Culture

BIRMINGHAM, Ala. - COVID-19, which has killed 1.7 million people worldwide, does not follow a uniform path.

Many infected patients remain asymptomatic or have mild symptoms. Others, especially those with comorbidities, can develop severe clinical disease with atypical pneumonia and multiple system organ failure.

Since the first cases were reported in December 2019, the SARS-CoV-2 virus that causes COVID-19 has surged into a pandemic, with cases and deaths still mounting. Ongoing observational clinical research has become a priority to better understand how this previously unknown virus acts, and findings from this research can better inform treatment and vaccine design.

University of Alabama at Birmingham researchers, led by first-author Jacob "Jake" Files and co-senior authors Nathan Erdmann, M.D., Ph.D., and Paul Goepfert, M.D., have now reported their observational study, "Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection," published in the Journal of Clinical Investigation.

In a commentary on the UAB study, published in the same issue, Phillip Mudd, M.D., Ph.D., and Kenneth Remy, M.D., both of Washington University, wrote, "The importance of these studies to provide context for the interpretation of immune responses generated by participants in COVID-19 vaccine trials, including how those responses change over time, cannot be over-emphasized. This information will be key in potential modifications to existing COVID-19 vaccines and treatments."

The UAB researchers obtained blood samples and clinical data from 46 hospitalized COVID-19 patients and 39 non-hospitalized individuals who had recovered from confirmed COVID-19 infection. Both groups were compared to healthy, COVID-19-negative controls. Importantly, most individuals in the hospitalized group had active SAR-CoV-2 viruses in their blood and were in the hospital at the time of sample collection. All individuals in the non-hospitalized group were convalescent at the time of sample collection.

From the blood samples, researchers were able to separate specific immune cell subsets and analyze cell surface markers. From this complex information, immunologists can analyze how each individual's immune system is responding during infection and during convalescence. Some of these results can reveal whether immune cells have become activated and exhausted by the infection. Exhausted immune cells may increase susceptibility to a secondary infection or hamper development of protective immunity to COVID-19.

In addition, the researchers were able to analyze changes over time, in two ways. The first was observing changes in surface markers over time, defined as days since the onset of symptoms for non-hospitalized samples. The second was directly comparing the frequencies of these markers between the first and second clinic visits for non-hospitalized patients who had blood samples collected at two sequential timepoints.

The most surprising finding involved non-hospitalized patients. While the UAB researchers saw upregulated activation markers in hospitalized patients, they also found several activation and exhaustion markers were expressed at higher frequencies in non-hospitalized convalescent samples.

Looking at these markers over time, it was apparent that immune dysregulation in the non-hospitalized individuals did not quickly resolve. Furthermore, the dysregulation of T cell activation and exhaustion markers in the non-hospitalized cohort was more pronounced in the elderly. "To our knowledge," the researchers reported, "this is the first description of sustained immune dysregulation due to COVID-19 in a large group of non-hospitalized convalescent patients."

For details of the comprehensive look at immune cells subsets during and after COVID-19 infection in hospitalized and non-hospitalized people, see the study, which includes an in-depth characterization of the activation and exhaustion phenotype of CD4+ T cells, CD8+ T cells and B cells.

The B and T cells from both patient cohorts had phenotypes consistent with activation and cellular exhaustion throughout the first two months of infection. And in the non-hospitalized individuals, the activation markers and cellular exhaustion increased over time. "These findings," Mudd and Remy said in their commentary, "illustrate the persistent nature of the adaptive immune system changes that have been noted in COVID-19 and suggest longer-term effects that may shape the maintenance of immunity to SARS-CoV-2."

A question now being explored, the UAB researchers say, is whether these observed immunologic changes are associated with symptoms experienced well beyond the acute infection, often described as "Long COVID."

Co-authors with Files, Erdmann and Goepfert in the Journal of Clinical Investigation report are Sushma Boppana, Mildred D. Perez, Sanghita Sarkar, Kelsey E. Lowman, Kai Qin, Sarah Sterrett, Eric Carlin, Anju Bansal, Steffanie Sabbaj, Olaf Kutsch and James Kobie, Division of Infectious Diseases, UAB Department of Medicine; and Dustin M. Long, Department of Biostatistics, UAB School of Public Health.

Carrageenans, biologically active polysaccharides isolated from red algae and widely used in the food industry as stabilizers, thickeners, or jelly agents have an express effect on the immune systems of mice, a study reports. The research was carried out by scientists from the School of Biomedicine of Far Eastern Federal University (FEFU), Far Eastern Branch of the Russian Academy of Sciences, and Vilnius University. A related article appears in the Journal of Biomedical Materials Research.

"The fact that carrageenan demonstrates immunosuppressive properties in a particular case does not make it generally dangerous or toxic though", says Aleksandra Kalitnik, one of the research authors, an Assistant Professor at the Department of Pharmacy and Pharmacology, FEFU School of Biomedicine.

The research reveals that carrageenans and the products of their partial degradation with low molecular weight are not pharmacologically inert. On the contrary, they are capable of suppressing the immune system. After adding carrageenans to the diet of lab mice for one week, the activity of their congenital immunity cells reduced and leukocyte count dropped.

