Culture

In the mid-14th century Europe was devastated by a major pandemic - the Black Death - which killed between 40 and 60 per cent of the population. Later waves of plague then continued to strike regularly over several centuries.

Plague kills so rapidly it leaves no visible traces on the skeleton, so archaeologists have previously been unable to identify individuals who died of plague unless they were buried in mass graves.

Whilst it has long been suspected that most plague victims received individual burial, this has been impossible to confirm until now.

By studying DNA from the teeth of individuals who died at this time, researchers from the After the Plague project, based at the Department of Archaeology, University of Cambridge, have identified the presence of Yersinia Pestis, the pathogen that causes plague.

These include people who received normal individual burials at a parish cemetery and friary in Cambridge and in the nearby village of Clopton.

Lead author Craig Cessford of the University of Cambridge said, "These individual burials show that even during plague outbreaks individual people were being buried with considerable care and attention. This is shown particularly at the friary where at least three such individuals were buried within the chapter house. Cambridge Archaeological Unit conducted excavations on this site on behalf of the University in 2017."

"The individual at the parish of All Saints by the Castle in Cambridge was also carefully buried; this contrasts with the apocalyptic language used to describe the abandonment of this church in 1365 when it was reported that the church was partly ruinous and 'the bones of dead bodies are exposed to beasts'."

The study also shows that some plague victims in Cambridge did, indeed, receive mass burials.

Yersinia Pestis was identified in several parishioners from St Bene't's, who were buried together in a large trench in the churchyard excavated by the Cambridge Archaeological Unit on behalf of Corpus Christi College.

This part of the churchyard was soon afterwards transferred to Corpus Christi College, which was founded by the St Bene't's parish guild to commemorate the dead including the victims of the Black Death. For centuries, the members of the College would walk over the mass burial every day on the way to the parish church.

Cessford concluded, "Our work demonstrates that it is now possible to identify individuals who died from plague and received individual burials. This greatly improves our understanding of the plague and shows that even in incredibly traumatic times during past pandemics people tried very hard to bury the deceased with as much care as possible."

Lugano, Switzerland, 17 June 2021 - Adding an immune checkpoint inhibitor to anti-HER2 treatment in breast cancer does not improve pathological complete response (pCR), according to the primary analysis of the IMpassion050 trial presented today during the ESMO Virtual Plenary. (1) The phase III trial is the first to report data comparing a neoadjuvant anti-HER2 based regimen with or without the anti-PD-L1 antibody atezolizumab in patients with high-risk, HER2-positive early breast cancer.

The standard treatment for high-risk, HER2-positive early breast cancer is dual anti-HER2 blockade plus chemotherapy. While antibody therapy may enhance innate and adaptive immunity and activate cellular cytotoxicity, there is evidence that combination with a checkpoint inhibitor may further enhance the immune response. (2) IMpassion050 evaluated the efficacy and safety of neoadjuvant atezolizumab versus placebo in patients receiving dose-dense anthracycline and taxane-based chemotherapy as a sequential treatment in combination with the antibodies pertuzumab and trastuzumab.

The trial enrolled 454 patients with high-risk HER2-positive early breast cancer, meaning they had a primary breast tumour size of >2 cm, and pathologic confirmation of nodal involvement. Patients were randomly allocated in a 1:1 ratio to the two treatment arms and received six months of neoadjuvant therapy. Following surgery, patients resumed their allocated treatment with atezolizumab versus placebo. Patients with pCR continued pertuzumab and trastuzumab while those with residual disease could switch to trastuzumab emtansine (T-DM1). (3)

The co-primary endpoints were pCR in the intention to treat (ITT) and PD-L1 positive populations. Event-free survival (EFS), overall survival and safety were secondary endpoints. The trial was stopped prematurely when the Independent Data Monitoring Committee judged that there was an unfavourable benefit-risk profile with the intervention. The data were analysed early, with three patients still to undergo surgery.

In the ITT population, pCR was achieved by 62.4% of the atezolizumab arm and 62.7% of the placebo arm (p= 1.0). In the PD-L1 positive population, pCR was achieved by 64.2% of the atezolizumab arm and 72.5% of the placebo arm (p= 0.2). Regarding safety, there were higher rates of grade 3/4 adverse events (AEs; 51.8% versus 43.6%) and serious AEs (19.5% versus 13.3%) in the neoadjuvant phase with atezolizumab versus placebo, respectively. During neoadjuvant treatment, four patients in the atezolizumab group died compared to no patient in the placebo group. Of the four deaths, two fatal events were assigned to study treatment- - one due to alveolitis and one due to septic shock, although it is not clear whether these were immune-related.

Lead author Prof Jens Huober, professor?of gynaecologic oncology at the Breast Centre St. Gallen, Switzerland, said: "Overall, the safety profile was consistent with other combination studies with atezolizumab, with no new side-effects. It is important to note that this was a selected population of high-risk HER2-positive patients to justify the potential toxicity of the additional drug and because patients with HER2-positive, node negative, smaller tumours do well with standard treatment."

Huober added: "The additional immunotherapy in this setting did not enhance the pCR rate in the overall population or in any subgroup. However, what counts for patients are EFS and overall survival (OS), which were secondary endpoints and we need longer follow-up for those results. In addition, there is some evidence in triple negative breast cancer that pCR may not be the best endpoint for measuring the efficacy of immunotherapy."

Commenting on the study, Dr Carmen Criscitiello, scientist and senior physician at the European Institute of Oncology in Milan, Italy said: "At trial level pCR is not a robust and validated endpoint for efficacy so the findings should be interpreted with caution until there are long-term results on EFS. In triple negative breast cancer, immune checkpoint inhibition added to standard neoadjuvant therapy modestly increased pCR rate in the GeparNUEVO (4) and KEYNOTE-522 studies (5) - yet EFS was significantly improved in both studies."

Criscitiello added: "In the metastatic setting, the benefit of adding an immune checkpoint inhibitor to chemotherapy is largely confined to the PD-L1 positive population. In the neoadjuvant setting, benefit in patients with triple negative breast cancer has been observed in the overall population and in both PD-L1 positive and negative subgroups. In the IMpassion050 PD-L1 positive group, the pCR rate was numerically inferior in the experimental arm compared to the control arm, suggesting a numerical opposite trend in PD-L1 negative tumours. This indicates the need to better investigate biological differences on the impact of PD-L1 by disease setting."

