Culture

In all animals, including humans, smell - the oldest of the five senses - plays a predominant role in many behaviors essential for survival and reproduction. It has been known since ancient times that animals react to odours.

Yet researchers are just beginning to elucidate the neural pathways and mechanisms responsible for odour-induced behavior. . A first step was made by showing the existence of a neural pathway connecting the olfactory and motor centers of the brain in invertebrates with the worm C. elegans and in vertebrates with the lamprey, a primitive, eel-like fish native to the Atlantic Ocean.

In a new study published in PLoS Biology, scientists at Université de Montréal, in Quebec, and the University of Windsor, in Ontario, show that an inhibitory circuit that releases the neurotransmitter GABA into the olfactory bulb strongly modulates behaviouralresponses to odours in lampreys. The study of these modulatory mechanisms allowed the researchers to discover a new pathway linking together olfactory and motor centers in the brain.
 

This discovery demonstrates that odourscan activate locomotor centers via two distinct brain pathways," said lead author Gheylen Daghfous, a researcher in the laboratory of UdeM neuroscience associate professor Réjean Dubuc, also a professor at Université du Québec à Montréal. "This work shed snew light on the evolution of the olfactory systems in vertebrates."

He added: "It is well-known that animals are attracted to odors, whether it be a dog tracking its prey or a shark attracted to blood. On the other hand, we are only beginning to understand how the brain uses odors to produce behavior. Our study revealed a new brain highway dedicated to transmitting smell information to the regions controlling movements."

Funded by the Great Lakes Fishery Commission (GLFC), with the Canadian Institutes of Health Research (CIHR) and the Natural Sciences Research Council of Canada (NSERC), the study is the result of a long-standing collaboration between Dubuc and Windsor's Barbara Zielinski.

"Our purpose was to identify the neural circuitry linking olfaction to locomotion in lampreys," a parasitic type of fish that attach themselves to other fish and suck their blood, leaving a gaping wound, said Dubuc. "Lampreys invaded the Great Lakes decades ago and have decimated large populations of fish, with major commercial impact. The GLFC is looking for new means to control lamprey populations, and attracting them using olfactory stimuli is one such avenue."

New Orleans (October 27, 2018)--Researchers will gather today to discuss the potential for hibernation and the related process, torpor, to aid human health in spaceflight at the American Physiological Society's (APS) Comparative Physiology: Complexity and Integration conference in New Orleans.

To survive times when food is scarce and temperatures are low, some animals enter hibernation--a physiological process that reduces their normal metabolism to low levels for days or weeks at a time. These periods of low metabolism, known as torpor, allow the animal's body temperature to fall to just above the surrounding air temperature, thus conserving energy. Humans do not naturally undergo torpor, but scientists are interested in the idea of producing states of "synthetic" torpor in certain situations, including spaceflight, explained symposium co-chair Hannah Carey, PhD, from the University of Wisconsin School of Veterinary Medicine. "Harnessing naturally evolved torpor to benefit human spaceflight." "Synthetic torpor could protect astronauts from space-related health hazards and simultaneously reduce demands on spacecraft mass, volume and power capacities," said Matthew Regan, PhD, also from the University of Wisconsin School of Veterinary Medicine and symposium co-chair.

The symposium will explore how synthetic torpor might be induced by the brain, its similarities and differences to sleep, and how it could benefit astronauts. Speakers will include Carey; Matteo Cerri, MD, PhD, from the University of Bologna in Italy; Vladyslav Vyazovskiy, PhD, from the University of Oxford in the U.K.; and astronaut Jessica Meir, PhD, from NASA.

Studying hibernation in mammals--how they are able to safely lower their body temperature and metabolism for extended periods of time--may also aid treatment of people experiencing traumatic medical events, such as stroke, cardiac arrest and severe blood loss. Animals that use torpor have a natural resistance to various injuries that can happen due to lack of blood flow. They are also resistant to radiation injury--such a resistance would be especially beneficial to humans in deep space. Carey will discuss why use of synthetic torpor based on the biology of natural hibernators is preferable to current medical practices that use hypothermia-based methods to treat trauma patients. She will also discuss how hibernation research can identify how to create synthetic torpor for space travel.

How the nervous system reduces metabolic activity during torpor is unknown. However, many of the organs that regulate metabolism are controlled by nerve cells (neurons) located in the raphe pallidus, an area of the brainstem that controls the production of heat in mammals. "For an animal to enter torpor, the neurons within the raphe pallidus have to be inhibited," Cerri explained. If function in these cells is not suppressed, "their activity would counteract the hypothermia induced by torpor," he said. Cerri will present preliminary results identifying neurons projecting to the raphe pallidus and involved in torpor-related activity.

