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Scientists at Washington University School of Medicine in St. Louis have developed a chemical compound that interferes with a key feature of many viruses that allows the viruses to invade human cells. The compound, called MM3122, was studied in cells and mice and holds promise as a new way to prevent infection or reduce the severity of COVID-19 if given early in the course of an infection, according to the researchers.
In an interesting twist, the compound targets a key human protein called transmembrane serine protease 2 (TMPRSS2) that coronaviruses harness to enter and infect human cells.
The study is published online Oct. 11 in the Proceedings of the National Academy of Sciences.
“Great vaccines are now available for SARS-CoV-2, but we still need effective antiviral medications to help curb the severity of this pandemic,” said senior author James W. Janetka, PhD, a professor of biochemistry & molecular biophysics. “The compound we’re developing prevents the virus from entering cells. We are examining the therapeutic window within which the molecule can be administered to mice and protect them from disease. Our ultimate goal is to advance the molecules into an inhibitor that can be taken by mouth and that could become an effective part of our armamentarium of inhibitors of COVID-19.”
The new drug compound potently blocks TMPRSS2 and another related protein called matriptase, which are found on the surface of the lung and other cells. Many viruses — including SARS-CoV-2, which causes COVID-19, as well as other coronaviruses and influenza — depend on these proteins to infect cells and spread throughout the lung. After the virus latches onto a cell in the airway epithelia, the human protein TMPRSS2 cuts the virus’s spike protein, activating the spike protein to mediate fusion of the viral and cellular membranes, initiating the process of infection. MM3122 is blocking the enzymatic activity of human protein TMPRSS2. When the enzyme is blocked, it perturbs the activation of the spike protein and suppresses membrane fusion.
“The SARS-CoV-2 virus hijacks our own lung cells’ machinery to activate its spike protein, which enables it to bind to and invade lung cells,” Janetka said. “In blocking TMPRSS2, the drug prevents the virus from entering other cells within the body or from invading the lung cells in the first place if, in theory, it could be taken as a preventive. We’re now testing this compound in mice in combination with other treatments that target other key parts of the virus in efforts to develop an effective broad-spectrum antiviral therapy that would be useful in COVID-19 and other viral infections.”
Studying cells growing in the lab that were infected with SARS-CoV-2, MM3122 protected the cells from viral damage much better than remdesivir, a treatment already approved by the Food and Drug Administration for patients with COVID-19. An acute safety test in mice showed that large doses of the compound given for seven days did not cause any noticeable problems. The researchers also showed that the compound was as effective against the original Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV).

Cervical cancer screening saves lives — no one disputes that.
But University of New Mexico researchers have found that many women are screened too often, leading to unnecessary procedures that may carry their own harms, while some women are not getting tested often enough, putting them at higher risk for poor outcomes.
The team led by Cosette Wheeler, PhD, Regent’s Professor in the UNM Department of Pathology and director of the Center for HPV Protection at the UNM Comprehensive Cancer Center, looked at compliance with updated national guidelines for cervical cancer screening issued in 2012.
The new recommendations for women aged 30-64 at average risk for cervical cancer called for co-testing for human papillomavirus (HPV) and liquid-based cytology — an updated version of the traditional Pap smear — every five years, or every three years for cytology alone.
The researchers studied statewide data collected by the New Mexico HPV Pap Registry, established in 2006 to evaluate cervical-cancer screening delivery, and report in the Journal of the National Cancer Institute that 65 percent of New Mexico women screened in 2019 with a normal prior co-test had undergone re-screening within the previous three years — far more often than recommended.
At the same time, 6.5% of women screened with a prior negative co-test and 14.9% of women with a prior negative cytology alone were not re-tested for more than five and up to seven years. These findings were concerning, given that negative cytology alone does not provide the same assurance that a negative co-test does for having a low risk of cervical cancer.

