Culture

An in vitro study conducted by a group of researchers at São Paulo State University (UNESP) in Araraquara, Brazil, shows how fungi and bacteria can activate genes associated with head and neck tumors, as the metabolism of biofilms (communities in which these microorganisms self-organize in a structured and coordinated manner) stimulate tumor cells by favoring the cell signaling pathways required for tumor development and resistance to treatment. The findings include entirely novel information on the links between microbial biofilms and cell behavior in head and neck cancer.

The researchers discovered that metabolites secreted by biofilms, termed the secretome, can modulate the expression of proto-oncogenes and cell cycle genes associated with tumor cell growth and survival. Their analysis of gene expression focused on two signaling pathways (EGFR/RAS/RAF/MEK/ERK and EGFR/PI3K/AKT/mTOR) that play a key role in tumor cell proliferation, differentiation, and survival. Alterations to gene expression in these pathways are highly prevalent in various types of tumor.

The researchers analyzed head and neck and oral cavity squamous carcinoma cells. Squamous cell carcinoma is the most common type of mouth cancer, which produces functional and aesthetic changes that degrade the patient’s quality of life.

The cells were challenged via stimulation by metabolites from biofilms of Candida albicans fungi and Staphylococcus aureus bacteria. These microorganisms are very frequent in users of dentures: prior research found both in 30%-40% of subjects examined.

Oral microbiota is known to play an important role in the development of cancer. Genetic markers associated with the presence of microorganisms have been identified for some types, such as stomach cancer, but there is no consensus regarding the most prevalent genes linked to head and neck cancer, and no molecular markers had hitherto been found for this disease, especially HPV-negative cancer, which has a worse prognosis.

According to a report on the study published in Frontiers in Cellular and Infection Microbiology, metabolites from C. albicans and S. aureus biofilms can endanger the homeostasis of normal and neoplastic oral epithelial cells, altering the expression of important genes such as CDKN1A, Bcl-2, PI3K, BRAF, hRAS and mTOR, impairing cell viability and survival, and disrupting the cell cycle profile.

The study was supported by FAPESP and the National Council for Scientific and Technological Development (CNPq). The project was also awarded funding by Colombia’s COLCIENCIAS and SAPIENCIA agencies (2015 call for doctorates abroad), and involved partnerships with UNESP’s Araraquara Dental School (FOAr) and Araraquara School of Pharmaceutical Sciences (FCFAr).

Understanding the cell cycle is important because cancer entails unchecked cell division and growth, with tumor cells potentially invading tissues and organs throughout the body. Failure of the inhibitors of this cycle and excessive signaling by cell division regulators can lead to tumor progression.

The oral microbiome is a diversified community of microorganisms with as many as 700 species of viruses, protozoans, bacteria and fungi. When biofilms develop, they produce metabolites that alter the immune response and can lead to chronic inflammation and even production of cancerous substances.

According to Paula Aboud Barbugli, a professor at FOAr-UNESP and co-leader of the study, the findings show that “molecules secreted by these microorganisms in biofilms may modulate host cell activities even far away from the primary infection site”.

For Carlos Eduardo Vergani, also a professor at FOAr-UNESP and principal investigator for the project, the results serve as a warning on the treatment of cancer patients who have dentures. “Control of biofilms, including denture and oral cavity hygiene, is extremely important to minimize inflammatory processes, as shown by our prior research and the study just published, which points to interference with the expression of genes associated with tumor progression,” Vergani told Agência FAPESP.

Another study led by Vergani and published in 2017 showed that soluble factors in methicillin-sensitive C. albicans and S. aureus biofilm promoted cell death and inflammatory responses.

According to a report issued in March by Brazil’s National Cancer Institute (INCA), some 22,800 new cases of laryngeal and oral cavity cancer are reported each year, most of them in male patients.

Future

The COVID-19 pandemic forced the group to interrupt the clinical trial they had planned to conduct on the basis of their research. Barbugli said a PhD project supervised by another member of the group and approved by the Ministry of Health’s Research Ethics Committee (CONEP) will investigate the prevalence of C. albicans and S. aureus biofilms in the dentures and oral cavities of head and neck cancer patients treated at Araraquara’s Santa Casa de Misericórdia Hospital to understand how they influence prognosis in these cases.

For Vergani, the results obtained so far pave the way for future metabolomics and proteomics research into oral biofilms.

Geothermal ecosystems, such as volcanoes and hot terrestrial and deep-sea springs, are characterized by severe conditions. The temperatures are high and the environment could be extremely acidic or very alkaline. Moreover, there are chemically active compounds in them that can be fatal to living organisms, because they are capable of destroying the membrane of an ordinary cell.

"Exclusively very adapted microorganisms can exist here. They do not only have unique protective systems but are also able to get energy from chemical transformations of those substances that are available to them. Humans are actively using the peculiarities of their metabolism, for example some enzymes help biologists to amplify DNA molecules in a test tube," says Vitaly Kadnikov, Ph.D., senior researcher at the Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences and the principal investigator of the grant from the Russian Science Foundation.

New and so far poorly understood analogs of these natural ecosystems (called simply thermal) are places of hydrocarbon production, that is, oil wells and coal pits. The latter is the research object of a group of scientists from the Federal Research Centre "Fundamentals of Biotechnology" of RAS (Moscow) and Tomsk State University (Tomsk). The authors studied quarries near the city of Kiselevsk, Kemerovo region, and took samples of soil layers from places where there were signs of an underground fire-heated soil, smoke and where steam is coming out to the surface. They characterized the chemical and mineralogical composition of the samples to understand what substances could be used for energy by the bacteria that colonize the coal. Then biologists determined the composition of microbial communities from each layer by analyzing the DNA from it, namely, the gene sequence of one of the ribosome subunits usually used for such purposes.