Criscitiello said the findings on safety should be examined carefully given the curative setting. She said: "Toxicity is more or less in line with what has been reported with similar combinations in other settings. There is a need to investigate if there is any link between atezolizumab and the treatment-related deaths, although - except alveolitis - they were not typical immune-related side-effects. In the curative setting we should be even more conservative and cautious when we look at the toxicity that may be induced by a new treatment. So far, this combination has not demonstrated an improvement in pCR rate, so the balance between risk and benefit should be carefully monitored before considering this therapeutic strategy."

A study performed by researchers at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) from the Spanish National Research Council (CSIC) in collaboration with Stony Brook University (USA) proposes a new strategy for the development of new drugs based on the inhibition of tyrosine kinase enzymes, molecules that activate and trigger many cellular processes. The results have been published in the Chemistry - A European Journal.

The new approach is based on the regulation of the signaling cascade of tyrosine kinases, and could lead to the development of improved and more selective tools for research, diagnosis or treatment of some diseases.

Tyrosine kinases are a set of enzymes that are essential for communication between the cells of our body, which trigger biochemical reactions that are important for life. "The dysfunction of these enzymes is related to serious diseases such as diabetes, some neurological disorders and many types of cancer," explains Ignacio Alfonso, a researcher at the IQAC-CSIC.

They activate different signaling pathways

Cell signaling is the process by which cells communicate. In the cell there are many types of receptors or specific proteins that recognize the proteins synthesized by the body and make the cell respond to them. One of the most important are tyrosine kinases.

"Cells receive signals from the environment when a molecule (a hormone, for example) binds to one of these receptors. The receptor recognizes the molecule and triggers a series of chemical reactions", explains Alfonso. This allows cells to work to control vital functions of the body, such as cell multiplication or destruction. Each process has its own signaling path. After the first molecule in the signaling pathway receives the signal, another molecule is activated, then another and another, and so on throughout the signaling cascade until cellular function is fulfilled. "The abnormal activation of signaling pathways can lead to diseases, such as cancer", says the researcher.

Kinases are a family of molecules that activate many different signaling pathways, which implies that they themselves participate in all of these processes. "When you want to avoid any of these processes, a research strategy is to inhibit kinases, blocking them with synthetic molecules. But this strategy is not very selective, since other important pathways may be inhibiting," warns Alfonso. In fact, the similarity between kinases and their functional versatility (the same kinase acts on different molecules and is involved in different processes) has made it difficult to design specific inhibitors to modulate pathological situations or dissect different functions in basic research.

Target: the place where kinases act

It is here where this work proposes an alternative strategy: not to inhibit the kinases, but to cover and block the molecules on which the kinases act. The tool for this would be artificial synthetic receptors, that is, synthetic molecules that would protect the place where the kinases exert their action. "Our group has designed molecules that interact with the substrates of the kinase, and not with the kinase" explains Alfonso. "We have prepared artificial molecular 'cages', made up of pseudopeptides, that are able to modulate the activity of these enzymes" clarifies the researcher.

"This complementary approach paves the way for selective modulation of an individual kinase-stimulated signaling pathway, without interfering with other functions of the kinase," explains Todd Miller from Stony Brook University. "This technology would enable investigators to dissect the contributions of specific signaling pathways in cellular function".

Despite being a proof-of-concept study, the results of this study could lead to more selective modulators/inhibitors of these kinases that would be used as research tools for the full understanding of this complex communication network. "This approach generates basic knowledge, which could be essential to better understand key biological functions and the origin of many diseases", concludes Dr. Alfonso.

The German National Academy of Sciences Leopoldina and the German Council for Sustainable Development (RNE) have published a joint position paper presenting paths to climate neutrality by 2050. In it, the Leopoldina and the RNE highlight options for action to effect the changes needed within society, at political level and in the business world, in view especially of the urgency and the historic dimensions of the transformation we face. With the paper, the Leopoldina and the RNE are consciously not seeking to engage in a race to set the most ambitious target. They are instead offering an options paper for setting the right course and covering the key implementation steps. The position paper was presented at the RNE's 20th annual conference and was handed over to the Federal Chancellor, Dr Angela Merkel.

"The opportunities presented by the European Green Deal, the new US administration and additional climate commitments made by, for example, China and the G7 must now be exploited to expand and reinforce international climate protection alliances," says Prof. (ETHZ) Dr Gerald Haug, President of the German National Academy of Sciences Leopoldina. "In addition to a global carbon price, what's needed are foresighted, cross-sector investments in infrastructure expansion and in new climate-friendly technologies," Haug continues.

Dr Werner Schnappauf, Chairman of the RNE, points to the importance of the project often being underestimated: "Action on an entirely different scale is needed to bring about a real transformation. A fundamental change in direction is necessary in order to achieve climate neutrality. The decarbonisation of industry alone will require up to four times the current volume of energy from renewable sources." This illustrates how quickly renewable energies and the related networks need to be expanded in the years to come, he says. "As much green electricity as possible being made available as quickly and as affordably as possible will be crucial here," Schnappauf emphasises. The citizens need to be involved and their engagement promoted to achieve the changes this entails, he says. "This challenge of the century calls for swift action that does justice to our responsibility towards the young and future generations," says Schnappauf.

The authors focus on carbon emissions trading as the lead instrument with which to realise the transformation, embedded in an overall climate policy strategy that includes regulatory framework, funding and governance policy. A broad mobilisation of private capital will also be needed, they argue, which in turns requires long-term security of investment.

Another key assertion of the position paper is that climate protection can only unfold the necessary impact if pursued at the European level as part of the European Green Deal and ultimately also globally. In addition to options in the area of market policy action, the authors address the issues of financing, foreign policy, international solidarity, social equity and education.

The joint position paper can be found here: http://www.leopoldina.org/en/climate-neutrality

Abu Dhabi, UAE: Trans-Neptunian Objects (TNOs), small objects that orbit the sun beyond Neptune, are fossils from the early days of the solar system which can tell us a lot about its formation and evolution.