A world-first study from Edith Cowan University (ECU) has found whole fat milk is just as good for kids as low fat.
The research, published by the American Journal of Clinical Nutrition today, suggests current public health advice recommending children over the age of two consume low fat dairy products may need to be revised.
ECU’s Associate Professor Therese O’Sullivan led the investigation into the consumption of full-fat dairy products in children as part of the Milky Way study.
Over a three-month period, 49 healthy children aged four to six were randomly allocated to receive either whole fat or low-fat dairy products in place of their normal dairy intake.
Dairy products were home delivered every fortnight in plain packaging at no cost to the participants, to ensure purchase price wasn’t a factor.
Neither group knew whether they were consuming whole fat or low-fat dairy, while any left over products were weighed each fortnight to assess the children’s overall intake.

On phagocytic cells, also called macrophages, and other immune cells the ligand for CD47, namely SIRPa, can be found. When SIRP? binds to CD47, this triggers a signal which prevents the killing of the target cell. Most tumor cells also produce high amounts of CD47 and hence prevent being attacked by immune cells. Current tumor therapies using antibodies could block CD47 and at the same time activate immune cells. Nevertheless, serious side effects to healthy organs and blood cells limit this approach.

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Most people have already experienced first-hand how important a healthy microbiome is when they had to take a broad-spectrum antibiotic. Unfortunately, the drug does not only destroy the pathogens. It also affects the ‘good’ bacteria in the bowel that otherwise occupy the most important niches and help fend off pathogens. This protective mechanism is called colonisation resistance. But which bacterial species are ‘good’, or ‘commensal’ in technical terms, and how can they protect against colonisation, i.e. how can they prevent pathogens from settling? Prof. Till Strowig, HZI, and Prof. Bärbel Stecher, LMU München, decided to take a closer look at these questions.
Klebsiella pneumoniae has a strong opponent
The intestinal inhabitant Klebsiella pneumoniae is one of the most dreaded hospital germs, as it can cause severe pneumonia, urinary tract infections or even sepsis in weakened patients. It is increasingly resistant to common antibiotics and can facilitate further infections. In collaboration with partners in Magdeburg and Hannover, the HZI department led by Till Strowig, was able to isolate strains of a related bacterium from the intestine that are highly effective against K. pneumoniae. This species, identified as Klebsiella oxytoca, uses the same sugars as the pathogen, but it does it more efficiently so that there is not enough left for the pathogen to survive. “K. oxytoca can specifically force out multiresistant K. pneumoniae bacteria because it effectively blocks the niche to be occupied by the hospital germ,” explains Strowig. The scientists were also able to show in mice that these bacteria help the bacterial composition inside the intestines regenerate more quickly after antibiotic therapy and ensure that protection against infections is restored.
“First we wanted to find out how susceptible healthy adults and children are to colonisation with multi-resistant K. pneumoniae bacteria,” says lead author Lisa Osbelt to explain the study approach. For this study, the scientists took stool samples from 100 healthy people and incubated them with the germ overnight. The next day, the growth of the bacteria was measured. It revealed a great variability in the colonisation depending on each individual’s microbial community in the intestine. Next, the group examined the samples in which the germ had grown poorly; in many of them K. oxytoca could be identified. The researchers then tested the behaviour of the two bacteria in different mouse models and found that the addition of K. oxytoca can significantly reduce susceptibility to the hospital germ. When germ-free mice were colonised with different groups of bacteria (12 bacterial strains in total), three additional strains cooperated with K. oxytoca for the protective effect.
How ‘good’ E. coli bacteria can protect against salmonella infection
One of the best-known bacteria in the human gut is Escherichia coli, or E. coli for short. It is frequently mentioned in headlines as a ‘bad’ bacterium because it is considered an indicator of faecal contamination of drinking water, and certain variants can cause infections. But the bacterium has many different strains and, besides the pathogenic variants, there are also commensal representatives. However, so far little is known about the role of these variants for human health. Bärbel Stecher and her team at the Max von Pettenkofer-Institute at the LMU found out some time ago that commensal E. coli protect against salmonella infection. Again, it is their sugar consumption that limits the growth of the salmonellae by depriving them of food.
In the current study, the researchers were able to demonstrate that this protective effect of E. coli also depends on the microbial environment in the gut. This means that it depends on which microorganisms are still present, in other words, whether E. coli is in good company. “If there are lachnospiraceae present in our model that can also metabolise simple sugars, E. coli can provide protection — otherwise, it can’t,” explains Stecher. She adds: “Overall, we now understand better why probiotics may also help in some people but not in others. The reason for it is the microbial environment, which varies greatly from person to person.”
About mice and men: a step towards a protective bacterial cocktail?
Studying hundreds of bacteria and other microorganisms of the microbiota for their effects is an incredibly complex undertaking — even in mice. With their mouse model developed in Munich, the scientists can investigate the colonisation and influence of pathogens in a specifically targeted manner. A synthetic cocktail of 12 bacterial strains colonises germ-free mice stably over several generations and forms an intestinal microbiota representative of mice. Both studies involving Klebsiella and E. coli respectively use this model to carefully identify the interdependencies in the intestinal flora. But even in mice, it becomes clear how complex the interdependencies are. However, the studies of the microbiota researchers give us hope, because they show once again that we are on the right track with regard to the processes in the intestine.
“The use of live bacteria, so-called probiotics, for the treatment of patients with existing colonisation and as preventive administration after antibiotic therapy is generally conceivable’, says Till Strowig confidently. Bärbel Stecher adds: “The utilisation of a broad sugar range plays a major role for the design of these bacterial cocktails, and a protective cocktail must always contain more than one bacterium.”