It turned out that more than a dozen groups of microorganisms live in the Kuzbass quarry, the bacteria mostly. Archaea which are considered to be common inhabitants of extreme ecosystems turned out to be no more than 3%; they are all chemolithoautotrophs converting ammonia into nitrite. The latter compound became "food" for another small group of organisms that metabolize it into nitrate, which people use, for example, as fertilizer.

The representatives of the Chlorobacteria predominated among the bacteria, often found in ecosystems with a high carbon dioxide content; they are also capable of converting poisonous carbon monoxide into CO2. This might be applied for new air purification technologies wherever a furnace is used. Some bacteria found in coal seams can oxidize hydrogen with water formation.

There have also been found microbes that utilize methane as a growth substrate. Many of the identified organisms can fix carbon dioxide and grow autotrophically, but there have been those that feed on the dead remains of their fellows. The Kuzbass quarry turned out to be a well-balanced microbial community, surpassing similar objects studied earlier in China, the US, and Altai in diversity.

"Our research is another step towards understanding how these relatively young ecosystems emerged, what connections they have and whether we can use them. They have much in common with those that form around hot springs. Who knows, maybe they comprise very specific organisms that will help to develop new ways of obtaining valuable biotechnological products by using hydrogen and carbon monoxide generated during coal gasification," says Vitaly Kadnikov.

BOSTON -- A multidisciplinary team from MassGeneral Hospital for Children (MGHfC), Brigham and Women's Hospital and other institutions have identified the mechanism of how an extremely rare but serious post-COVID-19 complication develops in children and adolescents. Led by MGHfC pediatric pulmonologist Lael Yonker, MD, researchers determined that viral particles remaining in the gut long after an initial COVID-19 infection can travel into the bloodstream, instigating the condition called Multisystem Inflammatory Syndrome in Children (MIS-C).

The syndrome can occur several weeks after an initial infection; symptoms include high fever, abdominal pain, vomiting, diarrhea, rash and extreme fatigue. The hyperinflammatory response and "cytokine storm" seen in MIS-C can lead to extensive damage in the heart, liver and other organs.

Eighty percent of children hospitalized with MIS-C develop severe cardiac pathology and face a prolonged hospital stay and extensive recovery period. Current treatment strategies include an aggressive, long-term course of steroids and intravenous immunoglobulin.

MIS-C occurs in less than 1 percent of children with confirmed SARS-CoV-2 infection. As of May 3, 2021, the U.S. Centers for Disease Control and Prevention reported 3,742 children diagnosed with MIS-C and 35 deaths. U.S. statistics are skewed heavily toward Latino and Black children, with a total of 63 percent in cases with race or ethnicity listed.

In their recent study published in the Journal of Clinical Investigation, which included 100 children (19 with MIS-C, 26 with COVID-19 and 55 healthy controls), the researchers provide insight into the mechanics of MIS-C and identify potential biomarkers for early disease detection, treatment and prevention. They also describe the successful treatment of a 17-month-old infant with MIS-C.

"When we realized that 95 percent of the children with MIS-C had SARS-CoV-2 viral particles in their stool but no or low levels of particles in their noses or throats, we investigated further and found that viral material lingering in the gut long after the first COVID-19 infection could lead to MIS-C," says Yonker, lead author of the paper. The team hypothesized that SARS-CoV-2 viral particles found in the gastrointestinal tract of children move into the bloodstream, leading to the hyperinflammatory immune response characteristic of MIS-C. "This is the first study showing viral particles in the blood of MIS-C coinciding with the hyperinflammatory response," says Yonker.

Co-senior author Alessio Fasano, MD, head of MGHfC's Division of Pediatric Gastroenterology and Nutrition, is an expert on the mechanics of intestinal immune responses to pathogens. In 2000, Fasano and his team at the University of Maryland School of Medicine discovered zonulin, a protein that regulates intestinal permeability by opening the tight junctions between gut epithelial cells in the small intestine.

This opening of the spaces between epithelial cells allows the passage of substances from the gut lumen into the bloodstream, including gluten, which can cause symptoms for people genetically predisposed to celiac disease. In the early 2000s, Fasano developed larazotide acetate to work as a zonulin blocker in the treatment of celiac disease.

Prior to the advent of COVID-19, Fasano and Moshe Arditi, MD, director of the Infectious and Immunological Diseases Research Center at Cedars-Sinai in Los Angeles, co-authored a paper about a study on Kawasaki disease, a condition very similar to MIS-C, in which they showed that mice with elevated zonulin levels could be successfully treated with larazotide acetate. Subsequently, Arditi, Yonker and Fasano showed that the immune response in MIS-C is consistent with superantigenic activation. "The large spike protein--the superantigen--basically holds onto a T-cell and makes it fire off a continuous immune response," says Yonker.

In the current study, the researchers measured high levels of SARS-CoV-2 virus in the stools and high levels of zonulin in the blood of children with MIS-C. When they subsequently found viral particles in the blood, Fasano suggested the use of larazotide acetate as a therapeutic. Encouraging preliminary data on the efficacy of larazotide acetate in treating the first case of MIS-C, after obtaining compassionate use permission from the Food and Drug Administration, opened up the possible use of larazotide acetate as the first oral treatment for COVID-19 and its complications.