A new study led by Mohamad Ali-Dib, a research scientist at the NYU Abu Dhabi Center for Astro, Particle, and Planetary Physics, reports the significant discovery that two groups of TNOs with different surface colors also have very different orbital patterns. This new information can be compared to models of the solar system to provide fresh insights into its early chemistry. Additionally, this discovery paves the way for further understanding of the formation of the Kuiper Belt itself, an area beyond Neptune comprised of icy objects, that is also the source of some comets.

In the paper, The rarity of very red TNOs in the scattered disk, published in The Astronomical Journal, the researchers explain how they studied the chemical composition of TNOs in order to understand the dynamical history of the Kuiper Belt. TNOs are either deemed "Less Red" (often referred to as Gray), or "Very Red" (often referred to as Red) based on their surface colors. By re-analyzing a 2019 data set, the researchers discovered that gray and red TNOs have vastly different orbital patterns. Through additional calculations, the researchers determined that the two groups of TNOs formed in different locations, and this led to the dichotomy in both their orbits and colors.

Many models of the solar system have been designed to show how the Kuiper Belt has evolved, but these models only study the origins of its orbital structure or colors, not both simultaneously.

"With more data, our team's work could be applied to more detailed solar system models and has the potential to reveal new insights about the solar system and how it has changed over the course of time," said Ali-Dib.

(Boston)--An intrauterine fracture is a rare finding during routine prenatal imaging. This condition can be due to maternal trauma, genetic disorders of the skeleton, as well as other predisposing maternal metabolic and vascular disorders. Genetic disorders that have previously been reported to cause intrauterine fracture include brittle bone disease (osteogenesis imperfecta or OI), osteopetrosis, hypophosphatasia and Ehlers-Danlos syndrome (EDS).

Now for the first time, researchers from Boston University School of Medicine (BUSM) report a new genetic cause, unrelated to OI, for the 23 fractures that occurred in-utero to a mother with EDS hypermobility type.

EDS is a disease that weakens the bones and connective tissues of your body. It can make joints loose and skin thin and easily bruised. It also can weaken blood vessels and organs. There are 13 types of EDS. The most common, and generally considered the least severe, is hypermobile EDS (hEDS). While there are genetic tests for some subtypes of EDS, no genetic test has been developed for diagnosing hEDS.

Following the birth, the mom, infant and dad were enrolled in BUSM's Ehlers-Danlos Clinical Research Program. After evaluation of the family, including documenting medical history and physical findings, DNA samples were taken from each of them. The DNA was evaluated and confirmed that the infant had no pathologic genetic mutations associated with OI. However, several new gene mutations including one gene, CCDC134, that has been identified as causing bone fragility, was identified in the infant.

According to the researchers, this case report clearly demonstrates that there is at least one other genetic cause for infantile fractures other than OI and child abuse (non-accidental trauma) that is associated with EDS. "Therefore we are recommending that the additional gene we identified as being the likely cause for this infant's fractures, be included in the genetic panel for bone fragility and that careful consideration be given for other causes of infantile fractures other than OI and non-accidental trauma," said corresponding author, Michael F. Holick, PhD, MD, professor of medicine, physiology and biophysics and molecular medicine at BUSM.

While acknowledging that child abuse is a serious problem that needs to be dealt with appropriately, Holick believes misdiagnosing child abuse can also have devastating long-term consequences for both the child and the parents. "If this infant were brought into the hospital with an upper respiratory tract infection at eight weeks of age, an x-ray of his chest would have revealed healing fractures of his arms and multiple healing fractures of his ribs. A skeletal survey would have revealed the healing fractures in both his legs. He would have been tested and found not to have OI, and therefore the diagnosis for the fractures would have been that they were caused by non-accidental trauma. The child would have been immediately removed from the care of his parents and the parents would have been accused of felony child abuse. It is hoped that this case report will now give reconsideration for diagnosing child abuse solely based on x-ray findings of a fracture or fractures with a negative genetic test for OI," he said.

Holick stresses that by better understanding how this pathologic genetic mutation affects the skeleton to cause fractures provides the scientific community with the ability to develop new strategies for treatment. "We will be able to develop new approaches not only for treating bone fragility in infants with this genetic disorder, but also for treating bone brittleness associated with osteoporosis, which is associated with enormous cost both in terms of quality of life and medical expenses," Holick said.

New study challenges long-standing assumptions about disease severity in infants, and suggests that standard qPCR interpretations underestimate the true burden of other highly contagious diseases, such as COVID-19 and influenza.

Pertussis, also known as "whooping cough," remains a significant cause of death in infants and young children around the world and, despite global vaccination programs, many countries are experiencing a resurgence of this highly contagious disease.

A new study by Boston University School of Public Health and the University of Georgia's Odum School of Ecology presents evidence that could help explain this resurgence: asymptomatic individuals. Lots of them.

Published in the journal eLife, the study suggests that most adults and many children who contract pertussis display no symptoms at all--a reversal of what many experts have long believed about an infection that can cause months of violent coughing fits and "whooping" sounds.

The paper builds upon a 2015 study in which the researchers discovered a series of weakly positive pertussis infections after collecting nasal swab samples from 2,000 mother/infant pairs in Zambia every 2-3 weeks for several months, using quantitative PCR (qPCR) diagnosis. In a standard qPCR analysis, these low-intensity signals would be discounted as false-positive results. But the repeated clusters of mother/infant cases, which illustrated a natural arc of infection as the infection ran its course, suggested that these weak PCR signals provided important information about disease.

"The fact that we found concordance within the mother/infant pairs told us that, in all likelihood, even the weakly affected mothers are contagious at close range, and are probably infecting their babies," says Dr. Christopher Gill, co-lead author of the study and associate professor of global health at BUSPH. Asymptomatic spread is not a unique phenomenon with infectious diseases, he says, but as the world has seen with COVID-19, the ability to detect asymptomatic infections early and accurately through qPCR can provide vital information about the epidemiology and burden of diseases.

"This was a quest to understand weakly positive qPCR and then determine what proportion of pertussis transmissions are coming from asymptomatic people," Gill says.

To confirm that these weak signals were accurate and relevant, the researchers conducted a closer analysis for the eLife study, and discovered additional evidence supporting the likelihood of asymptomatic transmission. The cluster of weak signals aligned with stronger signals, indicating that they occurred during an outbreak; the clusters reflected the natural rise and fall of an epidemic; signals were strongly clustered within mother/infant pairs; and the stronger the qPCR signal, the more likely individuals were to experience symptoms.

