Culture

CHICAGO: A new breast cancer study brings reassuring findings for women with early-stage breast cancer who were forced to delay their cancer operations because of the Coronavirus Disease 2019 (COVID-19) pandemic. A longer time from diagnosis to surgical treatment does not lower overall survival of women with early-stage breast cancer who underwent delayed operations before the pandemic, according to the study results, which are published as an "article in press" on the Journal of the American College of Surgeons website in advance of print.

The researchers also found no survival decrease with operative delays in women with estrogen-sensitive, early-stage breast cancer who received neoadjuvant endocrine therapy (NET). NET is preoperative hormone treatment with anti-estrogen drugs such as tamoxifen or aromatase inhibitors.

Patients with estrogen receptor (ER)-positive breast cancer, whose cancer is fueled by estrogen, typically receive anti-estrogen therapy after surgical removal of the tumor or breast. However, endocrine therapy was recommended nationwide as the initial treatment of ER-positive breast cancer during pandemic-related surgical delays, said lead study author Christina Minami, MD, MS, an associate surgeon at Brigham and Women's Hospital, Boston.

"Usually we take these patients with very small tumors directly to surgery, so it is a big change in practice to first put those patients on tamoxifen or an aromatase inhibitor," Dr. Minami said. "What we can say from our findings is that despite the delay in surgical therapy, because you were on neoadjuvant endocrine therapy, we do not think that your survival will at all be impacted."

The study included data from nearly 379,000 patients in two groups. One group had ductal carcinoma in situ (DCIS), the earliest form of breast cancer, also called stage 0 or noninvasive. The other group had small invasive tumors--stage I and limited stage II--that had not spread to nearby lymph nodes and were ER-positive.

Surgical intervention delays due to COVID-19

These groups, Dr. Minami said, represent most breast cancer patients who needed to postpone their nonurgent operations early in the COVID-19 outbreak according to the surgical prioritization recommendations of the COVID-19 Pandemic Breast Cancer Consortium. In March, the Consortium recommended NET for patients with ER-positive DICS and ER-positive, invasive early-stage breast cancer while they waited for their operations.1 At that time, the Consortium included the American Society of Breast Surgeons, National Accreditation Program for Breast Centers, National Comprehensive Cancer Network, American College of Surgeons Commission on Cancer, and American College of Radiology.

To better understand the ramifications of these surgical delay tactics, the researchers conducted this study using the National Cancer Database and analyzed data for 378,839 patients with early-stage breast cancer treated from 2010 to 2016. Cosponsored by the ACS and the American Cancer Society, this database includes information on more than 70 percent of newly diagnosed cancer cases in the United States and is the largest cancer registry of its kind.

The researchers evaluated whether longer time to surgical treatment up to one year after diagnosis had an association with final pathologic staging of the cancer or with five-year overall survival.

Increased "upstaging"

In women with invasive early-stage breast cancer, a longer time to the initial cancer operation showed no association with pathologic upstaging, the researchers reported. Upstaging is a change to a higher cancer stage based on surgical and pathologic findings, compared with the clinical stage--what a surgeon determined from physical examination and imaging results.

Women with ER-positive DCIS, however, had a slightly increased odds of pathologic upstaging with a surgical delay exceeding 60 days, the researchers reported. Patients whose DCIS was ER-negative (not estrogen-fueled) had a higher risk of upstaging only if they underwent an operation more than 120 days after diagnosis; they had an odds of 1.36 to 1 compared with patients who underwent surgical treatment within the first 60 days, according to the article.

This increase in upstaging among DCIS patients had no impact on their overall survival, Dr. Minami said.

She stressed, however, that the patient population in their study differs from the patients who received NET during the pandemic. Before the pandemic, NET was not in wide use for U.S. patients with early-stage, ER-positive breast cancer.2 Study participants who received NET from 2010 to 2016 did so for specific reasons, such as older age and coexisting illnesses, whereas in the pandemic, NET recipients were "almost an unselected population," Dr. Minami explained.

She added that although the researchers used "the best data currently available to study the possible outcomes of oncologic surgical delays," determination of the actual impact of COVID-19-related surgical delays requires study in patients treated during this time.

Despite this study limitation, senior study author Elizabeth Mittendorf, MD, PhD, FACS, professor of surgery at Brigham and Women's Hospital, said she has found the study findings helpful to share with her patients who experienced surgical delays.

"We can tell our patients they can still expect an excellent prognosis from their early-stage hormone receptor-positive cancer and that their excellent prognosis is not negatively impacted by this delay they have experienced," Dr. Mittendorf said.

Ants are the most successful social insects and play an important role in modern terrestrial ecosystems. The origin and early evolution of ants have attracted lots of attention.

Among the earliest fossil ants known, haidomyrmecine "hell ants" from Cretaceous amber reveal an ancient and dramatic early burst radiation of adaptive forms.

Hell ants possessed bizarre scythe-like mouthparts along with a striking array of horn-like cephalic projections. But how did this type of ant evolve? This question was long a mystery.

Now, however, an international research team co-led by Prof. WANG Bo from the Nanjing Institute of Geology and Palaeontology (NIGPAS) of the Chinese Academy of Sciences has confirmed the special trap-jaw predation mechanism of hell ants, providing new insights into their evolution.

The study was published in Current Biology on August 6.

The research team conducted morphological and anatomical analysis of the heads of all hell ants in the amber specimens, in combination with a special predator specimen, and confirmed the "trap-jaw" predation mechanism adopted by hell ants from their morphological and functional aspects.

The scientists reported an instance of fossilized predation that provides direct evidence for the function of dorsoventrally expanded mandibles and elaborate horns.

Their findings confirmed the hypothesis that hell ants captured other arthropods between mandible and horn in a manner that could only be achieved by articulating their mouthparts in an axial plane perpendicular to that of modern ants.

The head capsule and mandibles of hell ants are uniquely integrated as a consequence of this predatory mode and covary across species, while no evidence has been found of such modular integration in extant ant groups.

The results of this study suggest an extinct early burst adaptive radiation into morphospace that was unoccupied by any living taxon. This radiation was triggered by an innovation in mouthpart movement and subsequent modular covariation between mandible and horn.