"Our hypothesis was that larazotide would reduce the hyperinflammation by closing the tight junctions and preventing the large spike proteins of the SARS-CoV-2 virus from entering the bloodstream," says Fasano.

Adds Yonker: "Our next plan is to develop a clinical trial to study the effect of larazotide on clinical outcomes in MIS-C. To go from characterizing a new disease, to understanding its cause, to identifying a possible new treatment is just incredible."

Cells are the building blocks of life, present in every living organism. But how similar do you think your cells are to a mouse? A fish? A worm?

Comparing cell types in different species across the tree of life can help biologists understand how cell types arose and how they have adapted to the functional needs of different life forms. This has been of increasing interest to evolutionary biologists in recent years because new technology now allows sequencing and identifying all cells throughout whole organisms. "There's essentially a wave in the scientific community to classify all types of cells in a wide variety of different organisms," explained Bo Wang, an assistant professor of bioengineering at Stanford University.

In response to this opportunity, Wang's lab developed an algorithm to link similar cell types across evolutionary distances. Their method, detailed in a paper published May 4 in eLife, is designed to compare cell types in different species.

For their research, the team used seven species to compare 21 different pairings and were able to identify cell types present in all species along with their similarities and differences.

Comparing cell types

According to Alexander Tarashansky, a graduate student in bioengineering who works in Wang's laboratory, the idea to create the algorithm came when Wang walked into the lab one day and asked him if he could analyze cell-type datasets from two different worms the lab studies at the same time.

"I was struck by how stark the differences are between them," said Tarashansky, who was lead author of the paper and is a Stanford Bio-X Interdisciplinary Fellow. "We thought that they should have similar cell types, but when we try analyzing them using standard techniques, the method doesn't recognize them as being similar."

He wondered if it was a problem with the technique or if the cell types were just too different to match across species. Tarashansky then began working on the algorithm to better match cell types across species.

"Let's say I want to compare a sponge to a human," said Tarashansky. "It's really not clear which sponge gene corresponds to which human gene because as organisms evolve, genes duplicate, they change, they duplicate again. And so now you have one gene in the sponge that may be related to many genes in humans."

Instead of trying to find a one-to-one gene match like previous methods for data matching, the researchers' mapping method matches the one gene in the sponge to all potentially corresponding human genes. Then the algorithm proceeds to figure out which is the right one.

Tarashansky says trying to find only one-to-one gene pairs has limited scientists looking to map cell types in the past. "I think the main innovation here is that we account for features that have changed over the course of hundreds of millions of years of evolution for long-range comparisons."

"How can we use the ever-evolving genes to recognize the same cell type that are also constantly changing in different species?" Said Wang, who is senior author of the paper. "Evolution has been understood using genes and organismal traits, I think we are now at an exciting turning point to bridge the scales by looking at how cells evolve."

Filling in the tree of life

Using their mapping approach, the team discovered a number of conserved genes and cell type families across species.

Tarashansky said a highlight of the research was when they were comparing stem cells between two very different flatworms.

"The fact that we did find one-to-one matches in their stem cell populations was really exciting," he said. "I think that basically unlocked a lot of new and exciting information about how stem cells look inside a parasitic flatworm that infects hundreds of millions of people all over the world."

The results of the team's mapping also suggest there's a strong conservation of characteristics of neurons and muscle cells from very simple animal types, such as sponges, to more complex mammals like mice and humans.

"That really suggests those cell types arose very early on in animal evolution," Wang said.

Now that the team has built the tool for cell comparison, researchers can continue to collect data on a wide variety of species for analysis. As more datasets from more species are collected and compared, biologists will be able to trace the trajectory of cell types in different organisms and the ability to recognize novel cell types will improve.

"If you only have sponges and then worms and you're missing everything in between, it's hard to know how the sponge cell types evolved or how their ancestors have diversified into sponges and worms," said Tarashansky. "We want to fill in as many nodes along the tree of life as possible to be able to facilitate this type of evolutionary analysis and transfer of knowledge across species."

One in five women experience pain during intercourse. The latest edition of the Diagnostic and Statistical Manual of Mental Disorders, the bible of American psychiatrists, lists it under "genito-pelvic pain or penetration disorder." However, this type of pain is not purely psychological.

Provoked vestibulodynia is a condition experienced by approximately 8% of women in North America. It is characterized by severe pain at the vaginal opening during sexual intercourse or when inserting tampons. To reduce the burning sensation, many women apply lidocaine, an anesthetic cream.

A new study of 108 couples found cognitive-behavioural therapy (CBT) for couples to be more effective than lidocaine. The study was conducted by Sophie Bergeron, professor in the Psychology Department in the Faculty of Arts and Science at Université de Montréal, director of the UdeM Sexual Health Laboratory and holder of the Canada Research Chair in Intimate Relationships and Sexual Wellbeing, and Natalie O. Rosen of Dalhousie University. Marc Steben and Marie-Hélène Mayrand of Université de Montréal, Marie-Pier Vaillancourt-Morel of Université du Québec à Trois-Rivières, Serena Corsini-Munt of the University of Ottawa, and Isabelle Delisle also contributed to the study, which has just been published in the Journal of Consulting and Clinical Psychology.

