Culture

Benign breast diseases (BBD), which are non-cancerous disorders of the breast, such as lumps, are known to increase the chances of subsequent breast cancer. Now a team of Spanish researchers have found that the way BBD is detected as part of a national screening programme is an indication of which are more likely to become cancerous.

The findings from a team led by Professor Xavier Castells, head of the epidemiology department at the Hospital del Mar Medical Research Institute, Barcelona, Spain, will be presented at the 12th European Breast Cancer Conference on Saturday.

BBD detected on the first occasion a woman attends for breast screening (usually at the age of 50 in Spain and many other European countries with national screening programmes) is classified as "prevalent" BBD, whereas those detected on subsequent visits, which occur every two years in Spain, are classified as "incident" BBD.

Dr Marta Román, a senior researcher in the epidemiology department at the Hospital del Mar Medical Research Institute, told the conference: "Our results show that women with a benign breast disease diagnosed from the second screening onwards have a significantly higher subsequent risk of breast cancer than those with a BBD diagnosed on their first mammographic screening."

The researchers analysed data from 629,087 women who underwent 2,327,384 screening mammograms between 1995 and 2015, and they followed them until 2017. They found that women diagnosed with incident BBD had a 2.67-fold increased chance of developing breast cancer than women with no BBD, while women with prevalent BBD had a 1.87-fold increased risk.

They also classified the BBDs as non-proliferative or proliferative, depending on whether or not the breast tissue showed an increase in the growth of certain cells, such as the ductal cells found in ductal hyperplasia in which there is an overgrowth of cells lining the ducts inside the breast.

They found that women with proliferative BBD had a 3.28-fold increased chance of breast cancer compared to women with no breast disease, while women with non-proliferative BBD had a 1.96-fold increased risk.

Dr Román said: "We found the highest risk of breast cancer in women with incident, proliferative BBD. They had a nearly four-fold increased risk of breast cancer compared to women with no BBD."

Women with an incident, non-proliferative BBD had a 2.39-fold increased chance of subsequently developing breast cancer compared to women with no BBD; women with prevalent, proliferative BBD had a 2.85-fold increased risk; and women with prevalent, non-proliferative BBD had a 1.63-fold increased risk.

The researchers hope that their findings will be useful in designing personalised breast cancer screening strategies in order to improve the effectiveness of breast cancer screening.

"The likelihood that a woman will benefit from screening mammography depends on her risk for developing clinically significant breast cancer in her lifetime," said Dr Román. "Taking individual risk factors beyond age into account should enable the classification of women into groups at varying risk of breast cancer. Personalised risk-based screening going beyond the current 'one-size fits all' recommendation may increase the effectiveness of breast cancer screening. Including information from BBD, in addition to other factors, to develop risk-based screening approaches can help with the prediction of whether a woman would develop breast cancer in a defined period.

"Different screening strategies can be considered for each woman based on her personal risk of breast cancer: by modifying the screening interval, which could be annual, or every two or three years, the method of screening, for instance, mammogram, ultrasound or magnetic resonance imaging, or the age range in which the woman is invited for screening participation."

Dr Román and her colleagues believe these findings will help clinicians to understand the different risks associated with BBD and to improve the accuracy of breast cancer risk predictions.

In a statement before the conference, Professor Xavier Castells said: "Clinicians involved in the management of women with BBDs could offer targeted surveillance strategies considering, in addition to other factors, if the BBD was found at first or in subsequent screening examinations. Also, this information will be included in an individualised model that can be used to predict an individual woman's risk of developing breast cancer in five or ten years' time. We have tested this in the context of a screening programme, which also includes information on breast density, age, family history of breast cancer and mammographic features."

The team is part of MyPebs: an international randomised controlled trial, funded by the European Union that investigates whether a risk-based breast cancer screening strategy, based on a clinical risk score, is more effective than standard screening. This international project, which started in July 2019, will recruit 90,000 participants from six countries [1] and follow them for four years.

Co-chair of EBCC12, Professor Javier Cortes, is clinical investigator of the breast cancer research programme at Vall d'Hebron Institute of Oncology, Barcelona, and head of the breast cancer programme at the IOB Institute of Oncology, Madrid and Barcelona, and was not involved with this research. He commented: "We know that population-based breast cancer screening programmes save lives by detecting cancer at an early stage. However, it can raise questions about not only the best way of treating women with cancer that may never become a problem in their lifetimes, but also what to do about women with benign breast disease.

"No patient wants to have screening mammograms more often than is needed, but patients and clinicians want to be sure that if benign breast disease does develop into cancer, it can be detected quickly. The results from this study provide us with useful information that can improve the accuracy of breast cancer risk prediction models so that we can tailor surveillance strategies for patients with this disease."

(ends)

Abstract no: 15, "Differences in breast cancer risk after a benign breast disease according to the screening type", Proffered papers session: "Are your breasts still at risk?", Saturday, 16.00-16.45 hrs, Channel 3 (Dr Román's presentation will be at 16.10 hrs).
[1] The countries taking part in the MyPebs trial are: France, Belgium, Israel, Italy, the UK and Spain.

Four out of five people experiencing the recent loss of smell and/or taste tested positive for COVID-19 antibodies--and of those who tested positive, 40 percent did not have cough or fever, reports a new study in PLOS Medicine by Prof. Rachel Batterham at University College London and colleagues.

COVID-19 can cause loss of taste and smell, but the prevalence of COVID-19 antibodies in people reporting these symptoms is unknown, and the significance of loss of smell and/or taste as a predictor of COVID-19 is not well understood. To estimate the seroprevalence of SARS-CoV-2 antibodies in people with acute loss of their sense of smell and/or taste, researchers enrolled 590 people self-reporting a loss of taste/smell in the previous month. Following verification of symptoms via a telemedicine consultation, 567 participants with smell and/or taste loss participants underwent a SARS-CoV-2 antibodies test.

78% had SARS-CoV-2 antibodies, and participants with loss of smell were almost 3 times more likely to have SARS-CoV-2 antibodies compared to those with loss of taste, suggesting that a loss of smell is a highly specific symptom of COVID-19. Of the 78% of participants testing positive for antibodies, 40% had neither cough nor fever. While the study had limitations, such as the self-reporting of smell/taste changes and the lack of a control group, the researchers believe the evidence indicates that loss of smell should be taken into greater consideration in COVID-19 public health measures such as testing, case isolation, and treatment strategies.