The paper leaves many questions unanswered, but one thing is clear: although carrageenans are a permanent component of the human diet, their medical potential is extremely underestimated.

"Immunosuppressants are used to treat different disorders, such as allergies and autoimmune diseases: multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, systemic scleroderma, dermatomyositis, and others. Usually, these diseases are associated with the hyperactivation of some parts of the immune system and/or with the reduced production or functional activity of immunosuppressive cells. A misbalance between inflammation and suppression may lead to the development of an excessive immune response to a patient's own antigens. Currently, we cannot confirm carrageenans are immunosuppressants. However, we established they are able to suppress the activity of peritoneal phagocytes (abdominal immune cells) in mice. It is still unclear whether it is for good or bad. Certainly, it can be beneficial for some conditions associated with immune system hyperactivation," says Aleksandra Kalitnik.

According to the scientist, it is too soon to start thinking about the development of a carrageenan-based immunosuppressive drug. The biological properties of carrageenans require further fundamental research that might take years.

The team believes that red algae polysaccharides can react with cell receptors directly (in case of in vitro experiments) or indirectly (when taken orally). Namely, they react with the receptors of immune cells in the gastrointestinal tract that, in turn, pass the information on to the immune cells of the blood.

"We would like to find out the way carrageenans influence cell receptors and signal paths that are involved in increasing and decreasing the leukocyte level. Such a study would help us better understand the potential of carrageenans as pharmacological substances or bio-additives that could reduce immune system hyperactivation. At the current stage, we only observed the effect of immunosuppression, namely the reduction of leukocyte count and activity," added Aleksandra Kalitnik.

The study did not cover the carrageenans that are used in the food industry and consumed by people. Food carrageenans have to meet strict requirements, including the maximum allowed molecular mass and dosage. The dosages of food carrageenans are lower than those used in the experiment by several orders of magnitude. Moreover, food products do not contain pure carrageenan. It is consumed together with proteins and other substances that considerably affect its properties.

"The microbial populations of the gastrointestinal tracts of mice and men are quite different, and carrageenan might have no suppressing effect on the human immune system. To put it simply, carrageenan can become an immunosuppressor if needed and demonstrate immune-modulating properties in other cases, supporting the natural protective functions of the body. This fact is confirmed by some experimental data," concluded Aleksandra Kalitnik.

What The Study Did: This study identified racial/ ethnic, sex, age, language, and socioeconomic differences in accessing telemedicine for primary care and specialty ambulatory care; if not addressed, these differences may compound existing inequities in care among vulnerable populations.

Authors: Srinath Adusumalli, M.D., M.Sc., of the Hospital of the University of Pennsylvania in Philadelphia, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.31640)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Scientific articles in the field of physics are mostly very short and deal with a very restricted topic. A remarkable exception to this is an article published recently by physicists from the Universities of Münster and Düsseldorf. The article is 127 pages long, cites a total of 1075 sources and deals with a wide range of branches of physics - from biophysics to quantum mechanics.

The article is a so-called review article and was written by physicists Michael te Vrugt and Prof. Raphael Wittkowski from the Institute of Theoretical Physics and the Center for Soft Nanoscience at the University of Münster, together with Prof. Hartmut Löwen from the Institute for Theoretical Physics II at the University of Düsseldorf. The aim of such review articles is to provide an introduction to a certain subject area and to summarize and evaluate the current state of research in this area for the benefit of other researchers. "In our case we deal with a theory used in very many areas - the so-called dynamical density functional theory (DDFT)," explains last author Raphael Wittkowski. "Since we deal with all aspects of the subject, the article turned out to be very long and wide-ranging."

DDFT is a method for describing systems consisting of a large number of interacting particles such as are found in liquids, for example. Understanding these systems is important in numerous fields of research such as chemistry, solid state physics or biophysics. This in turn leads to a large variety of applications for DDFT, for example in materials science and biology. "DDFT and related methods have been developed and applied by a number of researchers in a variety of contexts," says lead author Michael te Vrugt. "We investigated which approaches there are and how they are connected - and for this purpose we needed to do a lot of work acting as historians and detectives," he adds.

The article has been published in the journal Advances in Physics, which has an impact factor of 30.91 - making it the most important journal in the field of condensed matter physics. It only publishes four to six articles per year. The first article on DDFT, written by Robert Evans, was also published in Advances in Physics, in 1979. "This makes it especially gratifying that our review has also been published in this journal," says secondary author Hartmut Löwen. "It deals with all the important theoretical aspects and fields of application of DDFT and will probably become a standard work in our field of research."

One of the physiopathological characteristics of COVID-19 that has most baffled the scientific and medical community is what is known as "silent hypoxemia" or "happy hypoxia". Patients suffering this phenomenon, the causes of which are still unknown, have severe pneumonia with markedly decreased arterial blood oxygen levels (known as hypoxemia). However, they do not report dyspnea (subjective feeling of shortness of breath) or increased breathing rates, which are usually characteristic symptoms of people with hypoxemia from pneumonia or any other cause.