Unclear causation

The causes of provoked vestibulodynia have yet to be determined. There is a lengthy list of risk factors, including biomedical factors such as repeated infections causing inflammation in the vulvar area (cystitis, vaginal infections), the use of certain oral contraceptives, genetic predisposition, marital factors, and depression and anxiety. Abnormalities in the pelvic floor muscles are also associated with provoked vestibulodynia, but it is not known whether they are a consequence of the pain or its cause. Similarly, it is unclear whether anxiety is a cause or a result, but it has been found that the higher the level of anxiety, the greater the pain.

"Psychological intervention is recommended because once pain sets in, it has such a negative impact on sexuality and on the relationship that it becomes very important to break the vicious cycle of fear and avoidance," says Sophie Bergeron. "The pain often leads to loss of desire in women and frustration in both partners. This is a real problem; it's not imaginary."

Few validated treatments

Couple therapy is commonly offered by psychologists and sexologists. In the case of provoked vestibulodynia, the partner plays a critical role and can help alleviate the problem or aggravate it. It is therefore every important to include the partner in the intervention. However, some interventions were not previously supported by evidence.

Now for the first time, a randomized clinical trial has compared the efficacy of couple CBT and lidocaine.

Therapy was found to be more effective than lidocaine application in reducing women's fear of pain, sexual distress and alarm, and in improving their sexual experience. After six months, the women were twice as satisfied with their sex lives and their partners three times as satisfied.

Nature of the sessions

The couples attended acceptance and commitment therapy (ACT) sessions for 12 weeks.

"Acceptance means that instead of trying to get a person to change their thinking, we encourage them to accept it," Bergeron explains. "We practice cognitive defusion, a technique that creates a psychological distance between the person and his or her thoughts. At the beginning of the therapy, the women define themselves by their genito-pelvic pain. The therapy helps them reduce the hold those thoughts have over them. We also try to break the sexuality = pain association and replace it with new associations, such as sexuality = pleasure with my partner, intimacy with my partner."

The therapy also looks at sexual motivations. What is it about sexuality that is important to the couple? "We try to explore other aspects of sexuality that are pleasurable," she says. "In terms of behaviour, we can help them expand their repertoire of sexual activities that don't cause pain. Generally, it's vaginal penetration that's painful, so we try not to always focus on that."

Finally, the therapy works on the couple's emotional regulation. "When one partner reacts to a painful experience with anger or frustration, it only makes the problem worse. We help the couple manage their emotional relationship. We get the partner to be more empathetic to the woman's experience of pain and the woman to be more empathetic to her partner's frustration. We help them see themselves as a united team."

The importance of the partner in therapy

According to Sophie Bergeron, the partner's involvement "helps alleviate the woman's pain because she is no longer alone with her pain." Both partners report they understand the problem and the other's experience better, and they are relieved to be able to work together to improve the situation.

At the end of the therapy, couples report satisfaction with having reclaimed their sexuality in a non-threatening way by refocusing on pleasurable experiences rather than allowing the pain to take control. This treatment could well be effective for other types of genito-pelvic pain as well.

While some studies suggest female patients treated by female physicians have better outcomes, there does not appear to be a relationship between operator and patient gender and outcome in patients undergoing coronary angioplasty or stenting. These are the results of a first-of-its-kind study by the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) and published in Catheterizations and Cardiovascular Interventions.

The study looked at procedures performed by 385 male interventional cardiologists, and 18 female interventional cardiologists at 48 non-federal hospitals across the state of Michigan. Female interventional cardiologists continue to be markedly under-represented and only perform a small percentage of cases, with women accounting for only 4.5% of interventional cardiologists and performing only 3% of procedures.

Despite interventional cardiology remaining an overwhelmingly male-dominated specialty, female physicians in this field stand out as excellent practitioners. Coronary angioplasties done by female physicians were more frequently rated as appropriate as compared to procedures performed by their male counterparts, among those studied. Female interventional cardiologists also more frequently prescribe recommended medical therapies than male interventional cardiologists. No differences in death, kidney injury, major bleeding or blood transfusions were found between patients treated by male or female interventional cardiologists.

"While the overall care processes and outcomes in Michigan were great, and similar for operators of either sex, the female physicians scored higher on appropriateness and post-procedural therapy These findings would benefit female trainees who are considering interventional cardiology but are concerned about perceived barriers," says the lead author of the study, Prasanthi Yelavarthy, MD.

Gurm is an interventional cardiologist at the Michigan Medicine Frankel Cardiovascular Center, and Yelavarthy is a house officer at Michigan Medicine.

BMC2 is a collaborative consortium of health care providers in the State of Michigan comprised of three statewide quality improvement projects:

A prospective multicenter statewide registry of consecutive percutaneous coronary interventions (BMC2 PCI).

A prospective, longitudinal multicenter statewide registry of vascular surgeries and carotid interventions (BMC2-Vascular surgery).

Michigan TAVR, a structural heart quality improvement initiative focused on transcatheter aortic valve replacement in collaboration with the Michigan Society of Thoracic and Cardiovascular Surgeons.

All projects are designed to improve quality of care and patient outcomes. The collaboration across BMC2 overcomes the barriers of traditional market and academic competition. All projects collect, audit and organize data and report procedural variables and outcomes to individual operators and institutions.

Journal

Catheterization and Cardiovascular Interventions

DOI

10.1002/ccd.29774

CHAMPAIGN, Ill. -- Advanced microscope technology and cutting-edge geological science are giving new perspectives to an old medical mystery: How do kidney stones form, why are some people more susceptible to them and can they be prevented?

In a new paper published in the journal Nature Reviews Urology, researchers from the University of Illinois Urbana-Champaign, Mayo Clinic and other collaborators described the geological nature of kidney stones, outlined the arc of their formation, established a new classification scheme and suggested possible clinical interventions.