These findings also have significant implications for policy makers globally, as most countries do not recommend self-isolation and testing based on acute loss of smell/taste. This study suggests that an over-reliance on cough and fever as the main symptoms of COVID-19 may be flawed and that loss of smell needs to be urgently recognized globally as a key symptom of COVID-19.

Prof. Rachel Batterham, who led the study, said "Early self-recognition of COVID-19 symptoms by the members of the public, together with rapid self-isolation and PCR testing are vital in order to limit spread of the disease. Currently, most countries around the world do not recognize sudden loss of smell as a symptom of COVID-19.

78% of participants in our community-based study with sudden onset loss of smell or taste had SARS-CoV-2 antibodies. The vast majority had mild symptoms and 40% did not report having a fever or cough. Our findings suggest that people who notice a loss in their ability to smell every day house-hold odors such as garlic, coffee and perfumes should self-isolate and seek PCR testing. Loss of sense of smell needs to be recognized globally by policy makers as a key symptom of COVID-19."

The first comprehensive study of DNA changes in healthy and diseased human bladder tissue has revealed that 'cancer-driving' mutations are common in healthy bladder tissue. The study, conducted by scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators, provides an unprecedented view of the first steps towards bladder cancer.

Published today (1 October 2020) in Science, the research uncovered high variation in the number and types of changes between individuals, indicating that a wide range of factors influence how bladder cancer develops. The researchers also provided new insights into the link between smoking and bladder cancer, whereby bladder tissue is exposed to tobacco chemicals present in urine.

More than 10,000 people are diagnosed with bladder cancer every year in the UK, with around 5,000 deaths. Around 60 per cent of new cases occur in people aged 75 and over. Around half of bladder cancer cases are estimated to be preventable. Early diagnosis is also crucial, with 95 per cent of those diagnosed early surviving for one year or more, dropping to 36 per cent for late stage diagnosis*.

Cancers occur due to changes in DNA, known as somatic mutations, which continuously occur in all of our cells throughout life. Some somatic mutations, particularly those affecting known 'cancer genes', confer a competitive advantage that allows these mutated cells to expand more rapidly than normal cells and can lead to disease.

Technological developments have enabled the detection of somatic mutations linked to cancer in normal tissues, providing insights into the earliest stages of cancer and raising the prospect of early detection and treatment strategies**.

This new study used DNA sequencing to better understand the genetic changes in healthy and diseased bladder tissue. Clinicians from the University of Cambridge provided donated bladder tissue from five people with bladder cancer and 15 people with no history of cancer.

Researchers at the Wellcome Sanger Institute then took 2,097 biopsies from the tissue samples, using a technique called laser-capture microscopy to isolate segments of just a few hundred cells. DNA from these samples was genome sequenced and the sequences were analysed to characterise the landscape of somatic mutations.

The team found an unexpectedly high variability in the number and types of mutations and in the frequency of 'cancer-driving' mutations between individuals, suggesting that a wide range of factors affect the accumulation of mutations in the bladder. Some of these factors could be identified by their 'mutational signature' - tell-tale patterns of mutation in the genome caused by a certain chemical or process.

The study identified a new mutational signature associated with smoking, shedding light on why tobacco is the single greatest risk associated with bladder cancer. Though the bladder does not come into contact with smoke directly, the chemicals in tobacco products are filtered out of the body by the kidneys and come into contact with the bladder in the urine.

Andrew Lawson, first author of the study from the Wellcome Sanger Institute, said: "One of the questions we sought to answer with this study was why bladder cancers have some of the highest mutation rates and cancer-driving mutations of any cancer type, even though the cells in the bladder divide slowly, reducing the chance of a genetic error. The high patient-to-patient variation in which genes were mutated and in the types of mutations may be consistent with the wide variety of factors that can contribute to bladder cancer. Further studies on the causes behind this variation could help uncover hidden causes of bladder cancer."

The researchers were surprised to find that mutations in key cancer genes such as TP53, FGFR3 and TERT were largely absent from healthy bladder tissue, despite the high number of mutations overall. As mutations in these genes are common in bladder tumours, their presence is a strong indicator that disease has set in.

Thomas Mitchell, a senior author of the study from Cambridge University Hospitals and the Wellcome Sanger Institute, said: "Like many cancers, early diagnosis of bladder cancer gives the patient a much greater chance of survival. The presence of mutations in key cancer genes in bladder tumours that are usually absent in normal tissue opens up the possibility of looking for these changes in fragments of DNA that are present in urine. These 'liquid biopsies' could be a non-invasive way to screen for bladder cancer earlier, which could help reduce the number of people who die from this disease."

Dr Inigo Martincorena, lead author of the study from the Wellcome Sanger Institute, said: "This study reveals an unexpectedly rich landscape of mutation and selection in normal bladder, with large differences across individuals driven to some extent by our daily exposures. Thanks to technical advances, our understanding of how our cells mutate, compete and evolve as we age have been transformed over the last few years. In addition to shedding light on the origins of cancer and informing early detection efforts, these observations raise questions about the possible role of these widespread mutations in ageing and other diseases."

The COVID-19 pandemic has created a flood of potentially substandard research amid the rush to publish, with a string of papers retracted or under a cloud and a surge in submissions to pre-print servers where fewer quality checks are made, a leading ethicist has warned in the Journal of Medical Ethics.

This has implications for patients, clinicians, and potentially government policy, says Adjunct Professor Katrina Bramstedt, Bond University, Queensland, Australia and Secretary General at Luxembourg Agency for Research Integrity.

The rapid spread of COVID-19 and its transition into a global pandemic propelled researchers to begin the search for treatments and vaccines in earnest.

Scientific and medical Journals have since been flooded with submissions, while thousands of papers, which have not undergone thorough quality checks, have been posted on preprint servers.

As of 7 May 2020, 1221 studies on COVID-19 were registered on the international clinical trial registry site, ClinicalTrials.gov.

And as of 31 July 2020, 19 published articles and 14 preprints about COVID-19 have been retracted, withdrawn, or had serious doubts raised about the integrity of their data, formally known as an expression of concern.

Most of these papers came from Asia (n=19; 57.5%), with over half coming from China (n=11; 58%).

But as the author points out: "No research team is exempt from the pressures and speed at which COVID-19 research is occurring. And this can increase the risk of honest error as well as deliberate misconduct."

