Culture

Presently, Earth is the only known location where life exists in the Universe. This year the Nobel Prize in physics was awarded to three astronomers who proved, almost 20 years ago, that planets are common around stars beyond the solar system. Life comes in various forms, from cell-phone-toting organisms like humans to the ubiquitous micro-organisms that inhabit almost every square inch of the planet Earth, affecting almost everything that happens on it. It will likely be some time before it is possible to measure or detect life beyond the solar system, but the solar system offers a host of sites that might get a handle on how hard it is for life to start.

Mars is at the top of this list for two reasons. First, it is relatively close to Earth compared to the moons of Saturn and Jupiter (which are also considered good candidates for discovering life beyond Earth in the solar system, and are targeted for exploration in the coming decade). Second, Mars is extremely observable because it lacks a thick atmosphere like Venus, and so far, there are pretty good evidence that Mars' surface temperature and pressure hovers around the point liquid water--considered essential for life--can exist. Further, there is good evidence in the form of observable river deltas, and more recent measurements made on Mars' surface, that liquid water did in fact flow on Mars billions of years ago.

Scientists are becoming increasingly convinced that billions of years Mars was habitable. Whether it was in fact inhabited, or is still inhabited, remains hotly debated. To better constrain these questions, scientists are trying to understand the kinds of water chemistry that could have generated the minerals observed on Mars today, which were produced billions of years ago.

Salinity (how much salt was present), pH (a measure of how acidic the water was), and redox state (roughly a measure of the abundance of gases such as hydrogen [H2, which are termed reducing environments] or oxygen [O2, which are termed oxidising environments; the two types are generally mutually incompatible]) are fundamental properties of natural waters. As an example, Earth's modern atmosphere is highly oxygenated (containing large amounts of O2), but one need only dig a few inches into the bottom of a beach or lake today on Earth to find environments which are highly reduced.

Recent remote measurements on Mars suggest its ancient environments may provide clues about Mars' early habitability. Specifically, the properties of pore water within sediments apparently deposited in lakes in Gale Crater on Mars suggest these sediments formed in the presence of liquid water which was of a pH close to that of Earth's modern oceans. Earth's oceans are of course host to myriad forms of life, thus it seems compelling that Mars' early surface environment was a place contemporary Earth life could have lived, but it remains a mystery as to why evidence of life on Mars is so hard to find.

Australian researchers have uncovered a metabolic system which could lead to new strategies for therapeutic cancer treatment.

A team at Flinders University led by Professor Janni Petersen and the St Vincent's Institute of Medical Research have found a link between a metabolic system in a yeast, and now mammals, which is critical for the regulation of cell growth and proliferation.

"What is fascinating about this yeast is that it became evolutionarily distinct about 350 million years ago, so you could argue the discovery, that we subsequently confirmed occurs in mammals, is at least as ancient as that," said Associate Professor Jonathon Oakhill, Head, Metabolic Signalling Laboratory at SVI in Melbourne.

This project, outlined in a new paper in Nature Metabolism, looked at two major signalling networks.

Often referred to as the body's fuel gauge; a protein called AMP-Kinase, or AMPK, regulates cellular energy, slowing cell growth down when they don't have enough nutrients or energy to divide.

The other, that of a protein complex called mTORC1/TORC1, which also regulates cell growth, increases cell proliferation when it senses high levels of nutrients such as amino acids, insulin or growth factors.

A hallmark of cancer cells is their ability to over-ride these sensing systems and maintain uncontrolled proliferation.

"We have known for about 15 years that AMPK can 'put the brakes on' mTORC1, preventing cell proliferation" says Associate Professor Oakhill. "However, it was at this point that we discovered a mechanism whereby mTORC1 can reciprocally also inhibit AMPK and keep it in a suppressed state.

Professor Petersen, from the Flinders Centre for Innovation in Cancer in Adelaide, South Australia says the experiments showed the yeast cells "became highly sensitive to nutrient shortages when we disrupted the ability of mTORC1 to inhibit AMPK".

"The cells also divided at a smaller size, indicating disruption of normal cell growth regulation," she says.

"We measured the growth rates of cancerous mammalian cells by starving them of amino acids and energy (by depriving them of glucose) to mimic conditions found in a tumour.

"Surprisingly, we found that these combined stresses actually increased growth rates, which we determined was due to the cells entering a rogue 'survival' mode.

"When in this mode, they feed upon themselves so that even in the absence of appropriate nutrients the cells continue to grow.

"Importantly, this transition to survival mode was lost when we again removed the ability of mTORC1 to inhibit AMPK."

These findings provide a new opportunity for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumour microenvironment, the research concludes.

Gatersleben, 20.01.2020 The development of next-generation-sequencing (NGS) has enabled researchers to investigate genomes that might previously have been considered too complex or too expensive. Nevertheless, the analysis of complex plant genomes, which often have an enormous amount of repetitive sequences, is still a challenge. Therefore, bioinformatics researchers from Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Martin Luther University Halle-Wittenberg (MLU) and Leibniz Institute of Plant Biochemistry (IPB) have now published "Kmasker plants", a program that allows the identification of repetitive sequences and thus facilitates the analysis of plant genomes.

