Culture

NEW YORK, June 7, 2021--Recent studies suggest that new brain cells are being formed every day in response to injury, physical exercise, and mental stimulation. Glial cells, and in particular the ones called oligodendrocyte progenitors, are highly responsive to external signals and injuries. They can detect changes in the nervous system and form new myelin, which wraps around nerves and provides metabolic support and accurate transmission of electrical signals. As we age, however, less myelin is formed in response to external signals, and this progressive decline has been linked to the age-related cognitive and motor deficits detected in older people in the general population. Impaired myelin formation also has been reported in older individuals with neurodegenerative diseases such as Multiple Sclerosis or Alzheimer's and identified as one of the causes of their progressive clinical deterioration.

A new study from the Neuroscience Initiative team at the Advanced Science Research Center at The Graduate Center, CUNY (CUNY ASRC) has identified a molecule called ten-eleven-translocation 1 (TET1) as a necessary component of myelin repair. The research, published today in Nature Communications, shows that TET1 modifies the DNA in specific glial cells in adult brains so they can form new myelin in response to injury.

"We designed experiments to identify molecules that could affect brain rejuvenation," said Sarah Moyon, Ph.D., a research assistant professor with the CUNY ASRC Neuroscience Initiative and the study's lead author. "We found that TET1 levels progressively decline in older mice, and with that, DNA can no longer be properly modified to guarantee the formation of functional myelin."

Combining whole-genome sequencing bioinformatics, the authors showed that the DNA modifications induced by TET1 in young adult mice were essential to promote a healthy dialogue among cells in the central nervous system and for guaranteeing proper function. The authors also demonstrated that young adult mice with a genetic modification of TET1 in the myelin-forming glial cells were not capable of producing functional myelin, and therefore behaved like older mice.

"This newly identified age-related decline in TET1 may account for the inability of older individuals to form new myelin," said Patrizia Casaccia, founding director of the CUNY ASRC Neuroscience Initiative, a professor of Biology and Biochemistry at The Graduate Center, CUNY, and the study's primary investigator. "I believe that studying the effect of aging in glial cells in normal conditions and in individuals with neurodegenerative diseases will ultimately help us design better therapeutic strategies to slow the progression of devastating diseases like multiple sclerosis and Alzheimer's."

The discovery also could have important implications for molecular rejuvenation of aging brains in healthy individuals, said the researchers. Future studies aimed at increasing TET1 levels in older mice are underway to define whether the molecule could rescue new myelin formation and favor proper neuro-glial communication. The research team's long-term goal is to promote recovery of cognitive and motor functions in older people and in patients with neurodegenerative diseases.

Just a few bacterial taxa found in ecosystems across the planet are responsible for more than half of carbon cycling in soils. These new findings, made by researchers at Northern Arizona University and published in Nature Communications this week, suggest that despite the diversity of microbial taxa found in wild soils gathered from four different ecosystems, only three to six groups of bacteria common among these ecosystems were responsible for most of the carbon use that occurred.

Soil contains twice as much carbon as all vegetation on earth, and so predicting how carbon is stored in soil and released as CO2 is a critical calculation in understanding future climate dynamics. The research team, which included scientists from Pacific Northwest National Laboratory, Lawrence Livermore National Laboratory, University of Massachusetts-Amherst, and West Virginia University, is asking how such key bacterial processes should be accounted for in earth system and climate models.

"We found that carbon cycling is really controlled by a few groups of common bacteria," said Bram Stone, a postdoctoral researcher at the Center for Ecosystem Science and Society at Northern Arizona University who led the study. "The sequencing era has delivered incredible insight into how diverse the microbial world is," said Stone, who is now at Pacific Northwest National Laboratory. "But our data suggest that when it comes to important functions like soil respiration, there might be a lot of redundancy built into the soil community. It's a few common, abundant actors who are making the most difference."

Those bacteria—Bradyrhizobium, the Acidobacteria RB41, and Streptomyces—were better than their rarer counterparts at using both existing soil carbon and nutrients added to the soil. When carbon and nitrogen were added, these already dominant lineages of bacteria consolidated their control of nutrients, gobbling up more and growing faster relative to other taxa present. Though the researchers identified thousands of unique organisms, and hundreds of distinct genera, or collections of species (for example, the genus Canis includes wolves, coyotes, and dogs), only six were needed to account for more than 50 percent of carbon use, and only three were responsible for more than half the carbon use in the nutrient-boosted soil.

Using water labeled with special isotopes of oxygen, Stone and his team sequenced DNA found in soil samples, following the oxygen isotopes to see which taxa incorporated it into their DNA, a signal that indicates growth. This technique, called quantitative stable isotope probing (qSIP), allows scientists to track which bacteria are growing in wild soil at the level of individual taxa. Then the team accounted for the abundance of each taxon and modeled how efficiently bacteria consume soil carbon. The model that included taxonomic specificity, genome size, and growth predicted the measured CO2 release much more accurately than models that looked only at how abundant each bacterial group was. It also showed that just a few taxa produced most of the CO2 that the researchers observed.

"Better understanding how individual organisms contribute to carbon cycling has important implications for managing soil fertility and reducing uncertainty in climate change projections," said Kirsten Hofmockel, Microbiome Science Team Lead at Pacific Northwest National Laboratory and a co-author of the study. "This research teases apart taxonomic and functional diversity of soil microorganisms and asks us to consider biodiversity in a new way."

"The microbial demographic data that this technique reveals lets us ask more nuanced questions," said Stone. "Where we used to characterize a microbial community by its dominant function, the way a whole state is often reported to have voted 'for' or 'against' a ballot proposition, now, with qSIP, we can see who is driving that larger pattern—the 'election results,' if you will—at the level of individual microbial neighborhoods, city blocks.

"In this way, we can start to identify which soil organisms are performing important functions, like carbon sequestration, and study those more closely."

