Culture

A war between India and Pakistan using less than 1 percent of nuclear weapons worldwide could lead to the worst global food losses in modern history, according to a Rutgers co-authored study that is the first of its kind.

Sudden global cooling from a limited nuclear war along with less precipitation and sunlight "could disrupt food production and trade worldwide for about a decade - more than the impact from anthropogenic climate change by late (21st) century," the study says.

While the impacts of global warming on agricultural productivity have been studied extensively, the implications of sudden cooling for global crop growth are little understood, notes the study in the journal Proceedings of the National Academy of Sciences.

"Our results add to the reasons that nuclear weapons must be eliminated because if they exist, they can be used with tragic consequences for the world," said co-author Alan Robock, a Distinguished Professor in the Department of Environmental Sciences in the School of Environmental and Biological Sciences at Rutgers University-New Brunswick. "As horrible as the direct effects of nuclear weapons would be, more people could die outside the target areas due to famine."

Robock co-authored a recent study in the journal Science Advances estimating that more than 100 million people could die immediately if India and Pakistan wage a nuclear war, followed by global mass starvation. The study focused on a war scenario that could occur between the neighboring nations in 2025, when they could have a combined 400 to 500 nuclear weapons.

For the new study, scientists used a scenario of 5 million tons of black smoke (soot) from massive fires injected into the upper atmosphere that could result from using only 100 nuclear weapons. That would cool the Earth by 1.8 degrees Celsius (3.2 degrees Fahrenheit) and lead to 8 percent lower precipitation and less sunlight for at least five years.

Scientists included those climate changes in computer simulations by six different crop models for four major crops that account for 90 percent of global cereal production in terms of calories. The scientists found that corn calorie production would fall by 13 percent, wheat by 11 percent, rice by 3 percent and soybeans by 17 percent over five years. Total first-year losses of 12 percent would be four times larger than any food shortage in history, such as those caused by historic droughts and volcanic eruptions.

Analyses of food trade networks show that domestic reserves and global trade can largely buffer the loss of food production in the first year. But multiyear losses would reduce domestic food availability, especially in food-insecure countries.

By year five, corn and wheat availability would decrease by 13 percent globally and by more than 20 percent in 71 countries with a total of 1.3 billion people. Corn production in the United States and Canada - representing more than 40 percent of global production - would drop by 17.5 percent.

Robock said the scenario with 5 million tons of smoke was developed more than a decade ago. Scientists now think that 16 million tons of smoke could arise from a nuclear war between India and Pakistan since they now have more and bigger weapons and their potential targets are larger. This means the impacts could be three-fold larger.

Next steps include analyzing the impacts of more scenarios, including those generating more smoke. Scientists also want to study the economic impacts in greater detail, including food hoarding by countries and refusals to trade it. They will also look into other impacts of nuclear war, using more models and studying more crops, extreme cold snaps and greater fluctuations in ultraviolet light.

Scientists at Nanyang Technological University, Singapore (NTU Singapore), Massachusetts Institute of Technology (MIT), and Brown University have developed new approaches that significantly improve the accuracy of an important material testing technique by harnessing the power of machine learning.

Nano-indentation - the process of poking a sample of a material with a sharp needle-like tip to see how the material responds by deforming - is important in many manufacturing applications, but its poor accuracy in obtaining certain key mechanical properties of a material, has prevented it from being used widely in industry.

Using the standard nano-indentation process and feeding its experimentally-measured data to a neural network machine learning system, the scientists developed and 'trained' the system to predict samples' yield strength 20 times more accurately than existing methods.

The new analytical technique could reduce the need for time-consuming and costly computer simulations, to ensure that manufactured parts used in structural applications such as airplanes and automobiles, and those made from digital manufacturing techniques such as 3D printing are safe to use in real-life conditions.

The senior corresponding author of this paper, NTU Distinguished University Professor Subra Suresh, who is also the university president, said: "By incorporating the latest advances in machine learning with nano-indentation, we have shown that it is possible to improve the precision of the estimates of material properties by as much as 20 times. We have also validated this system's predictive capability and accuracy enhancement on conventionally manufactured aluminum alloys and 3D-printed titanium alloys. This points to our method's potential for digital manufacturing applications in Industry 4.0, especially in areas such as 3D-printing."

The findings will be published in the Proceedings of the National Academy of Sciences of the United States of America this week.

Material benefits from a hybrid approach

The method, developed by the team of researchers from NTU, MIT, and Brown, is a hybrid approach that combines machine learning with state-of-the-art nano-indentation techniques (See illustration in the Note to Editors).

The process first starts with pressing a hard tip - typically made of a material like diamond - into the sample material at a controlled rate with precisely calibrated force, while constantly measuring the penetration depth of the tip into the material being deformed.

The challenge arises because the process of decoding the resulting experimentally-measured data is extremely complex and is currently preventing the widespread use of the nano-indentation testing technique, in the manufacturing of aircraft and automobiles, according to NTU Professor Upadrasta Ramamurty, who holds the President's Chair in Mechanical and Aerospace Engineering and Materials Science and Engineering at NTU.

To improve accuracy in such situations, the NTU-MIT-Brown team developed an advanced neural network - a computing system modelled loosely on the human brain - and 'trained' it with a combination of real experimental data and computer-generated data. Their "multi-fidelity" approach real experimental data as well as physics-based and computationally simulated "synthetic" data (from both two-dimensional and three-dimensional computer simulations) with deep learning algorithms.

MIT principal research scientist and NTU Visiting Professor Ming Dao said that previous attempts at using machine learning to analyse material properties mostly involved the use of "synthetic" data generated by the computer under unrealistically perfect conditions - for instance where the shape of the indenter tip is perfectly sharp, and the motion of the indenter is perfectly smooth. The measurements predicted by machine learning were inaccurate as a result.

Training the neural network initially with synthetic data, then incorporating a relatively small number of real experimental data points, however, can substantially improve the accuracy of the results, the team found.