The new results also suggest that hell ant cephalic integration - analogous to the vertebrate skull - triggered a pathway for an ancient adaptive radiation and expansion into morphospace unoccupied by any living taxon.

Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition. Experts from Charité - Universitätsmedizin Berlin, the University of Bonn, the German Center for Neurodegenerative Diseases (DZNE), the Helmholtz Centre for Infection Research (HZI) and the German Center for Infection Research (DZIF), along with colleagues from a nationwide research network, present these findings in the scientific journal Cell.

Most patients infected with the coronavirus SARS-CoV-2 show mild or even no symptoms. However, 10 to 20 percent of those affected develop pneumonia during the course of COVID-19 disease, some of them with life-threatening effects. "There is still not very much known about the causes of these severe courses of the disease. The high inflammation levels measured in those affected actually indicate a strong immune response. Clinical findings, however, rather tend to indicate an ineffective immune response. This is a contradiction," says Joachim Schultze, professor at the University of Bonn and research group leader at the DZNE. "We therefore assume that although immune cells are produced in large quantities, their function is defective. That is why we examined the blood of patients with varying degrees of COVID-19 severity," explains Leif Erik Sander, Professor of Infection Immunology and Senior Physician Charité's Medical Department, Division of Infectious Diseases and Respiratory Medicine.

High-precision methods

The study was carried out within the framework of a nationwide consortium - the "German COVID-19 OMICS Initiative" (DeCOI) - resulting in the analysis and interpretation of the data being spread across various teams and sites. Joachim Schultze was significantly involved in coordinating the project. The blood samples came from a total of 53 men and women with COVID-19 from Berlin and Bonn, whose course of disease was classified as mild or severe according to the World Health Organization classification. Blood samples from patients with other viral respiratory tract infections as well as from healthy individuals served as important controls.

The investigations involved the use of single-cell OMICs technologies, a collective term for modern laboratory methods that can be used to determine, for example, the gene activity and the amount of proteins on the level of single, individual cells - thus with very high resolution. Using this data, the scientists characterized the properties of immune cells circulating in the blood - so-called white blood cells. "By applying bioinformatics methods on this extremely comprehensive data collection of the gene activity of each individual cell, we could gain a comprehensive insight of the ongoing processes in the white blood cells," explains Yang Li, Professor at the Centre for Individualised Infection Medicine (CiiM) and Helmholtz Centre for Infection Research (HZI) in Hannover. "In combination with the observation of important proteins on the surface of immune cells, we were able to decipher the changes in the immune system of patients with COVID-19," adds Birgit Sawitzki, Professor at the Institute of Medical Immunology on Campus Virchow-Klinikum.

"Immature" cells

The human immune system comprises a broad arsenal of cells and other defense mechanisms that interact with each other. In the current study, the focus was on so-called myeloid cells, which include neutrophils and monocytes. These are immune cells that are at the very front of the immune response chain, i.e. they are mobilized at a very early stage to defend against infections. They also influence the later formation of antibodies and other cells that contribute to immunity. This gives the myeloid cells a key position.

"With the so-called neutrophils and the monocytes we have found that these immune cells are activated, i.e. ready to defend the patient against COVID-19 in the case of mild disease courses. They are also programmed to activate the rest of the immune system. This ultimately leads to an effective immune response against the virus," explains Antoine-Emmanuel Saliba, head of a research group at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg.

But the situation is different in severe cases of COVID-19, explains Sawitzki: "Here, neutrophils and monocytes are only partially activated and they do not function properly. We find considerably more immature cells that have a rather inhibitory effect on the immune response." Sander adds: "The phenomenon can also be observed in other severe infections, although the reason for this is unclear. Many indications suggest that the immune system stands in its own way during severe courses of COVID-19. This could possibly lead to an insufficient immune response against the corona virus, with a simultaneous severe inflammation in the lung tissue."

Approaches to therapy?

The current findings could point to new therapeutic options, says Anna Aschenbrenner from the LIMES Institute at the University of Bonn: "Our data suggest that in severe cases of COVID-19, strategies should be considered that go beyond the treatment of other viral diseases." The Bonn researcher says that in the case of viral infections one does not actually want to suppress the immune system. "If, however, there are too many dysfunctional immune cells, as our study shows, then one would very much like to suppress or reprogram such cells." Jacob Nattermann, Professor at the Medical Clinic I of the University Hospital Bonn and head of a research group at the DZIF, further explains: "Drugs that act on the immune system might be able to help. But this is a delicate balancing act. After all, it's not a matter of shutting down the immune system completely, but only those cells that slow down themselves, so to speak. In this case these are the immature cells. Possibly we can learn from cancer research. There is experience with therapies that target these cells."

Nationwide team effort

In view of the many people involved, Schultze emphasizes the cooperation within the research consortium: "As far as we know, this study is one of the most comprehensive studies to date on the immune response in COVID-19 based on single cell data. The parallel analysis of two independent patient cohorts is one of the strengths of our study. We analyzed patient cohorts from two different sites using different methods and were thus able to validate our findings directly. This is only possible if research data is openly shared and cooperation is based on trust. This is extremely important, especially in the current crisis situation."

Despite our broad understanding of the different brain regions activated during rapid-eye-movement sleep, little is known about what this activity serves for. Researchers at the University of Bern and the Inselspital have now discovered that the activation of neurons in the hypothalamus during REM sleep regulates eating behaviour: suppressing this activity in mice decreases appetite.

While we are asleep, we transition between different phases of sleep each of which may contribute differently to us feeling rested. During (rapid eye movement) REM sleep, a peculiar sleep stage also called paradoxical sleep during which most dreaming occurs, specific brain circuits show very high electrical activity, yet the function of this sleep-specific activity remains unclear.

Among the brain regions that show strong activation during REM sleep are areas that regulate memory functions or emotion, for instance. The lateral hypothalamus, a tiny, evolutionarily well conserved brain structure in all mammals also shows high activity during REM sleep. In the awake animals, neurons from this brain region orchestrate appetite and the consumption of food and they are involved in the regulation of motivated behaviours and addiction.