In bioinformatics, the term k-mer is used to describe a nucleotide sequence of a certain length "k". By defining and counting such sequences, researchers can quantify repetitive sequences in the genome they are studying and assign them to corresponding positions. As early as 2014, researchers at IPK in Gatersleben used this approach to develop the in-silico (computer-based) tool "Kmasker". It was used to detect repetitions in the characterisation of the barley genome (Schmutzer et al., 2014).

The use of NGS is becoming more and more important, but the error-free composition of complex genomes from NGS results is still a challenge. For this reason, the researchers recently decided to revive and expand this initial proof-of-concept project. Under the leadership of Dr. Thomas Schmutzer, formerly from the research group "Bioinformatics and Information Technology" at IPK and now affiliated with the MLU, scientists from the MLU, the IPK, Wageningen University & Research and the IPB Halle worked in close cooperation on the redesign and development of "Kmasker plants". This collaboration was largely supported by the two service centres "GCBN" and "CiBi" from the German Network for Bioinformatics Infrastructure "de.NBI".

"Kmasker plants" allows for the rapid and reference-free screening of nucleotide sequences using genome-wide derived k-mers. In extension to the previous version, the bioinformatics tool now also enables comparative studies between different cultivars or closely related species, and supports the identification of sequences suitable as fluorescence in situ hybridisation (FISH) probes or CRISPR/Cas9-specific guide RNAs. Furthermore, "Kmasker plants" has been published with a web service that contains the pre-computed indices for selected economically important crop plants, such as barley or wheat. Dr. Schmutzer emphasises that "this tool will enable plant researchers all over the world to test plant genomes and thus, for example, identify repeat free parts of their sequence of interest." Rather, he believes that the enhanced features will make it possible to detect sequence candidate regions that have multiplied in the genome of one species but are missing in other species or occur in smaller copy numbers. This is a common effect that contributes to phenotypic variation of agronomic importance in various crops. A significant example is the Vrn-H2 gene, which is present in a single copy in winter barley, while it is missing in barley spring lines.

The "Kmasker plants" web-service is now available as part of the IPK Crop Analysis Tool Suite (CATS) and therefore as a service of the de.NBI Service Platform. Alternatively, the "Kmasker plants" source code can directly be accessed and installed via GitHub.

Many teenagers are struggling to control their impulses on the internet, in a scramble for quick thrills and a sense of power online, potentially increasing their risks of becoming cyber criminals.

A new study by Flinders Criminology analysed existing links between legal online activities and cybercrime- for example, how viewing online pornography progresses to opening illegal content, and motivations to evolve from online gaming to hacking.

Newly published in the European Society of Criminology, the authors outline why illegal online activity involving adolescents from 12-19 years of age is encouraged by the idea the internet blurs normal social boundaries amongst young users tempted into wrongdoings they wouldn't contemplate in the outside world.

Flinders Criminologist Professor Andrew Goldsmith says illegal online activity is especially attractive for adolescents already prone to curiosity and sneaky thrill seeking, but the internet encourages new levels experimentation which are easily accessible.

"The internet allows young people to limit their social involvement exclusively to particular associations or networks, as part of a trend we've termed 'digital drift'. From a regulatory perspective, we're finding this poses significant challenges as it degrades young people's impulse controls."

"It's becoming increasingly important to understand the connection between young people's emotional drivers and committing crimes, as well as human-computer interactions to establish why the internet easily tempts young users into digital piracy, pornography and hacking."

"We're using the word seduction to describe the processes and features intrinsic to the online environment that make online activity both attractive and compelling." "For some young people, the Internet is like a seductive swamp, very appealing to enter, but very sticky and difficult to get out of."

Professor Goldsmith says there needs to be a deeper understanding of the influential technologies regularly used by young people, recognizing that not all motivations for transgression indicate a deep criminal pathology or criminal commitment.

"Policy should consist of interventions that take into account the lack of worldly experience amongst many young offenders. Online technologies render the challenge of weighing up potential risks and harms from actions even harder. A propensity for thrill-seeking common especially among young males encouraged by the Internet can create a form of short-sightedness towards consequences."

"Effective government responses must reflect on the range of motivations young people bring to, and find in, their online behaviours, not least of all in order to garner support amongst young people when it comes to effective regulatory changes."

Scientists from the University of Surrey and University of Geneva have discovered that the bacterium which causes bovine TB can survive and grow in small, single-celled organisms found in soil and dung. It is believed that originally the bacterium evolved to survive in these single-celled organisms known as amoebae and in time progressed to infect and cause TB in larger animals such as cattle.

