Culture

Mathematical modeling of processes in neurons to assist the treatment of epilepsy and depression

image: Mathematical modeling of electro-mechanical processes in neurons to assist the treatment of epilepsy and chronic depression by focused ultrasound.

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Peter the Great St.Petersburg Polytechnic University

Russian and British scientists study the approaches to mathematical modeling of electromechanical processes in neurons of the brain.

Researchers from Peter the Great St.Petersburg Polytechnic University (SPbPU) in collaboration with colleagues from the University College London under the framework of "Project 5-100" study the effect of neural stimulation by ultrasonic waves and analyzing the influence of ultrasonic wave parameters on the excitation of electrical signals in the nerves. The obtained results have a great practical value for further studies related to the issues of human brain modeling. These results are aimed at the improvement of the methods used to treat a range of severe neurological and mental disorders, including epilepsy and chronic depression.

According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, one of the most common neurological diseases on a global scale. Besides, more than 264 million people from all age groups suffer from depression. Dysfunction of neurons in the brain can be the cause of both diseases.

"We have proposed and tested various hypotheses regarding the physics of the process of ultrasonic neural stimulation, - explains Vladimir Filkin, a member of the scientific group, a graduate student of the Higher School of Mechanics and Control Processes SPbPU" Currently, the researchers obtained a mathematical model of this fundamental process, which will be useful for the effective algorithm of using the ultrasound to treat patients and conduct all kinds of research.

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Peter the Great Saint-Petersburg Polytechnic University

The influence of social norms and behaviour on energy use

The research method used is the same as that employed in the testing of drugs for medicine. This means applying randomization methods in the analysis of electric energy consumption in households: a randomly selected sample group, made up of hundreds of thousands of people that are all clients of the same Italian company Eni gas e luce, were sent a document containing a comparison of their energy consumption with that of other households, with positive messages aimed at those that were more efficient. In what ways did people assimilate this information and consequently change their behaviour and energy consumption?

This is the question that lies at the heart of the research conducted by the Italian team from the RFF CMCC European Institute on Economics and the Environment (EIEE), composed of Jacopo Bonan, Cristina Cattaneo, Giovanna d'Adda and Massimo Tavoni, and published in the latest edition of the prestigious Nature Energy journal with the title "The interaction of descriptive and injunctive social norms in promoting energy conservation".

The results obtained from the study outline how a variation in the contents of the document sent to the sample group influenced their energy consumption. For example, the less efficient clients discovered through these documents that they were consuming more than other similar households, and that efficiency was a prized attribute. These clients, that were shown consistent social norms, then went on to have the largest decrease in energy consumption after receiving the document. To the contrary, the document received by the more efficient households, on top of approval for having saved on energy also revealed that conforming to the behaviour of other families would have meant increasing their energy consumption. This led the more efficient clients to have a smaller decrease in energy use in response to the document, as the two social norms were in contrast with each other. A detailed analysis was able to distinguish and isolate the impact of the specific contents of the document from that of the characteristics of individual clients, particularly with regards to initial consumption.

The results demonstrate a synergy between different types of social norms: the people that most reduced their consumption were those that, from the information received, understood that they were using more electric energy than their neighbours, and at the same time learnt that less consumption of energy is a socially recognised value.

Another important result that emerges from the study, exemplified by the virtuous client, reveals the hidden risks of messages that are based on social norms and how they can become ineffective if they contain contrasting messages. In fact, these clients learnt that energy conservation is a valued social norm but at the same time discovered that the behaviour of their neighbours didn't reflect this value. To induce the virtuous clients to further reduce their consumption it was therefore necessary to strengthen the message in favour of energy efficiency.

The authors explain that the results of the study contain important lessons for the realization of information campaigns that aim to maximise behavioural change. Areas in which these could be applied effectively include tax evasion, philanthropy or the use of water resources. In all these cases the Italian team's research has a high scientific relevance. It is an innovative study not only in the application of methods, theories and competences of behavioural science to research on energy, but also in its engagement with energy providers that took an active role in the research efforts. Public and private policymakers in the energy sector are therefore among the parties interested in understanding how messages and information can contribute to change the behaviour and consumption patterns of people.

This level of innovation and multidisciplinarity, that brings together experts in energy technology and behavioural science, is one of the characteristics that defines the RFF CMCC European Institute on Economics and the Environment (EIEE). Born from a collaboration between the CMCC Foundation and the US based think tank RFF, this institution combines different competences in the study of environmental economics in support of sustainable development.

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CMCC Foundation - Euro-Mediterranean Center on Climate Change

Outcome of 2016 US election associated with poorer mental health in Clinton voters

There were 54.6 million more days of poor mental health among adults in states that voted for Hillary Clinton in December 2016, compared to October 2016, according to a study published in the Journal of General Internal Medicine. No such increase in poor mental health following the 2016 US election was observed in states that voted for Donald Trump. The increase in average number of poor mental health days per person in Clinton-voting states largely persisted in the six months after the election.

Comparing states in which Trump had received the most votes with states in which Clinton had received the most votes, a team of researchers from the University of California, San Francisco, USA, and Duke University, Durham, NC, USA found that in Clinton-voting states, the average number of days on which adults reported experiencing poor mental health in the last 30 days increased by 0.50 days, from 3.35 days in October to 3.85 days in December 2016.

Brandon Yan, the corresponding author said: "The additional half a day per adult translated into 54.6 million more days of poor mental health in December 2016 alone for the 109.2 million adults living in Clinton-voting states."

The rise in poor mental health days in Clinton-voting states in December 2016 was primarily observed in adults aged 65 and older, women, and white individuals. No changes in poor mental health days were statistically detected among younger age groups, men, or racial and ethnic minority groups in December 2016 in either Clinton- or Trump-voting states.

In states that voted for Clinton, the authors also observed a 2 percentage point increase in the number of people who reported at least 14 days of poor mental health in the last 30 days in December 2016, compared to October 2016, while no such rise was observed in Trump-voting states.