Consuming large amounts of daily caffeine may increase the risk of glaucoma more than three-fold for those with a genetic predisposition to higher eye pressure according to an international, multi-center study. The research led by the Icahn School of Medicine at Mount Sinai is the first to demonstrate a dietary - genetic interaction in glaucoma. The study results published in the June print issue of Ophthalmology may suggest patients with a strong family history of glaucoma should cut down on caffeine intake.

The study is important because glaucoma is the leading cause of blindness in the United States. It looks at the impact of caffeine intake on glaucoma, and intraocular pressure (IOP) which is pressure inside the eye. Elevated IOP is an integral risk factor for glaucoma, although other factors do contribute to this condition. With glaucoma, patients typically experience few or no symptoms until the disease progresses and they have vision loss.

"We previously published work suggesting that high caffeine intake increased the risk of the high-tension open angle glaucoma among people with a family history of disease. In this study we show that an adverse relation between high caffeine intake and glaucoma was evident only among those with the highest genetic risk score for elevated eye pressure," says lead/corresponding author Louis R. Pasquale, MD, FARVO, Deputy Chair for Ophthalmology Research for the Mount Sinai Health System.

A team of researchers used the UK Biobank, a large-scale population-based biomedical database supported by various health and governmental agencies. They analyzed records of more than 120,000 participants between 2006 and 2010. Participants were between 39 and 73 years old and provided their health records along with DNA samples, collected to generate data. They answered repeated dietary questionnaires focusing on how many caffeinated beverages they drink daily, how much caffeine-containing food they eat, the specific types, and portion size. They also answered questions about their vision, including specifics on if they have glaucoma or a family history of glaucoma. Three years into the study later they had their IOP checked and eye measurements.

Researchers first looked at the relationship looked between caffeine intake, IOP and self-reported glaucoma by running multivariable analyses. Then they assessed if accounting for genetic data modified these relationships. They assigned each subject an IOP genetic risk score and performed interaction analyses.

The investigators found high caffeine intake was not associated with increased risk for higher IOP or glaucoma overall; however, among participants with the strongest genetic predisposition to elevated IOP - in the top 25 percentile - greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence. More specifically, those who consumed the highest amount of daily caffeine- more than 480 milligrams which is roughly four cups of coffee - had a 0.35 mmHg higher IOP. Additionally, those in the highest genetic risk score category who consumed more than 321 milligrams of daily caffeine - roughly three cups of coffee - had a 3.9-fold higher glaucoma prevalence when compared to those who drink no or minimal caffeine and in lowest genetic risk score group.

"Glaucoma patients often ask if they can help to protect their sight through lifestyle changes, however this has been a relatively understudied area until now. This study suggested that those with the highest genetic risk for glaucoma may benefit from moderating their caffeine intake. It should be noted that the link between caffeine and glaucoma risk was only seen with a large amount of caffeine and in those with the highest genetic risk," says co-author Anthony Khawaja, MD, PhD, Associate Professor of Ophthalmology University College London (UCL) Institute of Ophthalmology and ophthalmic surgeon at Moorfields Eye Hospital. "The UK Biobank study is helping us to learn more than ever before about how our genes affect our glaucoma risk and the role that our behaviors and environment could play. We look forward to continuing to expand our knowledge in this area."

Terpenoids are omnipresent in almost all living organisms. Prenylated indoles are prominent representatives that usually display potent medicinal properties (e.g. tryprostatin B). Therefore, significant efforts have been devoted to indole prenylation over the past decades. The known protocols often require a multi-step procedure and rely on the use of stoichiometric promoters. From the viewpoint of step- and atom-economy, developing a direct catalytic C2 prenylation of indoles is highly desirable yet challenging, because the nucleophilicity of C2 site is weaker than that of other two positions (N, C3).

In biosynthesis, enzymatic indole prenylation proceeds through a Friedel-Crafts SN1-type alkylation with a prenyl cation-pyrophosphate ion (PPi) derived from dimethylallyl pyrophosphate (DMAPP). Inspired by this mechanism, recently, a team led by Prof. Qing-An CHEN from Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) developed a regioselective C2 prenylation of indoles enabled by Lewis acid catalysis. By employing cheap 2-methyl-3-buten-2-ol (tert-prenol) as precursor and Lewis acid AlCl3 as catalyst, various tryptophol and tryptamine derivatives can undergo C2 prenylation with high selectivity. Notably, this practical strategy can be applied to the late-stage diversification of tryptophan-based peptides. These results were published in Chinese Journal of Catalysis.

Prof. CHEN stated: "Our work represents an old reaction for new use. For anyone engaged in chemistry, it is difficult to imagine that tryptophol and tryptophan-based peptides can undergo Friedel-Crafts reaction with high selectivity, because of the presence of diverse free NH and OH. More importantly, this strategy can greatly shorten the synthesis of indole alkaloid tryprostatin B."

HOUSTON - (June 7, 2021) - If identical versions of 20 people lived out their lives in dozens of different worlds, would the same people be popular in each world?

If you substitute "fruit flies" for "people" in that question, you have a fair description of a Rice University study showing that the evolution of social structures and the positions of individuals within those structures are based partly on genetics.

Cloned fruit flies played a starring role in the study that researchers jokingly likened to "The Truman Show," with video cameras observing how the flies behaved in a controlled environment.

In the study published online this week in Nature Communications, Rice bioscientists Eric Wice and Julia Saltz measured the social interactions between individual flies in 98 genetically identical groups. Each group contained 20 clones. The 20 differed from one another genetically, but the same clones were included in each of the 98 groups, which lived in separate enclosures under different environmental conditions.

Wice and Saltz found the same clones occupied the same social positions in each enclosed "world," regardless of variation in living conditions.

"Social structure varies tremendously across the animal world, and the big question we're interested in is 'How did this variation evolve?'" said Saltz, associate professor of biosciences at Rice. "For evolution to occur, social structure must be heritable, and we showed that it is."