During the study, published in The ISME Journal, scientists sought to understand more about the bacterium Mycobacterium bovis (M. bovis), which causes bovine TB, and how it can survive in different environments. To do this scientists infected a type of amoebae known as Dictyostelium discoideum with M.bovis. Unlike other bacterium which were digested and used as a food source by the amoebae, M.bovis was unharmed and continued to survive for two days. In-depth analysis showed that the bacterium uses the same genes to escape from amoebae that it uses to avoid being killed by immune cells in larger animals such as cattle and humans.

Scientists also discovered that M. bovis remained metabolically active and continued to grow, although at a slower pace, at lower temperatures than expected.

Previously it was thought the bacterium could only replicate at 37?C, the body temperature of cattle and humans; however, replication of the bacterium was identified at 25 ?C. Researchers believe that the bacterium's ability to adapt to ambient temperatures and survive in amoebae may partially explain high transmission rates of the bacterium between animals.

Bovine TB is a hugely underestimated problem worldwide and England has the highest incidence of infection in Europe. Cattle found to have bovine TB are legally required to be slaughtered due to the high risk of the disease entering the food chain and spreading to humans. 32,793 cattle were slaughtered in England in 2018 in a bid to curtail the spread of the disease.

Lead author Professor Graham Stewart, Head of the Department of Microbial Sciences at the University of Surrey, said: "Despite implementation of control measures, bovine TB continues to be a major threat to cattle and has an enormous impact on the rural economy. Understanding the biology behind the TB disease and how it spreads is crucial for a balanced discussion on this devastating problem and to developing preventative measures to stop its spread.

"An important additional benefit is that our research shows the potential for carrying out at least some future TB research in amoebae rather than in large animals."

The international team works on a computational model able to predict the properties of new molecules based on the analysis of fundamental chemical laws. The project was supported by the Russian Science Foundation (title "Using AI methods for the planning of chemical synthesis").

Co-author, Associate Professor Timur Madzhidov, explains, "We offered a way to insert the preexisting chemical equations into some frameworks of machine learning. It was tested on the predictions of tautomeric constants and acidity, which are linked by the Kabachnik equation. Using the functional interdependency between them, the neural network learns how to predict both these properties."

Prototropic tautomerism is the phenomenon of reversible isomerism, in which isomers (substances having the same qualitative and quantitative composition, but differing in structure and properties) easily transition into each other due to the transfer of a hydrogen atom.

"Tautomeric transformations are very common for organic compounds, being known for about half of all discovered compounds. For example, one of the mechanisms of spontaneous mutations is tied to the tautomeric transformations of DNA nucleic base. That why tautomerism must be taken into account when registering new compounds, during the computer design of new medications and the search for molecules with preconditioned properties," adds Madzhidov.

The results of this research can help increase the precision of prediction of physicochemical properties of designed medication and materials, as well as correctly forecast the parameters of chemical reactions.

A new study by the University of Barcelona (UB) concluded that irregularity in eating schedules during the weekend, named by the authors as eating jet lag, could be related to the increase of body mass index (BMI), a formula that measures weight and height to determine whether someone's weight is healthy.

These results, published in the science journal Nutrients, were independently taken from factors such as the quality of the diet, level of physical activity, social jet lag (difference in sleeping schedules during weekends) and chronotype (natural predisposition to a certain sleeping schedule).

According to the researchers, this is the first study that shows the importance of regularity in eating schedules -including weekends- to control weight, and could be an element to consider as part of nutrition guidelines to prevent obesity.

The study, jointly led by Maria Izquierdo Pulido, from the Department of Nutrition, Food Sciences and Gastronomy of the UB and INSA-UB, and Trinitat Cambras, from the Department of Biochemistry and Physiology of the UB, is part of the doctoral thesis of the researcher María Fernanda Zerón Rugerio, first author of the article. Other participants in the article are Álvaro Hernáez, from the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBERobn), and Armida Patricia Porras Loaiza, from Universidad de las Américas Puebla (Mexico).

The importance of the biological clock in nutrition

During the last years researches proved the body understands calories differently depending on the time of the day. Eating late can be related to a higher risk of obesity. According to Maria Izquierdo Pulido, "this difference is related to our biological clock, which organizes our body to understand and metabolize calories consumed during the day". At night, however, "it gets the body ready for fasting while we sleep".

"As a result -the researcher continues-, when intake takes place regularly, the circadian clock ensures that the body's metabolic pathways act to assimilate nutrients. However, when food is taken at an unusual hour, nutrients can act on the molecular machinery of peripheral clocks (outside the brain), altering the schedule and thus, modifying the body's metabolic functions".

The new study was carried out on a population of 1,106 young people (aged between eighteen and twenty-two) in Spain and Mexico. Researchers analyzed the relation between the body mass index and the variability in eating timing during weekends compared to the rest of the days. To do so, authors used a new marker that gathers changes in eating times (breakfast, lunch and dinner) at weekends: the eating jet lag, presented for the first time in this study.

"Our results show changing the timing of the three meals during the weekend is linked to obesity. The highest impact on the BDI could occur when there is a 3.5-hour difference in eating schedules. After this, the risk of obesity could increase, since we saw individuals who showed a 3.5-hour eating jet lag increased their BDI in 1.3. kg/m2", says María Fernanda Zerón Rugerio.

