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Survival Of The Kindest: A New Mantra To Rebuild The Global Economy – Forbes

January 5th, 2021 1:48 am

Lessons from nature may hold deeper insights into how to build back a more resilient and kinder ... [+] economic system

That our current global economic system is broken is no surprise. The question is where to turn to for hope. New insights from nature may provide the answer.

The "Fearless Girl" statue, a four-foot statue of a young girl, defiantly looks up the iconic Wall ... [+] Street "Charging Bull" sculpture in New York City

Underlying economic injustices have been magnified by the coronavirus pandemic. Historically underrepresented groups have all fared worse off over the past 12 months since the outbreak of the virus. A younger generation now faces a historic amount of debt, similar to having faced a World War, in addition to the challenges of irreversible climate change and global biodiversity collapse.

24 Feb 2020: Indian billionaire Mukesh Ambani (L) added $18 billion to his wealth during the ... [+] pandemic, as Microsoft value rose by almost $500 billion in 2020. Seen here with Microsoft CEO Satya Nadella (R)

A closer examination of this growing inequality reveals just how fragile current economic structures have become, with social unrest bubbling just under the surface in many countries around the world. As hundreds of millions continue to face prolonged lockdowns, higher health risks, lost schooling, mass unemployment and economic ruin, ten billionaires alone saw their wealth increase by $450 billion during the pandemic. The wealthiest 2000 billionaires in the world saw their assets hit new highs, increasing toover $10 trillion in value. An economic system with such disparities, that rewards those with access to capital, is not sustainable.

Political leaders around the world performed poorly in responding to the coronavirus crisis (Bill Gates questioned whether any country merited an A grade for their response).

A new Covid-19 stimulus plan was signed by President Trump at the end of 2020

These very same political leaders (many of whom are increasingly authoritarian) are now using taxpayer funds or future borrowing to roll out multi-trillion dollar pandemic stimulus packages around the world. Rather than coordinating such a financial injection to ensure a global economy is rebuilt in a way that is more just, equitable, innovative and harmonious with nature, the world is seeing a fragmented patchwork of short term, reactive measures that do not address the structural faults in the global economy, or appear to be coordinated in any way to address global systemic risks.

The multi-trillion dollar opportunity is being squandered, and history shows that this will be an expensive mistake.

There are small windows in history when human value systems shift so fundamentally in a short period of time that the entire economic system is forever altered after such crises. In several instances, these shifts in human values have improved the state of the world. For example:

Slavery abolished by mid-1850s

Eleanor Roosevelt and 'The Universal Declaration of Human Rights'

U.S. Civil Rights activist Rosa Parks seated toward the front of the bus, Montgomery, Alabama, 1956. ... [+]

Swedish climate activist Greta Thunberg is pictured during a "Fridays for Future" protest in front ... [+] of the Swedish Parliament Riksdagen in Stockholm on October 9, 2020.

The last decade has seen a regression of much of the progress of the 20th century as inequality of opportunity has risen around the world. The international responses to the 2008 and 2011 financial crises were wasted, as the then $1 trillion stimulus packages coordinated via the E.U., G20, World Bank and IMF ended up recreating existed cleavages in society, which were already unsustainable, as a decade of austerity eroded critical social safety nets around the world.

With social cohesion breaking down and irreversible climate change soon upon us, the time for timid steps are over.

A strong articulation of which values will need to change is needed to build a more robust ... [+] post-pandemic economy

Building back better must mean that the means should justify the ends. There cannot be a rush toward more a sustainable economy that create new green monopolies. The growth must be inclusive.

The core to building back a better economic system will require the architects of the post-pandemic economic order to come to terms with a foundational error in science from 150 years ago, that continues to plague the global economy today.

It is to do with a fundamental misunderstanding of the natural world, which led to the birth of modern economic thinking. It is this system of incentives that now define the winners and losers of the global economic system, including its impact on the society and the environment.

Advances today in molecular biology and advanced genetics are revealing new insights into how misguided this science was 150 years ago, and the profound implications for how the economic system can be redesigned.

Charles Darwin, English naturalist, wrote the first unifying theory of evolution

In 1859, a 48-year old Charles Darwin famously completed his iconic book the On the Origin of Species, after travelling the world on a scientific expedition on board The Beagle. Origin of Species became the seminal work that provided a unifying theory for evolution and natural selection for the first time. Indeed, the full title of the book was, On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. It became the predominant doctrine of many leading thinkers of the time such as Alfred Wallace and Thomas Malthus.

At the core, was an assumption that there were winners and losers in evolution. This led to the term the Survival of the Fittest to explain who the winners of evolution were. This process was termed Natural Selection.

The notion of a Natural Selection of winners was swiftly taken up by researchers at the time as the lens through which to study nature, wildlife and biology. European biologists were captivated by the notion that brutal forces of nature defined that only the fittest or most selfish would survive. Darwins work led to a unifying-theory of a well-structured biological pecking order, explained by a simplified and precise mathematical formula that defined the position of each species, with the most powerful on top. It was very Victorian England.

A lion epitomizing 'survival of the fittest' against a zebra

Nothing exemplified this more than the imagery of the powerful, carnivorous lion chasing its herbivorous prey across the plains of Africa. A process of natural selection would determine which species would be at the top of the food chain, a product of what skills they needed to survive over thousands of years of evolution. Those at the top of these biological pyramids could expect to die of old age, whereas life for other creatures lower down would be brutal, short and defined by constantly being on their guard.

Although a fringe notion at the time in the 1860s, it would take another seventy years for Darwins theories of evolution, natural selection and the survival of the fittest to become mainstream by the 1930s.

This theory of natural selection explained by the concept of survival of the fittest then went on to dominate scientific thinking for the next 100 years through to today.

President Franklin D. Roosevelt endorses New Deal candidates during a radio broadcast from his Hyde ... [+] Park home. | Location: Hyde Park, New York, USA.

Darwins theories originated in evolutionary biology, but soon infused itself into the leading economic, social and political thinkers of the time.

In the fervent first three decades at the start of the 20th century with a World War, a Spanish Flu pandemic, a Great Depression and New Deal Recovery, economists and political scientists were searching for new unifying economic theories to find an alternative economic models than one of dominant robber baron monopolies built during the modern industrial revolutions of the late 19th and early 20th century.

Darwins ideas around survival of the fittest soon fit in well with notions of what was seen as a natural order for business, economics and the social sciences.

The New York Stock Exchange on Wall Street epitomizes the aggressive form of shareholder capitalism ... [+] that drives the global economy today

Iterations of this brutal winner rises to the top world became core to business and economic thinking over the course of the twentieth century. This mantra defined internal working cultures within companies, competition regulations, and core decision-making at the very top of corporations where the Board of Directors had a disproportionate say over the direction of a company, overriding concerns from employees, the environment, suppliers, and the local community. It was a scarcity mindset where there was only room on top for just a handful of organizations or leaders. Relatively little effort was made to invest in alternative, more collaborative business models or ecosystems.

It was a way of thinking that valued competition above collaboration, selfishness above empathy, aggression above pacifism.

Traders work during the opening bell at the New York Stock Exchange (NYSE) on March 19, 2020, at ... [+] Wall Street in New York City.

For over a century, it was believed that only the most self-serving businesses or leaders (usually alpha-male) should be allowed to survive. The thinking was that this would create a fitter and more robust economic system as a whole. Even if every decade, the list of most valuable businesses may change as different sectors reached their zenith, there was faith that shareholder capitalism would lead to a better outcome for society. GDP and market capitalization became the new Gods.

However, what it ended up creating was a more brutal version of business. One where quarterly results trumped all decision-making within a company. Business executives would do anything to hit quarterly targets. Other stakeholders (customers, employees, suppliers, the environmental, the local community) were given significantly lower weight, and were usually seen as marketing gimmicks.

Facebook has been seen catering more to shareholder interest than that of its users

Even companies whose humble origins once gave hope that such a system could be upended - companies like Google and Facebook - have now become the poster children for this winner takes all business model. Just as banks were too big to fail a decade ago, Big Techs dominance has created major weaknesses in modern economic and social systems. The pursuit of quarterly profits mean that efforts such as ethical A.I. or ensuring full external oversight of operations, were scaled back.

For national economies to build back better, this broken model of shareholder capitalism has to be fundamentally addressed as part of any stimulus package.

It requires re-evaluating what Survival of the Fittest means.

Emperor Penguin chicks in the Weddell Sea, Antarctica.

In recent years, new advancements in molecular biology and DNA technology have fundamentally challenged Darwins thinking and inferences on natural selection.

It has allowed biologists to go further and deeper in their understanding of evolution, and question whether natural selection really was due to a survival of the fittest. Indeed, it questioned what fittest actually meant.

Studying fossils, ancient DNA and using large datasets and machine learning to develop unprecedented insights, scientists have been able to peer back through deep time to see when various species started to evolve along the tree of life.

Scientists are making new discoveries about evolution, using new techniques of big data and machine ... [+] learning to peer further into each species' evolution and genetic code

A search through deep time reveals that species that have survived the longest are ones that live in groups, have symbiotic relationships with other species and who behave kindly within the communities that they live in. This completely flips on its head some of thinking from 150 years ago that only humans had higher faculties of intelligence, empathy and peaceful co-existence in group settings.

Taking these learnings from nature and transplanting them into our current economic systems has fundamental implications for how to build back better and the sorts of institutions that will be needed. Lets first understand the science behind Survival of the Kindest.

It turns out that species that live in groups - whether herds, shoals or flocks - tended to have survived as a species for longer than those that are more solitary.

Herd animals have been found to have evolved and survived for longer than many apex predators like ... [+] lions

Hammerhead sharks evolved 20 million years ago, less than half the time than bluefin tuna

A British Used Postage Stamp Showing Portrait of Charles Darwin and Finches, depicting his Theory of ... [+] Evolution

Charles Darwin did not have the ability to study the deep genetics of species when writing Origin of Species. Otherwise, he may have concluded the importance of a community surviving, rather than individual animals.

A more recent and deeper understanding of wildlife has revealed how dependent many species are on symbiotic relationships. The survival of one is highly dependent on the existence of another species. This is not an extractive, food-dependency, but one where the presence of both species working in harmony leads to flourishing communities growing.

Here are some notable examples:

Coral reefs are the one of earths most complex ecosystems, containing over 800 species of corals and ... [+] one million animal and plant species.

Oceanic whitetip shark with Pilot Fish swims under sea surface in the open sea, Red Sea, Egypt

Meerkat family on lookout

So collaboration - rather than competition - with different animals is critical to the survival of both species. Certain species have even developed evolutionary traits (such as the rear legs of the urchin crab) to take into account this symbiotic relationship with other species. Again, these were observations that Charles Darwin was unable to take as he rushed around the world taking observations of plants, animals and fossils he could see in the time he had available.

Frans de Waal's work has been published as New York Times bestsellers

Some of the most seminal work on animal intelligence and animal empathy has been done by Frans de Waal of Emory University. His detailed studies of chimpanzees and other Great Apes have revealed previously unrecognized behavioral patterns in animals where kindness and collaboration are rewarded in communities in which they live.

This reward structure means that apes that demonstrate the greatest empathy and collaboration often receive the highest rewards. Also chimpanzees given a free choice between helping only themselves or helping themselves plus a partner, prefer the latter.

This flips on the head the notion that nature is selfish, brutish and short for animals compared with human existence. It has given rise to an entire new field of study for morality grounded in biology, centered around values of cooperation,altruism, and fairness.

The complex and collaborative societal structures of apes are only just being understood

Such research is challenging some of the root causes of natural selection and the simplistic reasoning behind Survival of the Fittest.

As such knowledge is being revealed, it raises the question whether a new theory is needed to explain natural selection over deep time.

Perhaps it is less Survival of the Fittest and more Survival of the Kindest.

Could Survival of the Kindest be a new organizing principle for the post-pandemic economic order?

Taking this new understanding from biology into our economic systems, opens up radically new possibilities.

These new possibilities challenge the current orthodoxy that business systems should only incentivize strong corporations that seek to defeat competition, maximize corporate behavior that is self-serving and diminish the responsibility to other stakeholders (such as customers, suppliers, workers, the environment, the community) in order to only satisfy only one stakeholder - the shareholders as represented by a Board of Directors.

If kindness becomes an attribute that is core to how a business or economic system is evaluated, a different form of organization may emerge. An organization that sees their duty as performing a societal duty, much like a village market or local neighborhood grocery store performs. An organization that seeks to serve in a more balanced way rather than aggressively extract value from others in its ecosystem.

Senate Hearings in July 2020 call upon Amazon CEO Jeff Bezos (top, C), Facebook CEO Mark Zuckerberg ... [+] (top, R), Google CEO Sundar Pichai (bottom, L), and Apple CEO Tim Cook on the dominance of technology companies

Advances in technology (such as open source software) has opened up new and innovative collaborative business models that could create more symbiotic corporate relationships with a wider ranger of participants, rather than the natural monopolies that the tech giants of the FAANGs (Facebook, Amazon AMZN , Apple AAPL , Netflix NFLX , Google GOOG , Microsoft MSFT ) have created.

Survival of the Kindest will take a new form of regulatory mindset, as well as leadership mindset at every level of an organization. It means a fundamental evaluation of what kindness means, and how this value can be demonstrated toward a customer, an employee, a supplier and the environment.

Unity and diversity partnership as heart hands in a group of diverse people connected together ... [+] shaped as a support symbol expressing the feeling of teamwork and togetherness.

Creating an economic system that rewards kindness over power, may start to right the injustice and fragility with the current economic model. If it is the key to longevity for many species in deep time, there may be valuable lessons for the way that humans should be thinking about organizing society.

It may also require a new set of systems thinkers in Board Rooms and among regulators to start to rethink how the global economy needs to be built back. Getting thinkers who operate the current to imagine a radically different future is akin to asking a lion to design a system that would better suit healthy gazelle populations.

Those who have demonstrated such kindness may be the most credible role models to start that reconstruction. It will take a different sort of organizational muscle and diverse talent to build such kinder organizations, but one that is not that hard to find if one knows where and how to look.

Baby elephant showing affection to it's mother on the Masai Mara in Kenya

The extension from biology to political-economy seem may appear far-fetched, but as the economic system stretches further and further into the natural world, there are more connections than may immediately be imagined. And advances in science and technology are revealing just how little we truly understand about ourselves and the planet.

It is clear the world needs to move beyond the pithy slogans of build back green, and build back better, into something more substantive.

Perhaps this starts with Building back Kinder.

Original post:
Survival Of The Kindest: A New Mantra To Rebuild The Global Economy - Forbes

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The Nashville bombing suspect sent packages to people across the country containing typed conspiracy theories about September 11 and lizard people,…