Patients with "silent hypoxemia" often suffer a sudden imbalance, reaching a critical state that can be fatal. Normally, individuals (healthy or sick) with hypoxemia report a feeling of shortness of breath and a higher breathing rate, thus increasing the body's uptake of oxygen. This reflex mechanism depends on the carotid bodies. These small organs, located on either side of the neck next to the carotid artery, detect the drop in blood oxygen and send signals to the brain to stimulate the respiratory centre.

A group of researchers from the Seville Institute of Biomedicine - IBiS/University Hospitals Virgen del Rocío y Macarena/CSIC/University of Seville, led by Dr. Javier Villadiego, Dr. Juan José Toledo-Aral and Dr. José López-Barneo, specialists in the physiopathological study of the carotid body, have suggested in the journal Function, that "silent hypoxemia" in COVID-19 cases could be caused by this organ being infected by the coronavirus (SARS-CoV-2).

This hypothesis, which has attracted the interest of the scientific community for its novelty and possible therapeutic significance, comes from experiments that have revealed a high presence of the enzyme ECA2, the protein the coronavirus uses to infect human cells, in the carotid body. In patients with COVID-19, the coronavirus circulates in the blood. Therefore, researchers suggest that infection of the human carotid body by SARS-CoV-2 in the early stages of the disease could alter its ability to detect blood oxygen levels, resulting in an inability to "notice" the drop in oxygen in the arteries. If this hypothesis, which is currently being tested in new experimental models, is confirmed, this would justify the use of activators of the carotid body independent of the oxygen sensing mechanism as respiratory stimulants in patients with COVID-19.

Although plants are anchored to the ground, they spend most of their lifetime swinging in the wind. Like animals, plants have 'molecular switches' on the surface of their cells that transduce a mechanical signal into an electrical one in milliseconds. In animals, sound vibrations activate 'molecular switches' located in the ear. Scientists from the CNRS, INRAE, Ecole Polytechnique, Université Paris-Saclay and Université Clermont-Auvergne (1) have found that in plants, rapid oscillations of stems and leaves due to wind may activate these 'switches' very effectively. They could allow plants to 'listen' to the wind. This is a key advantage in preparing them for storms, by modulating their growth. This work was published in PNAS on December 28, 2020.

How can cells adhere to surfaces and move on them? This is a question which was investigated by an international team of researchers headed by Prof. Michael Hippler from the University of Münster and Prof. Kaiyao Huang from the Institute of Hydrobiology (Chinese Academy of Sciences, Wuhan, China). The researchers used the green alga Chlamydomonas reinhardtii as their model organism. They manipulated the alga by altering the sugar modifications in proteins on the cell surface. As a result, they were able to alter the cellular surface adhesion, also known as adhesion force. The results have now been published in the open access scientific journal eLife.

Background and methodology

In order to move, the green alga has two thread-like flagella on its cell surface. The alga actually uses these flagella for swimming, but it can also use them to adhere to surfaces and glide along them. The researchers now wanted to find out how movement and adhesion on the part of the alga can be manipulated. "We discovered that proteins on cell surfaces that are involved in this process are modified by certain sugars. If these sugar chains on the proteins are altered, this enables their properties to be altered," explains Michael Hippler from the Institute of the Biology and Biotechnology of Plants at Münster University. Experts then describe such proteins as being N-glycosylated - a modification in which carbohydrates are docked onto amino groups. Alterations to these sugar modifications by genetically manipulating the algae showed that the adhesion force of the algae and, as a result, any adhesion to surfaces were reduced. At the same time, there was no change in the cells gliding on the surface. The much-reduced force with which the mutants adhere to surfaces is therefore still sufficient, under laboratory conditions, to enable gliding to take place.

In order to study these processes, the researchers first used so-called insertional mutagenesis and the CRISPR/Cas9 method to deactivate genes which encode enzymes relevant to the N-glycosylation process. "The next step was to analyse the sugar modifications of these genetically altered algae strains using mass spectrometry methods," says Michael Hippler, explaining the team's approach. In order to visualise the cell-gliding, the researchers used a special method of optical microscopy - total internal reflection fluorescence microscopy (TIRF). This method is frequently used to carry out examinations of structures which are located very close to a surface. For this purpose, a fluorescent protein was expressed in the flagella of the algae in order to make the flagella and the cell-gliding visible.

In order to measure how much force was used in adhering the individual cells to the surface, atomic force microscopy was used and micropipette adhesion measurements were undertaken in collaboration with groups at the University of Liverpool (UK) and the Max Planck Institute of Dynamics and Self-Organization in Göttingen. "This enabled us to verify that adhesion forces in the nanometre range are reduced by altering the protein sugar modifications," adds Kaiyao Huang.

The two flagella on the green alga resemble for example not only the flagella of sperm but also other movable flagella. These are usually called 'cilia' and are also found in the human body - for example in the respiratory tracts. "If we transfer our findings to human cells, sugar-modified proteins could be used to change the interaction of sperm or cilia with all sorts of surfaces," say Kaiyao Huang and Michael Hippler.