They also report that the training with synthetic data can be done ahead of time, with a small number of real experimental results to be added for calibration when it comes to evaluating the properties of actual materials.

Prof Suresh said: "The use of real experimental data points helps to compensate for the ideal world that is assumed in the synthetic data. By using a good mix of data points from the idealised and real-world, the end result is drastically reduced error."

In addition to Prof Subra Suresh, Prof Ming Dao and Prof Upadrasta Ramamurty, the list of authors include graduate student Punit Kumar from NTU, and Prof George Em Karniadakis and graduate student, Lu Lu, from Brown University.

A powerful Monash Biomedicine Discovery Institute (BDI) collaboration has revealed that a bacterial superbug can prevent stem cells in the gut from carrying out their vital role of regenerating the inner lining of the intestine. This causes potentially severe disease, particularly in the elderly.

The research found that Clostridioides difficile infection, the most common cause of hospital-acquired diarrhoea, damages colonic stem cells via a toxin called TcdB, impairing tissue repair in the gut and recovery from disease. This understanding may now lead to new treatments or prevention methods.

C. difficile is responsible for more than half of all hospital infections related to the intestine and more than 90 per cent of mortalities resulting from these infections.

It grows after antibiotic treatment is administered to a patient, where it can upset the host-microbial balance in the gut allowing the bacterium to colonise.

The superbug can be transmitted from animals to humans and vice-versa and is now being uncovered in patients who have not had a recent hospital visit or taken a recent course of antibiotics. Instances have also been seen in a younger demographic than previously recorded.

The findings could have wider implications for those going through treatments for cancer such as chemotherapy and radiation therapy that also damage the gut.

The study, published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) today, was led by senior authors Professor Dena Lyras, an expert in infectious diseases, and Professor Helen Abud, an expert in stem cell biology, in conjunction with US collaborator Professor Borden Lacy from Vanderbilt University Medical Center in Nashville, Tennessee, who specialises in the structure of toxins. Joint first authors were Dr Steven Mileto (Lyras lab) and Dr Thierry Jardé (Abud lab).

"Our study provides the first direct evidence that a microbial infection alters the functional capacity of gut stem cells," Professor Abud said.

"It adds a layer of understanding about how the gut repairs after infection and why this superbug can cause the severe damage that it does. The reason it's important to have that understanding is that we're rapidly running out of antibiotics - we need to find other ways to prevent and treat these infections," she said.

"It shows that the toxins C. difficile makes are very important - TcdB targets the stem cells and damages them directly" Professor Lyras said.

"As a consequence the gut can't be repaired. So where it normally takes five days to regenerate the gut lining, it can take more than two weeks. This can leave patients (particularly people aged over 65 years and who are already debilitated) with pain, life-threatening diarrhoea and other serious conditions.

"By understanding this new mechanism of damage and repair, maybe we can find ways to prevent the damage happening or develop new treatments," Dr Jardé said.

The findings might also apply to other infections that behave in similar ways.

"There are a lot of different conditions that can make the gut more vulnerable - maybe there's a common way we can target them too instead of thinking in isolation about an infectious disease problem," said Dr Mileto.

The work was funded by a joint National Health and Medical Research Council project grant gained by the two senior Monash BDI investigators. Professor Lyras was also supported by the Australian Research Council.

While concerns loom over an impending recession caused by the spread of COVID-19, policymakers and business leaders have implemented radical strategies, such as slashing interest rates to invigorate the U.S.'s weakened economy. Research and Development (R&D) has long been key in the nation's economic prospects and according to new research from the University of California San Diego, the country's ability to maintain its competitive edge in this area largely depends on managers in R&D being less averse to risk.

R&D is important for the success of companies and is essential in boosting economic growth; however, it is generally an expensive and complex undertaking. For example, the decline in new drugs and breakthrough therapeutics--despite increased R&D spending--has been attributed in part to a lack of risk-taking by pharmaceutical and biotech companies. This has been cause for concern among research and investor communities, who point to slowdowns of paradigm-shifting discoveries in the past quarter century.

According to the authors of a National Bureau of Economic Research (NBER) working paper, encouraging appropriate risk-taking is the key to successful R&D programs. However, their research shows that the required tolerance of failure in pursuit of reward is not a disposition that is equally shared across R&D managers, which is troublesome for the advancement of science.

The paper's co-author, Joshua Graff Zivin, a professor of economics with UC San Diego's School of Global Policy and Strategy gives an example of how the risky exploration of unproven scientific pathways led to the discovery of immunotherapy's now-heralded role in cancer treatment.

"When immunologist James Allison developed an antibody that he felt was ready for pharmaceutical development, biotech companies repeatedly turned him away after dismissing his ideas as too farfetched," Graff Zivin said. "However, he persevered and today, drugs based on his initial ideas are now poised to become among the most clinically and commercially successful cancer drugs on the market."

He added, outside-the-box decision-making can aid in the race to develop a vaccine to stop the spread of COVID-19.

Why firms should recruit R&D managers who have an "appetite for risk"

To understand how managers respond to risk when making R&D decisions, the researchers conducted a series of experiments with master's degree students in a program focused on the intersection of business and technology. Many of these students go on to work at investment firms or serve as managers making R&D decisions at companies in the health and technology sectors.

The nearly 200 MBA and Master of Finance participants from UC San Diego's Rady School of Management were asked to assume the role of a R&D director at a private company. In a tournament-style structure, students had to "bet" on their preferred research projects from a series of hypothetical proposals that had been judged and scored by an objective, outside science advisory panel. The proposals were scored on a scale of high-variance projects (i.e. with riskier outcomes) and low-variance projects (i.e. with more predicable outcomes).

The experiments provided financial rewards that disproportionately encouraged the choice of riskier projects. Despite this, participants routinely chose the low-variance investments, consistently showing a distaste for projects that had greater uncertainty.