In a new study, researchers headed by Prof. Dr. Antoine Adamantidis at the University of Bern set out to investigate the function of the activity of hypothalamic neurons in mice during REM sleep. They aimed at better understanding how neural activation during REM sleep influences our day-to-day behaviour. They discovered that suppressing the activity of these neurons decreases the amount of food the mice consume. "This suggests that REM sleep is necessary to stabilize food intake", says Adamantidis. The results of this study have been published in the journal Proceedings of the National Academy of Sciences (PNAS).

Long-lasting effect on neuronal activity and feeding behavior

The researcher discovered that specific activity patterns of neurons in the lateral hypothalamus that usually signal eating in the awake mouse are also present when the animals were in the stage of REM sleep. To assess the importance of these activity patterns during REM sleep the research group used a technique called optogenetics, with which they used light pulses to precisely shut down the activity of hypothalamic neurons during REM sleep. As a result, the researchers found that the activity patterns for eating were modified and that the animals consumed less food.

"We were surprised how strongly and persistently our intervention affected the neural activity in the lateral hypothalamus and the behaviour of the mice", says Lukas Oesch, the first author of the study. He adds: "The modification in the activity patterns was still measurable after four days of regular sleep." These findings suggest that electrical activity in hypothalamic circuits during REM sleep are highly plastic and essential to maintain a stable feeding behaviour in mammals.

It is a question of quality

These findings point out that sleep quantity alone is not solely required for our well-being, but that sleep quality plays a major role in particular to maintain appropriate eating behaviour. "This is of particular relevance in our society where not only sleep quantity decreases but where sleep quality is dramatically affected by shift work, late night screen exposure or social jet-lag in adolescents", explains Adamantidis.

The discovered link between the activity of the neurons during REM sleep and eating behaviour may help developing new therapeutical approaches to treat eating disorders. It might also be relevant for motivation and addiction. "However, this relationship might depend on the precise circuitry, the sleep stage and other factors yet to be uncovered", adds Adamantidis.

Rhythms produced by the brain can reliably be used to predict how sensitive we are to pain, new research shows.

The living brain is constantly producing regular rhythmic patterns of activity, which can be compared to musical notes. Scientists at the University of Birmingham in the UK, and the University of Maryland School of Dentistry in the US, have successfully demonstrated that one particularly prevalent pattern of brain activity, called alpha waves, strongly relates to the body's susceptibility or resilience to pain.

Alpha waves oscillate between 8-14 Hz, with the peak frequency varying across individuals. The researchers demonstrated how a measurement of an individual's alpha wave frequency can be used as a reliable pain indicator.

The study, led by graduate student Andrew Furman and published in the journal Cerebral Cortex, suggests that these alpha waves could be used to help clinicians understand how susceptible a patient to experience severe pain post-surgery.

Dr David Seminowicz of the University of Maryland School of Dentistry is co-author of the study. He explains: "Understanding a patient's pain sensitivity could be really important in, for example, deciding whether an elective procedure is the best option or planning post-surgery rehabilitation. Pain management drugs or techniques such as mindfulness meditation can also be used before surgery to help minimise pain."

Dr Ali Mazaheri, from the University of Birmingham's School of Psychology and Centre for Human Brain Health and also co-author of the study, adds: "Severe pain following surgery is often also a good indicator of whether or not a patient is likely to go on to develop chronic pain. Understanding whether or not a person is at high risk of developing these symptoms will help patients and clinicians make better informed choices about the best course of treatment."

Alpha waves are just one type of electrical activity going on continually in our brains. They're thought to be most present when a person is awake, but maybe idle. In our sensory systems, their presence signals that a particular part of the system has 'closed down' for processing. When the waves are reduced, that system is ready to start working again.

For most people these oscillations occur continuously in the brain at frequencies of between 8-14Hz. Previous research carried out by the group showed that people with alpha waves occurring at the higher end of this scale were more resilient to pain, while those at the lower end were more susceptible.

In this experiment, the team wanted to find out whether, by taking an initial measurement of the subject's alpha waves, it was possible to predict their reaction to pain.

The researchers tested 61 healthy participants, both men and women, aged between 21 and 42. Alpha waves were measured in each participant using electroencephalography (EEG) and then participants were each exposed to two different pain episodes. In the first of these a cream containing capsaicin - the active ingredient in chilli peppers - was applied to produce sensitised skin; in the second participants underwent repeated applications of heat. After eight weeks, the subjects returned to repeat the experiment.

The results showed that measuring alpha waves did give a reliable indication of a person's susceptibility or resilience to pain. These results were reliable both in the initial assessment and in the eight-week follow up.

In Birmingham, these principles are already being tested in partnership with clinicians at the Heartlands and Queen Elizabeth Hospitals. Dr Mazaheri is leading a study investigating the use of alpha waves and the pain experience of lung cancer patients undergoing lung biopsies.

"We know that lung surgery is a particularly painful procedure, with between 40 and 60 per cent of patients going on to develop debilitating pain after surgery," explains Dr Mazaheri. "By predicting which patients are likely to develop this pain, we can start to explore other options, such as radiotherapy, or make sure that intensive rehabilitation programmes are in place to support those patients through recovery."

The team is currently actively seeking funding to continue this work.

Researchers have identified a pattern of longer-term symptoms likely to be experienced by people who were hospitalised with the COVID-19 infection.

They include fatigue, breathlessness, psychological distress - including problems with concentration and memory - and a general decline in quality of life.

Some patients, particularly those who had been in intensive care, had symptoms associated with cases of PTSD (post-traumatic stress disorder).

The findings provide the first detailed insight into problems facing patients recovering from COVID-19 in the UK.

Dr Manoj Sivan, Associate Clinical Professor at the University of Leeds and a Consultant in Rehabilitation Medicine at Leeds General Infirmary, supervised the research project. He said: "COVID-19 is a new illness and we have very little information on longer term problems in individuals after discharge from hospital."

"The emerging evidence is that for some, the road to recovery may take months and it is vital specialist rehabilitation is on hand to support them. This research gives an important insight into patient needs, and that will help shape services in the community."

The findings - Post-discharge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation - have been published in the Journal of Medical Virology.

