Culture

When a new virus emerges, biologists rush to reconstruct its genome - a prerequisite for future diagnostic and vaccine development. The challenge with viral sequencing during an outbreak is that a sample from a patient, like saliva from a COVID-19 patient that was used for the very first SARS-COV-2 coronavirus sequencing effort, contains genomes of many other, often harmless, viruses. Not to mention hundreds of much larger bacterial genomes that live in our mouth and make it difficult to find the viral sequences among them.

It raises the challenge of metagenome sequencing, reading hundreds of genomes at once, a more difficult computational problem than sequencing a single genome. Metagenome sequencing results in 1000s sequences representing pieces of various viral and bacterial genomes and it remains unclear which of these pieces represent the genome of the pathogen. The next task, known as metavirome sequencing, is to identify various viral sequences (hidden among much longer bacterial sequences!) and stitch them together into a complete viral genome of a pathogen that caused the outbreak.

There was no specialized viral metagenome assembler until recently. But the joint team of Russian and US researchers from Saint-Petersburg State University and University of California at San Diego just released the metaviralSPAdes assembler (published in journal Bioinformatics on May 16) that turns the analysis of the metavirome sequencing results into an easy task.

Biologists still cannot read the entire genome in the same way we read a book from the beginning to the end - instead they read small snippets of a genome. Genome assembly is not unlike putting together a puzzle from a million such pieces, and it is often viewed as one of the most difficult algorithmic problems in bioinformatics. Nevertheless, the most widely used genome assembler today, called SPAdes, was used in nearly 9000 papers. It was used to analyze pathogens causing MERS in Saudi Arabia (Cotten et al., Lancet 2013), Ebola in Congo (Maganga et al., New England Journal of Medicine, 2013), gonorrhoea in England (Chisholm et al., Sex Transm Infect, 2016), meningitis in Ghana (Kwambana-Adams et al., BMC Infectious Diseases 2016), dengue in Sumatra (Sasmono et al., Am. J. Trop. Med. Hyg. 2017), and dozens other outbreaks in the last eight years since SPAdes was released.

However, metagenome assembly of a 1000 genomes is much more difficult than assembly of a single genome. It is not unlike putting together a 1000 puzzles (each with a million pieces!) at once, from a huge pile of a billion pieces from all these puzzles, all mixed together in a single bag. However, three years ago, the same Russian-US team that developed SPAdes, also developed metaSPAdes to address these challenges. metaSPAdes has quickly become a leading metagenomic assembler that has already been applied in over 500 metagenomic projects.

However, it is not trivial to extract viral sequences from a huge metaSPAdes output, as a virus genome is hiding among thousands of pieces of reconstructed bacterial genomes.
New metaviralSPAdes assembler not only finds such pieces of viral sequences but also stitches them together into the completed genome.

The COVID-19 pandemic is a wake-up call for biologists studying transmission of viruses from animal to humans. It emphasizes the importance of viral surveillance in various animal hosts such as going to caves where bats live, collecting their fecal samples, and studying the huge repertoire of bat viruses BEFORE rather than AFTER a pandemic strikes. Bats have an unparalleled immune system that allows them to co-exist with a multitude of viruses that can kill humans. However, in addition to the logistics of collecting all such samples, building a census of various viral genomes across various animals is a difficult computational problem.

With metaviralSPAdes at hand, biologists can now reconstruct these viral genomes in bats or any other potential sources of future pandemics.

The hypothesis that blood clotting disorders may explain some of the worst symptoms of COVID-19, including respiratory failure and pulmonary fibrosis, was suggested in mid-April by researchers in Brazil affiliated with the University of São Paulo’s Medical School (FM-USP) via an article accepted for publication by the Journal of Thrombosis.

In less than a month, the topic had been highlighted in articles posted to the websites of Science and Nature, both of which are among the world’s leading scientific publications.

One of the first scientists to report the “thrombotic nature” of the disease caused by the novel coronavirus (SARS-CoV-2) was Elnara Negri, a researcher and pulmonologist at Hospital das Clínicas, the hospital complex run by FM-USP – the largest in Latin America – and Hospital Sírio-Libanês, a leading private hospital also in São Paulo City.

“Around March 25, we were treating a patient whose breathing was rapidly deteriorating,” Negri told Agência FAPESP. “When she was intubated, I observed that her lungs were easy to ventilate. They weren’t hardened and stiff, as you’d expect in someone with acute respiratory distress. Shortly thereafter, I noticed that the patient had an ischemic toe.”

The latter condition has been referred to as COVID-toe and can affect all ten toes. It is caused by the obstruction of the small blood vessels that circulate blood in the feet. Negri observed a similar phenomenon many years ago in patients who underwent open heart surgery with extracorporeal circulation.

“In the old days, a device was used to pump oxygen into the blood, and clots would form inside the blood vessels. I’d seen the condition before and knew how to treat it,” she said.

Negri prescribed heparin, one of the most widely used anti-coagulant drugs worldwide. In under 18 hours, the patient’s oxygen saturation improved, and her angry red toe regained a healthy pink color. The same effect was achieved with other patients treated at the Sírio-Libanês. “Since that day, we’ve treated approximately 80 COVID-19 patients, and so far, none of them has died. Four are currently in the ICU [intensive care unit]. The rest are in the ward or have been discharged,” Negri said.

Most studies show that severe COVID-19 patients require 28 days of mechanical ventilation on average, whereas those treated with heparin typically improve after ten to 14 days of intensive care.

An article by Negri and colleagues describing their clinical experience with the first 27 patients who were treated with the protocol developed at Sírio-Libanês is available on medRxiv as a preprint (not yet peer-reviewed) version.

Pathological evidence

Shortly after the first successful administration of heparin, Negri shared the finding with colleagues Marisa Dolhnikoff and Paulo Saldiva, pathologists at FM-USP who are coordinating the autopsies of patients who die from COVID-19 at Hospital das Clínicas.

Using a minimally invasive technique developed during a project supported by FAPESP, the pathologists observed focal bleeding associated with mini-clots (microthrombi) in the small blood vessels of the lungs due to platelet clumping (more at: agencia.fapesp.br/32955 and agencia.fapesp.br/32810).