In another experiment with the same group, students were randomly assigned a budget and were asked to invest in a simulated portfolio where again they had to choose between risky and non-risky projects to invest in. Much to the researchers' surprise, participants again consistently chose to invest in projects with the safest outcomes, especially among those with smaller budgets.

"Though our participants are trained and incentivized to take on more risk in exchange for more reward, they did not behave this way," Graff Zivin said. "Our study points to potential inefficiencies in the research investment process, and the results could help explain low rates of breakthrough innovation."

Who among the group were most comfortable with risk-taking enterprises? Of the subjects, 52 percent were classified as risk-averse, 36 percent were risk-neutral and 12 percent were risk-loving. They found that decision-makers who are risk-loving were most likely to fund breakthrough projects.

The authors concluded, "Our results showing that participants 'hard-wired' as risk-loving made better investment decisions indicates that firms aiming to encourage more innovation may want to include the risk preferences of those workers in charge of research and development as a factor in their hiring and promotion decisions."

Scientists have discovered a possible link between Parkinson's disease and a gene impacted by a neurotoxin found in blue-green algae.

University of Queensland scientist Dr Jacob Gratten said the findings increased the understanding of the environmental risk factors of Parkinson's disease.

"We looked for a link between Parkinson's and changes in the human genome that control how genes are turned on and off, because these changes can be influenced by the environment," Dr Gratten said.

"We found a gene, previously not known to be linked to Parkinson's, which displayed reduced activity in people with the disease.

"This same gene is known to be targeted by a blue-green algae neurotoxin."

Blue-green algae is found in inland waterways and poses a health risk to people, domestic animals and stock that come into contact with the toxic algal blooms.

The research team at MRI-UQ made the discovery in collaboration with Professor George Mellick at Griffith University and colleagues from New South Wales and New Zealand.

Their findings are the culmination of more than a decade of scientific effort.

Neurotoxins released by blue-green algae reduce activity of the gene identified in the study.

Researchers predict this will lead to higher oxidative stress levels in nerve cells associated with Parkinson's disease, which can lead to cell death.

Dr Gratten said that while the study does not provide a direct link with Parkinson's, blue-green algae had previously been associated with other neurodegenerative diseases such as motor neurone disease.

"This gives us confidence that we're moving in the right direction towards understanding the environmental causes of Parkinson's disease," Dr Gratten said.

UQ geneticist Professor Peter Visscher, from the the Institute for Molecular Bioscience, who co-led the study, said Parkinson's disease affects 1 in 100 people over 60-years-old and that figure is projected to double by 2040 as the population ages.

"This disease destroys lives and devastates families, so we're determined to unlock the mystery behind Parkinson's," Professor Visscher said.

"More work is needed to confirm our findings, and to explore other possible explanations for the link between this gene and Parkinson's disease, such as pesticides."

African swine fever (ASF) is a devastating infectious disease in swine and has been catastrophic for the global pig industry. In 2018, ASFV was transmitted to pigs in China and ten other Asian countries, which mauled heavily pig industry in these areas. The fact demonstrates that ASF is hard to be controlled by culling infected pigs alone in China, and the development and application of an efficacious vaccine is urgently needed. Different vaccine strategies for ASF have been evaluated in the past decades. Some gene-deleted attenuated ASFVs, but not Inactivated vaccines, DNA vaccines, subunit vaccines, and adenovirus-vectored vaccines, have shown potential as ASF vaccines, while it is not known if they could convert to more virulent strains during their replication in pigs. In the present study, Chen and his colleagues used the Chinese ASFV HLJ/18 as a backbone and generated a series of gene-deleted viruses (Figure 1), and demonstrated that HLJ/-18-7GD (genes encoding MGF505-1R, MGF505-2R, MGF505-3R, MGF360-12L, MGF360-13L, MGF360-14L, and CD2v deleted) is a safe and effective vaccine against ASFV.

The biggest concern with a live attenuated vaccine is whether the vaccine seed virus could convert to a virulent strain during replication in vaccinated animals. To evaluate the biosafety of HLJ/18-7GD, groups of SPF pigs were intramuscularly inoculated with 100 fold vaccine dose of HLJ/18-7GD and observed for 21 days. Blood samples were collected from the pigs on days 5, 10, and 15 p.i. and spleen and lymph nodes were collected from each pig euthanized on day 21 p.i. to detect viral DNA by qPCR. Viral DNA was not detected in any samples collected. All pigs survived without any ASF clinical signs during the three-week observation period. The authors blindly passed the viral DNA-negative blood of the HLJ/18-7GD-inoculated pigs for four more passages, but viral DNA was not detected in any samples collected from these pigs. To further investigate the replication of HLJ/18-7GD in pigs, 14 seven-week-old SPF pigs were inoculated with a limit dose (500 fold vaccine dose) of the virus, and two pigs were euthanized on days 2, 5, 8, 10, 12, 16, and 21 p.i., respectively. The blood and organs of these pigs were collected for viral DNA detection. Viral DNA was just detected in some lymph nodes of one or two pigs that were euthanized on days 5, 8, 10, 12, and 16 p.i.. The lymph nodes that had the highest viral DNA copies were homogenized and inoculated into four more pigs, and viral DNA was detected in two lymph nodes of one pig that was euthanized on day 10 p.i.. The virus was not detected in any subsequent pigs inoculated with the viral DNA-positive lymph node homogenates. These results indicate that, after intramuscular injection, the HLJ/18-7GD virus is only maintained for a short period in certain lymph nodes of pigs, and does not appear in the blood or any other organs of pigs; therefore, HLJ/18-7GD is highly unlikely to convert to a virulent strain during its replication in pigs.