"The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature," Illinois geology professor Bruce Fouke said. "We are bringing together geology, biology and medicine to map the entire process of kidney stone formation, step by step. With this road map in hand, more effective and targeted clinical interventions and therapies can now be developed."

Kidney stones are a painful problem that will strike one in 10 adults in their lifetime and send half a million people in the United States to emergency rooms each year, according to the National Kidney Foundation. Yet little is understood about the geology behind how kidney stones form, Fouke said.

Previous work from Fouke's group found that kidney stones form in the same way as geological stones in nature: Rather than crystalizing all at once, they partially dissolve and re-form multiple times, contrary to doctors' belief that they form suddenly and intact.

In the new work, the research team - brought together by the Mayo Clinic and Illinois Alliance for Technology-Based Healthcare - describes in detail the multiple phases kidney stones go through in forming, dissolving and re-forming, documented through high-resolution imaging technologies. The findings defy the typical classification schemes doctors use, which are based on bulk analyses of the type of mineral and the presumed location of formation in the kidney. Instead, the researchers developed a new classification scheme based on which phase of formation the stone is in and which chemical processes it is undergoing.

"If we can identify these phase transformations, what makes one step to go to another and how it progresses, then perhaps we can intervene in that progression and break the chain of chemical reactions happening inside the kidney tissues before a stone becomes problematic," said Mayandi Sivaguru, the lead author of the study and assistant director of core facilities at the Carl R. Woese Institute for Genomic Biology at Illinois.

One particularly revelatory finding was in the very beginnings of kidney stone formation: Stones start as microspherules, or tiny droplets of mineral, which merge to form larger crystals throughout kidney tissues. Normally they are flushed out, but when they coalesce together to form larger stones that continue to grow, they can become excruciatingly painful and even deadly in some cases, Fouke said.

"Stone formation is part of a natural, healthy process within kidneys where these tiny mineral deposits are shuttled away and excreted from the body," Fouke said. "But then there is a tipping point when those same mineral deposits start to grow together too rapidly and are physically unable to leave the kidney."

As the stone goes through the formation process, more microspherules merge, lose their rounded shape and transform into much larger, perfectly geometric crystals. Stones go through multiple cycles of partially dissolving - shedding up to 50% of their volume, the researchers found - and then growing again, creating a signature pattern of layered crystals much like those of agates, coral skeletons and hot-spring deposits seen around the world.

"Looking at a cross-section of a kidney stone, you would never guess that each of the layers was originally a bunch of little balls that lined up and coalesced. These are revolutionary new ways for us to understand how these minerals grow within the kidney and provide specific targets for stone growth prevention," Fouke said.

The study authors outlined several possible clinical interventions and treatment targets based on this expanded knowledge of kidney stone formation. They hope that researchers and clinicians can explore and test these options, from drug targets to changes in diet or supplements that could disrupt the chemical and biological cascade driving kidney stone formation, Sivaguru said.

To aid in this testing, Fouke's group developed the GeoBioCell, a microfluidic cartridge designed to mimic the intricate internal structures of the kidney. The group hopes the device can accelerate not only research, but also clinical diagnostic testing and the evaluation of potential therapies, especially for the more than 70% of kidney stone patients with recurring stones.

"Ultimately, our vision is that every operating room would have a small geology lab attached. In that lab, you could do a very rapid diagnostic on a stone or stone fragment in a matter of minutes, and have informed and individualized treatment targets," Fouke said.

Discovered by Victor Hess in 1912, cosmic rays, relativisitic particles that shower Earth, contribute a signicant part of the energy density in the universe and carries unambiguous informations on various astrophysical processes . Yet until now, origin of cosmic rays is still a mystery.

A key problem in understanding the origin of cosmic rays is the searching for the acceleration site up to or even beyond Ultra-high energy (UHE). Such extreme accelerators are dubbed as PeVatrons. However, composed of subatomic particles, such as protons or atomic nuclei, cosmic rays are charged and lose the direction information in propagating in the magnetic field in the interstellar medium, which make it impossible to identify the PeVatrons from direct cosmic ray measurement. On the other hand, UHE γ-rays, those fall in peta-electronvolt (1015 eV) range, are produced unavoidably inside or in the vicinity of PeVatrons. γ-rays are not charged and travel straight , thus they can be regarded as the straightforward signature to identify PeVatrons.

A new observatory, the Large High Altitude Air Shower Observatory (LHAASO) located at Sichuan, China, detected dozen Ultra-high Energy gamma-ray sources, opening a new window into the γ-ray sky, which indicate that the existence of a population of PeVatrons in our Galaxy.

In this article, though not fully installed, the half Kilometer Square Array (KM2A), one of the three interconnected detectors that constitute LHAASO, reported 12 PeVatrons with the statistical significance greater than 7 standard devition after observation using 11 months data. Of these sources, two have been detected with energy over 0.8 PeV, an energy equivilant to accelerate an electron with electric potential of 0.8 million billion electronvolts, and one with highest energy exceeded 1.4 PeV.

The 12 γ-ray emitting regions identified by LHAASO prompts the presence of active or recent PeVatrons. Team led by Professor YANG Ruizhi from the University of Science and Technology of China discussed some possible candidates, including pulsar wind nebulae, supernova remnants and star-forming regions, with multi-wavelength data.