Wice, a Ph.D. student in Saltz's lab, said even though genetic variation explained just part the variation in flies' social network positions, the heritability estimates that he and Saltz discovered are enough to fuel evolutionary change.

"For us to know whether or not the structure of social groups and the structure of networks will evolve over time, we have to know the genetic basis of how individuals are nested within their social networks and we also have to know how natural selection acts on social group structure," Wice said. "We studied both of those things simultaneously in this experiment, which hadn't been done before."

Wice said previous research had shown that the structure of social networks can evolve by natural selection, but few genetic components of social network structure had been described.

"We kind of integrated those things simultaneously to see how the structure of social groups will evolve and how it could potentially respond to selection," Wice said.

Wice said the study found the amount of variation in social position that was explained by genetics "was on the order of like 2.4% to 16.6%." And given that virtually all living creatures exhibit some form of social organization, the researchers' findings could apply to species as varied as humans and bacteria, Wice said.

Some studies have explored whether human popularity might also be partly explained by genetics, Saltz said. But she added it is essentially impossible to design an empirical test.

"The best way to do that would be to get identical twins, and 'Truman Show' them," she said, referring to the 1998 film in which the title character unwittingly lives in a controlled environment as part of a reality TV show. "You'd put one twin in one Truman Show bubble and the other twin in the other Truman Show bubble, and then see if they end up having the same identical-twin friends."

In essence, that describes the experiment she and Wice conducted with the flies.

"Any two genotypes in our sample are as closely related genetically as two randomly chosen people," Wice said. "But we can essentially make photocopies of each one of the flies and test, basically, the identical twins over and over."

And because Wice gathered data on social interactions by videotaping flies in each enclosure, running the experiment was a lot like producing 98 simultaneous Truman Shows, but "with 20 Trumans in each show," Wice said.

Positions within social networks were measured in five ways based on thousands of interactions between flies that were tallied and cataloged by computer software that "watched" dozens of hours of video of the 98 groups. Though the word "popularity" doesn't appear in the paper, Saltz said it's apt because some of the key parameters measured were equivalent to "how many friends you have and whether your friends are friends with each other or not."

Remarkably, Wice and Saltz found that social position within networks remained the same, even when they varied the environment by changing the quality of food in the enclosures. In some, food contained more protein and in others more carbohydrates. In other instances, flies had fewer available calories. In all, there were five types of food, and roughly 20 groups of flies living on each type.

"Our findings show that we expect social structure to evolve differently in different nutritional environments," Wice said. "That's significant, but further research is needed to determine what kind of changes arise from nutritional differences."

Ultimately, Wice and Saltz would like to know more about the ways that nutrition, aggressive behavior and other factors influence the evolution of social structure.

"What creates social structure?" Saltz said. "Group structures are inherently emergent properties of many different individuals, and there must be some underlying principles that shape the evolution of those structures."

The fact that an individual's position within a social network is dependent on the behavior of other individuals complicates that study of evolutionary social structure, Wice said, noting that some of the tools used in their analysis did not exist when Wice began Ph.D. studies five years ago.

"It's not independent data, and that violates a lot of statistical tests and assumptions," Wice said. "The tools are improving all the time, and it wouldn't surprise me if new tools came out in the next five years that will allow us and learn even more from the data we're collecting today."

This research was supported by the National Science Foundation (1856577), a Rosemary Grant from the Society for the Study of Evolution and the Houston Livestock Show and Rodeo.

The kidneys are a target organ of COVID-19 and are affected very early in the course. However, this is precisely where there is strong prognostic potential: As early as last spring, COVID-19-associated nephritis was identified as an early warning signal for severe courses of the infectious disease and studies to that effect were published [1]. In that regard, the research group led by Professor Oliver Gross, Department of Nephrology and Rheumatology at Göttingen University Medical Center (UMG), screened 223 patients in a study and included 145 of them as a predictive cohort. Study endpoints were ICU admission or mortality. As a result, early urinary changes that are easily detectable using test strips indicated a more severe COVID-19 course. When combined as a predictive system (urine and serum markers), it was possible to predict outcomes. "This means that kidney values are a seismograph for the course of COVID-19 disease," explained Prof. Gross, the head of the study, at the Opening Press Conference of the 2021 ERA-EDTA Congress.

The S3 guideline [2] provides general recommendations for inpatient therapy of patients with COVID-19 recommendations and states, inter alia, that "in the case of proven 'SARSCoV-2 infection' and hospitalization, urinalysis (repeated where necessary) including determination of albuminuria, hematuria, and leukocyturia should be performed."

Kidney involvement is more than just a predictive marker for the course of the disease, however, but also a very important risk factor for mortality. Several studies [3, 4] have shown that in patients with COVID-19, kidney involvement, i.e., albuminuria (and/or hematuria), often occurs early on in the course of the disease. A Chinese study [5] concluded that kidney involvement in COVID-19 patients dramatically worsened the outcome of the novel viral disease and increased mortality by a factor of ten (1.25% of patients without kidney involvement died vs. 11.2% of patients with kidney involvement). Until now, the occurrence of acute kidney injury (AKI) was the only known independent predictor of mortality [2], but it seems that early signs of kidney involvement, such as proteinuria, hypoproteinemia and antithrombin III deficiency have predictive importance [1]. This raises the question of whether and what specific long-term impacts on the kidneys can be expected after COVID-19.