Chen and his colleagues then evaluate the protective efficacy of HLJ/18-7GD in clean commercial pigs with intramuscular and oral challenge, respectively, as the oral route is how pigs are mainly infected with ASFV in nature. All of results demonstrated that HLJ/18-7GD provides similar protection in both farmed and SPF pigs. To evaluate the long-term protection of HLJ/18-7GD, a group of pigs were vaccinated once with 10 fold vaccine dose and challenged the pigs at 10 weeks post-vaccination. These results showed that the long-lasting immunity induced by a single dose of 10 fold vaccine dose of HLJ/18-7GD could provide solid protection against lethal ASFV challenge, which suggests that twice administrations of HLJ/18-7GD with the same high dose could protect pigs for their entire lives.

Chen and his colleagues also evaluated the safety of HLJ/18-7GD in pregnant sows, and found that all primiparous sows at different pregnant stages inoculated with 10 fold vaccine dose of HLJ/18-7GD remained healthy and delivered their piglets on the expected dates, indicating that inoculation with HLJ/18-7GD will not cause disease or abortion in pregnant sows or affect the health of the piglets.

The HLJ/18-7GD does not grow in any cell lines, which means that the vaccine must be produced in primary cells. HLJ/18-7GD grows well in porcine bone marrow cells (PBMs) and at least 200,000 doses of vaccine could be produced from PBMs derived from one piglet. Therefore, using these primary cells for large-scale production of HLJ/18-7GD is feasible and cost-effective.

These important results confidently presented the evidence that HLJ/18-7GD is safe and effective against ASFV, which will play an important role in the control of ASFV.

Tokyo, Japan - Scientists from Tokyo Metropolitan University have discovered that Drosophila flies lose long-term memory (LTM) of a traumatic event when kept in the dark, the first confirmation of environmental light playing a role in LTM maintenance. The team also identified the specific molecular mechanism responsible for this effect. LTMs are notoriously difficult to erase; this work may lead to novel treatments for sufferers of trauma, perhaps even the erasure of life-altering traumatic memories.

It is impossible to remember everything that happens to us in a day. But a particularly shocking event may be consolidated into our long-term memory (LTM), whereby new proteins are synthesized and the neuronal circuits in our brain are modified. Such memories may be devastating to a victim, potentially triggering post-traumatic stress disorder (PTSD). Yet physiologically speaking, keeping a memory is far from a trivial process; active maintenance is required to keep the changes, protecting against the constant cellular rearrangement and renewal of a living organism. Despite the importance of understanding how memory works in the brain, the mechanism by which this occurs is not yet understood and is a key topic for neuroscience today.

It is well known that light, particularly the cycle of night and day, plays an important role in regulating animal physiology. Examples include circadian rhythm, mood and cognition. But how about long-term memory? Thus, a team led by Prof. Takaomi Sakai from Tokyo Metropolitan University set out to study how light exposure affects the memory of diurnal Drosophila fruit flies. As an instance of long-term memory or trauma, they used the courtship conditioning paradigm, where male flies are exposed to female flies which have already mated. Mated females are known to be unreceptive and exert a stress on male flies which fail to mate. Once the experience is committed to long-term memory, they no longer attempt to court female flies, even when the females around them are unmated.

The team found that conditioned male flies kept in the dark for 2 days or more no longer showed any reluctance to mate, while those on a normal day-night cycle did. This clearly shows that environmental light somehow modified the retention of LTM. This was not due to lack of sleep; flies on a diurnal cycle were slightly sleep deprived to match with flies in the dark, with no effect on the results. Thus, they focused on a protein in the brain called the Pigment-dispersing factor (Pdf), known to be expressed in response to light. For the first time, they found that Pdf regulated the transcription of a protein called the cAMP response element-binding protein (CREB) in the mushroom bodies, a part of the brain of insects known to be implicated in memory and learning. Thus, they identified the specific molecular mechanism by which light affects the retention of long-term memory.

Traumatic experiences are very difficult to forget and can severely impair a victim's quality of life. But the team's discoveries show that these memories can, in fact, be significantly affected by environmental factors in living organisms. This opens up the exciting possibilities of new treatments for victims of trauma, perhaps even the ability to erase traumatic memories which prevent them from leading normal lives.

Protein aggregation and misfolding underpins several neurodegenerative diseases such as Huntingdon's and Alzheimer's. Proteins can also become aggregated or denatured under conditions of stress, such as extreme heat. A new study published March 12 in the open-access journal PLOS Biology by Kotaro Tsuboyama and Yukihide Tomari of The University of Tokyo, Japan, and colleagues reveals a newly discovered class of proteins in both humans and flies which protect vulnerable proteins from becoming aggregated or denatured in extreme heat and other stresses - a function previously only known in "extremophile" organisms such as heat-loving bacteria. The proteins, discovered through a serendipitous observation, may find applications in biotechnology and protection from neurodegenerative disease.

Proteins are molecular tools held in their active folded shape by weak attractions between amino acids. Heat can disrupt these attractions, changing protein shape and causing them to clump together. This also stops them from functioning. An entire class of proteins--the "molecular chaperones"--use cellular energy in the form of ATP to either refold or dispose of misfolded proteins. But for proteins in most organisms, temperatures close to the boiling point of water irreversibly destroy their structure.

In the course of their research on an entirely different question, while trying to purify a structurally unstable fly protein called Ago2, the authors found that liquid extracted by breaking open fly cells contained some factor that stabilized the protein. Unexpectedly, this stabilizing activity remained even after boiling this liquid and removing aggregated proteins; similar protein stabilization was caused by the boiled liquid from human cells. Further biochemical testing confirmed that proteins were responsible for the stabilizing effect.

Heat inactivates and aggregates proteins by exposing hydrophobic (oily) amino acids, which then clump back together. So the authors reasoned that any protein remaining soluble after boiling would be enriched in hydrophilic (water-loving) amino acids. They confirmed that hypothesis by analyzing the mix of proteins remaining in the boiled liquid. They then used bioinformatic approaches to identify hundreds of proteins in the human proteome with high proportions of hydrophilic amino acids and high levels of "intrinsically disordered regions," sequences known not to fold into specific shapes. That disorder, they reasoned, would likely allow the protein to drape around other proteins like a shield, protecting against misfolding. They dubbed these putative protectors "Hero" (HEat Resistant Obscure) proteins, with a nod to the Japanese word hero-hero, which means flimsy, loose, or flexible.