Lack of synchrony between the social and body time

To explain the link between eating jet lag and obesity, authors suggest individuals to undergo a chronodisruption, that is, a lack of synchrony between internal time of the body and social time. "Our biological clock is like a machine, and is ready to unchain the same physiological and metabolic response at the same time of the day, every day of the week. Fixed eating and sleep schedules help the body to be organized and promote energy homeostasis. Therefore, people with a higher alteration of their schedules have a higher risk of obesity", notes Cambras.

More research is needed to reveal the physiological mechanisms and metabolic alterations behind the eating jet lag and its link to obesity. However, authors highlight the importance of keeping regular eating and sleeping schedules to preserve health and wellbeing. "Apart from diet and physical exercise, which are two pillars regarding obesity, other factor to be considered is regular eating schedules, since we proved it has an impact on our body weight", notes Izquierdo Pulido.

Studying the long term effects of eating jet lag

The study notes the importance of doing research on the relation between time irregularity and the evolution of weight over time, as well as conducting the study on populations with different social and economic characteristics, metabolic features and different age. "Variability in eating schedules during weekends compared to week days can happen chronically during someone's life. Future studies should evaluate the effect of this chronic variability through the eating jet lag, on the evolution of weight", conclude researchers.

UNIVERSITY PARK, Pa. -- During the past 20 years, insecticides applied to U.S. agricultural landscapes have become significantly more toxic -- over 120-fold in some midwestern states -- to honey bees when ingested, according to a team of researchers, who identified rising neonicotinoid seed treatments in corn and soy as the primary driver of this change. The study is the first to characterize the geographic patterns of insecticide toxicity to bees and reveal specific areas of the country where mitigation and conservation efforts could be focused.

According to Christina Grozinger, Distinguished Professor of Entomology and director of the Center for Pollinator Research, Penn State, this toxicity has increased during the same period in which widespread decline in populations of pollinators and other insects have been documented.

"Insecticides are important for managing insects that damage crops, but they can also affect other insect species, such as bees and other pollinators, in the surrounding landscape," she said. "It is problematic that there is such a dramatic increase in the total insecticide toxicity at a time when there is also so much concern about declines in populations of pollinating insects, which also play a very critical role in agricultural production."

The researchers, led by Maggie Douglas, assistant professor of environmental studies, Dickinson College, and former postdoctoral fellow, Penn State, integrated several public databases -- including insecticide use data from the U.S. Geological Survey, toxicity data from the Environmental Protection Agency, and crop acreage data from the U.S. Department of Agriculture -- to generate county-level annual estimates of honey bee "toxic load" for insecticides applied between 1997 and 2012. The team defined toxic load as the number of lethal doses to bees from all insecticides applied to cropland in each county.

The researchers generated separate estimates for contact-based toxic loads, such as when a bee is sprayed directly, and oral-based toxic loads, such as when a bee ingests the pollen or nectar of a plant that has recently been treated. They generated a map of predicted insecticide toxic load at the county level. Their results appear today (Jan. 21) in Scientific Reports.

The team found that the pounds of insecticides applied decreased in most counties from 1997 to 2012, while contact-based bee toxic load remained relatively steady. In contrast, oral-based bee toxic load increased by 9-fold, on average, across the U.S. This pattern varied by region, with the greatest increase -- 121-fold -- seen in the Heartland, which the U.S. Department of Agriculture defines as all of Iowa, Illinois and Indiana; most of Missouri; and part of Minnesota, Ohio, Kentucky, Nebraska and South Dakota. The Northern Great Plains had the second highest increase at 53-fold. This region includes all of North Dakota and part of South Dakota, Nebraska, Colorado, Wyoming, Montana and Minnesota.

"This dramatic increase in oral-based toxic load is connected to a shift toward widespread use of neonicotinoid insecticides, which are unusually toxic to bees when they are ingested," said Douglas.

The most widely used family of insecticides in the world, neonicotinoids are commonly used as seed coatings in crops, such as corn and soybean. Some of the insecticide is taken up by the growing plants and distributed throughout their tissues, while the rest is lost to the environment.

"Several studies have shown that these seed treatments have negligible benefits for most crops in most regions," said Grozinger. "Unfortunately, growers often don't have the option to purchase seeds without these treatments; they don't have choices in how to manage their crops."

The researchers suggest that the common method of evaluating insecticide use trends in terms of pounds of insecticides applied does not give an accurate picture of environmental impact.

"The indicator we use -- bee toxic load -- can be considered as an alternative indicator in cases where impacts to bees and other non-target insects is a concern," said Douglas. "This is particularly relevant given that many states have recently developed 'Pollinator Protection Plans' to monitor and address pollinator declines. Ultimately, our work helps to identify geographic areas where in-depth risk assessment and insecticide mitigation and conservation efforts could be focused."

