Culture

An unprecedented genetic plasticity and a putative function of NA

"Influenza viruses have an inherent high mutation rate," explains Prof. Martin Schwemmle of the Medical Center - University of Freiburg and coordinator of this study. "We therefore first tested the bat flu virus' genetic stability to assess its natural mutational potential in cell culture". To their surprise, within a short period of time all isolated viruses acquired specific amino acid mutations in the viral hemagglutinin (HA) and a truncated neuraminidase (NA) surface glycoprotein. The scientists performed further experiments and showed that these amino acids changes in HA enabled an NA independent viral growth. "Using a variety of mutant viruses, we finally demonstrated that in the absence of a mutated HA, functional NA is required for viral spread". While the role of the mysterious NA protein has been unknown so far, the researchers found some evidence that its function could be to downregulate cellular MHC-II surface levels to subsequently allow efficient release of infectious viruses from infected host cells.

Potentially low risk for humans

Concerning the potential spill-over risk of the bat influenza virus to the human population, Prof. Schwemmle is cautiously optimistic as he says, "Ferrets are the best small animal model to study human pathogenicity and transmission of sialic acid dependent influenza A viruses. Assuming ferrets are also the appropriate model to study bat flu viruses that instead use MHC-II for cell entry, our study does not provide any indications that these viruses can cause or transmit disease to contact animals. Therefore, the results can be interpreted as that there iscurrently a low zoonotic potential. However, due to the genetic plasticity of these viruses any precise prediction is difficult".

Nevertheless, this work has raised several open questions that remain to be answered: first, is bat influenza virus NA downregulating MHC-II surface expression and, if so, what is the underlying mechanism? Second, is it possible that bat influenza virus HA proteins can gain affinity to novel cell entry receptors due to their flexibility to accommodate amino acid mutations in HA? "We are currently looking into these questions in greater detail," says Prof. Schwemmle.

All living organisms exist and function only in cooperation with an abundance of symbiotic microorganisms, and have developed together with them over the course of the earth's history. This central finding of modern life sciences has led researchers worldwide to analyse the highly complex interactions and long-term bonds of host organisms and microbes in ever greater detail. Gradually, they want to achieve a new functional understanding of biology and the development of life. In the analysis of the complex interactions within the so-called metaorganism, the unit consisting of a body and the totality of its microbial colonisation, in short the microbiome, scientists use techniques such as genome sequencing. These technologies make it possible to analyse genetic information from large quantities of biological sample material and, thanks to new high-throughput methods, quickly assign it to specific organisms and, in some cases, to possible functions.

Scientists from all working groups at Kiel University involved in the Collaborative Research Centre (CRC) 1182 "Origin and Function of Metaorganisms" have now compared various sequencing techniques in an extensive comparative study using various model organisms: On the one hand to assess their optimal areas of application, and on the other hand to identify possible similarities between different multicellular host organisms and their microbiomes. A surprising result of the study presented here is that organisms living on land generally have a significantly different microbiome than species living in water. The researchers interpret this as an indication that microorganisms may have played a key role in the evolutionary transition from purely aquatic life to life on land. The new research results were published last week in the renowned scientific journal Microbiome.

The microbiome and adaptation to terrestrial life

In the new study, the scientists of the CRC 1182 used the opportunity to compare the microbiomes of many different model organisms - from simple sponges to vertebrates, including humans. They examined sample material from the various subprojects of the collaborative research project for patterns in the composition of microbial communities and compared different methods of the two most important sequencing technologies. By chance, they came across an interesting observation: the microbiome of terrestrial organisms, regardless of their kinship relationships, differs significantly from those of aquatic organisms - in which all analytical techniques coincided. Terrestrial organisms have a lower diversity of microorganisms contained in their microbiome.

A possible explanation for the differences in the composition of the microbiome could be that former aquatic organisms were forced to acquire new microbial communities upon the colonisation of the land. The transition from water to land, which began about 500 million years ago, might have been dependent on a change in the microbiome. "Just as adaptation to life on land brought about gradual, but massive morphological changes, such changes apparently also took place in the terrestrial host-associated microbiome," says John Baines, Professor for Evolutionary Genomics at Kiel University. "In order to cope with the new environmental conditions, living organisms may have resorted to terrestrially adapted microbes to maintain their vital functions," Baines continues.

Choosing the right tool

In addition to these revealing findings on a possible influence of microbiota on the course of evolution, the new CRC 1182 study also provides an aid in choosing the appropriate analytical method for the investigation of a given microbial community. On the one hand, certain sequencing methods provide only a rough identity of the microorganisms present in a sample. These comparatively inexpensive methods - such as the so-called '16s rRNA gene amplicon' method - use individual marker genes from which it is possible to deduce the associated living organisms.