Brandon Yan said: "It is notable that following the election the proportion of those with 14 or more days of poor mental health also increased, which may suggest that some individuals may newly meet diagnostic criteria for major depressive disorder."

The authors analyzed data on 499,201 adults collected in 2016 and 2017 as part of the Behavioral Risk Factor Surveillance System, a joint state and federal annual household survey. By comparing each monthly cohort of survey respondents, they studied changes in three mental health indicators - total days of poor mental health in the last 30 days, 14 days or more of poor mental health in the last 30 days and being diagnosed with a depressive disorder - in Clinton- and Trump-voting states in the six months following the November 2016 election, compared to the six months before the election.

The authors also found that a 10-percentage point higher margin of victory for Trump in the state was associated with 0.41 fewer days of poor mental health in Trump-voting states. The inverse is also statistically true. In Clinton-states, a 10-percentage point higher margin of victory for Clinton in the state predicted 0.41 more days of poor mental health.

Overall, the findings suggest that the outcome of the 2016 election had a negative impact on mental health for voters of the candidate that lost the election.

Brandon Yan said: "Depression rates - which were assessed by asking people if they had ever been diagnosed with a depressive disorder - also started rising in January 2017 in Clinton-voting states and in February 2017 in Trump-voting states. These increases in depression rates continued into the second quarter of 2017." The authors suggest that the rise in depression rates in Trump states suggests that there were likely other coinciding factors contributing to depression, such as rising opioid deaths which especially affected many states that voted for Trump.

The authors caution that the cross-sectional observational nature of the study does not allow for conclusions about cause and effect. Because the respondents' candidate preference and party affiliation were unknown, the authors relied on the candidate's margin of victory or loss in a state to assess which candidate's voters experienced changes in mental health.

Brandon Yan said: "Given our findings for 2016, primary care providers, mental health professionals, and the public should not overlook the potential effects from the 2020 election. Health care providers could play a proactive role in monitoring for clinically relevant signs of mental health deterioration and offering appropriate support and intervention following the 2020 election."

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Springer

Seven different 'disease forms' identified in mild COVID-19

In a study recently published in the top journal "Allergy", a team of MedUni Vienna scientists led by immunologist Winfried F. Pickl and allergologist Rudolf Valenta (both from the Center for Pathophysiology, Infectiology and Immunology) showed that there are seven "forms of disease" in COVID-19 with mild disease course and that the disease leaves behind significant changes in the immune system, even after 10 weeks. These findings could play a significant role in the treatment of patients and in the development of a potent vaccine.

In the study involving 109 convalescents and 98 healthy individuals in the control group, the researchers were able to show that various symptoms related to COVID-19 occur in symptom groups. They identified seven groups of symptoms: 1) "flu-like symptoms" (with fever, chills, fatigue and cough), 2) ("common cold-like symptoms" (with rhinitis, sneezing, dry throat and nasal congestion), 3) "joint and muscle pain", 4) "eye and mucosal inflammation", 5) "lung problems" (with pneumonia and shortness of breath), 6) "gastrointestinal problems" (including diarrhoea, nausea and headache) and 7) "loss of sense of smell and taste and other symptoms".

"In the latter group we found that loss of smell and taste predominantly affects individuals with a 'young immune system', measured by the number of immune cells (T lymphocytes) that have recently emigrated from the thymus gland. This means that we were able to clearly distinguish systemic (e.g., groups 1 and 3) from organ-specific forms (e.g. groups 6 and 7) of primary COVID-19 disease," says Pickl.

COVID-19 fingerprint in the blood

At the same time, the scientists established that COVID-19 leaves behind long detectable changes in the blood of convalescents, very similar to a fingerprint. For example, the number of granulocytes, which are otherwise responsible in the immune system for fighting bacterial pathogens, is significantly lower than normal in the COVID-19 group. Pickl explains: "However, both the CD4 and CD8 T cell compartment developed memory cells and CD8 T cells remained strongly activated. This indicates that the immune system is still intensively engaged with the disease several weeks after initial infection. At the same time, the regulatory cells are greatly diminished - and that is likely a dangerous mix, which could lead to autoimmunity." Furthermore, increased levels of antibody-producing immune cells were detected in the blood of convalescents - the higher the fever of the affected patient during the mild course of the disease, the higher were the antibody levels against the virus.

"Our findings contribute to a better understanding of the disease and help us in the development of potential vaccines, since we now have access to promising biomarkers and can perform even better monitoring," the scientists emphasize. "Above all, the study shows that the human immune system "doubles up" when defending against COVID-19 with the combined action of immune cells and antibodies - like the defence in a modern soccer team - and that the cells are also able to memorise certain "moves" on the part of the virus (Note: "memory") and respond to them. Now it is a matter of implementing these findings and using them for the development of highly-effective COVID-19 vaccines."

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Medical University of Vienna

New study by ESMT Berlin shows political commitment increasingly important for CEOs

Political and social engagement is a relevant topic for European business leaders. CEOs are increasingly making public statements on political issues in order to make a positive contribution to socially relevant topics. These are the findings of a recent study conducted by ESMT Master's in Management graduate Christoph Cewe in cooperation with United Europe e.V. The study surveyed 40 leaders of large European companies. Of those surveyed, 77.5 per cent believe that managing directors should take a stand on political issues, and 62.5 per cent state that they are also (very) likely to express themselves in sociopolitical terms. The most frequently reported motives for taking a public stance are to contribute to society (78 %) and to express corporate values (72 %).

The study entitled "The political CEO: Rationales behind CEO sociopolitical activism" explores the question of how and why CEOs and managing directors of European companies increasingly take a public stance on political and social issues that have no direct connection to their core business. Examples are climate change, immigration policy and the unconditional basic income.

"The results of the study show that managing directors express themselves publicly, primarily on political issues, so that they can use their influence to make a positive contribution on socially relevant topics. Personal motives and potential advantages for shareholders do not play a greater role," says Christoph Cewe. "European CEOs want to add value to the substantive discourse with their public statement, but do not want to take a party-political stance. Thus, ecological, economic and social issues are identified as the most suitable topics for public comment. Less than one in ten of the CEOs surveyed stated that it is appropriate to take a party political stance in public.