Thanks to the marine worm Platynereis dumerilii, an animal whose genes have evolved very slowly, scientists from CNRS, Université de Paris and Sorbonne Université, in association with others at the University of Saint Petersburg and the University of Rio de Janeiro, have shown that while haemoglobin appeared independently in several species, it actually descends from a single gene transmitted to all by their last common ancestor. These findings were published on 29 December 2020 in BMC Evolutionary Biology.

Having red blood is not peculiar to humans or mammals. This colour comes from haemoglobin, a complex protein specialized in transporting the oxygen found in the circulatory system of vertebrates, but also in annelids (a worm family whose most famous members are earthworms), molluscs (especially pond snails) and crustaceans (such as daphnia or 'water fleas'). It was thought that for haemoglobin to have appeared in such diverse species, it must have been 'invented' several times during evolution. But recent research has shown that all of these haemoglobins born 'independently' actually derive from a single ancestral gene.

Researchers from the Institut Jacques Monod (CNRS/Université de Paris), the Laboratoire Matière et Systèmes Complexes (CNRS/Université de Paris), the Station Biologique de Roscoff (CNRS/Sorbonne Université), the Universities of Saint Petersburg (Russia) and Rio de Janeiro (Brazil), conducted this research on Platynereis dumerilii, a small marine worm with red blood.

It is considered to be an animal that evolved slowly, because its genetic characteristics are close to those of the marine ancestor of most animals, Urbilateria(1). Studying these worms by comparing them with other species with red blood has helped in tracing back to the origins of haemoglobins.

The research focused on the broad family to which haemoglobins belong: globins, proteins present in almost all living beings that 'store' gases like oxygen and nitric oxide. But globins usually act inside the cells because they do not circulate in the blood like haemoglobin.

This work shows that in all species with red blood, it is the same gene that makes a globin called 'cytoglobin' that independently evolved to become a haemoglobin-encoding gene. This new circulating molecule made oxygen transport more efficient in their ancestors, who became larger and more active.

Scientists now want to change scale and continue this work by studying when and how the different specialized cells of bilaterian vascular systems emerged.

(1)Urbilateria is the last common ancestor of bilaterians, i.e. animals with bilateral (left-right) symmetry and complex organs, apart from species with simpler organization such as sponges and jellyfish.

After "COVID-19," the term that most people will remember best from 2020 is likely to be "social distancing." While it most commonly applied to social gatherings with family and friends, it has impacted the way many receive medical care. Historically, the United States has been relatively slow to broadly adopt telemedicine, largely emphasizing in-person visits.

However, the COVID-19 pandemic, especially in the spring of 2020, necessitated increased use of virtual or phone call visits, even prompting the Center for Medicare and Medicaid Services (CMS) to relax some of its regulations, primarily for video-based telemedicine. These large scale changes made telemedicine exponentially more popular than it had been even at the start of the calendar year.

But while this was a positive for those who otherwise would have delayed or foregone care due to the pandemic, a new study led by researchers in the Perelman School of Medicine at the University of Pennsylvania, published in JAMA Network Open, uncovered significant inequities, particularly by race/ethnicity, socioeconomic status, age, and when someone needed to use a language other than English.

"As we begin to establish novel ways of caring for our patients via telemedicine, it is critical that we make the foundation of this new way forward equitable," said the study's senior author, Srinath Adusumalli, MD, an assistant professor of Cardiovascular Medicine and the University of Pennsylvania Health System assistant chief medical information officer for connected health. "We hope that regulatory and payer organizations recognize potential inequities that could be introduced by policies they create -- which might include not reimbursing for telephone visits, and potentially leading to lack of access to care for particular patient populations, specifically those disproportionately affected by events like the COVID-19 crisis."

The researchers, who included the study's lead author, Lauren Eberly, MD, a clinical fellow in Cardiovascular Medicine, examined data for nearly 150,000 patients of a large, academic medical system. All of these patients had been previously scheduled to have a primary care or ambulatory specialty visit between March 16 and May 11, 2020. This time period coincided with the first surge of coronavirus in the health system's region, and was also amid stay-at-home orders in the area.

Of the patients who had visits previously scheduled, a little more than half, roughly 81,000 (54 percent), conducted their visits via telemedicine, the data showed. And within that segment, less than half, nearly 36,000, (46 percent) had visits conducted via video.

When these visits were broken down by the patients' characteristics, some clear inequities were found. Overall, patients who were older than 55 were 25 percent less likely than the average patient to successfully participate in a telemedicine visit, with people older than 75 being 33 percent less likely. People who identified as Asian were 31 percent less likely to conduct a telemedicine visit, and those who did not speak English were 16 percent less likely. Using Medicaid for insurance also made patients less likely to successfully conduct a telemedicine visit by 7 percent.

Because of the relaxation of CMS rules surrounding video-based telemedicine early in the pandemic, it's important to consider that mode of telemedicine in a class by itself. So when those numbers were examined, some of the same groups showed even less favorable numbers than they had for overall telemedicine use. For instance, people over 55 were at least 32 percent less likely to conduct a video visit, with those over 75 being 51 percent less likely.