"It is important to note that the calculation of bee toxic load provides information about the total toxicity of insecticides applied to a landscape," said Grozinger. "It does not calculate how much of that insecticide actually comes in contact with bees, or how long the insecticide lasts before it is broken down. Future studies are needed to determine how toxic load associates with changes in populations of bees and other insects."

This research is part of a larger project to investigate the various stressors impacting pollinator populations across the United States. One tool created within this research project is Beescape, which allows users to explore the stressors affecting bees in their own communities.

Biophysicists from the MIPT Center for Molecular Mechanisms of Aging and Age-Related Diseases have teamed up with colleagues from Canada, the U.S., Japan, France, and Germany to shed light on the structure and functioning mechanism of the CysLT receptors, which regulate inflammatory responses associated with allergic disorders. Their findings are reported in Nature Communications.

Cellular communication refers to the interactions between cells in an organism. It allows millions of cells to work together, managing bodily processes that are crucial for survival. Cells communicate via protein molecules called receptors, which exist on the cell and organelle surfaces, as well as in the cytoplasm. When a receptor binds a particular molecule, this triggers a specific response. A molecule that binds to a specific receptor is called a ligand.

G protein-coupled receptors, or GPCRs, are molecular machines incorporated into cell membranes. CysLT1R and CysLT2R are members of the GPCR family. Their ligands are highly potent lipids called peptide (cysteinyl) leukotrienes, or CysLTs.

Both of the receptor subtypes CysLT1 and CysLT2 are known to regulate allergic inflammatory responses. For over two decades, asthma and associated conditions have been treated with drugs that inhibit the CysLT1 receptor. Many patients, however, do not respond to this treatment. At the same time, the role of the CysLT2 receptor in the physiology and pathogenesis of the inflammatory response remains poorly studied. It was not until recently that CysLT2R was suggested as a potential drug target in the treatment of atopic asthma, brain injury, and central nervous system disorders, as well as certain cancers.

As of today, the development of more effective medications for asthma and associated conditions is hindered by the lack of information on how and to what ligands the CysLT receptors bind. Their functioning mechanisms have not been clearly understood either, as this requires high-resolution structural biology data. Once these are available, researchers can proceed using computer simulations.

In molecular modeling, docking is a method for determining the preferred orientation and conformation of the ligand within the protein binding site. Knowing the spatial structure of a given receptor with angstrom precision, as well as the chemical structure of the ligand, enables biologists to predict the spatial structure of the corresponding receptor-ligand complex and calculate the free energy of its formation. Hence, determining the spatial structure of such complexes is crucial to understanding their function.

In their recent study, researchers from the Moscow Institute of Physics and Technology identified the most critical ligand-binding determinants of the CysLT1 and CysLT2 receptors based on the structural analysis the team performed for CysLT2R and the structural data on CysLT1R published by the laboratory in October.

"The new structures have greatly improved the accuracy of ligand docking and helped us better understand the properties of ligands with respect to both receptors. Now we know how to alter drug design templates to inhibit the activity of both the CysLT1 and CysLT2 receptors or do that selectively for either of them," commented Anastasiia Gusach, a PhD student at MIPT and a junior researcher at the MIPT Laboratory of Structural Biology of G Protein-Coupled Receptors.

In the future, these structures could be further developed to serve as drug candidates or tool compounds, aiding in understanding the specific role of each of the CysLT receptor subtypes in various physiological and pathological processes.

"Recently obtained results suggest that addressing both the CysLT1 and CysLT2 receptors as a drug target or even inhibiting CysLT2R alone will offer a more effective alternative to CysLT1R-selective drugs, especially in severe asthma cases. In addition, CysLT2R is emerging as a potential drug target for patients with brain injury and neurodegenerative disorders. All of the above makes CysLT2R promising for research. In this study, we described four crystal structures of CysLT2R in complex with three ligands blocking the CysLT1 and CysLT2 receptors," said Alexey Mishin, a senior researcher at the MIPT Laboratory of Structural Biology of G Protein-Coupled Receptors.

Another great application of the structural information obtained in the study is the possibility to rationalize the effects of point mutations in which a "foreign" amino acid appears in the amino acid sequence of a protein, which in turn influences receptor activity. For this reason, the researchers accumulated information on mutations in the sequence of the CysLT2 receptor from 60,000 healthy individuals and mapped the positions of the new amino acids on the receptor structure. They found that about a quarter of these mutations were located in functionally important regions and may influence what processes the receptor will activate or deactivate when it interacts with its ligand.

This implies that with the rapid development of genome sequencing technologies and the accumulation of large volumes of statistical data, structure-function studies will not only allow accurate prediction of disease for every patient but will also enable predicting drug efficacy and improving patient safety based on how these variations in genes affect the response to certain medications.

Hershey, Pa. -- Patient enrollment in clinical trials as the first course of treatment after cancer diagnosis is low, despite the fact that enrollment may increase life expectancy, according to researchers at Penn State. They also found that white males with private health insurance and metastatic cancers treated at academic medical centers are more likely than other groups to enroll in clinical trials.