January 5th, 2021 1:48 am

The Telegraph

While most scientists look at Covid-19 as a viral respiratory illness, Nir Barzilai takes a slightly different perspective. Instead Barzilai, founder of the Institute of Ageing Research at the Albert Einstein College of Medicine in New York, sees it as a disease of ageing. The grim statistics show that he has a point. In Europe, people over 60 have accounted for 90% of fatalities since the start of August. While the impact of Covid-19 has been universal, older people have been disproportionally affected. This virus has no eyes, but it could see immediately who is old and more vulnerable, says Barzilai. For Barzilai and other geroscientists scientists who study the biology of ageing this represents an opportunity. They have long argued that we need a different perspective for tackling many chronic diseases, from cancer to Alzheimers. As all of these illnesses become more common with age, geroscientists have suggested that therapies attempting to reverse some of the cellular mechanisms of ageing, might make older individuals more resilient to a whole range of diseases. The premise of this approach is that while we typically measure age chronologically, the number of years we have been alive, your biological age says far more about your health. Biological age is indicated through various biomarkers ranging from the length of telomeres the tips of chromosomes to changes in DNA expression, and even your gut microbiome. Some 55-year-olds may be biologically equivalent to 45, making them more resilient to disease, while others may be far older, due to lifestyle or genetics. Since the 1930s, scientists have identified certain drugs which appear capable of reversing biological ageing in mice. Over the past nine months, the pandemic has provided increasing evidence they may be capable of doing the same in humans. Covid has moved anti-ageing from hope to promise, says Barzilai. The promise is that ageing is flexible, and can be manipulated, is something weve shown again and again in animals. The eight hallmarks of ageing Geroscientists have defined eight hallmarks of biological ageing, which when targeted can improve health and lifespan in animals. These hallmarks range from declining immune function, to a decrease in the quality and quantity of mitochondria the energy factories of our cells and an impaired ability of cells to perform garbage disposal and remove toxins or viruses. There are drugs which can target some hallmarks of ageing, including resveratrol a compound found naturally in foods such as blueberries but the impact of Covid-19 has sparked particular interest in a cheap, commonly available medication called metformin, which has been used to treat diabetes for over fifty years, due to its ability to lower glucose levels. But recently, epidemiologists have begun to notice people taking it for diabetes also appeared to have reduced rates of cardiovascular disease and cancer. When the pandemic began, an early study from a hospital in Wuhan sparked particular interest. It showed diabetics taking metformin were much less likely to die of Covid-19 than diabetics not on the drug. Geroscientists around the world took note. Because of the number of people contracting Covid-19, we could gather data on metformin and its impact on reducing mortality, which would otherwise have taken years to collect, says Vadim Gladyshev, a biochemist at Harvard Medical School. Soon, further studies yielded similar findings. Doctors at the University of Minnesota found metformin lowered mortality rates across more than 6,000 Covid-19 patients with diabetes, albeit only in women. Barzilai believes he understands why. In a paper published earlier this year, he showed that metformin targets all eight hallmarks of ageing at the same time. Now, this accumulation of evidence has helped convince investors to provide $75 million in funding for a landmark randomised control trial called TAME. Intended to begin in June 2021, it aims to see whether giving metformin to older people for four to five years, can give them more years of good health. If this proves successful, it could see metformin licensed by regulators as the worlds first clinically proven anti-ageing therapy. AI recommendations In April, Edwin Lam, a pharmacologist at Thomas Jefferson University, was looking at AI-based predictions of potential Covid-19 treatments and found a drug called rapamycin ranked higher than many highly touted alternatives. Rapamycin is currently used to prevent organ transplant rejection, but geroscientists have been interested in its effects on longevity for decades. It specifically targets a pathway called mTOR, a major driver of many of the cell degradation processes that occur with ageing. Because rapamycin inhibits mTOR, it can help reactivate different parts of the immune system, making them behave like a younger person. Boston-based biotech company resTORbio have previously shown that forms of rapamycin can reduce rates of respiratory infections in over 65s. They are now conducting a clinical trial in the US, looking at whether giving rapamycin to nursing home residents on a daily basis, could protect them from becoming severely infected with Covid-19. If successful, it could pave the way for rapamycin becoming a new treatment for protecting older people from seasonal infections, and future viral outbreaks. New hope for Alzheimers The renewed interest in biological ageing as a result of Covid-19, could also yield benefits for other diseases linked to the ageing process, in particular Alzheimers. For years, pharma companies have attempted to develop treatments which target the accumulation of amyloid proteins in the brain during the course of the disease. With Covid-19 increasing the spotlight on how ageing makes people more vulnerable to disease, Alzheimers scientists have begun to consider alternative approaches. I think neurologists are becoming more open to the idea that we have been too insensitive to the ageing context in which Alzheimers occurs, says Jeffrey Cummings, professor of neurology at UCLA. Most patients have the onset of their disease in their 80s, where you get this accumulation of multiple adverse influences on cognitive function. One particular clue about how to prevent this accumulation may lie in our DNA. As we age, telomeres become shorter, leading to a variety of cell changes. However, in 1984 biologists Elizabeth Blackburn and Carol Greider discovered an enzyme produced in cells called telomerase which naturally prevents telomere shortening, a finding which won them the 2009 Nobel Prize. Telomerase levels also decline with age, but in recent years pharma companies have begun to wonder whether artificially boosting telomerase through drugs, could prevent age-related diseases. Seoul-based pharma company GemVax have developed a product named GV1001 which boosts telomerase levels in cells, with the aim of seeing whether it can prevent decline in Alzheimers patients and prevent the onset of the disease altogether. In a recent Phase II clinical trial of moderate to severe Alzheimers patients, they reported promising results on an assessment tool called the severe impairment battery (SIB) scale. The results exceeded our expectations, said Jay Sangjae Kim, chairman of GemVax. With the major test a Phase III trial which is set to get underway in 2021 still to come, the results must be viewed cautiously, but the success of GV1001 has the potential to yield a new frontier of telomerase based drugs for age related diseases.

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The Nashville bombing suspect sent packages to people across the country containing typed conspiracy theories about September 11 and lizard people,...

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Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity – Science Advances

January 5th, 2021 1:47 am

Abstract

Various characteristics of cancers exhibit tissue specificity, including lifetime cancer risk, onset age, and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels. Here, we study the role of synthetic lethality in cancer risk. Analyzing normal tissue transcriptomics data in the Genotype-Tissue Expression project, we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. Consistently, more cSL gene pairs become up-regulated in cells treated by carcinogens and throughout premalignant stages in vivo. We also show that the tissue specificity of numerous tumor suppressor genes is associated with the expression of their cSL partner genes across normal tissues. Overall, our findings support the possible role of synthetic lethality in tumorigenesis.

Cancers of different human tissues have markedly different molecular, phenotypic, and epidemiological characteristics, known as the tissue specificity in cancer. Various aspects of this intriguing phenomenon include a considerable variation in lifetime cancer risk, cancer onset age, and the genes driving the cancer across tissue types. The variation in lifetime cancer risk is known to span several orders of magnitude (1, 2). Such variation cannot be fully explained by the difference in exposure to carcinogens or hereditary factors and has been shown to strongly correlate with differences in the number of lifetime stem cell divisions (NSCD) estimated across tissues (2, 3). As claimed by Tomasetti and Vogelstein (2), these findings are consistent with the notion that tissue stem cell divisions can propagate mutations caused either by environmental carcinogens or random replication error (4). In addition, the importance of epigenetic factors in carcinogenesis has long been recognized (5), and Klutstein et al. (6) have recently reported that the levels of abnormal CpG island DNA methylation (LADM) across tissues are highly correlated with their cancer risk. Although both global (e.g., smoking and obesity) and various cancer typespecific (e.g., HCV infection for liver cancer) risk factors are well known (7), no factors other than NSCD and LADM have been reported to date to explain the across-tissue variance in lifetime cancer risk.

Besides lifetime cancer risk, cancer onset age, as measured by the median age at diagnosis, also varies among adult cancers (1). Although most cancers typically manifest later in life [more than 40 years old (1, 8)], some such as testicular cancer often have earlier onset (1). Many tumor suppressor genes (TSGs) and oncogenes are also tissue specific (911). For example, mutations in the TSG BRCA1 are predominantly known to drive the development of breast and ovarian cancer but rarely other cancer types (12). In general, factors explaining the overall tissue specificity in cancer could be tissue intrinsic (10, 13), and their elucidation can further advance our understanding of the forces driving carcinogenesis.

Synthetic lethality/sickness (SL) is a well-known type of genetic interaction, conceptualized as cell death or reduced cell viability that occurs under the combined inactivation of two genes but not under the inactivation of either gene alone. The phenomenon of SL interactions was first recorded in Drosophila (14) and then in Saccharomyces cerevisiae (15). In recent years, much effort has been made to identify SL interactions specifically in cancer, since targeting these cancer SLs (cSLs) has been recognized as a highly valuable approach for cancer treatment (1619). The effect of cSL on cancer cell viability has led us to investigate whether it plays an additional role even before tumors manifest, i.e., during carcinogenesis. In this study, we quantify the level of cSL gene pair co-inactivation in normal (noncancerous) human tissue as a measure of resistance to cancer development (termed cSL load, explained in detail below). We show that cSL load can explain a considerable level of the variation in cancer risk and cancer onset age across human tissues, as well as the tissue specificity of some TSGs. Together, these correlative findings support the effect of SL in impeding tumorigenesis across human tissues.

To study the potential effects of cSL in normal, noncancerous tissues, we define a measure called cSL load, which quantifies the level of cSL gene pair co-inactivation based on gene expression of normal human tissues from the Genotype-Tissue Expression (GTEx) dataset (20). Specifically, we used a recently published reference set of genome-wide cSLs that are common to many cancer types, identified from both in vitro and The Cancer Genome Atlas (TCGA) cancer patient data (21) via the identification of clinically relevant synthetic lethality (ISLE) (table S1A) (22, 23). For each GTEx normal tissue sample, we computed the cSL load as the fraction of cSL gene pairs (among all the genome-wide cSLs) that have both genes lowly expressed in that sample (Methods; illustrated in Fig. 1). We further defined tissue cSL load (TCL) as the median cSL load value across all samples of each tissue type in GTEx (Methods and table S2A). We then proceed to test our hypothesis that TCL can be a measure of the level of resistance to cancer development intrinsic to each human tissue (outlined in Fig. 1).

This diagram illustrates the computation of cSL load for each sample and each tissue type (i.e., TCL) and depicts the outline of this study, where we attempted to explain the tissue-specific lifetime cancer risk, cancer onset age, and TSGs using TCL. See main text and Methods for details.

SL is widely known to be context specific across species, tissue types, and cellular conditions (24). In theory, a cancer-specific cSL gene pair can be co-inactivated in the normal tissue without reducing normal cell fitness, while conferring resistance to the emergence of malignantly transformed cells due to the lethal effect specifically on the cancer cells. Different normal tissues can have varied TCLs (representing the levels of cSL gene pair co-inactivation) as a result of their specific gene expression profiles, and we hypothesized that normal tissues with higher TCLs should have lower cancer risk, as transforming cancerous cells in these tissues will face higher cSL-mediated vulnerability and lethality. To test this hypothesis, we obtained data on the tissue-specific lifetime cancer risk in humans (Methods) and correlated that with the TCL values computed for the different tissue types. We find a strong negative correlation between the TCL (computed from older-aged GTEx samples, age 50 years) and lifetime cancer risk across normal tissues (Spearmans = 0.664, P = 1.59 104; Fig. 2A and table S2A). This correlation is robust, as comparable results are obtained when this analysis is carried out in various ways (e.g., different cutoffs for low expression of genes, different cSL network sizes, and different cancer typenormal tissue mappings; fig. S1 and note S3). We also showed that this correlation is not confounded by the number of poised genes associated with bivalent chromatin, variation in cancer driver gene expression, and immune cell or fibroblast abundance (notes S11 to S13 and figs. S12 to S14). Notably, the cSL load varies with age due to age-related gene expression changes, and the correlation with lifetime cancer risk is not found when the TCL is computed on samples from the young population (20 age < 50 years, Spearmans = 0.0251, P = 0.901; fig. S2A); this is consistent with the observation that lifetime cancer risk is mostly contributed by cancers occurring in older populations (1). We still see a marked negative correlation between TCL and lifetime cancer risk when analyzing samples from all age groups together (Spearmans = 0.49, P = 0.01; fig. S2B). Repeating these analyses using different control gene pairs including (i) random gene pairs, (ii) shuffled cSL gene pairs, and (iii) degree-preserving randomized cSL network (same size as the actual cSL network; note S4) results in significantly weaker correlations (empirical P < 0.001; fig. S3, A to C, and note S4), confirming that the associations found with cancer risk results from a cSL-specific effect.

(A) Scatterplot showing Spearmans correlations between lifetime cancer risk and TCL computed for the older population (age 50 years) (ranked values are used as lifetime cancer risk spans several orders of magnitude.) (B) Lifetime cancer risks across tissues were predicted using linear models (under cross-validation) containing different sets of explanatory variables: (i) TCL only, (ii) the number of stem cell divisions (NCSD) only, and (iii) TCL and NSCD (27 data points). The prediction accuracy is measured by Spearmans , shown by the bar plots. The result of a likelihood ratio test between models (ii) and (iii) is also displayed. (C) A similar bar plot as in (B) comparing the predictive models for cancer risk involving the following variables: (i) TCL only, (ii) the LADM only, and (iii) TCL and LADM combined (21 data points only due to the smaller set of LADM data). A model containing all the three variables does not increase the prediction power (Spearmans = 0.77 under cross-validation) and is not shown. (D) Bar plot showing the correlations between lifetime cancer risk with TCLs computed (age 50 years) using subsets of cSLs: hcSLs, lcSLs, and all cSLs. Spearmans and P values are shown. The hcSLs and lcSLs are identified using data of matched TCGA cancer types and GTEx normal tissues (Methods), which correspond to only a subset of tissue types. To facilitate comparison, here, the correlation for all cSLs was also computed for the same subset of tissues, and therefore, the resulting correlation coefficient is different from that in (A).

While the randomized cSL networks used in the control tests described above provide significantly weaker correlations with cancer risk than those observed with cSLs, many of these correlations are still significant by themselves (fig. S3, B and C). This suggests that there may be a possible association between the expression of single genes in the cSL network (cSL genes) and cancer risk. To investigate this, we computed the tissue cSL single-gene load (SGL; the fraction of lowly expressed cSL genes) for each tissue (Methods). We do find a significant negative correlation between tissue SGL levels and cancer risk (Spearmans = 0.49, P = 0.01; fig. S3D and note S5). This correlation vanishes when we use random sets of single genes (fig. S3F). However, after controlling for the single-gene effect, the partial correlation between TCL and cancer risk is still highly significant (Spearmans = 0.69, P = 6.10 105; fig. S3G), pointing to the dominant role of the SL genetic interaction effect (note S5).

We next compared the predictive power of TCL to those obtained with the previously reported measures of NSCD (2, 3) and LADM (6), using the set of GTEx tissue types investigated here (Methods). We first confirmed the strong correlations of NSCD and LADM with tissue lifetime cancer risk in our specific dataset (Spearmans = 0.72 and 0.74, P = 2.6 105 and 1.3 104, respectively; fig. S4). These correlations are stronger than the one we reported above between TCL and cancer risk. However, adding TCL to either NSCD or LADM in linear regression models leads to enhanced predictive models of cancer risk compared to those obtained with NSCD or LADM alone [log-likelihood ratio (LLR) = 2.18 and 2.39, P = 0.037 and 0.029, respectively]. Furthermore, adding TCL to each of these factors increases their prediction accuracy under cross-validation (Spearmans s from 0.67 and 0.69 with NSCD and LADM alone to 0.71 and 0.77, respectively; Fig. 2, B and C). LADM and NSCD are significantly correlated (Spearmans = 0.66, P = 0.02), while the TCL correlates only in a borderline significant manner with either NSCD (Spearmans = 0.57, P = 0.06) or LADM (Spearmans = 0.52, P = 0.08). Together, these observations support the hypothesis that TCL is associated with tissue cancer risk, with a partially independent role from either NSCD or LADM.

We have shown results that support the role of TCL in impeding cancer development, and we reason that such an effect is dependent on the notion that many of the cSLs are specific to cancer while having weaker or no lethal effects in normal tissues. We tested and found that the co-inactivation of cSL gene pairs is under much weaker negative selection in GTEx normal tissues versus matched TCGA cancers [Wilcoxon rank sum test P = 2.93 106 (fig. S5A), also shown using cross-validation (note S7)]. Moreover, we hypothesize that those cSLs with the highest specificity to cancer (i.e., with the strongest SL effect in cancer and no or the weakest effect on normal cells) should have the strongest effect on cancer development. To test this, we identified the subset of such cSLs (termed highly specific cSLs or hcSLs) and those with the lowest specificity to cancer (termed lowly specific cSLs or lcSLs; Methods) and recomputed the TCLs of all normal GTEx tissues using these two cSL subsets, respectively. The TCLs computed from the hcSLs correlate much stronger with cancer lifetime risk than those computed from the lcSLs (Spearmans = 0.593 versus 0.319; Fig. 2D), testifying that these cSLs with high functional specificity to cancer are more relevant to carcinogenesis. These hcSLs are enriched for cell cycle, DNA damage response, and immune-related genes [false discovery rate (FDR) < 0.05; table S5 and Methods], which are known to play key roles in tumorigenesis.

We have thus established that TCL in the older population is inversely correlated with lifetime cancer risk across tissues. We next hypothesized that higher cSL load in a given normal tissue in the young population may delay cancer onset, which typically occurs later (age >40 years) (1). To test this, we use the median age at cancer diagnosis (1) of a certain tissue as its cancer onset age (table S3 and Methods). We find that the TCL values (for age 40 years) are markedly correlated with cancer onset age (Spearmans = 0.502, P = 0.011; Fig. 3A). This result is again robust to variations in our methods to compute TCL and cancer onset age (fig. S6, table S3, and note S3). We note that the cancer onset age is not significantly correlated with lifetime cancer risk (Spearmans = 0.279, P = 0.28).

(A) Scatterplot showing Spearmans correlations between cancer onset age and TCL (age 40 years). (B) Bar plot showing the correlations between cancer onset age with TCLs computed (age 40 years) using subsets of cSLs: hcSLs, lcSL, and all cSLs. Spearmans and P values are shown. As in Fig. 2D, this analysis was done for a subset of GTEx normal tissues for which we had matched TCGA cancer types to identify the hcSLs and lcSLs (Methods); therefore, the correlation result for all cSLs is also different from that in (A).

Similar to our earlier analysis, we see that the TCLs computed from the hcSLs correlate much stronger with onset age than those from the lcSLs or all cSLs (Spearmans = 0.603 versus 0.157; Fig. 3B and fig. S7A) and also stronger than those obtained from control tests performed as before (empirical P < 0.001; fig. S7, B to D). As with the case of cancer risk, the observed correlation is dominated by the SL genetic interaction effects rather than the single-gene effects (fig. S7, E to G, and note S5).

