Culture

More than half of pregnant women recently admitted to a UK hospital with covid-19 infection were from black or other ethnic minority groups, finds a national surveillance study published by The BMJ today.

Most women had good outcomes, and transmission of covid-19 to infants was uncommon, but the researchers say the high proportion of women from black or minority ethnic groups admitted with infection "needs urgent investigation and explanation."

Published evidence on the rate, transmission, and effect of covid-19 infection in pregnancy remains limited, but evidence from other similar viral illnesses suggest that pregnant women and their babies are at greater risk of severe illness and death.

So a team of researchers, led by Professor Marian Knight from the Nuffield Department of Population Health, University of Oxford, set out to describe the characteristics and outcomes of pregnant women admitted to a UK hospital with covid-19, in order to inform ongoing guidance and management.

Their findings are based on data from the UK Obstetric Surveillance System (UKOSS) for pregnant women admitted to obstetric units in the UK with confirmed covid-19 infection between 1 March and 14 April 2020.

A total of 427 pregnant women were admitted to hospital with covid-19 during the study period. Most were in the late second or third trimester.

More than half (56%) were from black or other ethnic minority groups (25% of women were Asian and 22% were black), 70% were overweight or obese, 40% were aged 35 or over, and a third had pre-existing conditions.

Forty one (10%) of women needed respiratory support in a critical care unit, and five (1%) women died (three as a direct result of complications of covid-19 and two from other causes).

Twelve (5%) babies born to study mothers tested positive for covid-19, six of them within the first 12 hours after birth.

The high proportion of women from black and other minority ethnic groups admitted to hospital with covid-19 remained after excluding major urban centres from the analysis. This is of concern and should be investigated further, say the authors.

The researchers point to some study limitations that may have influenced their results. Nevertheless, they say these data suggest that most women do not have severe illness and that transmission of covid-19 to infants is uncommon. They also support guidance for continued social distancing measures in later pregnancy.

However, the high proportion of women from black or minority ethnic groups admitted with infection needs urgent investigation and explanation, they conclude.

A Roadmap to fast-track flourishing green roofs, walls and facades in Australian cities released today promotes six positive actioned based strategies to help grow green cities.

Researchers collaborating on the project also say the recommendations could provide a COVID-19 stimulus and support recovery.

A Roadmap for green roofs, walls and facades in Australia's urban landscapes 2020-2030 recommends establishing an industry Knowledge Hub, strong government leadership, policies combining incentives and regulation, and education and advocacy to ensure standards in design, installation and maintenance.

Compiled by the University of Melbourne and the UNSW Sydney with funding from HORT Innovation, it draws on the collective knowledge of over 60 experts in the building and horticultural industries, government agencies and universities.

Roadmap author, University of Melbourne Associate Professor Nick Williams, said while COVID-19 was not part of the core research, learnings from the pandemic illustrate the potential for green roofs, walls and facades on environmental, economic and social benefits, including adapting cities to climate change, bringing nature back to city centres for workers and residents, and importantly, creating jobs.

"The upheaval brought to the way we live and work by the pandemic is an opportunity for developers and building managers to rethink apartment and office building design.

"Rooftop and podium level green roofs, viewed through many building windows but easily accessible from lunch-rooms could help alleviate the high demand for inner city green space seen during the pandemic, and along with good hygiene practices help office workers feel safer in communal areas."

Co-author Professor Leisa Sargent, Senior Deputy Dean of the UNSW Business School added: "Retrofits of this type could receive a business tax incentive to stimulate the construction industry as they create workplaces that improve employee productivity and wellbeing.

"Green roofs, walls and facades require a diverse mix of professions and trades to build them and many jobs will be created as the sector grows. In Toronto, a 2009 bylaw that made green roofs mandatory on large new buildings is estimated to have created 1600+ jobs in their construction and 25 jobs annually to maintain them."

Australian cities are lagging behind many of their international counterparts in the implementation of these green infrastructure technologies but researchers point to the City of Melbourne as an example of government that promotes green cities and is tailoring policies to encourage green infrastructure via a planning scheme amendment, through its Green Our City Strategic Action Plan, and recently releasing a tool to measure and improve vegetation cover on new developments, particularly on private land.

"We want Melbourne to remain a place where people want to live and work. This means planning for a city with health and wellbeing of residents and workers front and centre," City of Melbourne Councillor Cathy Oke said.

"One way that we can do this is through designing in and encouraging more green spaces in our city. The City of Melbourne's Green Factor Tool will assist developers to increase greening within proposed new buildings, by measuring the quality and quantity of green infrastructure, such as green roofs, walls and gardens."

Jock Gammon, the managing director of Junglefy, one of Australia's leading living infrastructure companies and Roadmap contributor agrees.

"We don't want people to escape the city to enjoy the benefits nature brings. The adoption of living infrastructure helps create thriving, vibrant, healthy spaces where humans and nature intertwine," Mr Gammon said. "With limited opportunities to include nature in our cities due to urban density, there is a need, now more than ever to breathe life back into our cities."

A large study of middle-aged women shows that age-related changes in skeletal muscle are part of everyday life for women in their fifties. During this time, women transition from perimenopause to postmenopause and the production of estrogen ceases. Loss of estrogen has an effect on muscles and leads to a decline in muscle mass. Physical activity in all of its forms may help maintain muscle mass in midlife.