Dr. Nicholas G. Zaorsky, an assistant professor of radiation oncology, Penn State College of Medicine, led a team of Penn State Cancer Institute researchers who analyzed data from more than 12 million patients with 46 different types of cancer between 2004 and 2015 in the National Cancer Database. They found that only 11,576 (0.1%) of those patients were enrolled in clinical trials as their first course of therapy following diagnosis.

According to Dr. Niraj J. Gusani, professor of surgery, Penn State College of Medicine, and senior author of the study, which published in the Journal of the National Comprehensive Cancer Network in November 2019, the low enrollment is troubling because clinical trials may be beneficial for patients.

"Major advances in cancer treatment have been supported by clinical trials," Gusani said. "By volunteering to participate in a trial, patients may help further the field of research and gain access to new treatments."

Zaorsky, Gusani and their team found that patients with cancer treated in clinical trials, when matched and compared to similar patients not treated on trials, lived longer. They report that patients with cancer in clinical trials at the first course of therapy had a median survival of seven and half months more than those not enrolled in a trial.

According to Zaorsky, previous evaluations of whether clinical trials improved survival compared patients who were enrolled in trials against those not enrolled in trials -- but didn't account for factors like age, race, gender and cancer type.

The researchers performed a stratified analysis in which they matched each patient who participated in a clinical trial with another patient who was not enrolled in a trial that had ten similar characteristics -- including cancer type, age, race, insurance type, disease stage, and whether or not surgery or chemotherapy were part of the treatment plan.

"If you're going to evaluate whether clinical trial enrollment is beneficial for patients, you have to try and match each patient to someone who has a similar cancer and sociodemographic profile," Zaorsky said. "Otherwise, it is like comparing apples to oranges."

While the survival trend was evident across cancer types, the researchers said that this may not necessarily be true for the general population. In their analysis, they determined that the patients who enrolled in clinical trials at first course of therapy tended to be white males with private insurance, metastatic disease, who had no other chronic medical conditions and were treated at academic medical centers.

"If clinical trials are going to be used to determine standards of care for the general population, then the study participants need to be representative of the general population -- and this study shows that often this isn't the case," Gusani said.

According to Zaorsky, increasing patient enrollment in clinical trials cannot happen without first improving the infrastructure of clinical trial design and management. Patients may not live close to locations where clinical trials are offered. Even if they are in close proximity to a center offering clinical trials, the trials may not be for their type or stage of cancer.

Gusani suggests that the biggest barrier to clinical trial enrollment is the stigma around them. Patients may feel they are 'guinea pigs' in experiments and that they are receiving substandard care. In reality, trials emphasize patient safety at every stage and are carefully regulated and monitored by institutional review boards.

"The increased level of quality control in clinical trials may be beneficial for patients," Zaorsky said. "Patients who go onto a clinical trial must be treated per protocol, meaning that there are many quality measures that must be met, and that there are many other health care providers looking over the patient's care."

Allegedly, they should not exist in the brain, the so-called precapillary sphincters - a kind of squeezing 'muscle clamp' between the larger and smaller vessels of the bloodstream.

Nevertheless, Assistant Professor Søren Grubb from the Department of Neuroscience at the University of Copenhagen has indeed shown the sphincters in mice.

'In the early '10s, a Japanese review study concluded that there was no evidence that pre-capillary sphincters should exist in the heart, brain and muscular connective tissue,' he says and continues:

'Since then, scientists have focused a lot on pericytes - muscle cells that can regulate the resistance in the smallest blood vessels. At the same time, however, they have somehow missed a great resistance right between some arterioles and capillaries: The sphincters. Perhaps because the discovery of the pericytes has received more attention among all the blood vessels of the brain'.

Functions as a water faucet or a sluice system

As blood flows through the brain, it flows from arteriole to vein through the capillaries. The latter are the smallest blood vessels in the body, but incredibly important. It is here that the blood and the brain exchange oxygen and nutrients.

Søren Grubb explains that the precapillary sphincters may be compared to a kind of thermostat that distributes the pressure between the branches of the blood vessels. A bit like a faucet adjusting the pressure between a water pipe and a garden hose.

As the muscle clamp relaxes, more blood cells will flow through its passage and the pressure in the following blood vessels will increase. When the clamp contracts, a bottleneck forms, which lowers the pressure further down the blood flow.

'In this way, it also works a bit like a sluice system to irrigate fields: You may have a roaring river, but by diverting water from the river and making sluices that can regulate the amount of water for each field, you can distribute the water to many areas, says Søren Grubb.

'Conversely, if the sluice shuts down or is clogged, the field will quickly dry out', he adds.

Potential for dementia and migraine

Based on that picture, Søren Grubb assumes that the pre-capillary sphincters may play a major role for disturbances of the brain's blood supply and blood pressure.

If the assumption holds true, the discovery of the clamping muscles in the brain will potentially affect the treatment of diseases such as migraine, Alzheimer's and vascular dementia - all associated with an accumulation of waste products that may stem from blood vessel defects.