To further corroborate the relevance of cSL load to carcinogenesis, we next investigated whether carcinogen treatment in normal (noncancer) cell lines and primary cells in vitro can lead to cSL load decrease. First, we analyzed gene expression data from a recent study where human primary hepatocytes, renal tube epithelial cells, and cardiomyocytes were treated with the carcinogen and hepatotoxin thioacetamide-S-oxide (25). We computed the cSL load in each cell type after treatment versus control and found a significant decrease of cSL load only in the hepatocytes (Wilcoxon rank sum test P = 0.014; Fig. 4A), which is consistent with thioacetamide-S-oxides role as a hepatotoxin and a carcinogen primarily in the liver. Second, we collected the gene expression signatures of chemotherapy drug treatments in a total of four primary cells and normal cell lines from the Connectivity Map (CMAP) (26). We quantified the drug-induced cSL load changes indirectly from the gene signatures (Methods), comparing the strongly mutagenic DNA-targeting drugs (n = 6) including alkylating agents and DNA topoisomerase inhibitors to the weak/nonmutagenic taxanes and vinca alkaloids (n = 5), which act on the cytoskeleton and not directly on DNA (27). We find that the strong mutagenic chemotherapy drugs lead to a significantly larger decrease in cSL load (Fig. 4B, P = 0.03 from a linear model controlling for cell type; Methods). The strong mutagenicity of alkylating agents and DNA topoisomerase inhibitors is consistent with their mechanisms of actions; they are also World Health Organization class I carcinogens (28), supported by incidence of secondary cancers in patients treated by these drugs for their primary cancers (29). In contrast, taxanes and vinca alkaloids have shown negative or weak/inconclusive results in mutagenic tests (27, 30). These results are not likely affected by cell death, as the cSL decreased specifically only for the two classes among all tested chemotherapy drugs. Although the CMAP dataset used for this analysis does not include cell viability information, the gene expression of the cells does not show an apoptotic signature after the drug treatment.

(A) Box plots showing the cSL loads in control versus thioacetamide-S-oxidetreated samples in human primary hepatocytes (liver), renal tube epithelial cells (kidney), and cardiomyocytes (heart), using the data from (25). One-sided Wilcoxon rank-sum test P values are shown. (B) Box plots showing the cSL load changes after treatment by different classes of chemotherapy drugs in four cell types, using the CMAP data (26). Asterisk indicates that the cSL load change is estimated indirectly from the CMAP drug treatment gene expression signatures (Methods). Strongly mutagenic drugs (n = 6), including alkylating agents (green points) and DNA topoisomerase inhibitors (purple points), lead to a significantly larger cSL load decrease compared to weak or nonmutagenic drugs (n = 5), including taxanes (red points) and vinca alkaloids (blue points); P = 0.03 from a linear model controlling for cell type. HA1E is an immortalized kidney cell line; PHH, primary human hepatocyte; ASC, adipose-derived stem cell; SKB, human skeletal myoblast. (C) Box plots showing the cSL load in samples of different stages of premalignant lesions in the lung (including normal tissue and lung squamous cell carcinoma) (28). The cSL load shows an overall decreasing trend from normal to different pre-cancer stages to cancer (one-sided Wilcoxon rank sum test of normal versus cancer P = 4.47 105; ordinal logistic regression has negative coefficient 28.7, P = 5.89 107).

Further beyond these in vitro findings, analyzing a recently published lung cancer dataset (31), we find that cSL load decreases progressively as cancers develop from normal tissues throughout the multiple stages of premalignant lesions in vivo (normal versus cancer Wilcoxon rank sum test P = 4.47 105, ordinal logistic regression P = 5.89 107 with negative coefficient 28.7; Fig. 4C). These results provide further evidence supporting cSL as a factor that may be involved in cancer development.

Given the role of cSLs in cancer development, we turned to ask whether cSL may also contribute to the tissue/cancer-type specificity of TSGs (10, 32). Specifically, we reasoned that the loss of function of a gene is unlikely to have cancer-driving effects in tissues where its cSL partner genes are lowly expressed, due to the synthetic lethal effect of such co-inactivation on the emerging cancer cells. In other words, this gene is unlikely to be a TSG in such tissues. To study this hypothesis, we obtained a list of TSGs together with the tissues in which their loss is annotated to have a tumor-driving function from the COSMIC database (table S6A) (11). We further identified the cSL partner genes of each such TSG using ISLE (Methods and table S6B) (22). In total, there are 23 TSGs for which we were able to identify more than one cSL partner gene. Consistent with our hypothesis, we find that in most of the cases, the cSL partner genes of TSGs have higher expression levels in the tissues where the TSGs are known drivers compared to the tissues where they are not established drivers (binomial test for the direction of the effect P = 0.023; Fig. 5A). We identified 10 TSGs whose individual effects are significant (FDR < 0.05) and cSL specific (as shown by the random control test), and all these 10 cases exhibit the expected direction of effect (labeled in Fig. 5A and table S6C; two example TSGs, FAS and BRCA1, are shown in Fig. 5B, details are in fig. S8 and Methods). Reassuringly, these findings disappear under randomized control tests involving random partner genes of the TSGs and shuffled TSGtissue type mappings (note S9), further consolidating the role of cancer-specific cSLs of normal tissues in cancer risk and development.

(A) For each tissue-specific TSG gene Gi, the expression levels of its cSL partner genes in the tissue type(s) where gene Gi is a TSG were compared to those where gene Gi is not an established TSG, using GTEx normal tissue expression data. The volcano plot summarizes the result of comparison with linear models. Positive linear model coefficients (x axis) mean that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where gene Gi is a TSG. Many cases have near-zero P values and are represented by points (half-dots) on the top border line of the plot. Overall, there is a dominant effect of the cSL partner genes of TSGs having higher expression levels in the tissues where the TSGs are known drivers (binomial test P = 0.023). All TSGs with FDR < 0.05 that also passed the random control tests are labeled. (B) Examples of two well-known TSGs, FAS and BRCA1, are given. The heatmaps display the normalized expression levels of their cSL partner genes (rows) in tissues of where these two genes are known to be TSGs [according to the annotation from the COSMIC database (11)] and in tissues where they are not established TSGs (columns), respectively. High and low expressions are represented by red and blue, respectively. For clarity, one typical tissue type where the TSG is a known driver (e.g., testis for FAS) and three other tissue types where the TSG is not an established driver (and the least frequently mutated) are shown.

In this work, we show that the cSL load in normal tissues is a strong predictor of tissue-specific lifetime cancer risk and is much stronger than the pertaining predictive power observed on the individual gene level. Consistently, we find that higher cSL load in the normal tissues from young people is associated with later onset of the cancers of that tissue. As far as we know, no other factor has been previously reported to be predictive of cancer onset age across tissues. Furthermore, cSL load decreases upon carcinogen treatment in vitro and during cancer development through stages of precancerous lesions in vivo. Last, we show that the activity status of cSL partners of TSGs can explain their tissue-specific inactivation.

We have shown that the correlation between cSL and cancer risk in normal tissues may be explained by the fact that many of the cSLs are specific to cancer and have weak or no functional lethal effect in the normal tissues (Figs. 2D and 3B and fig. S5); therefore, normal tissues can bear relatively high cSL loads without being detrimentally affectedquite to the contrary, they become more resistant to cancer due to the latent effect of these cSLs on potentially emerging cancer cells. We emphasize that while we quantified the cSL loads using the normal tissue data from GTEx, the set of cSLs we used was derived exclusively in cancer from completely independent cancer datasets (and without using any information regarding lifetime cancer risk, onset, or tumor suppressor tissue specificity), so there is no circularity involved. The cSL load in normal tissues was computed to reflect the summed effects of individual cSL gene pairs. The underlying assumption is that the low expression of each cSL gene pair is synthetic sick (i.e., reducing cell fitness to some extent) and that the effects from different cSL gene pairs are additive, consistent with the ISLE method of cSL identification (22). Many experimental screenings of SL interactions also rely on techniques such as RNA interference that inhibits gene expression rather than completely knocks out a gene (33), and it is evident that most of the resulting SL gene pairs have milder than lethal effects. While these cSLs likely act via a diverse range of biological pathways and thus do not provide pathway-specific mechanisms, the additive cancer-specific lethal effect of such cSL gene pairs, however, could form a negative force impeding cancer development from normal tissues.

Obviously, as we are studying the across-tissue association between cSL load and cancer risk, it is essential to focus on cSLs that are common to many cancer types (i.e., pan-cancer). Therefore, we focused on cSLs identified computationally by ISLE via the analysis of the pan-cancer TCGA patient data (22). In contrast, most experimentally identified cSLs are obtained in specific cancer cell lines and are thus less likely to be pan-cancer [and possibly, less clinically relevant (22)]. However, for completeness, we also compiled a set of experimentally identified cSLs from published studies (22, 34) (note S1 and table S1B). The corresponding TCL values computed using this set of cSLs correlate significantly with lifetime cancer risk but not with cancer onset age; the correlation with cancer risk is also markedly weaker than that obtained from ISLE-derived cSLs [Spearmans = 0.433, P = 0.024 (fig. S9A), control tests and detailed analysis are explained in note S4]. These experimentally identified cSLs can explain some cases of tissue-specific TSGs including BRCA1 and BRCA2 (fig. S9E) but do not result in overall significant accountability for a large proportion of TSGs present in the analysis (like in Fig. 5A). This corroborates the importance of pan-cancer cSLs and their relevance to cancer risk.

TCL is not likely to be a corollary of NSCD and LADM [while LADM was thought to be closely related to NSCD (6)], as the cSL load is computed by analyzing expression data of bulk tissues, where stem cells occupy only a minor proportion. We have shown that TCL significantly adds to either NSCD or LADM in predicting lifetime cancer risk (Fig. 2, B and C), which also suggests that cSL load is an independent factor correlated with cancer risk with unique underlying mechanisms. Furthermore, NSCD is measured as the product of the rate of tissue stem cell division and the number of stem cells residing in a tissue (2), and we confirmed that TCL is correlated with lifetime cancer risk independent of both of these components (partial Spearmans = 0.510 and 0.567, P = 0.007 and 0.002, respectively; fig. S10, A and B). We additionally tested and verified that proliferation indices computed for the bulk normal tissues do not correlate with lifetime cancer risk across tissues (Spearmans = 0.062, P = 0.77; fig. S10C and note S10). Furthermore, we verified that our observed correlations are not confounded by the number of samples from each cancer or tissue type (fig. S11).

Since cSL load can vary with age, one may wonder whether cSL load could be extended to correlate with age-specific cancer risk within a tissue (as opposed to across tissues). However, variations in cancer risk across tissues and across ages can be driven by different factors. We did not find a consistent correlation between cSL load computed by age range and age-specific cancer risk in all tissue types (note S14 and fig. S15). Another extension to our current research question is studying the effect of higher-order genetic interactions on cancer risk, which is plausible but challenging to study due to the limited knowledge available on such complex interactions.

While revealing cSL as a previously unknown factor associated with cancer development, our study has several limitations. First, because of the importance of using pan-cancer cSLs as discussed above, we mainly relied on the cSLs computationally inferred by ISLE (22) as one of the most comprehensive pan-cancer cSL datasets. However, current cSL prediction algorithms are far from perfect and should not be regarded as the gold standard for general cSL identification. Only a minor fraction of the large number of predicted cSLs have been experimentally validated only in specific cell types. The cSLs inferred by ISLE should be best viewed as a set of candidate cSL pairs that emerge from genetic screen data in vitro but with further support from patient and phylogenetic data. Future studies that provide experimentally validated pan-cancer cSLs are needed to consolidate our current findings. Second, we have relied on analyzing the gene expression data of bulk tissues from GTEx and not the expression data of the specific cells of origin of the corresponding cancers. More refined future analysis is desirable using single-cell data across normal human tissues as such data becomes more widely available. Last, our study does not establish a causal relationship between the cSL load and the risk of cancer, as it is challenging to experimentally perturb a large number of cSLs simultaneously. The results shown are descriptive and association based, and the causal role of SLs in carcinogenesis remains to be studied mechanistically.

Together, our findings demonstrate strong associations between SL and cancer risk, onset time, and context specificity of tumor suppressors across human tissues. This suggests that beyond the effect on cancer after it has developed, cSL could also play an important role during the entire course of carcinogenesis, although further studies are needed to establish causality. While SL has been attracting tremendous attention as a way to identify cancer vulnerabilities and target them, this is the first time that its potential role in mediating cancer development is uncovered.

The cSL gene pairs computationally identified by the ISLE (identification of clinically relevant SL) pipeline were obtained from (22). We used the cSL network identified with FDR < 0.2 for the main text results, containing 21,534 cSL gene pairs, which is a reasonable size representing only about one cSL partner per gene on average. This also allows us to capture the effects of many weak genetic interactions. Nevertheless, we also used the cSL network with FDR < 0.1 (only 2326 cSLs) to demonstrate the robustness of the results to this parameter (notes S1 and S3). Each gene pair is assigned a significance score [the SL-pair score defined in (22)], that a higher score indicates that there is stronger evidence that the gene pair is SL in cancer. Out of these, we used 20,171 cSL gene pairs whose genes are present in the GTEx data (table S1A). The experimentally identified cSL gene pairs were collected from 18 studies [obtained from the supplementary data 1 of Lee et al. (22) except for those from Horlbeck et al. (34)]. Horlbeck et al. (34) provided a gene interaction (GI) score for each gene pair in two leukemia cell lines. Gene pairs with GI scores of <1 in either cell line were selected as cSLs. A total of 27,975 experimentally identified cSLs were obtained, out of which 27,538 have both their genes present in the GTEx data (table S1B).

The V6 release of GTEx (20) RNA sequencing (RNA-seq) data [gene-level reads per kilobase of transcript, per million mapped reads (RPKM) values] was obtained from the GTEx Portal (https://gtexportal.org/home/). The associated sample phenotypic data were downloaded from dbGaP (35) (accession number phs000424.vN.pN). For comparing the level of negative selection to co-inactivation of cSL gene pairs between normal and cancer tissues, the RNA-seq data of TCGA and GTEx as RNA-seq by expectation-maximization (RSEM) values that have been processed together with a consistent pipeline that helps to remove batch effects were downloaded from UCSC Xena (36). The expression data for each tissue type (normal or cancer) was normalized separately (inverse normal transformation across samples and genes) before being used for the downstream analyses. We mapped the GTEx tissue types to the corresponding TCGA cancer types (table S2B), resulting in one-on-many mappings, e.g., the normal lung tissue was mapped to both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).

Lifetime cancer risk denotes the chance a person has of being diagnosed with cancer during his or her lifetime. Lifetime cancer risk data (table S2A) are from Tomasetti and Vogelstein (2), which are based on the U.S. statistics from the SEER (Surveillance, Epidemiology, and End Results) database (1). We derived the cancer onset age based on the age-specific cancer incidence data from the SEER database with the standard formula (37). Specifically, for each cancer type, SEER provides the incidence rates for 5-year age intervals from birth to 85+ years old. The cumulative incidence (CI) for a specific age range S is computed from the corresponding age-specific incidence rates (IRi, i S) as CI = 5i S IRi, and the corresponding risk is computed as risk = 1 exp(CI). The onset age for each cancer type (table S3) was computed as the age when the CI from birth is 50% of the lifetime CI (i.e., birth to 85+ years old). Usually, the onset age defined as such is between two ages where the actual CI data are available, so the exact onset age was obtained by linear interpolation. Alternative parameters were used to define onset age (note S3) to show the robustness of the correlation between TCL and cancer onset age based on different definitions.

For each sample, we computed the number of cancer-derived SL gene pairs that have both genes lowly expressed and divided it by the total number of cSLs available to get the cSL load per sample. In the ISLE method described in (22), low expression was defined as having expression levels below the 33 percentile in each tissue or cell type. Thus, the ISLE-derived cSL gene pairs were shown to exhibit synthetic sickness effects when both genes in the gene pair are expressed at levels below the 33 percentile in each tissue, even though this appears to be a very tolerant cutoff (22). We therefore adopted the same criterion for low expression for the main results, although we also explored other low expression cutoffs to demonstrate the robustness of the results (note S3).

TCL of each tissue type is the median value of the cSL loads of all the samples (or a subpopulation of samples) in that tissue, with the cSL load of a sample computed as above. For example, TCL for the older population (age 50 years) is the median cSL load for the samples of age 50 years in each tissue type. For analyzing the correlation between the TCLs computed from GTEx normal tissues and cancer risk, we mapped the GTEx tissue types to the corresponding cancer types for which lifetime risk data are available from Tomasetti and Vogelstein (2), resulting in 16 GTEx types mapped to 27 cancer types (table S2A). Gallbladder nonpapillary adenocarcinoma and osteosarcoma of arms, head, legs, and pelvis are not mapped to GTEx tissues and excluded from our analysis. Similarly for the correlation between TCLs and cancer onset age, we mapped GTEx tissue types to the tissue sites from the SEER database (as given in the data slot site recode ICD-O-3/WHO 2008) by their names (table S3).

To investigate the effect on the single-gene level, we computed the cSL SGL in a paralleling way to the computation of the cSL load. Among all the unique genes constituting the cSL network (i.e., cSL genes), we computed the fraction of lowly expressed cSL genes for each sample as the cSL SGL, where low expression was defined in the same way as the computation of cSL load as elaborated above. Similarly, tissue cSL SGL is the median value of the cSL SGLs of all the samples in a tissue.

The lifetime cancer risks across tissue types were predicted with linear models containing three different sets of explanatory variables: (i) the number of total stem cell divisions (NSCD) alone, (ii) TCL alone, and (iii) NSCD together with TCL. LLR test was used to determine whether model (iii) (the full model) is significantly better than model (i) (the null model) in predicting lifetime cancer risks. The three models were also used to predict the lifetime cancer risks with a leave-one-out cross-validation procedure, and the prediction performances were measured by Spearman correlation coefficient. A similar analysis was performed to predict lifetime cancer risks across tissue types with three linear models involving the level of abnormal DNA methylation levels of the tissues (6): (i) the number of LADM alone, (ii) TCL alone, and (iii) LADM together with TCL.