"We already knew that estrogen has a role in the regulation of muscle properties," says doctoral student Hanna-Kaarina Juppi. "By following the hormonal status, measuring many aspects of muscles and by taking into consideration the simultaneous chronological aging of women going through menopausal transition, we were able to show that the decrease of muscle mass takes place already in early postmenopause."

In the current study, muscle size was measured in the perimenopausal state and right after entering postmenopause, when menstruation had permanently stopped. Women were on average 51-and-a-half years old at the beginning of the study and 53 years old at the final measurements, so the average duration of menopausal transition was one-and-a-half years. The time it takes a woman to go through menopause is unique: in this study it varied from less than six months to more than three years. During this time, the decrease in muscle mass was on average one percent.

Juppi continues: "The observed change does not seem like much, but what is meaningful is that the decline happens in a short period of time and can have an impact on metabolism, as muscles are important regulators of whole-body metabolism."

Physical activity was found to be positively associated with the maintenance of muscle mass during the menopausal transition. Women who were more active had higher muscle mass before and after menopause compared to the less active women. It seems that even though menopause alone decreases muscle mass, staying physically active throughout middle age can help women to slow the change.

The current study was conducted in the Gerontology Research Center and Faculty of Sport and Health Sciences, and is part of a larger study, Estrogenic Regulation of Muscle Apoptosis (ERMA), led by Academy Research Fellow Eija Laakkonen. More than a thousand women between the ages of 47 and 55 from the Jyväskylä region participated in the ERMA study. At the beginning of the study, 381 of them were perimenopausal, while 234 reached early postmenopause during the study. The research was funded by the Academy of Finland and the European Commission.

Knowing what cancer will do next could lessen the likelihood of it becoming resistant to treatment. A new Canadian study investigates how cancer adapts its metabolism to potentially overcome therapies still in development.

"Several clinical trials have failed because metabolism is such an adaptive process by which cancer cells gain drug resistance," says Michael Aregger, a co-lead author and Research Associate working with Jason Moffat, Professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto, who co-led the work. "If you know how cells are able to adapt to perturbations, maybe we can target them more specifically to avoid resistance from developing."

The research was also led by Brenda Andrews and Charles Boone, University Professor and Professor of molecular genetics at the Donnelly Centre, respectively, and Chad Myers, a Professor of computer science at the University of Minnesota-Twin Cities.

The study, published in the journal Nature Metabolism, is the first to investigate global changes in cancerous cells as they adapt to a shortfall of critical nutrients such as fat molecules, or lipids, which make up the cell's outer envelope.

When cancer cells are unable to make their own lipids, they gobble them up from their environment to ensure a steady supply of these essential building blocks, the study found. Lipids also serve as fuel and chemical signals for communication between cells, among other roles.

The switch in metabolism could be bad news for drugmakers seeking to target cancer by reducing its lipid reserves. In particular, drugs that inhibit an enzyme called FASN, for fatty acid synthase, involved in an early step of lipid synthesis, are being explored in patient trials. Fatty acids are precursors of larger lipid molecules and their production is increased in many cancers thanks to elevated FASN levels, which are also associated with poor patient prognosis.

The U of T study suggests that the effectiveness of FASN inhibitors could be short-lived owing to cancer's ability to find another way to procure lipids.

"Because FASN is upregulated in many cancers, fatty acid synthesis is one of the most promising metabolic pathways to target" says Keith Lawson, a co-lead author and PhD student in Moffat's lab enrolled in the Surgeon-Scientist Program at the Faculty of Medicine. "Given that we know there is a lot of plasticity in metabolic processes, we wanted to identify and predict ways in which cancer cells can potentially overcome the inhibition of lipid synthesis."

To block fatty acid synthesis, the researchers employed a human cell line from which the FASN coding gene was removed. Using the genome editing tool CRISPR, they deleted from these cells all ~18,000 or so human genes, one by one, to find those that can compensate for the halt in lipid production. Such functional relationships are also referred to as 'genetic interactions'.

Data analysis, performed by Maximilian Billmann, a co-lead author and a postdoctoral fellow in Myers' lab at Minnesota-Twin Cities, revealed hundreds of genes that become essential when cells are starved of fat. Their protein products clustered into well-known metabolic pathways through which cells hoover up dietary cholesterol and other lipids from their surroundings.

Cells' intake of cholesterol has become textbook knowledge since it was discovered half a century ago, winning a Nobel Prize and inspiring the blockbuster drug statin and many others. But the new study found that one component of this process remained overlooked all this time.

The gene encoding it was only known as C12orf49, named after its location on chromosome 12. The researchers re-named the gene LUR1, for lipid uptake regulator 1, and showed that it helps switch on a set of genes directly involved in lipid import.

"This was a big surprise to us that we were able to identify a new component of the process we thought we knew everything about," says Aregger. "It really highlights the power of our global genetic interaction approach that allowed us to identify a new player in lipid uptake in a completely unbiased way."

By a remarkable coincidence, two groups working independently in New York and Amsterdam also linked C12orf49 to lipid metabolism, lending further support for the gene's role in this process. The New York team published their findings in the same journal issue as Moffat and colleagues.