Already, the research group Lauritzen Lab, of which Søren Grubb is part, has tested a model for migraine with aura. The model confirms the hypothesis, but the Assistant Professor emphasises that further research is still needed in connection with disorders:

'We have shown that the precapillary sphincter is found in the brain. The rest is still speculative. But perhaps more researchers will start working on it, now that they know that the sphincters are there'.

Scientists at UCL have discovered how immune cells, essential for tackling life-threatening infections and cancers, are able to 'recycle' material within themselves in order to stay healthy and function, a breakthrough finding which could lead to more effective immunotherapies.

In the study, published in Cell Reports, researchers investigated how 'autophagy' - the natural physiological process of 'self-eating' which allows intracellular components, such as mitochondria, to be degraded and replaced - takes place in liver-based T cells.

T cells are a subset of lymphocytes (white blood cells) that play a key role in protecting against chronic liver infection and tumours.

Researchers discovered that T cells in the liver had an enhanced rate of autophagy and that this is enabled by the presence and action of a soluble messenger protein found in the liver: the cytokine 'interleukin-15' (IL-15).

This is the first study to identify that IL-15 can boost autophagy in human T cells and researchers believe this new understanding could enable emerging immunotherapies, such as CAR T cell therapy, to be positively manipulated to boost T cell health and survival.

Corresponding author, Dr Leo Swadling (UCL Infection & Immunity), said: "The liver is a common site for chronic viral infection and tumours and T cells play a key role in protecting against these.

"T cells living within the liver must adapt to the stressful microenvironment, with low levels of oxygen and an abundance of inhibitory signals, to find ways of maintaining prolonged survival and functionality.

"We discovered that a population of T cells able to live exclusively within the human liver can switch on autophagy to maintain nutrient supply and renew organelles like mitochondria to maintain their fitness. We could imprint this same adaptation on T cells taken from blood by exposing them to the cytokine IL-15."

The research team were assisted by surgeons and the Tissue Access for Patient Benefit project (TAPb) at The Royal Free Hospital, London, and gained rare access to live immune cells from human liver samples.

Several cutting-edge single cell technologies were used to compare autophagy in the T cells from these liver samples to T cells in the blood.

Lead author, Professor Mala Maini (UCL Infection & Immunity), said: "Understanding how human T cells are adapted for autophagy opens up the possibility of manipulating this dynamic process, which could enable a wide range of new and effective therapeutic possibilities.

"For instance, we can now investigate whether modulating autophagy rates can be used to improve emerging immunotherapies for cancer and chronic viral infection (such as TCR-redirected T cells and CAR T cells), where T cells must persist and function in diverse tumour and tissue microenvironments."

Quebec City, January 20, 2020--To better treat people with depression, not only must we treat the neurons affected by the disease, but we must also restore the integrity of the barrier that regulates exchanges between blood circulation and the brain. This is the conclusion of a study published today in PNAS by Université Laval researchers and their international collaborators.

"Between 30% and 50% of those suffering from depression respond either poorly or not at all to antidepressants," says main author Caroline Ménard, professor at Université Laval's Faculty of Medicine and researcher at the Cervo Brain Research Centre. "This suggests that biological mechanisms other than those directly affecting neurons are at play," adds professor Ménard, who also holds the Sentinel North Research Chair on the Neurobiology of Stress and Resiliency.

Caroline Ménard and her colleagues showed in 2017 that the appearance of depressive symptoms in mice subjected to social stress was linked to increased permeability of the blood-brain barrier. They also discovered that this permeability is due to a decrease in a protein called claudin-5.

"In the study published today, we wanted to find out what causes the decrease in claudin-5 in mice under social stress and why some mice are resilient to social stress while others exhibit depressive symptoms," explains Professor Ménard.

The researchers examined blood-brain barrier cells in depressed stressed mice, resilient stressed mice, and control mice. Their observations show that the epigenetic processes that allow the expression of the claudin-5 gene are more readily activated in resilient mice. They also observed that the resilient mice produce less of one of the proteins that inhibit expression of the claudin-5 gene.

Conversely, depressed stressed mice express more of an enzyme called HDAC1 that triggers a loss of claudin-5. "When a chemical compound is used to block HDAC1, the depressive mice produce more claudin-5 and their social interactions spontaneously increase," says Professor Ménard.

Thanks to the Douglas Bell Canada Brain Bank, the researchers were able to verify whether the same mechanisms were present in humans. "We found that expression of HDAC1 was greater in depressed people without treatment at the time of death than in subjects who were taking antidepressants or in the control group. This increase correlated with a decrease in claudin-5."

These results suggest that efforts to develop better treatments for depression should not be limited to finding new molecules that target affected neurons. Researchers must also find a way to close the gaps in the blood-brain barrier to ensure its proper functioning. "For now, we don't know of any molecules that increase the expression of claudin-5 and would allow us to directly restore the barrier's impermeability," adds Professor Ménard. "Our future work will focus on evaluating the effect of different pharmacological approaches and lifestyle habits on the integrity of this barrier in order to promote resilience."