The data on acute kidney injury (AKI) are relatively clear-cut: In cases of AKI, kidney function recovers after seven days, as distinguished from AKD ('acute kidney disease'), in which recovery of kidney function takes longer, namely up to 90 days. However, there are also many patients in whom kidney function does not recover at all, but gradually deteriorates over the further course of disease, i.e., who develop chronic kidney disease. Kellum et al. [6] showed that there was no recovery of kidney function in a total of 41.2% of patients with stage 2 and stage 3 AKI. Relapses and long-term restriction of kidney function occurred in as many as 14.7% of those who initially recovered. The same working group also showed that these patients had a significantly worse outcome (mortality, need for dialysis) one year after acquiring the AKI. Similar warning signals about chronic kidney failure after COVID-19 are now reaching us from China [7]: "So we can say that just over half of the patients who acquire an AKI will subsequently develop chronic kidney disease. This rate can also be expected after a COVID-19-associated AKI. It's important to bring those affected into nephrological aftercare so that the loss of kidney function is slowed down or, if possible, stopped by giving adequate therapy," explains Prof. Gross.

But what about patients who have not experienced acute kidney failure, but 'only' some initial renal dysfunction? Here too, the expert advises caution and aftercare: "There are ongoing studies with results still pending, but molecular SARS-CoV-2-associated tissue changes have already been detected in various organs in which viral replication has been detected." In that respect, long-term damage to the affected organs and post-COVID entities can be expected.

The most important conclusion drawn by the expert is that, "The kidney must be at the center of COVID-19 aftercare, in addition to the lungs, the heart and the nervous system. This is all the more important because early treatment can halt the loss of kidney function, and in recent years, especially, some new, effective therapies such as SGLT-2 inhibitors have been launched on the market to meet that need. Nowadays, the need for dialysis can often be delayed for years, even decades, if treatment is rigorously provided from the outset. Given that kidney disease does not produce symptoms until very late, we would like to make people who have had COVID-19 disease aware of the possibility of long-term consequences on the kidneys. It's important that general practitioners check their patients' kidney values (GFR, albuminuria) on a regular basis - similarly to other groups at risk of kidney disease, such as patients with diabetes mellitus and high blood pressure."

It was clear at a relatively early stage of the pandemic that SARS-CoV-2 causes a wide range of symptoms; in addition to typical respiratory symptoms, patients also had neurological symptoms (starting with anosmia), gastrointestinal symptoms, elevated liver values, and renal, urinary or hematological changes, for example. The fact that such findings occurred not only in severely ill patients with general organ dysfunction suggested that the virus may potentially cause disorders in various organs directly, i.e. that it causes a multi-system disease.

In spring 2020, at the very beginning of the pandemic, the authorities in Hamburg ordered autopsies be performed on all patients who had died with COVID-19. This resulted in one of the world's largest autopsy databases in which data on all organ systems were gathered. The autopsies carried out by forensic pathologists in Hamburg have provided the basis for many organ-related COVID-19 research projects.

One of last year's most frequently cited nephrologic studies, led by Prof. Tobias Huber, UKE Hamburg, showed [1] that the viral load (measured as the number of copies per cell) in the deceased was highest in the respiratory tract and second highest in the kidneys, followed by lower levels in heart and liver, brain and blood. Old age and the number of comorbidities, above all, were associated with multi-organ and renal tropism.

All in all, the Hamburg studies indicate that the diversity of symptoms in SARS-CoV-2 infections might also be related to the wide range of organs infected by the virus.

Association of SARS-CoV-2 organotropism with acute kidney damage

Compared to other intensive care patients with severe infections or sepsis, COVID-19 patients have a significantly higher rate of acute kidney injury (AKI) (56.9% versus 37.2%) [10]. Renal replacement therapy is required by 4.9%, compared to 1.6%. A study [3] of 5,216 US veterans with COVID-19 showed an average AKI incidence of 32%, which means that one in three developed acute kidney injury. 12% needed kidney replacement therapy (dialysis), and nearly half (47%) of the patients had not recovered renal function by discharge. "These are dramatic figures", explained Professor Tobias Huber, UKE Hamburg, at the Opening Press Conference of the 2021 ERA-EDTA Congress. "We know from major AKI studies that some patients whose kidney function does not recover after AKI subsequently transition to chronic kidney disease."

AKI was associated with the risk of mechanical ventilation (OR 6.46), the risk of mortality (OR 6.71) and prolonged in-patient treatment (OR 5.56). Predictors of acute kidney failure were age, obesity, diabetes mellitus, hypertension, restriction of kidney function (lower filtration rate/ eGFR), male gender and Afro-American descent.

Another major autopsy study conducted by Prof. Huber's team in Hamburg [4] explored the hypothesis that renal tropism may be independently correlated with outcome. In 63 autopsies with a similarly high comorbidity rate as in other studies, the virus was directly detected in the kidneys of 60% of the cases. This also correlated with age, number of coexisting diseases and male gender. The time interval between COVID-19 diagnosis and date of death was significantly shorter when the virus was detectable in the kidneys (approx. 14 versus 21 days). Renal tropism was also associated with the incidence of acute kidney injury: Of a total of 40 patients, seven had no AKI (three of the seven having renal viral infection), compared to 33 patients with AKI (23 of the 33 having virus detected in the kidney). The virus was isolated from tubule cells of autopsied kidney tissue, and subsequent cell infection experiments showed that the viruses were active and capable of replication, increasing a thousand-fold in 48 hours.

Together these studies identified SARS CoV-2 as a multi-tropic virus with affinity for the kidney potentially explaining why kidney injury is so frequently occurring in COVID-19 patients.

Various viruses and bacteria have long been known to cause autoimmune diseases where there is such a predisposition. This phenomenon also seems to play a major role in SARS-CoV-2, especially in severe courses. The body's own immune cells are activated, with the formation of autoantibodies that attack the body's own healthy cell structures (proteins, autoantigens); deposits of immune complexes can then trigger severe inflammatory processes and cell destruction in the body.