Negri, Dolhnikoff, Saldiva and colleagues recently wrote to the editor of the Journal of Thrombosis and Haemostasis, describing their findings. Entitled “Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19”, this is the first article in the scientific literature to report this topic. Fully peer-reviewed and accepted for publication by the journal, the study could potentially revolutionize treatment of the disease.

Paradigm shift

SARS-CoV-2 was not the first coronavirus (CoV) to cause a public health crisis. The 2002-04 global outbreak of severe acute respiratory syndrome (SARS) caused almost 800 deaths, and Middle East respiratory syndrome (MERS) has killed 850 people since 2012. Both are coronavirus diseases. Neither has reached Brazil so far.

“Patients with SARS or MERS develop a strong inflammatory reaction in the lungs, and this can lead to a condition known as acute respiratory distress,” Negri said. “The pulmonary alveoli, the tiny sacs in which carbon dioxide is exchanged for oxygen, fill up with dead cells, pus, and other inflammatory substances, hardening the lung tissue and impairing oxygenation of the organism.”

COVID-19 is different, at least initially, Negri added. SARS-CoV-2 does not cause severe inflammation of the lungs but does cause desquamation of the alveolar epithelial tissue.

“The epithelial cells die after being infected, fall into the alveolar lumen and leave the basement membrane exposed,” she said. “The organism’s defense system thinks the region is raw or ulcerated and assumes there’s a risk of hemorrhage, triggering a storm of interleukins [proteins that act as immune signalers] and what we call a ‘coagulation cascade’. The platelets begin clumping together to form clots and ‘plug the leak’.”

The clots block the lung’s small blood vessels and cause microinfarcts (cellular death or tissue necrosis). The regions of tissue that die due to a lack of blood supply are replaced by scar tissue in a process called fibrosis. In addition, microthrombi at the alveolar-blood vessel interface prevent the passage of oxygen to smaller arteries.

“This explains why COVID-19 patients may not have difficulty breathing even though their oxygen saturation is low. Many come to hospital walking and talking and very soon have to be intubated,” Negri said.

If the intravascular clotting is not rapidly treated, microinfarcts and fibrosis tend to spread throughout the lungs. Opportunistic bacteria and fungi may infect the damaged tissue and cause pneumonia, as SARS-CoV-2 leads to a decrease in the number of immune cells (lymphopenia). The patient may develop acute respiratory distress at the end of this process.

Heparin helps avert this outcome via two mechanisms. Negri found that the drug dissolves the microthrombi that prevent oxygen from flowing from the alveoli to the pulmonary blood vessels and contributes to the regeneration of the vascular endothelium, the layer of epithelial cells that line the interior of blood vessels.

“Damaged endothelium is like a road full of potholes. It hinders the flow of blood and leads to more clotting. This creates a snowball effect,” Negri said.

A third possible mechanism of action of heparin was described by a study recently conducted at the Federal University of São Paulo (UNIFESP) with FAPESP’s support. In vitro experiments by the biomedical scientist Helena Bonciani Nader and colleagues showed that heparin brings about a 70% reduction in cell invasion by SARS-CoV-2 (more at: agencia.fapesp.br/33200).

“There may be an anti-viral effect, which should be investigated in greater depth. As I like to say, we’re changing tires without stopping the car,” Negri said.

In Negri’s opinion, however, many lives may have been lost because patients diagnosed with COVID-19 were treated from the start as cases of acute respiratory syndrome and placed in ICU beds with lower levels of hydration and more intense mechanical ventilation. “These two approaches worsen the thrombotic condition. We need to change the treatment paradigm,” she said.

Negri would like heparin to be administered as soon as the oxygen saturation level falls below 93%, which may happen between the seventh and tenth days after the onset of flu-like symptoms and can be detected by a physician in a private or public clinic.

“It’s pointless to buy the drug from a pharmacy and swallow a pill,” she warned. “That will have no therapeutic effect and could cause bleeding. It must be injected, and a medic must calculate the right dose.”

It should be stressed that heparin has significant effects on various physiological processes, and if the drug is administered without medical supervision, it can endanger the patient’s life. Self-medication and failure to take side effects into account are particularly hazardous in the case of treatment for COVID-19.

Definitive evidence

A randomized clinical trial will be needed to demonstrate the therapeutic efficacy of heparin in COVID-19 patients. This means there need to be two randomly chosen groups with similar characteristics, only one of which receives the drug. The results for this group are then compared with the outcomes for the group not given the drug.

The FM-USP researchers plan to begin this project shortly, in partnership with colleagues at the University of Toronto (Canada) and the University of Amsterdam (Netherlands). They are only waiting for approval from the Ethics Committee at Hospital das Clínicas and Brazil’s National Research Ethics Committee (CONEP).

“The trial will entail giving heparin to patients who come to the outpatient clinic with low oxygen saturation levels and seeing if treatment with the anti-coagulant can avoid the need for mechanical ventilation,” Negri said.

The article “Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19” by Marisa Dolhnikoff, Amaro Nunes Duarte-Neto, Renata Aparecida de Almeida Monteiro, Luiz Fernando Ferraz da Silva, Ellen Pierre de Oliveira, Paulo Hilário Nascimento Saldiva, Thais Mauad, and Elnara Marcia Negri can retrieved from onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14844.

Journal

Journal of Thrombosis and Haemostasis

DOI

10.1111/JTH.14844

The Milky Way, the whiteish strip of light which is prominent in both the summer and the winter skies, is the densest part of the disc of the Galaxy which we are inside. However, over very long periods it has not always looked the same, and its evolution is a challenge to current astrophysics.

To study this evolution, ESA's Gaia mission is measuring the luminosities, positions, motions, and the chemical composition of a large number of individual stars in our Galaxy.

Combining apparent luminosity with measured distance, astronomers at the IAC have found the intrinsic luminosity of 24 million stars within a sphere of 6,500 light years around our Sun. Comparing their luminosities and colours with accurate models of stars they have obtained the most detailed evolutionary history of the Milky Way up to now.

Irregular rate

"We might well have expected that the Milky Way did not form stars at a constant rate throughout its history, but we didn't expect such well defined periods of great activity", comments Tomás Ruiz Lara, an IAC astrophysicist and the first author of the article.