For each pair of GTEx normalTCGA cancer of the same tissue type (table S2B), we computed the fraction of samples where a cSL gene pair i has both genes lowly expressed (defined above) among the normal samples (fni) and cancer samples (fci) and computed a specific score as rsi = fni fci. We selected the hcSLs as those whose specific scores are greater than the 75% percentile of all scores and lcSLs as those with a score below the 25% percentile (table S4, A and B). We compared SL significance scores between the hcSLs and lcSLs in each tissue using a Wilcoxon rank sum test. For each type of the GTEx normal tissues used in this analysis (i.e., those that can be mapped to TCGA cancer types), we also computed the TCL as above but using the hcSLs, lcSLs, or all cSLs, respectively, and analyzed their correlation with lifetime cancer risk or cancer onset age across the tissues.

We designed an empirical enrichment test as below to account for the fact that each cSL consists of two genes. For the hcSLs in each tissue type and each given pathway from the Reactome database (38), we computed the odds ratio (OR) for the overlap between the genes in hcSLs and the genes within the pathway based on the Fishers exact test procedure, with the background being all the genes in the ISLE-inferred cSLs. A greater than 1 OR indicates that the hcSLs are positively enriched for the genes of the pathway. To determine the significance of the enrichment, we repeatedly and randomly sampled the same number of cSLs as that of the hcSLs, computed the ORs similarly, and computed the empirical P value as the fraction of cases where the OR from the random cSLs is greater than that from the hcSLs. We corrected for multiple testing across pathways with the Benjamini-Hochberg method.

The phase I CMAP (26) data were downloaded from the Gene Expression Omnibus database (GSE92742). Level 5 data that represent the consensus perturbation-induced differential expression signature were used. We focused on CMAP data that involve treatment by specific classes of chemotherapy drugs (mutagenic: alkylating agents and DNA topoisomerase inhibitors; nonmutagenic: taxanes and vinca alkaloids) in normal cell lines or primary cells. We identified a total of 11 drugs tested in four cell types. Given the signature (z score) of a drug treatment in a cell, we estimated the drug-induced cSL load change as follows1|S|((i,j)SI(zi<0.5zj<0.5)(i,j)SI(zi>0.5zj<0.5))where S is the set of cSLs, and |S| is the total number of cSL gene pairs. A gene pair is denoted by (i, j), and zi and zj are the z scores of gene i and gene j, respectively. I() is the indicator function. Intuitively, the above formula quantifies the number of cSL gene pairs where both genes are down-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load increase), minus the number of cSL gene pairs where either gene is up-regulated with a z score cutoff of 0.5 (i.e., contributing to cSL load decrease), normalized by the total number of cSL gene pairs. We then tested whether the mutagenic drugs lead to a larger decrease in cSL load compared to nonmutagenic drugs with a linear model that controls for both cell type and drug.

We obtained the list of TSGs and their associated tissue types from the COSMIC database (11) (https://cancer.sanger.ac.uk/cosmic/download, the Cancer Gene Census data; table S6A). For each TSG, their cSL partner genes were identified using the ISLE pipeline (22) with an FDR cutoff of 0.1 (table S6B). Here, the FDR cutoff is more stringent than that used for the pan-cancer genome-wide cSL network (FDR < 0.2 for the main results) since, here, FDR correction was performed for each TSG, corresponding to a much lower number of multiple hypotheses. As a result, the FDR correction has more power, and a relatively more stringent cutoff can give rise to a more reasonable number of cSL partner genes per TSG. We focused our analysis on 23 TSGs for which more than one cSL partner genes were identified (no cSL partner was identified for most of the other TSGs). The expression levels of the cSL partner genes were then compared between tissue type(s) where the TSG is a known driver and the rest of the tissues where the TSG is not an established driver with linear models. Specifically, the expression levels of the cSL partners were modeled with two explanatory variables: (i) driver status of the TSG in the tissue (binary) and (ii) cSL partner gene (categorical, indicating each of the cSL partner genes of a TSG). The coefficient and P value associated with variable (i) were used to analyze the general trend of differential expression among the cSL partner genes. Positive coefficients of variable (i) means that the expression levels of the cSL partner genes are, on average, higher in the tissue(s) where the TSG is a known driver compared to those in the tissues where the TSG is not an established cancer driver.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors – PRNewswire

January 5th, 2021 1:47 am

MILWAUKEE, Dec. 30, 2020 /PRNewswire/ -- Versiti Blood Centers and premier partner Noodles & Company are dishing out discounts for life-saving donations during National Blood Donor Month this January.

Since 2016, Noodles & Company has supported Versiti's mission by aligning as a community partner and donating over $1.3 million in discounts and coupons to blood donors. Throughout January 2020, all attempting blood donors will receive a coupon redeemable for $4 off their order when they donate at a Versiti donor center or select community blood drive.

January is National Blood Donor Month, which highlights the critical need for blood during winter when donations often decline. Donors of all blood types are needed, but especially O negative blood donors who carry the universal blood type given to people in emergency situations.

To schedule an appointment, visit versiti.org.

About Versiti Blood Centers Versiti is a not-for-profit organization headquartered in Milwaukee that specializes in blood services, esoteric diagnostic testing, organ, tissue and stem cell donation, medical services and leading-edge research. Founded in 1947, Versiti is the primary provider of blood products and services for more than 250 hospitals in five midwestern states: Illinois, Indiana, Michigan, Ohio and Wisconsin. Versiti collects more than 602,000 units of blood each year at 35 permanent donation sites and more than 12,000 community blood drives. For more, visit versiti.org.

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Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors - PRNewswire

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January 2021: 2020 Papers of the Year – Environmental Factor Newsletter

January 5th, 2021 1:47 am

Research funded by grantsPFAS linked with liver injury in children

Exposure to per- and polyfluoroalkyl substances (PFAS) in the womb may increase liver injury risk in children, according to NIEHS-funded researchers. This study is the first to examine the impact of early life exposures to a PFAS mixture on child liver injury. PFAS, a large group of synthetic chemicals found in a variety of consumer products, have been linked to immune dysfunction, altered metabolism, brain development, and certain cancers.

The study used data from 1,105 mothers and their children enrolled in the Human Early-Life Exposome, or HELIX, study in Europe. Using computational modeling, the scientists found that higher exposures to PFAS during pregnancy were associated with higher levels of liver enzymes in children. High liver enzyme levels may point to nonalcoholic fatty liver disease (NAFLD). The researchers also identified a profile for children at high risk for liver injury, characterized by high prenatal PFAS exposures.

Citation: Stratakis N, Conti DV, Jin R, Margetaki K, Valvi D, Siskos AP, Maitre L, Garcia E, Varo N, Zhao Y, Roumeliotaki T, Vafeiadi M, Urquiza J, Fernandez-Barres S, Heude B, Basagana X, Casas M, Fossati S, Grazuleviciene R, Andrusaityte S, Uppal K, McEachan RRC, Papadopoulou E, Robinson O, Haug LS, Wright J, Vos MB, Keun HC, Vrijheid M, Berhane KT, McConnell R, Chatzi L. 2020. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children. Hepatology 72(5):17581770. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a1))

In an NIEHS-funded study, researchers uncovered a previously unknown way that genes code for proteins. Rather than directions going one way from DNA through messenger RNA (mRNA) to proteins, the study showed that RNA can modify how DNA is transcribed into mRNA and translated to produce proteins.

Using mouse stem cells, the scientists found that mRNA modifies how DNA is transcribed using a reversible chemical reaction called methylation, which can change the activity of a DNA segment without changing the sequence. The researchers identified and characterized several proteins that recognized the methylated mRNA. They also discovered a group of RNAs called chromosome-associated regulatory RNAs (carRNAs) that used the same methylation process and controlled how DNA was stored and transcribed. The team found that a specific methylation modification, N6-methyladenosine, served as a switch to control carRNA levels, which regulated DNA transcription.

Citation: Liu J, Dou X, Chen C, Chen C, Liu C, Xu MM, Zhao S, Shen B, Gao Y, Han D, He C. 2020. N 6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 367(6477):580586. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a1))

Loss of the enzyme topoisomerase 1 (TOP1) leads to DNA damage in neurons and neurodegeneration, according to an NIEHS-funded study. TOP1 plays an important role in facilitating the expression of long genes that are important for neuronal function. The data suggest that TOP1 maintains proper gene function in the central nervous system.

The researchers deleted TOP1 in mouse neurons and examined behavior, development, and underlying indicators of neurodegeneration, such as inflammation. Mice lacking TOP1 showed signs of early neurodegeneration, with brains 3.5-times smaller at postnatal day 15 compared with controls. Although neurons developed normally, mice without TOP1 showed motor deficits, exhibited lower levels of nicotinamide adenine dinucleotide (NAD-plus) a compound critical in energy metabolism and died prematurely. However, when these mice received supplemental NAD-plus, they lived 30% longer, had less inflammation, and showed improved neuronal survival.

Citation: Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, Simon JM, Yuan H, Li Z, McConnell MJ, Zylka MJ. 2020. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun 11(1):1962. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dert/index.htm#a4))

NIEHS grantees found that a protein known as XPA bends DNA and pauses in response to DNA damage, revealing the location of damaged DNA and potentially promoting the recruitment of DNA repair proteins. Using single molecule experiments and imaging techniques, the researchers observed the biochemistry of a living cell.

The researchers used a new method to calculate the molecular weight of small proteins bound to DNA and tracked proteins involved in DNA repair in 3D using real-time single molecule imaging. XPA cycled through three distinct states on DNA: rapidly hopping over long distances of the DNA strand; slowly sliding over short ranges of DNA while bending local DNA regions; and pausing and forming complexes with bent DNA. XPA paused more frequently in the presence of more DNA damage. The work provided insight into a new damage sensor role for XPA.

Citation: Beckwitt EC, Jang S, Detweiler IC, Kuper J, Sauer F, Simon N, Bretzler J, Watkins SC, Carell T, Kisker C, Van Houten B. 2020. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nat Commun 11(1):1356. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dert/index.htm#a2))

NIEHS grantees found that individual cells in a population respond differently to estrogen stimulation at both the level of single cells and alleles, which are other possible forms of a gene. These differences were not explained by estrogen receptor levels in the cells or receptor activation status.

The researchers treated human breast cancer cells with estrogen and examined two genes, GREB1 and MYC, whose activities are regulated by estrogen. Unexpectedly, individual cells exhibited large differences in the level of gene activation, even between alleles within the same cell. The scientists used automated high-throughput technologies to test small molecule inhibitors of the estrogen receptor regulators. One inhibitor, called MS049, markedly increased the response of individual alleles to estrogen. The researchers altered estrogenic response by inhibiting estrogen receptor regulators, establishing a previously unrecognized regulation path for estrogen to activate genes at the single cell level.

Citation: Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. 2020. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 48(4):18001810. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/index.htm#a3))

NIEHS grantees showed that mice exposed to e-cigarette smoke (ECS) were more likely to develop lung adenocarcinomas, a type of lung cancer. They also found that exposed mice had higher levels of bladder urothelial hyperplasia, an abnormal increase in epithelial cells that can precede development of bladder tumors.

The researchers exposed one group of mice to ECS aerosols generated from e-juice containing nicotine and compared them to a second group of mice exposed to a control aerosol without ECS. A third group of mice was exposed only to filtered air. Of the ECS mice, 22.5% developed lung adenocarcinomas and 57.5% developed urothelial hyperplasia. Mice with ECS-induced lung adenocarcinomas were not more prone to developing urothelial hyperplasia, which suggested that the two outcomes were divergent events and might involve different mechanisms.

Citation: Tang MS, Wu XR, Lee HW, Xia Y, Deng FM, Moreira AL, Chen LC, Huang WC, Lepor H. 2019. 2019. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proc Natl Acad Sci U S A 116(43):2172721731. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dert/index.htm#a1))

NIEHS grantees identified a novel pathway that controls the metabolic response of astrocytes, which are brain and spinal cord cells essential to maintaining central nervous system (CNS) health. Although astrocytes perform various functions, such as providing nerve cells with nutrients, they have been linked to CNS inflammation and multiple sclerosis (MS).

Using a mouse model of MS, researchers found that during the progressive phase of the disease, brain astrocytes switched on metabolic pathways that activated a protein called the mitochondrial antiviral signaling (MAVS) protein. It led to activation of several proinflammatory genes, triggering inflammation in the brain and spinal cord. If the scientists gave the mice the drug miglustat before the onset of MS, they were able to suppress MAVS activation and subsequent inflammation. The findings suggest a new role for MAVS in CNS inflammation and a potential therapeutic target for MS.

Citation: Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. 2019. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179(7):14831498.e22. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a3))

NIEHS-funded researchers found that a mutation in the ultraviolet irradiation resistanceassociated gene (UVRAG), which is involved in cell regulation, can disrupt autophagy in mice. Autophagy is the process of removing damaged cells so the body can regenerate newer cells. The scientists say the UVRAG mutation causes increased inflammatory response and tumor development. The study provides the first genetic evidence connecting UVRAG suppression to autophagy regulation, inflammation, and cancer predisposition.

The researchers generated mice that expressed UVRAG with a frameshift mutation, which is a deletion or insertion in DNA that shifts the way the sequence is read. After inducing sepsis or intestinal colitis, they found that mice with the UVRAG mutation displayed increased inflammatory responses in both conditions and increased spontaneous tumor development compared with wild-type mice. The results indicate UVRAG could be one reason people are more susceptible to cancers as they age.

Citation: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O'Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/index.htm#a4))

Exposure to polybrominated biphenyl (PBB) 153, a type of brominated flame retardant, alters DNA methylation in sperm, according to NIEHS grantees. DNA methylation refers to heritable changes in gene expression that occur with no alteration in the DNA sequence. Because PBB153 is toxic to living organisms following direct exposure, the study suggests it may also harm future generations.

The results of a Michigan PBB study showed that PBB153 was associated with gene methylation events in mens sperm. Based on this information, the research team conducted sperm studies and determined that exposure to PBB153 decreased methylation at regions of DNA that control imprinted genes, which are essential for fetal growth and play an important role in other aspects of development. These effects could explain some of the endocrine-related health effects that have been observed among children of PBB-exposed parents.

Citation: Greeson KW, Fowler KL, Estave PM, Thompson SK, Wagner C, Edenfield RC, Symosko KM, Steves AN, Marder EM, Terrell ML, Barton H, Koval M, Marcus M, Easley CA 4th. 2020. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci Rep 10(1):8567. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dert/index.htm#a4))

NIEHS grantees determined that in mice, air pollution may play a role in the development of cardiometabolic diseases, such as diabetes, with effects comparable to eating a high-fat diet (HFD). They also established that effects were reversed when exposure to air pollution stopped.

The scientists divided male mice into three categories: those that received clean filtered air; those exposed to concentrated particulate matter 2.5 air pollution; and those that received clean filtered air and were fed an HFD. After 14 weeks, team members measured insulin resistance and glucose levels and assessed epigenetic changes, or chemical tags, that attach to DNA and affect gene expression.

Air pollution exposure was comparable to eating an HFD. Mice in the air pollution and HFD groups had impaired insulin resistance, high glucose, and reduced metabolism. After removing air pollution from the environment, health and epigenetic changes reversed within eight weeks.

Citation: Rajagopalan S, Park B, Palanivel R, Vinayachandran V, Deiuliis JA, Gangwar RS, Das LM, Yin J, Choi Y, Al-Kindi S, Jain MK, Hansen KD, Biswal S. 2020. Metabolic effects of air pollution exposure and reversibility. J Clin Invest 130(11):60346040. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/index.htm#a3))

NIEHS researchers learned that mineralocorticoid receptors (MRs) control the gene profiles of neurons within the CA2 brain region, which is associated with learning and memory. MRs are a type of steroid receptor activated by corticosteroid hormones. The findings revealed the essential roles of MRs in the development and maintenance of CA2 neurons, as well as CA2-related behaviors.

In response to environmental stress, the body secretes corticosteroids that bind to MRs or glucocorticoid receptors and that induce gene expression changes in the brain. The CA2 region of the mouse and human hippocampus is enriched with MRs. Neuronal deletion of MRs at embryonic, early postnatal development, or adulthood stages in mice led to significantly reduced expression of CA2 molecular markers. Mice with CA2-targeted deletion of MRs showed disrupted social behavior and altered responses to novel objects. Therefore, MRs control both the identity and function of CA2 neurons.

Citation: McCann KE, Lustberg DJ, Shaughnessy EK, Carstens KE, Farris S, Alexander GM, Radzicki D, Zhao M, Dudek SM. 2019. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol Psychiatry; doi: 10.1038/s41380-019-0598-7 [Online 19 November 2019]. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dir/index.htm#a2))

NIEHS researchers discovered a novel symbiotic interaction between mammalian cells and bacteria that boosts nicotinamide adenine dinucleotide biosynthesis in host cells. NAD is a cofactor that exists in all cell types and is necessary for life. Decreased levels of NAD are associated with aging, and elevated levels of its biosynthesis are important to sustain the higher metabolic needs of tumors.

The researchers showed that cancer cell lines infected with Mycoplasma hyorhinis were protected against toxicity by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which halt NAD biosynthesis. This same effect was observed in vivo, when infected versus noninfected cancer cells were injected in mice. Using a variety of screens and techniques, they showed that this resistance was the result of bacteria providing alternative NAD precursors to mammalian cells through the bacterial nicotinamidase PncA, bypassing the NAMPT-dependent pathway.