Some nephrological diseases are likewise of autoimmunological etiology, one example being systemic lupus erythematosus (SLE), a chronic, mostly relapsing-remitting inflammatory disease with life-threatening courses in some cases. Manifestations occur on the skin and in organs such as the lungs, heart, CNS, muscles/joints - and the kidneys. Lupus nephritis (kidney inflammation) occurs in almost three out of four cases and determines the outcomes of SLE. Many SLE patients are therefore treated or co-managed by nephrologists, with the aim of avoiding chronic kidney disease and the necessity for chronic dialysis treatment. The causes of SLE are multifactorial (e.g. genetic predisposition, hormonal and environmental triggers). In SLE, antiphospholipid antibodies (aPLs; i.e., autoantibodies against phospholipid-binding proteins) are often found, but also in other autoimmune diseases of the vascular system presenting variable clinical pictures. aPLs can interfere with the clotting system, so there is usually a tendency to thrombosis, and severe complications in pregnancy are also possible in affected women.

More and more similarities between severe COVID-19 and SLE or autoimmune diseases have meanwhile been described. An increase in autoantibody-forming lymphocytes (B cells) and their activation are also observed in critically ill COVID-19 patients, as in acute SLE relapses [2]. aPLs have also been detected in COVID-19 patients, and aPL concentrations correlated with the severity of the disease [2]. There are also some interesting clinical parallels: A pioneering study from Germany [3] shows that early kidney involvement (proteinuria, hematuria) can determine outcomes in COVID-19 patients - as is the case with SLE.

A new study on the subject has now been published by the working group led by Prof. Wolfram Ruf, Mainz, in the renowned journal Science [1]. The study showed for the first time that antiphospholipid antibodies bind to the 'EPCR LBPA' complex. This molecule complex is located at the biochemical interface of the innate immune or pathogen defense system and the clotting system. It is a lipid-protein receptor complex consisting of endosomal LBPA (lysobisphosphatidic acid from endosomes) and the EPC (endothelial protein C) receptor located on the interior surface (endothelium) of the blood vessels. In this complex, the EPC receptor presents LBPA as a pathogenic cell surface antigen. aPL binding to the EPCR-LBPA complex then activates both the endosomal inflammatory pathway and the coagulation cascade. This leads to interferon production in immune cells and to a special expansion of B cells, which then produce further autoantibodies in a self-reinforcing autoimmune signaling loop. With regard to therapy, the study also showed that, in the lupus mouse model, the specific pharmacological blockade of this EPCR-LBPA signaling inhibited severe aPL-related damage.

"Even if the pathogenic mechanism and significance of autoantibody formation in COVID-19 are not yet fully understood, it is possible that the autoimmune response, once triggered, could be the real cause of many severe COVID-19 courses", commented Prof. Dr. Julia Weinmann-Menke, Mainz, the DGfN Press Officer, at the Opening Press Conference of the ERA-EDTA Congress. She and her colleagues at the universities of Mainz, Greifswald (Prof. Dr. Jens Fielitz) and Berlin are therefore planning a cooperative clinical research project to further investigate this autoimmune disease and to find new approaches for immunological COVID-19 therapies. "Our project is based on the hypothesis that an infection-associated autoimmune response by autoantibodies is implicated in many cases of organ damage in patients with severe COVID-19," explains Prof. Weinmann-Menke. The study aims to establish a high-throughput test procedure (multiplex assay) that can be used to identify specific immune responses (immunoproteomics) to autoantigens (especially against cerebral, cardiac and renal proteins) that occur in COVID-19. Autoantibody-forming memory B cells, and the specificity of autoantibodies (tissue specificity and cross-reactivity with other organs) are to be analyzed by conducting in vitro tests. The glycosylation of autoantibodies, which is known to enhance their effect in many cases, is also to be investigated.

"Immunomodulatory therapies used or being tested in the treatment of nephrological autoimmune diseases such as SLE may also be successful in severe COVID-19 courses", concludes Prof. Weinmann-Menke. "We hope that new diagnostic options for patients will provide us with better risk assessment and more targeted therapeutic approaches, also for non-COVID-associated immune phenomena."

The battle against antibiotic-resistant bacteria: A new study at Tel Aviv University revealed a mechanism through which "good" viruses can attack the systems of "bad" bacteria, destroy them and block their reproduction. The researchers demonstrated that the "good" virus (bacteriophage) is able to block the replication mechanism of the bacteria's DNA without damaging its own, and note that the ability to distinguish between oneself and others is crucial in nature. They explain that their discovery reveals one more fascinating aspect of the mutual relations between bacteria and bacteriophages and may lead to a better understanding of bacterial mechanisms for evading bacteriophages, as well as ways for using bacteriophages to combat bacteria.

The study, published recently in PNAS - Proceedings of the National Academy of Sciences, was led by Prof. Udi Qimron, Dr. Dor Salomon, Dr. Tridib Mahata and Shahar Molshanski-Mor of the Sackler Faculty of Medicine. Other participants included Prof. Tal Pupko, Head of the Shmunis School of Biomedicine and Cancer Research and also of the new AI and Data Science Center ; Dr. Oren Avram of the George S. Wise Faculty of Life Sciences; and Dr. Ido Yosef, Dr. Moran Goren, Dr. Miriam Kohen-Manor and Dr. Biswanath Jana of the Sackler Faculty of Medicine.

Prof. Qimron explains that the antibiotic resistance of bacteria is one of the greatest challenges faced by scientists today. One potential solution may lie in further investigation of the targeted eradication of bacteria by "good" bacteriophages; namely, understanding bacteriophage mechanisms for taking over bacteria as a basis for the development of new tools to combat bacterial pathogens.

With this intention in mind, the current study unveiled the mechanism by which the bacteriophage takes control of the bacteria. The researchers found that a bacteriophage protein uses a DNA-repair protein in the bacteria to "cunningly" cut the bacteria's DNA as it is being repaired. Since the bacteriophage's own DNA has no need for this specific repair protein, it is protected from this nicking procedure. In this way the "good" bacteriophage does three important things: it distinguishes between its own DNA and that of the bacteria, destroys the bacteria's genetic material, and blocks the bacteria's propagation and cell division.