Inhibiting LUR1, or other components of lipid import, along with FASN could lead to more effective cancer treatments. Such combination therapies are thought to be less susceptible to emerging drug resistance because the cells would have to simultaneously overcome two obstacles--blocked lipid production and import--which has a lower probability of occurring.

"Therapeutic context that comes out of our work is that you should be targeting lipid uptake in addition to targeting lipid synthesis and our work highlights some specific genes that could be candidates," says Lawson.

As co-author, Research Associate Ayrat Bilyalov explains, the work on photodynamic therapy has been ongoing for 5 years. The group comprises medical professionals from Kazan Federal University and Medical Center of the Presidential Administration of Kazakhstan.

Photodynamic therapy (PDT) is one of the most promising methods of treating localized tumors. PDT can be used for treatment in almost all major locations as an independent method or in combination with traditional types of treatment (surgery, radiation, and chemotherapy). Depending on the stage, nature and form of tumor growth, various laser irradiation options have been developed to increase the effectiveness of photodynamic therapy.

The method is based on the introduction of photosensitizers into the patient's body that selectively accumulate in the tumor tissue. The main idea of this method is to produce singlet oxygen and other active radicals to destroy tumor cells.

In addition to the direct phototoxic effect on tumor cells, in photodynamic therapy, an important role in the destruction mechanism is also played by a reduction in the blood supply to the tumor tissue caused by damage to the endothelium and blood vessel thrombosis, and cytokine reactions caused by stimulation of the production of tumor necrosis factor, interleukins, activation of macrophages and leukocytes.

The results of clinical and preclinical trials prove that PDT can be used in many types and localizations of tumors.

A quarter of a century has passed since the beginning of widespread clinical use of photodynamic therapy in Russia, but clear and unambiguous treatment recommendations are not yet available. Limited possibilities of using photodynamic therapy as a part of high-tech medical care program and high costs of photosensitizers in most cases are the obstacles to the full implementation of the method in cancer centers.

A potential direction for the development of this technique is the search for new photosensitizers and the expansion of indications for the use of PDT. A patent for fluorescent diagnostics of parathyroid tumors has already been obtained, and clinical trials are planned to study the effectiveness of PDT in a number of new locations of malignant tumors (bladder cancer, primary and metastatic liver cancer, localized and disseminated melanoma, etc.).

By generalizing a classical statistical model and adapting it for use in analyzing the extremes of rainfall in large datasets, researchers, including KAUST's Raphaël Huser, have devised a more efficient and flexible analytical tool that promises to improve the prediction of flood risk and other extreme weather phenomena.

Rare extreme weather events, such as floods, extreme winds, high temperatures and drought, can be devastating, but predicting the frequency and severity of such conditions remains one of the key challenges in statistical science. Even large, long-term data sets over extensive areas may include very few extreme events, making it exceptionally difficult to predict future events with accuracy.

"There are classically two ways to model extreme events, the 'block maximum' approach, where we look at the largest events in blocks of time and the 'threshold exceedance' approach, which selects the top few percent of events across the entire timeframe of the dataset," explains Huser, who undertook the work in collaboration with U.S.-based colleagues Gregory Bopp and Benjamin Shaby. "Previous work has developed new tools to apply the threshold exceedance approach; in this study we generalized a classical block maximum model for application to extreme precipitation."

The block maximum approach has a long tradition in the statistics of extremes, but it has a high computational cost that limits its application to the large-scale datasets now routinely acquired in weather prediction. This approach is also unable to capture the observed weakening of the dependence between nearby conditions as events become more extreme.

The team's approach addresses both of these shortcomings by adapting a relatively inflexible, but computationally efficient, max-stable model using Bayesian inference, which is a statistical estimation approach that provides a natural way of incorporating expert opinion and accounting for various sources of variability.

"Our Bayesian model has a lot of parameters and hidden random effects, which need to be jointly estimated," says Huser. "Beyond the computational challenge, simply developing the model itself and deriving its theoretical properties was a major challenge. There is a reason why classical max-stable models have been used extensively for a long time--it is not straightforward to generalize them and come up with more realistic and flexible models."

The model was able to capture the observed patterns in extreme precipitation events occurring along the coast and mountain range borders in northeast America, demonstrating its potential for predicting flood risk.

"Our model could also easily be adapted to other types of environmental datasets, such as wind and temperature, giving it very wide applicability," notes Huser.

71 patients with severe lung injury were admitted to four intensive care units at Bordeaux University Hospital and their data were collected and evaluated over a period of six weeks (March/April 2020). AKI was defined using KDIGO criteria and ADQI according to the Acute Disease Quality Initiative (ADQI) 16 workgroup.