Leonhard Birnbaum, member of the board of management of E.ON SE, Günther H. Oettinger, former EU commissioner and president of United Europe e.V., and Jörg Rocholl, president of ESMT, engaged in an intensive exchange on the study "The Political CEO" on Monday, October 26. "At United Europe we support business leaders who are committed to the European idea. For many European CEOs, political commitment is a relevant topic, but CEOs do not bear political responsibility. They must be able to maintain a balance between business competence, public credibility, and an understandable interest in social processes," says Günther H. Oettinger.

Jörg Rocholl adds, "Authenticity and competence are the most important prerequisites for a public statement by managing directors. Lack of credibility can have immediate negative consequences, not only for the CEO personally, but for the entire company." The discussion was moderated by Ulrike Guérot, professor for European politics and democracy research at the Danube University Krems.

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ESMT Berlin

Root bacterium to fight Alzheimer's

A bacterium found among the soil close to roots of ginseng plants could provide a new approach for the treatment of Alzheimer's. Rhizolutin, a novel class of compounds with a tricyclic framework, significantly dissociates the protein aggregates associated with Alzheimer's disease both in vivo and in vitro, as reported by scientists in the journal Angewandte Chemie.

The area around the roots of plants is a complex ecosystem with numerous interactions between plants and diverse microorganisms. The so-called rhizosphere has been neglected in the search for new drugs, though it has much to offer. A team working with YoungSoo Kim (Yonsei University, Incheon, South Korea) and Dong-Chan Oh (Seoul National University, South Korea) has now identified a natural substance called rhizolutin that may provide a basis for novel Alzheimer's disease treatments. Rhizolutin is produced by a Streptomyces strain that grows in the root zone of ginseng plants. Ginseng is an Asian plant used in traditional medicine, where it is said to be a tonic.

Through cultivation in a medium fortified with ginseng powder, the researchers were able to increase the rhizolutin production of the bacterium by a factor of ten. This allowed them to determine the structure of this novel compound, which turns out to be a unique framework made of three rings bound together (a 7/10/6-tricyclic dilactone flanked by a seven-membered and a six-membered lactone ring).

A screening of natural product libraries indicated that rhizolutin is a drug lead that can dissociate amyloid-β (Aβ) plaques and tau tangles (fiber-like aggregates of tau proteins), both of which are typical hallmarks of Alzheimer's disease. Such deposits form when amyloid-β proteins fold incorrectly to form β-sheets, which can aggregate to form insoluble plaques and fibers. These lead to the death of nerve cells, nerve inflammation, brain atrophy, and the cognitive losses these entail. No effective treatment for Alzheimer's disease has been found.

Through a variety of in vitro and in vivo experiments, the team was able to demonstrate that rhizolutin leads to clear dissociation of insoluble Aβ and tau aggregates. In cultures of neuronal and glial cells, rhizolutin was able to markedly reduce the inflammatory processes and cell death caused by Aβ. Rhizolutin was also able to significantly dissociate the Aβ plaques present in the brains of mice with Alzheimer's. The process seems to be similar to the removal of incorrectly folded proteins through immunotherapy. Computer simulations suggest that rhizolutin enters into the hydrophobic regions of the aggregated β-sheets, initiating the dissociation.

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Wiley

First light on a next-gen astronomical survey toward a new understanding of the cosmos

image: The Sloan Digital Sky Survey's fifth generation made its first observations earlier this month. This image shows a sampling of data from those first SDSS-V data. The central sky image is a single field of SDSS-V observations. The purple circle indicates the telescope's field-of-view on the sky, with the full Moon shown as a size comparison. SDSS-V simultaneously observes 500 targets at a time within a circle of this size. The left panel shows the optical-light spectrum of a quasar--a supermassive black hole at the center of a distant galaxy, which is surrounded by a disk of hot, glowing gas. The purple blob is an SDSS image of the light from this disk, which in this dataset spans about 1 arcsecond on the sky, or the width of a human hair as seen from about 21 meters (63 feet) away. The right panel shows the image and spectrum of a white dwarf --the left-behind core of a low-mass star (like the Sun) after the end of its life.

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Image Hector Ibarra Medel, Jon Trump, Yue Shen, Gail Zasowski, and the SDSS-V Collaboration. Central background image: unWISE / NASA/JPL-Caltech / D.Lang (Perimeter Institute).

Pasadena, CA-- The Sloan Digital Sky Survey's fifth generation collected its very first observations of the cosmos at 1:47 a.m. on October 24, 2020. This groundbreaking all-sky survey will bolster our understanding of the formation and evolution of galaxies--including our own Milky Way--and the supermassive black holes that lurk at their centers.

The newly-launched SDSS-V will continue the path-breaking tradition set by the survey's previous generations, with a focus on the ever-changing night sky and the physical processes that drive these changes, from flickers and flares of supermassive black holes to the back-and-forth shifts of stars being orbited by distant worlds. SDSS-V will provide the spectroscopic backbone needed to achieve the full science potential of satellites like NASA's TESS, ESA's Gaia, and the latest all-sky X-ray mission, eROSITA.

"In a year when humanity has been challenged across the globe, I am so proud of the worldwide SDSS team for demonstrating--every day--the very best of human creativity, ingenuity, improvisation, and resilience. It has been a challenging period for the team, but I'm happy to say that the pandemic may have slowed us, but it has not stopped us" said SDSS-V Director Juna Kollmeier.

As an international consortium, SDSS has always relied heavily on phone and digital communication. But adapting to exclusively virtual communication tactics was a challenge, as was tracking global supply chains and laboratory availability at various university partners while they shifted in and out of lockdown during the final ramp-up to the survey's start. Particularly inspiring were the project's expert observing staff, who worked in even-greater-than-usual isolation to shut down, and then reopen, operations at the survey's mountain-top observatories.