Defining the relationship between sleep and torpor has been fraught with controversy, but the two states appear to be intimately linked because of the neuronal connections they share. Research suggests that lack of available food sources may cause mammals to conserve energy and lower their body temperature, two hallmark characteristics of torpor. However, "less is known about the specific fasting-related signals which initiate entry into torpor," Vyazovskiy said. He will discuss the connection between sleep and torpor and why more research is needed to determine how torpor affects brain function in animals.

Some of the physiological adaptations that animals exhibit--such as the low-oxygen environments that seals and penguins experience with deep diving or that birds experience on a high-altitude flight--are impossible for humans. Understanding how animals adapt in extreme conditions may play a positive role in human medical science, especially in the "extreme environment of space," Meir said. The increasingly real possibility of traveling to Mars--once just a science fiction story--emphasizes the need to resolve factors that have hampered the feasibility of long-duration spaceflight, including having an ample supply of food, water and breathable air. Finding a way to induce torpor in humans could help eliminate limiting factors as well as protect astronauts from harmful radiation. Meir's talk will provide insight from her unique perspective and experience as an astronaut, discussing the architecture for NASA's current and future human spaceflight missions.

San Diego, CA (October 27, 2018) -- Frailty is associated with lower likelihoods of being placed on the kidney transplant waitlist and of receiving a transplant, according to a study that will be presented at ASN Kidney Week 2018 October 23-October 28 at the San Diego Convention Center.

To investigate whether frailty in patients with kidney failure may affect their likelihood of receiving a kidney transplant, Christine Haugen, MD (Johns Hopkins Hospital) and her colleagues studied 7078 potential kidney transplant candidates from 2009 to 2017. Patients were considered frail if they had 3 or more of the following components: unintentional weight loss, decreased grip strength, slowed walking speed, and low activity.

Frail participants were 38% less likely to be listed for transplantation, had nearly twofold increased risk of dying while on the transplant waitlist mortality, and underwent transplantation at a 35% lower rate than nonfrail participants.

"Prehabilitation may be a useful tool to increase physiologic reserve and subsequently improve access to kidney transplantation among frail patients," said Dr. Haugen.

Oestrogens found naturally in cows' milk are likely to be safe for human consumption in adults, according to a new review published in the European Journal of Endocrinology. The review brings together scientific evidence from over a dozen rodent and human studies that examined the effects of ingesting oestrogen-containing cows' milk on fertility and the risk of cancer development. The findings of the review suggest that the levels of oestrogens found naturally in milk are too low to pose health risks to adults, and that there is no need for public concern.

Oestrogens, female sex hormones, are naturally present in cows' milk and, with over 160 million tons of cows' milk farmed in the EU in 2016 alone, it is a common constituent of the human diet. Intensive farming practices have been shown to increase the levels of oestrogens found in milk, which has raised concerns about their potentially detrimental effects on human health. Ingesting oestrogens may have wide-reaching effects on health, including reduced fertility, altered foetal development or an increased risk of hormone-related cancers.

In this review, Professor Gregor Majdic and Professor Tomaz Snoj from the University of Ljubljana in Slovenia, reviewed the scientific evidence from over a dozen studies that assessed the safety of ingesting oestrogen-containing milk, in both rodents and humans. In the majority of studies where rats were fed milk, or oestrogens derived from milk, no differences in reproductive health or cancer risk were observed. The studies that did report changes in reproductive function or other harmful effects investigated levels of oestrogens that greatly exceed the amount of milk a person might normally consume. Although some human studies have suggested that milk ingestion can affect growth hormone levels in children it remains unclear whether this association is related to ingestion of oestrogens, or whether there are any other adverse effects on their health. However, the strength of the evidence from the majority of the reviewed studies would suggest that oestrogen levels in milk are too low to affect the health of adults. Although, this study only examined the possible effects of oestrogens and not the other potential harmful or beneficial health effects of cows' milk.

Professor Gregor Majdic said, "The majority of studies we reviewed concluded that the concentrations of oestrogens found naturally in milk are too low to pose a risk to reproductive health or cancer development in adults. However, studies are lacking that look at any harmful effects of hormones from cows' milk on baby and child development and health."

One of the outstanding mysteries of the cerebral cortex is how individual neurons develop the proper synaptic connections to form large-scale, distributed networks. Now, an international team of scientists have gained novel insights from studying spontaneously generated patterns of activity arising from local connections in the early developing visual cortex. These early activity patterns serve as a template for the subsequent development of the long-range neural connections that are a defining feature of mature distributed networks.

In a recently published Nature Neuroscience article, scientists at the Max Planck Florida Institute for Neuroscience, Frankfurt Institute for Advanced Studies, Goethe University of Frankfurt, and the University of Minnesota detail how they investigated the visual cortex of the ferret, an ideal model system to explore the early development of networks in the cortex. These are composed of thousands of neurons and are distributed over millimetres of the cortical surface. In the visual cortex, network activity encodes specific features of the visual scene like the orientation of edges and the direction of object motion.