A recent study from the University of Helsinki reveals that inhibiting certain adhesion receptors on the surface of dendritic cells, the main antigen-presenting cells of the immune system, enhances antitumour responses.
Dendritic cells are the main antigen-presenting cells of the immune system and are essential for “kicking off” the immune response against infectious agents and tumours. Beta2-integrins are adhesion receptors found on the surface of these cells, which mediate the interactions between the cell and its environment.
“We have found that these integrin-mediated interactions dampen the functionality of dendritic cells and their migration. This happens by regulating the gene expression programme of the cell. In particular, integrins regulate epigenetic changes such as the chemical modifications of histones, the proteins that DNA is wrapped around to make chromatin. This affects how tightly DNA is wound around the histones and how ‘open’ the chromatin is — which in turn determines whether a specific gene expression can occur,” explains Susanna Fagerholm, from the University of Helsinki.
Importantly, the researchers found that when integrins are switched off, dendritic cells switch on a gene expression programme that makes them better at mediating T cell activation and tumour rejection. Increased tumour rejection can also be induced artificially by manipulating these pathways in normal dendritic cells.
This study reveals that beta2-integrins function as negative regulators of dendritic cell programming. By inhibiting these receptors, dendritic cells’ anti-tumour responses become more effective. “This works a bit like check-point inhibition, which targets T cells, but here the target is the dendritic cells. When we “release the breaks” of the dendritic cells, it makes them better at activating T cells. This opens up new possibilities for improving dendritic cell-based cancer immunotherapies already in use in the clinic,” Fagerholm concludes.
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Materials provided by University of Helsinki. Note: Content may be edited for style and length.

Who doesn’t like the smell of caramel? However, the olfactory receptor that contributes decisively to this sensory impression was unknown until now. Researchers at the Leibniz Institute for Food Systems Biology at the Technical University of Munich (LSB) have now solved the mystery of its existence and identified the “caramel receptor.” The new knowledge contributes to a better understanding of the molecular coding of food flavors.
Furaneol is a natural odorant that gives numerous fruits such as strawberries, but also coffee or bread, a caramel-like scent. Likewise, the substance has long played an important role as a flavoring agent in food production. Nevertheless, until now it was unknown which of the approximately 400 different types of olfactory receptors humans use to perceive this odorant.
Odorant receptors put to the test
This is not an isolated case. Despite intensive research, it is still only known for about 20 percent of human olfactory receptors which odorant spectrum they recognize. To help elucidate the recognition spectra, the team led by Dietmar Krautwurst at LSB is using a collection of all human olfactory receptor genes and their most common genetic variants to decipher their function using a test cell system.
“The test system we developed is unique in the world. We have genetically modified the test cells so that they act like small biosensors for odorants. In doing so, we specify exactly which type of odorant receptor they present on their cell surface. In this way, we can specifically investigate which receptor reacts how strongly to which odorant,” explains Dietmar Krautwurst. In the present study, the researchers examined a total of 391 human odorant receptor types and 225 of their most common variants.
Only two odorants for one receptor
“As our results show, furaneol activated only the OR5M3 odorant receptor. Even one thousandth of a gram of the odorant per liter is sufficient to generate a signal,” says first author of the study Franziska Haag. In addition, the team investigated whether the receptor also reacts to other odorants. To this end, the team examined 186 other substances that are key odorants and therefore play a major role in shaping the aroma of food. Of these, however, only homofuraneol was able to significantly activate the receptor.
This odorant is structurally closely related to furaneol. As shown by previous LSB studies, it imparts a caramel-like aroma to fruits such as durian. “We hypothesize that the receptor we identified, OR5M3, has a very specific recognition spectrum for food ingredients that smell caramel-like. In the future, this knowledge could be used to develop new biotechnologies that can be used to quickly and easily check the sensory quality of foods along the entire value chain,” says Dietmar Krautwurst. Although there is still a long way to go to understand the complex interplay between the approximately 230 key food-related odorants and human olfactory receptors, a start has been made, the molecular biologist adds.
Veronika Somoza, Director of the Leibniz Institute adds: “In the future, we will continue to use our extensive odorant and receptor collections at the Institute to help elucidate the molecular basis of human olfactory perception. After all, this significantly influences our food choices and thus our health.”