Some 13 billion years ago star formation was violent and sustained, but the rate at which stars formed declined gradually as time passed.

However, superposed on this simple behaviour, there were dramatic episodes of star formation, during which the rate grew to four times the normal value. The first took place some 5-6 billion years ago, followed by others, 2 billion, one billion, and one hundred million years ago. But it wasn't known what could provoke such violent events in a system as massive as our Galaxy.

For an answer to this question we need to know that the Milky Way, although in a relatively empty zone of the universe, is not completely isolated: together with our neighbour the Andromeda galaxy (M31) and tens of much smaller galaxies (called dwarfs) which go round it in orbit, it is part of the so-called Local Group.

Among the nearby dwarf galaxies, the Sagittarius dwarf is prominent, and currently is in full interaction with our Galaxy. But this is not happening only just now, complex simulations suggest that already some 5 to 6 billion years ago Sagittarius made its first approach to the Milky Way. This approach was repeated 2 and 1 billion years ago, coinciding exactly with the star formation events revealed in this study (as well as in the Sagittarius galaxy itself).

"Everything indicates -explains Carme Gallart, an IAC researcher and a member of the team- that these interactions between the two systems were able to stimulate the formation of new stars in our galaxy, drastically affecting its evolution. These results question some of the current models of star formation in galaxies, and put constraints on future theoretical studies".

An unexpected implication of this work is to situate our Solar System in its context. The Solar System formed some 4,700 billion years ago, from the collapse of a large cloud of gas and dust. "It is possible -comments Tomás Ruiz Lara- that our Sun was one of the many stars formed some 5,000 billion years ago as a consequence of the interaction between our Galaxy and the Sagittarius galaxy. It could be that we are witnessing one of the key astronomical events which gave rise to the world as we know it today".

Stem cell researchers at Lund University in Sweden have developed a new research model of the early embryonic brain. The aim of the model is to study the very earliest stages of brain to understand how different regions in the brain are formed during embryonic development. With this new insight, researchers hope to be able to produce different types of neural cells for the treatment of neurological diseases more efficiently. The study is published in the journal Nature Biotechnology.

In order to develop stem cell treatments for neurological diseases such as Parkinson's Disease, epilepsy and stroke, researchers must first understand how the human brain develops in the embryonic stage. With knowledge of how neural cells are formed at different developmental stages, researchers have the opportunity to develop new stem cell therapies more quickly in the laboratory.

"The challenge is that there are thousands of different sub-types of neural cells in the human brain, and for each disease we need to be able to produce exactly the right type of neural cell", says Agnete Kirkeby, researcher at the Wallenberg Centre for Molecular Medicine and the Department of Experimental Medical Science at Lund University.

Studies on how each individual neural cell forms in the embryo during brain development are essential for the researchers to be able to understand how to produce these specific cells in the laboratory.

Research on the early development of the human brain, from five days after the fertilisation of the cell to approximately seven weeks, have so far been difficult as researchers have not had access to human embryonic tissue from these early stages of development. Therefore, nearly all knowledge of the earliest development of the brain is based on studies in flies, chickens and mice.

"However, the composition of the human brain differs greatly from the animals' brains. Therefore, this period in the development of the human brain has long been viewed as the black box of neurology", says Agnete Kirkeby.

Together with colleagues from the University of Copenhagen and bioengineers Thomas Laurell and Marc Isaksson from the Faculty of Engineering at Lund University, Agnete and her team have now created a model that mimics the early developmentalstages of the human brain through the use of stem cells. The stem cells are cultivated in a custom-built cell culture chamber where they are exposed to an environment which resembles the environment in the early embryonic brain.

"In the laboratory model called MiSTR (Microfluidic-controlled Stem cell Regionalisation), we can create tissue that contains different brain regions next to each other, similar to an embryonic brain approximately four to five weeks after fertilisation."

"We start with a small group of cells that will form the brain and instruct the cells by exposing them to a gradient of a specific growth factor (WNT) so that they form different regions of the brain. Our model is better than previously published models because it is much more reproducible and contains more brain regions. We can now use it to study unknown characteristics in the early development of the human brain", explains Agnete Kirkeby.

Agnete Kirkeby believes that the new method may be used to investigate how brain cells in the early embryonic stages react to certain chemicals surrounding us in our daily lives

"This is a significant step forward for stem cell research. For the first time, we now have access to tissue that resembles the early embryonic brain and can therefore study processes behind brain development in a way that has not been possible before. We can for instance use it for testing how chemical substances in our environment might impact on embryonic brain development." explains Kirkeby.

Another aim for the future is to use the model to create a complete map of the development of the human brain. This will help to speed up the development of new stem cell treatments for neurological diseases.

"Once we have the map we will also become better at producing human neural cells in the laboratory that could be used for transplantations, regenerative therapy and to study the brain's function as well as different disease states. . It took us ten years to develop a stem cell treatment for Parkinson's disease because our methods were dependent on trial and error. Our goal is that this process will be much faster in the future for other diseases", concludes Agnete Kirkeby.

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Loss of Smell and Taste in 2013 European Patients With Mild to Moderate COVID-19

The COVID-19 pandemic has spread worldwide rapidly. Commonly reported symptoms, such as fever, cough, dyspnea, fatigue, and myalgia, are nonspecific, and the lack of testing in some European countries may make the diagnosis of COVID-19 challenging. However, two distinctive symptoms were identified recently: loss of smell and loss of taste. The authors from University of Mons; Mons, Belgium and Université Libre de Bruxelles; Brussels, Belgium used a standardized online questionnaire to collect clinical and epidemiologic data from 2,153 consecutive hospitalized and ambulatory patients in 18 European hospitals with mild-to-moderate COVID-19 to evaluate the prevalence and features of, as well as recovery from, smell dysfunction. The authors found that the prevalence of self-reported smell and taste dysfunction is higher than previously reported and may be characterized by different clinical forms. Their results suggest that anosmia may not be related to nasal obstruction or inflammation. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-2428.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Jerome R. Lechien, MD, PhD, MS, can be reached at Jerome.Lechien@umons.ac.be.