Confident in their findings, the researchers then compared the symptomatic cases to the asymptomatic cases and discovered that about 70% of infected mothers displayed no symptoms, and about 25% of infected babies displayed no symptoms. And infants with only mild symptoms (cough or runny nose) comprised over 50% of infections.

"We expected this in mothers, since pertussis becomes less severe with age and repeat exposure," says co-lead author Dr. Christian Gunning, post-doctoral researcher at UGA's School of Ecology. "But mild and asymptomatic infection in infants was assumed to be quite rare. And what we see here is the opposite--severe pertussis in infants is the exception rather than the rule."

The findings underscore the need for a shift in the way qPCR tests are interpreted, Gill says.

"Using a 'line in the sand' approach to interpret results is too simplistic and leads us to discard true and useful information," he says. "If one were trying to map a flu season, it would make more sense to use the weakly positive PCR results as an early warning of impending flu outbreaks, rather than waiting for symptomatic patients with very strong PCR results to start showing up in the ER."

Gunning agrees, saying disease surveillance plays an important role in preventing and responding to disease outbreaks. "Our results differ from traditional approaches that medical doctors use to diagnose and treat patients," he says. "When we tested many people many times, we could 'peer under the hood' and see a lot of hidden infections in this population."

Gunning says that a similar approach could help monitor for outbreaks of COVID. "To control disease outbreaks, we need to know when and where the disease has spread. New strategies like wastewater monitoring could leverage weak qPCR signals to give us a better, fasteridea of who's at risk, and allow us to more quickly intervene. And if you only look at sick people, you're going to miss a lot."

UTICA, NY -- More than 2 million coronary artery stents are implanted each year to help protect or restore normal blood flow to the heart, to treat patients suffering from angina or a heart attack due to coronary artery disease (CAD). While stents are highly effective and safe devices, scarring or clotting of unhealed stents can occur in a small percentage of subjects, leading to complications such as stent restenosis or thrombosis, which can be life-threatening. At present, approaches to understand stent healing based on their biological clotting status is unavailable in patients.

To devise a potential solution to this problem, Dr. Jason McCarthy, an Associate Professor at the Masonic Medical Research Institute (MMRI), and his team have developed a fluorescent probe that binds to activated platelets, one of the main cell types involved in the clotting and scarring process of improperly healed stents. "By using a new platelet-targeted molecular imaging agent coupled with fluorescence imaging, in particular intravascular catheter-based imaging, we are enabling a new approach to localize and visualize platelets during or after coronary stent implantation. This tool has the potential to enable clinicians to proactively treat patients before the development of occlusive stent clotting or scarring, as opposed to reactively, when the patient is symptomatic," said Dr. Jason McCarthy, co-senior author on the manuscript.

In a collaboration with Dr. Farouc A. Jaffer, an Interventional Cardiologist at Massachusetts General Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School, the team modified a drug called tirofiban, an FDA-approved compound known to bind to activated platelets, to enable a fluorescence-based strategy for the detection of platelet-rich clots in experimental subjects.

Stent implantation is a routine invasive procedure in which a stent is delivered over a coronary wire to the target lesion location. Given that clinicians already have intracoronary wire access during this procedure, performing imaging of platelet deposition using fluorescence-based catheters can be readily accomplished (fluorescence catheters have already been tested in patients). "Once the interventional cardiologist is ready to image platelet deposition on stents, a small amount of our new platelet-targeted imaging agent will be intravenously administered. After a few minutes, a fluorescence imaging catheter will be delivered down the coronary over the same wire, followed by an imaging pullback to visualize whether there are any platelets adhered to the stent, which may indicate that it is prone to further development of clots. This will give the clinician the option at the point-of-care to change pharmacological or interventional management of the patient to optimize their outcomes," said Dr. McCarthy.

The manuscript details the process by which the team created and tested the novel imaging agent. "This new agent provides tools that open up numerous possibilities for translational cardiovascular imaging, especially at the point-of-care," said Dr. Khanh Ha, co-author on the paper, and postdoctoral fellow at the MMRI, "With the imaging catheters already approved for clinical use, the goal was to create an imaging agent that would hopefully also prove clinically translatable."

Type 1 diabetes is a disorder in which the immune system inappropriately targets a class of cells in the pancreas known as β cells that produce the hormone insulin, which plays an important role in regulating bloodstream glucose levels and the metabolism of carbohydrates, lipids, and proteins. The loss of insulin causes a range of health problems for people with type 1 diabetes, and patients become dependent on insulin injections for their survival. Even with insulin therapy, people with type 1 diabetes have shortened lifespans and are at an elevated risk of developing myriad complications.

Previous studies have identified numerous genetic risk factors for type 1 diabetes. One notable finding is the importance of the HLA region, a part of the human genome that contains multiple genes and explains approximately 40-50% of the genetic risk for type 1 diabetes. However, studies of identical twins have identified cases in which one twin develops type 1 diabetes while the other twin does not--which indicates that genetic risk factors cannot fully explain the occurrence of type 1 diabetes. This finding is consistent with the known relevance of certain environmental factors. For example, most studies have found that breastfeeding and vitamin D consumption protect against type 1 diabetes and that cow's milk and the early introduction of gluten increase the risk of type 1 diabetes. Furthermore, microbes in the human gut play important roles in human health and digestion, and patients with type 1 diabetes often lack diversity in their gut microbiota.

To explain the risk factors for type 1 diabetes more fully, medical researchers have turned to the field of epigenetics, which studies how environmental and lifestyle factors can influence the expression of genes without altering the underlying DNA sequence. In recent years, various research groups have published studies confirming that epigenetic changes related to environmental conditions contribute to the development of type 1 diabetes. In a review article recently published in Chinese Medical Journal, a team of researchers from the Huazhong University of Science and Technology led by Drs. Cong-Yi Wang and Fei Xiong set out to summarize how epigenetic factors modulate the risks of type 1 diabetes. They also aimed to discuss the potential of these epigenetic factors to serve as markers for monitoring disease progression and as targets for therapeutics.