By using calcium imaging techniques, the scientists were able to visualize with unprecedented resolution spontaneous neural activity patterns, i.e. activity patterns that occurred in the absence of visual stimulation. To their great surprise, the spontaneous activity patterns in mature animals were highly correlated between distant populations of neurons - and in fact were so highly correlated that the activity of small populations of neurons could reliably predict coincident network activity patterns millimetres away, and these correlation patterns beautifully predicted the patterns of network activity evoked by visual stimulation.

In their next step, the researchers used this remarkable correspondence of spontaneous and visually-evoked network patterns to find out how these networks developed in the immature brain. By looking at the state of spontaneous activity patterns prior to eye opening, they expected to see a striking difference in the patterns of spontaneous activity because the long-range cortical connections that are thought to be the basis for distributed network activity patterns are absent in the immature cortex. To their surprise, they discovered robust long-range patterns of correlated spontaneous activity prior to eye opening, and found that they extended over distances comparable to what was seen in the mature brain.

Confronted with this paradox, the researchers first considered whether the correlated activity patterns could be spreading through chains of local cortical connections, similar to a forest fire. To test this intriguing possibility, scientists built a computational model of the neural circuitry in the early visual cortex. They found that by using a set of parameters that are consistent with the organization of local cortical connections, the model could precisely reproduce the patterns of spontaneous long-range correlations they had observed experimentally, without the need for long-range connections.

Taken together, these results suggest that long-range order in the early developing cortex originates from neural activity driven by short-range connections. In other words, local connections build a network activity scaffold. Following the well-accepted plasticity rule 'what fires together wires together', activity mediated by local connections can then guide the subsequent formation of long-range network connections. In a twist of the oft-used phrase, 'think globally, act locally', developing cortical circuits act locally to achieve global effects. Future studies will test the prediction that activity dependent plasticity mechanisms shape the structure of long-range connections based on the instructive activity patterns derived from local cortical connections.

October 26, 2018 - A new study published this week in the American Journal of Clinical Nutrition (AJCN) adds to the body of data demonstrating that bioactive compounds found in cocoa can keep the heart healthy --but two types of bioactives called flavanols and procyanidins behave differently in the body.

KEY FINDINGS

Healthy adults experienced improved blood vessel function along with improvements in blood pressure, arterial stiffness, and cholesterol after one month of once-daily consumption of an extract enriched in flavanols and procyanidins.

Only the group that consumed flavanols and procyanidins together experienced all benefits. The group that consumed the procyanidin-enriched extract only experienced a reduction in total cholesterol.

Consequently, improvements in blood vessel function, blood pressure, and arterial stiffness were shown to predominantly relate to the intake of flavanols, but not to the intake of the more abundant procyanidins and their gut microbiome-derived metabolites.

Bioactives are dietary compounds that can be beneficial to health. Comprised of two kinds of bioactives, namely flavanols and procyanidins, the cocoa flavanols present in cocoa have attracted considerable scientific attention in recent years. As both groups of compounds are also found in apples, grapes, berries, and some cereals and legumes, the use of cocoa extract as a model for flavanol- and procyanidin-containing foods is likely to generate insights relevant beyond cocoa. Multiple studies have shown that daily consumption of flavanols and procyanidins has led to improved blood pressure, cholesterol and the flexibility of blood vessels. But until now, it was less clear to what extent flavanols and procyanidins respectively contribute to the observed benefits, and whether or not they act synergistically. A paper published this week in AJCN by an international team of researchers, including scientists from Mars, Incorporated, is the first to begin to directly answer this question.

In a month-long randomized and double-blinded study, 45 healthy male adults were divided into three groups taking different amounts of flavanols and procyanidins to determine the effect of each on a range of cardiovascular endpoints. One group of participants consumed a cocoa extract containing 130 mg of a flavanol called (−)-epicatechin (pronounced "minus epicatechin") as well as 560 mg of procyanidins. The second group took cocoa extract capsules delivering a nearly equivalent amount of procyanidins (540 mg), but only 20 mg of (−)-epicatechin. The third group took placebo capsules that were free of both flavanols and procyanidins, but otherwise nutritionally matched to the capsules consumed by the other two groups. Importantly, all capsules were matched for their methylxanthine (caffeine and theobromine) amounts.

"We were able to confirm previous findings related to cocoa flavanols, and we gained novel insights into the respective contributions of flavanols and procyanidins in the context of their cardiovascular effects in humans. We found that the flavanols, especially (−)-epicatechin, represent the bioactives primarily responsible for the beneficial vascular effects observed after cocoa flavanol intake," said Christian Heiss, a clinical professor based at the University of Surrey and Surrey and Sussex Healthcare NHS Trust, and one of the researchers in the study. "Only the group taking 130 mg of (−)-epicatechin experienced both the acute and long-term beneficial effects related to flavanol and procyanidin intake." Acute responses included improvements in the ability of blood vessels to dilate. Long-term responses included improvements in blood pressure and arterial stiffness. The groups taking either a placebo or the low-epicatechin capsules experienced no significant changes in any of the above endpoints. "Although procyanidins did not directly improve blood vessel dilation, blood pressure or arterial stiffness, their intake did have a beneficial effect on blood lipids", continued Dr. Heiss. "Both groups taking capsules that contained procyanidins had a reduction in total cholesterol compared to the placebo control group after one month."