Citation: Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li J-L, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X. 2020. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab 31(3):564579.e7. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dir/index.htm#a3)) (Story)

New insights into how the liver adapts to an HFD may lead to novel treatments for obesity-related diseases such as NAFLD, according to a study by NIEHS researchers. They found that long-term consumption of a diet high in saturated fat led to dramatic reprogramming of gene regulation in the mouse liver.

NAFLD involves the buildup of excessive fat in the liver of an individual who is not a heavy user of alcohol, increasing the risk of liver damage. When the scientists fed mice an HFD, the mice became obese and showed other changes similar to metabolic syndrome in humans. Moreover, their livers became fatty and showed wide-ranging abnormalities at both molecular and cellular levels. The livers adaptation to the fat-rich diet was mediated by a protein called hepatocyte nuclear factor 4 alpha.

Citation: Qin Y, Grimm SA, Roberts JD, Chrysovergis K, Wade PA. 2020. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet. Nat Commun 11(1):962. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dir/index.htm#a3)) (Story)

An NIEHS study reported a concerning rise in the prevalence of antinuclear antibodies (ANAs), which are commonly used biomarkers for autoimmunity. ANAs, which are produced by a persons own immune system, bind to and sometimes attack healthy cells. This study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population. The findings may indicate an increase in autoimmune diseases.

Team members used the National Health and Nutrition Examination Survey to analyze serum ANAs in 14,211 participants aged 12 years and older from three time periods. ANA prevalence increased as follows.

The researchers found the largest ANA increases in adolescents, males, non-Hispanic whites, and adults older than 50 years compared with other subgroups.

Citation: Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol 72(6):10261035. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dir/index.htm#a4)) (Story)

Ubiquitin (Ub) stimulates the removal of topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) by tyrosyl-DNA phosphodiesterase 2 (TDP2) according to NIEHS researchers and their collaborators in Spain. The team also reported that TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ub interface. Because TDP2 works with a protein called ZATT to remove dangerous DNA-protein crosslinks, the work is important for understanding how cells handle this type of DNA damage.

Using X-ray crystallography and small angle X-ray scattering analysis, the scientists examined how Ub-dependent links and TDP2 function as they relate to DNA repair and other cellular pathways. Previous studies hypothesized that TDP2 interacts with K48-Ub chains to promote recruitment to TOP2-DPCs that are repaired using a proteasome-mediated TOP2 degradation pathway. However, the authors showed that TDP2 preferentially binds to K63-linked Ub3 and associates with K27 and K63 poly-Ub chains.

Citation: Schellenberg MJ, Appel CD, Riccio AA, Butler LR, Krahn JM, Liebermann JA, Cortes-Ledesma F, Williams RS. 2020. Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. Nucleic Acids Res 48(11):63106325. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a4))

NIEHS researchers and their collaborators concluded that a protein called tankyrase serves a critical role in mammalian embryonic genome activation (EGA). Using an in vitro culture system, the researchers identified and characterized tankyrase, a factor that allows EGA to occur. The characterization of tankyrase during the oocyte-to-embryo transition fills a gap in knowledge about how factors are activated in mammalian oocytes and early embryos and may lead to improved strategies for treating infertility.

Using a mouse model, the scientists depleted tankyrase from the embryos and observed that they could not perform EGA and stopped developing. They also found that tankyrase is necessary for gene transcription, protein translation, DNA damage repair, and modulation of beta-catenin in the early embryo. This study found a new role for tankyrase during normal development, revealing an essential function of this protein during the oocyte-to-embryo transition.

Citation: Gambini A, Stein P, Savy V, Grow EJ, Papas BN, Zhang Y, Kenan AC, Padilla-Banks E, Cairns BR, Williams CJ. 2020. Developmentally programmed tankyrase activity upregulates beta-catenin and licenses progression of embryonic genome activation. Dev Cell 53(5):545560.e7. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a3)) (Story)

NIEHS researchers showed that an enzyme called CLP1 plays an important role in transfer RNA (tRNA) processing by regulating the ligation of tRNAs. They also demonstrated that mature, functional tRNAs are generated from pre-tRNAs through a process called TSEN, or (tRNA splicing endonuclease)mediated splicing of introns. Mutations in CLP1 and the TSEN complex often lead to severe neurological disorders.

Using a technique that allowed Escherichia coli to produce several proteins at once, the scientists expressed and reconstituted the TSEN protein complex, which cleaved tRNA. TSEN complex alone was sufficient for removing tRNA introns, but CLP1, a binding partner for TSEN, was needed to correctly regulate the ligation step that generates mature tRNAs and tRNA intronic circular RNAs (tricRNAs). Genetic knockdown of CLP1 led to increases in mature tRNAs and tricRNAs, which suggested that CLP1 acts as a negative modulator of tRNA processing.

Citation: Hayne CK, Schmidt CA, Haque MI, Matera AG, Stanley RE. 2020. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage. Nucleic Acids Res 48(14):76097622. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a2))

Researchers at NIEHS and the National Toxicology Program developed the Tox21BodyMap to predict which organs in the human body may be affected by a chemical. The tool will help scientists generate novel hypotheses to test, prioritize chemicals for toxicity testing, and identify knowledge gaps.

To identify organs that could potentially be affected by a chemical, Tox21BodyMap used data from 971 high-throughput screening assays that evaluated approximately 10,000 unique chemicals. Specifically, it combined information about which gene an assay targets, how highly expressed that gene is in a human organ, and at what tested concentrations a chemical generated a positive assay result. The result was an overall picture of chemical bioactivity. The Tox21BodyMap provided multiple visualizations of the data, highlighting target organs on a map of the body, as well as showing a web of network connections and providing downloadable data.

Citation: Borrel A, Auerbach SS, Houck KA, Kleinstreuer NC. 2020. Tox21BodyMap: a webtool to map chemical effects on the human body. Nucleic Acids Res 48(W1):W472W476. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a4))

In pregnant women, polyunsaturated fatty acids and their metabolic derivatives called eicosanoids are associated with infant size at delivery, according to NIEHS scientists and their collaborators. This work also provides novel longitudinal characterization of eicosanoids in blood plasma during different gestational ages of pregnancy. The results link inflammatory eicosanoids with adverse fetal growth outcomes.

The blood plasma concentration of polyunsaturated fatty acids, including omega-3 and omega-6, in study participants was found to be higher in cases of low birth weight and lower in cases of higher birth weight. Lower and higher birth weights were defined as equal to or less than the 10th percentile and equal to or greater than the 90th percentile for gestational age, respectively. In addition, certain eicosanoids, which are known to derive from inflammatory processes from these fatty acids, were found to be exclusively higher in pregnancy cases, which resulted in low birth weight.

Citation: Welch BM, Keil AP, van't Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2020. Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: a nested case-control study. PLoS Med 17(8):e1003271. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a2))

Researchers at NIEHS and collaborators at the National Institute of Diabetes and Digestive and Kidney Diseases uncovered the neural basis behind the drive to select calorie-rich foods over nutritionally balanced diets. The findings partly explain the difficulty of dieting.

One group of mice received a standard diet (SD) consisting of regular chow, and another group ate an HFD. When the HFD mice were switched to a SD, they refused to eat. Even after fasting to stimulate their appetites, HFD mice preferred fatty food, rather than regular chow.

However, whenHFD mice were switched to a SD, regular chow no longer fully alleviated the response. The authors also saw that dopamine signaling, which is responsible for the pleasurable feelings from eating, were significantly diminished in the SD mice following HFD exposure.

Citation: Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, Kobzar NP, Salgado IA, Reddy DM, Sun F, Zhang Y, Li Y, Cui G, Krashes MJ. 2020. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23(10):12531266. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a4))

To uncover novel deletion patterns in mitochondrial DNA (mtDNA), NIEHS researchers and their collaborators developed LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. The team used the technique to reveal links between mitochondrial DNA replication, aging, and mitochondrial disease.

A mutation in POLG, a nuclear gene responsible for maintaining the mitochondrial genome, is known to be the most common cause of mitochondrial disease, a condition in which the mitochondria fail to produce enough energy for the body to function properly.

The scientists analyzed mtDNA from skeletal muscle biopsies of 41 patients with mitochondrial disease with wild-type and mutated POLG. They used LostArc to detect loss of mtDNA segments by mapping split-reads in the samples to a normal mtDNA reference. Thirty-five million deletion segments were detected in the biopsies. They spanned more than 470,000 unique segments, 99% of which were novel.

Citation: Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. 2020. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 21(1):248. (Synopsis(https://factor.niehs.nih.gov/2020/11/papers/dir/index.htm#a3))

Individual heterogeneity, or genetic variability among samples, can substantially affect reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), according to NIEHS scientists and their collaborators. iPSCs are stem cells that are derived from differentiated cells, such as fibroblasts, and they can both self-renew and are pluripotent, meaning they can be differentiated into other cell types. In a previous publication, the research team obtained fibroblasts from healthy diverse donors and observed that each persons fibroblasts had consistent differences in the ability to be reprogrammed to iPSCs. Ancestry was identified as a large contributing factor.

Using 72 dermal fibroblast-iPSCs from self-identified African Americans and White Americans, the researchers found ancestry-dependent and ancestry-independent genes associated with reprogramming efficiency. They also added 36 new genomic profiles of African American fibroblast-iPSCs pairs to publicly available databases, which will help address the underrepresentation of genomic data from non-European groups.

Citation: Bisogno LS, Yang J, Bennett BD, Ward JM, Mackey LC, Annab LA, Bushel PR, Singhal S, Schurman SH, Byun JS, Napoles AM, Perez-Stable EJ, Fargo DC, Gardner K, Archer TK. 2020. Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Sci Adv 6(47):eabc3851. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dir/index.htm#a2))

Researchers in the Division of the National Toxicology Program (DNTP) at NIEHS successfully compiled a rich resource to explore data on polycyclic aromatic compound (PACs) toxicity. This data-driven approach to contextualizing PAC hazard characterization allows researchers to predict eight different toxicity profiles of various PACs and other classes of compounds.

PACs are a structurally diverse class of human-made toxicants found widely in the environment. Unfortunately, information about human exposure and health effects of PACs is limited. To facilitate greater understanding of PAC toxicity in a cost-effective manner, DNTP researchers created an automated approach to identify PAC structures using computer workflows, algorithms, and clusters. Using existing data on similar compounds, the scientists categorized PACs based on structure and hazard characterization. The analysis results are available and searchable through an interactive web application.

Citation: Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2020. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol; doi:10.1021/acs.chemrestox.0c00213 [Online 16 October 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/12/papers/dir/index.htm#a1))

DNTP scientists and their collaborators used computational modeling to probe databases and to identify existing drugs that could be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.

Proteases are enzymes that break down proteins. An essential step in the formation of infectious viral particles is the breakdown of precursor viral proteins by viral proteases. A class of antiviral drugs called protease inhibitors block the activity of viral proteases. The main protease (Mpro) of SARS-CoV-2 is a proposed target for COVID-19 drugs. The structure and activity of Mpro is highly conserved across the coronavirus family. In this study, previous data on drug interactions with SARS-CoV Mpro were used to develop quantitative structure-activity relationship models, which the team used to virtually screen all drugs in the DrugBank database. They identified 42 drugs that could be repurposed against SARS-CoV-2 Mpro.

Citation: Alves VM, Bobrowski T, Melo-Filho CC, Korn D, Auerbach S, Schmitt C, Muratov EN, Tropsha A. 2020. QSAR modeling of SARS-CoV Mpro inhibitors identifies sufugolix, cenicriviroc, proglumetacin, and other drugs as candidates for repurposing against SARS-CoV-2. Mol Inform; doi:10.1002/minf.202000113 [Online 28 July 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/index.htm#a1))

DNTP scientists evaluated a high-throughput transcriptomics approach using liver and kidney tissue from 5-day assays in male rats to estimate the toxicological potency of chemicals.

Toxicity and carcinogenicity are typically assessed by the resource intensive two-year cancer bioassay. In the 5-day assays, the authors determined toxicological potency based on the most sensitive sets of genes active in the liver and kidney. For most chemicals, the results approximated the toxicological potency derived from the most sensitive histopathological effects independent of target tissue or organ observed in male rats in long-term assays. Notably, these approximations were similar in female rats, as well as in male and female mice. The findings suggest that estimates of transcriptomics-based potency from short-term in vivo assays can, in the absence of other data, provide a rapid and effective estimate of toxicological potency.

Citation: Gwinn WM, Auerbach SS, Parham F, Stout MD, Waidyanatha S, Mutlu E, Collins B, Paules RS, Merrick BA, Ferguson S, Ramaiahgari S, Bucher JR, Sparrow B, Toy H, Gorospe J, Machesky N, Shah RR, Balik-Meisner MR, Mav D, Phadke DP, Roberts G, DeVito MJ. 2020. Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes. Toxicol Sci 176(2):343354. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/index.htm#a1))

Researchers from DNTP studied the effects of gestational and postnatal boron exposure on developing rat pups. The team was the first to show that pups exposed to boric acid, an oxidized form of boron commonly found in the environment, gained significantly less weight during postnatal development.

Pregnant rats were exposed to varying concentrations of boric acid once daily by oral gavage dosing, a technique that administered it directly to the stomach. Food intake, body weight, boron blood plasma levels, and any signs of morbidity were evaluated during gestation. After birth, the pups received boric acid at the same concentration as their mothers, and the scientists monitored the same parameters in the pups for the next 28 days. The team observed that the pups that received the highest dose of boric acid had a 23% reduction in weight gain.

Citation: Watson ATD, Sutherland VL, Cunny H, Miller-Pinsler L, Furr J, Hebert C, Collins B, Waidyanatha S, Smith L, Vinke T, Aillon K, Xie G, Shockley KR, McIntyre BS. 2020. Postnatal effects of gestational and lactational gavage exposure to boric acid in the developing Sprague Dawley rat. Toxicol Sci 176(1):6573. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/index.htm#a1))

When scientists from DNTP analyzed the entire genetic code of tumors in rodent cancer studies, they determined that most rodent tumors whether arising spontaneously or induced by chemicals had DNA mutation signatures resembling those seen in human cancers.

Tumors can form as a result of DNA damage or they can arise spontaneously when physiological processes do not function properly. To understand the mechanism of cancer formation, members of the research team sequenced lung and liver tumor DNA from mice exposed to 20 carcinogens. They compared the sequences to those from tumors that formed spontaneously and from normal tissue. DNA signatures from exposure to 17 of the chemicals were similar to those from spontaneous tumors in mice. The finding suggests chemicals promote tumor formation through mechanisms that build on existing cancer processes.

Citation: Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, Adams DJ. 2020.The mutational signature profile of known and suspected human carcinogens in mice. Nat Genet 52(11):11891197. (Story)

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January 2021: 2020 Papers of the Year - Environmental Factor Newsletter

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Ozone in the air is bad for birds – Massive Science

January 5th, 2021 1:47 am

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

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Ozone in the air is bad for birds - Massive Science

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How good are the COVID-19 vaccines? – Massive Science

January 5th, 2021 1:47 am

In 2007, scientists developed a method to determine the sexes of Atlantic walruses using only their jaws' size and shape. Researchers have now put that sexing (identification of an organism's sex) method to the test with Pacific walruses.

There was some doubt about whether this technique would work for one, Pacific walruses are significantly larger than their Atlantic counterparts. This size difference shows even in individual body parts, including the mandibles.

Yet, the team, led by Nathan Taylor at the University of Alaska, Fairbanks, persisted in applying the sex identification strategy since, if successful, it would significantly reduce the time and financial commitment needed for researching preserved, unidentified walrus specimens. To distinguish between male and female Pacific walruses, they measured the length and height of the jawbone, the minimum jawbone depth (from about the middle point of the jaw to the back), and jaw thickness.

A female Pacific walrus and a calf

USFWS via Wikimedia

The scientists had to be mindful of whether the jawbones were "not fully fused" (not fully developed, unique to juvenile walruses) or "fused" (fully developed, the sign of a mature walrus). Walruses with partially fused mandibles were likely to yield misleading results.

For example, jaws from male walruses that had not yet fully fused were similar in dimensions to mature females' jaws. To ensure the results were accurate, they could only include fully matured, fused specimens.

After measuring 67 modern specimens (33 of which were male, 24 belonging to females, and ten unknown) and 11 archaeological samples, the researchers concluded that jaw size is indeed a reliable body part to distinguish between male and female walruses. The most significant differences were jaw length and thickness, with females notably smaller in both categories.

A male Pacific walrus

Joel Garlich-Miller, USFWS, via Wikimedia

With the original sexing method now confirmed to work for Pacific walruses, scientists will be better prepared to perform several types of analyses, including measuring stable isotopes, trace elements, and hormones in study animals, with greater confidence and less risk of misidentification.

This is a crucial finding, given the insufficient data on Pacific walrus populations, and will hopefully push conservation efforts for this species forward.

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How good are the COVID-19 vaccines? - Massive Science

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Global Companion Diagnostics Market Growth, Trends, and Forecasts Report 2020-2025: Companies Promoting Personalized Medicine and Targeted Therapy as…

January 2nd, 2021 5:54 pm

Dublin, Dec. 30, 2020 (GLOBE NEWSWIRE) -- The "Companion Diagnostics Market - Growth, Trends, and Forecasts (2020 - 2025)" report has been added to ResearchAndMarkets.com's offering.