Funded primarily by member institutions, along with grants from the Alfred P. Sloan Foundation, the U.S. National Science Foundation, and the Heising-Simons Foundation, SDSS-V will focus on three primary areas of investigation, each exploring different aspects of the cosmos using different spectroscopic tools. Together these three project pillars--called "Mappers"--will observe more than six million objects in the sky, and monitor changes in more than a million of those objects over time.

The survey's Local Volume Mapper will enhance our understanding of galaxy formation and evolution by probing the interactions between the stars that make up galaxies and the interstellar gas and dust that is dispersed between them. The Milky Way Mapper will reveal the physics of stars in our Milky Way, the diverse architectures of its star and planetary systems, and the chemical enrichment of our galaxy since the early universe. The Black Hole Mapper will measure masses and growth over cosmic time of the supermassive black holes that reside in the hearts of galaxies as well as the smaller black holes left behind when stars die.

"We are thrilled to start taking the first data for two of our three Mappers," added SDSS-V Spokesperson Gail Zasowski of the University of Utah. "These early observations are already important for a wide range of science goals. Even these first targets cover goals from mapping the inner regions of supermassive black holes and searching for exotic multiple-black hole systems, to studying nearby stars and their dead cores, to tracing the chemistry of potential planet-hosting stars across the Milky Way."

"SDSS-V will continue to transform astronomy by building on a 20-year legacy of path-breaking science, shedding light on the most fundamental questions about the origins and nature of the universe. It demonstrates all the hallmark characteristics that have made SDSS so successful in the past: open sharing of data, inclusion of diverse scientists, and collaboration across numerous institutions," said Evan Michelson, program director at the Sloan Foundation. "We are so pleased to support Juna Kollmeier and the entire SDSS team, and we are excited for this next phase of discovery."

SDSS-V will operate out of both Apache Point Observatory in New Mexico, home of the survey's original 2.5-meter telescope, and Carnegie's Las Campanas Observatory in Chile, where it uses the 2.5-meter du Pont telescope.

"SDSS V is one of the most important astronomical projects of the decade. It will set new standards not only in astrophysics but also in robotics and big data," said the observatory's Director Leopoldo Infante. "Consequently, to ensure its success, the Las Campanas Observatory is prepared to carry out the project with all the human and technical resources available on the mountain."

SDSS-V's first observations were gathered in New Mexico with existing SDSS instruments, as a necessary change of plans due to the pandemic. As laboratories and workshops around the world navigate safe reopening, SDSS-V's own suite of new innovative hardware is on the horizon---in particular, systems of automated robots to aim the fiber optic cables used to collect the light from the night sky. These will be installed at both observatories over the next year. New spectrographs and telescopes are also being constructed to enable the Local Volume Mapper observations.

"Carnegie has enabled SDSS to expand its reach to the Southern Hemisphere. I'm so pleased to see our role in this foundational effort expand with this next generation," concluded Carnegie Observatories Director John Mulchaey.

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Carnegie Institution for Science

How the immune system remembers viruses

When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen.

To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. Some of these short-lived effector cells - according to the generally accepted theory - turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter.

Memory cells and their origin

"Prevailing scientific opinion says that activated T cells first become effector cells and only then gradually develop into memory cells," says Dr. Veit Buchholz, a specialist in microbiology and working group leader at the Institute for Medical Microbiology, Immunology and Hygiene at TUM. "In our view, however, that isn't the case. It would mean that the more effector cells are formed after contact with the pathogen, the more numerous the memory cells would become." However, Buchholz and his colleagues observed a different course of events and have now published their results in the journal Nature Immunology.

"We investigated the antiviral immune responses resulting from individual activated T cells in mice and traced the lineage of the ensuing memory cells using single-cell fate mapping," reports first author Dr. Simon Grassmann. "Based on these experiments, we were able to show that certain 'T cell families' descended from individual cells form up to 1000 times more 'memory' than others. However, these long-term dominating T cell families only contributed little to the magnitude of the initial immune response, which was dominated by effector cells derived from other shorter-lived T cell families."

At the level of individual cells, it therefore became evident that development of effector and memory cells segregates at a much earlier stage than previously believed: "Already in the first week after the confrontation with the pathogen, we saw major differences in the transcriptomes of the detected T cell families," says Lorenz Mihatsch, also a first author of the study. "Normally at this time of the immune response CD8+ T cells are enriched in molecules that help to kill virus infected cells. However, we found no indication of these cytolytic molecules in the long-term dominating T cell families. Instead, they were already geared exclusively towards memory development at this early stage."

Optimization of vaccines

These results could help to improve vaccine development in the future, says Veit Buchholz: "To generate an optimal immune response through vaccination, the body needs to produce as many memory cells as possible. For that purpose, it is important to have a precise understanding of how individual T cells are programmed." Buchholz's study might also prove useful in helping to recognize sooner whether a new vaccine is effective. "To determine the long-term strength of an immune response, it could be helpful to measure the number of memory precursors within a few days of administering a vaccine," says Buchholz.

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Technical University of Munich (TUM)

Combo-drug treatment for Type 2 diabetes remains effective after two years

PHILADELPHIA - Patients with Type 2 diabetes often take metformin as first-line therapy to help stabilize their blood glucose. Eventually, some patients no longer respond to metformin and require additional treatment. A few years ago, pivotal short-term trials showed that a combination of two drugs controlled diabetes progression better than either single drug alone. Now, new research demonstrates that this drug combo of dapagliflozin and exenatide continues to stay effective, without loss of effect, after two years of continual use.

"Many therapies in diabetes management are short-lived, which is why it's useful to test for long-term effect," says senior author Serge Jabbour, MD, director of the division of endocrinology and the Diabetes Center at Thomas Jefferson University. "Our study showed that a combo regimen of dapagliflozin and exenatide continued to control patients' glucose for over two years. This is a very encouraging."

The results of this multi-center double-blind, phase 3, randomized controlled trial were published in the journal Diabetes Care.

A total of 695 adults whose Type 2 diabetes was not controlled with metformin, were randomly assigned to three study groups. One group received weekly exenatide injections in addition to metformin. Another group took daily dapagliflozin pills in addition to metformin, and a third group received both drugs together. The study was an extension study of the pivotal DURATION-8 trial, meaning that patients were given the option to continue in the trial longer.