They studied six Hero proteins in more detail, and showed that each could protect a set of delicate proteins from physical stresses, including heat and organic solvents. In cultured human cells, Hero proteins reduced the misfolding and aggregation of both TDP-43 and huntingtin, which are thought to drive pathogenesis in ALS (Amyotrophic lateral sclerosis, also known as motor neurone disease) and Huntington's disease, respectively. In a fly model of ALS, Hero proteins reduced neuronal dysfunction caused by TDP-43, and in normal flies, Hero overexpression increased longevity.

"Unlike chaperones, Hero proteins don't appear to use any ATP, and probably act on the functional form of their client proteins and prevent them from lapsing into misfolded states," Tomari said. "Their ability to protect proteins from multiple kinds of denaturing stresses may be useful in biotechnology applications in the purification of proteins, and the fact that they can block pathogenic aggregates in neurodegenerative disease models may make them attractive candidates for therapeutic development."

Maternal obesity increases the risk for obesity and metabolic perturbations in their offspring, but what are the mechanisms? In a new study published March 12 in the open-access journal PLOS Biology, Sebastien Bouret of the French National Institute of Health and Medical Research (INSERM) in Lille, France, and colleagues show that a key step in the process is the triggering of stress in a complex membrane system within all cells called the endoplasmic reticulum (ER). That stress leads to critical changes in the development of the hypothalamus, a part of the brain that controls hunger, satiety, and metabolic rate.

The ER constitutes the largest network of membranes within a cell, and plays a central role in the synthesis of proteins and many other biological processes. In response to cellular stress, the ER activates the so-called "unfolded protein response," whose normal function is to restore the cellular balance, but whose prolonged activation has been linked to obesity-induced insulin resistance and type 2 diabetes in adults. Because of this link, and because maternal obesity has also been linked to abnormal development of the hypothalamus, the authors asked whether ER stress might be tied directly to obesity-driven hypothalamic changes.

Working in mice, they began by showing that maternal obesity led to increased body weight in male offspring, with an increase in food intake, reduced oxygen consumption, and impaired glucose tolerance (female offspring were not affected, for reasons that remain to be explored). These changes were accompanied by ER stress in several tissues, including the arcuate nucleus of the hypothalamus, a key site for metabolic regulation. One known mechanism for that regulation is through signaling by the hormone leptin; leptin inhibits hunger, and maternal obesity is known to increase resistance to its effects.

The authors showed that all these changes could be mitigated by treating offspring with the naturally occurring bile acid tauroursodeoxycholic acid (TUDCA), which is known to promote refolding of proteins and alleviate ER stress. When the mice pups of obese mothers received TUDCA, neuronal development within their arcuate nucleus was normalized, leptin signaling was restored, and the alterations in body weight, glucose tolerance, and most other physiologic measures were reversed.

"Obesity is a complex phenomenon that likely has multiple drivers but the relative importance of maternal obesity-induced ER stress in promoting offspring obesity was not known," Bouret said. "The results from this study suggest it does play an important role by disrupting the development of brain pathways that control appetite" he adds. "Interestingly, TUDCA has been approved in the United States and Europe to treat specific liver and neurodegenerative disorders, raising the possibility that the clinical use of this ER stress-relieving drug could be expanded to treatment of childhood obesity, which now affects more than 40 million children worldwide."

Tuberculosis still represents the infectious disease with the highest fatality numbers. It is caused by mycobacteria, which mainly attack the lungs but can also affect almost any other organ. The fatty acid biosynthetic factory is an important target in the fight against this infectious bacterium. The fatty acid synthase (FAS) is considered one of the most complex cellular machines. The team led by Holger Stark and Ashwin Chari of the Max Planck Institute for Biophysical Chemistry has now discovered a protein that commands and controls FAS function. This finding not only opens up new therapeutic venues, particularly against tuberculosis. In biotechnological applications this new control unit enables the generation of tailor-made fatty acid synthases and specialized products that could only be synthesized from crude oil. This opens the prospects in 'green biotechnology'.

Fatty acid factories are indispensable for living organisms - as are the fatty acids they produce, which are often frowned upon as fatteners. Fatty acids serve as energy stores, building blocks for biological membranes, or cellular messenger substances. In yeast and higher organisms, FAS forms a higher order structure of several enzymes. In bacteria, isolated enzymes perform the same tasks. Although FAS architecture is considerably divergent in different organisms, the enzymes involved in fatty acid production are structurally very similar.

This is especially true for FAS enzymes from yeast, fungi and tuberculosis infectious mycobacteria. Therefore, findings on yeast FAS can be directly transferred to the bacterial fatty acid factory: If mycobacterial FAS are specifically inhibited, the pathogen's proliferation can be stopped - and this without affecting the fatty acid factory in human cells, since the two differ sufficiently in their three-dimensional architecture.

Shuttle through the fatty acid factory

In yeast, the FAS has the shape of a barrel and consists of two domes with a total of six reaction chambers. Just like its human counterpart, it forms fatty acids, mainly palmitic acid, from different molecular groups in seven individual reaction steps. Each of these steps is catalyzed by its own enzyme at a different part of the fatty acid factory. Therefore, the fatty acids must be transported from one enzyme to the next within the FAS. This task is performed by a molecular shuttle, the so-called acyl carrier protein (ACP). "We were particularly interested in understanding how this shuttling mechanism through the intricate FAS reaction chamber labyrinth works," project leader Chari says.

It actually took six years of work and two doctoral theses to answer this question - the results came as a big surprise to the researchers. PhD student Kashish Singh remembers the moment of shock when presenting the first results to Ashwin Chari: "Ashwin immediately saw that our purified FAS contained an additional subunit." His colleague Benjamin Graf adds: "Our first thought was that the sample was contaminated and the whole effort was futile."