Dr Stephen Halpin, Senior Research Fellow at the University of Leeds and Consultant with Leeds Teachings Hospitals NHS Trust, said: "This research follows our previous work of predicting COVID-19 patients' long-term needs based on previous coronavirus outbreaks of SARS in 2002 and MERS in 2012. The health problems are similar but on a larger scale given the number of people affected."

The research team - involving multidisciplinary specialists from the University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds Community Healthcare NHS Trust and Leeds Beckett University - followed 100 people recovering from COVID-19, four-to-eight weeks after being discharged from hospital in Leeds.

The COVID-19 survivors were divided into two groups: those who had become critically ill and needed intensive care - 32 people were in this category; and those who were treated on a ward without needing intensive care - 68 people were in this category.

Patients were contacted by a member of the hospital's rehabilitation team and asked a series of questions about their recovery and symptoms they were still experiencing.

Results

The most prevalent symptom was fatigue. More than 60 percent of people who had been treated on a ward reported fatigue, and one-third of them described it as moderate or severe. For patients who had been in intensive care, 72 percent reported fatigue. Of those, more than half said it was moderate or severe.

The second most common symptom was breathlessness. People in both groups said they had feelings of breathlessness which had not existed before they contracted COVID-19. This was higher in the group that had been the most ill, the intensive care group versus those who had been treated in a ward - 65.6 percent versus 42.6 percent.

The third most prevalent symptoms were neuropsychological. The research survey found that almost one quarter of the people who had been on a ward and just under a half of the people who had been in intensive care had some of the symptoms of PTSD.

Writing in the paper, the researchers said: "PTSD symptoms are a well-recognised component of post- intensive care unit syndrome caused by a variety of factors including fear of dying, invasive treatment, pain, delirium, inability to communicate, weakness, immobility, and sensory problems and sleep deprivation."

More than two-thirds (68.8 percent) of patients in the intensive care group and just under half (45.6 percent) of the other group said their overall quality of life had deteriorated.

The researchers say the rehabilitation needs of patients who did not require hospital care need to be further investigated and they are working on understanding this in future research.

BOSTON (Aug. 6, 2020)--Researchers at Tufts University School of Medicine and Tufts Graduate School of Biomedical Sciences have discovered neural mechanisms in mice specific to females that can shift estrogen from playing a protective role in glucose metabolism to one that is disruptive. The authors of the study, published online in the Proceedings of the National Academies of Sciences (PNAS), hypothesize that the metabolic "switch" mediated by estrogen may provide clues to the increased risk of insulin resistance and diabetes among post-menopausal women.

The study focused on a region of the brain called the ventromedial hypothalamus (VMH) and found that the removal of the metabotropic glutamate receptor 5 (mGluR5) in that area caused estrogen to reduce the activity of neurons important for glycemic control, leading to insulin resistance and glucose intolerance. These effects were opposite to the increased neuronal activity and enhanced glucose metabolism observed in mice with the receptor following estrogen delivery. The paradoxical outcome on glucose metabolism was seen in female, but not male, mice.

Prior research by others had indicated that the VMH region of the brain plays a role in managing appropriate levels of glucose production in the liver and utilization of circulating glucose by cells and tissues. Within the VMH, steroidogenic factor 1 (SF1) neurons are responsible for helping to regulate glucose as well as lipid levels, e.g. cholesterol and triglycerides. However, less was known about exactly how the VMH regulates glucose metabolism. Similarly, while the beneficial effects of estrogen have long been recognized, the mechanisms driving these effects remain poorly understood.

mGluR5 is highly expressed in the VMH and is known to regulate neuron activity in other parts of the brain. When the researchers knocked out the expression of mGluR5 specifically in the VMH using gene editing methods, they observed a reduction of SF1 neuron activity and a disruption of normal glucose regulation, but only in the female mice.

Knocking out mGluR5 in male mice did not have these effects and their glucose metabolism remained normal.

Noting different effects on glucose metabolism between male and female mice, the researchers examined the potential involvement of sex hormones. They discovered that estrogen, which normally promotes metabolic health in females, supports glycemic control only when mGluR5 is present in the VMH. Without mGluR5, estrogen actually suppresses the neurons responsible for regulating glucose - it becomes a metabolic liability.

"Our findings show that the glutamate receptor is essential for the effects of estrogen regulating proper glucose levels and utilization in females, whereas it does not appear to play that regulatory role in males. This could give us insight into many of the differences between men and women in their risk of diabetes and disease progression throughout life," said senior author Maribel Rios, researcher in neuroscience at Tufts School of Medicine and a member of the neuroscience and cell, molecular and developmental biology program faculties at Tufts Graduate School of Biomedical Sciences.

(Jena, Germany) The periodic system contains 118 chemical elements. However, only a few of them, such as hydrogen, carbon, nitrogen, oxygen and silicon, are of major importance in our daily lives. But things become really exciting from a chemical point of view when less well-known elements are involved. An international research group from Germany and Finland discovered astonishing and beautiful molecular structures when, instead of oxygen or sulphur, they used the element tellurium, which has a different weight, in ring-shaped hydrocarbon molecules. These compounds are distinguished by the fact that they are arranged in the crystal to form highly symmetrical tubes that interact with each other via the tellurium atoms.

Molecular rings are arranged into tubes

The semiconductor tellurium has similar chemical properties to the 'related' elements sulphur and selenium. It is therefore not surprising that the ring-shaped hydrocarbons, into which the team specifically incorporated tellurium atoms, also behave similarly to the corresponding known compounds that contain sulphur or selenium - at least when they are dissolved. Tellurium nevertheless occupies a special position.

"Something special happens when these substances form crystals," says Prof. Wolfgang Weigand of Friedrich Schiller University Jena, one of the two corresponding authors of the current publication on this topic. "Virtually infinitely long tubes are then formed, in which the ring-shaped molecules are held together by the tellurium atoms. This happens due to an unusually strong intermolecular interaction. As a result, very interesting structures are created, which we can observe here." Similar structures are already known in chemistry, for example those called metal-organic frameworks. "In contrast to those, however, our compounds are not coordination polymers," explains Weigand. "Therefore, they behave differently. This can be seen, for example, in the fact that they only make these supramolecular forms as crystals and not when they are dissolved." However, initial experimental findings show that atmospheric oxygen can oxidise the tellurium atoms and then link them together to form stacked compounds.