Meanwhile, some groups of people were shown to have significant disparities in video-based telemedicine even if they hadn't displayed them for overall telemedicine use. This likely means that they didn't have problems accessing telemedicine if it was phone or audio-based, but video was not as accessible to them. More, women were 8 percent less likely to participate in a video visit than men, Latinx patients were 10 percent less likely than White patients, and Black people 35 percent less likely than White people. Patients with lower household incomes were also less likely to conduct a video visit, with those making less than $50,000 being 43 percent less likely.

While the CMS has recently attempted to make phone call-based telemedicine easier to access from a reimbursement perspective, the researchers believe their findings show that there needs to be equal consideration for all forms of telemedicine moving forward.

"It is critical that complete payment parity for all types of telemedicine visits, by all insurance payers, is guaranteed permanently," Eberly said. "Less reimbursement for telephone visits may disproportionately and unjustly hurt clinics and providers that care for minority and poorer patients."

Penn Medicine has long implemented a practical approach to root out technical issues that may play a role in access issues. Specifically, professionals within the health system work with patients to assess whether they have the technical ability to successfully have a visit. That includes checking Wi-Fi speed and whether the patient has devices physically capable of conducting the visit.

Something since the start of the COVID-19 outbreak that Adusumalli said Penn Medicine addressed was the inequity found for non-English speakers.

"One concrete thing that has already been addressed, based on the results of this study, was adding one-click interpreter integration for more than 40 video-based languages and greater than 100 audio-based languages for both inpatient and outpatient telemedical care throughout our enterprise," he explained.

Moving forward, the researchers hope they can uncover more ways to make telemedicine work for everyone, including facilitating broadband and digital device access.

"We currently have broader research underway to better characterize what patient-specific and provide-specific barriers exist," Eberly said. "If we can understand these barriers, it could help guide telemedicine implementation strategies that will benefit everyone."

N-Aryl-C-nitroazoles are an important class of heterocyclic compounds. They are used as pesticides and fungicides. However, these substances could be toxic to humans and cause mutations. As they are not frequently used, there is little data about them in the medicinal chemistry literature. However, it has been suggested recently that the groups of compounds that are traditionally avoided can help to fight pathogenic bacteria. Yet, to reduce toxic effects, a great amount of work must be carried out at the molecular level, accurate optimization of the molecular environment of the nitro-heteroaromatic "warhead". The validity of this approach was demonstrated in the early 2000s through the development of anti-tuberculosis drugs delamanid and pretomanid, currently approved for medical use. They act like prodrugs, that is, the substance itself is inactive, but acquires new properties when it enters the human body.

In terms of this work, scientists from the Baltic Federal University together with colleagues from St. Petersburg State University, the L. Pasteur Research Institute of Epidemiology and Microbiology, and the Research Institute of Phthisiopulmonology in St. Petersburg, are looking for new effective antibacterial drugs, studying various nitrogen heteroaromatic compounds with a nitro group which might be used in medicine further. The compound OTB-021 was found to work well against drug-sensitive strains of tuberculosis pathogens, but was powerless against strains of pathogens that belong to the so-called ESKAPE panel. ESKAPE is an abbreviation for the names of bacterial species most often developing resistance to antibiotics: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter aerogenes. It is a kind of a pun: "eskape" sounds like "escape", and the bacteria of this panel are known to be resistant to most of the known antibiotics, that is, they seem to "escape" from drugs.

To understand how to modify the compound so that it could act on these pathogenic bacteria the scientists constructed two isomeric (identical in the atomic arrangement) series based on OTB-021. Side amino groups changed their position to make the aromatic nitrogen-rich core of the substance more compact, this should reduce the toxicity of the substance. The sensitivity of microorganisms to a new compound was tested via disk diffusion method. Zones of the inhibition of bacterial growth by antibiotic disks and dried solution of the compound in Petri dishes were measured.

It turned out that the ESKAPE bacteria were easily suppressed by the new substances. The minimal concentration of the chemical that prevents the growth of bacteria (μg / ml) for the tested substance shows a result comparable to the use of a ml of the antibiotic ciprofloxacin: for example, 0.3 μg / ml of an antibiotic for Enterococcus acts the same as 2 μg / ml of one of the new substances.

"Starting from the structure of the antimycobacterial OTB-021 which has no activity against ESKAPE pathogens, we developed, synthesized, and tested two isomeric series of novel analogs with an amino group that changes its position in the structure." These compounds can inhibit the growth of all ESKAPE pathogens. Probably, they will help to develop new effective drugs against bacterial diseases which are sometimes very difficult to treat," says Mikhail Krasavin, Doctor of Chemical Science, Professor of the Russian Academy of Sciences, professor and researcher at the Immanuel Kant Baltic Federal University.

The flag leaf is the last to emerge, indicating the transition from crop growth to grain production. Photosynthesis in this leaf provides the majority of the carbohydrates needed for grain filling--so it is the most important leaf for yield potential. A team from the University of Illinois and the International Rice Research Institute (IRRI) found that some flag leaves of different varieties of rice transform light and carbon dioxide into carbohydrates better than others. This finding could potentially open new opportunities for breeding higher yielding rice varieties. 