On admission as in-patients, patients' basal serum creatinine was 69±21 μmol/l on average (normal is up to 100 μmol/l, approximately, depending on test procedure); AKI was present in 8/71 patients (11%) at that time. The median follow-up was 17 (12-23) days; AKI developed in a total of 57/71 patients (80%), with 35% Stage 1, 35% Stage 2 and 30% Stage 3; of those patients, 18% (10/57) required renal replacement therapy (dialysis). Two of the 57 patients died within the first 72 hours. After three days, creatinine had fallen again in four of the remaining 55 patients (7%), indicating transient AKI. 51/55 patients (93%) had persistent AKI with increased protein excretion [median urinary protein/creatinine ratio of 82 (54-140) mg/mmol and albuminuria/proteinuria ratio of 0.23±20] - indicating predominantly tubulo-interstitial injury. Only two patients (4%) had elevated glucose excretion (glycosuria). Seven days after AKI development, six patients (11%) were still on dialysis, nine (16%) had serum creatinine >200 μmol/l, and a further four (7%) had died. Renal recovery occurred in 28% after seven days and in 52% after 14 days.

Reports from China indicate acute kidney injury in up to 15% of intensive-care COVID-19 patients [2], the kidney being the second most frequently damaged organ. In the U.S.A., AKI is observed in 20% of subjects [3]. The authors' hypothesis that these figures could be significantly higher in Western Europe was strongly verified by the study.

"Kidney involvement in critically ill COVID-19 patients was very common, at 80%, with AKI lasting longer than three days in most cases and almost one in five of those having to be dialyzed," commented Dr. Sébastien Rubin, Bordeaux. "This high rate of COVID-19-associated AKI cases is startling and shows how renotropic this novel virus can be."

"10% (6/57) of patients with AKI died and almost half the patients had still not shown renal recovery even after two weeks. That is, they had AKD", is a point emphasized by Professor Alberto Ortiz, editor-in-chief of CKJ, the official open access journal of the ERA-EDTA. "This study underscores the importance of follow-up nephrological care of patients after discharge from hospital. It is well known that AKI patients have a higher risk of developing CKD and ESRD later on, and good nephrological follow-up can prevent or at least slowdown that process."

Muskrat populations declined sharply across North America over the last 50 years or so, and wildlife scientists have struggled to understand why. A Pennsylvania research team investigated whether pathogens, parasites, environmental contaminants and disease may be contributing to this decline.

Trappers saw steep declines in muskrat harvest throughout the animal's native range, with decreases exceeding 50% in some states, according to David Walter, Penn State adjunct assistant professor of wildlife ecology in the College of Agricultural Sciences. In Pennsylvania, for example, according to the state Game Commission, the muskrat harvest declined from 720,000 in 1983 to 58,295 in 2010.

"Some of that decline can be attributed to a reduction in trapping activity, but clearly the muskrat population is significantly smaller than it used to be," he said. "A number of theories to explain the widespread muskrat declines have been proposed, including habitat loss, predation, environmental contamination and diseases. In this study, we examine a number of those possibilities."

To analyze trends in muskrat mortality, researchers pored over 131 articles, published from 1915 to 2019, from 27 U.S. states and nine Canadian provinces that contained information about muskrat exposure to diseases and contaminants and mortality events. Information collected from articles included; year of survey; location of survey; methodology; number of animals surveyed; pathogen or contaminant identities; and the presence or absence of associated disease, as evidenced by reported clinical signs or lesions.

Among the common factors reported associated with muskrat infections or mortality in some cases were: viruses including canine distemper virus, rabies and Aleutian mink disease virus; a variety of fungal infections; ailments such as tularemia and Tyzzer's disease; cyanobacteria, possibly indicating the presence of toxic algae; parasites including protozoans, trematodes, cestodes, nematodes and ectoparasites such as ticks; toxins, including heavy metals from industrial discharges and lead from ammunition deposits; and agricultural-related contaminants including pesticides, herbicides and insecticides.

Because of the wide range of differences in how the many authors had collected information about the factors in muskrat deaths, the researchers were unable to draw solid conclusions about which pathogens or contaminants may be contributing to declining muskrat populations. However, the findings, recently published in Frontiers in Veterinary Science, were the first holistic review of muskrat mortality ever compiled.

The study provides a baseline for understanding the potential role of pathogens, contaminants, parasites and diseases in the declines of muskrat populations across North America, noted lead researcher Laken Ganoe, who conducted the work as part of her master's degree thesis in wildlife and fisheries science.

"These data highlight critical knowledge gaps about muskrat health investigations and the circumstances surrounding and contributing to their decline that warrant future research efforts," she said. "There is still much that we do not understand about why muskrats are disappearing, and to protect them into the future we need to better understand not only disease dynamics, but how other factors such as ecosystem dynamics and climatic factors are playing a role as well."

In earlier research, done in collaboration with the Pennsylvania Game Commission, Ganoe collected muskrat carcasses from Pennsylvania trappers and conducted necropsies to develop a snapshot of muskrat health and exposure in the state, which included tissue sample collection and screening for a wide variety of pathogens and contaminants. She also captured muskrats, surgically implanted them with radio transmitters and then tracked them using radio telemetry, to determine their movement patterns, home range size and survival.

Key Takeaways:

The practice of pharmaceutical companies paying doctors as consultants has created longstanding concerns over possible conflicts of interest

New research has found that disclosure laws intended to shed "light" on the practice have served to discourage certain levels of prescriptions in the three categories studied

Disclosure laws resulted in a decline of the prescription of certain branded medications from 31 - 56 percent

Surprisingly, the prescription of generics in the same classes also declined from 25-33 percent.