A new way to store gas?

The German-Finnish research team has discovered that, due to their special cavities, these tellurium compounds in solid form have an extremely large surface area of nearly 1000 square metres per gram - or around two-and-a-half basketball courts. "It is in principle conceivable that gases, such as carbon dioxide, could be captured in these cavities," says Wolfgang Weigand. "However, it was important to us first of all to explore and study these exciting compounds." Further research is needed before practical applications could become possible.

"This research would not have been possible without the EU's Erasmus Programme," adds Jena chemist Weigand. "The idea for this work originally came from my former doctoral candidate, Dr Tobias Niksch, in Jena, and through a stay as a visiting scientist at the University of Oulu in Finland by my former Master's student, Marko Rodewald, in the group led by Prof. Risto Laitinen. We have had a very good relationship with the university for 15 years and we have frequently published research results together. And the theoretical calculations in this paper were done by one of Risto Laitinen's former doctoral candidates, who is now doing research at the University of Jyväskylä in Finland. This paper therefore shows how important exchanges and networking are for scientific progress. I'm already looking forward to doing further research on these interesting structures with our Finnish colleagues."

Beginning in March, as COVID-19 cases surged in various states in the U.S., the COVID-19 Pandemic Breast Cancer Consortium released recommendations that operations for ductal carcinoma in situ (DCIS) be deferred due to the pandemic. DCIS, which goes by many names including "stage 0" breast cancer, is a non-invasive form of cancer that begins in the milk ducts and is generally surgically excised. In approximately one in five cases, surgeons may find evidence of invasive cancer during surgery. During the pandemic, patients and clinicians expressed concern about what surgical delays might mean for patients' outcomes. A new study led by, investigators from Brigham and Women's Hospital, of more than 378,000 patients who were diagnosed with very early stage breast cancer between 2010 and 2016 offers new data and insights to help address these unknowns. The research team found that while increased time to surgery was associated with a small increase in pathological upstaging in DCIS patients, it did not impact overall survival. Results are published in the Journal of the American College of Surgeons.

"The most pressing question today is what will surgical delays due to the pandemic mean for patient outcomes, and the reality is that we will only have the answers years from now," said lead author Christina Minami, MD, MS, a surgeon in the Division of Breast Surgery at the Brigham. "In the meantime, these data should provide some reassurance and encouragement -- they don't indicate that outcomes will be changed dramatically. But we do encourage patients to follow up with their surgeons on a care plan as COVID-19 surges grow or subside locally."

Minami and colleagues leveraged data from the National Cancer Database for patients, which captures approximately 70 percent of newly diagnosed cancer in the U.S. All patients diagnosed January 1, 2010 to December 31, 2016 who underwent breast cancer surgery were identified. The team focused on patients with DCIS or early-stage (cT1-2N0) ER+ disease, an early form of breast cancer that may be susceptible to hormone therapy drugs.

More than 98 percent of patients with DCIS underwent surgery within three months. Among those who delayed surgery 60 days or longer, there was no significant difference in overall survival but there was a slight increase in upstaging. In patients with cT1-2N0 disease who were placed on neoadjuvant endocrine therapy -- a hormone therapy -- increased time to surgery did not impact stage or overall survival.

The authors note that extrapolating from the historical data to determine what this means for patients whose surgery has been delayed during the pandemic is challenging. Those who delayed surgery during the study period were a highly selective group -- they may not be representative of the wide swath of patients whose surgery was delayed due to the pandemic. In addition, the research team was only able to look at outcomes of three to four years -- understanding the longer-term effects of surgical delays may provide more meaningful insights for patients and clinicians.

"Anxiety for both surgeons and patients alike stems from the unknown -- what does a delay in surgery mean for our patients?" said Minami. "We sought to help address questions about outcomes. Ideally, we'd like to have randomized, controlled studies, but under the circumstances, we needed to take the more unconventional approach by looking at retrospective data."

Philadelphia and Newark, N.J. August 6, 2020 - A team of researchers from New Jersey Institute of Technology (NJIT) and Children's Hospital of Philadelphia (CHOP) have developed an algorithm through machine learning that helps predict sites of DNA methylation - a process that can change the activity of DNA without changing its overall structure - and could identify disease-causing mechanisms that would otherwise be missed by conventional screening methods.

The paper was published online this week by the journal Nature Machine Intelligence.

DNA methylation is involved in many key cellular processes and an important component in gene expression. Likewise, errors in methylation can be linked to a variety of human diseases. While genomic sequencing tools are effective at pinpointing polymorphisms that may cause a disease, those same methods are unable to capture the effects of methylation because the individual genes still look the same. Specifically, there has been considerable effort to study DNA methylation on N6-adenine (6mA) in eukaryotic cells, which include human cells, but while genomic data is available, the role of methylation in these cells remains elusive.

"Previously, methods that had been developed to identify these methylation sites in the genome were very conservative and could only look at certain nucleotide lengths at a given time, so a large number of methylation sites were missed," said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics (CAG) at CHOP and one of the senior co-authors of the study. "We needed to develop a better way of identifying and predicting methylation sites with a tool that could identify these motifs throughout the genome that may have a robust functional impact and are potentially disease causing."

In order to address this issue plaguing the research community, CAG and its partners at NJIT turned to deep learning. Zhi Wei, PhD, a professor of computer science at NJIT and a senior co-author of the study, worked with Hakonarson and his team to develop a deep learning algorithm that could predict where these sites of methylation happened, which would then help researchers determine the effect they might have on certain nearby genes.

Wei calls his software Deep6mA. To predict where these methylation sites might be found, Wei led the development of a neural network, which is a machine learning model that attempts to learn in similar ways to a brain. Neural networks have been utilized in cellular research before, but this is its first application to studyDNA methylation sites on natural multicellular organisms.

Wei cited four advantages of the new method: automation of the sequence feature representation of different levels of detail; integration of a broad spectrum of methylation sequences flanking genes of interest; enabling of the potential visualization of inherent sequence motifs for interpretation; and facilitation of model development and prediction in large-scale genomic data.