This study also looked at what happens to flavanols and procyanidins after they are consumed and enter the body. The results confirmed findings from earlier investigations, showing that flavanols and procyanidins are broken down by the microbiota in the human gut, resulting in the formation of compounds called gamma-valerolactones. Although gamma-valerolactones were proposed to be bioactive, potentially involved in mediating the cardiovascular benefits observed following the intake of flavanols and procyanidins, this study could not provide evidence in support of this notion. Gamma-valerolactones appeared not to be directly involved in mediating improvements in blood vessel dilation, blood pressure, and vascular stiffness, and thus appear not to be bioactive in the context of these cardiovascular effects. Procyanidins are more likely to have important indirect effects by protecting flavanols within a food during food processing as well as in the gastrointestinal tract from degradation and inactivation.

"Compared to other bioactives, we know quite a lot about cocoa flavanols today, but this study provides new and important insights," said Dr. Heiss. "It is critical to understand how these bioactives interact with each other and with the human body, in order to create a comprehensive basis for evidence-based recommendations about how much of these compounds, or the foods that contain them, people should be consuming for health maintenance and disease risk reduction."

"Mars has a long-term commitment to cocoa flavanol research, which started over 20 years ago," noted Dr. Hagen Schroeter, Chief Science Officer of MARS Edge. "This research builds on a number of well-designed small and medium-scale clinical cocoa flavanol-centric studies that together demonstrate flavanols and procyanidins have cardiovascular health benefits. These comprehensive and collaborative studies range from synthetic chemistry, analytics, and epidemiology to human metabolism and pharmacokinetics. Our aim now in partnering in the multiyear COSMOS clinical trial is to investigate at scale whether the health benefits of flavanols can be generalized to the population at large."

As we age, blood pressure, cholesterol, and stiffness of arteries increase. What is important is that they are each independently associated with an increased risk of cardiovascular disease and death. Consuming procyanidins and flavanols, like (−)-epicatechin, could therefore help people maintain their heart health. A five-year study in approximately 21,000 men and women across the U.S called COSMOS being run by Brigham and Women's Hospital, an affiliate of Harvard Medical School, in Boston, MA, and the Fred Hutchinson Cancer Research Center in Seattle, WA hopes to definitively study this topic. The COSMOS study, or "COcoa Supplement and Multivitamin Outcomes Study", now in its third year, is a large-scale, randomized, placebo-controlled, clinical dietary intervention trial testing the risks and benefits of supplemental cocoa extract (containing (−)-epicatechin and procyanidins) and a multivitamin in the primary prevention of cardiovascular disease and cancer. The primary outcomes of the study are heart attack, stroke, coronary revascularization, cancer and death.

The study was published in the American Journal of Clinical Nutrition and is freely available on their website here: https://academic.oup.com/ajcn/advance-article/doi/10.1093/ajcn/nqy229/5144478.

New Orleans (October 26, 2018)--Natural variation may help decide which rainbow trout strains are likely to survive worldwide global warming, according to a new study. The findings will be presented today at the American Physiological Society's (APS) Comparative Physiology: Complexity and Integration conference in New Orleans.

The increasing temperatures and resulting lower underwater oxygen levels linked to climate change will likely affect the habitats of cold-water fish such as rainbow trout. The resilience of this species to changes in its environment will ultimately help it survive the significant warming of its home tributaries.

Researchers from the University of British Columbia studied three strains of rainbow trout, one that originated in California and two native to Canada. They found that young fish (called "fry") from California were able to tolerate higher water temperatures and low-oxygen environments better than fry from Canada. There was no noticeable difference in tolerance levels as a whole among adult fish of the same strains. However, individual adult fish from all strains had varying heat and oxygen tolerance levels, with some individuals being hardier and others more vulnerable to climate stressors. "These differences represent naturally occurring variation," said Nicholas Strowbridge, first author of the study. The hardier fish "are just a bit more able to handle high temperatures and low oxygen," Strowbridge explained.

Taking advantage of the natural variation in individual rainbow trout constitution can serve two beneficial purposes. Singling out the stronger fish in hatcheries may help preserve rainbow trout species and also support the global recreational fishing industry as warming trends continue.