The growth of the global companion diagnostics market can be attributed to the rising focus on personalized medicine and the co-development of drug and diagnostic technologies. Additionally, rising cases of adverse drug reactions related to drugs, due to the lack of efficacy, drive the need for companion diagnostics.

One of the major factors driving the growth of the companion diagnostics market is the increasing demand for personalized medicines and awareness about the same, among the population. With companies increasing their collaborations for better biomarkers and diagnostics, in order to focus on cost regulations, there has been a significant number of opportunities for its applications in indications, like cancer, cardiovascular, and neurological disorders.

Key Market Trends

Application in Lung Cancer is expected to Dominate the Market over the Forecast Period

Companion diagnostic tests (CDXs) are considered mandatory in decision-making for treatment with targeted therapies in lung cancer. The emergence of immunotherapy has also given rise to the development of CDXs. Therascreen EGFR RGQ PCR Kit (Qiagen) and Cobas EGFR Mutation Test v2 (Roche Molecular Systems) are some of the many companion diagnostics available for lung cancer therapies.

Moreover, lung cancer is the most common form of cancer, and causes most cancer-related deaths, globally, as per the 2018 report by the World Health Organization. This translates to more demand for lung cancer companion diagnostics, which is expected to help the market growth.

North America Captured the Largest Market Share and is Expected to Retain its Dominance

North America dominated the overall companion diagnostics market, with the United States emerging as the major contributor to the market. The use of companion diagnostics is considered as an important treatment decision tool for a number of oncology drugs, which is also reflected in the way the FDA classifies these assays, in relation to risk.

In the United States, companion diagnostic assays are classified as IVD class III products, which represents a high-risk category, and consequently, the highest level of regulatory control. Hence, owing to high healthcare technology adoption rates and increasing demand for personalized medicine, the US companion diagnostics market is expected to register a substantial growth rate, during the forecast period.

Competitive Landscape

The presence of major market players, such as Abbott Laboratories, Agilent Technologies Inc., F Hoffmann-La Roche Ltd, Biomerieux SA, and Qiagen NV, is increasing the overall competitive rivalry of the market studied.

However, the issues associated with the high development cost and poor reimbursement are affecting the market negatively. Moreover, the rising focus of companies toward personalized medicine, co-development activities, and increased cases of adverse drug reactions is expected to boost the competitive rivalry in the market studied.

Key Topics Covered:

1 INTRODUCTION1.1 Study Deliverables1.2 Study Assumptions1.3 Scope of the Study

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS4.1 Market Overview4.2 Market Drivers4.2.1 Companies Promoting Personalized Medicine and Targeted Therapy as a New Treatment Option4.2.2 Increasing Cases of Adverse Drug Reactions4.2.3 Co-development of Drug and Diagnostic Technology4.3 Market Restraints4.3.1 High Cost of Drug Development and Associated Clinical Trials4.3.2 Reimbursement Issues among Many Countries4.4 Industry Attractiveness - Porter's Five Forces Analysis

5 MARKET SEGMENTATION5.1 By Technology5.1.1 Immunohistochemistry (IHC)5.1.2 Polymerase Chain Reaction (PCR)5.1.3 In-situ Hybridization (ISH)5.1.4 Real-time PCR (RT-PCR)5.1.5 Gene Sequencing5.1.6 Other Technologies5.2 By Indication5.2.1 Lung Cancer5.2.2 Breast Cancer5.2.3 Colorectal Cancer5.2.4 Leukemia5.2.5 Melanoma5.2.6 Other Indications5.3 By Geography

6 COMPETITIVE LANDSCAPE6.1 Company Profiles6.1.1 Abbott Laboratories6.1.2 Agilent Technologies Inc.6.1.3 F Hoffmann-La Roche Ltd6.1.4 Biomerieux SA6.1.5 Qiagen NV6.1.6 Siemens Healthcare6.1.7 Thermo Fisher Scientific Inc.6.1.8 Danaher Corporation (Beckman Coulter Inc.)

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/7z4nt2

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Global Research Antibodies and Reagents Market Report 2020-2027: Significant Opportunities from Emerging Asia-Pacific and Latin-American Markets -…

January 2nd, 2021 5:54 pm

Dublin, Dec. 31, 2020 (GLOBE NEWSWIRE) -- The "Research Antibodies and Reagents Market by Product {Antibodies [Type (Primary, Secondary), Production, Source, Research Area (Oncology, Neurology)], Reagents}, Technology (ELISA, Western Blot), Application, End User (Pharma, Academia) - Global Forecast to 2027." report has been added to ResearchAndMarkets.com's offering.

The research antibodies and reagents market is expected to grow at a CAGR of 5.6% from 2020 to 2027 to reach USD 6.32 billion by 2027.

Factors such as rising demand for protein therapeutics & personalized medicine, increasing investment in stem cell research, and rising need for biomarker identification represent high-growth opportunities for players during the forecast period. However, factors such as high cost and time related to identifying and developing potential antibodies are expected to hinder the growth of this market.

In 2020, based on type, the antibodies segment is projected to account for the largest share of this market. The large share of this segment is mainly attributed to increasing demand for antibodies for biomedical research, growing focus on protein and cell-based research, and increasing number of biomarker discovery.

On the basis of technology, in 2020, the flow cytometry segment is poised to command the largest share of the research antibodies and reagents market. The raising biomedical research for better diagnosis and therapy, initiatives for rising biomarker discovery, and growing cell & molecular-based research are the factors driving this growth of this segment.

In 2020, the proteomics segment is expected to command the largest share of the research antibodies and reagents market. Growing focus on protein-based research and the rising need for effective drugs using various protein-based disease profiling are the factors driving the growth of this segment.

The pharmaceutical and biotechnology industry is widely adopting research antibodies and reagents for proteomics research and drug discovery and development.

An in-depth analysis of the geographical scenario of the research antibodies and reagents market provides detailed qualitative and quantitative insights for the five major geographies (North America, Europe, Asia-Pacific, Latin America, and the Middle East & Africa) along with the coverage of major countries in each region. In 2020, North America is estimated to command the largest share of the research antibodies and reagents market, followed by Europe, Asia-Pacific, Latin America, and the Middle East & Africa.

Key Topics Covered:

1. Introduction1.1. Market Ecosystem1.1.1. Research Antibodies and Reagents Market1.1.2. Research Antibodies and Reagents Market, by Product1.2. Currency and Limitations1.3. Key Stakeholders

2. Research Methodology2.1. Research Process2.1.1. Secondary Research2.1.2. Primary Research

3. Executive Summary

4. Market insights4.1. Introduction4.2. Market Dynamics4.2.1. Drivers4.2.1.1. Rising Proteomics and Genomics Research Studies4.2.1.2. Increase in the Funding for Research Activities4.2.1.3. Growing Industry-Academia Collaboration4.2.2. Restraint4.2.2.1. High Cost and Time Related to Identification and Development of Potential Antibodies4.2.3. Opportunities4.2.3.1. Rising Demand for Protein Therapeutics and Personalized Medicines4.2.3.2. Rising Investment and Focus on Stem-Cell Research4.2.3.3. Rising Need for New Biomarker Identification4.2.3.4. Significant Opportunities from Emerging Asia-Pacific and Latin-American Markets4.2.4. Challenges4.2.4.1. Issues Related to Quality and Stability of Research Antibodies4.2.4.2. Intense Pricing Pressure on Leading Players

5. Research Antibodies and Reagents Market, by Product5.1. Introduction5.2. Antibodies5.2.1. Antibodies Market, by Type5.2.1.1. Primary Antibodies5.2.1.2. Secondary Antibody5.2.2. Antibodies Market, by Production Type5.2.2.1. Monoclonal Antibody5.2.2.2. Polyclonal Antibody5.2.2.3. Antibody Fragments5.2.3. Antibody Market, by Source5.2.3.1. Mouse5.2.3.2. Rabbit5.2.3.3. Other Sources5.2.4. Antibodies Market, by Research Area5.2.4.1. Oncology5.2.4.2. Infectious Diseases5.2.4.3. Cardiovascular Disease5.2.4.4. Immunology5.2.4.5. Neurology5.2.4.6. Stem Cell Research5.2.4.7. Other Research Areas5.3. Reagents5.3.1. Sample Preparation Reagents5.3.1.1. Media and Serum5.3.1.2. Stains and Dyes5.3.1.3. Probes5.3.1.4. Buffers5.3.1.5. Solvents5.3.2. Antibody Production Reagents5.3.2.1. Enzymes5.3.2.2. Proteins5.3.3. Other Research Reagents

6. Research Antibodies and Reagents Market, by Technology6.1. Introduction6.2. Flow Cytometry6.3. Immunofluorescence6.4. Enzyme-Linked Immunosorbent Assay6.5. Immunoprecipitation (IP)6.6. Multiplex Immunosorbent Assay6.7. Immunohistochemistry6.8. Western Blot6.9. Other Technologies

7. Research Antibodies and Reagents Market, by Application7.1. Introduction7.2. Proteomics7.3. Drug Discovery and Development7.4. Genomics

8. Research Antibodies and Reagents Market, by End User8.1. Introduction8.2. Pharmaceutical and Biotechnology Industry8.3. Academic and Research Institutes8.4. Contract Research Organizations

9. Research Antibodies and Reagents Market, by Geography

10. Competitive Landscape10.1. Introduction10.2. Key Growth Strategies10.3. Competitive Benchmarking10.4. Market Share Analysis

11. Company Profiles11.1. Business Overview11.2. Financial Overview11.3. Product Portfolio

For more information about this report visit https://www.researchandmarkets.com/r/q5a7ww

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USA Equities Corp (USAQ), Announces Revenues of $120000 for the 4th Quarter of 2020 and Projects Revenues in excess of $300000 for the 1st Quarter of…

January 2nd, 2021 5:54 pm

WEST PALM BEACH, FL, Dec. 30, 2020 (GLOBE NEWSWIRE) -- USA EQUITIES CORP. (OTCQB: USAQ) (the Company, we, or our) announced today that its revenues for the fourth quarter of 2020 would be approximately $120,000 and that its revenues would exceed $300,000 in the first quarter of 2021.

We introduced our QHSLab, Software as a Service (SaaS) platform, to 159 medical practices in June 2020. Through September, physicians in these practices provided 374 allergy patients with a QHSLab-generated allergen immunotherapy prescription, generating an estimated $664,608 in revenue for these physicians practices. In November, building on the capabilities of our QHSLab, we began shipping allergy diagnostic related products and immunotherapy treatments to these physicians in response to their requests based upon courses of treatment recommended for their patients by QHSLab. Our revenue in the fourth quarter will be $120,000 as a result of these sales. Based upon orders in hand and reasonably anticipated, revenues from our allergy diagnostic test kits and treatment programs should exceed $300,000 in the first quarter of 2021. Revenues from this program should continue to increase thereafter as we increase the number of physicians and medical practices utilizing QHSLab.

Based on our QHSLab allergy treatment systems success, we intend to increase our revenues by charging physicians a monthly subscription fee for the use of QHSLab. USAQ plans to introduce these physicians to additional point of care diagnostic, digital medicine, and treatments that our physician clients can use and prescribe. They will be paid under existing government and private insurance programs, based upon analyses conducted utilizing QHSLab.

The revenues we generated in the fourth quarter of 2020 and anticipated revenue in the first quarter of 2021 far exceed the revenue levels assumed by the equity research firm, Litchfield Hills Research, when it released its first analyst coverage report on USAQ. Litchfield Hills continue to rate our stock as a buy under its three-tiered rating system, with a target price of $5.00 per share.

About USA Equities Corp (OTCQB: USAQ)

On December 20, 2019 USA Equities Corp completed a share exchange whereby it acquired Medical Practice Income, Inc. (MPI). The Company is focused on value-based healthcare solutions, clinical informatics and algorithmic personalized medicine including digital therapeutics, behavior based remote patient monitoring, chronic care and preventive medicine. The Companys products are intended to allow the general practice physician to increase his revenues by cost effectively diagnosing and treating chronic diseases generally referred to specialists. The Companys products and information service portfolio are directed towards prevention, early detection, management, and reversal of cardio-metabolic and other chronic diseases. Our principal objectives are to develop proprietary software tools, devices, and approaches, providing more granular, timely, and specific clinical decision-making information for practicing physicians and other health care providers to address todays obese, diabetic and cardiovascular disease population. The Company is located in West Palm Beach, Florida. For more information, visit http://www.MedicalPracticeIncome.com/discover.

Forward-Looking Statements

Certain matters discussed in this press release are 'forward-looking statements' intended to qualify for the safe harbor from liability established by the Private Securities Litigation Reform Act of 1995. In particular, the Company's statements regarding trends in the marketplace, future revenues, future products and potential future results and acquisitions, are examples of such forward-looking statements. Forward-looking statements are generally identified by words such as may, could, believes, estimates, targets, expects, or intends and other similar words that express risks and uncertainties. These statements are subject to numerous risks and uncertainties, including, but not limited to, the timing of the introduction of new products, the inherent discrepancy in actual results from estimates, projections and forecasts made by management, regulatory delays, changes in government funding and budgets, and other factors, including general economic conditions, not within the Company's control. The factors discussed herein and expressed from time to time in the Company's filings with the Securities and Exchange Commission could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

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USA Equities Corp (USAQ), Announces Revenues of $120000 for the 4th Quarter of 2020 and Projects Revenues in excess of $300000 for the 1st Quarter of...

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Creative Medical Technology Holdings Announces Reversion of Liver Failure Using ImmCelz Personalized Cellular Immunotherapy in Preclinical Model -…

January 2nd, 2021 5:54 pm

PHOENIX, Dec. 29, 2020 /PRNewswire/ --(OTC-CELZ)Creative Medical Technology Holdings Inc. announced today novel data and patent filing No. 63131261 describing the ability of ImmCelz to reverse liver failure in the carbon tetrachloride preclinical model of hepatocyte necrosis.

These findings are the basis for a patent filing covering various means of generating the ImmCelz product in a hepatoprotective specific manner. The Company has previously reported that ImmCelz is capable of treating animal models of stroke,1 as well as inducing "immunological tolerance" in a model of autoimmune rheumatoid arthritis.2

The work is an extension of previously published findings of Dr. Thomas E. Ichim, in which mesenchymal stem cells were capable of inhibiting progression of liver failure.3

"I am proud of the work the team at Creative Medical Technologies is conducting in advancing the concept of immunologically-mediated regeneration,"said Dr. Ichim, Co-inventor of the patent. "ImmCelz is an advancement on our previous liver failure work due to the fact that we have shown transfer of regenerative activity from the stem cell to the immune cell. Immune cells possess ability to home to injured tissues faster than stem cells due to their smaller size. Additionally, immune cells possess immunological memory, which we believe may be applied to the concept of regeneration."

"While stem cell therapeutics are recognized as the future of medicine, I believe it is important to realize that many activities of stem cells are mediated by changes to the immune system," said Dr. Amit Patel, Board Member of the Company and Co-Inventor of the Patent Application. "ImmCelz represents a fundamental advancement in regenerative medicine in that instead of administering stem cells in the body to induce immune modulation, we actually optimize the immune modulation in the laboratory before injecting immune cells into the patient."

Being at the forefront in identifying novel regenerative treatment options, the Company possesses numerous issued patents in the area of cellular therapy, including patent no. 10,842,815 covering use of T regulatory cells for spinal disc regeneration, patent no. 9,598,673 covering stem cell therapy for disc regeneration, patent no. 10,792,310 covering regeneration of ovaries using endothelial progenitor cells and mesenchymal stem cells, patent no. 8,372,797 covering use of stem cells for erectile dysfunction, and patent no. 7,569,385 licensed from the University of California covering a novel stem cell type.

"Liver failure represents a significant unmet medical need and I am extremely excited that ImmCelz has the potential to help the numerous patients on the liver transplant waiting list who currently have no other option.

With growing validation and acceptance of such technologies, the company intends to continue to broaden its intellectual property portfolio by compiling research data and filing patents, in order to record early filing dates and increase the likelihood of our receiving patent issue.

We continue to welcome opportunities with collaborators and Key Opinion Leaders as we are dedicated to accelerating the further development of our technology."