The reason for the removal of the 33 papers isn't known in 3 cases, but data falsification, methodological issues, and concerns about interpretation of data and conclusions, as well as authorship and participant privacy issues were among the reasons in the other papers.

Two preprints (SSRN preprint server) and two research papers in The Lancet and New England Journal of Medicine were retracted because of unverifiable data common to all four.

And a preprint from the USA about COVID-19 antibody seroprevalence has come under scrutiny for an undisclosed conflict of interest.

There are obvious implications for the journal and the researchers involved, even if they are innocent of any research misconduct, points out the author. The evidence suggests that in such cases, the citations of prior collaborators can take a hit and fall by 8-9%.

But there are also implications for patients. "Patient harm that is significant, permanent and irreversible could result from using faulty research results from preprints as well as published papers," she says.

The rush to publish means there is less time for quality checks by researchers and their supervisors and for thorough reviews of study applications by research ethics committees, says Professor Bramstedt.

Added to which, these committees can't be expected to routinely include the key experts needed for COVID-19 research, such as immunologists, microbiologists and lung disease specialists.

Journals, too, rely on a fleet of peer reviewers, all of whom work on a voluntary basis and have competing demands on their time.

To counter these issues, the author suggests that the efficiency of the submission process is tightened up and that research ethics and integrity training be mandated for all researchers.

They should also have timely access to ethical advice on research dilemmas involving topics such as authorship disputes, image manipulation, citations and referencing, informed consent, ethical participant recruitment, etc.

Any infractions of policies and standards should have meaningful consequences to ward off repeat offences, she suggests, adding that it's important to publicise the results of any investigations, whatever the outcome.

In a personal comment, not found in the text, Professor Bramstedt emphasizes: "Research has the potential to enter the public domain and be used by many stakeholders, including governments and policy makers, so the data must be robust."

Journal of Medical Ethics editor, Professor John McMillan, adds: "Researchers face powerful headwinds against their efforts to further knowledge about COVID-19. The urgency for evidence, the rewards from finding a successful therapy or vaccine, and the prevalence of disinformation mean scientific integrity is critically important.

"Professor Bramstedt's report is an early warning for journals and preprint servers to be proactive and maintain rigour when assessing research."

Men predominate in more than 85% of COVID-19 decision-making and key advisory bodies around the globe, with gender parity in just 3.5%, reveals an analysis of the available data, published in the online journal BMJ Global Health.

This has become a "disturbingly accepted pattern of global health governance" that undermines the effectiveness of the pandemic response and ultimately costs lives, warn the authors.

There have been numerous global and national commitments to move towards gender-inclusive global health governance. But COVID-19 took the world by surprise, prompting many advisory groups and expert panels to be set up very quickly.

To find out just how gender inclusive and representative these bodies are, the authors collected information up to June 2020 on the membership of COVID-19 global and national decision-making and expert bodies for 193 UN Member States.

They did this through crowdsourcing, targeted searches of 'grey literature', such as unpublished research and policy statements, and outreach to national governments or World Health Organization (WHO) country offices.

Most of the information about membership, leadership, and areas of expertise was neither easily accessible nor publicly available, hampering efforts to obtain it and, "ultimately, the ability to hold countries accountable to previously made commitments," note the authors.

Their analysis included 115 expert and decision-making COVID-19 task forces from 87 countries. It revealed that men predominate in more than 85% of expert groups and task forces; women predominate in just over 1 in 10 (11.5%), with gender parity in a mere 3.5%. Similarly, 81% (65) were headed up by men at the time of the search.

Women make up 24%, 24%, and 37.5%, respectively, of the WHO's first, second, and third International Health Regulations Emergency Committees, for example.

And while expert groups more often had higher proportions of women or gender parity than decision-making committees, this most likely reflects potential societal biases and gender stereotyping around leadership, suggest the authors.

In the USA, for example, women make up just 9% of the White House Coronavirus Task Force, but 82.5% of the chief public health agency's COVID-19 Response Team.

The authors acknowledge that COVID-19 tends to be more severe and lethal among men. But women have been hit harder socially and economically, as a result of extended and unpaid caring responsibilities, heightened risk of domestic and sexual violence; and loss of access to maternal and reproductive health services during lockdown, they point out.

The Ebola and Zika pandemics were also associated with increased rates of maternal ill health and death as well as unwanted pregnancies and unsafe abortions, they note.

"A 'new default' mode of diverse and intersectional governance is sorely needed to face future crises head-on and guide a healthy and equitable COVID-19 recovery," they assert.

First, this should include truly representative membership of international and national task forces, spanning gender, ethnicity, race, culture, geography and disability.

Second, quick action in emergency scenarios is repeatedly used as a justification to sidestep transparency and restrict communication in the name of health security, when nothing could be further from the truth. "Closed-door governance" should be replaced by open and transparent communication and decision-making as the norm, they say.

And thirdly, data collection and governance policies must go beyond binary representation in order to produce results that are inclusive of the full gender spectrum.

"Reaching a critical mass of women in leadership - even as result of intentional selection or quotas - benefits governance processes through the disruption of groupthink, the introduction of novel viewpoints, a higher quality of monitoring and management, more effective risk management and robust deliberation," they write.

Countries with women at the helm have been associated with particularly effective COVID-19 responses, fewer cases, and lower death rates from the disease, they point out.

"Men dominating leadership positions in global health has long been the default mode of governing," excluding those "who offer unique perspectives, expertise and lived realities.

"This not only reinforces inequitable power structures but undermines an effective COVID-19 response - ultimately costing lives," they conclude.

Spinal cord injury often leads to permanent functional impairment. In a new study published in the journal Science researchers at Karolinska Institutet in Sweden show that it is possible to stimulate stem cells in the mouse spinal cord to form large amounts of new oligodendrocytes, cells that are essential to the ability of neurons to transmit signals, and thus to help repair the spinal cord after injury.

The spinal cord conveys signals from the brain to the rest of the body and spinal cord injury often leads to a degree of paralysis as some nerve fibers become transected and others, while intact, operate less efficiently. This impaired function is often caused by the loss of oligodendrocytes, a type of insulating cell that facilitates neuronal signalling.

In many organs, damaged tissue can be repaired by stem cells that create the cell types that have been lost. There are stem cells in the adult spinal cord, but these give rise primarily to scar forming cells after an injury. The scar tissue limits the extent of the damage but does not contribute to the replacement of lost cells.