(Vienna, Monday, 25 May, 2020) A new study presented today at the European Academy of Neurology (EAN) Virtual Congress shows the burden of potentially avoidable epilepsy-related deaths in young adults remains large, with those aged between 16 and 24 having a six-fold increased risk of epilepsy-related death.

The research found that mortality rates for epilepsy-related deaths did not decrease between 2009 (6.8 per 100,000) and 2015 (9.1 per 100,000), despite advances in treatment during this time. Young adult patients in their early 20s and 30s were found to be at the highest risk, with 78% of epilepsy-related deaths under the age of 55 years classified as potentially avoidable.

The study is being conducted in Scotland and looks to identify the burden of epilepsy-related deaths, what proportion of these are potentially avoidable, and ascertain the factors that may put patients at an increased risk.

The researchers collected anonymous data from healthcare settings for patients that died between 2009 and 2016, identifying 2,149 epilepsy-related deaths. 60% of these patients (1,276) had one or more seizure-related or epilepsy-related hospital admission in the years prior to death, yet less than a quarter (516) were seen in a neurology clinic. The most common causes of death within the study were sudden unexpected death in epilepsy (SUDEP), aspiration pneumonia, cardiac arrest, congenital malformation and alcohol-related deaths. The data will be compared with data from living patients with epilepsy of the same age and gender. These comparisons will focus on the patients' epilepsy type, socio-economic class, standards of care received, and the presence of additional disorders, such as depression.

Dr Gashirai Mbizvo, completing this Scottish Epilepsy Deaths Study (SEDS) at The University of Edinburgh, comments that "Epilepsy patients are at a higher risk of early death than the general population, but reasons for this are unclear. We hope that we can use this data to learn lessons and reduce the burden of epilepsy-related deaths in the future, many of which we believe are likely to be avoidable. Highlighting such risk factors, and identifying those that could be prevented, might lead to changes in epilepsy care and, ultimately, fewer epilepsy-related deaths in the future."

Epilepsy is a chronic noncommunicable disease of the brain that affects around 50 million people globally, making it one of the most common neurological diseases worldwide. It can cause seizures or periods of confusion in patients, which can either occur randomly or from triggers, such as a lack of sleep, stress or drinking alcohol. In many cases, people with epilepsy suffer from negative stigma and discrimination.

(Vienna, Sunday, 24 May, 2020) The extent and risks associated with recreational abuse of laughing gas and psychostimulants by young people have today been revealed in two studies reported at the European Academy of Neurology Virtual Congress.

In one study, researchers from Turkey reported increasing stimulant use among medical students approaching their final exams, despite the substantial risks to their health. In the second study, researchers from the Netherlands detailed the neurological outcomes associated with recreational use of laughing gas (nitrous oxide), suggesting that, for some individuals, permanent neurological damage can occur.

Increasing use of psychostimulants among medical students:

The increasing and widespread use of psychostimulants among medical students as they progress through their training has been revealed by a team of researchers from Istanbul in Turkey.

The team studied 194 medical students who completed an online survey evaluating their stimulant use, side effects, and academic performance grades. First-year students (n=93; control group) were compared with fourth-, fifth-, and sixth-year students (n=101; study group).

"Non-medical use of prescription stimulants has become a growing public health concern on university campuses over the past two decades," explained Dr Suna Ertu?rul from the Demiroglu Bilim University in Istanbul, Turkey, who presented the results of the study. "Medicine is one of the longest and most competitive degrees to study for and many students believe that using stimulants helps to enhance their academic performance and live an active life."

The Turkish researchers found that 16.1% of their study group were using psychostimulants such as methylphenidate and modafinil compared with 6.8% of the control group. Three-quarters of the study group reported experiencing side effects, including insomnia, high heartrates and agitation. No differences were observed in the academic performance between the stimulant users and non-users.

"Our study confirms that stimulant use increases during the course of studying for a medical degree, but that this does not improve academic performance as these students believe," said Dr Ertu?rul.

Recreational use of laughing gas:

The recreational use of laughing gas, which is used as an anaesthetic agent in dental practices and during labour, is on the increase, resulting in growing numbers of patients with neurological problems reporting to specialist outpatient clinics and emergency rooms.

"In our neurologic practice, we are seeing more and more patients with neurological problems resulting from recreational use of laughing gas," explained Dr Anne Bruijnes from the Zuyderland Medical Center in Heerlen, Netherlands, who presented the study findings at the meeting. "We saw our first patient in 2017, and since then the number has increased steadily, so we decided to conduct a retrospective study to describe the clinical features and outcomes of the patients we've seen."

According to the study team, 13 patients with an average age of 21 years were treated at the medical centre between 2017 and 2019. The most common symptoms reported were paresthesias (tingling and numbness in the hands, legs, arms and feet) and lower limb weakness. Eight patients (62%) were given a clinical diagnosis of axonal polyneuropathy, two (15%) showed evidence of spinal cord degeneration, and three (23%) showed clinical symptoms of both polyneuropathy and spinal cord degeneration (myelopolyneuropathy). All patients received vitamin B12 supplementation and were advised to stop using laughing gas.

Laughing gas usage is thought to be on the increase with one in 11 young people aged 16-24 using it annually. Many users are unaware of potential consequences, which can also include paranoia, breathing problems and even death.

"Most of our patients made a full recovery, however, some continued to have minor symptoms and three experienced difficulties with everyday activities and were referred to a rehabilitation physician," she said.

Dr Bruijnes believes the true extent of the laughing gas problem may not be known, with many abusers failing to seek medical help. "This is a major cause for concern," she said. "Whilst this study is on a relatively small sample, we know that laughing gas use is on the increase. We now know that it causes a vitamin B12 deficiency, which can affect the spinal cord and lead to permanent damage if not treated promptly."

SILVER SPRING, Md.--Researchers have discovered that anti-obesity medications such as phentermine and topiramate, used individually or in combination, can significantly reduce weight regain in patients after Roux-en-Y gastric bypass surgery, according to a retrospective study published online in Obesity, the flagship journal of The Obesity Society.

"Our study provides evidence that medications can help, especially in situations where the weight gain is occurring at a rapid rate. Characterization of weight regain as a rate is novel and adds to the understanding of this important clinical problem," said Nawfal Istfan, MD, PhD, associate professor of medicine at Boston University School of Medicine and attending physician at Boston Medical Center in Boston, Mass. Istfan is the corresponding author of the study.