New Rochelle, NY, October 26, 2018-Researchers have performed a careful comparison between locally generated, ischemia-induced, multipotent stem cells (iSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs) in an effort to determine which cell type has greater central nervous system (CNS) repair capacity. Their results show that the iSC characteristics make them more promising candidates as CNS injury therapeutics. The study is published in Stem Cells and Development, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here to read the full-text article free on the Stem Cells and Development website through November 26, 2018.

Takayuki Nakagomi, MD, PhD, with colleagues from the Hyogo College of Medicine and from the Kwansei Gakuin University School of Science and Technology, Hy?go, Japan, coauthored the article titled "Comparative Characterization of Ischemia-Induced Brain Multipotent Stem Cells with Mesenchymal Stem Cells: Similarities and Differences". Although evidence has shown that grafted mesenchymal stem cells can improve neuronal function after a stroke, most of these cells never reach the target injured brain regions. However, a regional induction of stem cells occurs after ischemia that may provide greater opportunity to restore neuronal function. Thus, the authors of this study extracted iSCs from the ischemic regions of post-stroke mice and collected and prepared MSCs from bone marrow. They then compared the gene and protein expression, multipotency, and neuronal differentiation capacity of the two stem cell types. Ultimately, many similarities were identified between MSCs and iSCs, but only iSCs exhibited the potential for neuronal differentiation, thus establishing a case for their exploration as CNS therapeutic agents.

"Having recently demonstrated that ischemia-induced multipotent stem cells are present within the post-stroke human brain, the authors here seek to clarify how the potential of this fascinating cell population differs from that of mesenchymal stem cells." says Editor-in-Chief Graham C. Parker, PhD, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI.

AURORA, Colo. (Oct. 26, 2018) - The neurologic effects and treatment options for exposure to biologic and chemical agents are outlined in a newly published article by neurologists from the University of Colorado School of Medicine who collaborated on the article with military physicians.

"We wrote this article to help neurohospitalists and other health care providers identify unusual neurologic illnesses that could result from potential biological or chemical attacks," said senior author Daniel M. Pastula, MD, MHS. "While we hope such attacks never happen, our goal is to provide a resource for health care providers so that we can all be prepared in an emergency."

Pastula is an assistant professor in the CU School of Medicine's Department of Neurology and in the Department of Medicine's Division of Infectious Diseases, and an assistant professor of epidemiology at the Colorado School of Public Health.

The article, "Neuroterrorism Preparedness for the Neurohospitalist," published October 21 in the journal The Neurohospitalist, provides an overview of biological and chemical agents that might be used in potential terror attacks. Such agents can affect the nervous system and lead to paralysis, respiratory failure, and/or encephalopathy.

In the article, the authors describe how to recognize, diagnose, treat, and report exposures to anthrax, botulism, brucella, plague, smallpox, organophosphates, nerve agents, cyanide, or carfentanil.

"Our goal is to better prepare health care providers to clinically recognize and help manage potential effects of such agents. Additionally, we stress the importance of collaborating with state and local health departments when use of such agents is suspected." Pastula said.

Proteins are the building blocks of the cell. They do most of the work and are essential for the structure, function and dynamic regulation of the cell and body's tissues and organs. Proteins rarely work alone, they interact, form protein complexes or bind DNA and RNA to control what a cell does. These complexes are key pieces of many important reactions within the cell, such as energy metabolism or gene regulation. Any change in those interactions, which can for example be caused by a mutation, can make the difference between health and disease. Hence, for understanding how cells operate, or what might go wrong in ill cells, it is essential to know how their building blocks interact.

New technologies allowed scientists during the last decades to understand the genetic information an organism possess, which of this information is actively used and which proteins are made by the cell in different circumstances. Now it is a big challenge to understand how biomolecules such as proteins and RNA messenger molecules combine to form the complexes required for a functional cell. In other words, we know the ten thousands of parts a cell is build off, but we don't know how they belong together.

In a paper published in Nature Communications, scientists at the Centre for Genomic Regulation (CRG) describe the development of a new method, named "rec-YnH", which was designed to understand the complexes formed between hundreds of proteins and RNAs at the same time.

The method, whose development was led by Sebastian Maurer in collaboration with the Luis Serrano laboratory, is the first technique that allows the detection of interactions between a large number of proteins and RNA molecules at the same time. The researchers put emphasis on the development of a doable and affordable method which is widely applicable.

"Our method reliably measures interactions between many proteins or many proteins and RNA fragments without the need for expensive, specialized equipment," explains Sebastian Maurer. "This methodology can be used by any standard biomedical research laboratory and will be useful for studying a particular process in the cell but also for researchers having to explore millions of protein interactions at a time to look for a complex involved in a particular disease," he concludes.

Two CRG laboratories successfully combined their expertise in bioinformatics, biochemistry and molecular biology to implement and validate the method. "Our collaboration resulted in an affordable and feasible method that produces high-quality maps of protein-protein and protein-RNA interactions", says Jae-Seong Yang, postdoctoral researcher and co-first author of the paper.