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Creativemedicaltechnology.comwww.StemSpine.comwww.Caverstem.comwww.Femcelz.com

1 Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com)2 Creative Medical Technology Holdings Reports Positive Preclinical Data on ImmCelz Immunotherapy Product in Rheumatoid Arthritis Model | BioSpace 3 Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice | Journal of Translational Medicine | Full Text (biomedcentral.com)

SOURCE Creative Medical Technology Holdings, Inc.

http://creativemedicaltechnology.com

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Revisiting Late-Onset Asthma: Clinical Characteristics and Association | JAA – Dove Medical Press

January 2nd, 2021 5:54 pm

Santiago Quirce,1 Enrico Heffler,2 Natalia Nenasheva,3 Pascal Demoly,4 Andrew Menzies-Gow,5 Ana Moreira-Jorge,6 Francis Nissen,7 Nicola A Hanania8

1Department of Allergy, La Paz University Hospital, IdiPAZ and Universidad Autnoma de Madrid, Madrid, Spain; 2Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, MI, Italy; 3Department of Allergology and Immunology of Russian Medical Academy for Continuous Medical Education, Moscow, Russian Federation; 4Department of Pulmonology, Division of Allergy, Hpital Arnaud de Villeneuve, University Hospital of Montpellier, Montpellier, France; 5Department of Respiratory Medicine, Royal Brompton Hospital, London, UK; 6Novartis Farmaceutica, S.A., Barcelona, Spain; 7London School of Hygiene and Tropical Medicine, London, UK; 8Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA

Correspondence: Santiago QuirceHospital Universitario La Paz, P. La Castellana, 261, Madrid, 28046 SpainEmail squirce@gmail.com

Abstract: The Global Initiative for Asthma (GINA) 2020 defines late-onset asthma (LOA) as one of the clinical phenotypes of asthma wherein patients, particularly women, present with asthma for the first time in adult life, tend to be non-allergic and often require higher doses of inhaled corticosteroids (ICS) or are relatively refractory to corticosteroid treatment. In this review, we examine the published literature improve the understanding of the following aspects of LOA: 1) the age cut-off for its diagnosis; 2) its distinct clinical phenotypes, characteristics and risk factors; and 3) its association with allergic comorbidities and conditions. Overall, our review reveals that clinicians and researchers have used multiple age cut-offs to define LOA, with cut-off ages ranging from > 12 years to 65 years. LOA has also been classified into several distinct phenotypes, some of which drastically differ in their clinical characteristics, course and prognosis. Although LOA has traditionally been considered non-allergic in nature, our review indicates that it is commonly associated with allergic features and comorbidities. Our findings suggest that there is an urgent need for the development of more clear clinical practice guidelines that can provide more clarity on the definition and other aspects of LOA. In addition, the association of LOA and allergy needs to be re-examined to frame a more optimal treatment strategy for patients with LOA.

Keywords: asthma, diagnosis, age of onset, allergy, allergic asthma, asthma phenotypes

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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The technological transformations that marked 2020 – Mint

January 2nd, 2021 5:54 pm

On 1 January 2020, I published my very first Ex Machina article of the year. Since it was also the beginning of a new decade, I made my own modest attempt at predicting the technological changes we could hope to expect in the coming years. I wrote about the promise of artificial intelligence, speech recognition and augmented reality, and how they would come together to let us speak to computers in novel ways. I argued that technology would transform our commute, eventually leading to a future of shared autonomous vehicles that would completely eliminate the need to own personal cars, etc. Finally, I spoke of personalized medicine and a future in which treatments could be calibrated to individual requirements, instead of being focused on discovering drugs that need to work on the entire human population.

What I did not predict was that in a couple of months, a global pandemic would bring the entire world to a grinding halt.

Much of what I had thought would happen will likely still come to passalthough in a slightly different way from what I had imagined. Now that companies have realized how easy it is to support working from home, many businesses are re-thinking their investments in commercial real estatecommitting themselves instead to enabling employees to work from wherever they might be at a given point in time.

In addition to all that I had anticipated, I believe this new mindset will eventually contribute to a fundamental alteration of our commute and be another catalyst for some of the urban mobility solutions. I had anticipated. And while autonomous transportation may not become a reality anytime soon, I am excited by the immediate promise that platform solutions of the likes of Beckn have to offer.

I had suggested in my article that computers might soon be able to speak coherently with us, but even I did not imagine wed get there so soon. The remarkable language abilities of OpenAIs Generative Pre-trained Transformer Ver 3 (GPT-3) technology took the world by storm this year. But while initial reports suggested that it would make computer communications indistinguishable from human speech, closer study revealed flaws in its output, as also practical limitations in working with very large data-sets. That said, I was heartened by the emergence of new techniques of artificial intelligence such as few-shot learning, and the promise that it could hold for data-starved countries like India.

But the technology breakthrough that everyone was focused on for all of 2020 was in medicine. On this front, my prediction at the beginning of the year fell well short of the mark. As hopeful as I still am for a future in which medicine will be personalized, the covid pandemic made it clear that there will always be a need for medical solutions that can be rolled out rapidly and at scale to the entire global population.

I am thankful that our investments in genetic technologies, the global interconnectedness of the scientific community and the manufacturing capabilities of pharmaceutical companies came together so well this past year to enable us to produce multiple vaccines for covid-19 in record time. I hope these demonstrations of success encourage us to invest in platform vaccine technologies, so that we are better placed to deal with such challenges that we will, no doubt, continue to face in the future.

But, more than anything else, the pandemic demonstrated the central role that technology now plays in society. From the contact-tracing apps that were all the rage in the early months of the diseases outbreak, to the remote-working solutions that brought us together even though we were far apart, it is clear that all aspect of our lives today are dependent on technology.

Our recent experiences will hopefully serve as the impetus we need to make sure that small businesses and ordinary citizens in this country get greater access to the internet, so that they can all partake in this future.

Early in the lockdown, the department of telecommunications relaxed the work-from-home restrictions that applied to technology companies registered as Other Service Providers (OSP)a relaxation that was made permanent before the end of the year with a radical overhaul of the entire OSP framework. Later in the year, the Union cabinet approved the Prime Minister Wi-Fi Access Network Interface, or PM Wani , a new regulation system for wifi that will encourage the rapid proliferation of digital technologies in India.

As good as these regulatory measures might be, we still need key technology legislation to bring us on par with the rest of the world. It was good to see that despite the constraints imposed by the pandemic, the meetings of the Joint Parliamentary Committee on data protection proceeded apace. Equally interesting was the governments interest in regulating non-personal data, making India the first country to attempt governing the entire data landscape.

As gruesome as the year has been, it has forced us to reconsider our relationship with technologyand to engage with it in different ways.

Rahul Matthan is a partner at Trilegal and also has a podcast by the name Ex Machina. His Twitter handle is @matthan

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The technological transformations that marked 2020 - Mint

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Predictive Oncology Announces Cancellation of Special Meeting in December 2020Reincorporation Proposal Received Overwhelming Support Among Shares…

January 2nd, 2021 5:54 pm

NEW YORK, Dec. 29, 2020 (GLOBE NEWSWIRE) -- Predictive Oncology (NASDAQ: POAI) (the Company), a knowledge-driven company focused on applying artificial intelligence (AI) to personalized medicine and drug discovery, today announced that its Board of Directors has decided to cancel its Special Meeting of Stockholders that was originally scheduled for December 1, 2020. On that date, the meeting was adjourned to December 30, 2020 because a quorum was not reached. As of December 30, 2020, approximately 47% of the outstanding shares as of the record date have been voted, and therefore a quorum has still not been reached. The Board of Directors has determined that it is not practical to incur the expense of adjourning the meeting further to continue to solicit proxies, because approval of the reincorporation proposal would require the affirmative vote of a majority of the Companys outstanding shares (not simply a majority of the shares voted).

The Board notes that, of the shares that were voted at the Special Meeting, nearly 88% of the shares were voted FOR the reincorporation from Delaware to Nevada. In the future, the Board intends to continue to seek stockholder approval for reincorporation, due in part to the oppressive franchise taxes charged by Delaware.

About Predictive Oncology Inc.

Predictive Oncology (NASDAQ: POAI) operates through three segments (Skyline, Helomics and Soluble Biotech), which contain four subsidiaries: Helomics, TumorGenesis, Skyline Medical and Soluble Biotech.

Helomics applies artificial intelligence to its rich data gathered from patient tumors to both personalize cancer therapies for patients and drive the development of new targeted therapies in collaborations with pharmaceutical companies. TumorGenesis Inc. specializes in media that help cancer cells grow and retain their DNA/RNA and proteomic signatures, providing researchers with a tool to expand and study cancer cell types found in tumors of the blood and organ systems of all mammals, including humans. Skyline Medical markets its patented and FDA cleared STREAMWAY System, which automates the collection, measurement and disposal of waste fluid, including blood, irrigation fluid and others, within a medical facility, through both domestic and international divisions. Soluble Biotech is a provider of soluble and stable formulations for proteins including vaccines, antibodies, large and small proteins and protein complexes.

Forward-Looking Statements

Certain matters discussed in this release contain forward-looking statements. These forward-looking statements reflect our current expectations and projections about future events and are subject to substantial risks, uncertainties and assumptions about our operations and the investments we make. All statements, other than statements of historical facts, included in this press release regarding our strategy, future operations, future financial position, future revenue and financial performance, projected costs, prospects, plans and objectives of management are forward-looking statements. The words anticipate, believe, estimate, expect, intend, may, plan, would, target and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Our actual future performance may materially differ from that contemplated by the forward-looking statements as a result of a variety of factors including, among other things, factors discussed under the heading Risk Factors in our filings with the SEC. Except as expressly required by law, the Company disclaims any intent or obligation to update these forward-looking statements.

Investor Relations Contact:

Hayden IRJames Carbonara(646)-755-7412

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Predictive Oncology Announces Cancellation of Special Meeting in December 2020Reincorporation Proposal Received Overwhelming Support Among Shares...

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Worldwide Industry for Microbiome Sequencing Services to 2025 – Increased Focus on Human Microbiome Therapy is Driving Growth – ResearchAndMarkets.com…

January 2nd, 2021 5:54 pm

The "Global Microbiome Sequencing Services Market (2020-2025) by Technology, Application, Research Type, Laboratory Type, End-Users, Geography and the Impact of Covid-19 with Ansoff Analysis" report has been added to ResearchAndMarkets.com's offering.

The Global Microbiome Sequencing Services Market is estimated to be USD 1.02 billion in 2020 and is expected to reach USD 2.31 billion by 2025, growing at a CAGR of 17.8%.

Microbiomes are a group of micro-organisms living on a human body. They live on the skin, eyes, saliva, mouth, and the gastrointestinal tract. The human microbiome contains thousands of bacterial species/microbes in diverse communities, along with their genes, proteins, and metabolites. An imbalance of these microbes can lead to life-threatening diseases. The study of Microbiome sequencing and its techniques relates to the study of the microbial composition of the human gut and to understand the resulting impact on health and disease development.

Microbiome sequencing is usually done to understand this microflora residing on the human body and further study human microbes and their role in related diseases. This study can also be helpful while analyzing the patient's response to a particular treatment. Effective understanding and application of microbiome sequencing services would help in the commercialization of personalized medicine and diet. Hence, the market is extensively driven by research-based communities, especially in the developed economies like the US, which has the presence of NHGRI (National Human Genome Research Institute) supporting the growth of the market.

Due to advancements in technology, there has been a rise in the NGS (Next-Gen Sequencing) to generate microbiome data. Besides, techniques such as novel high-throughput sequencing and new software tools are transforming microbiome studies by providing service at high quality, speed, and high cost. Many companies are additionally concentrating on novel exome sequencing and RNA sequencing applications in niche market segments.

Story continues

Specific factors that have led to the growth of this market are the rising use of microbiome in genomics, along with the reduced cost of sequencing. However, other factors such as the lack of expertise in the data analysis for the microbiomes with advanced tools shall hinder the growth of this market.

Market Dynamics

Drivers

Increased Focus on Human Microbiome Therapy

Reduction in the Cost of Sequencing

Human Microbiome as a New Validated Target for Drug Development

Human Microbiome Used as an Aid for Early Disease Detection and Diagnosis

Increasing Demand for NGS

Restraints

Lack of Skilled Professionals for Microbiome Sequencing Services

Lack of Awareness Among Physicians and Scientist about Advanced Tools for Data Analysis

Barriers in Proving the Causal Link Between Dysbiosis and Disease

Opportunities

Investigational New Drug (IND) Requirements for Fecal Microbiota

Increasing Collaborations Create Growth Opportunities

Increasing Research Investments and Technological Advancements

Why Buy this report?

The report offers a comprehensive evaluation of the Global Microbiome Sequencing Services Market. - The report includes in-depth qualitative analysis, verifiable data from authentic sources and projections about market size. The projections are calculated using proven research methodologies.

The report has been compiled through extensive primary and secondary research. The primary research is done through interviews, surveys and observation of renowned personnel in the industry.

The report includes in-depth market analysis using Porter's 5 force model and the Ansoff Matrix. The impact of Covid-19 on the market is also featured in the report.

The report also contains a competitive analysis using IGR Positioning Quadrants, Infogence's Proprietary competitive positioning tool.

Companies Mentioned

Baseclear B.V.

Clinical-Microbiomics A/S

Molzym GmbH & Co. Kg

Zymo Research Corp.

Rancho Biosciences

Microbiome Therapeutics, LLC.

Microbiome Insights Inc.

Openbiome

Resphera Biosciences, LLC.

MR DNA (Molecular Research LP)

Shanghai Realbio Technology Co., Ltd

Diversigen, Inc.

Merieux Nutrisciences Corporation

Metabiomics Corp.

Second Genome

LOCUS BIOSCIENCES, INC,

BioSpherex LLC

For more information about this report visit https://www.researchandmarkets.com/r/6xv3hj

View source version on businesswire.com: https://www.businesswire.com/news/home/20201229005159/en/

Contacts

ResearchAndMarkets.comLaura Wood, Senior Press Managerpress@researchandmarkets.com For E.S.T Office Hours Call 1-917-300-0470For U.S./CAN Toll Free Call 1-800-526-8630For GMT Office Hours Call +353-1-416-8900

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Worldwide Industry for Microbiome Sequencing Services to 2025 - Increased Focus on Human Microbiome Therapy is Driving Growth - ResearchAndMarkets.com...

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After accepting virtual trainers, AI-powered nutrition is the next step in keeping a healthy lifestyle – Geektime

January 2nd, 2021 5:54 pm

The day comes for all of us, and the day Im speaking of is that day when our once loose jeans and baggy shirt become a bit tighter around the waste. Its at that time we decide to get down to business, hit the gym, and skip the cookie aisle at the supermarket, because the diet starts now.

COVID hits and its not that easy to get our work out on. Still we wake every morning and go for a run, even buy weights, do the research and plan out are meals. After chugging down a protein shake, suddenly losing those extra pounds feels easy. However, then, with the runners high wearing off, a bag of Cheetos, a few beers, and more than one off-day later, and you realize that this is going to be an uphill battle.

Israeli startup Newt and its founder and CEO Gil Kerbs understand the struggle of maintaining a healthy diet and schedule. The company developed an AI-powered platform that uses your daily habits to generate a personalized regiment to keep your nutritional goals on track. Or as Gil puts it Our product interacts with users daily to understand and aggregate all information needed for health / nutrition based decisions, and then provides daily support to start shifting their behavior towards healthier habits.

With the year of COVID coming to a hopeful end, it was definitely a great year for remote technology, from medicine to fitness, the global pandemic did change the way people interact virtually. So how has personalized nutrition gained such popularity? GIl says that It's kind of the 'perfect storm'. We are so focused on our health and wellbeing due to the pandemic - we finally REALLY know that actively staying fit and healthy can help prevent harsh impacts from sickness, such as with COVID. We are also witnessing the rise of AI, allowing for true personalization - a personal fitness coach that is really 'personal', and now with Newt, a personal nutritionist that really tailors everything for you.

Gil explains that he sees preventative care as the future of personalized medicine, not only giving you the 'right' medicine when you need it but rather helping you make the right daily decisions that eventually shape your long term health.

Yeah, this is probably not the first fitness/nutrition app youve heard of, but Newt does things a little different, actually putting your habits in the center to better motivate you. But how is it done? In one word - "behavioral personalization". We are not aiming for a quick perfect, but for the closest to optimal that you can sustain for the long run. Our Behavioral expertise stretches from Prof. Adam Grant (Wharton, world leading motivation expert), and Stanford Mind&Body lab who focus on use of psychology for wellbeing. Our goal is to make not only the best clinical knowledge available, but rather to combine it with cutting edge psychology/behavior knowledge that makes behavior and diet change a real possibility in the long run."

Gils attachment to the subject comes from his years in the medical industry as part of Medtronic China, where he notes that it was very rewarding to help add 1-2 years to people's lives, but I wanted more - 20-30 more years, with better quality - and this could not be done when the patient is already in the OR. So, I got into preventative medicine, and there's nothing bigger for your long term health than your nutrition... All of us at Newt have this motivation - helping people keep healthy, by harnessing the strongest force available to everyone - daily nutrition."

He adds that although intervention healthcare isnt going anywhere and will maintain an important part of medical care but preventative can be better for humanity as a whole, Take cancer - surgery's solution is to take it out or 'kill it' (radiation), but not to solve what caused it, yet. This is a short term solution due to the limitations of our knowledge. Think about it this way - 5 year survival rates for various cancers are still very low, despite utilizing cutting edge technology to treat them. Preventative healthcare is much less 'high-tech', we don't need robots - nor huge amounts of dollars - it's rather cheap - and it really helps dramatically reduce chances of getting sick. The real problem is that it's a marathon, and not just a sprint intervention, making it psychologically harder. That's why we at Newt focus on behavior so much.

Founded in 2019, Newt has received backing from Welltech1 - a wellness microfund, and angel investors. And according to Gil, the company has a few partnerships in the works. Cool idea and all but why the name Newt? We wanted something short that sounds like nutrition, but is also a name of a character. We see Newt as a personal guide for nutrition. It's also a really cute animal, said Kerbs.

Ok, last thing, even though its been a weird year, were sure people will keep in the tradition of failing at their New Years resolutions (myself a victim), so we asked Gil to take from his nutritional expertise and offer some advice: ...In general I'd advise people that next time they 'fail' with a resolution, they should not beat themselves up about it, but rather think how to better approach it next time. Usually, there's a fun, easier way to achieve success and give you great results in the long run.

