progressing the largest and broadest global KRASG12Cinhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, over 4,000 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the United Arab Emirates, the European Union, Japan and Switzerland, and in Canada and Great Britain under the FDA's Project Orbis. Through Project Orbis, Amgen also has Marketing Authorization Applications (MAAs) for sotorasib in review in Australia, Brazil, Singapore and Israel. Additionally,Amgenhas submitted MAAs in South Korea, Turkey, Taiwan, Colombia, Thailand, Mexico, Hong Kong, Saudi Arabia, Argentina, Kuwait and Qatar.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.8

About CodeBreaKThe CodeBreaK clinical development program forAmgen's drug sotorasib is designed to treat patients with an advanced solid tumor with theKRASG12Cmutation and address the longstanding unmet medical need for these cancers.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients withKRASG12C-mutant solid tumors.7.8Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.7 The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been published.9

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRASG12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated (previous treatment with both platinum doublet chemotherapy and a checkpoint inhibitor), locally-advanced and unresectable or metastatic KRASG12C-mutated NSCLC.The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.

Amgenalso has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment. A Phase 2 randomized study will evaluate sotorasib in patients with stage IVKRASG12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201).For information, please visitwww.hcp.codebreaktrials.com.

LUMAKRAS(sotorasib)U.S.IndicationLUMAKRASis indicated for the treatment of adult patients withKRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Please see LUMAKRASfullPrescribing Information.

AboutAmgenOncologyAtAmgenOncology, our mission to serve patients drives all that we do. That's why we're relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage,Amgencontinues to advance the largest pipeline in the Company's history, moving with great speed to advance those innovations for the patientswhoneed them.

AtAmgen, we're advancing oncology at the speed of life.

For more information, follow us onwww.twitter.com/amgenoncology.

AboutAmgenAmgenis committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgenfocuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980,Amgenhas grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

Amgenis one of the 30 companies that comprise the Dow Jones Industrial Average and is also part of the Nasdaq-100 index. In 2021,Amgenwas named one of the 25 World's Best Workplaces by Fortune andGreat Placeto Work and one of the 100 most sustainable companies in the world byBarron's.

For more information, visitwww.amgen.comand follow us onwww.twitter.com/amgen.

1Siegel RL, et al. CA Cancer J Clin. 2022;72:7-33.2Tempero MA, et al. J Natl Compr Canc Netw. 2021;19:439-457.3Wang-Gillam A, et al. Eur J Cancer. 2019;108:78-87.4Nassar AH, et al. N Engl J Med. 2021;384:185-1875Cox AD, et al. Nat Rev Drug Discov. 2014;13:828-851.6Canon J, et al.Nature. 2019;575:217223.7Skoulidis F, et al.N Engl J Med.2021;384:2371-2381.8Hong DS, et al.N Engl J Med. 2020;383:1207-1217.9Fakih MG, et al, Lancet Oncol. 2022.

SOURCE: Amgen

Originally posted here:
Lumakras (sotorasib) shows encouraging and clinically meaningful anticancer activity in patients with KRAS G12C-mutated advanced pancreatic cancer in...

This is not the same phenomenon as everybody who is throwing up their hands and saying let me out of here, said McLaughlin, who runs an annual program for new college presidents and also advises experienced presidents. These are more typical, expected tenures.

At the same time, she said, there is no question that these leaders are exhausted.

Its been a slog, McLaughlin said. They have had to spend their time making difficult decisions, many of which are controversial . . . They have been missing what presidents talk about is the joyful aspects of their jobs.

The highest positions in higher education leadership typically turn over every 10 to 15 years, but this transition comes at an inflection point for the industry. The new generation of presidents who fill these openings will have to tackle a host of issues, including the use of online education, the changing demographics of students, the increasingly unaffordable cost of a degree, the public perception of higher education, and questions about diversity and inclusion, tenure and academic freedom.

It is a time when new leadership will be grappling with what could be called new questions or maybe persistent questions, but which are being asked simultaneously with more urgency than before, McLaughlin said.

The Tufts president, Anthony Monaco, 62, who played a key role in working with the Broad Institute to develop COVID-19 testing that enabled a return to in-person learning this fall, said he has no immediate plans for his next chapter after serving 12 years as the schools leader. He said he hopes to continue to work to solve societal challenges from a new post in academia or another sector.