"Interactions between proteins and RNA are key for many biological processes including gene regulation, and our method is the first that can detect interactions between hundreds of proteins and RNAs at the same time. Having such an efficient new tool at hand will be extremely helpful to answer important questions related to many diseases," states co-first author of the study and CRG researcher Mireia Garriga.

Experts from the HSE Centre for Business Tendency Studies (CBTS) analysed for the first time the growth of the manufacturing industry in CIS countries between 2004 and 2016. It was conducted within the framework of a regional project of the United Nations Industrial Development Organization (UNIDO) "Improvement of industrial statistics and development of indicators of industrial performance for policy-relevant analysis in CIS countries".

The CBTS analysis, which covered the trends and scale of this growth, demonstrated a global slowdown in the long-term macroeconomic development of the region. During the period under review, CIS countries were not able to take advantage of various economic growth opportunities to boost their industrial potential. The results of the study were presented in the UNIDO report Industrial Development in CIS Countries: Are There Conditions for Re-Industrialization Capacity Building?

This research was conducted by CBTS Deputy Director and UNIDO Consultant Liudmila Kitrar jointly with Georgy Ostapkovich, CBTS Director, and experts Tamara Lipkind, Irina Kulikova and Dmitry Chusovlyanov.

Experts from HSE CBTS compared metrics on the manufacturing industries of CIS countries between 2004 and 2016. This approach allowed them not only to analyse the industrial development of CIS countries together, but also to see the role of each country reviewed in the project.

The results showed a global macroeconomic slowdown as concerns long-term steady growth in all countries. Additionally, CBTS experts saw evidence of a recession in the cyclical development of most economies in the region.

Experts believe price shocks on oil markets made the situation even worse for oil-exporting nations. For importers, oil revenues were partially neutralised by a deficit on the domestic market, as well as by the side effects of Russia's recession.

Practically all countries boosted value added of trade and services over the decade under review. This occurred alongside a drop in the size of the industrial market. This premature deindustrialisation, particularly under conditions of unstable revenues, made it impossible to maintain adequate economic growth rates. This also limited the number of new technologies that could be introduced.

The industrial markets of most CIS countries traditionally relied on low-tech production, while imports largely met domestic needs for high-tech products. It was harder for the majority of countries in the region to produce high-tech products due to labour-intensive assembly processes. At the same time, exports from the region mostly consisted of resource- and labour-intensive products, which were greatly exposed to external shocks.

Over the decade, a cluster of countries with solid industrialisation, high production and export potential, and regional influence of manufacturing had formed in the CIS. These countries include Russia, Kazakhstan, Ukraine, and Belarus. Azerbaijan and Armenia were catching up in terms of development and industrialization. Kyrgyzstan, Moldova, and Tajikistan continued expanding the large-scale processing of resources-based and low-tech production.

The region did not experience a noticeable growth in employment in the formal sector of the manufacturing industry, and it was shown that this sector was not a critical source of new jobs. Only Russia, Belarus, and Ukraine demonstrated a high level of industrial employment (over 18% of those employed in these countries worked in manufacturing) as a sign of real and timely industrialization.

WASHINGTON, Oct. 25, 2018 -- Space is full of potentially dangerous radiation. Here on Earth, our atmosphere and magnetic field protect us from the worst of it. Astronauts on a deep-space mission would need other forms of protection. In collaboration with National Chemistry Week, this Reactions video is all about chemistry in space: https://youtu.be/MV5PGjWl2Yc.

Results from a phase 2 randomised trial suggest that a new investigational antibiotic is as effective as the current standard-of-care antibiotic for the treatment of complicated urinary tract infections (UTIs) caused by several multidrug resistant Gram-negative bacteria.

The findings, published in The Lancet Infectious Diseases, indicated that patients treated with the siderophore-based drug, cefiderocol, had a higher and more sustained level of pathogen eradication and similar clinical outcomes to those treated with the current standard of care, imipenem-cilastatin.

Cefiderocol is novel in its approach to overcoming the three main mechanisms of antibiotic resistance used by Gram-negative bacteria--two outer membranes that make it hard for antibiotics to penetrate, porin channels which can adapt and change to block the antibiotic entry, and efflux pumps that expel antibiotics back out of the cell and make the drugs ineffective.

"Cefiderocol acts as a trojan horse," explains Dr Simon Portsmouth, Shionogi Inc, USA, who led the research. "The drug uses a novel mechanism of cell entry that takes advantage of the bacteria's need for iron to survive. During an acute infection, one of our innate immune responses is to create an iron-poor environment. In response, bacteria increase their iron intake. Cefiderocol binds to irons and is transported through the extra outer membrane by the bacterium's own iron-transport system. These iron channels also enable the drug to bypass the bacteria's porin channels and gain repeat entry even if the bacterium has evolved efflux pumps." [1]

The findings highlight the potential of cefiderocol as an important new option for treating highly resistant Gram-negative bacteria, once approved. Cefiderocol's effect on carbapenem-resistant strains--which cause some of the hardest-to-treat infections in health-care settings, and for which there is no antibiotic alternative that does not have serious side effects or other complications--could not be properly evaluated because the carbapenem drug imipenem-cilastatin was used as the active control treatment.