CATONSVILLE, MD, June 8, 2020 - It's not uncommon for U.S. pharmaceutical companies to pay medical doctors to promote their medications. Questions over possible conflicts of interest have led to introduction of laws that require payment disclosure so that the public can see which pharmaceutical companies are paying which doctors.

Researchers studied the impact of payment disclosure laws in Massachusetts and compared that impact with neighboring states that do not have such laws to determine whether the laws are making a difference.

They found that the Massachusetts disclosure law did result in a decline in prescriptions in all three drug classes studied: statins, antidepressants and antipsychotics.

The research study, to be published in the June edition of the INFORMS journal Marketing Science, is titled "Let the Sunshine In": The Impact of Industry Payment Disclosure on Physician Prescription Behavior. It is authored by Tong Guo of Duke University, and S. Sriram and Puneet Manchanda of the University of Michigan.

"U.S. pharmaceutical companies spent more than $6 billion as marketing payments to physicians between 2013 and 2015," said Guo. "The long-held financial relationship between the industry and the clinical practice has led some states to create disclosure laws on the assumption that disclosure of the payments would increase public scrutiny and persuade firms to decrease such payments or cause physicians to prescribe certain medicines more conservatively, or switch to less expensive generic alternatives."

The INFORMS Marketing Science journal article reported that state lawmakers believed that through enhanced disclosure, some physicians also may be less willing to accept marketing payments from drug companies, or they would be more motivated to switch from prescribing branded drugs to generic ones.

"Our study examined the Massachusetts open payment law that went into effect in July 2009 to determine how physician prescription behavior changed as a result," said Manchanda. "We used outpatient prescription information at the claim level during a six-year period, from January 2006 through December 2011."

Study co-author Sriram added, "Our results revealed that, on average, the disclosure law resulted in a decline in the prescription of branded drugs in Massachusetts. Specifically, the intervention led to a 46-54 percent decrease for branded statins, a 50-56 percent decrease for branded antidepressants, and a 31-32 percent decrease for branded antipsychotics, when we considered physicians in the state of Massachusetts, and then compared their patterns with those of physicians in neighboring states."

"Although less pronounced, the prescriptions of generic drugs in all three drug classes also declined as a result of the disclosure, suggesting an overall decline in prescriptions in these three categories. As generic drug manufacturers do not usually make payments to physicians, we conjecture that the reduction in prescriptions was likely driven by self-monitoring among physicians to curb "over-diagnosis" rather than changes in how firms deliver payments."

Charcot-Marie-Tooth (CMT) disease is the most common form of inherited neuropathies. A genetic mutation causes the insulating myelin layer of peripheral nerves to become progressively damaged, resulting in severe disabilities in the case of CMT type 4B, for instance. Since the molecular basis is largely unknown, this type of CMT is untreatable and incurable to this day. Now researchers from the Leibniz-Forschungsinstitut fuer Molekulare Pharmakologie (FMP) in Berlin, in collaboration with colleagues from Milan, Paris and Mexico, have been able to highlight a new molecular mechanism: According to their discovery, the protein Rab35 and the mTOR signaling pathway it regulates play a central role in the formation of myelin sheaths in the peripheral nervous system. First in-vivo experiments show that new therapies can be derived from the findings. The work has now been published in the prestigious journal Nature Communications.

Many of our nerve cords (axons) are enveloped by a myelin sheath, which ensures that signals can be sent near instantaneously from the brain to muscles and organs. However, genetically programmed defects in myelination occur among the broad group of inherited neuropathies, disrupting this signaling process. This results in the onset of a variety of neurological deficits occurring in peripheral nerves and the degeneration of the nerve cords. This is the case with Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy. CMT type 4B is characterized by a very early onset of the disease; sufferers are often already confined to a wheelchair in their teens. In the worst case, neurodegeneration spreads to the respiratory tract, which can lead to death by respiratory failure. At present, there is no prospect of a cure.

Unexpected interaction partners

It is therefore all the more important to explore the largely unknown molecular mechanisms of the disease. This is exactly what scientists from the Leibniz-Forschungsinstitut fuer Molekulare Pharmakologie (FMP) in Berlin have done, in collaboration with teams of researchers led by Professor Alessandra Bolino (IRCCS Ospedale San Raffaele University, Milan), Professor Arnaud Echard (Sorbonne Université / Institut Pasteur, Paris) and Professor Genaro Patino-Lopez (Hospital Infantil, Mexico).

Researching the protein Rab35, the Berlin team led by Linda Sawade and Professor Volker Haucke discovered more or less by chance that this small GTPase, which is involved in the regulation of intracellular membrane transport, interacts with three proteins associated with CMT 4B: Owing to a gene mutation, MTMR2, MTMR5 and MTMR13 do not function properly in CMT 4B patients, or they are completely lacking.

These three critical proteins belong to the group of myotubularin-related (MTMR) phosphatidylinositol (PI) phosphatases that specifically hydrolyze the endosomal signaling lipids PI(3)P and PI(3,5)P2 at the 3'-phosphate group, i.e. they remove phosphates from lipids.

Rab35 regulates myelin sheath formation

"Our study revealed that the protein Rab35 regulates the longitudinal growth of the myelin sheath by binding and recruiting the two pseudophosphatases MTMR13 and MTMR5, and hence, also the active phosphatase MTMR2 bound to it in a complex," reported Linda Sawade, lead author of the study.