Weight regain after gastric bypass surgery is well recognized, normally occurring two years after the surgery and ultimately affecting 25 percent of patients. It is becoming increasingly urgent to mitigate its occurrence and preserve the metabolic and medical benefits of weight loss surgery. The application of pharmacologic agents to deal with this specific problem has been limited in the medical literature.

Researchers used the electronic medical records of nearly 1,200 multi-ethnic patients who underwent Roux-en-Y gastric bypass surgery between 2004 and 2015 at Boston Medical Center. The evaluation of weight regain was made by comparing each patient's weight during subsequent, post-operative office visits to nadir weight (lowest weight after Roux-en-Y gastric bypass surgery), taking into consideration the interval during which weight regain occurred. Seven time intervals were used in the analysis ranging from before surgery to 6 years after surgery. Patients prescribed anti-obesity medications and who came for follow-up visits were classified as adherent users, whereas those who missed follow-up visits were considered non-adherent.

After using three independent statistical models, researchers demonstrated that anti-obesity medications decrease cumulative weight regain by about 10 percent relative to nadir weight and reduce the odds of rapid weight-regain occurrence after Roux-en-Y gastric bypass surgery. Researchers also found that of the 760 patients who achieved nadir weight and are at risk for weight regain, 350 were documented users of anti-obesity medications.

These results take into account that patients typically lost weight when taking anti-obesity medications and regained weight during intervals when the medications were not prescribed. Additionally, patients started anti-obesity medications at different stages and used them at variable and intermittent periods.

The authors noted that the full potential of phentermine and topiramate and newer anti-obesity medications to counter weight recidivism and prevent the reoccurrence of obesity-related comorbidities need to be explored in further prospective clinical trials. Guidelines also need to be established for initiating and monitoring the potential long-term use of anti-obesity medications after bariatric surgery.

"One of the ways to address this particular set of limitations in future study with a prospective clinical trial would be to set specific protocols regarding use of anti-obesity medications by providers. Specifically, providing education for providers on individual anti-obesity medications for them to understand mechanisms of action, then separately creating a clinical workflow to incorporate use of anti-obesity medications, in particular settings of weight recidivism," said Crystal Johnson-Mann, MD, assistant professor, Department of Surgery, Division of Gastrointestinal Surgery, at the University of Florida College of Medicine in Gainesville. "For optimal results in a prospective trial, individual prescribing tendencies (or lack of prescribing) needs to be eliminated and be uniform across all of the providers involved in the care of these patients post-operatively."

Maximizing the protection of life on Earth requires knowledge of the global patterns of biodiversity at multiple dimensions, from genetic diversity within species, to species and ecosystem diversity. Yet, the lack of genetic sequences with geographic information at global scale has so far hindered our ability to map genetic diversity, an important, but hard to detect, biodiversity dimension.

In a new study, researchers from the Universities of Copenhagen and Adelaide have collected and georeferenced a massive amount of genetic data for terrestrial mammals and evaluated long-standing theories that could explain the global distribution of genetic diversity. They found that regions of the world rich in deep evolutionary history, such as Northern Andes, the Eastern Arc Mountains, Amazonia, the Brazilian Atlantic forest, the central America jungles, sub-Saharan Africa and south-eastern Asia are also strongholds of genetic diversity. They also show that the relatively stable climate in these regions during the past 21'000 years contributes significantly to this intraspecific richness.

"Genetic diversity within species is a critical component of biodiversity, playing two important roles at the same time. It reflects species evolutionary history and defines their capacity to adapt under future environmental change. However, and despite the predictions of major biodiversity theories, the actual global distribution of genetic diversity remained, so far, a mystery. Recent collective efforts to populate public databases with genetic sequences and their localities allowed us to evaluate these theories and generate the first global maps of genetic diversity in terrestrial mammal assemblages", says Spyros Theodoridis, Postdoctoral Researcher at the Center for Macroecology, Evolution and Climate, GLOBE Institute, and lead author of the study.

"The tropics, and more specifically tropical mountain regions, host large amounts of the global pool of genetic diversity. These arks of biodiversity are under a high pressure today due to climate and land-use change. The conservation of genetic diversity in these areas should be a priority in on-going conservation efforts", says David Nogues-Bravo, the senior author of the study and Associate Professor at the University of Copenhagen.

The study also evaluated the effects of climate change during the last 21'000 years in shaping current patterns of genetic diversity. Regions of the world that experienced less severe change in temperature and precipitation harbor higher levels of genetic diversity, potentially due to reduced population extinctions. It also suggests that past inter-annual precipitation variability contributes to higher genetic diversity possibly through population adaptive divergence.

"While we show that areas of high genetic diversity tend to occur in regions where climates have remained relatively unchanged during past periods of global-scale climate change, many of these regions are forecast to experience major climate disturbances in the near future. Unfortunately, this is likely to lead to a loss of genetic diversity in many biodiversity hotspots", says Damien Fordham, Associate Professor at The University of Adelaide's Environment Institute and a coauthor of the study.

"The identified correlations of genetic diversity with evolutionary history and past climate change allowed us to develop predictive models at global scale, particularly in regions that lack sufficient data, such as the tropics. These predictions constitute a first step towards filling major gaps of knowledge for genetic diversity, and can inform and be further validated by field-work campaigns in data-poor regions of the Earth", says Carsten Rahbek, head of the Center for Macroecology, Evolution and Climate.

Russian researchers from HSE University and Open University for the Humanities and Economics have demonstrated that artificial intelligence is able to infer people's personality from 'selfie' photographs better than human raters do. Conscientiousness emerged to be more easily recognizable than the other four traits. Personality predictions based on female faces appeared to be more reliable than those for male faces. The technology can be used to find the 'best matches' in customer service, dating or online tutoring.

The article 'Assessing the Big Five personality traits using real-life static facial images' will be published on May 22 in Scientific Reports.

Physiognomists from Ancient Greece to Cesare Lombroso have tried to link facial appearance to personality, but the majority of their ideas failed to withstand the scrutiny by modern science. The few established associations of specific facial features, such as facial width-to-height ratio, with personality traits are quite weak. Studies asking human raters to make personality judgments based on photographs have produced inconsistent results, suggesting that our judgments are too unreliable to be of any practical importance.