In the current study, the researchers carefully characterised spinal cord stem cells at a genetic level in mice, and found that the stem cells' DNA was receptive to signals that stimulate the formation of new oligodendrocytes.

"We found that the stem cells were not locked into forming scar tissue and understood how we could nudge them in another direction to also form cells that contribute to repair," says the study's first author Enric Llorens-Bobadilla, researcher at the Department of Cell and Molecular Biology at Karolinska Institutet.

By controlling which genes were activated in the stem cells, the researchers were able to stimulate an abundant generation of new oligodendrocytes, which led to improved nerve fibre function in the damaged spinal cord.

"This shows that it's possible to affect stem cells in the nervous system so that they contribute more to functional recovery," says principal investigator Jonas Frisén, professor at the Department of Cell and Molecular Biology, Karolinska Institutet. "Although the studies were done in mice and are not directly translatable to humans, they indicate a conceptually new strategy for stimulating repair after damage to the nervous system."

A team of researchers, led by the University of Bristol, has revealed our most ancient ancestors were ecologically diverse, despite lacking jaws and paired fins.

Long before they evolved out of the water, our ancient ancestors were simple fish-like creatures, but without fins or chins, who survived by filtering nutrients from sediment.

They have long been thought of as the lazy lumps who spent most of their lives resting on or near to the sea floor. The belief was that everything changed with the evolution of jawed vertebrates whose paired fins made them the super-swimmers and active predators, driving their jawless relatives to extinction.

However, a new study published in the journal Current Biology overturns this classical evolutionary story.

Researchers from the University of Bristol used computer simulations to explore how avatars of our extinct ancestors interacted with water currents. These experiments revealed the bizarre spikes and spines that ornamented the heads of these jawless vertebrates were actually hydrodynamic adaptations, passively generating lift from water currents flowing over the body. The varying head shapes of different species allowed them to adapt to different positions, some high, others low, within the water. Our ancient ancestors were already ecologically diverse, long before the evolution of their jawed vertebrate relatives.

Dr Humberto G. Ferron, a postdoctoral researcher from the University of Bristol and one of the paper's co-authors, said: "The evolution of jaws and fins have classically been seen as the key evolutionary inventions that allowed vertebrates to diversify their lifestyles.

"In this context, jawless ancestors, characterized by the presence of heavy rigid headshields, were assumed to be cumbersome fish-like creatures, living on the bottom of rivers and seas, with poor manoeuvrability."

The question of how our ancient ancestors made a living has long been a mystery because there are no animals like them alive today. The 'osteostracans' (their latin name, meaning bony shells) were heavily armoured, encased in thick bone from snout to tail. They lacked a rear pair of legs and some had none at all; many possessed bizarre horn-like extensions from the front of their heads.

Ferrón and colleagues tackled this problem using state-of-the-art computational engineering techniques that simulate the behaviour of fossil avatars in water currents.

Dr Imran Rahman, from the Oxford University Museum of Natural History, said: "The application of computational fluid dynamics, has allowed us to study the swimming performance of ancient vertebrates and learn more about their position in evolutionary history.

Dr Carlos Martinez Perez, from the University of Valencia (Spain), added: "Our simulations reveal that the different species of osteostracans show equally different hydrodynamic efficiencies. Some of them performed better when moving close to the sea floor or riverbed while others performed better when swimming freely in the water."

Professor Phil Donoghue, another Bristol co-author, concluded: "The different species' body shapes are adapted to different environments, revealing distinct lifestyles among these groups of jawless early vertebrates.

"Our results calls into question the prevailing view that these extinct groups of jawless vertebrates were ecologically constrained, and reveals the main evolutionary hypothesis for the origin of jawed vertebrates is more complex than previously thought."

A tiny flatworm found commonly on the coasts of western Europe and North America is living proof that species may be able to evolve and adapt to rapid climate change.

Research by the University of Plymouth examined the extent to which the intertidal flatworm Procerodes littoralis was able to regenerate and repair itself when challenged with different sea water conditions.

Repeating a study conducted more than a century earlier it was shown that the response of individuals had changed markedly since then.

The original study was conducted by Dorothy Jordan Lloyd, who was based at the Marine Biological Association in Plymouth, and focussed on individuals found in Wembury Bay, Plymouth.

It was published in 1914, and the current study - led by BSc (Hons) Marine Biology graduate Katharine Clayton - replicated it in terms of the processes followed and the precise locations from which samples were collected.

When tested across a range of different concentrations of salt water in the laboratory, scientists showed the flatworm was able to regenerate following minor injuries at lower salinities than were recorded originally.

They also demonstrated that while in 1914 there was an optimum salinity level for individuals to regenerate this is no longer the case, suggesting individuals have extended their tolerance range in the intervening 104 years.

Scientists also examined rainfall levels for the Wembury Bay area and found they had increased between 1914 and 2018, which is likely to result in exposure to lower salinities in the intertidal region, where the flatworm is found.

Put together, they say it shows how individual species may be able to adapt and survive the localised effects of climate change which, if correct, provides some of the first evidence of evolutionary rescue taking place in the wild.

Katharine Clayton began the study as part of her undergraduate degree and wrote it up for her final year dissertation. Now pursuing a PhD at the University of Exeter, she said: "When we first began looking at this flatworm, we were interested in how it tolerated salinity levels in it natural habitat. However, we quickly found out about Dorothy's study in 1914 so it became a perfect test of how an individual population had adapted to changes within its immediate environment. The findings provide really interesting evidence of the impacts of climate change, but it has also been inspiring for me to revisit Dorothy's work and highlight a pioneering female scientist of her time."

The research's co-author, Professor of Marine Zoology John Spicer, supervised Katharine's work and is a world-leading authority on how marine species can adapt to climate change. He added: "There has been an idea around for the last 15 to 20 years called evolutionary rescue where, faced with rapid climate change, animals evolve to survive. Many, including myself, have doubted the possibility of such rescue, especially over such a short space of time in terms of species evolution. But this study shows it may well be possible in the wild because, in comparing two identical experiments 100 years apart, the animal has changed how it works, its physiology.

"It is proof that evolutionary rescue may exist in the wild, not just in the laboratory, and is a major step forward in our understanding of how species can adapt as the environment around them changes. With the two studies being conducted 50 years before and after the start of the Anthropocene, it also provides a fascinating insight into the effect humans are having on species with whom we share our planet."