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After accepting virtual trainers, AI-powered nutrition is the next step in keeping a healthy lifestyle - Geektime

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The Error of Fighting a Public Health War With Medical Weapons – WIRED

January 2nd, 2021 5:53 pm

Heres the wild part, the most 2020 thing about 2020: That schismthat conflict between public health and private well-being, between personal liberties and communal gainis as old as pandemics. The germ of the idea was, in fact, the idea of the germ.

In the mid-1800s, physicians and scientists were starting to come around to the long-gestating idea that diseases could be caused by wee, invisible critters that jumped from person to persona contagium animatum, as 16th-century thinkers put it. They didnt know what viruses or bacteria were, but they knew something was carrying illness.

The contagionists had their opposite number: scientists who in 1948 the researcher Edwin Ackerknecht famously called anticontagionists. Oh, they believed that some diseases spread by some agent, person-to-person. Smallpox and syphilis, maybe. Those were contagious. But they werent epidemicsyellow fever, cholera, or the plague, things that seemed to spread seasonally, or in specific places, or only among specific kinds of people. Nobody knew how. They didnt know anything about food- and waterborne pathogens, about differences between viruses and bacteria, about surface-borne fomites that transmitted disease in some cases, while exhaled droplets and aerosols might in others. Absent any of that? Well, maybe it was something atmospherica cloud of illness, a miasma, maybe even the filth of poverty and pre-sanitation cities. (Its telling that scientists are still fighting over the idea of an airborne contagium animatum, even today.)

But the anticontagionists knew one thing for sure. Those big three epidemicswith typhus thrown in sometimes, toowere the things that had, since the 14th century, caused governments to take population-scale measures to control them. That meant quarantines, travel restrictions, business closureswhat today we might call lockdowns. And that made the anticontagionists nuts. They said that lockdowns, then as now, were bad for business; losses incurred as a result outweighed those caused by the epidemic itself. In the midst of the 19th centurys Industrial Revolution, anything that inhibited business was an inhibition of freedom itself. Quarantines meant, to the rapidly growing class of merchants and industrialists, a source of losses, a limitation to expansion, a weapon of bureaucratic control that it was no longer willing to tolerate, Ackerknecht wrote. Contagionism would, through its associations with the old bureaucratic powers, be suspect to all liberals, trying to reduce state interference to a minimum. Anticontagionists were thus not simply scientists, they were reformers, fighting for the freedom of the individual and commerce against the shackles of despotism.

Also, by saying that disease came from lack of sanitation and poor hygiene, the pro-filth contingent was sometimes quietly and sometimes loudly associating disease with ethnicity and socioeconomic status. It was immunological social Darwinism; if poor and nonwhite people got sick first, or more often, that proved to some reformers that those people made bad personal choices (rather than indicating a failure of the systems around them). In that light, identifying filth as the generator of epidemics paved the way for the hygiene movement, showed the moral and physical superiority of unpoor whites, and provided a rationale for slum clearance and residential zoning laws. Squint at redlining and you see not just the geography of racism but also a colonial cordon sanitaire.

To be fair, as one historian notes, the (paltry) science of miasmas did suggest that quarantines would actually make epidemic diseases worse, because they amplified the confinement and lousy conditions that spread the disease. And if you read miasma as the conditions that make a disease spread, well, thats also the point Im trying to make, so yeah. These were good-faith scientific arguments that also happened to be politically motivated economic and philosophical ones, tinged by racism.

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The Error of Fighting a Public Health War With Medical Weapons - WIRED

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Moderna, Pfizer vaccine trials were the highest of quality: vaccine expert – Yahoo Money

January 2nd, 2021 5:52 pm

The Guardian

Republicans say they will reject presidential electors from states where Trump campaign contested results unless audit completedTed Cruz of Texas, Ron Johnson of Wisconsin and nine other Republican US senators or senators-elect said on Saturday they will reject presidential electors from states where Donald Trump has contested his defeat by Joe Biden, unless and until [an] emergency 10-day audit of such results is completed.The move is largely symbolic and unlikely to overturn the presidential election. Nonetheless, it adds to a sense of deepening crisis affecting US democracy.Trump has refused to concede, though Biden won more than 7m more votes nationally and took the electoral college by 306-232, a margin Trump called a landslide when he won it over Hillary Clinton in 2016.The Trump campaign has lost the vast majority of more than 50 lawsuits it has mounted in battleground states, alleging electoral fraud, and before the supreme court.On Friday, a federal judge dismissed a suit lodged by a House Republican which attempted to give the vice-president, Mike Pence, who will preside over the certification of the electoral college result on Wednesday, the power to overturn it.Nonetheless, the senators and senators-elect who issued a statement on Saturday followed Senator Josh Hawley of Missouri in committing to challenging the result.Objections are also expected from a majority of House Republicans. Objections must be debated and voted on but as Democrats control the House and the Senate majority leader, Mitch McConnell, and other senior Republicans have voiced opposition, the attempt to disenfranchise a majority of Americans seems doomed to fail.On Saturday, Senator Lisa Murkowski of Alaska said she would vote to certify the results, writing: The oath I took at my swearing-in was to support and defend the constitution of the United States, and that is exactly what I will do. Pat Toomey of Pennsylvania, a state where Trump has sued, said he would vigorously defend our form of government by opposing this effort to disenfranchise millions of voters in my state and others.But Cruz and Johnson were joined by Senators James Lankford (Oklahoma), Steve Daines (Montana), John Kennedy (Louisiana), Marsha Blackburn (Tennessee) and Mike Braun (Indiana). Senators-elect Cynthia Lummis (Wyoming), Roger Marshall (Kansas), Bill Hagerty (Tennessee) and Tommy Tuberville (Alabama) also signed on.The election of 2020, they said, like the election of 2016, was hard fought and, in many swing states, narrowly decided. The 2020 election, however, featured unprecedented allegations of voter fraud, violations and lax enforcement of election law, and other voting irregularities.No hard evidence for such claims has been presented. Federal officials including former attorney general William Barr and Christopher Krebs, a cyber security chief fired by Trump, have said the election was secure.Regardless, the senators said Congress should immediately appoint an electoral commission, with full investigatory and fact-finding authority, to conduct an emergency 10-day audit of the election returns in the disputed states. Once completed, individual states would evaluate the commissions findings and could convene a special legislative session to certify a change in their vote, if needed.The senators made reference to the contested election of 1876, which ended in the appointment of such a commission.We should follow that precedent, they said. Most well-informed observers would suggest otherwise, given that process put an end to post-civil war Reconstruction and led to the institution of racist Jim Crow laws across the formerly slave-owning south.In August, the Pulitzer-winning historian Eric Foner told the Guardian: The election of 1876 would not have been disputed at all if there hadnt been massive violence in the south to prevent black people from voting and voter suppression like we have today. Now, voter suppression is mostly legal.Presciently, given baseless claims that voting under a pandemic was abused by Democrats, he added: Today, I can certainly see the Trump people challenging these mail-in ballots: Theyre all fraudulent, they shouldnt be counted. Challenging peoples voting.Cruz, like Hawley, is prominent among Republicans expected to run for president in 2024, and thus eager to appeal to supporters loyal to Trump. On Saturday, Christine Pelosi, daughter of House speaker Nancy Pelosi and a member of the Democratic National Committee, referred to the bitter 2016 primary when she tweeted: Ted Cruz is defending Trumps assaults on democracy with more energy than he defended his own family against Trumps assaults on his wife and father.The Democratic strategist Max Burns wrote: The exact same Senate GOP that refused to allow a single witness during President Trumps impeachment trial now wants to call a bunch of witnesses to investigate Joe Bidens 2020 victory.Biden did not immediately comment. In Congress, the Connecticut senator Richard Blumenthal branded the statement pathetic, un-American and an attack on our democracy. Amy Klobuchar, from Minnesota, said Biden will be inaugurated on 20 January, and no publicity stunt will change that.Trump did not immediately comment but his campaign tweeted: THANK YOU! The Arizona congressman Paul Gosar hailed the senators as patriots.But there was also criticism from the right. Joe Walsh, a former congressman who ran against Trump in 2020, wrote: They cite ZERO evidence of voter fraud Donald Trumps single greatest legacy is the destruction of truth.Walsh added: These Republicans know this is bad for the country. But they dont care. They believe its good for them politically. They are placing their own interests before the countrys interests.With unintended irony or simple bad faith the senators and senators-elect said their allegations are not believed just by one individual candidate. Instead, they are widespread. Reuters/Ipsos polling, tragically, shows 39% of Americans believe the election was rigged. That belief is held by Republicans (67%), Democrats (17%), and Independents (31%). Whether or not our elected officials or journalists believe it, that deep distrust of our democratic processes will not magically disappear. It should concern us all. And it poses an ongoing threat to the legitimacy of any subsequent administrations.Marc Elias, a leading Democratic elections lawyer, said of the senators: History will remember and curse them for their cowardice and treachery.

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Moderna, Pfizer vaccine trials were the highest of quality: vaccine expert - Yahoo Money

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Celebrate the new year with this New Year’s Eve fireworks show in SF – Yahoo News

January 2nd, 2021 5:52 pm

The Telegraph

Donald Trump was dealt a stinging rebuke by Republican senators last night as Congress overrode his veto of a sweeping defence bill. It was the first time in Mr Trump's four years as president that Congress had blocked his veto power. Many Republican senators joined Democrats in an 81-13 vote to override, well over the two thirds majority required. As a result the annual $740 billion National Defense Authorization Act to fund the military in 2021 will become law. Mr Trump had called the result, which was expected, a "disgraceful act of cowardice" and the Republican leadership in Congress "weak". The bill will provide a three per cent pay raise for US troops and included elements relating to defence policy, troop levels, weapons systems and military construction. Mr Trump had vetoed it, arguing it allowed for the renaming of military bases that honour Confederate generals, and that it limited his ability to bring troops home from Afghanistan and Germany. He also tried to link passage of the bill to measures targeting social media companies. Throughout Mr Trump's term Republican senators had been highly reluctant to break so publicly with him. He had vetoed eight previous bills and none were overridden. But with less than three weeks left in office Mr Trump's influence with Republican senators appeared to have receded markedly. Mitch McConnell, the Republican leader in the Senate, said: "It's time for us to deliver this bill. It's our chance to remind brave service members and their families that we have their backs." It came as Republicans also faced a deepening split over Mr Trump's last ditch attempt to overturn the US presidential election result. Over 140 Republicans in the House of Representatives may be ready to back a move not to certify the outcome at a joint session of Congress on Jan 6, it emerged. But even with that level of support the attempt to block the result still had no chance of success. Mr McConnell privately urged colleagues to accept the election result, and called his own vote on Jan 6 the "most consequential I have ever cast". In an open letter Ben Sasse, the Republican senator from Nebraska, accused colleagues of "playing with fire". He said: "Lets be clear what is happening here. We have a bunch of ambitious politicians who think theres a quick way to tap into the presidents populist base without doing any real, long-term damage. But theyre wrong. "Adults dont point a loaded gun at the heart of legitimate self-government." The move to oppose the election results was ignited by Josh Hawley, a Republican senator from Missouri. He will object, forcing a two-hour debate, followed by a vote in the Senate, and in the House of Representatives. The session in Congress will take place a day after two run-off races in Georgia, which will determine whether Republicans or Democrats control the Senate. David Perdue, one of two Republican candidates, announced he would spend the final days of the campaign in quarantine after possible exposure to the coronavirus. Meanwhile, it emerged that staffing changes were to be made to the Secret Service's presidential detail when Joe Biden takes office on Jan 20. Mr Biden's camp was said to have expressed concerns that current agents might be politically supportive of Mr Trump. Mr Trump cut short a trip to Florida and headed back to Washington on New Year's Eve. In a New Year video message he hailed "historic victories" on the economy and fighting the pandemic. He said: "We have to be remembered for what's been done." In the final weeks of his term the president was also facing an ongoing battle with Republicans in Congress, including Mr McConnell, after he called for an increase in stimulus cheques to Americans. He also faced growing friction with Iran.

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Celebrate the new year with this New Year's Eve fireworks show in SF - Yahoo News

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The movie industry will strengthen again around April or May: Screenvision CEO – Yahoo Money

January 2nd, 2021 5:52 pm

The Guardian

Republicans say they will reject presidential electors from states where Trump campaign contested results unless audit completedTed Cruz of Texas, Ron Johnson of Wisconsin and nine other Republican US senators or senators-elect said on Saturday they will reject presidential electors from states where Donald Trump has contested his defeat by Joe Biden, unless and until [an] emergency 10-day audit of such results is completed.The move is largely symbolic and unlikely to overturn the presidential election. Nonetheless, it adds to a sense of deepening crisis affecting US democracy.Trump has refused to concede, though Biden won more than 7m more votes nationally and took the electoral college by 306-232, a margin Trump called a landslide when he won it over Hillary Clinton in 2016.The Trump campaign has lost the vast majority of more than 50 lawsuits it has mounted in battleground states, alleging electoral fraud, and before the supreme court.On Friday, a federal judge dismissed a suit lodged by a House Republican which attempted to give the vice-president, Mike Pence, who will preside over the certification of the electoral college result on Wednesday, the power to overturn it.Nonetheless, the senators and senators-elect who issued a statement on Saturday followed Senator Josh Hawley of Missouri in committing to challenging the result.Objections are also expected from a majority of House Republicans. Objections must be debated and voted on but as Democrats control the House and the Senate majority leader, Mitch McConnell, and other senior Republicans have voiced opposition, the attempt to disenfranchise a majority of Americans seems doomed to fail.On Saturday, Senator Lisa Murkowski of Alaska said she would vote to certify the results, writing: The oath I took at my swearing-in was to support and defend the constitution of the United States, and that is exactly what I will do. Pat Toomey of Pennsylvania, a state where Trump has sued, said he would vigorously defend our form of government by opposing this effort to disenfranchise millions of voters in my state and others.But Cruz and Johnson were joined by Senators James Lankford (Oklahoma), Steve Daines (Montana), John Kennedy (Louisiana), Marsha Blackburn (Tennessee) and Mike Braun (Indiana). Senators-elect Cynthia Lummis (Wyoming), Roger Marshall (Kansas), Bill Hagerty (Tennessee) and Tommy Tuberville (Alabama) also signed on.The election of 2020, they said, like the election of 2016, was hard fought and, in many swing states, narrowly decided. The 2020 election, however, featured unprecedented allegations of voter fraud, violations and lax enforcement of election law, and other voting irregularities.No hard evidence for such claims has been presented. Federal officials including former attorney general William Barr and Christopher Krebs, a cyber security chief fired by Trump, have said the election was secure.Regardless, the senators said Congress should immediately appoint an electoral commission, with full investigatory and fact-finding authority, to conduct an emergency 10-day audit of the election returns in the disputed states. Once completed, individual states would evaluate the commissions findings and could convene a special legislative session to certify a change in their vote, if needed.The senators made reference to the contested election of 1876, which ended in the appointment of such a commission.We should follow that precedent, they said. Most well-informed observers would suggest otherwise, given that process put an end to post-civil war Reconstruction and led to the institution of racist Jim Crow laws across the formerly slave-owning south.In August, the Pulitzer-winning historian Eric Foner told the Guardian: The election of 1876 would not have been disputed at all if there hadnt been massive violence in the south to prevent black people from voting and voter suppression like we have today. Now, voter suppression is mostly legal.Presciently, given baseless claims that voting under a pandemic was abused by Democrats, he added: Today, I can certainly see the Trump people challenging these mail-in ballots: Theyre all fraudulent, they shouldnt be counted. Challenging peoples voting.Cruz, like Hawley, is prominent among Republicans expected to run for president in 2024, and thus eager to appeal to supporters loyal to Trump. On Saturday, Christine Pelosi, daughter of House speaker Nancy Pelosi and a member of the Democratic National Committee, referred to the bitter 2016 primary when she tweeted: Ted Cruz is defending Trumps assaults on democracy with more energy than he defended his own family against Trumps assaults on his wife and father.The Democratic strategist Max Burns wrote: The exact same Senate GOP that refused to allow a single witness during President Trumps impeachment trial now wants to call a bunch of witnesses to investigate Joe Bidens 2020 victory.Biden did not immediately comment. In Congress, the Connecticut senator Richard Blumenthal branded the statement pathetic, un-American and an attack on our democracy. Amy Klobuchar, from Minnesota, said Biden will be inaugurated on 20 January, and no publicity stunt will change that.Trump did not immediately comment but his campaign tweeted: THANK YOU! The Arizona congressman Paul Gosar hailed the senators as patriots.But there was also criticism from the right. Joe Walsh, a former congressman who ran against Trump in 2020, wrote: They cite ZERO evidence of voter fraud Donald Trumps single greatest legacy is the destruction of truth.Walsh added: These Republicans know this is bad for the country. But they dont care. They believe its good for them politically. They are placing their own interests before the countrys interests.With unintended irony or simple bad faith the senators and senators-elect said their allegations are not believed just by one individual candidate. Instead, they are widespread. Reuters/Ipsos polling, tragically, shows 39% of Americans believe the election was rigged. That belief is held by Republicans (67%), Democrats (17%), and Independents (31%). Whether or not our elected officials or journalists believe it, that deep distrust of our democratic processes will not magically disappear. It should concern us all. And it poses an ongoing threat to the legitimacy of any subsequent administrations.Marc Elias, a leading Democratic elections lawyer, said of the senators: History will remember and curse them for their cowardice and treachery.

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The movie industry will strengthen again around April or May: Screenvision CEO - Yahoo Money

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