Published in the Journal of Experimental Botany, this study explores flag leaf induction--which is the process that the leaf goes through to "start up" photosynthesis again after a transition from low to high light. This is important because the wind, clouds, and movement of the sun across the sky cause frequent fluctuations in light levels. How quickly photosynthesis adjusts to these changes has a major influence on productivity. 

For the first time, these researchers revealed considerable differences between rice varieties in the ability of flag leaves to adjust to fluctuating light. They also showed that the ability to adjust differs between the flag leaf and leaves formed before flowering. Six rice varieties chosen to represent the breadth of genetic variation across a diverse collection of more than 3000 were analyzed as a first step in establishing if there was variation in ability to cope with fluctuations in light. 

In this study, they discovered the flag leaf of one rice variety that began photosynthesizing nearly twice (185%) as fast as the slowest. Another top-performing flag leaf fixed 152% more sugar. They also found large differences (77%) in how much water the plant's flag leaves exchanged for the carbon dioxide that fuels photosynthesis. Additionally, they found that water-use efficiency in flag leaves correlated with water-use efficiency earlier in development of these rice varieties, suggesting that water-use efficiency in dynamic conditions could be screened for at younger stages of rice development. 

"What's more, we found no correlation between the flag leaf and other leaves on the plant, aside from water-use efficiency, which indicates that both kinds of leaves may need to be optimized for induction," said Stephen Long, Illinois' Ikenberry Endowed University Chair of Crop Sciences and Plant Biology. "While this means more work for plant scientists and breeders, it also means more opportunities to improve the plant's photosynthetic efficiency and water use. Improving water use is of increasing importance, as agriculture already accounts for over 70% of human water use, and rice is perhaps the largest single part of this."

Confirming their previous study in New Phytologist, they found no correlation between data collected in fluctuating and steady-state conditions, where the rice plants were exposed to constant high light levels. This finding adds to a growing consensus that researchers should move away from research dependent on steady-state measurements. 

"We're realizing the need for our experiments to more accurately reflect the reality that these plants experience out the field," said first-author Liana Acevedo-Siaca, a postdoctoral researcher at Illinois. "We need to focus our efforts on capturing the dynamic conditions so we can improve crops to be productive in the real world, not laboratories." 

LOS ANGELES -- Scientists from the UCLA Jonsson Comprehensive Cancer Center have developed a simple, high-throughput method for transferring isolated mitochondria and their associated mitochondrial DNA into mammalian cells. This approach enables researchers to tailor a key genetic component of cells, to study and potentially treat debilitating diseases such as cancer, diabetes and metabolic disorders.

A study, published today in the journal Cell Reports, describes how the new UCLA-developed device, called MitoPunch, transfers mitochondria into 100,000 or more recipient cells simultaneously, which is a significant improvement from existing mitochondrial transfer technologies. The device is part of the continued effort by UCLA scientists to understand mutations in mitochondrial DNA by developing controlled, manipulative approaches that improve the function of human cells or model human mitochondrial diseases better.

"The ability to generate cells with desired mitochondrial DNA sequences is powerful for studying how genomes in the mitochondria and nucleus interact to regulate cell functions, which can be critical for understanding and potentially treating diseases in patients," said Alexander Sercel, a doctoral candidate at the David Geffen School of Medicine at UCLA and co-first author of the study.

Mitochondria, often known as the 'powerplant' of a cell, are inherited from a person's mother. They rely on the integrity of the mitochondrial DNA to perform their essential functions. Inherited or acquired mutations of the mitochondrial DNA can significantly impair energy production and may result in debilitating diseases.

Technologies for manipulating mitochondrial DNA lag behind advances for manipulating DNA in the nucleus of a cell and could potentially help scientists develop disease models and regenerative therapies for disorders caused by these mutations. Current approaches, however, are limited and complex, and for the most part can only deliver mitochondria with desired mitochondrial DNA sequences into a limited number and variety of cells.

The MitoPunch device is simple to operate and allows for consistent mitochondrial transfers from a wide range of mitochondria isolated from different donor cell types into a multitude of recipient cell types, even for non-human species, including for cells isolated from mice.

"What sets MitoPunch apart from other technologies is an ability to engineer non-immortal, non-malignant cells, such as human skin cells, to generate unique mitochondrial DNA-nuclear genome combinations," said co-first author Alexander Patananan, a UCLA postdoctoral scholar, who now works at Amgen. "This advance allowed us to study the impact of specific mitochondrial DNA sequences on cell functions by also enabling the reprogramming of these cells into induced pluripotent stem cells that were then differentiated into functioning fat, cartilage, and bone cells."

MitoPunch was created in the labs of Dr. Michael Teitell, director of the Jonsson Cancer Center and professor of pathology and laboratory medicine, Pei-Yu (Eric) Chiou, professor of mechanical and aerospace engineering at the UCLA Henry Samueli School of Engineering and Applied Science, and Ting-Hsiang Wu, from ImmunityBio, Inc., Culver City, CA.