The study team applied this algorithm to three different types of representative organisms: A. thaliana, D. melanogaster, and E.coli, the first two being eukaryotic. Deep6mA was able to identify 6mA methylation sites down to the resolution of a single nucleotide, or basic unit of DNA. Even in this initial confirmation study, the researchers were able to visualize regulatory patterns that they had been unable to observe using previously existing methods.

"One limitation is that our proposed prediction is purely based on sequence information," Wei said in his discussion statement of the study. "Whether a candidate is a 6mA site or not will also depend on many other factors. Methylation, including 6mA, is a dynamic process, which will change with cellular context. In the future, we would like to take other factors into consideration [such as] gene expression. We hope to predict 6mA across cellular context by integrating other data."

"We already know that a number of genes have a disease-causing mechanism brought about by methylation, and while this study was not done in human cells, the eukaryotic cell models were very comparable," Hakonarson said. "Genomic scientists looking to translate their findings into clinical applications would find this tool very useful, and the level of precision could eventually lead to the discovery of specific cells or targets that are candidates for therapeutic intervention."

WASHINGTON (Aug. 6, 2020) -- George Washington University (GW) researchers found five biomarkers, medical indicators found in the blood, associated with higher odds of clinical deterioration and death in COVID-19 patients. Published in Future Medicine, these findings will help physicians better predict outcomes for COVID-19 patients in the U.S.

"When we first started treating COVID-19 patients, we watched them get better or get worse, but we didn't know why," said Juan Reyes, MD, co-author of the study and assistant professor of medicine at the GW School of Medicine and Health Sciences. "Some initial studies had come out of China showing certain biomarkers were associated with bad outcomes. There was a desire to see if that was true for our patients here in the U.S."

The research team evaluated 299 patients diagnosed with COVID-19 admitted to GW Hospital between March 12 and May 9, 2020. Of these patients, 200 had all five biomarkers being evaluated - IL-6, D-dimer, CRP, LDH and ferritin. Elevated levels of these biomarkers were associated with inflammation and bleeding disorder, showing an independent increased risk for ICU admission, invasive ventilatory support, and death. The highest odds of death occurred when the LDH level was greater than 1200 units/l and a D-dimer level was greater than 3 μg/ml.

"We hope these biomarkers help physicians determine how aggressively they need to treat patients, whether a patient should be discharged, and how to monitor patients who are going home, among other clinical decisions," said Shant Ayanian, MD, first author of the study and assistant professor of medicine at the GW School of Medicine and Health Sciences.

Currently, physicians determine risk for COVID-19 deterioration and death based on age and certain underlying medical conditions, like having an immunocompromised state, obesity, and heart disease. Performing a simple blood test for patients admitted to the emergency department, then also making decisions based on biomarkers present, may further aid point-of-care clinical decision making. Reyes, Ayanian, and the GW research team will continue to analyze this data to help physicians make more informed decisions for patients, as well as help hospitals that may need to stratify resources.

"The association between biomarkers and clinical outcomes in novel coronavirus pneumonia in a US cohort" was published in Future Medicine and is available at https://www.futuremedicine.com/doi/10.2217/bmm-2020-0309.

Bacteria are always with us: These tiny organisms are found within and on our body as is the case with all animals and plants. As part of a healthy microbiome they ensure our wellbeing. But if the microbial community gets dysbalanced, infections can follow. Even in soil and water they are a crucial component of the respective environments and their functioning.

Still, we are just beginning to understand these essential unicellular organisms. The Jena microbiologist Prof. Kai Papenfort and his team were able to shed more light on this subject with their latest publication in the journal eLife. They discovered a new mechanism of autoregulation during gene expression that relies on small regulatory ribonucleic acids (sRNAs) and the major endoribonuclease RNase E.

"This autoregulation controls gene expression - that means, the proteins are synthesized based on genetic information. Bacteria use this process to adapt to their environment for example," explains Papenfort, Chair of General Microbiology at the Friedrich Schiller University Jena. The sRNAs play a decisive role in gene regulation. Through their interaction with the messenger RNA they influence the structure or metabolism of the bacterium, among other things.

"Based on the collected data, we were able to show that sRNAs from a specific section of the messenger RNA serve as autoregulatory elements. That allows negative feedback control at the post-transcriptional level," says Papenfort. Negative feedback regulation is very common in biology. It often has a stabilising effect. For example, in humans both the regulation of body temperature and blood pressure are due to negative feedback regulation. Normally, the feedback controls are triggered by the corresponding proteins during transcription. "It is notable, that the autoregulatory small RNAs we have discovered are independent of auxiliary transcription factors. Therefore, they provide a more rapid response," continues Papenfort.

With the findings from this study, Papenfort's team contributes to the research of the Cluster of Excellence "Balance of the Microverse" at the Friedrich Schiller University Jena. Its goal is to generate a holistic understanding of microorganisms, their interaction and communication with each other and with their environment.

Bacteria are survival artists: When they get nutrition, they multiply rapidly, albeit they can also survive periods of hunger. But, when they grow too quickly, their ability to survive is hampered, as studies by a research team at the Technical University of Munich (TUM) on E. coli bacteria show. The results could help increase the effectiveness of antibiotics.

"The fitness of bacteria is more complex than expected," explains Ulrich Gerland, professor for the theory of complex biosystems at the Technical University of Munich. The physicist has been studying the survival strategies of E. coli bacteria for several years.

The unicellular organisms, which go by the Latin name Escherichia coli and support digestion in the large intestine of mammals, are a popular model organism. They facilitate investigations into the way living beings can adapt to changing environmental conditions.

Surviving hard times

"We have known for some time that biological fitness depends on two things: the growth rate when food is available and the ability to survive periods of nutrient deficiency," explains the scientist. "What was not clear is how these two factors are related."

For the first time, Gerland and his team have now systematically investigated the extent to which fast or slow growth influences the survivability of E. coli bacteria: "It turns out that changes in growth conditions have a direct impact on death rates. These follow a simple law: The best-nourished and fastest-growing bacteria are the first to die when deprived of food."