Cross-linked polymers are structures where large molecular chains are linked together, allowing exceptional mechanical properties and chemical resistance to the final product. However, their modification is not easy. Now, scientists at Tokyo Institute of Technology develop a method that allows the fusion of different polymers together easily, allowing the precise tuning of the properties of the final material by selecting appropriate base polymers and mixing them at the right proportion.

Polymers, large molecular chains composed of small repeating subunits, can be found all around us and also within us. DNA and proteins are some familiar natural polymers. In contrast, synthetic polymers, such as plastics, were first produced about a century ago, but have since then found their way into our everyday lives because of their amazing properties. Polymers can be tailored according to their constituent subunits to confer them with many desirable characteristics, such as mechanical strength, stretchability, permeability, and so on.

Another way to obtain even more functionalities in polymers is by cross-linking them. Cross-linked polymers (CPLs) are polymers that are linked together using special cross-linker molecules. Certain CPLs exhibit outstanding properties due to their interlocked tridimensional structures. Motivated by the potential applications, a research team from Tokyo Institute of Technology (Tokyo Tech) led by Professor Hideyuki Otsuka has recently achieved a breakthrough in this field: they managed to cross-link different CPLs together through an unprecedented approach. "The development of a novel method to fuse different CPLs would bring a revolution in the field, as their mechanical properties can be easily and systematically tuned in an operationally simple process," explains Otsuka.

The researchers achieved this feat by switching things up in the cross-linker molecule they used. For a CPL to have self-healing capabilities, which is very attractive for many applications, the polymers have to be joined by what is known as dynamic covalent bonds. These bonds also allow for fusing different types of CPLs, but the carbon molecules used in currently available linkers are prone to oxidizing, which complicates the fusion and processing of CPLs in bulk. What this research team did was employ a linker molecule, called BiTEMPS, that cross-links polymers through a central sulfur-sulfur (S-S) covalent bond. This bond can be temporarily cleaved in half at temperatures higher than 80°C, which allows for exchange among different polymer at the free ends, called TEMPS radicals (see Figure 1). Through this cleaving and re-joining process, different CPLs can be fused together. One of the main advantages of the TEMPS radicals is that they are highly stable against oxygen, meaning that all the processing can be done without requiring oxygen care.

To prove the usefulness of their approach, the researchers cross-linked two types of CPLs, one of them much more elastic than the other. By hot-pressing their mixture, they managed to fuse the CPLs together, and the mechanical properties of the final material were dependent on the ratio of the raw CPLs used. "The mechanical properties of the fused samples could be widely tuned to make them as soft and elastic as desired. As the variety of available polymers is almost infinite, it should be possible to generate materials that exhibit a broad spectrum of physical properties using our method by judiciously choosing appropriate polymer compositions and mixing ratios," concludes Otsuka. This innovative method will significantly advance the field of CPLs, allowing for the development of highly tailored materials for specialized applications.

Camas, a seed-producing forb, grows in prairie and wetland habitats in the Pacific Northwest (PNW) and carries profound prehistoric and current significance as a food resource and article of commerce among indigenous cultures of the PNW. The forb once flourished among the region but decreased in population after the conversion to modern forms of agricultural production.

The establishment of new camas populations in prairie and wetland restoration sites in the PNW has become challenging, though. According to plant pathologist Gretchen Freed, camas populations are readily established when grown in a monoculture setting for seed increase and bulb production at the nursery.

"Camas is a keystone component of native plant restoration efforts in ephemeral wetland and prairie ecosystems in the PNW," says Freed. "Fungal communities associated with camas seeds may provide inoculum for colonization of seedling tissues to support the establishment of camas populations in diverse plant communities. Yet little is known about the composition of the fungal communities associated with camas."

"Seeds likely harbor communities that co-occur with camas plants and facilitate the annual growth cycle of plant tissues and the decomposition of plant debris in the soil," says Freed. "Seed taxa may influence the local adaptation of camas seedlings to new wetland environments."

To learn more, Freed and colleagues conducted the first comprehensive study of above- and below-ground fungal communities associated with camas using samples from wetland habitats in Oregon, Idaho, and a home garden plot in Washington. They found that the local environment of each sampled camas population had a significant impact on above-ground fungal community diversity. However, the below-ground fungal communities detected in plant tissues and closely associated soils are similar among the camas sampled in the wetland habitats.

Additionally, they found that camas plant roots may be preferentially colonized by endophytic fungi recruited from nearby soil communities suggesting that plants limit complexity of fungal communities.

The discovery of the diversity among fungal taxa present in the different types of tissues from a native plant that grows for many years is a unique opportunity to explore the endophytes that promote plant population longevity within diverse plant communities.

"What surprised us the most was the number of endophytic fungal taxa that are present among the camas seeds, roots, rhizospheres, and leaves. It is curious whether these taxa may be required for the establishment of camas populations."

This information may help native prairie and wetland restoration scientists restore camas populations in the PNW.