The new finding was that Rab35 binds this lipid phosphatase complex, and therefore plays a key role in regulating myelin sheath formation. The detection was confirmed in knock-out micethat specifically lack the Rab35 protein in Schwann cells - the cells in the peripheral nervous system that form myelin sheaths. Loss of the Rab35 protein led to the abnormalities and, eventually, the degenerative destruction (demyelination) of myelin sheaths in the sciatic nerve.

Inhibition of mTORC1 proves effective

Coincidentally, the researchers observed an abnormally elevated activity of the mTORC1 signaling pathway- one of the central signaling complexes for regulating myelin sheath formation in nerve tissue. Pharmacological inhibition of the hyperactive mTORC1 signaling complex using the drug Rapamycin partially rescued nerve damage in knock-out mice. Further experiments on cultured cells in which Rab35 expression had been suppressed confirmed the positive effects of mTORC1 inhibition on defective myelin sheaths.

The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P2 lipids. "We assume that this pathological process results from an impaired recruitment of MTMR complexes," explained biochemist and cell biologist Linda Sawade. "Conversely, this would mean that Rab35 normally suppresses the activity of mTORC1 by recruiting MTMR phosphatases to lysosomes."

Findings have an impact beyond basic research

In a nutshell, the results have a great impact for basic research: Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1.

The results also offer a glimmer of hope to CMT4B patients: Therapeutic treatment using mTORC1-inhibiting drugs such as Rapamycin could improve disease progression. It would be the first treatment option for this serious condition.

Group leader Professor Dr. Volker Haucke: "Our work has led to the discovery of a new molecular mechanism in a particularly severe form of inherited neuropathy that is highly clinically relevant and that we now want to explore in greater depth with the Milan team led by Alessandra Bolino."

The intestinal epithelium is the inner layer of the intestinal wall, which separates host tissue from the intestinal microbiota. This layer of cells plays a crucial role in water, electrolyte and nutrient absorption, while limiting the entry of bacteria, viruses, fungi, toxins and antigens into host tissue to ensure intestinal homeostasis. The diverse functions carried out by the intestinal epithelium are supported by multiple specialised intestinal epithelial cells, which are replaced every three to five days from a pool of intestinal stem cells. This makes the intestinal epithelium one of the most rapidly renewing tissues in adult mammals.

Which pathways govern intestinal epithelial differentiation under constitutive conditions? Epithelial differentiation is largely controlled by the tissue-specific activity of transcription factors. Access to DNA is provided by accessible chromatin (euchromatin), while compacted heterochromatin limits access of transcription factors to DNA. Researchers at the TU Dresden Center for Regenerative Therapies (CRTD) have now investigated the significance of the regulation of heterochromatin formation in the intestinal epithelium and published their findings in the renowned international scientific journal Gut.

In their study, Prof. Sebastian Zeißig's team demonstrated the essential role of the SETDB1 protein involved in heterochromatin formation during intestinal epithelial cells differentiation, and its importance in preventing inflammation. The scientists observed in mice the consequences of the enzyme loss in the intestinal stem cells: Endogenous retroviruses, which represent a relevant part of the human genome, accumulate within a few days, which leads to DNA damage, inflammatory cell death, and loss of intestinal epithelial stem cells as well as of differentiated epithelial cells. This limits the absorption of fluid and nutrients, causes intestinal inflammation and inevitably leads to death within a few days.

"Our study reveals a fundamental importance of SETDB1 and heterochromatin formation in the maintenance of epithelial genome stability and the control of intestinal homeostasis," explains Prof Sebastian Zeißig, CRTD research group leader and physician at the Medical Clinic I of the University Hospital Carl Gustav Carus Dresden. "It remains to be seen whether mutations in this gene can also contribute to intestinal inflammation in humans, for example, in inflammatory bowel diseases."

Researchers from Russia, Germany, Finland and the U.S. have studied more than 300 quasars -- spinning black holes that produce beams of plasma. The team has found that the shape of these so-called astrophysical jets changes from parabolic to conical at some distance from the black hole, reminiscent of the iconic flared jeans of the '70s. By effectively measuring these "cosmic pants," the researchers aim to interpret the workings of the central engine that accelerates matter to nearly the speed of light at the centers of remote active galaxies. The study is reported in the Monthly Notices of the Royal Astronomical Society.

Beacons of the universe

Quasars are among the brightest objects in the universe, despite being billions of light years away from the Earth. They are sometimes called beacons, and what they help us navigate is not only the remote cosmic past and intricate structure of the universe, but our own planet, too. Because they are so remote, quasars can be used as stable reference points in the sky for measuring the Earth's rotation and the coordinates of objects on the planet's surface. This principle underlies GPS, GLONASS, and other positioning systems.

A quasar is so bright it can be discerned from an enormous distance. Shown in figure 1, it hosts a spinning supermassive black hole that weighs up to several billion times as much as our sun. Matter around the black hole falls onto it, carrying a magnetic field. The field lines are akin to wires with charged particles strung on them like beads. Figure 2 illustrates that as the magnetic field lines rotate, plasma accelerates to nearly the speed of light. The resulting outflows are called astrophysical jets, and it is because of them that quasars are such dazzling objects.