First regulator of fatty acid synthase

But Chari interpreted the results of his doctoral students differently: What if the building block is not an impurity at all, but a previously unknown, integral part of the FAS? After two more years of hard work, it was clear: The building block indeed belongs to the FAS. The researchers from Göttingen gave it the name gamma subunit. "With the harsher purification methods used so far, it probably was dissociated from the FAS, which probably explains how the gamma subunit was overlooked in the many decades of FAS research," Chari comments.

The next challenge for the PhD students was to solve the three-dimensional structures of the FAS with and without gamma subunit to elucidate the function of this component. To do this, Graf and Singh combined X-ray structure analyses with cryo-electron microscopy. "The lengthy experiments have paid off. We were able to prove that the gamma subunit is aids in the initial step of fatty acid production, the subunit resets the fatty acid factory to the starting position. From this state, fatty acid production can start and the gamma subunit defines the functional compartment within FAS. In doing so, it changes the FAS structure in such a way that the ACP shuttle's path is much shorter," explains Max Planck Director Stark.

Benefits for medicine and biotechnology

The understanding of FAS activity control is an important breakthrough in research into fatty acid synthase. "Our findings open up new possibilities to enzymatically modify FAS in yeasts or to develop novel active compounds in the future that inhibit the fatty acid biosynthetic factory in mycobacteria. This could make FAS an even better starting point in the fight against this infectious disease," Chari stresses. New therapeutic approaches are increasingly important because there is a growing number of resistant tuberculosis pathogens. According to the World Health Organisation (WHO), around nine million people worldwide are infected with tuberculosis every year, around 1.4 million die each year as a result of the disease.

The improved methods developed by the researchers in Göttingen could also lead to new insights into FAS function in human cells, which could possibly be used in the fight against cancer, which require a lot of energy for their rapid growth. Many tumor types have far more fatty acid biosynthetic factories for this purpose than normal body cells. Reducing their fatty acid production could also inhibit proliferation of cancer cells.

The researchers led by Stark and Chari see further important applications in biotechnology. Fatty acids are components of cosmetics, soaps, and flavorings, but they are also contained in active pharmaceutical ingredients and biofuels. For the researchers, there are chances to produce fatty acids more sustainably: "Up to now, the fatty acids required for this purpose have mainly been produced chemically from crude oil or extracted laboriously from oil-containing plants. Yeast cells with tailor-made fatty acid factories could produce fatty acids with the desired properties. These could replace fossil fuels in the future," reports Chari.

H2020 European Research Council, Agence Nationale de la Recherche, Israel Science Foundation, Alex Grass Center for Drug Design and Synthesis

Clinicians combat the drug resistances of some cancer types by using a combination of different drugs. To make this approach more effective, chemists have designed a chemical conjugate that can simultaneously attack several cellular targets using different modes of action. Such a single-drug therapy would increase the chances of killing all cancer cells, the authors state in the journal Angewandte Chemie.

The most frequently clinically applied chemotherapeutic drug is cisplatin, a metal complex based on the platinum(II) ion. The drug's mode of action is binding to the DNA in the tumor cells, where it distorts the DNA structure and ultimately triggers cell death. Other chemicals facilitate the interaction of cisplatin with DNA, and they are often combined with cisplatin for chemotherapy. The photodynamic therapy (PDT) approach, in contrast, relies on the activation of a metal complex by laser light. A reactive form of oxygen is formed, which interferes with cell metabolism, triggering cell death.

"In clinical protocols, each drug is administered separately and may not reach the tumor at the same time or at a fixed ratio," says Prof. Gilles Gasser from the Paris Sciences et Lettres (PSL) University in Paris, France, who is one of the leading authors of the study. His group, in collaboration with Prof. Dan Gibson's group from Hebrew University, Jerusalem, Israel, combined cisplatin, phenylbutyrate, which is a chemical enhancer for cisplatin, and a PDT drug, which is a metal complex based on ruthenium(II), into a single compound called Ru-Pt. The idea was that the three drugs in conjunction could travel the bloodstream intact and enter their target tumor cells, which would reduce side effects and the need to adjust the dosages.

The scientists have designed the phototherapeutic Ru(II) half of Ru-Pt so that it can be excited with laser light in the deep red section of the wavelength spectrum, which penetrates deeply in the biological tissue. The cisplatin and phenylbutyrate containing half of Ru-Pt was designed as a prodrug, which would be activated by cellular components inside the cell. Both therapeutic components were attached to each other by a molecular spacer. "The correct spacer length was critical to ensure that both drug compounds will not interfere with each other, but the molecule remains small, water-soluble, and able to travel across membranes," Gasser says.

The researchers added Ru-Pt to some normal and cancer cell lines and found that Ru-Pt was significantly more efficient in killing cancer cells than the single compounds Ru(II) and Pt(IV). The authors also reported that the irradiated samples had significantly higher tumor-killing rates, which means that the specific drug activation in tumor tissue is possible. And finally, Ru-Pt had a ten times higher efficiency for drug-resistant cell lines than the single reagents. These results demonstrate the high potential of multimodal drugs for developing more selective and effective drugs that have fewer side effects and allow for a simple handling for an effective cancer treatment.

Already considered a global epidemic, human obesity continues to be on the rise. According to the Centers for Disease Control, more than 40% of the U.S. population is considered obese.

The gamut of adverse health effects associated with obesity is broad, including such devastating illnesses as type 2 diabetes, coronary artery disease, stroke, sleep apnea and certain forms of cancer. Patients often suffer depression, loss of mobility, social isolation and inability to work.

With costs approaching $316 billion dollars annually in the U.S., understanding how to quell obesity will result not only in a healthier population, but could also help reduce runaway medical costs.

Despite the looming need to address obesity, the causes are not well understood. Researchers generally agree that genetic and gut microbiome composition and activity are important factors in determining who is obese and who isn't.