In an e-mail to the campus Monday morning, he thanked students, faculty, and staff for what he called an incredible personal and professional journey. Now, he wrote, is the time for a new leader with a bold vision and fresh energy.

Tufts is an esteemed university that is poised to become even greater, Monaco wrote.

Monacos announcement follows that of MIT president L. Rafael Reif, who last week announced that he will retire at the end of the year after more than a decade of service. Biddy Martin, president of Amherst College, plans to step down this summer after 11 years on the job. Dartmouth College president Philip Hanlon announced last month that he will step down in June 2023 after 10 years. Laurie Leshin also recently said she will depart Worcester Polytechnic Institute this spring to become director of the Jet Propulsion Laboratory and vice president of Caltech. And Sister Janet Eisner plans to step down after serving as president of Emmanuel College for 43 years.

In an interview on Sunday, Monaco said he is proud of the work that Tufts has accomplished during his tenure in the areas of climate change, health disparities, civic engagement, and mental health.

We have been able to have a profound impact in many different areas, he said.

Monaco said he found camaraderie during the pandemic in working with other presidents from around the region who met regularly to develop COVID protocols. Monaco was a key leader during the outbreak and helped create the COVID-19 testing program with the Broad Institute that proved pivotal in allowing universities to stay open during the pandemic.

We [presidents] shared our anxieties and plans to overcome them, he said. It was really tough for a lot of leaders to manage the rising rates of positivity . . . and by being together and sharing expertise, it really helped overall in managing such a difficult situation.

The biggest challenge for any university president, Monaco said, is trying to keep the institution focused on its long-term goals while dealing with the immediate challenges that inevitably arise. The pandemic, he said, was a prime example.

Youre trying to look toward the future while the external environment is changing rapidly and often unexpectedly, he said.

A geneticist by training, Monaco ran a center for human genetics at Oxford University in the United Kingdom before becoming pro-vice-chancellor for planning and resources at Oxford in 2007.

In an e-mail to the Tufts community on Monday, Peter R. Dolan, the chairman of the universitys board of trustees, thanked Monaco on the boards behalf for his steadfast leadership of the university, for his dedication to Tufts, and for the clear moral compass and intellectual rigor that have guided him as president.

Dolan credited Monaco for doubling the universitys endowment from $1.4 billion in 2011 to $2.8 billion today and nearly doubling undergraduate applications, from 17,097 for the class entering in fall 2011 to over 34,000 for the current admissions cycle. He also praised him for the 2016 acquisition of the School of the Museum of Fine Arts in Boston.

Monaco oversaw the university during a time of profound societal upheaval. In 2019, the university removed the Sackler name from its medical school programs and facilities, an effort to distance itself from the family and its company, Purdue Pharma, which admitted to playing a key role in fueling the opioid addiction epidemic. Also in 2019, Monaco was vocal in his support for the Deferred Action for Childhood Arrivals program, or DACA, opposing former president Donald Trumps attempt to end it.

Monaco said he wishes he had made greater strides toward expanding the universitys capacity to respond to the mental health needs of students.

Im worried that the mental health rise is not abating, he said.

Monaco said he hoped Tufts next president will focus on expanding the universitys profile as a research institution. During his tenure, he said, the university developed more masters and PhD programs. The next leader, he said, should focus on attracting more funding for research.

A. David Paltiel, professor of health policy and management at Yale School of Public Health, worked with Monaco and other college leaders in the months leading up to the reopening of campuses in the fall of 2020, as they developed a testing system that involved sending massive numbers of samples from colleges across the region to the Broad Institute in Cambridge to be processed.

Monaco was among the first college administrators to recognize that frequent, routine testing of asymptomatic people was the key to keeping campuses open, Paltiel said.

Monaco, he said, was also cognizant of his surroundings, recognizing the risks posed by the fact that Tufts is located in a residential area of Medford and Somerville.

President Monaco totally understood that his responsibility extended beyond the Tufts campus, Paltiel said. His outreach efforts allayed a lot of skepticism and fear. And, thanks largely to him, the Tufts campus remained among the very safest places in Middlesex County.