Daily exposure chemicals called phthalates, used in the manufacture of plastic food containers and many cosmetics, may lead to roughly 100,000 premature deaths among older Americans each year, a new study shows. The resulting annual economic burden is between $40 billion and $47 billion, a value more than quadruple that of previous estimates.
For decades, phthalates have been shown to pose a potential danger to human health because the chemicals can interfere with the function of hormones, signaling compounds made in glands that circulate to influence processes throughout the body, experts say. Exposure is believed to occur through buildup of these toxins as consumer products break down and are ingested, with exposure linked to obesity, diabetes, and heart disease.
Led by researchers at NYU Grossman School of Medicine, the new investigation of more than 5,000 adults between the ages of 55 and 64 showed that those with the highest concentrations of phthalate in their urine were more likely to die of heart disease than those with lesser exposure.
Similarly, Americans in this high-exposure group were more likely to die of any cause than those in low-exposure groups. However, high levels of the toxins did not appear to increase risk of death due to cancer.
“Our findings reveal that increased phthalate exposure is linked to early death, particularly due to heart disease,” says study lead author Leonardo Trasande, MD, MPP. “Until now, we have understood that the chemicals connect to heart disease, and heart disease in turn is a leading cause of death, but we had not yet tied the chemicals themselves to death.”
Trasande cautions that the new study does not establish a direct cause and effect association between phthalate exposure and early deaths, in part because the specific biological mechanism that would account for the connection remains unclear. The study investigators say they plan to further study the role these chemicals may play in hormone regulation and inflammation in the body.