One important mechanism of epigenetics is DNA methylation, which refers to the presence of chemical tags called methyl groups on DNA. DNA methylation patterns influence whether and how strongly a gene is expressed, and past studies have identified numerous methylation sites that influence the risk of type 1 diabetes. Some of these methylation sites lie within the previously mentioned HLA regions, which is highly relevant to type 1 diabetes. Other methylation sites affect the INS gene, which is second only to the HLA region in terms of influencing the risk of type 1 diabetes.

Another mechanism of epigenetics is chemical modification of histones, which are proteins around which DNA strands are wound. Several studies have reported abnormal histone modification patterns in patients with type 1 diabetes. These modifications may increase the risk of type 1 diabetes by influencing the expression of genes related to inflammation and immunity, and the elevated blood glucose levels associated with type 1 diabetes may also cause abnormal histone modification patterns.

Epigenetic effects can also be expressed in the form of noncoding RNAs, which are RNA molecules that have functional roles other than the standard role of providing instructions for protein synthesis. Noncoding RNAs are a diverse class of genetic molecules, and they can bind DNA, other RNA strands, and proteins. Through their various actions, they can promote or suppress the expression of certain genes. Recent studies have yielded evidence that noncoding RNAs can contribute to type 1 diabetes by influencing the immune system and causing β cell dysfunction.

Dr. Wang explains, "Given the relationship between epigenetic changes and type 1 diabetes, various epigenetic changes could serve as markers for disease progression and treatment effects or even as targets for future therapeutics. For example, noncoding RNAs can be measured noninvasively, while changes in DNA methylation levels and patterns for particular genes could indicate that a genetically predisposed person is developing type 1 diabetes." Furthermore, the researchers cite studies that have yielded evidence that drugs that alter DNA methylation could benefit patients with type 1 diabetes.

Dr. Xiong concludes, "Based on existing literature, it is clear that environmental insult-induced epigenetic changes modulate the expression of critical genes relevant to the initiation and progression of autoimmunity and β cell destruction and are therefore implicated in the development of type 1 diabetes." This information will be valuable to medical researchers who wish to develop new ways to predict the onset of type 1 diabetes, assess the condition's severity and progression, and provide patients with effective treatment options.

New technologies allow users to do things like race their real bikes against other real people in a virtual world, and a new study outlines what motivates people to use these online platforms. The findings offer insights for future iterations of these technologies - and how to market them.

At issue are "mixed-reality sports": augmented reality platforms that incorporate virtual, online elements and real-world athletic endeavors. For example, Zwift is a platform that allows users to ride their real bicycles, but transfers their efforts to a virtual space depicting real-world courses - allowing them to race against other cyclists who are not physically present.

"We know that mixed-reality sports are attracting a lot of users," says Bill Rand, co-author of the paper and an associate professor of marketing in North Carolina State University's Poole College of Management. "We want to know what benefits people see in these technologies. What about risks? And how do those risks and benefits affect their actual use?

"This matters because once we understand why people are using, or not using, these technologies, we can figure out how to make the technologies for appealing for users - and also how to market them more effectively."

For this study, the researchers conducted a survey of 284 Zwift users in Germany, Austria and Switzerland. The survey collected data on each study participant's background, their motivations for using Zwift, any concerns they had about the platform, and the extent to which they felt they would continue using Zwift in the future. The researchers were then able to review each study participant's use of Zwift for 30 days after taking the survey. The study design allowed the researchers to identify any relationships between a study participant's motivations, perceived risks, their expectations for using Zwift, and their actual use of Zwift.

One of the things researchers found surprising was that users were simply not motivated by competing against other users within the game environment itself.

"The Zwift platform is designed specifically to enable competition, either informally amongst friends, or in formal races involving many competitors," Rand says. "However, we found that even the people who take part in the formal races are not strongly motivated by these in-game contests."

Instead, researchers found that four other drivers were associated with Zwift use: health consciousness; using Zwift to train for real-world competitions; socializing with others; and the ability to customize and upgrade their gaming experience by modifying their jerseys, "earning" access to new bike styles, and so on.

"To provide a more profound explanation of the quantitative results, we also conducted 14 interviews with platform users," says Daniel Westmattelmann, corresponding author of the paper, an assistant professor of sports management at the University of Münster and a former professional cyclist. "It was fascinating to see that even elite athletes who have won Tour de France stages, for example, are strongly motivated to use the platform more intensively because of customizing or socializing elements."

The researchers also found that study participants who had privacy concerns about Zwift engaged with the platform less frequently.

"There are a variety of these mixed-reality sports platforms out there, such as Peloton, with varying ratios of virtual elements to real-world elements," Rand says. "And this field is likely to grow. Our work gives us insight into what may be motivating participants on these platforms.

"For example, the ability to customize your avatar appears to be important. Social interaction and online communities are important. Health and fitness are important. Privacy concerns are important.

"Understanding the things that are important to users can help developers of next-generation mixed-reality sports technologies design more appealing products," Rand says. "And can help marketers determine which aspects of these products to highlight for consumers."

The paper, "Apart we ride together: The motivations behind users of mixed-reality sports," appears in the Journal of Business Research. The paper was co-authored by Jan-Gerrit Grotenhermen, Marius Sprenger and Gerhard Schewe of the University of Münster.

When astronomers using NASA's Hubble Space Telescope uncovered an oddball galaxy that looked like it didn't have much dark matter, some thought the finding was hard to believe and looked for a simpler explanation.

Dark matter, after all, is the invisible glue that makes up the bulk of the universe's matter. All galaxies appear to be dominated by it; in fact, galaxies are thought to form inside immense halos of dark matter.

So, finding a galaxy lacking the invisible stuff is an extraordinary claim that challenges conventional wisdom. It would have the potential to upset theories of galaxy formation and evolution.

To bolster their original finding, first reported in 2018 (Dark Matter Goes Missing in Oddball Galaxy (hubblesite.org)), a team of scientists led by Pieter van Dokkum of Yale University in New Haven, Connecticut, followed up their initial study with a more robust Hubble look at the galaxy, named NGC 1052-DF2. Scientists refer to it simply as "DF2."

"We went out on a limb with our initial Hubble observations of this galaxy in 2018," van Dokkum said. "I think people were right to question it because it's such an unusual result. It would be nice if there were a simple explanation, like a wrong distance. But I think it's more fun and more interesting if it actually is a weird galaxy."