The US Centers for Disease Control and Prevention (CDC) estimate that antibiotic-resistant microorganisms cause more than two million infections in the USA each year, resulting in at least 23,000 deaths. A 2014 Review on Antimicrobial Resistance predicted that by 2050, the global cost of antibiotic resistance will rise to as such as £100 trillion and account for 10 million deaths every year.

Antibiotic resistance has been identified as one of the biggest threats to human health globally. While the antibiotic arsenal dwindles in effectiveness, new antibiotics with novel modes of action are urgently needed. WHO considers carbapenem-resistant, Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae as the highest priority and critical for development of new antibiotics. Previous studies have demonstrated that cefiderocol is active against all three multidrug-resistant pathogens.

As part of the US Food and Drug Administration (FDA) approach to fast-tracking antibiotic development [2], this study randomised 448 adults (aged 18 or older) who had been hospitalised with a complicated UTI or uncomplicated pyelonephritis (inflammation of the kidney dur to a bacterial infection) to receive three daily infusions of cefiderocol (300 patients) or imipenem-cilastatin (148 patients) for seven to 14 days. In total, 252 patients treated with cefiderocol and 119 with imipenem-cilastatin had a Gram-negative uropathogen and were included in the efficacy analysis. The majority of participants had Escherichia coli, Klebsiella pneumoniae, or P aeruginosa infections (figure 2).

Results suggested that cefiderocol was as effective as imipenem-cilastatin in a combined evaluation of the clinical and microbiological response with efficacy rates of 73% (183/252 patients) and 55% (65/119 patients) respectively seven days after treatment was stopped. This difference was mainly driven by the sustained antibacterial activity of cefiderocol whilst the clinical responses were highly similar (90% vs 87%).

Overall, cefiderocol was well tolerated with similar numbers of adverse events to that of imipenem-cilastatin (41% [122/300 patients] vs 51% [76/148 patients]). Gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) were the most common adverse events in both groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). Fourteen (5%) participants in the cefiderocol group and 12 (8%) in the imipenem-cilastatin group reported at least one serious adverse event, with C difficile colitis the most common.

Dr Portsmouth says: "Cefiderocol was found to be both safe and tolerable in a population of older patients who were very ill with complex comorbid conditions and a wide range of multidrug-resistant pathogens. Our results support cefiderocol as a novel approach that might be used to overcome Gram-negative resistance." [1]

"Ongoing clinical trials of pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia, and a study in patients with carbapenem-resistant infections, will provide additional important information about cefiderocol." [1]

The authors note that an important limitation of the study was the exclusion of patients with carbapenem-resistant infections because the comparator was a carbapenem.

Writing in a linked Comment, Dr Angela Huttner, Geneva University Hospitals, Switzerland, discusses the importance of assessing the post-market clinical experience of the drug: "The FDA's new guidance on complicated urinary tract infection endpoints, issued in June 2018, calls for complete clinical resolution and changed the cutoff for microbiological response to bacterial counts of less than 1 × 103 CFU/mL. An accelerated process to get new antibiotics to market was urgently needed, and regulatory bodies responded. But any trial launched more than four months ago (including an ongoing phase 3 cefiderocol trial, NCT02714595) will now be adhering to outdated standards and requirements. There is still no guidance on measuring baseline or emerging resistance; this too will fall to post-market development. Although these results are promising with regard to obtaining approval for cefiderocol and in the context of increasing antimicrobial resistance, scepticism will persist until more evidence is available. Cefiderocol remains on the fast track to approval. This is welcome news, as long as those in post-market clinical medicine understand the deal we have made: it will fall to us to continue the drug's clinical development, while managing its appropriate use and conservation, and thus take its true measure."

(Philadelphia, PA) - Researchers have discovered that inhibiting CDK9, a DNA transcription regulator, reactivates genes that have been epigenetically silenced by cancer. Reactivation leads to restored tumor suppressor gene expression and enhanced anti-cancer immunity. It is the first time this particular kinase has been linked to gene silencing in mammals.

Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research & Molecular Biology at the Lewis Katz School of Medicine at Temple University (LKSOM), led the research. The paper appears in the journal Cell.

It has been established that epigenetic mediators of gene silencing present new targets for cancer drugs. Hanghang Zhang, PhD, of the Fels Institute for Cancer Research & Molecular Biology at LKSOM, the first author on the report, performed a live cell drug screen with genetic confirmation to identify CDK9 as a target and to develop and test an effective inhibitor - MC180295. The new drug is highly selective, potentially avoiding the side effects associated with inhibiting the cell cycle. In the study it showed broad effectiveness against cancer both in vitro and in vivo. The drug was discovered in collaboration with investigators at the Moulder Center for Drug Discovery at the Temple University School of Pharmacy.