MitoPunch builds upon prior technology and a device called a photothermal nanoblade, which the team developed in 2016. But unlike the photothermal nanoblade, which requires sophisticated lasers and optical systems to operate, MitoPunch works by using pressure to propel an isolated mitochondrial suspension through a porous membrane coated with cells. The researchers propose that this applied pressure gradient creates the ability to puncture cell membranes at discrete locations, allowing the mitochondria direct entry into recipient cells, followed by cell membrane repair.

"We knew when we first created the photothermal nanoblade that we would need a higher-throughput, simpler to use system that is more accessible for other laboratories to assemble and operate," said Teitell, who is also the chief of the division of pediatric and developmental pathology and a member of the UCLA Broad Stem Cell Research Center. "This new device is very efficient and allows researchers to study the mitochondrial genome in a simple way -- swapping it from one cell into another -- which can be used to uncover the basic biology that governs a broad range of cell functions and could, one day, offer hope for treating mitochondrial DNA diseases."

AURORA, Colo. (Dec. 29, 2020) - College football players may underestimate their risk of injury and concussion, according to a new study published today in JAMA Network Open.

Christine Baugh, PhD, MPH, assistant professor of medicine at the University of Colorado School of Medicine and member of the CU Center for Bioethics and Humanities, is the corresponding author of the article, "Accuracy of US College Football Players' Estimates of Their Risk of Concussion or Injury."

Baugh and co-authors report on survey results of 296 college football players from four teams in the Power 5 Conferences of the National Collegiate Athletic Association. Athletes were surveyed in 2017. The researchers found that between 43 percent and 91 percent of respondents underestimated their risk of injury and between 42 percent and 63 percent underestimated their risk of concussion.

To measure the accuracy of football players' risk estimations, the researchers modeled individual athletes' probabilities of sustaining a concussion or injury and compared model estimates to athlete perceptions. While recognizing that many people underestimate health risks, the authors point out that the risks college football athletes face may be more severe or debilitating than those faced by many in the general population. Given this elevated risk profile, they say it is concerning that athletes tend to underestimate the likelihood of these risks. These results raise questions about informed consent and how much risk should be acceptable in the context of a game, Baugh and her co-authors write.

"That athletes underestimated their risk of concussion and injury in this study raises important ethical considerations," Baugh and her colleagues write. "What is the threshold for college athletes to be sufficiently informed of the risks and benefits of football to make decisions that align with their values and preferences?"

People have puzzled for years why pathogen Phytophthora infestens causes the devastating late blight disease, source of the Irish Potato famine, on potatoes, but has no effect at all on plants like apple or cucumber. How are apple trees and cucumber plants able to completely shake off this devastating pathogen? Agricultural scientists have wondered for years: if this resistance is so complete and persists over so many generations, is there some way we could transfer it to susceptible plants like wheat and thereby stop disease?

Why is it so important to determine the molecular basis of nonhost resistance?

There are many examples of plants that are susceptible to one pathogen but able to resist another closely related pathogen. By uncovering the mechanism behind resistance, we can obtain a deeper understanding of the plant immune system and can also uncover previously unknown aspects of immune signaling and regulation, which can help scientists improve resistance against a broader spectrum of pathogens.

This question has always been important as pathogens are a consistent threat to agriculture, limiting how much food is produced and where crops can be grown. Scientists continue to learn ways to reduce the impact of disease, through the development of pesticides, implementing new practices in the field, and breeding crops with enhanced resistance.

However, the modern world inadvertently undermines these efforts in a number of ways. Globalization and increased movement have contributed to the spread of pathogens into new environments. A prominent example is the recent emergence of wheat blast disease caused by the fungus Magnaporthe oryzae, which for a long time was unable to colonize wheat.

"The field of nonhost resistance sets out to identify novel ways to engineer resistance to these plant pathogens, guided by approaches that already exist in nature," explained Matthew Moscou, a scientist at The Sainsbury Laboratory in Norwich, United Kingdom. "This question is fundamental to understanding why some plants get infected by a particular pathogen and others don´t, and, vice versa, why a given pathogen can only successfully colonize a limited number of plant species, which collectively form its host range."

What do we know about nonhost resistance?

Scientists have learned that nonhost resistance is a feature controlled by many genes and largely governed by the characteristic attributes of a given plant-pathogen constellation. Pre-existing and induced physical barriers, such as the plant cuticle, and the secretion of antimicrobial molecules are often key factors in nonhost resistance. More recently scientists have recognized the interplay of host NLR-type immune sensors and secreted pathogen effector proteins as another important determinant of nonhost resistance.

What don't we know about nonhost resistance?

"While the contribution of microbial commensals (microbes that naturally inhabit plant organs without causing any harm) to plant immunity has emerged during the past few years, their explicit role in nonhost resistance has not been demonstrated yet", said Ralph Panstruga, a scientist at RWTH Aachen University in Germany. "Our knowledge on nonhost resistance largely relies on findings obtained in a handful of (model) angiosperm plant species that are genetically very tractable. We do not know yet to what extent these insights can be generalized, especially with respect to non-angiosperms."