The two classes of drugs act additively, improving the effects on a number of diabetes indicators. Dapagliflozin belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors that cause excess glucose to be excreted in the urine. Exenatide belongs to a class of drugs called glucagon-like peptide-1 receptor agonists (GLP-1RAs), which enhance glucose-dependent insulin secretion, lower hepatic glucose output, slow gastric emptying and increase satiety. Together, the two drugs promote and maintain better glucose control and produce additive weight loss and improve blood pressure.

The results confirmed that the group of patients receiving both drugs had better glycemic control than patients receiving just one of the drugs - and demonstrated, for the first time, that the effect was stable for the duration of the extended two-year study period. The study also showed a clinically relevant reduction in weight and blood pressure, measures that can contribute to Type-2 diabetes and overall health. The researchers saw no unexpected safety concerns related to the drug combination in the study participants.

Other studies with both drugs have also suggested that metabolic markers such as lipid profile also improved.

"These two classes work synergistically to help control a Type-2 diabetes patient's glucose levels, and other measures associated with diabetes," says Dr. Jabbour. "We can now feel more confident about prescribing these medications long term."

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Thomas Jefferson University

Do octopuses' arms have a mind of their own?

video: In the experiments that tested for proprioception, the octopuses tended to use "straight" movements, aimed at either the left or right side of the maze. In the experiments that tested for tactile discrimination, the octopuses chose to use slower "search" movements.

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Reproduced with permission from Elsevier. Originally published 10 Sep 2020 by Current Biology in "Use of Peripheral Sensory Information for Central Nervous Control of Arm Movement by Octopus vulgaris"

Often described as aliens, octopuses are one of most unusual creatures on the planet, with three hearts, eight limbs and a keen intelligence. They can open jars, solve puzzles and even escape from their tanks, aided by their eight ultra-flexible and versatile arms. But determining how exactly octopuses control all eight limbs is a puzzle that scientists are still trying to crack.

"Octopus arms are completely unique. First off, there are eight of them, each with over 200 suckers that can feel, taste and smell the surroundings. And everything is moveable. The suckers can grasp, and the arms can twist in an almost limitless number of ways," said Dr. Tamar Gutnick, an octopus researcher formerly at the Okinawa Institute of Science and Technology Graduate University (OIST). "So this raises a huge computational issue for the brain and their nervous system has to be organized in a really unusual way to deal with all this information."

Octopuses have an extensive nervous system, with over 500 million neurons, similar in number to that of a dog. But unlike dogs and other vertebrates, where the majority of neurons are in the brain, over two thirds of the octopuses' neurons are located within their arms and body.

With such a strangely-built nervous system, scientists have long suspected that octopuses' arms may have a mind of their own and act autonomously from the central brain. Research has shown that octopuses' arms use reflex loops to create coordinated movements, and some octopuses can even distract predators by discarding limbs that continue to move for long periods of time.

"Some scientists think about octopuses as nine-brained creatures, with one central brain and eight smaller brains in each arm," said Dr. Gutnick. But her new research, published in Current Biology, suggests that the arms and the brain are more connected than previously thought.

Dr. Gutnick and her colleagues have shown that octopuses are capable of learning to associate inserting a single arm into a specific side of a two-choice maze with receiving a food reward, even when neither the reward nor the arm in the maze are visible to the octopus. But crucially, while the learning process takes place in the central part of the brain, the information needed for the brain to choose the correct path is detected only by the arm in the maze.

"This study makes it clear that octopus's arms don't behave totally independently from the centralized brain - there's information flow between the peripheral and central nervous system," said Dr. Gutnick. "Rather than talking about an octopus with nine brains, we're actually talking about an octopus with one brain and eight very clever arms."

Navigating the maze

The scientists tested whether single arms were able to provide the brain with two different types of sensory information - proprioception (the ability to sense where a limb is and how its moving) and tactile information (the ability to feel texture).

Humans have a strong sense of proprioception. Sensory receptors located within skin, joints and muscles provide feedback to the brain, which stores and constantly updates a mental map of our body. Proprioception allows us to walk without looking at our feet and touch a finger to our nose with our eyes closed.

But whether octopuses have the same ability is not yet proven.

"We don't know whether an octopus actually knows where its arm is, or what its arm is doing," said Dr. Gutnick. "So our first question was - can the octopus direct its arm, based only on sensing where its arm was, without being able to see it?"

The researchers created a simple Y-shaped opaque maze and trained six common Mediterranean octopuses to associate either the right or left path with a food reward.

Rather than slowly exploring the internal shape of the maze, the octopuses immediately used fast arm movements, pushing or unravelling their arm straight through the side tube into the goal box. If they pushed their arm into the right goal box, they could retrieve the food, but if their arm entered the wrong goal box, the food was blocked by a net and the scientists removed the maze.

Five out the of the six octopuses eventually learned the correct direction to push or unroll their arm through the maze in order to get the food.

"This shows us that the octopuses clearly have some sense of what their arm is doing, because they learn to repeat the movement direction that resulted in a food reward," said Dr. Gutnick. "It's unlikely to be to the same extent as humans have with our mental maps and the representations we have of our body in the brain, but there is some sense of self-movement from the arms that is available to the central brain."

The team then explored whether octopuses were able to determine the correct path when using a single arm to sense the texture of the maze.

The researchers presented another six octopuses with a Y-shaped maze where one side tube was rough, and the other side tube was smooth. For each octopus, picking either the rough side or the smooth side of the maze led to a food reward.

After many trials, five out of the six octopuses were able to successfully navigate the maze, regardless of whether the correct texture was located on the left or right side tube, showing that they had learnt which texture was correct for them. This time, the octopuses opted for a slower searching movement inside the maze, first determining a side tube's texture and then deciding whether to continue down that side tube, or to switch sides.