Nevertheless, there are strong theoretical and evolutionary arguments to suggest that some information about personality characteristics, particularly, those essential for social communication, might be conveyed by the human face. After all, face and behaviour are both shaped by genes and hormones, and social experiences resulting from one's appearance may affect one's personality development. However, the recent evidence from neuroscience suggests that instead of looking at specific facial features, the human brain processes images of faces in a holistic manner.

Researchers from two Moscow universities, HSE University (Higher School of Economics) and Open University for the Humanities and Economics, have teamed up with a Russian-British business start-up BestFitMe to train a cascade of artificial neural networks to make reliable personality judgments based on photographs of human faces. The performance of the resulting model was above that discovered in previous studies which used machine learning or human raters. The artificial intelligence was able to make above-chance judgments about conscientiousness, neuroticism, extraversion, agreeableness, and openness based on 'selfies' the volunteers uploaded online. The resulting personality judgments were consistent across different photographs of the same individuals.

The study was done in a sample of 12 thousand volunteers who completed a self-report questionnaire measuring personality traits based on the "Big Five" model and uploaded a total of 31 thousand 'selfies'. The respondents were randomly split into a training and a test group. A series of neural networks were used to preprocess the images to ensure consistent quality and characteristics, and exclude faces with emotional expressions, as well as pictures of celebrities and cats. Next, an image classification neural network was trained to decompose each image into 128 invariant features, followed by a multi-layer perceptron that used image invariants to predict personality traits.

The average effect size of r = .24 indicates that AI can make a correct guess about the relative standing of two randomly chosen individuals on a personality dimension in 58% of cases as opposed to the 50% expected by chance. In comparison with the meta-analytic estimates of correlations between self-reported and observer ratings of personality traits, this indicates that an artificial neural network relying on static facial images outperforms an average human rater who meets the target in person without prior acquaintance. Conscientiousness emerged to be more easily recognizable than the other four traits. Personality predictions based on female faces appeared to be more reliable than those for male faces.

There are a vast number of potential applications to be explored. The recognition of personality from real-life photos can complement the traditional approaches to personality assessment in situations where high speed and low cost are more important than high accuracy. Artificial intelligence can be used to propose products that are the best fit for the customer's personality or to select the possible 'best matches' for individuals in dyadic interactions, such as customer service, dating or online tutoring.

Meiosis is essential to sexual reproduction. For almost 15 years, it has been commonly held that retinoic acid, a molecule derived from vitamin A, triggers meiosis in mammalian germ cells. Yet, in joint articles published in Science Advances ( 22 May 2020 ), french researchers from the Institut de Biologie Valrose (CNRS / INSERM / Université Côte d'Azur) and the IGBMC (CNRS / INSERM / University of Strasbourg), with their colleagues, demonstrate that meiosis in mice begins and proceeds normally even in the absence of retinoic acid. These findings set the stage for new research in the field of reproductive biology.

Meiosis is an essential process that results in novel assortments of chromosomes for the transmission of unique sets of genes to offspring. Beginning with a diploid[1] germ cell (an oogonium in females or a spermatogonium in males), it yields haploid[2] gametes (oocytes in females or spermatozoa in males). The union of an oocyte and a spermatozoon combines both parental haploid genomes in a single diploid cell destined to give rise to an embryo, marking the start of the next generation.

In mammals, cells found in developing gonads (ovaries in females or testes in males) provide germ cells with structural support, nourishment, and protection. They also emit molecular signals that determine what will become of the germ cells. One of the signalling molecules is retinoic acid, widely thought to trigger germ cell meiosis. Despite the 2011 publication of findings casting doubt on this assumption, the idea that retinoic acid is a switch for meiosis has risen to the status of dogma.

Together with colleagues,[3] scientists from the Institut de Biologie Valrose in Nice and the IGBMC in Strasbourg conducted two complementary studies of the mouse foetal ovary to clarify the role of this molecule, by (i) inhibiting its synthesis and (ii) removing its receptors. Neither approach prevented normal initiation of meiosis in germ cells. Furthermore, viable infant mice were born after fertilization of oocytes lacking retinoic acid receptors, proving that these cells are functionally intact.

These twin studies therefore refute the dogma of a retinoic acid trigger for meiosis in germ cells, ending a debate that has lasted nearly a decade and a half. By dismissing a long-held tenet, these findings invite the scientific community to reconsider its working assumptions and investigate new leads in the search for the real signals controlling initiation of germ cell meiosis.

Organisms carry long-term "memories" of their ancestral homelands that help them adapt to environmental change, according to a new study that involved raising chickens on the Tibetan Plateau and an adjacent lowland site.

The study provides new insights into how creatures adapt to changing environments, a topic that's especially relevant today in the context of rapid climate change, which is creating challenges for plants and animals worldwide.

The chicken was domesticated from the red jungle fowl in South Asia and Southeast Asia at least 4,000 to 4,500 years ago. It was brought to the Tibetan Plateau by about 1,200 years ago, where it acquired high-altitude adaptations such as an increase in oxygen-carrying red blood cells.

In a set of experiments by University of Michigan biologists and their Chinese colleagues, researchers hatched and reared hundreds of chickens on the Tibetan Plateau, at an elevation of nearly 11,000 feet, and at an adjacent lowland site in China's Sichuan Province. Some of the eggs from lowland chickens were hatched on the plateau, and some high-altitude eggs were hatched at a site 2,200 feet above sea level.

The goal was to assess the relative contributions of two types of phenotypic change--meaning changes to an organism's observable physical characteristics or traits--to the process of environmental adaptation. "Plastic" phenotypic changes involve altered gene activity but no rewriting of the genetic code in DNA molecules, while mutations cause altered gene activity by modifying the sequence of letters in the code itself.

Evolutionary biologists have debated the relative roles of plastic and mutation-induced changes in adaptation, and whether the former serve as stepping stones to the latter.

In the chicken study, researchers were specifically interested in how organisms readapt when reintroduced to ancestral environments. They found that plastic changes play a more prominent role when organisms return to an ancestral home than when they adapt to new environments.