Healthy full-term infants born during the COVID-19 pandemic had substantially shorter hospital stays than those born before the pandemic, with no change in hospital readmissions after discharge, according to a new study led by researchers at Children’s Hospital of Philadelphia (CHOP), in collaboration with colleagues at the Yale School of Medicine, Nemours duPont, and Epic Systems Corporation. The findings, published today in Pediatrics, suggest shorter hospital stays for healthy term infants might be safe outside of a pandemic scenario, with implications for health care costs and best practices.
“The COVID-19 pandemic forced hospitals to change policies and procedures around childbirth, including expediting discharges for healthy term infants, which provided a natural experiment that allowed us to compare outcomes before and during the pandemic,” said Sara Handley, MD, MSCE, an attending neonatologist with the Division of Neonatology at Children’s Hospital of Philadelphia and first author of the study. “These findings suggest that shorter hospital stays after birth among healthy term infants may be safe with respect to infant rehospitalization, though examination of additional outcomes is needed.”
To compare hospital stays and rehospitalizations before and during the pandemic, the researchers analyzed data using Epic Systems Corporation’s Cosmos research platform, an application that aggregates electronic health record (EHR) data submitted voluntarily by health systems for research. The researchers pulled data from 35 health systems and compared short hospital length of stay following birth (defined as two nights or less following a vaginal birth and three nights or less following a cesarean birth) and infant rehospitalization within a week of discharge from the hospital between the COVID-19 era (March 1 to August 31, 2020) and the pre-pandemic era (defined as March 1 to August 31 in 2017, 2018, and 2019).
Evaluating a total of 202,385 infants during the pre-pandemic and pandemic periods, the researchers found that short hospital stays were 51% more common during the COVID-19 era. The proportion of infants with a short hospital stay increased from 28.5% to 43.0% for all births during the pandemic (vaginal: 25.6% to 39.3%, cesarean: 40.1% to 61.0%). For vaginal births, there was an increase in those discharged after one night during the pandemic and a decline in those staying for two nights. Similarly, there was an increase in two-night stays for cesarean deliveries and reductions of three- and four-night stays during the pandemic.
Despite shorter hospital stays, infant rehospitalizations within a week of discharge from the hospital decreased slightly during the pandemic (1.2% to 1.1%). The association between short birth hospitalization length of stay and infant rehospitalization did not differ significantly between eras.
“These findings suggest that shared decision making between families and clinicians, as was likely the case during COVID-19, resulted in safe earlier discharge with respect to infant hospitalization,” said Heather H. Burris, MD, MPH, an attending neonatologist with the Division of Neonatology at Children’s Hospital of Philadelphia and senior author of the study. “Further study of mitigating factors such as home services, telemedicine visits, and other supports that may have changed during the pandemic are warranted. Additionally, investigation of the pandemic’s impacts on other infant and maternal outcomes are critical before changing birth hospitalization policy.”
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Materials provided by Children’s Hospital of Philadelphia. Note: Content may be edited for style and length.

The German company CureVac announced Tuesday that it was withdrawing its mRNA vaccine for Covid-19 from the approval process in Europe. The company pulled the plug after determining that it might take until June for regulators to make a ruling about the vaccine.With other mRNA vaccines from Moderna and Pfizer-BioNTech already in wide distribution, the company decided it was time to give up on its initial efforts to address the Covid-19 emergency.“The pandemic window is closing,” Franz-Werner Haas, CureVac’s chief executive, said in an interview.The company will also terminate its advance agreement with the European Commission to buy 405 million doses of the vaccine after its approval. .But in the longer term, CureVac is not out of the Covid-19 vaccine business. The company is partnering with the pharmaceutical giant GSK to start a clinical trial of a new version of the vaccine they hope will be more effective. The companies are also investigating how to combine seasonal booster shots to work against both Covid-19 and influenza.Founded 20 years ago, CureVac pioneered early research on mRNA vaccines along with the German firm BioNTech and the U.S. company Moderna. At the start of the Covid-19 pandemic, all three companies developed new vaccines against the coronavirus.While Moderna and BioNTech moved swiftly into clinical trials, CureVac was slower to find partners to support its vaccine’s development. Nevertheless, some experts saw promise in the CureVac shot, hoping that it could help address the global shortfall in Covid vaccines.The European Medicines Agency gave CureVac special priority for its application, cutting the time needed for authorization. But in June, the company made a disappointing announcement: A clinical trial found that the vaccine’s efficacy was just 47 percent. By comparison, the vaccines from BioNTech and Moderna had efficacies around 95 percent.Despite that disappointment, CureVac went ahead with its application for authorization in Europe, and submitted a final data package in September. In its updated application, CureVac asked that the vaccine be considered only for people under 65 years old. In that group, the clinical trial had found a moderately higher vaccine efficacy, of 53 percent.The European regulators’ response was less than encouraging. “We were not being lined up for emergency review,” said Dr. Klaus Edvardsen, the company’s chief development officer.CureVac’s Covid-19 vaccine is now the seventh to be abandoned after entering clinical trials. Last month, Sanofi announced it was giving up on its mRNA vaccine.But CureVac’s newer version may have more success. In August, the company shared the results of an experiment on monkeys, showing that the new vaccine generated 10 times more antibodies against the coronavirus than the original one did. CureVac will begin testing it in people in the next couple of months.Dr. Haas said the company’s strategy is now “to be fast with a second generation rather than to be very late with the first generation.”