Importantly, the team found that for both types of mazes, once octopuses had learnt the correct association, they could successfully navigate the maze using arms that hadn't been used before. "This further rules out the idea that each arm could be learning the task independently - the learning occurs in the brain and then the information is made available to each arm."

But where this information is stored within the brain, Dr. Gutnick isn't sure, and is a question left for future experiments.

"The brain of octopuses is so different - it's still a black box to us really," she said. "There's so much more to learn."

Credit: 
Okinawa Institute of Science and Technology (OIST) Graduate University

Higher risk of future fecal incontinence after sphincter injuries

image: Maria Gyhagen, MD/PhD, Sahlgrenska Academy, University of Gothenburg.

Image: 
Photo: Sodra Alvsborg Hospital

The risk of subsequent fecal incontinence and intestinal gas leakage is significantly higher among women who, during childbirth, have suffered a sphincter injury and consequent damage to the anal sphincter muscle, was shown in a new study from the University of Gothenburg.

Most births in Sweden occur without complications for the mother and child. Mild perimeal tears are relatively common, but self-healing usually takes place. Alternatively, these tears can be sutured without lasting ill-effects.

However, damage to the ring of muscles around the anus -- the anal sphincter, the focus of the current study -- also sometimes occurs. In Sweden, according to the latest statistics in the Swedish Medical Birth Register, approximately one woman in 20 sustain a rupture of the anal sphincter the first time she gives birth.

The study was based on register data on 7,741 women who gave birth to two children between 1992 and 1998. This information was combined with their responses to a questionnaire about fecal incontinence symptoms and, if the women had current symptoms, how these were affecting them some 20 years later, when they were aged 50-60.

The results, published in the American Journal of Obstetrics and Gynecology, show that for women sustaining sphincter injuries at the first birth, the risk of sphincter injury rose threefold at the second; and, moreover, the likelihood of future fecal incontinence increased with the number of injuries.

Of the women who avoided sphincter injury entirely in two vaginal births, 11.7% reported some degree of fecal incontinence 20 years later. The corresponding proportion among those who incurred sphincter damage at one of the births was 23.8%, and at both births 36.1%.

Severe fecal incontinence followed a similar pattern: from 1.8% in the women without sphincter damage to 5.4% and 9% after, respectively, one or two births causing sphincter injury. Leakage of liquid feces and gas was most common; in severe cases, solid feces were leaked as well.

"For women affected by sphincter damage who have had fecal incontinence later in life, there are few or no effective surgical treatments, and it often leads to chronic suffering, with social isolation as a result. Preventing sphincter injuries is the paramount measure," says Maria Gyhagen, researcher in obstetrics and gynecology at Sahlgrenska Academy, University of Gothenburg, and gynecologist at Södra Älvsborg Hospital in Borås, who was responsible for the study.

Although a sphincter injury can occur without known risk factors, the likelihood is greater in first-time mothers; after previous sphincter damage; during an assisted delivery using a ventouse suction cup and forceps; and, if the baby is large, at the first vaginal birth after a previous cesarean section. An elevated risk of fecal incontinence after ventouse delivery was demonstrated in a previous study from the same research group.

"In this study, we've been able to determine how sphincter injuries are associated with involuntary intestinal incontinence much later on in life, which has been questioned before. This must be taken into consideration in counseling for mothers-to-be whose risk of injury is highest," Gyhagen concludes.

Credit: 
University of Gothenburg

Follow your gut: How farms protect from childhood asthma

We are born into an environment full of small organisms called microbiota. Within the first minutes and hours of our lives, they start challenging but also educating our immune system. The largest immune organ is our gut, where maturation of the immune system and maturation of the colonizing bacteria, the gut microbiome, go hand in hand. After profound perturbations in the first year of life, the maturation process, the composition of the gut microbiome gradually stabilizes and accompanies us for our lives. Previous research of the Munich scientists showed an asthma-protective effect by a diverse environmental microbiome, which was particularly pronounced in farm children. The question now was whether this effect could be attributed to the maturation process of the early gut microbiome.

Farm life boosts gut microbiome maturation in children
The researchers analyzed fecal samples from more than 700 infants partly growing up on traditional farms between the age of 2 and 12 months who took part in PASTURE - a European birth cohort, which runs for almost 20 years now with funding from the European Commission.

"We found that a comparatively large part of the protective farm effect on childhood asthma was mediated by the maturation of the gut microbiome in the first year of life" states Dr. Martin Depner, biostatistician at Helmholtz Zentrum München, and further concludes: "This suggests that farm children are in contact with environmental factors possibly environmental microbiota that interact with the gut microbiome and lead to this protective effect."

The researchers anticipated effects of nutrition on the gut microbiome maturation but were surprised to find strong effects of farm-related exposures such as stays in animal sheds. This emphasizes the importance of the environment for the protective effect. In addition, vaginal delivery and breastfeeding fostered a protective microbiome in the first two months of life.

Furthermore, the researchers discovered an inverse association of asthma with measured level of fecal butyrate. Butyrate is a short chain fatty acid which is known to have an asthma protective effect in mice. The researchers concluded that gut bacteria such as Roseburia and Coprococcus with the potential of producing short chain fatty acids may contribute to asthma protection in humans as well. Children with a matured gut microbiome showed a higher amount of these bacteria (Roseburia and Coprococcus) compared to other children.

"Our study provides further evidence that the gut may have an influence on the health of the lung. A mature gut microbiome with a high level of short chain fatty acids had a protective effect on the respiratory health of the children in this study. This suggests the idea of a relevant gut-lung axis in humans", says Dr. Markus Ege, professor for clinical-respiratory epidemiology at the Dr. von Hauner Children's Hospital. "This also means, however, that an immature gut microbiome may contribute to the development of diseases. This emphasizes the need for prevention strategies in the first year of life, when the gut microbiome is highly plastic and amenable to modification."

Probiotic prevention strategies
The researchers demonstrated that the asthma protective effect is not dependent on one single bacteria only, but on the maturation of the entire gut microbiome. This finding questions the approach of using single bacteria as probiotics for the prevention of asthma. Probiotics should rather be tested with respect to their sustained effect on the compositional structure of the gut microbiome and its maturation early in life.