To support the detection of UHE γ-rays, the team led by Professor LI Cheng from the University was responsible for the design and quality assurance/check of over 3000 high-dynamic-range large-size photodetectors for muon detectors of KM2A and Water Cherenkov Detector Array (WCDA), another component of LHAASO.

The team led by Professor AN Qi from the University designed, tested, and installed the readout electronics system for the 8'' and 20'' PMTs in WCDA, which achieves high precsion time and charge measurement over a large input dynamic range of 1 Photon Electron (P.E.) ~4000/2000 P.E..

Full article was published on Nature.

With comprehensive multi-wavelength data, researcher will be able to firmly identify and locate PeVatrons in the future. Longer observation and full installation of LHAASO is also expected to provide more detailed information on reported PeVatrons and to discover even more PeVatrons, which would advance the understanding of the origin of cosmic rays.

Press release - Abstract 481: Effects of testosterone therapy on morphology and grade of NAFLD in obese men with functional hypogonadism and type 2 diabetes

According to a new study, testosterone therapy may reduce non-alcoholic fatty liver disease in obese men with functional hypogonadism and type-2 diabetes.

Testosterone therapy may help obese men with functional hypogonadism and type-2 diabetes reduce the prevalence of non-alcoholic fatty liver disease (NAFLD), according to a study being presented at the 23rd?European Congress of Endocrinology (e-ECE 2021), on Tuesday 25 May 2021 at 14:00 CET (http://www.ece2021.org). The two-year study found that therapy with testosterone undecanoate normalised testosterone levels, reduced NAFLD, and suppressed the symptoms of hypogonadism in men living with these conditions.

NAFLD is emerging as a public health issue worldwide. It is estimated that prevalent cases will increase 21% by 2030, from 83.1 million to 100.9 million. NAFLD is more commonly found in people with type-2 diabetes, and is linked to obesity, insulin resistance and atherogenic dyslipidemia. NAFLD refers to excess fat accumulation in the liver, in the absence of excessive alcohol consumption. Alcohol consumption of less than 30 g (3.75 units) per day for men is used as the cut-off to diagnose NAFLD. As an increasing global health issue, this study and its findings may be a promising area for further research.

Dr Kristina Groti Antonic and her team from the University of Ljubljana, Slovenia, carried out a large study on the effects of testosterone therapy on glycemic control, metabolic parameters, vascular function and morphology in obese men with hypogonadism and type-2 diabetes mellitus. They presented a part of this study at e-ECE 2021 in which they evaluated the effects of testosterone therapy on morphology and grade of NAFLD in this population. The two-year clinical trial saw 55 males with functional hypogonadism and type-2 diabetes participate. The first year focused on a double blind, placebo-controlled study and the following year was used for follow-up.

During the study, the participants were randomised into two groups. The first group received testosterone undecanoate during both years of the study, while the second group received a placebo in the first year and testosterone therapy in the second year. A range of tests including testosterone levels, prostate specific antigen and routine blood tests were assessed at the beginning of the trial, 12 and 24 months. Liver ultrasounds for NAFLD grade assessments were performed at the beginning and after two years, which showed an improvement in NAFLD grades after two years of the trial.

Dr Kristina Groti Antonic shared that, "improvement of NAFLD grade was a result of improved insulin resistance, reduction in body mass index and body weight, along with changes in body composition. As we know, testosterone increases lean body mass at the expense of fat mass, either alone or in combination with behavioral and lifestyle modifications. Testosterone with its anti-inflammatory effects also reduced chronic inflammatory state in the liver. Our study shows that testosterone therapy could be used as a suitable therapy for obese men living with non-alcoholic fatty liver disease, and therefore the findings can be used to tackle this growing pandemic."

This knowledge could help obese men living with functional hypogonadism and type-2 diabetes experience normalised testosterone levels and reduced prevalence of non-alcoholic fatty liver disease.

Summary: A new study published by the open access publisher Frontiers shows the usefulness of opportunistically collected specimens, such as stranded carcasses, to study elusive species. The researchers used stable isotope analysis of skin, muscle, and bone tissue of Sowerby’s beaked whales to study their spatial ecology. They found that the species exhibits both short- and long-term habitat fidelity. The results are published in Frontiers in Conservation Science and show the importance of such studies for marine wildlife conservation.

A mysterious whale species

Beaked whales, a species of toothed whales, make up more than 25% of extant cetaceans (dolphins, porpoises, and whales), but are elusive and notoriously difficult to study. They live in deep waters and stay away from shores. Due to a lack of observations from the wild, little is known about their ecology and biology. Because of this, they are considered 'data deficient' by the IUCN Red List and developing conservation plans is challenging.

Some species of beaked whales have never been observed alive and are only known from stranded carcasses. "Beaked whales are really cool, but most people haven't heard of them because they are so enigmatic. Whales are generally large and charismatic - we can go on whale watching trips and see them in the wild, yet there are entire groups of whale species we know almost nothing about," says Dr Kerri Smith, of the University of Texas El Paso and the Smithsonian National Museum of Natural History, United States.

Sowerby's beaked whales (Mesoplodon bidens) were first described more than 200 years ago, yet little is known about this species. The species' geographic range is thought to cover much of the North Atlantic Ocean. Stranded animals have been collected from both North American and European waters, but it is unknown if the species is structured into spatially separate subpopulations or if there is one continuous and highly mobile population.