This news is embargoed until Oct. 1, 2020, 11:00 a.m. ET and should follow the announcement of the EHT collaboration, which will also be posted via EurekAlert!.

If a picture is worth a thousand words, what might the first horizon-scale image of a black hole tell us? A new paper by researchers from the Event Horizon Telescope (EHT) collaboration, which famously imaged M87's central black hole, has provided a number of enlightening answers. Based on an analysis of the black hole's shadow, the team conducted a unique test of general relativity, deepening understanding about the unusual properties of black holes and ruling out many alternatives. This research, published in Physical Review Letters, was led by Dimitrios Psaltis (IAS Member, 2001-03) of the University of Arizona, Lia Medeiros of the Institute for Advanced Study (IAS), and Feryal Özel (IAS Member, 2002-05) and Pierre Christian, both of the University of Arizona, and was co-authored by the EHT collaboration.

The intense gravity of a black hole curves spacetime, acting as a magnifying glass and causing the black hole shadow to appear larger. By measuring this visual distortion, the research team found that the size of the black hole shadow corroborates the predictions of general relativity. A test of gravity at the edge of a supermassive black hole represents a first for physics and offers further proof that Einstein's theory remains intact even under the most extreme conditions.

"This is really just the beginning. We have now shown that it is possible to use an image of a black hole to test the theory of gravity," explained Medeiros. "This test will be even more powerful once we image the black hole in the center of our own galaxy and in future EHT observations with additional telescopes that are being added to the array."

The black hole shadow is unlike the shadows encountered in everyday life. Whereas a physical object casts a shadow by preventing light from passing through it, a black hole can create the effect of a shadow by siphoning light towards itself. While light cannot escape from the interior of a black hole, it is possible--though unlikely--for light to escape from the region surrounding the event horizon, depending on its trajectory. The result is a murky no man's land just beyond the point of no return, which appears to observers as a shadow.

Gravitational tests have been conducted in a variety of cosmic settings. During the 1919 solar eclipse, the first evidence of general relativity was seen based on the displacement of starlight, traveling along the curvature of spacetime caused by the sun's gravity. More recently, tests have been conducted to probe gravity outside the solar system and on a cosmological scale. Examples include the detection of gravitational waves at the Laser Interferometer Gravitational-Wave Observatory (LIGO). Gravitational waves propagate through the fabric of spacetime like ripples on a pond given the dynamic nature of spacetime as predicted by general relativity.

The new EHT paper focuses on a previously unexplored parameter space for black hole research. In addition to providing a brand-new test for all alternative formulations of gravity, it also connects the constraints from black hole images to those from other gravitational experiments. The supermassive black hole at the center of M87 studied by the EHT collaboration is 6.5 billion times more massive than the sun. In contrast, gravitational wave detectors monitor stellar mass black holes that range from five to several dozen solar masses. Such diverse perspectives are essential to a more comprehensive understanding of the underlying nature of black holes.

The nearly circular shape of the black hole shadow, as observed, may also lead to a test of the general relativistic no-hair theorem, which states that a black hole is described entirely by its mass, spin, and electrical charge. In other words, two black holes that possess the same mass, spin, and electrical charge would be considered indistinguishable--similar to the identical nature of like subatomic particles. Should geometric irregularities be detected it would potentially indicate the existence of additional black hole properties beyond mass, spin, and electrical charge.

In a separate study, "A Parametric Model for the Shapes of Black Hole Shadows in Non-Kerr Spacetimes," published in The Astrophysical Journal this year, Medeiros, Psaltis, and Özel explore the size and shape of the black hole shadow by modeling several different spacetimes and theories of gravity. The black hole shadow depends only on the geometry of the surrounding spacetime and not on the astrophysics of the accretion process.

The ongoing work of the EHT collaboration and its members will continue to bring light to both the hidden framework and visible features of black holes.

The human gut contains a diverse ecosystem of microbes: mainly bacteria, as well as viruses and fungi, termed the gut microbiota. Recent years have shown that the gut microbiota have widespread effects on the overall functioning of the host's body.

Normally infants receive gut bacteria from the mother at birth. Some of these maternal bacteria grow out in the infant as they aid the infant in digesting breast milk.

Birth by Cesarean section (C-section) has been shown to be especially detrimental to normal gut microbiota development. During birth by C-section infants are not exposed to maternal fecal microbes and this prevents the natural transfer of microbes from mother to baby.

In the recently reported study, researchers of mainly the University of Helsinki evaluated whether the disturbed intestinal microbiota development could be restored in term Cesarean section infants by postnatal, orally-delivered maternal fecal microbiota transplantation (FMT). FMT has been successfully used in adults to normalize gut microbiota composition and cure diseases such as recurrent Clostridium difficile infections.

The results of the study are published in the scientific journal Cell.

"Birth by C-section is associated with an increased risk of many immune-related diseases, suggesting that the lack of maternal microbes in early life may have long-term consequences on the health of the child. This proof-of-concept study demonstrates that the intestinal microbiota of infants born by C-section can be postnatally restored by maternal FMT and provides further support for the natural transfer of gut microbiota from mother to infant," says Willem M de Vos, Professor of Human Microbiomics who was a senior author on the study.

The procedure reduces risks that abnormal gut microbiota may confer

The researchers applied FMT immediately after birth by using the infants' own mothers' fecal samples. Because feces can contain dangerous pathogens, these were first carefully screened. Out of 17 tested mothers, 7 had pathogen-free samples and were selected for the study.

All seven C-section born infants that received the FMT remained healthy and experienced no negative effects from the treatment. Their gut microbiota composition was monitored for 3 months and compared the composition to that of untreated C-section born infants and vaginally born infants.

"The gut microbiota of the FMT-treated infants became very quickly similar to that of vaginally born infants. It did not resemble that of the untreated C-section born infants, showing that the treatment was effective in restoring normal microbiota development," says Dr. Katri Korpela, first author on the study.

"This simple procedure can normalize gut microbiota colonization and development in C-section born infants, which will likely contribute to reduced risk of developing chronic diseases that abnormal gut microbiota may confer," adds Dr. Otto Helve MD, specialist in pediatric infectious diseases and shared first author of the study.

"This procedure should be only performed after careful screening of the mother for potential pathogens," stresses Professor Sture Andersson MD, neonatologist who also was a senior author on the publication.