"These findings reveal a mechanism by which past experience affects future evolution," said Jianzhi Zhang, the study's senior author and a professor in the U-M Department of Ecology and Evolutionary Biology.

"Our findings contribute to the recent debate on the relative roles of plastic and genetic changes in adaptation and reveal the importance of considering whether the environment is changing to a novel or ancestral one."

The findings are scheduled for publication May 22 in the journal Science Advances.

To study the relative roles of plastic and DNA-sequence changes, the researchers looked at gene-expression differences between lowland and Tibetan chickens in five tissue types: brain, liver, lung, heart and muscle. To do that, they analyzed RNA transcriptomes from cells in those tissues.

The genome is made of DNA that contains the instructions needed to build an organism. For those instructions to be carried out, DNA must be read and transcribed into messenger RNA molecules.

By analyzing the entire collection of RNA sequences in a cell, known as the transcriptome, researchers can determine when and where genes are turned on and off. Gene-expression studies provide snapshots of actively expressed genes under various conditions.

Changes in gene activity alter an organism's phenotype, which includes its morphology, behavior and physiology. The term phenotypic plasticity refers to environmentally induced phenotypic changes that do not involve genetic mutations.

In the chicken study, the researchers found that while many mutation-induced phenotypic changes were necessary when the animals first adapted to the Tibetan Plateau, plastic changes largely transformed the transcriptomes to the preferred state when Tibetan chickens were brought back to the lowland.

A similar result was seen with egg "hatchability," the fraction of fertilized chicken eggs that hatched in the study.

When lowland eggs were incubated on the unfamiliar Tibetan Plateau, hatchability was significantly lower than that of Tibetan chicken eggs. But when Tibetan eggs were incubated in the lowland--an environment familiar from the distant past--there was no significant difference in hatchability between the two groups.

The egg result suggests that adaptive mutational changes are needed when an organism is brought to an unfamiliar environment for the first time, while plastic changes will do the trick when those same creatures return to an ancestral home.

Zhang's team also analyzed transcriptomes from previous studies of guppies and E. coli bacteria and found comparable results--regardless of whether the new environment was more stressful or less stressful than the ancestral environment.

"In summary, our work uncovers a phenomenon conserved from bacteria to vertebrates that organisms remember their ancestral environments in the form of phenotypic plasticity," the authors wrote.

Bottom Line: Patients with metastatic pancreatic cancer who had germline or somatic mutations in DNA repair genes had better clinical outcomes after platinum-based chemotherapy, as compared with patients without these mutations.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research

Authors: The senior author was Eileen O'Reilly, MD, medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC). The lead author was Wungki Park, MD, medical oncologist at MSKCC.

Background: Metastatic pancreatic cancer is associated with a challenging prognosis with a relative five-year survival rate of 2.9 percent. The current standard of care for metastatic pancreatic cancer includes platinum-based chemotherapy. "Unfortunately, there are no validated biomarkers to predict which patients might benefit from standard treatment," said O'Reilly.

Biomarkers are biological features, such as DNA mutations, that can be used to predict prognosis or response to treatment. DNA mutations may be found in one or both copies of the gene. Furthermore, mutations may be germline mutations, which are inherited and are found in every cell of the body, or they may be somatic, which arise after conception and are not found in every cell.

Approximately 5 to 9 percent of patients with pancreatic cancer have germline or somatic mutations in the BRCA1, BRCA2, and/or PALB2 genes, according to O'Reilly. The proteins encoded by these genes are involved in a form of DNA repair known as homologous recombination (HR). Results from recent clinical trials showed that patients with germline mutations in BRCA1, BRCA2, and/or PALB2 had clinical responses to platinum-based chemotherapy or the PARP inhibitor olaparib (Lynparza).

"These studies demonstrate that germline mutations in BRCA1, BRCA2, or PALB2 are valuable biomarkers to predict response to treatment," said Park. "This led us to ask whether the benefit was limited to germline mutations only, or whether somatic mutations in these genes or mutations in other HR genes are also associated with responses to platinum-based chemotherapy."

How the Study was Conducted: In this study, Park, O'Reilly, and colleagues analyzed the association between mutations in HR genes and clinical outcome. The study included 262 patients with metastatic pancreatic cancer, who underwent both germline and somatic sequencing using the MSK-IMPACT sequencing test. The researchers analyzed 17 HR genes included in both the somatic and germline panels of the MSK-IMPACT gene set. Analysis of sequencing data allowed the researchers to determine whether mutations were germline or somatic, in core HR genes (BRCA1, BRCA2, or PALB2) or in noncore HR genes (such as ATM, CHEK2, BAP1, RAD51, FANCA, and 9 others), and in one or both copies of each gene.

Results: Out of 262 patients, 50 patients had mutations in HR genes; 40 patients had germline mutations, and 10 had somatic mutations. Thirty-one patients had mutations in core genes, while 19 patients had mutations in noncore genes. Twenty-nine patients had mutations in both copies of a gene, and 21 patients had mutations in only one gene copy.

The median overall survival for the entire cohort of 262 patients was 15.5 months. Overall survival was similar between patients with germline mutations and those with somatic mutations. Thus, these subgroups were combined in the ensuing analyses.

The authors found that for the 35 patients who were treated with first-line platinum-based chemotherapy, those with mutations in HR genes had greater overall survival compared with those without mutations in these genes (25.1 months vs. 15.3 months), suggesting that mutations in HR genes may be associated with enhanced overall survival. Furthermore, patients with HR mutations had a 44 percent lower risk of disease progression than patients without these mutations after first-line treatment with platinum-based chemotherapy. The lower risk of disease progression was observed regardless of whether the mutations were in core or noncore HR genes.

Among patients with mutations in HR genes, those who were treated with platinum-based chemotherapy had higher progression-free survival (PFS) than those who received non-platinum treatment (12.6 months vs. 4.4 months). For the patients with mutations in both gene copies, those who were treated with platinum-based chemotherapy had greater PFS than those treated with other therapies (13.3 months vs. 3.8 months). This association was not observed for patients with mutations in only one gene copy, suggesting that platinum-based chemotherapy may provide a greater clinical benefit in patients with mutations in both copies of HR genes.