As interest and understanding of the human microbiome increases, researchers are increasingly looking to the gut for answers that can lead to new, more effective diagnostics and therapies.

The trillions of microbes in the human gut perform a vast range of critical functions in the body and have even been implicated in mood and behavior. Among microbes' critical responsibilities are the micro-management of nutrients in the food we digest - one of the reasons for their central role in the regulation of body weight.

In a new study, "Temporospatial shifts in the human gut microbiome and metabolome after gastric bypass surgery," recently published in npj Biofilms and Microbiomes, ASU researcher Zehra Esra Ilhan, ASU Biodesign professor Rosa Krajmalnik-Brown--and researchers from Mayo Clinic and Pacific Northwest National Laboratory, have taken another step in understanding how the gut changes after gastric bypass surgery (also known as Roux-en-Y gastric bypass surgery).

"Our findings highlight the importance of changes in mucosal and fecal microbiomes that are reflected on gut metabolism after surgery," said Ilhan. The microbial changes after surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes."

In addition to the expected weight reduction and improvement in obesity-related comorbidities after gastric bypass surgery, the researchers observed that the impact of surgery is not limited to fecal communities; mucosal communities are altered as well. Changes in the microbiome were linked to increased concentrations of branched-chain fatty acids (amino acid fermentation products) and an overall decrease in primary and secondary bile acid concentrations in fecal samples. Bile is an alkaline fluid that aids digestion.

"Previous bariatric surgery-microbiome studies in humans relied largely on fecal samples because sampling through the intestinal mucosal membrane requires an invasive procedure," said Ilhan, lead researcher for the study. At the time of the study, Ilhan was a doctoral student in Krajmalnik-Brown's lab. She is currently conducting research at INRAE-French National Institute for Agriculture, Food and Environment.

Bariatric surgery is an operation that causes people to lose weight by making changes to the digestive system. These changes are physiological and chemical and include gastric restriction, malabsorption, bile acid metabolism, and chemical signaling.

"The mucus membrane is a critically important site for host-microbe interactions. We understood that with fecal sampling, we had an underrepresented picture of how the mucosal communities actively interact with host immune system and epithelial cells," said Ilhan. (Epithelial cells are cells that line the surfaces of your body.)

Although gastric bypass surgery has been successful for many patients suffering from morbid obesity, it is a serious, invasive procedure that is not without risk and expense. In addition, some patients regain the weight they have lost, perhaps because they lack the favorable microbes necessary for permanent weight loss.

"Understanding the microbial behavior in the gut could potentially lead to a creating a probiotic that could replace surgery - or an improved indicator to identify the best candidates for surgery and sustained weight loss," said Krajmalnik-Brown.

In the longitudinal study, subjects provided fecal samples and rectal mucosal samples. The rectal mucosal samples were collected via un-sedated flexible sigmoidoscopy at baseline, and again at 12 months post-gastric bypass surgery. Researchers analyzed microbial DNA that was extracted from the fecal and mucosal samples. Fecal metabolites were analyzed using high-throughput metabolomics approaches.

A tell-tale indicator of pathology in obese patients has been found in the gut, where a markedly lower diversity of microbial communities is observed. A high diversity of gut microbes is essential to good health.

In 2009, Krajmalnik-Brown's research team showed for the first time that gastric bypass surgery produced profound changes in the composition of microbial communities in the gut. The gut flora of post-surgical gastric bypass patients showed a marked difference from obese and normal weight patients.

In a 2017 study, the team took another step by comparing how microbes and the metabolome (the metabolome is the total number of metabolites present within an organism, cell or tissue) change after gastric bypass surgery and lap band surgery.

The 2017 study demonstrated that gastric bypass surgery caused a dramatic reorganization of the gut, which increases microbial diversity. Changes in the gut microbiota related to lap band surgery (also known as laparoscopic adjustable gastric banding) were mild and accompanying weight loss was less pronounced. Earlier studies have demonstrated that fat is reduced and weight loss triggered when germ-free mice receive a fecal transplant from mice who had undergone gastric bypass surgery.

Krajmalnik-Brown's team is currently working on a project funded by the National Institutes of Health in which the main goal is to quantify the contribution of the microbiome to the host energy balance. This project is intended to move the field from associations to causality and help identify how microbes and metabolites can fight obesity.

Krajmalnik-Brown is a professor in the ASU School of Sustainable Engineering and Built Environment and faculty in the School of Life Sciences. At the Biodesign Institute, she practices as part of the Swette Center for Environmental Biotechnology.

Krajmalnik-Brown is also known for her research into the role of the microbiome in those with autistic spectrum disorder.

Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK090379

Nagoya University researchers and colleagues have revealed the nerve circuitry regulating the response of a tiny soil worm to changing temperatures. The findings, published in the journal Proceedings of the National Academy of Sciences, help clarify one way the nervous system translates external signals into behaviours.

One of the fundamental questions of neurobiology is: how does the brain determine if an external stimulus is good or bad? Animal behaviour depends on this ability. For example, the scent of a predator elicits a fear response, while the scent of a potential mate elicits mating behaviour.

The nematode Caenorhabditis elegans is about one millimetre long and lives in the soil, feeding on microbes. It is often used as a model organism for biological studies in diverse fields, such as development, neurobiology and aging.

Generally, a lab C. elegans will migrate towards a cooler temperature when placed in a warmer environment than the one it was cultivated in, and vice versa. Molecular neurobiologists Shunji Nakano and Ikue Mori of Nagoya University and colleagues wanted to understand the molecular and neurological underpinnings behind this behaviour.

Using genetic and imaging tools, the scientists found that a temperature-sensing nerve cell in the worms, called AFD, transmits signals that activate or inhibit its receiving nerve cell, called AIY.

The scientists exposed freely moving worms to either a good or bad external temperature stimulus. The first 'good' signal started below the worms' cultivation temperature and gradually warmed towards it. The other 'bad' signal started at the cultivation temperature and gradually warmed above it.