While there is a lot we don't know about nonhost resistance, recent advances in technology, such as DNA sequencing methods, will make it easier for scientists to learn more. As for understanding the contribution of microbial commensals, scientists have recently been able to explore this aspect through reconstitution experiments with synthetic microbial communities in combination with germ-free plant systems. These tools were only recently established for some model plant species and are not yet available for many agriculturally important crops.

What can come from answering this question?

Learning more about nonhost resistance will help scientists better appreciate that susceptibility and resistance are the extreme outcomes of interactions between plants and pathogens, with all kinds of intermediate forms possible. Scientists may also discover undiscovered of plant pathogens on some species, which will enhance disease control strategies. Answering this question will also help scientists further comprehend whether microbial commensals contribute to resistance, which could form the basis for future plant protection measures. Finally, these insights will complete our picture of the plant immune system.

For the full review, read "What is the Molecular Basis of Nonhost Resistance?" published in the November issue of the MPMI journal. This article is the first in a series of ten reviews exploring the top 10 unanswered questions in molecular plant-microbe interactions, which came out of a crowdsourcing initiative spearheaded by the MPMI journal's editorial board at the 2019 International Congress on Molecular Plant-Microbe Interactions in Glasgow, Scotland.

When meeting attendees Panstruga and Moscou heard about the quest to identify the top 10 unanswered questions in MPMI, they were immediately fascinated. When they saw the final list, they were drawn to the question about nonhost resistance, a plant defense that provides immunity to all members of a plant species against a microorganism that is harmful to other plant species.

"Since we both have published expertise in the area of nonhost resistance, it was somewhat self-evident that we could contribute with a review article to this relevant question," said Panstruga. "We felt for quite some time that some concepts and terms in the field are ambiguous and possibly misleading, and that it would be just the right time to sum up the present knowledge, but also to clarify a few aspects and to raise a few fresh ideas."

ADELPHI, Md. -- Multi-domain operations, the Army's future operating concept, requires autonomous agents with learning components to operate alongside the warfighter. New Army research reduces the unpredictability of current training reinforcement learning policies so that they are more practically applicable to physical systems, especially ground robots.

These learning components will permit autonomous agents to reason and adapt to changing battlefield conditions, said Army researcher Dr. Alec Koppel from the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, Army Research Laboratory.

The underlying adaptation and re-planning mechanism consists of reinforcement learning-based policies. Making these policies efficiently obtainable is critical to making the MDO operating concept a reality, he said.

According to Koppel, policy gradient methods in reinforcement learning are the foundation for scalable algorithms for continuous spaces, but existing techniques cannot incorporate broader decision-making goals such as risk sensitivity, safety constraints, exploration and divergence to a prior.

Designing autonomous behaviors when the relationship between dynamics and goals are complex may be addressed with reinforcement learning, which has gained attention recently for solving previously intractable tasks such as strategy games like go, chess and videogames such as Atari and Starcraft II, Koppel said.

Prevailing practice, unfortunately, demands astronomical sample complexity, such as thousands of years of simulated gameplay, he said. This sample complexity renders many common training mechanisms inapplicable to data-starved settings required by MDO context for the Next-Generation Combat Vehicle, or NGCV.

"To facilitate reinforcement learning for MDO and NGCV, training mechanisms must improve sample efficiency and reliability in continuous spaces," Koppel said. "Through the generalization of existing policy search schemes to general utilities, we take a step towards breaking existing sample efficiency barriers of prevailing practice in reinforcement learning."

Koppel and his research team developed new policy search schemes for general utilities, whose sample complexity is also established. They observed that the resulting policy search schemes reduce the volatility of reward accumulation, yield efficient exploration of an unknown domains and a mechanism for incorporating prior experience.

"This research contributes an augmentation of the classical Policy Gradient Theorem in reinforcement learning," Koppel said. "It presents new policy search schemes for general utilities, whose sample complexity is also established. These innovations are impactful to the U.S. Army through their enabling of reinforcement learning objectives beyond the standard cumulative return, such as risk sensitivity, safety constraints, exploration and divergence to a prior."

Notably, in the context of ground robots, he said, data is costly to acquire.

"Reducing the volatility of reward accumulation, ensuring one explores an unknown domain in an efficient manner, or incorporating prior experience, all contribute towards breaking existing sample efficiency barriers of prevailing practice in reinforcement learning by alleviating the amount of random sampling one requires in order to complete policy optimization," Koppel said.

The future of this research is very bright, and Koppel has dedicated his efforts towards making his findings applicable for innovative technology for Soldiers on the battlefield.

"I am optimistic that reinforcement-learning equipped autonomous robots will be able to assist the warfighter in exploration, reconnaissance and risk assessment on the future battlefield," Koppel said. "That this vision is made a reality is essential to what motivates which research problems I dedicate my efforts."

The next step for this research is to incorporate the broader decision-making goals enabled by general utilities in reinforcement learning into multi-agent settings and investigate how interactive settings between reinforcement learning agents give rise to synergistic and antagonistic reasoning among teams.

According to Koppel, the technology that results from this research will be capable of reasoning under uncertainty in team scenarios.