Author's Comments: "Our data support the use of platinum-based chemotherapy as first-line treatment for patients with defects in various HR genes," said O'Reilly. "The results underscore the importance of genetic testing in newly diagnosed patients to help refine treatment decisions."

"HR deficiency defined by pathogenic mutation of core HR genes and loss of both copies of either core or noncore HR genes confers the greatest platinum sensitivity," said Park. "Patients with these deficiencies represent the optimal subgroup for therapies that target DNA repair pathways, such as platinum-based chemotherapy." He noted that these deficiencies could also be predictive of response to other targeted developmental therapeutics in DNA repair pathways, to other PARP inhibitors, and to immunotherapy, although additional research into these will be needed.

"Identifying factors associated with treatment response may also help us understand why some patients' tumors do not respond to treatment and why some that respond ultimately develop resistance," Park added.

Study Limitations: A limitation of the study is that the analysis was performed on a highly selected group of patients and therefore may not represent all patients with pancreatic cancer. "While the data are very compelling, we need to validate the results prospectively in wider and larger datasets," noted O'Reilly.

Additional challenges included low sample purity, limited tissue availability, and other technical limitations.

A team of researchers from the University of Southampton, the University of Bath and King's College London, have provided compelling evidence of the impact of adversity in childhood on neuropsychological functioning in adulthood. They also showed that neuropsychological difficulties may explain why early adversity is linked to attention deficit hyperactivity disorder (ADHD) in later life.

Their study, published in the journal Psychological Medicine, analysed neuropsychological function in 70 young adults who were exposed to severely depriving conditions in Romanian orphanages during Nicolae Ceausescu's regime and subsequently adopted by British families. The adoptees were compared to 22 British adoptees of similar ages who had not suffered childhood deprivation.

As part of the research, the adoptees were asked to carry out tests to assess their neuropsychological functioning in five areas: controlling their responses (inhibitory control), prospective memory, decision-making, emotional recognition and cognitive ability (IQ). Prospective memory is the ability to remember to do something in the future, such as remembering to go to an appointment or what you need to buy if you don't have a shopping list. ADHD and autism spectrum disorder (ASD) symptoms were assessed through questionnaires completed by their parents.

The results showed that the Romanian adoptees had lower IQs and performed less well on the other four tests when compared to the adoptees who had not suffered deprivation. The adoptees with the lowest IQs and the greatest problems in prospective memory were more likely to show ADHD symptoms in adulthood than those without neuropsychological difficulties. The researchers found no direct link between ASD symptoms and neuropsychological performance.

The latest research is part of the wider English and Romanian Adoptees study, a collaborative study between the University of Southampton and King's College London which began shortly after the fall of the communist regime in Romania.

Children living in the institutions were subjected to extremely poor hygiene, insufficient food, little affection and no social or cognitive stimulation. The study analyses the mental health and brain development of 165 children who spent time in Romanian institutions and who were adopted by families in the UK when aged between two weeks and 43 months.

The principal investigator of the study is Professor Edmund Sonuga-Barke, who began the study whilst working at the University of Southampton and is now based at the Institute of Psychiatry, Psychology & Neuroscience at King's College London.

Speaking of the latest research, Professor Sonuga-Barke said: "This study contributes to our changing understanding of the power of the early environment to shape brain development -showing that the effects of institutional deprivation on cognition can still be seen after more than twenty years of positive experience in high functioning and loving adoptive families leads us to acknowledge that there are limits to the brain's recuperative powers."

Dr Dennis Golm, Lecturer in Psychology at the University of Southampton, said: "The study highlights that institutional deprivation can have long-lasting effects on a range of neuropsychological functions that are important in everyday life, such as memory and general intellectual ability. Our findings also emphasise the importance of improving the quality of care for children in institutions."

DURHAM, N.C. -- Much like people, fruit flies must decide when the time and place are right to make a move on a mate. Male fruit flies use cues such as age and pheromones to gauge their chances of success, but just how they do that on a molecular level was a mystery.

New research suggests that the answer lies, in part, in their DNA. A new study finds that the scent of other flies, coupled with signals from a male's internal hormones, alter the activity of a gene that controls how turned on he is by pheromones when he reaches maturity.

A female fruit fly's outer shell -- her "cuticle" -- gives off waxy-smelling molecules that act as aphrodisiacs. Normal male fruit flies follow a female around to get a whiff before deciding to pursue her further.

But previous studies found that males raised alone, deprived of the odor of other flies, can't pick up the scent as well when they reach adulthood. Scent-deprived males show less interest in females, and are more likely to lose a girl to another guy.

It makes sense because growing up alone could signal that future mating options may be slim -- why put in the effort? On the other hand, males raised in groups respond more strongly to pheromones than their socially isolated counterparts, presumably because they may face stiff competition later on, and must step up their game with the ladies.

In the new study, published May 22 in Science Advances, researchers have figured out how males dial their scent sensitivity up or down to court when conditions are right for mating.

Fruit flies don't have noses to smell with -- they use their antennae. There, olfactory neurons detect odor molecules wafting past and send the information to the brain.

Duke University biologist Pelin Volkan and colleagues raised some male fruit flies in groups, and isolated others in separate vials.

The researchers found that when a male grows up in a group, around the odors of other flies, a "courtship" gene called fruitless is switched on in his olfactory neurons as he ages. This makes him better at detecting the scent of other flies and more likely to outcompete rival males for mates.

A key trigger for this activity is the loosening of a coiled material called chromatin that controls access to the fruitless gene's "on" switch.

In contrast, social isolation keeps this region of chromatin packed so tightly that the gene can't be read off by the cell.

The researchers also found that the effects were reversible. When they wafted pheromone by the socially isolated males, or transferred them to vials with other flies, the chromatin unwound and returned the fruitless gene to its "open for business" state.

"People always ask: how does this relate to human sexuality?" Volkan said.

The connection between what happens in fruit flies and sexual behavior in humans isn't clear-cut, Volkan said. Humans don't have a fruitless gene, for one. And the chain of causation from genes and hormones to behavior is much more complex. But by understanding the epigenetic changes that allow organisms to selectively tune into sensory input, or block it out, researchers say the work could point to new ways to treat people with autism and other sensory processing disorders.