The evolution of epidemic and endemic strains of the cholera-causing bacterium Vibrio cholerae in Argentina has been mapped in detail by researchers at the Wellcome Sanger Institute, the London School of Hygiene and Tropical Medicine, the University of Cambridge and the INEI-ANLIS "Dr Carlos G. Malbrán", Argentina. The teams used whole genome sequencing to study the bacteria circulating during the 1991-1998 outbreak of cholera in the country.

The data have influenced health policy in Argentina, where the national alert surveillance system now uses whole-genome sequencing to distinguish between pandemic and non-pandemic lineages of V. cholerae bacteria. The study is published in Nature Communications today (1 October).

Cholera, caused by strains of V. cholerae bacteria, currently affects 47 countries world-wide and claims the lives of nearly 100,000 people a year*. Since the 1800s, there have been seven cholera pandemics around the globe, causing millions of deaths. The current pandemic, which began in the 1960s, is caused by a single lineage of V. cholerae, called 7PET. While South and Central Latin America have largely recovered from the outbreaks that began in Haiti in 2010, the lineage continues to circulate the globe and is the cause of the world's largest cholera epidemic, ongoing in Yemen, where hundreds of thousands have been infected**, ***.

In a new study, the team sequenced the genomes of a unique set of historical V. cholerae samples, held at INEI-ANLIS "Dr. Carlos G. Malbrán", the national reference laboratory of Argentina. By re-analysing the past, the international team of researchers hope to understand better the future patterns of disease, and to enable rapid alerts for new introductions of pandemic lineages.

Using phylogenetic analysis, they confirmed that the 1992 outbreak of cholera in Argentina was caused by one introduction of 7PET V. cholerae bacteria, originally introduced into Peru. The bacteria then evolved very little during the six years of the epidemic. This was in contrast to the diverse, multiple endemic strains of V. cholerae circulating at the same time. Previous work by the team has shown that while endemic strains can make people ill, they seem to lack the potential to spread quickly and cause an epidemic****.

Matthew Dorman, first author on the study from the Wellcome Sanger Institute said: "When a 7PET pandemic strain enters into Latin America from elsewhere, it can cause massive epidemics, such as those seen in Peru in the 1990s and Haiti in 2010. If we are to control cholera epidemics efficiently, it is vital that we are able to distinguish and understand the differences between the local, endemic V. cholerae that co-exist alongside 7PET during a cholera epidemic. Our study elaborated the genomic evolutionary history of these two types together in a single country, during a decade where there were major cholera outbreaks in this region."

The findings have been used by public health authorities in Argentina, where the national alert system has now been changed to distinguish between pandemic 7PET lineage and local V. cholerae lineages using whole-genome sequencing.

Dr Josefina Campos, senior author from INEI-ANLIS "Dr. Carlos G. Malbrán", Buenos Aires, Argentina said: "Thanks to a comprehensive surveillance and reporting system, the reference laboratory in Argentina contains a snapshot of an entire epidemic. This gave us a unique opportunity to understand the detailed evolution of V. cholerae bacteria in our country. We will be able to use these data and this experience to inform how we monitor and respond to any future cholera outbreaks - bacteria that cause epidemics pose a very different risk to those that do not; this is simple information that is critical for disease control. We are the first national reporting system in the world to use genomic data to monitor cholera like this."

Professor Nick Thomson, senior author from the Wellcome Sanger Institute and the London School of Hygiene and Tropical Medicine said: "Detailed studies like this contribute to our growing understanding of how cholera is moving across the globe: evidence to inform improved control strategies as well as identify areas for further research. Our challenge is to better understand why such a simple bacterium continues to pose such a threat to human health, with this study we are a little step closer."

A study published in Science on October 2 suggests that prioritizing aquatic environments in conservation programs for the Amazon region can be up to six times more efficient than focusing on the protection of terrestrial species, as is usual.

The conclusion is based on simulations using georeferenced field data on species diversity, weather and topography, among other things. The simulations enabled the researchers to identify the most important areas for the conservation of each group of species.

When conservation planning focuses on terrestrial species, they found, the protection achieved for aquatic species is only 22% of that obtained for terrestrial species, whereas when it focuses on the animals that inhabit rivers and lakes, the benefits reach 84% of the protection for species that live on land for the same financial cost.

The study was supported by São Paulo Research Foundation - FAPESP and led by researchers at the University of São Paulo's Luiz de Queiroz College of Agriculture (ESALQ-USP) in Brazil and Lancaster University in the UK.

"We know more about terrestrial species and so they end up influencing the choice of priority areas for conservation. It's assumed that aquatic biodiversity will benefit to the same extent. We set out to see whether this was so, given the considerable differences between the two environments. We concluded that it wasn't and that prioritizing terrestrial biodiversity doesn't guarantee the same degree of protection for aquatic biodiversity," said Cecília Gontijo Leal, first author of the article. The study was conducted while she was on a postdoctoral research internship at ESALQ-USP with a scholarship from São Paulo Research Foundation - FAPESP.

Beyond land and water

In preparing the simulations, the group analyzed data for 1,500 terrestrial species (plants, birds, and beetles) and aquatic species (fish, dragonflies, other insects) collected in 377 localities and 99 forest river channels (igarapés) in Paragominas and Santarém, Pará state. In these two municipalities, more than 40% of the forest cover has been cleared to make way for agricultural activities.

The analysis started from the assumption that aquatic environments are not isolated but interconnected, as water permeates terrestrial ecosystems and transports nutrients and species, as well as playing an important role in many ecological processes.

"Rivers are normally used as borders for conservation units, and catchment areas aren't totally protected because they aren't well-represented. Xingu Indigenous Park in the state of Mato Grosso is a classic case. The headwaters are outside the area of the park, and all the effects of deforestation, however distant, reach the indigenous communities and the biodiversity inhabiting the protected territory," Leal said.

According to the researchers, the benefits can be six times greater when planning includes both aquatic and terrestrial biodiversity data, compared with the way it is done now. When no data is available, simply including connectivity as a factor at least doubles the efficiency of conservation. The group found that the change of approach to include connectivity alone would increase the benefits to aquatic species by 75%-100% in Paragominas and by 130%-175% in Santarém, practically without losses to terrestrial species and using the same amount of financial resources.

"Conservation planning is usually delimited by an area, or polygon, on which efforts will focus. This is typically based on knowledge of terrestrial biodiversity. In our study we analyzed a large amount of data and showed what should be obvious considering the importance of water in the region," said Silvio Ferraz, a professor at ESALQ-USP, Leal's postdoctoral research advisor and another co-author of the study.