Stable isotope analysis to study elusive animals

Stable isotopes get incorporated into different tissue types through diet. The rate at which stable isotopes get incorporated into a tissue depends on the tissue's growth and replacement rates. For example, skin turnover rates are faster than those of muscle, which in turn are faster than the turnover of bone. Stable isotope analysis is an efficient tool that can be used when traditional techniques, such as GPS tracking and camera recording from field observations, can't be applied. It can be used to answer ecological and biological questions about a species' diet or spatial origin across time.

To better understand the species' spatial range, the researchers measured the carbon isotope (δ13C) and nitrogen isotope (δ15N) composition of skin, muscle, and bone tissue of Sowerby's beaked whales from the east and west Atlantic. The 102 samples were collected from museum specimens, stranded carcasses, and bycaught animals, and included females and males from all ages.

A treasure trove of data

When researchers work with specimens of opportunity, there is little control over how samples were collected. "In our study, the majority of our specimens came from strandings and fisheries bycatch; since these specimens represent only a small portion of all Sowerby's beaked whales, we only have a few pieces of a large, complex puzzle. Those pieces can tell us a lot, however, and the more we study these whales, the more we will learn about their distributions, behavior, and lives."

The results show that there are at least two subpopulations of Sowerby's beaked whales, one each in the eastern and western Atlantic. "Our study has two major results. First, it demonstrates the power of specimens of opportunity to answer fundamental ecological questions - these specimens are treasure troves of data waiting for someone to query them," says Smith. "Second, it provides some of the first data about Sowerby's beaked whale long-term distribution and population structure, something that would be nearly impossible to learn by studying living whales in their habitat. We can learn a lot about beaked whale ecology from specimens of opportunity." The researchers suggest genetic analysis to explore possible genetic differentiation between the two populations.

The findings have implications for marine wildlife conservation. The two populations found here likely have different conservation needs. Smith concludes: "A key action to take going forward is generating more fundamental data through studies like this one - successful conservation action requires a strong foundation of reliable data, and there is still so much we do not know about beaked whales and many other marine species. As we learn more about them and their habitats, we may need to set aside important habitats as marine protected areas. Additional research to identify the potential influence of fishing activities and naval sonar on critical beaked whale habitats is also needed."

What The Study Did: This study evaluates the association between bitter taste receptor types (supertasters who experience greater intensity of bitter tastes; tasters; and nontasters who experience low intensity of bitter tastes or no bitter tastes) and outcomes after infection with SARS-CoV-2.

Authors: Henry P. Barham, MD, Sinus and Nasal Specialists of Louisiana in Baton Rouge, is the corresponding author.

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What The Study Did: Researchers examined if circulating sex hormones are associated with disease severity in patients with COVID-19.

Authors: Sandeep Dhindsa, M.D., of the St Louis University School of Medicine and Abhinav Diwan, M.D., of the Washington University School of Medicine, both in St. Louis, are the corresponding authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

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What The Study Did: Rates of depression, anxiety, suicidal thoughts and posttraumatic stress disorder among current and former coal miners in the United States were examined in this study.

Authors: Drew Harris, M.D., of the University of Virginia in Charlottesville, is the corresponding author.

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While we sleep, the brain produces particular activation patterns. When two of these patterns - slow oscillations and sleep spindles - gear into each other, previous experiences are reactivated. The stronger the reactivation, the clearer will be our recall of past events, a new study reveals.

Scientists have long known that slow oscillations (SOs) and sleep spindles - sudden half-second to two-second bursts of oscillatory brain activity - play an important role in the formation and retention of new memories.

But experts in the UK and Germany have discovered that the precise combination of SOs and sleep spindles is vital for opening windows during which memories are reactivated; helping to form and cement memories in the human brain.

Researchers at the University of Birmingham and Ludwig-Maximilians-University Munich today published their findings in Nature Communications.

Co-author Dr Bernhard Staresina, from the University of Birmingham's School of Psychology, commented: "Our main means of strengthening memories while we sleep is the reactivation of previously learnt information, which allows us to solidify memories in neocortical long-term stores.

"We have discovered an intricate interplay of brain activity - slow oscillations and sleep spindles - which create windows of opportunity enabling this reactivation."

Co-author Dr Thomas Schreiner, from Ludwig-Maximilians-University, Munich, commented: "Memory reactivation is specifically bound to the presence of SO-spindle complexes. These results shed new light on the memory function of sleep in humans and emphasise the importance of orchestrated sleep rhythms in strengthening our powers of recall and orchestrating the creation of memories."

Before this study, evidence of the brain's capacity to reactivate memories during sleep was scarce, but the team devised novel tests where participants were shown information before taking a nap and closely monitored brain activity during non-rapid eye movement (NREM) sleep using EEG recording. Those taking part were then tested on their memory recall after waking up, allowing the researchers to link the extent of memory reactivation during sleep to memory performance.

The results revealed reactivation of learning material during SO-spindle complexes, with the precision of SO-spindle coupling predicting how strongly the memory would be reactivated by the brain. This in turn predicted the level of memory consolidation across participants and the subsequent clarity of recall.

HOUSTON - (May 25, 2021) - Sometimes things are a little out of whack, and it turns out to be exactly what you need.

That was the case when orthoferrite crystals turned up at a Rice University laboratory slightly misaligned. Those crystals inadvertently became the basis of a discovery that should resonate with researchers studying spintronics-based quantum technology.

Rice physicist Junichiro Kono, alumnus Takuma Makihara and their collaborators found an orthoferrite material, in this case yttrium iron oxide, placed in a high magnetic field showed uniquely tunable, ultrastrong interactions between magnons in the crystal.

Orthoferrites are iron oxide crystals with the addition of one or more rare-earth elements.