Fat bacteria - poor fitness

So, a good diet is bad for the fitness of bacteria. But why? To find an answer to this question, the TUM researchers carried out a number of experiments: First, cultures of E. coli bacteria were provided nutrient solutions with different compositions.

In the second step, the unicellular organisms were put on a zero diet. Throughout the entire period, the scientists examined whether and how quickly the cells multiplied, and how long they survived.

The fight for survival

The research showed that regardless of how well or poorly they were previously fed, bacteria stopped reproducing when they were deprived of food. In this "maintenance phase," organisms struggle for bare survival. All available energy sources - for example, the cellular remains of dead bacteria - are used to sustain the metabolism.

In this extreme situation, many cells die of starvation within a few days. However, the death rate is particularly high among rapidly growing E. coli bacteria. "They are primed for rapid growth and waste energy resources. This leads to their demise during the hunger phase," explains Gerland.

As it turns out, the abundantly fed bacteria have an increased need for energy, as further experiments prove. Surviving times of scarcity is more difficult for organisms with a high energy consumption. "We now understand why evolution doesn't favor the fastest possible reproduction," says Gerland. "The biological fitness that is crucial for the survival of a species builds on a balance between growth and survivability."

Antibiotic therapy with a carrot and a stick

The research results may find application in the future, for example, to improve the effect of antibiotics: "Applying a carrot and stick principle, intestinal bacteria growth could be stimulated by consuming a sweet dish. This would weaken the bacteria if an antibiotic against an intestinal infection is then administered," explains Gerland. However, it is still too early for concrete recommendations. More research will be necessary.

Taking advantage of a total lunar eclipse, astronomers using NASA's Hubble Space Telescope have detected Earth's own brand of sunscreen - ozone - in our atmosphere. This method simulates how astronomers and astrobiology researchers will search for evidence of life beyond Earth by observing potential "biosignatures" on exoplanets (planets around other stars).

Hubble did not look at Earth directly. Instead, the astronomers used the Moon as a mirror to reflect sunlight, which had passed through Earth's atmosphere, and then reflected back towards Hubble. Using a space telescope for eclipse observations reproduces the conditions under which future telescopes would measure atmospheres of transiting exoplanets. These atmospheres may contain chemicals of interest to astrobiology, the study of and search for life.

Though numerous ground-based observations of this kind have been done previously, this is the first time a total lunar eclipse was captured at ultraviolet wavelengths and from a space telescope. Hubble detected the strong spectral fingerprint of ozone, which absorbs some of the sunlight. Ozone is important to life because it is the source of the protective shield in Earth's atmosphere.

On Earth, photosynthesis over billions of years is responsible for our planet's high oxygen levels and thick ozone layer. That's one reason why scientists think ozone or oxygen could be a sign of life on another planet, and refer to them as biosignatures.

"Finding ozone is significant because it is a photochemical byproduct of molecular oxygen, which is itself a byproduct of life," explained Allison Youngblood of the Laboratory for Atmospheric and Space Physics in Boulder, Colorado, lead researcher of Hubble's observations.

Although ozone in Earth's atmosphere had been detected in previous ground-based observations during lunar eclipses, Hubble's study represents the strongest detection of the molecule to date because ozone - as measured from space with no interference from other chemicals in the Earth's atmosphere - absorbs ultraviolet light so strongly.

Hubble recorded ozone absorbing some of the Sun's ultraviolet radiation that passed through the edge of Earth's atmosphere during a lunar eclipse that occurred on January 20 to 21, 2019. Several other ground-based telescopes also made spectroscopic observations at other wavelengths during the eclipse, searching for more of Earth's atmospheric ingredients, such as oxygen and methane.

"One of NASA's major goals is to identify planets that could support life," Youngblood said. "But how would we know a habitable or an uninhabited planet if we saw one? What would they look like with the techniques that astronomers have at their disposal for characterizing the atmospheres of exoplanets? That's why it's important to develop models of Earth's spectrum as a template for categorizing atmospheres on extrasolar planets."

Her paper is available online in The Astronomical Journal.

Sniffing Out Planetary Atmospheres

The atmospheres of some extrasolar planets can be probed if the alien world passes across the face of its parent star, an event called a transit. During a transit, starlight filters through the backlit exoplanet's atmosphere. (If viewed close up, the planet's silhouette would look like it had a thin, glowing "halo" around it caused by the illuminated atmosphere, just as Earth does when seen from space.)

Chemicals in the atmosphere leave their telltale signature by filtering out certain colors of starlight. Astronomers using Hubble pioneered this technique for probing exoplanets. This is particularly remarkable because extrasolar planets had not yet been discovered when Hubble was launched in 1990 and the space observatory was not initially designed for such experiments.

So far, astronomers have used Hubble to observe the atmospheres of gas giant planets and super-Earths (planets several times Earth's mass) that transit their stars. But terrestrial planets about the size of Earth are much smaller objects and their atmospheres are thinner, like the skin on an apple. Therefore, teasing out these signatures from Earth-sized exoplanets will be much harder.

That's why researchers will need space telescopes much larger than Hubble to collect the feeble starlight passing through these small planets' atmospheres during a transit. These telescopes will need to observe planets for a longer period, many dozens of hours, to build up a strong signal.

To prepare for these bigger telescopes, astronomers decided to conduct experiments on a much closer and only known inhabited terrestrial planet: Earth. Our planet's perfect alignment with the Sun and Moon during a total lunar eclipse mimics the geometry of a terrestrial planet transiting its star.

But the observations were also challenging because the Moon is very bright, and its surface is not a perfect reflector because it is mottled with bright and dark areas. The Moon is also so close to Earth that Hubble had to try and keep a steady eye on one select region, despite the Moon's motion relative to the space observatory. So, Youngblood's team had to account for the Moon's drift in their analysis.

Where There's Ozone, There's Life?

Finding ozone in the skies of a terrestrial extrasolar planet does not guarantee that life exists on the surface. "You would need other spectral signatures in addition to ozone to conclude that there was life on the planet, and these signatures cannot necessarily be seen in ultraviolet light," Youngblood said.