"Especially in the Amazon, everything revolves around water. Nutrient, organic matter, and aquatic species all move on the surface. What we didn't expect was that if conservation focused on aquatic fauna and on maintaining this movement there would be such a large gain compared with the benefit when focusing solely on terrestrial biodiversity," Ferraz said.

Besides being more effective for biodiversity, the integrated approach has the advantage of costing the same amount. "What's most important is integrated planning. It doesn't cost more and doesn't mean significant losses for terrestrial biodiversity. On the contrary," Leal said. "Even in situations where the aquatic biodiversity data isn't as plentiful as ours, just including aquatic connectivity makes delimitation of the area to be conserved much more intelligent, doubling the protection for aquatic species."

Leal and Ferraz are members of the Sustainable Amazon Network (RAS), an initiative that has over 30 partner institutions in Brazil and elsewhere, with some 100 researchers and graduate students working together on science-based projects to strengthen sustainability in the region.

The group now plans to apply the approach to the entire Amazon region, compiling the available data. Extending the study area will reinforce the results and could serve as a guide to help prioritize areas for protection or even create new conservation units. The method could also be tested on other areas that are important to conservation outside the Amazon.

Freshwater ecosystems occupy less than 1% of Earth's surface and correspond to only 0.01% of all the water on the planet. Yet they are home to some 10% of all known species, including a third of all vertebrates.

Since 1970, the populations of freshwater environments have dwindled by 83%, while terrestrial environments have lost 40%. More than 80% of the world's freshwater fish species live in tropical regions including the Amazon.

A study in mice conducted by the UAB shows that social isolation worsens the effects of Alzheimer's disease, with hyperactivity levels reaching up to twice as much as in the pathology itself

- The research also confirms an increase in the asymmetric atrophy of the hippocampus, a brain area central to memory

- The study was published in a special edition of Frontiers in Psychiatry entitled Death and Mourning Processes in the Times of the Coronavirus Pandemic (COVID-19), dedicated to assessing the effects of this pandemic

Researchers at the Department of Psychiatry and Legal Medicine and at the Institut de Neurociències (INc) of the Universitat Autònoma de Barcelona (UAB) have conducted a study which allows estimating, from the viewpoint of translational neuroscience, the effects of isolation in the current pandemic scenarios in elderly patients with dementia. The findings also may serve as a guide to the rethinking of vital conditions after the Covid-19 crisis. The study was published in Frontiers in Psychiatry, in a special edition of Frontiers in Psychiatry entitled Death and Mourning Processes in the Times of the Coronavirus Pandemic (COVID-19), dedicated to assessing the effects of this pandemic.

The researchers analysed the effects of isolation in male mice models suffering from advanced stages of Alzheimer's disease through a series of behavioural tests, which could be compared to several areas found in elderly residence homes. They compared these results with mice models of Alzheimer's that were not isolated, and with other healthy animal models undergoing a normal ageing process. The study was conducted with male mice because these are more affected by Covid-19 and are also the ones to show more deterioration of the neuro-immuno-endocrine system and worse survival conditions when suffering dementia.

The main findings demonstrate that isolation exacerbates hyperactivity up to twice as normal in mice with Alzheimer's disease, and also causes the appearance of strange behaviours. This increase was demonstrated consistently in the gross motor skills, related to the movement of arms, legs, feet or the entire body. However, it also affected fine motor skills, small movements made by hands, wrists, fingers, toes, lips and tongue. The isolated animals showed emotional patterns comparable to anxiety and changes in their stress management strategies.

"The results are concerning, given that anxiety is one of the main neuropsychiatric symptoms associated with dementia, which produces a large burden on the caregiver and, in some cases, makes clinical management a challenge", points out Aida Muntsant, first autor of the research, which is included as part of her PhD thesis.

Effects of isolation on memory

Researchers also analysed the effects of isolation on other neuropathological variables, and obtained different results. "Although the characteristic variables of the disorder, like taupathy, were not modified, some others such as asymmetric hippocampal atrophy increased with isolation. This dysfunction was recently described in human patients with dementia and modelled here for the first time with animal models of Alzheimer's disease. The finding is important, given that asymmetry has been linked to greater vulnerability to stress factors", states Lydia Giménez-Llort, Professor in Psychiatry and researcher at the INc directing the study.

The study also confirmed that the mice suffering from Alzheimer's disease lost body and renal mass, effects which also have been observed in Covid-19 patients, although the loss was greater with those in isolation. The loss in spleen mass, an important organ of the peripheral immune system, was only observed in isolated animals.

Rethinking isolation among the elderly

"Thinking of what the post-Covid-19 era will be like for the elderly implies a great deal of effort in redesigning all conditions of life, interventions in care and rehabilitation, and the management of forced solitude as part of new physical distancing measures. Therefore, it is necessary and urgent to estimate the impact these measures will have on the more vulnerable elderly population, such as those suffering from dementia", the researchers point out.

The study also highlights the need for personalised interventions adapted to the heterogeneous and complex clinical profile of people with dementia, and to consider how all of this affects the obligations of caregivers, whether they be professionals or members of the patient's family.

COLUMBUS, Ohio -- We hear sounds in part because tiny filaments inside our inner ears help convert voices, music and noises into electrical signals that are sent to our brains for processing. Now, scientists have mapped and simulated those filaments at the atomic level, a discovery that shed lights on how the inner ear works and that could help researchers learn more about how and why people lose the ability to hear.

The findings, published last week in the Proceedings of the National Academy of Sciences, involve very fine filaments in the inner ear called tip links. When sound vibrations reach the inner ear, the vibrations cause those tip links to stretch and open ion channels of sensory cells within the inner-ear cochlea, a tiny snail-shaped organ that allows our brains to sense sound. When tip links open those channels, that act triggers the cochlear electrical signals that we interpret as sound.

Tip links are crucial to hearing; their malfunction causes hearing loss and balance disorders. Tip links are made of proteins -- cadherin-23 and protocadherin-15 -- that scientists have learned are involved in inherited deafness. Scientists knew that tip links were important to hearing and balance, but until this study, did not know how tip links were structured at the atomic level.

Essentially, said Marcos Sotomayor, associate professor of chemistry and biochemistry at The Ohio State University and lead author of the study, scientists previously had low-resolution images of tip links. This work gave them high-resolution images -- and showed a key connection between the two proteins that form tip links.