Magnons are quasiparticles, ghostly constructs that represent the collective excitation of electron spin in a crystal lattice.

What one has to do with the other is the basis of a study that appears in Nature Communications, where Kono and his team describe an unusual coupling between two magnons dominated by antiresonance, through which both magnons gain or lose energy simultaneously.

Usually, when two oscillators resonantly couple, one gains energy at the expense of the other, conserving total energy, Kono said.

But in antiresonant (or counterrotating) coupling, both oscillators can gain or lose energy at the same time through interaction with the quantum vacuum, the zero-point field predicted to exist by quantum mechanics.

Think of it as an ephemeral seesaw that can be forced to bend in the middle.

Makihara and co-authors Kenji Hayashida of Hokkaido University and physicist Motoaki Bamba of Kyoto University used the discovery to show via theory the likelihood of significant quantum squeezing in the ground state of the coupled magnon-magnon system.

In the squeezed state, the amount of fluctuation, or noise, of a measurable quantity associated with the magnons can be suppressed, with simultaneously increased noise in another quantity, Kono said. "It's related to the Heisenberg uncertainty principle in which a set of variables is correlated, but if you try to precisely measure one, you lose information about the other. If you squeeze one, uncertainty about the other grows.

"Usually, in order to create a quantum squeezed state, one has to strongly drive the system using a laser beam. But Takuma's system is intrinsically squeezed; that is, it can be described as an already squeezed state," he said. "This could become a useful platform for quantum sensing applications."

Makihara said the unique state is achieved with a strong magnetic field like that used in magnetic resonance imaging. The field applies torque to the magnetic moments in atoms, in this case those of the orthoferrite. That causes them to rotate (or precess).

That takes a powerful field. The Kono lab's RAMBO -- the Rice Advanced Magnet with Broadband Optics -- is a unique spectrometer developed with physicist Hiroyuki Nojiri at Tohoku University that allows researchers to expose materials cooled to near absolute zero to powerful magnetic fields up to 30 tesla in combination with ultrashort laser pulses.

"We were saying, 'What can we study with RAMBO? What new physics is there in this unique regime?'" said Makihara, now a graduate student at Stanford University. "Orthoferrites have these magnons that shift up to 30 tesla and frequencies in the terahertz regime. The initial measurements weren't that interesting.

"But then we received crystals (grown by Shanghai University physicist Shixun Cao and his group) that didn't have perfectly parallel faces," he said. "They were kind of cut at an angle. And one day, we loaded the crystal on the magnet at such an angle that the magnetic field was not applied along the crystal axis.

"We expected the magnon frequency to just shift up with the magnetic field, but when it was tilted, we saw a small gap," Makihara said. "So, after discussing this finding with Professor Bamba, we explicitly requested crystals that were cut at different angles and measured those, and saw this huge degree of anti-crossing. That's the signature of ultrastrong coupling."

Antiresonance always exists in light-matter and matter-matter interactions but is a minor presence compared to the dominant resonant interaction, the researchers noted. That was not the case with the orthoferrites studied by the Kono lab.

Exposing the material to a high magnetic field and tilting the crystal with respect to the field pumped antiresonance that equaled and even surpassed the resonance.

If additional rotating magnetic fields (for instance, from circularly polarized light) are introduced, the precessing moments strongly interact with fields that rotate with the moments (the co-rotating fields), whereas they weakly interact with fields that rotate in the opposite directions (the counterrotating fields).

In quantum theory, Bamba said, these so-called counterrotating interactions lead to bizarre interactions where both the light and matter subsystems can gain or lose energy at the same time. The interactions between the magnetic moments and the counterrotating fields are considered antiresonant and normally have little effect. However, in the matter-matter coupled system studied at Rice, the antiresonant interactions could be made dominant.

"The strength of the co-rotating and counterrotating interactions is usually a fixed constant in a system, and the effects of the co-rotating interactions always dominate those of the counterrotating interactions," Kono said. "But this system is counterintuitive because there are two independent coupling strengths, and they are incredibly tunable via crystal orientation and magnetic field strength. We can create a novel situation where effects from the counterrotating terms are more dominant than from the co-rotating terms.

"In light-matter systems, when the frequencies of light and matter become equal, they mix together to form a polariton," he said. "Something similar happens in our case, but it's between matter and matter. Two magnon modes hybridize. There is a long-standing question of what happens when the degree of hybridization becomes so high that it even exceeds the resonance energy.

"In such a regime, exotic phenomena are predicted to occur due to counterrotating interactions, including a squeezed vacuum state and a phase transition into a novel state where static fields spontaneously appear," he said. "And we found that we can achieve such conditions by tuning the magnetic field."

The new study advances the Kono team's efforts to observe the Dicke superradiant phase transition, a phenomenon that could create a new exotic state of matter and lead to advances in quantum memory and transduction. The lab found a promising approach for realizing it in matter-matter coupling in 2018, reporting its discovery in Science.

The discovery also demonstrates that orthoferrite in a magnetic field could serve as a quantum simulator, a simple and highly tunable quantum system that represents a more complex one with an intractable number of interacting particles or an experimentally inaccessible regime of parameters, Kono said.

Tunable magnon-magnon coupling in orthoferrites can be used to provide insight into the nature of the ground state of an ultrastrong, coupled light-matter hybrid, he said.

Kono said their findings will also prompt a search for more materials that exhibit the effect. "Rare-earth orthoferrites is a big family of materials, and we studied just one," he said.