On Earth, ozone is formed naturally when oxygen in the Earth's atmosphere is exposed to strong concentrations of ultraviolet light. Ozone forms a blanket around Earth, protecting it from harsh ultraviolet rays.

"Photosynthesis might be the most productive metabolism that can evolve on any planet, because it is fueled by energy from starlight and uses cosmically abundant elements like water and carbon dioxide," said Giada Arney of NASA's Goddard Space Flight Center in Greenbelt, Maryland, a co-author of the science paper. "These necessary ingredients should be common on habitable planets."

Seasonal variability in the ozone signature also could indicate seasonal biological production of oxygen, just as it does with the growth seasons of plants on Earth.

But ozone can also be produced without the presence of life when nitrogen and oxygen are exposed to sunlight. To increase confidence that a given biosignature is truly produced by life, astronomers must search for combinations of biosignatures. A multiwavelength campaign is needed because each of the many biosignatures are more easily detected at wavelengths specific to those signatures.

"Astronomers will also have to take the developmental stage of the planet into account when looking at younger stars with young planets. If you wanted to detect oxygen or ozone from a planet similar to the early Earth, when there was less oxygen in our atmosphere, the spectral features in optical and infrared light aren't strong enough," Arney explained. "We think Earth had low concentrations of ozone before the mid-Proterozoic geological period (between roughly 2.0 billion to 0.7 billion years ago) when photosynthesis contributed to the build up of oxygen and ozone in the atmosphere to the levels we see today. But because the ultraviolet-light signature of ozone features is very strong, you would have a hope of detecting small amounts of ozone. The ultraviolet may therefore be the best wavelength for detecting photosynthetic life on low-oxygen exoplanets."

NASA has a forthcoming observatory called the James Webb Space Telescope that could make similar kinds of measurements in infrared light, with the potential to detect methane and oxygen in exoplanet atmospheres. Webb is currently scheduled to launch in 2021.

PROVIDENCE, R.I. [Brown University] -- Two federal environmental standards regulating lead hazards in homes and child care facilities have different maximum thresholds, a discrepancy putting more than 35,000 kids in the United States at increased risk of lead poisoning.

That's according to a new study led by a Brown University researcher as the U.S. Environmental Protection Agency (EPA) moves to revise protective standards for dust lead levels on floors and windowsills in buildings constructed before 1978. 

"Lead exposure presents a major risk to hundreds of thousands of children across the nation, and it's imperative that federal EPA regulations offer a clear and consistent standard to reduce that risk," said Joseph Braun, an associate professor of epidemiology at Brown. "Currently, these standards are counterproductive to public health."

In 2019, the EPA tightened the standard for the amount of residential dust lead considered hazardous to children from 40 micrograms per square foot (μg/ft2) to 10 on floors, and from 250 μg/ft2 to 100 on windowsills. The change came after a federal appeals court ordered the agency to reduce dust lead hazard standards after a 2016 lawsuit filed by environmental groups.

Traditionally, the residential standard had been the same as the clearance standard for dust lead levels after completing lead abatement work -- yet despite the more aggressive standard imposed after the court's order, the EPA left the post-abatement clearance standard where it has stood since 2001. Both standards fall under the Toxic Substances Control Act, which authorizes EPA to impose restrictions related to chemical substances.

Conceivably, a risk assessment could identify a dust lead hazard above 10 μg/ft2 but below 40 μg/ft2 on the floor of a home where there is a child with lead poisoning. Braun, an expert on children's environmental health, said an abatement contractor could theoretically do nothing, but given the discrepancy in standards, the unit would pass the clearance. 

"When I read this, initially, I thought this is absolutely crazy," Braun said. 

So Braun and his coauthors wanted to find out how many extra cases of lead poisoning would result from the post-abatement clearance standard being higher than the dust lead hazard standard. 

Their study, published on July 28 in Pediatric Research, found that children in homes with floor dust lead loadings between 10 and 40 μg/ft2 had nearly four times the risk of lead poisoning compared to children from homes with floor dust lead loadings at or under 10 μg/ft2. They estimated that 36,700 cases of childhood lead poisoning - nearly 7% of U.S. children between the ages of 1 and 5 with lead poisoning -- were attributable to this regulatory discrepancy. 

Dust from lead-based paint is a common cause of lead poisoning in young children, Braun said, and so the implications of the double standard are significant. Their greater hand-to-mouth behavior makes them vulnerable to lead exposure.

"I have a two-and-a half year old who puts everything in his mouth," Braun said. "That's how they explore their environment at this age."

Lead poisoning can cause learning disabilities and behavioral problems that last a lifetime and affect kids from all social and economic levels, though those living at or below the poverty line in older housing are at greatest risk. Earlier work by Braun and his colleagues found higher blood lead levels and risk of lead poisoning among Black children compared to white.

For the new study, the researchers looked at 250 children from Cincinnati living in homes built before 1978 -- the year lead-based paints were banned for residential use -- whose mothers participated in a longitudinal pregnancy and birth cohort study between 2003 and 2006. 

Researchers took samples of floor and interior windowsill dust lead loadings with wipes over a 1-square foot area when participants joined the study, when their children turned 1 year old and again when they turned 2. Blood samples were also collected from the children at these same times.

The study adds to a vast body of scientific research guiding housing and environmental policymakers. But Braun points out that the bulk of these studies were completed 20 and 30 years ago when lead exposure was much higher.

"The fact that we're still seeing these relationships at contemporary levels of lead exposure indicates that this is still a significant problem, so that's the real contribution here," Braun said.

The EPA has issued a proposed rule to align the post-abatement clearance standard with the tighter standard revised in 2019. Its two-month public comment period ends on Aug. 24. An EPA spokeswoman said Braun's study will be considered when developing a final rule along with all other feedback received.

Braun said the proposed change still won't go far enough to protect children. In 2012, the U.S. Centers for Disease Control and Prevention acknowledged there is no known safe blood lead level.

The study found children were at 45% higher risk of having blood poisoning at the newly revised floor dust lead hazards of 10 μg/ft2 compared to a more stringent standard of 5 μg/ft2.

"Reducing sources of lead exposure in children is imperative to optimize children's health," Braun said.