Reaching for the sky

Astronomers have previously thought that almost every jet is shaped like a narrow cone, expanding sideways after it leaves the black hole region.

After observing hundreds of quasars for two decades via a network of radio telescopes scattered around the globe, the authors of the new study have challenged this assumption. They produced images of over 300 quasar jets monitored by the MOJAVE program and ran an automated analysis of their shapes. As a result, the team discovered 10 quasars with parabola-shaped jets evolving into cones. This transformation could be discerned owing to the relative proximity of the quasars involved: Each of the 10 turned out to lie "mere" millions of light years away. The "bootleg flaring" occurred at a distance of roughly several dozen light years from the black hole.

"The mechanism behind the formation and acceleration of jets in remote active galaxies has not been fully understood so far, yet it is crucial that we figure out how these cosmic accelerators work," said Professor Yuri Kovalev from the Moscow Institute of Physics and Technology (MIPT) and Lebedev Physical Institute of the Russian Academy of Sciences.

"The region where jets originate is difficult to discern. It is very compact, and the distance to these objects is so great that everything blurs together. So while multiple theoretical models were available, there were no observational data to test them against. Our study is the first to report the detailed geometry of jets based on observations of large numbers of quasars," the astrophysicist added.

Comprehending the unseen

The geometry of the jet results from an intricate interplay between the internal and external forces, the magnetic field, the plasma, and the interstellar gas. The astrophysicists found an elegant way to account for these factors. A central engine consisting of a spinning black hole and a magnetic field provides a limited power supply and cannot push particles to higher and higher velocities indefinitely, just like a rocket engine. It was known before that plasma speeds up easily only up to a certain point. After that the acceleration is so slow it effectively stops. It is at this point that the pants flare.

"Earlier studies pointed to the shift in quasar jet shape observed in a few galaxies. However, they did not draw the conclusion that it was a property of all quasars rather than the individual objects concerned. We have pinned this effect on the internal characteristics of jets, and that explanation turned out to be neat and intuitive," commented Dr. Elena Nokhrina from MIPT.

Scientists now have a new way to evaluate the speed of black hole rotation and make sense of the mechanism behind the formation of the incredibly focused and rapid jets of plasma in quasars, which are so bright they are visible from billions of light years away.

One of the key objectives for contemporary chemistry is to improve thermomechanical properties of polymers, in particular, thermostability of bioplastics.

In this paper, the team concentrated on researching oligomer and polymer materials with macrocyclic compounds characterized by enhanced thermostability. "Such products have lower vitrification temperatures, which makes them more malleable in comparison with commercial polylactic acid," says co-author, Research Associate Pavel Padnya.

Polycondensation products of lactic acid (poly- and oligolactides) are of great interest for targeted drug delivery and implant design. A width of the range of their applications is due to a number of practically important properties, such as biocompatibility and biodegradability, non-toxicity and mechanical strength.

"Modification of the obtained polymers with various additives can improve their properties and expand possible applications. One of the strategies to increase the stability of materials in biological media and to make drug loading possible is to obtain branched, or, as they are called, star-shaped polymers," explains Padnya.

"We've been working on this topic for five years thanks to Russian Science Foundation's funding. We have had some non-trivial results for biodegradable polymers," adds team leader, Professor Ivan Stoikov.

In the course of the study, new functional star-shaped polymers of lactic acid were obtained. Researchers chose macrocyclic compounds, thiacalixarenes, as the "crosslinking units" of polymer chains. An important result of this work is that the dependence of the structure of the obtained oligo- and polymer products on the synthesis temperature and the nature of the solvents used, as well as on the spatial structures selected for the "crosslinking" of chains of macrocyclic compounds, was established.

This development can have a significant impact on the use of polymers in medicine: it turned out that the obtained compounds have an affinity for a certain type of xanthene dyes - a means for medical diagnostics and the study of biochemical processes in cells.

In October 2015, a spectacular rockfall occurred in the Swiss Alps: in the late morning hours, a large, snow-covered block with a volume of more than 1500 cubic meters suddenly detached from the summit of Mel de la Niva. It fell apart on its way downslope, but a number of boulders continued their journey into the valley. One of the large boulders came to a halt at the foot of the summit next to a mountain hut, after travelling more than 1.4 kilometers and cutting through woods and meadows.

On the Moon, time and again boulders and blocks of rock travel downslope, leaving behind impressive tracks, a phenomenon that has been observed since the first unmanned flights to the Moon in the 1960s. During the Apollo missions, astronauts examined a few such tracks on site and returned displaced rock block samples to Earth. However, until a few years ago, it remained difficult to gain an overview of how widespread such rock movements are and where exactly they occur.

Researchers at the Max Planck Institute for Solar System Research (MPS) in Germany and ETH Zurich have analyzed an archive of more than two million images of the lunar surface and present the first global map of rockfalls on the Moon in today's edition of Nature Communications.

"The vast majority of displaced boulders on the Moon have a diameter of between seven and ten meters," explains Valentin Bickel of MPS and ETH Zurich, first author of the new study. "Earlier space probes that have studied the Moon were unable to detect such small features on a global scale," he adds. It was not until 2010, with the launch of NASA's Lunar Reconnaissance Orbiter, that imagery of the entire lunar surface, with the necessary spatial resolution and coverage, has been available.