Further studies on cow milk
Nutritional aspects analyzed in this study may serve as prevention strategies such as consumption of cow's milk. Unprocessed raw milk, however, cannot be recommended because of the risk of life-threatening infections such as EHEC. Scientists at the Dr. von Hauner Children's Hospital are currently running a clinical trial on the effects of minimally processed but microbiologically safe milk for the prevention of asthma and allergies (MARTHA trial).

Helmholtz Zentrum München
Helmholtz Zentrum München is a research center with the mission to discover personalized medical solutions for the prevention and therapy of environmentally-induced diseases and promote a healthier society in a rapidly changing world. It investigates important common diseases which develop from the interaction of lifestyle, environmental factors and personal genetic background, focusing particularly on diabetes mellitus, allergies and chronic lung diseases. Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,500 staff members. It is a member of the Helmholtz Association, the largest scientific organization in Germany with more than 40,000 employees at 19 research centers.

Credit: 
Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH))

Analyzing biological and chemical damage on 20th-century construction materials

image: Photo of Dr Iratxe Ibarrondo using portable high-resolution spectroscopic techniques to analyse the impact on 20th-century construction materials of the environment and biological conditions in the surrounding area.

Image: 
Iratxe Ibarrondo / UPV/EHU

It is customary for the research conducted in the IBeA research group in the UPV/EHU's department of Analytical Chemistry to be approached from a multidisciplinary perspective. One of the group's lines of work is the diagnosis and restoration of historical and cultural heritage for which spectroscopic analytical techniques are used. Although the group's research has until now focussed on historical monuments, right now they have begun to study the origin and types of deterioration of a range of synthetic materials used in 20th-century buildings.

New construction materials are made up of synthetic materials featuring concrete, reinforced concrete, mortars and bricks. Once the work has been completed, the materials are at the mercy of the environment: the degrading agents in the surrounding area, such as acid gases in the atmosphere, water seepage, and lichens, among other things, can cause physical, chemical and biological damage. "The increasing contamination of the environment, the atmosphere and aquatic media is clear," said the researcher Iratxe Ibarrondo, "and we wanted to find out the effect exerted by chemical agents emerging from contamination and materials and the type of compounds that are formed as a result of chemicals reacting with each other".

The high-resolution spectroscopic analysis techniques used by the IBeA research group are essential when characterizing not only the original compounds of the stone materials but also the compounds formed as a result of deterioration processes. Raman analyses made in situ in the buildings have allowed the use of this technique to be proposed as a protocol to diagnose the type of environmental damage affecting 20th-century buildings in the process of refurbishment and renovation. Furthermore, by means of analyses conducted with greater resolution in the lab, they have been able to determine the types of damage found in new construction materials as well as the way in which they occurred. "We have managed to identify many different degradation compounds," explained the author of the research.

Method for measuring environmental contamination based on lichen pigments

In addition, "we analysed the effects that can be caused by lichens or biological agents in these materials; the kind of reactions they cause or which take place in their presence as well as the damage that can be detected in the materials. The fact is that materials of this type tend to be in a very poor condition and display serious degradation problems", added Ibarrondo. That way they managed to establish that lichens play an active role in biodegradation processes: they discovered that they absorb different types of atmospheric particles, incorporate them into their metabolisms and synthesise new biominerals (minerals not found in the original stone substrate).

Finally, by using carotenoid pigments from the lichens, they developed a new method of measuring the degree of environmental contamination. "We established that lichens are highly resistant in contaminated environments, and in addition, the carotenoids they synthesise when contamination levels change and when greater degrees of oxidation are reached," explained Dr Ibarrondo.

In the researcher's view, "this research has opened up new paths, mainly ones relating to biological agents. They can be analysed better and more deeply and under no circumstances should they be underestimated because they cause significant damage". The research group collaborates with professionals in architecture, and "we saw that it is possible to establish this collaboration in the form of a protocol". Ibarrondo is hoping that, depending on the case, when a building project is designed, there will be a possibility of receiving advice about the effects exerted by the environment on the materials. "Building professionals see the type of deterioration the materials undergo, but we analytical chemists can determine the problem with greater precision. But that will be the next step; it is not yet reality".

Credit: 
University of the Basque Country

New UTSA research identifies link between food insecurity and unengaged distance learning

How do you feel when you're hungry? Are you at your best? A new study by the UTSA Urban Education Institute (UEI) found that food insecure students in San Antonio struggled with distance learning and academic engagement more than their peers.

The findings linking food insecurity and learning signify how hunger and larger issues of family instability during the ongoing pandemic threaten student growth.

"It is well understood that we all have basic needs that must be met if we are to pursue and realize our fullest potential," said Mike Villarreal, UEI director. "It is urgent that we as a community find effective ways to care for and respond to families in crisis so children won't lag behind their peers in cognitive, emotional, and physical development."

The research, as part of a multi-part Teaching and Learning In the Time of COVID-19 survey project, found that 26 percent of local K-12 students and parents surveyed said they were experiencing food insecurity, meaning food ran out and there was no money to buy more.

The UEI spent the spring and summer surveying almost 2,000 K-12 public school students, parents and teachers across eight Bexar County school systems for the overall project. This research is helping local education leaders plan and improve their operations during the pandemic.

Families in each school system reported experiencing food insecurity, with the highest rates of 49 percent found in Edgewood ISD and 41 percent in both Harlandale and Southwest ISDs. Other school-district-level data can be found in the report.

Bexar County's pre-pandemic rates of food insecurity already were hovering at about 14 percent in 2018. That number nearly doubled for public school families by spring of 2020.

"A majority of our public school children depend on our public schools for food, safety and community. The pandemic not only stranded students, but also caused many of them and their parents (48%) to lose their jobs or suffer pay cuts," Villarreal said.

Schools responded quickly with massive technology and meal distributions for students learning at home.