"Now, we can see down to the atom, and we can create physics-based movies of how these tip links respond to sound-generated forces," Sotomayor said. "That can tell us a great deal more about how these work and what happens when they stop working."

The researchers isolated parts of the tip-link proteins and used X-ray crystallography -- a method that allows scientists to obtain atomic-resolution structures of biomolecules -- to build atomic models of the complete tip-link part made of the protocadherin-15 protein, and of its connection to cadherin-23.

Work on these proteins started more than a decade ago when Sotomayor obtained the first structures of the tips of cadherin-23 and protocadherin-15 and discovered that these proteins interact using an extended molecular "handshake." In the study published last week, researchers showed that connection uses two molecular "handshakes" that strengthen the filament. These "handshakes" are thought to be essential for hearing and balance in inner ears of all vertebrates.

The researchers used atomic models to conduct computer simulations of tip links to see them in action.

"These are the most complete and advanced molecular models and simulations of the tip link to date and required the use of massive computational resources," Sotomayor said.

The simulations, performed on supercomputers from the Ohio Supercomputer Center, the Texas Advanced Computing Center and the Pittsburgh Supercomputing Center, used up to a thousand computing cores working in parallel for months. Those simulations revealed the complex dynamics of tip links when responding to sound. The simulation trajectories, similar to molecular "movies," highlight conditions in which tip links can behave as soft springs or stiff cables pulling on the ion channels that allow us to hear.

"The structures also reveal tip-link sites that are mutated in inherited deafness," Sotomayor said. "So we can try to understand what is happening with the tip links when you have these sites modified by mutations, not only by looking at the static structures but also at the simulated trajectories of tip links responding to sound."

All the parts of our ears are designed to transform sound waves into electrical signals for our brains to process. Sound first reaches the outer ear and then travels to the middle ear, where it hits the tympanic membrane that causes bones inside the middle ear to move. That movement causes the sound vibrations to continue into the inner ear, where, eventually, the vibrations reach the cochlea to become electrical signals for the brain. The process happens fast, in a few millionths of a second, but if any part of the system fails, the sound signal either becomes muddled or does not reach the brain at all.

Tip links are some of the smallest parts of an already tiny and complex system. They are attached to the tops of microscopic hairs that are much smaller than the hairs on your head or the fine hairs inside our ears that start to become visible in the mirror with age. The microscopic hairs in the inner-ear cochlea are located atop sensory cells called "hair cells" and are positioned in a bundle that moves with sound vibrations. The force of the hair-cell bundle movement causes the tip links to open very small channels that let positively charged ions move from outside the cell to inside the cell, creating the basis for the electrical signals that will move from the cochlea to the human brain.

Similar hair cells are located in the inner-ear vestibular system in charge of our sense of balance. When we move our heads, vestibular hair-cell bundles shear and stretch their tip links to trigger electrical signals that the brain uses to maintain our balance and gaze.

"If you don't have the tip link, you can't hear, and you can't balance," Sotomayor said. "They are essential."

This new understanding of the atomic structure of tip-link proteins, Sotomayor said, could help researchers and doctors understand more about why tip links fail -- and, potentially, how to prevent failure. The two proteins that form tip links, cadherin-23 and protocadherin-15, are also found in the brain and in eye photoreceptors. When these proteins are completely non-functional, profound deafness is accompanied by progressive blindness in a disease called Usher syndrome. The new structures of protocadherin-15 are guiding the efforts of various research groups trying to use engineered versions of this protein for Usher syndrome gene therapy.

A group of researchers at the University of Ottawa has been looking for ways to improve enzyme design methodologies and recently published their findings in Nature Communications.

Enzymes are used in many industrial and biotechnological applications. With their numerous beneficial properties, they are the most efficient catalysts known - they even have the power to accelerate chemical reactions by more than a billion times. But since the number of naturally occurring enzyme activities is limited, the number of applications also remains limited. While researchers have succeeded in creating artificial enzymes, their catalytic efficiency doesn't reach the same level as that of natural enzymes.

We talked to senior author Roberto Chica, Full Professor in the Department of Chemistry and Biomolecular Sciences at the University of Ottawa, to learn more about his findings.

Can you please tell us more about artificially designed enzymes?

"Over the past 20 years, researchers have successfully designed artificial enzymes from scratch for a variety of model organic transformations. This was done using a procedure called 'computational enzyme design' where a catalytic site was computationally built onto a pre-existing protein scaffold devoid of the target catalytic activity.

While successful, this approach has exclusively yielded artificial enzymes displaying catalytic efficiencies that are orders of magnitude lower than those of natural enzymes, requiring subsequent optimization using what is called 'directed evolution' to improve activity. Directed evolution is a process whereby random mutations are introduced into a protein to generate a large library of mutant enzymes, which are then screened to identify beneficial mutations. It often requires multiple rounds of random mutagenesis and screening to increase activity significantly."

How does your research relate to directed evolution?

"In our work, we reveal how directed evolution improves the catalytic efficiency of a computationally designed biocatalyst by approximately 1000-fold by tuning the ensemble of structural sub-states that the enzyme can sample to favor those that are catalytically competent.

Based on these observations, we engineer an artificial biocatalyst with a catalytic efficiency on par with that of the average natural enzyme."

What is the impactful discovery?

"We developed a novel computational procedure for enzyme design that is more accurate than previous methods because it allows to approximate the intrinsic flexibility of the protein scaffold used as a template for design."

Why is this important?

"This is important because previous methods focused on creating a stable structure that ignores the inherent dynamism in natural enzymes, which is crucial to their function (i.e. enzymes must "move" to be efficient catalysts).

Previously, it was not known whether an artificial enzyme displaying a catalytic efficiency on par with that of a natural enzyme could be computationally designed. We show that this is possible but only by using a structural ensemble of protein templates approximating conformational flexibility instead of a single template as previously done.

The results presented in our manuscript suggest that computational enzyme design using a structural ensemble could prevent the need for directed evolution by allowing catalytically competent sub-states to be sampled during the design procedure."

What are the potential applications of your research?

"If we could design, from scratch, enzymes that can catalyze any target chemical reaction with high efficiency, it would open the door to highly valuable biotechnologies that are currently inaccessible using natural enzymes."

Is there anything you'd like to add?

Yes, research took place from 2018 to 2020, at the University of Ottawa and the University of California, San Francisco.