"In addition to reactivating tumor suppressor genes, CDK9 inhibition induces sensitivity to the immune checkpoint inhibitor α-PD-1 in vivo," said Issa. "It is an excellent target for epigenetic cancer therapy."

The cerebellum can't get no respect. Located inconveniently on the underside of the brain and initially thought to be limited to controlling movement, the cerebellum has long been treated like an afterthought by researchers studying higher brain functions.

But researchers at Washington University School of Medicine in St. Louis say overlooking the cerebellum is a mistake. Their findings, published Oct. 25 in Neuron, suggest that the cerebellum has a hand in every aspect of higher brain functions -- not just movement, but attention, thinking, planning and decision-making.

"The biggest surprise to me was the discovery that 80 percent of the cerebellum is devoted to the smart stuff," said senior author Nico Dosenbach, MD, PhD, an assistant professor of neurology, of occupational therapy and of pediatrics. "Everyone thought the cerebellum was about movement. If your cerebellum is damaged, you can't move smoothly ­-- your hand jerks around when you try to reach for something. Our research strongly suggests that just as the cerebellum serves as a quality check on movement, it also checks your thoughts as well -- smoothing them out, correcting them, perfecting things."

Dosenbach is a founding member of the Midnight Scan Club, a group of Washington University neuroscientists who have taken turns in an MRI scanner late at night, scanning their own brains for hours to generate a massive amount of high-quality data for their research. A previous analysis of Midnight Scan Club data showed that a kind of brain scan called functional connectivity MRI can reliably detect fundamental differences in how individual brains are wired.

Postdoctoral researcher and first author Scott Marek, PhD, decided to apply a similar analysis to the cerebellum. In the better-known cerebral cortex -- the crumpled outer layer of the brain -- wiring maps have been drawn that connect distant areas into networks that govern vision, attention, language and movement. But nobody knew how the cerebellum is organized in individuals, partly because a quirk of MRI technology means that data obtained from the underside of the brain tend to be low quality. In the Midnight Scan Club dataset, however, Marek had access to more than 10 hours of scans on each of 10 people, enough to take a serious look at the cerebellum.

Using the cortex's networks as a template, Marek could identify the networks in the cerebellum. Notably, the sensory networks are missing -- vision, hearing and touch -- and only 20 percent of the cerebellum is devoted to movement, roughly the same amount as in the cerebral cortex. The remaining 80 percent is occupied by networks involved in higher-order cognition: the attention network; the default network, which has to do with daydreaming, recalling memories and just idly thinking; and two networks that oversee executive functions such as decision-making and planning.

"The executive function networks are way overrepresented in the cerebellum," Marek said. "Our whole understanding of the cerebellum needs to shift away from it being involved in motor control to it being more involved in general control of higher-level cognition."

The researchers measured the timing of brain activity and found that the cerebellum was consistently the last step in neurologic circuits. Signals were received through sensory systems and processed in intermediate networks in the cerebral cortex before being sent to the cerebellum. There, the researchers surmise, the signals undergo final quality checks before the output is sent back to the cerebral cortex for implementation.

"If you think of an assembly line, the cerebellum is the person at the end who inspects the car and says, 'This one is good; we'll sell it,' or 'This one has a dent; we have to go back and repair it,'" Dosenbach said. "It's where all your thoughts and actions get refined and quality controlled."

People with damage to their cerebellum are known to become uncoordinated, with an unsteady gait, slurred speech and difficulty with fine motor tasks such as eating. The cerebellum also is quite sensitive to alcohol, which is one of the reasons why people who have had too many drinks stumble around. But the new data may help explain why someone who is inebriated also shows poor judgment. Just as a person staggers drunkenly because his or her compromised cerebellum is unable to perform the customary quality checks on motor function, alcohol-fueled bad decisions might also reflect a breakdown of quality control over executive functions.

Marek also performed individualized network analyses on the 10 people in the data set. He found that while brain functions are arranged in roughly the same pattern in everyone's cerebellum, there is enough individual variation to distinguish brain scans performed on any two participants. The researchers are now investigating whether such individual differences in cerebellar networks correlate with intelligence, behavior, personality traits such as adaptability, or psychiatric conditions.

"Many people who are looking at links between brain function and behavior just ignore the cerebellum," Dosenbach said. "They slice off that data and throw it away, because they don't know what to do with it. But there are four times as many neurons in the cerebellum as in the cerebral cortex, so if you're leaving out the cerebellum, you've already shot yourself in the foot before you started. The promise of imaging the whole human brain at once is to understand how it all works together. You can't see how the whole circuit works together when you're missing a major piece of it."