Prof. Qimron adds: "The bacteriophage takes advantage of the bacterial DNA's need for repair, while the bacteriophage itself has no need for this specific kind of repair. In this way the bacteriophage destroys the bacteria without suffering any damage to itself. The ability to distinguish between oneself and others is of enormous importance in nature and in various biological applications. Thus, for example, all antibiotic mechanisms identify and neutralize bacteria only, with minimal effect on human cells. Another example is our immune system, which is geared toward maximum damage to foreign factors, with minimal self-injury."

The researchers discovered the process by searching for types of bacterial variants not impacted by this bacteriophage mechanism - those that have developed "immunity" to it. This inquiry led them to the specific bacterial mechanisms affected by the bacteriophage takeover. "We found that the 'immune' bacterial variants simply stopped repairing their DNA in ways that are vulnerable to the bacteriophage attack, thereby evading the bacteriophage's destructive mechanism. Shedding more light on the ways in which bacteriophages attack bacteria, our findings may serve as a tool in the endless battle against antibiotic-resistant bacteria," concludes Prof. Qimron.

Wider clean chemistry applications of the extraordinary Vortex Fluidic Device - invented by Flinders University's Professor Colin Raston - are likely in the wake of new research that has been published outlining the seemingly endless possible uses.

The defining paper on understanding fluid flow in the Vortex Fluidic Device has just been comprehensively explained in an article published in Nanoscale Advances (DOI: 10.1039/D1NA00195G).

This took more than 100,000 experiments to work out - and Professor Raston hopes this publication will encourage more researchers to embrace the VFD and explore yet more innovative applications for this ingenious device.

"How fluid flows is one of the grand challenges of science," says Professor Raston. "What we have been doing with the VFD provides answers for liquids subjected to mechanical energy."

Since 2013, Professor Raston has been working with his team to explore the possibilities of the VFD, which is capable of controlling chemical reactivity, materials processing and probing the structure of self-organised systems, enabling rapid and now predictable modifications.

The VFD has shown its capability in the synthesis of esters, amides, ureas, imines, alpha-amino phosphates, beta-Keto esters, modified amino acids and the local anaesthetic, lidocaine.

Professor Raston says the high-tech, yet simple device can be used in medical and pharmaceutical research, food processing, materials processing and more, aligned with a range of industries - all with a focus on cleaner, greener and cheaper production - and he hopes that the new conclusive summaries about the VFD experiments will see it embraced by more research organisations around the world, and be taken up by industry.

"The topological fluid flows, which were established as 'spinning top' flow, double helical flow and specular flow, account for all the processing outcomes and applications of the VFD - this is an exciting discovery," says Professor Raston.

"We have established the topological features of high shear fluid flow in the vortex fluidic device at sub-micron dimensions, at a critical tilt angle of 45 degrees, being the optimal angle for myriad applications of the device."

The proposed flow patterns in the VFD provide insights that allow accurate prediction and control the formation of nanostructures in the VFD and chemical reactions. The flow patterns also provide an understanding of the advantages of VFD processing relative to using other methods, showing the VFD processing to be without precedent.

As the latest example of green chemistry innovation, PhD candidate Matt Jellicoe has led research into using the VFD to control the coating of particles without using other waste generating reagents.

The paper - High shear spheroidal topological fluid flow induced coating of polystyrene beads with C60 spicules, by Matt Jellicoe, Kasturi Vimalanathan, Jason Gascooke, Xuan Luo and Colin Raston, has been published by Royal Society of Chemistry's ChemComm (10.1039/d0cc07165j).

"I believe the outcome of this research to be significant because we demonstrate the coating of particles 2-6 microns in diameter with zero waste and up to 98% efficiency. This could be beneficial towards the pharmaceutical companies which coat drugs with significant lower yield, thus leading to run off of dangerous chemicals into freshwater streams and the air," says Mr Jellicoe.

He expects the next stage of testing will investigate the possibility of using the VFD as a drug-coating device.

"This may significantly reduce the effects on the environment," says Mr Jellicoe, "and this is what excites me the most. The potential impact, especially on the environment and the economy, could be unfathomable."

A world-first international study led by the University of South Australia has identified a new drug to stop athletes developing dementia after sustaining repeated head injuries in their career.

The link between concussion and neurogenerative diseases is well established, but new research findings could halt the progression of chronic traumatic encephalopathy (CTE) in sportspeople who sustain repeated blows to the head.

CTE is a progressive and fatal brain disease associated with the accumulation of a protein known as hyperphosphorylated tau which affects cognition and behaviour.

In a paper published in Scientific Reports, UniSA Emeritus Professor Bob Vink and colleagues show how repeated concussions can cause CTE and a way to block it with a specially developed drug.

The findings will potentially have significant implications for athletes who play contact sports - such as boxers and footballers - as well as military veterans sustaining head injuries in conflict.

The team of researchers from Adelaide, Melbourne and the United States say the brain releases a neurotransmitter called substance P in the event of a head injury, causing abnormal amounts of the tau protein to collect inside neurons.

"Tau protein tangles are a feature of CTE, which reportedly leads to memory problems, confusion, personality changes, aggression, depression and suicidal thinking," Prof Vink says.

"Our research shows that by blocking substance P with a specific drug, we can prevent the tau protein tangles from developing in the brain and causing neurological problems."

The treatment was successfully tested in animal models, giving hope that CTE can be prevented in humans.

Prof Vink says the next step is human clinical trials, but that could take several years given that currently CTE can only be diagnosed post-mortem.

A study of 14,000 Americans over 25 years, published in Alzheimer's and Dementia in March, showed that people who sustained even one head injury were 25 per cent more likely to develop dementia later in life. This risk increased with multiple traumatic brain injuries.

The Guardian also reported in April that an analysis of late AFLW player Jacinta Barclay's brain uncovered neurological damage at age 29, highlighting the risks of repeated concussions to both sexes. Previous research has focused on the impact of brain injuries in male athletes, but females are more likely to sustain concussions.