AFD was activated by both warming signals. But it then sent stimulating molecules to AIY in the case of the good signal, and inhibiting ones during the bad one. The result shows how the same nerve cell can send signals that convey opposite messages.

Genetic studies further revealed three specific genes, and the enzymes and proteins they encode, that are involved in this response: kin-4, mec-2, and dgk-1. "These three genes are evolutionarily conserved in mammals, including humans," says Nakano. "A similar mechanism thus might be present in the nervous systems of higher organisms."

The team next plans to identify other stimuli that elicit similar neuronal responses in C. elegans.

BEER-SHEVA, ISRAEL...March 13, 2020 - Although aquaculture in treated wastewater is practiced worldwide, there is scant scientific research concerning whether organic micropollutants are present at safe levels for consumption.

A new study in Aquaculture by researchers at Ben-Gurion University of the Negev has determined that organic micropollutants (OMPs) in the water - trace elements of heavy metals, pharmaceuticals and personal care products as well as pesticides, solvents, and detergents - result in minimal accumulation in fish. Additionally, the wastewater does not appear to affect other commercially important traits of fish.

"The presence of micropollutants in water can lead to toxic biological effects in fish including mutations, and feminization of male fish from being exposed to endocrine disrupting OMPs," says Prof. Dina Zilberg, a researcher in the BGU French Associates Institute for Agriculture and Biotechnology of Drylands, Jacob Blaustein Institutes for Desert Research.

Tertiary wastewater treatment (TTWW) is the third and final stage of the cleaning process that improves wastewater quality before it is reused, recycled or discharged to the environment. The treatment removes remaining inorganic compounds and substances, such as the nitrogen and phosphorus, but not the organic compounds.

In the laboratory study, juvenile Carp (Cyprinus carpio) were raised in 0%, 50% and 100% TTWW for five months. Seven out of 40 screened OMPs were detected in the water samples at least once. Out of the 19 analyzed OMPs in fish tissues, four were detected in exposed fish. Carbamazepine, an anticonvulsant and diclofenac, an anti-inflammatory, were detected in the muscle and liver of fish grown in 50% and 100% TTWW at measurable concentrations. Carbamazepine-epoxide and Benadryl (diphenhydramine) concentrations were below the limit of quantification (LOQ) in the muscle of the exposed fish, while diphenhydramine was detected above the LOQ level in two liver samples of fish grown in 100% TTWW.

"Based on the findings, TTWW can be successfully used for growing fish, and TTWW-grown fish met all the existing standards for heavy metals accumulation," Zilberg says. "However, further investigation on OMPs accumulation in different species of edible fish with different feeding habits is required to ensure public health when using TTWW for aquaculture."

Research conducted by the Royal Veterinary College (RVC), in collaboration with Max Planck Institute of Colloids and Interfaces and University College London (UCL), has found new insights into how a bone acts as an organ to regulate its shape and quantity to protect itself from breaking.

Bones can change their shape throughout our life by regulating bone formation and resorption processes, which is often a response to forces which press, pull and twist the skeleton during everyday movements and exercise. The purpose of this shaping is to limit any risk of fracture.

Straight vs. curved

Understanding that a bone's fracture resistance is based on engineering rules which would predict a completely straight shape to be optimal, the research team sought to understand why most of our bones are curved if the goal of these changes in shape is to prevent fracture. Whilst undertaking this study, the team knew that other important questions would likely also be answered, for instance, learning whether the beneficial effects of exercise on our skeletons might be long-lived.

Researchers from the Max Planck Institute of Colloids and Interfaces in collaboration with researchers from RVC and UCL used computational methods on 4D in vivo high-resolution micro-computed tomography to monitor shape changes in an entire bone over an extended period after highly controlled exposure to a known force. The team employed a novel approach to quantify 3D bone formation and resorption surfaces validated by conventional histology and how these relate to local stress in bone tissue caused by physiological force.

The research was undertaken to reveal the location and extent of force-related resorption and formation at the whole bone level and to determine if the changes are, as has been predicted for many years, rapidly reversible.

Curving process needs to be highly targeted

The results indicate that the bone's response to these forces varies along its length to make the bone more curved in most parts and that these shape changes are very long-lived. The researchers found that the curving process needed to be highly targeted; some short-term gains were rapidly lost through resorption, but others were preserved.

From precise mapping of the change over-time, researchers showed that the reversible and preserved bone changes were distinguishable on the basis that they initially targeted either local resorption or formation. It was a surprise to the team that the preserved increases in bone curvature operate independently of local stress levels.

Increased curvature engenders a built-in warning mechanism

The findings provide experimental evidence by which 'Harold Frost's long-held theoretical framework' can be adjusted with an added hierarchy based upon fracture resistance. While some benefits of exercise-related load will gradually disappear, others will be preferentially retained. They also indicate that increased curvature engenders a built-in warning mechanism predicting how best to respond to physiological forces in the future.

The changes in curvature do not compromise the strength, as increased quantity compensates for this beneficial change in bone shape. Hajar Razi, Postdoctoral Researcher at the Max Planck Institute of Colloids and Interfaces, explains: "We know for quite some time that bone adapts to mechanical forces, here in this study we show that, at the organ-level, this adaptation is non-linear with respect to the local mechanical stimuli. In fact, bone response to mechanical stimulation we observed implies an adaptation to a bigger goal: to achieve a larger bone curvature adjusted for load predictability."

This study implies that new 'intelligent' bone therapies, which interact with physiological forces to selectively preserve overall curvature to resist fracture, would be more desirable. Existing osteoporosis treatments do not currently target the bone regions that most dramatically contribute to bending strength; they instead have generalised anti-resorptive/pro-formative effects. Follow-up tracking of bone shape modifications after orthopaedic surgery may also be beneficial and a more long-term view should be taken to monitoring the effects of exercise on skeletal health.