Determining the amount of the galaxy's dark matter hinges on accurate measurements of how far away it is from Earth.

If DF2 is as far from Earth as van Dokkum's team asserts, the galaxy's dark-matter content may only be a few percent. The team's conclusion is based on the motions of the stars within the galaxy; their velocities are influenced by the pull of gravity. The researchers found that the observed number of stars accounts for the galaxy's total mass, and there's not much room left for dark matter.

However, if DF2 were closer to Earth, as some astronomers claim, it would be intrinsically fainter and less massive. The galaxy, therefore, would need dark matter to account for the observed effects of the total mass.

A Better Yardstick
Team member Zili Shen, from Yale University, says that the new Hubble observations help them confirm that DF2 is not only farther from Earth than some astronomers suggest, but also slightly more distant than the team's original estimates.

The new distance estimate is that DF2 is 72 million light-years as opposed to 42 million light-years, as reported by other independent teams. This places the galaxy farther than the original Hubble 2018 estimate of 65 light-years distance.

The research team based its new result on long exposures with Hubble's Advanced Camera for Surveys, which provide a deeper view of the galaxy for finding a reliable yardstick to nail down the distance. They targeted aging red giant stars on the outskirts of the galaxy that all reach the same peak brightness in their evolution. Astronomers can use the stars' intrinsic brightness to calculate vast intergalactic distances. "Studying the brightest red giants is a well-established distance indicator for nearby galaxies," Shen explained.

The more accurate Hubble measurements solidify the researchers' initial conclusion of a galaxy deficient in dark matter, team members say. So the mystery of why DF2 is missing most of its dark matter still persists.

"For almost every galaxy we look at, we say that we can't see most of the mass because it's dark matter," van Dokkum explained. "What you see is only the tip of the iceberg with Hubble. But in this case, what you see is what you get. Hubble really shows the entire thing. That's it. It's not just the tip of the iceberg, it's the whole iceberg."

The team's science paper has appeared in The Astrophysical Journal Letters.

A Stealthy Galaxy
DF2 is a giant cosmic cotton ball that van Dokkum calls a "see-through galaxy," where the stars are spread out. The galactic oddball is almost as wide as the Milky Way, but it contains only 1/200th the number of stars as our galaxy.

The ghostly galaxy doesn't appear to have a noticeable central region, spiral arms, or a disk. The team estimates that DF2 contains at most 1/400th the amount of dark matter than astronomers had expected. How the galaxy formed remains a complete mystery based on the team's latest measurements.

DF2 isn't the only galaxy devoid of dark matter. Shany Danieli of the Institute for Advanced Study in Princeton, New Jersey, used Hubble in 2020 to obtain an accurate distance to another ghostly galaxy, called NGC 1052-DF4 (or simply DF4), which apparently lacks dark matter, too.

The researchers think both DF2 and DF4 were members of a collection of galaxies. However, the new Hubble observations show that the two galaxies are 6.5 million light-years away from each other, farther apart than they first thought. It also appears that DF2 has drifted away from the grouping and is isolated in space.

Both galaxies were discovered with the Dragonfly Telephoto Array at the New Mexico Skies observatory.

"Both of them probably were in the same group and formed at the same time," Danieli said. "So maybe there was something special in the environment where they were formed."

The researchers are hunting for more of these oddball galaxies. Other teams of astronomers are searching, too. In 2020, a group of researchers uncovered 19 unusual dwarf galaxies they say are deficient in dark matter (Off the Baryonic Tully-Fisher Relation: A Population of Baryon-dominated Ultra-diffuse Galaxies - IOPscience). However, it will take uncovering many more dark matter-less galaxies to resolve the mystery.

Nevertheless, van Dokkum thinks finding a galaxy lacking dark matter tells astronomers something about the invisible substance. "In our 2018 paper, we suggested that if you have a galaxy without dark matter, and other similar galaxies seem to have it, that means that dark matter is actually real and it exists," van Dokkum said. "It's not a mirage."

The intestinal disease necrotizing enterocolitis is a leading cause of death among premature infants born in the U.S. and across the globe. Characterized by excessive inflammation that can cause tissue decay in the bowels, the disease provides a pathway for infectious and deadly bacteria to enter the bloodstream.

Despite four decades of research, effective treatments remain elusive, and mortality rates in babies who develop the disease have remained essentially unchanged, hovering at about 30%.

Now, a study led by researchers at Washington University School of Medicine in St. Louis has identified, in mice, a protein in the immune system that may protect babies from necrotizing enterocolitis (NEC) and lead to the development of new treatments.

The findings are published online June 15 in Cell Reports Medicine.

"Necrotizing enterocolitis is a serious, fast-acting condition that can lead to death within hours," said the study's senior author, Misty Good, MD, an assistant professor of pediatrics in the Division of Newborn Medicine. "We don't know why NEC happens, and we can try to treat it with antibiotics and surgical removal of the dead tissue; however, in severe cases, many babies will still die. No treatments stop the disease from progressing, but our hope is that the protein we've identified will change that."

The scientists focused on Interleukin-22 (IL-22), a protein that regulates immune responses and helps maintain a healthy gut microbiome in adults.

Over the years, research has suggested that IL-22 has a critical role in adult gastrointestinal diseases. Consequently, potential treatments involving IL-22 are being studied in COVID-19 illness, alcohol-induced liver disease, and graft-versus-host disease that develops after organ or bone marrow transplants. However, IL-22's role in newborns' intestines has been unclear.

To better understand the protein's role, the researchers created a mouse model to examine IL-22 signaling and production in healthy intestines and in intestines damaged by NEC. They analyzed IL-22 levels before and after birth and into adulthood, which for mice begins when they are weaned, at about 28 days old. In both the healthy and diseased intestines, the researchers documented low postnatal IL-22 production up until day 21, when production skyrocketed for the mice and continued into adulthood.

The researchers also studied tissue samples from preemies who did and did not develop NEC. The scientists found low levels of IL-22 in all of the intestinal samples. And in the babies who had developed NEC, an appropriate immune response had not been mounted in the intestines.