Laura Krantz can be reached at laura.krantz@globe.com. Follow her on Twitter @laurakrantz and on Instagram @laurakrantz.

Continued here:
President of Tufts University to retire - The Boston Globe

image:Image Caption: The image of a clock with brightfield macrophage images around it shows how circadian changes of cell surface heparan sulfate proteoglycans, shown in pink, impedes phagocytosis of fluorescently labeled amyloid-beta, shown in green. As time goes on, and we have a reduction in heparan sulfate proteoglycans, we see an increase in phagocytosis, demonstrated by the bright green cells shown on the left of the clock. This image was made using our fluorescent microscopy cell images with an artistic rendering of the heparan sulfate proteoglycans from the app, Wombo. The clock was made using photoshop and clip art. view more

Credit: Gretchen Clark, made using Wombo (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

Researchers report that the immune cells responsible for clearing away a key protein that builds up in the brains of patients with Alzheimer's disease operate according to daily circadian rhythms. The discovery, reported by Jennifer Hurley of Rensselaer Polytechnic Institute and colleagues in a new study publishing February 10th in the journal PLOS Genetics, provides a potential explanation for the link between Alzheimer's disease and disruptions to a person's sleep cycle.

Alzheimer's disease is known to be associated with disruptions in circadian rhythms, the 24-hour cycle that controls many aspects of human behavior and physiology. For example, sleep disruptions begin years before symptoms of Alzheimer's disease appear and are linked to more severe symptoms and a higher risk of developing the disease.

In the new paper, researchers investigated a molecular mechanism potentially responsible for the connection between Alzheimer's disease and circadian rhythms. They measured the activity of immune cells responsible for clearing away proteins called amyloid-beta that build up as plaques in the brains of people with Alzheimer's disease. Using cultures of these cells grown in the lab, they discovered that the immune cells clear away the amyloid-beta on an oscillating daily cycle controlled by circadian rhythms. However, when cells lost that rhythm, the daily cycle disappeared. They further established that the underlying cause of this oscillation was changes in the number of molecules of a certain protein, heparan, on the cell's surface. The protein they identified responds to circadian rhythms and previously had been shown to play a role in clearing amyloid-beta proteins.

The new findings uncover a mechanism that links the disruption of circadian rhythms to Alzheimer's disease. The study further highlights the role of immune cells in this relationship. While more studies will be necessary, the new findings present the possibility that, if the daily clearance of amyloid-beta proteins through this mechanism can be maintained, patients may be less likely to develop Alzheimer's disease and to exhibit less severe symptoms.

Hurley adds, Understanding how our circadian rhythms can regulate cell-surface heparan levels to control the build-up of amyloid-beta may lead to the development of chronotherapeutics that alleviate the symptoms of Alzheimers Disease as well as other inflammatory diseases.

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In your coverage, please use this URL to provide access to the freely available article in PLOS Genetics:

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009994

Citation: Clark GT, Yu Y, Urban CA, Fu G, Wang C, Zhang F, et al. (2022) Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates. PLoS Genet 18(2): e1009994. https://doi.org/10.1371/journal.pgen.1009994

Author Countries: United States, China

Funding: This work was supported by an NIH-National Institute of Biomedical Imaging and Bioengineering Grant U01EB022546 (to J.M.H) (https://www.nibib.nih.gov/), an NIH-National Institute of General Medical Sciences Grant R35GM128687 (to J.M.H.) (https://www.nigms.nih.gov/), an National Science Foundation CAREER Award 2045674 (to J.M.H.) (https://www.nsf.gov/), National Institutes of Health grants 1RF1AG069039 (to C.W.), DK111958 and CA231074 (to R.J.L.) (https://www.nih.gov/), Rensselaer Polytechnic Startup funds (to J.M.H.) (https://www.rpi.edu/), a gift from the Warren Alpert Foundation (to J.M.H.) (https://warrenalpert.org/), and a NIH-National Institute of Aging T32 Fellowship AG057464 (to G.T.C.) (https://www.nia.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Experimental study

Cells

Competing interests: The authors have declared that no competing interests exist.

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.

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Immune cells that clear away Alzheimer's disease protein are controlled by circadian rhythms - EurekAlert