"Despite many obstacles and regulations by the federal government, districts pivoted quickly and offered free meals with little to no questions asked while physical campuses were closed," Villarreal said. "Their efforts were heroic - and yet there is still more work to be done. Our research is intended to support our school leaders by providing them rigorous and actionable research and nurturing an ongoing community conversation about the challenges and solutions in education."

Some of the key findings in the research report include:

26 percent of students and parents surveyed said they were experiencing food insecurity

Families in each school system surveyed reported having experienced food insecurity, with the highest rates of 49 percent found in Edgewood ISD and 41 percent in Harlandale and Southwest ISDs

A higher incidence of food insecurity was correlated with higher numbers of children in households

Food insecure high school students were less motivated during distance learning. While food insecure high school students represented 20 percent of all high school students, they represented 65 percent of high students who said they never turned in assignments

Food insecure high school students were also overrepresented among those who said they were never engaged by school lessons.

Credit: 
University of Texas at San Antonio

Novel technique spotlights neuronal uptake of amyloid beta in Alzheimer's disease

image: Confocal images of cells with and without the cellular prion protein (labeled red), showing uptake of amyloid beta (labeled green) in cells with the prion protein (above) and no uptake in cells lacking the prion protein (below). (Magenta is membrane dye and blue is nuclear dye.)

Image: 
Graham Roseman, UCSC

One of the hallmarks of Alzheimer's disease is the formation of amyloid plaques--sticky clumps of a protein called amyloid beta--that collect between neurons in the brain. Increasingly, however, attention has turned from these insoluble plaques to soluble forms of amyloid beta that can be taken up into neurons and are highly neurotoxic.

A new study by researchers at the University of California, Santa Cruz, pinpoints a segment of the amyloid beta protein that is recognized by receptors involved in neuronal uptake of this toxic peptide. The researchers used a novel approach to study the mechanisms of cellular uptake of amyloid beta. Their findings, published November 2 in Proceedings of the National Academy of Sciences, suggest that targeting this process may be a promising approach for Alzheimer's drug development.

"There are many different ways that amyloid beta can be toxic inside cells, so wouldn't it be nice if we could block its uptake by neurons? This is a pathway we can target," said corresponding author Jevgenij Raskatov, assistant professor of chemistry and biochemistry at UC Santa Cruz.

In the new study, Raskatov teamed up with co-corresponding author Glenn Millhauser, distinguished professor of chemistry and biochemistry at UCSC, to study the interactions of amyloid beta with the cellular prion protein. Millhauser's lab studies the structure and function of the prion protein, a membrane protein found on the surfaces of various cell types, including neurons in the brain.

Previous studies by other researchers have indicated that the normal cellular prion protein (not the abnormal variant that causes prion diseases) binds to clumps of amyloid beta and is involved in uptake and neurotoxicity. The UCSC researchers, led by graduate student Alejandro Foley and postdoctoral researcher Graham Roseman, sought to test whether the prion protein also acts as a receptor to take up soluble forms of amyloid beta, and to identify the site within amyloid beta that binds to this receptor.

The researchers took an approach based on previous work from Raskatov's lab using mirror-image versions of amyloid beta to show that cellular uptake is mostly mediated by receptors on the cell surface. In the earlier work, researchers compared the uptake of natural amyloid beta with a synthetic version in which the arrangement of the atoms in the protein's amino acids is a mirror image of the natural arrangement. This rearrangement subtly changes the protein's structure in ways that would interfere with its binding to a receptor, so the finding that cellular uptake of the mirror-image version was greatly reduced pointed to receptor-mediated uptake.

Amyloid beta can be different lengths, but the most toxic variant is 42 amino acids long. To isolate the site involved in receptor binding, the researchers created a library of peptide segments of amyloid beta composed of, for example, just amino acids 1 through 16 or 1 through 30. For each segment, they made a version with natural amino acids (the "L stereoisomer") and one with mirror-image amino acids (the "D stereoisomer").

After testing all the peptides in the library for cellular uptake, they found that amino acids 1-30 showed the same stereoselectivity as full-length amyloid beta, with much greater uptake of the L form than the D form. In addition, this segment is completely soluble and does not form aggregates because it is missing a long hydrophobic domain involved in the aggregation of amyloid beta into clumps and fibrils.

"With this shortened amyloid beta, we are able to decouple cellular uptake from aggregation, giving us a great model for studying uptake," Raskatov said.

By assessing amyloid beta uptake in cells with and without the prion protein, the researchers demonstrated for the first time the prion protein's role in cellular uptake of soluble amyloid beta, consistent with its selectivity for the L stereoisomer of amyloid beta.

The non-aggregating amyloid beta segment 1-30 showed the same prion-dependent uptake and stereoselectivity. The researchers also used nuclear magnetic resonance spectroscopy to gather detailed information about the interactions involved in the binding of amyloid beta to the cellular prion protein.

Their findings show that the binding of amyloid beta at the cell surface, leading to its internalization, is largely due to the amino acid sequence 1-30 and not the state of aggregation. When amyloid beta molecules begin to aggregate, they form "oligomers" consisting of a small number of molecules stuck together that are still soluble and can be taken up by neurons. These soluble oligomers are increasingly considered to be the form of amyloid beta that triggers the pathological processes leading to Alzheimer's disease, but there are many different aggregated forms.

"There are different levels of aggregation, different sizes and types of oligomers, and a big question has been which forms are internalized and cause neurotoxicity," Raskatov said. "Our findings suggest that any form in which that sequence of amino acids is exposed will bind to the prion protein."

According to Millhauser, "The initial steps leading to Alzheimer's disease may be the prion protein-mediated transport of soluble amyloid beta into neurons, where it then clumps, forming toxic aggregates that ultimately lead to the characteristic plaques associated with the disease."

Although the prion protein seems to be responsible for most of the amyloid beta uptake, the study suggests other receptors may offer alternate routes. Nevertheless, drugs that target the 1-30 segment of amyloid beta or the sites it binds to on receptors may hold therapeutic potential for treating Alzheimer's disease.

"Our findings open up new avenues for understanding Alzheimer's and suggest promising strategies for therapeutics," Millhauser said.

Credit: 
University of California - Santa Cruz