"Immune cells in the neonatal intestine have shown an inability to produce adequate amounts of IL-22 to control the progression of NEC," said Good, who treats patients at St. Louis Children's Hospital and is also co-program director of the university's Neonatal-Perinatal Medicine Fellowship. As a member of the scientific advisory council of the Necrotizing Enterocolitis Society, Good has led an effort involving seven medical centers that have developed a large biorepository of samples from infants affected by NEC.

Good surmised that immature intestines are associated with a lack of IL-22 production, a theory strengthened by the fact that premature infants weighing less than 3 pounds 5 ounces are most at risk for NEC. Typically, the more premature a baby is, the lower the baby's weight and the more undeveloped a baby's gastrointestinal immune system is. Harmful bacteria can get cross the gut barrier and activate the immune system. And because the immune system of preemies isn't fully developed, it leads to an exaggerated inflammatory response that can lead to tissue death.

The researchers' findings of low levels of IL-22 in neonatal tissues led to their next step: injecting the mice with IL-22. The protein aids in controlling inflammation while promoting regeneration of tightly packed cells lining the intestine. IL-22 can help strengthen the intestinal walls, creating a barrier in the gut that allows for nutrient absorption while preventing toxic or otherwise hostile microorganisms from seeping into the bloodstream.

"Interestingly, our work demonstrated that treatment with IL-22, in mice, protects the newborn intestine against damage caused by NEC," Good said. "Our study represents a substantial advance in understanding the role of IL-22 in early life and sets the stage for new ways to treat NEC in the future."

TAMPA, Fla. (June 17, 2021) - Tests that analyze biomarkers are used during cancer management to guide treatment and provide information about patient prognosis. These tests are often performed on tissue biopsy samples that require invasive procedures and can lead to significant side effects. In a new article published in the Journal for ImmunoTherapy of Cancer, Moffitt Cancer Center researchers show that PET/CT images can be used to measure levels of the PD-L1 biomarker of non-small cell lung cancer (NSCLC) patients in a non-invasive manner and, in turn, predict a patient's response to therapy.

Checkpoint inhibitors, drugs used to reactive the immune system by targeting the PD1/PD-L1 signaling pathway, are commonly used to treat patients with NSCLC. While this type of therapy has greatly improved patient outcomes, it only works for roughly half of this patient population. To avoid treating those who may not respond, checkpoint inhibitor therapy is often limited to patients whose surgical biopsy specimen is shown to express the PD-L1 biomarker. However, performing an invasive surgery is associated with inherent risks, and occasionally the biopsy sample is not adequate to perform diagnostic testing or the testing procedure itself may fail. Therefore, researchers are trying to develop alternative strategies to identify patients who should be treated with targeted agents such as checkpoint inhibitors.

Moffitt researchers wanted to take advantage of the capabilities of computer deep learning to develop a new framework to measure PD-L1 biomarker levels in NSCLC patients in a non-invasive manner. They chose to use features of PET/CT scan images, such as shape, size, pixel intensity and textures to train computers to measure PD-L1 expression. They developed a deep learning score to predict PD-L1 expression, and after validation through different patient cohorts were able to use their model to predict checkpoint inhibitor outcomes in NSCLC patients.

"These data demonstrate the feasibility of using an alternative non-invasive approach to predict expression of PD-L1," said Matthew Schabath, Ph.D., associate member of the Cancer Epidemiology Department. "This approach could help physicians determine optimum treatment strategies for their patients, especially when tissue samples are not available or when common testing approaches for PD-L1 fail."

"This study is important, as it is the single largest multi-institutional radiomic study population of NSCLC patients to date treated with immunotherapy to predict PD-L1 status and subsequent treatment response using PET/CT scans," said Robert Gillies, Ph.D., chair of the Department of Cancer Physiology at Moffitt. "Because images are routinely obtained and are not subject to sampling bias per se, we propose that the individualized risk assessment information provided by these analyses may be useful as a future clinical decision support tool pending larger prospective trials."

The Black Sea is an unusual body of water: below a depth of 150 metres the dissolved oxygen concentration sinks to around zero, meaning that higher life forms such as plants and animals cannot exist in these areas. At the same time, this semi-enclosed sea stores comparatively large amounts of organic carbon. A team of researchers led by Dr Gonzalo V. Gomez-Saez and Dr Jutta Niggemann from the University of Oldenburg's Institute for Chemistry and Biology of the Marine Environment (ICBM) has now presented a new hypothesis as to why organic compounds accumulate in the depths of the Black Sea - and other oxygen-depleted waters in the scientific journal Science Advances.

The researchers posit that reactions with hydrogen sulfide play an important role in stabilizing carbon compounds. "This mechanism apparently contributes to the fact that there is more than twice as much organic carbon in the waters of the Black Sea as in oxygen-rich marine areas," says Niggemann. "This provides a negative feedback in the climate system that could counteract global warming over geological periods."

In the Black Sea, which covers an area almost twice the size of France, conditions rarely found in other marine regions have prevailed for around 7,000 years: stable stratification largely prevents the mixing of surface and deep waters. The water in the upper 150 metres is low in salt and oxygen-rich, and comes mainly from rivers like the Danube. Below that, there is a layer of higher density saline water that flows into the Black Sea from the Mediterranean via the Bosporus.

"When you open a water sample from the deeper areas of the Black Sea, the smell of rotten eggs almost knocks you over," Niggemann says. On the surface, however, there is no indication that the Black Sea is a stagnant body of water in which, due to the lack of oxygen, bacteria produce foul-smelling hydrogen sulfide.

Hydrogen sulfide reacts with dissolved organic matter

As the new study shows, this highly reactive molecule binds with substances from a diverse group of carbonaceous materials that are present in every litre of seawater. These substances are known as dissolved organic matter (DOM) - a complex mixture of countless different molecules that are the product of decomposed organic matter or bacterial metabolic processes.

"We were able to show very clearly that hydrogen sulfide reacts with the extremely diluted organic matter directly in the water," Niggemann explains. The products of the reaction are potentially more durable than the starting materials and therefore accumulate in the water.

The team compared water samples from different locations in the Black Sea and other seas and rivers. Using various analytical methods, including the ultrahigh resolution mass spectrometer of the Marine Geochemistry research group at the University of Oldenburg, the researchers were able to characterize the dissolved organic matter in detail.