The result is a map of the lunar surface between 80 degrees northern and southern latitude that shows 136,610 rockfalls with diameters of more than two and a half meters. "For the first time, this map enables us to systematically analyze the occurrence and causes of rockfalls on another celestial body", says Dr. Urs Mall from MPS.

Previously, scientists had assumed that lunar quakes in particular were responsible for the displacement of boulders. The new global map of rockfalls indicates that impacts from asteroids may play a much more important role. They are apparently - directly or indirectly - responsible for more than 80 percent of all observed rockfalls.

"Most of the rockfalls are found near crater walls," says Prof. Dr. Simon Loew of ETH Zurich. Some of the boulders are displaced soon after the impact, others much later. The researchers hypothesize that impacts cause a network of cracks that extend in the underlying bedrock. Parts of the surface can thus become unstable even after very long periods of time.

Surprisingly, even in the oldest lunar landscapes, which formed up to 4 billion years ago or even earlier, traces of rockfall events can be found. Since such imprints would typically disappear after a few million years, these surfaces are apparently still subject to erosion through rockfall, even billions of years after they were formed.

"Apparently, impacts influence and modify the geology of a region over very, very long time scales," says Bickel. The results also suggest that very old surfaces on other airless bodies such as Mercury or the large asteroid Vesta may still be evolving as well.

Mount Sinai researchers have found that myocardial injury (heart damage) is prevalent among patients hospitalized with COVID-19 and is associated with higher risk of mortality. More specifically, a serious myocardial injury can triple the risk of death. The results were published in the June 5 issue of the Journal of the American College of Cardiology.

“There has been a lot of speculation about how COVID-19 affects the heart and blood vessels, and with what frequency. Our observational study may help to shed some light on this. We found that 36 percent of patients who were hospitalized with COVID-19 had elevated troponin levels—which represents heart injury—and were at higher risk of death,” says lead author Anu Lala, MD, Assistant Professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai. “These findings, which are consistent with reports from China and Europe, are important for clinicians. If COVID-19-positive patients arrive in the emergency room and their initial test results show troponin levels are elevated, doctors may be able to better triage these patients and watch over them more closely, but this remains a testable hypothesis.”

A team of investigators analyzed electronic health records of nearly 3,000 adult patients with confirmed positive COVID-19 admitted to five New York City hospitals within the Mount Sinai Health System between February 27 and April 12, 2020 (The Mount Sinai Hospital, Mount Sinai West, Mount Sinai Morningside, Mount Sinai Queens, and Mount Sinai Brooklyn). The median age for patients analyzed was 66, and roughly 60 percent were male. One-quarter of all patients self-identified as African American, and 27 percent self-identified as Hispanic or Latino. Roughly 25 percent of the patients had a history of heart disease (including coronary artery disease, atrial fibrillation and heart failure) and roughly 25 percent had cardiovascular disease risk factors (including diabetes or hypertension).

Mount Sinai researchers found that 36 percent of hospitalized COVID-19 patients had myocardial injury. For those with substantial injury, their risk of death was three times higher than COVID-19-positive patients without myocardial injury.

To get this information, researchers focused on the patients’ levels of troponin—proteins that are released when the heart muscle becomes damaged—and their outcomes. (Higher troponin levels mean greater heart damage.) All patients had a blood test for this within 24 hours of admission and were grouped into three categories: 64 percent were in the normal range (0.00-0.03 ng/mL); 17 percent had mild elevation (between one and three times the upper limit of normal, or >0.03-0.09 ng/mL), and 19 percent had higher elevation (more than three times the upper limit of normal, or >0.09 ng/mL). Higher troponin levels were more prevalent in patients who were over 70 years old and had previously known conditions including diabetes, high blood pressure, atrial fibrillation, coronary artery disease and heart failure. Researchers made adjustments for these factors in the analysis.

Then, they analyzed the associated risk of death after adjusting for factors including age, sex, body mass index, history of cardiovascular disease, medication, and illness at hospital admission. They found patients with milder forms of myocardial injury were associated with lower likelihood of hospital discharge and a 75 percent higher risk of death compared to patients with normal levels. Patients with higher troponin concentrations were associated with a three times higher risk of death compared to those with normal levels. Additionally, when adjusting for relevant factors including heart disease, diabetes and high blood pressure, troponin was independently associated with risk of death. More specifically, heart injury seems to be a more important indicator in predicting risk of death than a history of heart disease.

“The study concludes that myocardial injury is common among patients hospitalized with COVID -19 but is more often mild and associated with low-level troponin elevation. Despite low levels, even small amounts of heart injury could be linked to a pronounced risk of death, and COVID-19 patients with a history of cardiovascular disease are more likely to have myocardial injury when compared to patients without heart disease,” explains Dr. Lala.

“Myocardial injury is frequent in COVID-19 patients, but the question is what is the main etiology? Is this by direct effect of the virus into the myocardium, or is it an indirect effect of the cytokine storm also into the myocardium, or a procoagulant causing coronary thrombotic ischemia? These are questions that need to be addressed in future studies,” says senior author Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital. “Additionally, we now need to follow COVID-19 patients with myocardial injury to learn more about the consequences.”