Monash University researchers have provided a fundamental advance regarding how T cells become activated when encountering pathogens such as viruses.

The recent study published in Science, co-led by Professor Nicole La Gruta, Professor Jamie Rossjohn and Professor Stephanie Gras with first author Dr Pirooz Zareie from the Monash Biomedicine Discovery Institute, have found that T Cells need to recognise pathogens in a particular orientation in order to receive a strong activating signal.

T cells play a key role in the immune system by eliminating invading pathogens, such as viruses, and it is crucial to understand the factors that determine how and why T cells become activated after recognizing these pathogens.

T cells express on their surface a T cell receptor (TCR) that recognizes and binds to virus fragments (antigens) presented by infected cells. This recognition event can lead to T cell activation and killing of infected cells.

"The central issue is that there are millions of different T cell receptors (TCRs) in the human body, and a vast array of viruses, making it difficult to understand the rules around how T cell receptor recognition of a virus drives T cell activation. Indeed, it is a problem that has remained contentious for over 25 years" says Professor La Gruta.

"Our study has shown that the orientation in which the T cell receptor binds is a primary factor determining whether the T cell receives an activating signal," Professor La Gruta said.

"This is an advance in our fundamental understanding of how a T cell needs to 'see' pathogenic antigens in order to be activated," she said. "It has clarified a critical mechanism essential for effective T cell immunity. It is also relevant to the ongoing development of immunotherapies that aim to boost the activation of T cells."

Dr Pirooz Zareie stated: "a combination of technologies, including super-resolution microscopy, X-ray crystallography at the Australian Synchrotron, biochemical assays and using in vitro and in vivo experimental models from a variety of labs led to the findings."

The study represented a cross-disciplinary collaboration between researchers from the University of Utah, National University of Singapore, University of New South Wales and Monash University.

Niigata, Japan - A comprehensive investigation on cells and colony motion offers new insight into the proliferative and epithelial regenerative capacities of human primary oral keratinocyte cultures with implications for quality control of engineered cells used in regenerative medicine. Dr. Kenji Izumi and his colleagues, Dr. Emi Hoshikawa and Dr. Taisuke Sato, modified the optical flow (OF) protocol originally presented in their 2019 paper to add the capacity to determine the threshold of the cells/colony motion speed required to differentiate substandard oral keratinocyte populations before manufacturing a tissue-engineered oral mucosa tissue construct. Interdisciplinary collaboration was critical to the success of this study, with Dr. Izumi and Dr. Hoshikawa, both experts in the fields of oral keratinocyte biology, relying on the image analysis and mathematics expertise provided by Dr. Sato to enhance the protocol proceeding OF algorithm implementation. Oral mucosa keratinocytes are currently employed in regenerative dentistry and extra-oral regenerative medicine and distinguishing cellular health is critical for manufacturing high-quality products used in cell-based therapies. While previous studies have non-invasively characterized the optimal metabolic activities of oral mucosa tissue-engineered grafts, the non-invasive measurements for first passaged (p1) oral keratinocytes have not developed yet as a tool for quality control of cells. The researchers first determined the specific spatio-temporal growth pattern of p1 cells, allowing them to set correlative estimates that reduced the time of microphotography from 24 hours to 4 hours, resulting in fewer image analyses. Cells/colony proliferation and motion speed of each frame was then assessed by applying the OF algorithm with image segmentation. As noted by Dr. Izumi "dynamic image-based analysis, rather than static image analysis such as observation of colony shape, allowed us to focus on cells/colony motion of oral keratinocytes in our cell culture system in which cells do not form densely-packed colonies". Using this approach, the mean motion speed (MMS), a marker of locomotive ability, was evaluated. As expected, this analysis validated their prior finding that the MMS of oral keratinocytes is positively correlated with proliferative capacity. Surprisingly, the team found this was not the only cellular characteristic associated with MMS, as histologic evaluation of cells showed epithelial regenerative potential is correlated with motion speed. The ability to assess both the proliferative capacity and epithelial regenerative capacity of mid-phase oral keratinocytes using the MMS threshold make this a more robust and predictive quality screening tool to ensure that the cells are suitable for clinical application.

Taking their investigation one step further, the researchers compared the growth characteristics of p1 oral keratinocytes exposed to metabolic challenge with those under standard conditions: "The creative point in this study was that we coerced cells in culture under a couple of poor conditions, which we called "challenged" protocols, to debilitate cells," said Dr. Izumi. "Then, we extrapolated the "threshold" in our own culture condition." The proliferative potential of cells grown in differing conditions was compared, and the population doubling times was calculated to determine the MMS threshold indicative of cells suitable for transfer to 3D culture conditions. In their specific culture system, a motion index less than 40 μm/h reflected cellular damages induced by metabolic challenges and subpar cell colonies. However, these results have a wider application, with the motion index functioning as a threshold to determine the quality of cultured cells in different culture conditions, as observed by Dr. Izumi: "Depending on different type of cells, the details of the algorithm need to be considered and adjusted. More importantly, the "threshold" is necessary to be determined by different type of cells, culture media, and culture conditions." Given that the motion index is correlated with characteristics intimately connected to cell quality and clinical use, such as proliferation and epithelial regeneration, it can function as a reliable indicator of quality control. "Since the non-invasive and quantitative monitoring of cells allows multiple observations over time, it is useful for quality control of cells in regenerative medicine and contributes to cell-manufacturing industry." However, Dr. Izumi notes it has applications beyond even regenerative medicine, such as cancer research. Ultimately, the team hopes to increase the accuracy of the motion speed measurement in the future and elucidate the molecular relationship underlying the correlation between locomotion and proliferation of oral keratinocytes, which contributes to determining critical quality attributes of oral keratinocytes.