They found that almost a fifth of the organic molecules in the anoxic areas of the Black Sea contained sulfur - significantly more than in other seas. In addition, the team was able to establish that a high proportion of these compounds are only found in these areas, leading the researchers to conclude that the sulfur compounds form there through chemical reactions in the sulfidic water.

Negative feedback relevant on geological time scales

Given that huge amounts of carbon are stored in dissolved organic matter - the world's oceans contain roughly as much dissolved organic carbon as there is CO2 in the Earth's atmosphere - the results of this new study are also relevant for the climate. "The volume of ocean waters completely depleted of oxygen quadrupled between 1960 and 2010.

Consequently, this sulfur-based mechanism of carbon storage could influence the chemistry of the oceans in the future," says Gomez-Saez, the lead author of the study. But this negative feedback is too weak to have a noticeable impact on climate change under the current conditions, he adds. In geological history, however, there have been several periods during which large areas of the oceans were oxygen-deficient. During these periods this effect could have contributed to long-term removal of carbon dioxide from the atmosphere.

The water samples from the Black Sea were taken during an expedition with the research vessel Maria S. Merian. In addition to the team from the ICBM, researchers from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) in Bremerhaven, the MARUM - Center for Marine Environmental Sciences of the University of Bremen, and the Max Planck Institute for Marine Microbiology in Bremen participated in the study.

Woodlands along streams and rivers are an important part of California's diverse ecology. They are biodiversity hotspots, providing various ecosystem services including carbon sequestration and critical habitat for threatened and endangered species. But our land and water use have significantly impacted these ecosystems, sometimes in unexpected ways.

A team of researchers, including two at UC Santa Barbara, discovered that some riparian woodlands are benefitting from water that humans divert for our own needs. Although it seems like a boon to these ecosystems, the artificial supply of water begets an unintended dependence on this bounty, threatening the long-term survival of natural forest communities. The paper, published in the Proceedings of the National Academy of Sciences, spotlights the need for changes in the way water is managed across the state.

"We need to be more intentional in incorporating ecosystem water needs when we manage water--both for aquatic organisms and species on land," said lead author Melissa Rohde, a groundwater scientist at The Nature Conservancy who led the research as a doctoral student at State University of New York College of Environmental Science and Forestry (SUNY-ESF). "These forest ecosystems are in a precarious state because we have disrupted the natural hydrologic processes that these plant species rely upon to support and sustain key life processes."

In California's Mediterranean climate, plants and animals have adapted to rely on precipitation and soil moisture recharge during the rainy winter and spring seasons for reproduction and growth during the typically dry summers. Once soil moisture is exhausted, tree species often found in stream corridors, such as willows, cottonwoods and oaks, typically use deeper groundwater. However, the researchers discovered the story was more complicated.

By analyzing five years of vegetation greenness data from satellite imagery, the authors found that in some cases, these ecosystems were affected by "subsidies of water" delivered via human regulation of rivers, agricultural canals and discharges from wastewater treatment plants. Altered streamside woodlands in the most arid regions of the state stayed greener longer into the dry season and were less responsive to changes in groundwater levels than natural ecosystems.

"Although this seems like a good news story -- trees benefit from anthropogenic water management -- there is an important caveat," said co-author Michael Singer, a researcher at UC Santa Barbara's Earth Research Institute and a professor at Cardiff University in the United Kingdom. "In channels and canals with severely altered flow regimes, there are few if any opportunities for these trees to spawn new offspring. This means that once these riparian woodlands die off, they will not be replaced through forest succession."

Many of the most-altered stream ecosystems are in California's Central Valley, the state's agricultural hub, which produces a third of the produce for the United States. Following the Gold Rush in the 1850s, massive human settlement led to clearing of 95% of the natural floodplain woodlands across the region. These isolated and restricted riparian, or streamside, forests now provide important habitat for threatened and endangered species like the California red-legged frog, Chinook salmon and Swainson's hawk.

As water is rerouted from rivers into canals to accommodate urbanization and the multibillion-dollar agricultural industry, it creates an artificially stable environment for riparian woodland ecosystems. This encourages a "live fast, die young" community that favors trees that peak and then decline within a few decades. Key ecosystem functions -- such as the regeneration of new forest stands and their development over time -- are being compromised by the extensive alterations to streamflow and to river channels, which are fixed in place and no longer create new floodplain areas where young trees can establish.

"We call these forests the 'living dead' because the forest floor is devoid of saplings and younger trees that can replace the mature trees when they die," Rohde said. This has repercussions related to habitat for endangered species, biodiversity, carbon sequestration and climate change.

"California is one of the most biodiverse regions in the world, containing more species than the rest of the United States and Canada combined," said Rohde. "In the midst of the sixth mass extinction, the long-term sustainability of California's river ecosystems and the preservation of the rare and endemic species that live within them now rely on the deliberate, coordinated management of resource and government agencies."

This study is part of a $2.5 million suite of projects that the collaborators at SUNY-ESF, UC Santa Barbara and Cardiff University have funded throughout the U.S. Southwest and France. The investigators also include UCSB geography professor Dar Roberts, one of the study's co-authors. The goal is to develop water stress indicators for dryland riparian forest ecosystems threatened by climate change and increasing human water demand.

Rhode and The Nature Conservancy will use the insights from the study to provide scientific guidance to California natural resource agencies for sustainably managing groundwater-dependent ecosystems throughout the state. As Singer pointed out, the findings pertain to the recent sustainable groundwater legislation passed in California. The Sustainable Groundwater Management Act, requires all groundwater stakeholders to agree on sustainability targets for groundwater usage to support urban areas, agriculture, industry and ecology.

The research team used publicly available online data and Google Earth Engine, an open-source tool for analyzing data from satellites and other global spatial datasets. "Our methods and findings open up a whole new world of interdisciplinary research possibilities and ways that water practitioners can consider ecosystem water needs to achieve sustainable water management," Rohde said.

John Stella, a SUNY-ESF professor and principal investigator on the National Science Foundation grant that funded the study, characterized the work as "groundbreaking" for the way it "combined several big datasets in an innovative way to understand how climate and water management interact to put these sensitive ecosystems at risk."

"[The] findings are important for sustainably managing groundwater, not only throughout California, but in water-limited regions worldwide," Stella said. "By creatively harnessing and integrating these large environmental datasets, we can now answer resource management questions at a scale that was previously impossible."