Carried like stowaways in the guts of international travelers, new and potentially deadly strains of antimicrobial resistant superbugs may be coming to a community near you, suggests new research from Washington University School of Medicine in St. Louis.

"Even before the COVID-19 pandemic, we knew that international travel was contributing to the rapid global increase and spread of antimicrobial resistance," said Alaric D'Souza, an MD/PhD student at Washington University and a co-first author of the study to be published June 6 in Genome Medicine. "But what's new here is that we've found numerous completely novel genes associated with antimicrobial resistance that suggest a worrisome problem on the horizon."

The research confirms that international travelers often return home with an unexpected bounty of new bacterial strains jostling for position among the thousands that normally reside within the gut microbiome.

Poverty, poor sanitation and changing agricultural practices have turned many low-income, developing regions into hot spots for diseases spread by bacteria, including infections that are increasingly resistant to a range of antibiotic drug treatments.

High-population densities make it easy for these bacteria to be shared among community residents and travelers through exposure to contaminated drinking water and food, or poorly sanitized restrooms, restaurants, hotel rooms and public transportation. Back at home, travelers run the risk of transferring these novel bacteria to family, friends and other community residents.

The research, conducted with Maastricht University in the Netherlands, involved analyzing bacterial communities in the gut microbiomes of 190 Dutch adults before and after travel to one of four international regions where the prevalence of resistance genes is high: Southeastern Asia, South Asia, North Africa and Eastern Africa.

Fecal samples analyzed as part of the study were randomly selected from a larger, multicenter investigation of about 2,000 Dutch travelers, the majority of whom were tourists, known as the Carriage Of Multi-resistant Bacteria After Travel (COMBAT) study.

"We found significant travel-related increases in the acquisition of resistance genes, abundance and diversity encoded by bacteria that are endemic to the region visited," D'Souza said. "These findings provide strong support for international travel as a vector for the global spread of clinically important antimicrobial resistance genes and highlight the need for broader surveillance of antimicrobial resistant bacteria in the gut microbiomes of returning travelers."

The new study was designed by co-senior authors John Penders, a medical microbiologist at Maastricht University, and Gautam Dantas, PhD, a professor of pathology & immunology at Washington University. Manish Boolchandani, PhD, a member of the Dantas Lab during the research and a 2020 graduate of the university's doctoral program in Computational and Systems Biology, is also a first author on the paper.

The World Health Organization, the U.S. Centers for Disease Control and Prevention, and other agencies have described the rapid spread of antimicrobial resistance as one of the most serious public health threats now facing the world -- a looming medical catastrophe that could outweigh the chaos created by the COVID-19 pandemic.

"While previous studies have scanned travelers' stool samples for well-known antimicrobial resistant bacteria, we used a combination of whole metagenome shotgun sequencing and functional metagenomics to identify both known and novel genes that code for antimicrobial resistance," Dantas said.

More traditional genomic techniques look for distinctive genetic signatures of individual pathogens. But such tests can only find known pathogens, while metagenomic sequencing can identify all organisms present in a given sample: good bacteria, dangerous bacteria and even those that are completely new.

In all, the researchers detected 121 antimicrobial resistance genes across the gut microbiomes of the 190 Dutch travelers. More than 40% of these resistance genes (51 of them) were only discovered using the more sensitive metagenomics technique, suggesting that potentially dangerous genes are being missed by the more conventional approaches.

Equally concerning, the study's results confirmed that 56 unique antimicrobial resistance genes had become part of the travelers' gut microbiomes during their trips abroad, including several mobile, high-risk resistance genes, such as extended-spectrum β-lactamases (ESBL) and the plasmid-borne colistin resistance gene, mcr-1.

Resistance to beta-lactam antibiotics is emerging worldwide and confers broad resistance to treatment by penicillins and other important antibiotics.

The mcr-1 genes protect bacteria from another antimicrobial drug called colistin, which is the last-resort treatment for infections by multidrug-resistant gram-negative bacteria. If colistin resistance spreads to bacteria that are resistant to other antibiotics, those bacteria could cause truly untreatable infections, the CDC has warned.

Because metagenomic analysis allows researchers to study all the bacteria and genes in a collection of gut microbiome samples as one, large mixed community of organisms, it also provides opportunity to explore complex ecological interactions between these organisms.

While bacteria may slowly evolve resistance from repeated exposures to antibiotics over time, diverse bacterial communities also share antimicrobial resistance genes through a more rapid process known as horizontal transfer, usually via the exchange of mobile genetic elements that allow snippets of DNA to jump from one bacterium to another.

"Since genes that code for resistance to different classes of antibiotics are often located on the same mobile elements, a single horizontal exchange has the potential to convert bacteria previously susceptible to antibiotics into a multi-drug resistant organism," said Dantas.

Researchers also used metagenomic techniques to piece together important contextual information about resistance gene location and function.

"There was significant association of resistance genes with mobile genetic elements, a primary way that resistance genes spread among bacteria," D'Souza said. "Though our study was unable to demonstrate resistance genes are carried by pathogenic bacteria, it's clear that this is possible. Additionally, international travelers have the potential to introduce resistance genes into their own communities when they return home, and future studies directly addressing this possibility are a priority."

Added Dantas: "Identifying new antimicrobial resistant bacteria and genes could play an important role in slowing the global spread of resistance and guide potential treatments for related diseases. Our study lays the groundwork for those efforts by offering new insight into the genetic mechanisms that underlie the rapid acquisition and sharing of antimicrobial resistance genes across people's gut microbiomes during international travel."

In the present study, Dr. Hidetoshi Hayashi (Professor, Nagoya City University) and collaborators screened small-molecule compounds that suppress UPR, using Myanmar wild plant extracts library. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. They isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure-activity relationship of periplocin revealed that cardiac glycosides, basically used for cardiac insufficiency therapy, also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to the understanding of the pathological or physiological importance of UPR signaling.