More complex methods such as the so-called 'metagenomic shotgun' sequencing make it possible to record and evaluate all the genetic information in a sample. For example, they can identify individual bacterial species within the microbiome and are also able to deduce microbial functions. In comparison, however, they are more cost-intensive, their informative value depends more on the specific field of application and they are therefore currently less standardised than simpler methods.

New insights into the course of evolution

In the future, the Kiel researchers, together with their international colleagues, want to understand more precisely what role microorganisms played in the transition from an aquatic to a terrestrial way of life over the course of earth's history. "There are many indications that symbiotic microorganisms have also played a role in major evolutionary transitions," stresses CRC 1182 spokesperson Professor Thomas Bosch. "It is therefore our goal to identify the specific evolutionary mechanisms that caused the diversification of the microbiome parallel to the colonization of the land," continues Bosch.

Duchenne muscular dystrophy (DMD) is a rare but devastating genetic disorder that causes muscle loss and physical impairments. Researchers at the University of Missouri School of Medicine have shown in a mouse study that the powerful gene editing technique known as CRISPR may provide the means for lifelong correction of the genetic mutation responsible for the disorder.

Children with DMD have a gene mutation that interrupts the production of a protein known as dystrophin. Without dystrophin, muscle cells become weaker and eventually die. Many children lose the ability to walk, and muscles essential for breathing and heart function ultimately stop working.

"Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model," said Dongsheng Duan, PhD, Margaret Proctor Mulligan Professor in Medical Research in the Department of Molecular Microbiology and Immunology at the MU School of Medicine and the senior author of the study. "However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells."

In collaboration with other MU colleagues and researchers from the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine and Duke University, Duan explored whether muscle stem cells from mice could be efficiently edited. The researchers first delivered the gene editing tools to normal mouse muscle through AAV9, a virus that was recently approved by the U.S. Food and Drug Administration to treat spinal muscular atrophy.

"We transplanted AAV9 treated muscle into an immune-deficient mouse," said Michael Nance, a MD-PhD program student in Duan's lab and the lead author of the paper. "The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene."

The researchers' reasoning was correct, as they found abundant edited cells in the regenerated muscle. They then tested if muscle stem cells in a mouse model of DMD could be edited with CRISPR. Similar to what they found in normal muscle, the stem cells in the diseased muscle were also edited. Cells regenerated from these edited cells successfully produced dystrophin.

"This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases," Duan said. "Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patient's life."

With more study, the researchers hope this stem cell-targeted CRISPR approach may one day lead to long-lasting therapies for children with DMD.

Fungicides are worldwide used in agriculture. Large amounts of applied fungicides leak into nearby surface waters. The effects of these substances on aquatic organisms are poorly understood and not specifically addressed in the EU regulatory frameworks with respect to the protection of surface waters. Scientists at the Leibniz-Institute of Freshwater Ecology and Inland Fisheries (IGB) have found that pollution by fungicides can have unforeseen but far-reaching consequences for the functioning of aquatic systems - like indirect effects on the development of algal blooms.

The researchers investigated whether fungicides regularly used in agriculture such as tebuconazole or azoxystrobin influence the growth of aquatic fungi. In water bodies, fungi act as decomposers, but also as pathogens or parasites of other aquatic organisms. The research team was able to show that fungicides at concentrations similar to those found in natural water bodies drastically decreased infection of cyanobacteria by parasitic fungi. Cyanobacteria - formerly called blue-green algae - often grow disproportionally, causing blooms that can be toxic to humans and animals. "By infecting cyanobacteria, parasitic fungi limit their growth and thus reduce the occurrence and intensity of toxic algal blooms," says IGB researcher Dr. Ramsy Agha, head of the study. "Whereas we usually perceive disease as a negative phenomenon, parasites are very important for the normal functioning of aquatic ecosystems and can - as in this case - also have positive effects. Pollution by fungicides can interfere with this natural process", the researcher adds.

The research team, together with colleagues from the University of Minho in Portugal, has already been able to show in other studies that fungicides have a negative effect on the growth of aquatic fungi. Like in the recent study, they investigated the interaction between parasitic fungi and their hosts in the presence of fungicides. For example, they showed that the infection of water fleas with yeast fungi decreased under commonly occurring fungicide concentrations in the lake water.

There are only rough estimates of the proportion of fungi in aquatic microbial communities in the various types of water. In some freshwaters they can probably account for up to 50 percent of microorganisms with cell nuclei. Fungi hold many important ecological roles in aquatic ecosystems; as decomposers of organic matter and as a part of the food chain. Regarding the latter, fungi are a food source for higher trophic levels.

Despite their importance, aquatic fungi are not specifically addressed in the EU regulatory frameworks. To protect the ecology of waters from adverse effects of plant protection products (PPP), a prospective risk assessment is conducted by the European Food Safety Authority (EFSA) prior to authorization of active ingredients and their formulated products. The EFSA guidance document (EFSA, 2013) requires toxicity data for three taxonomic groups: plants, invertebrates and a fish species, representing a simplified vision of aquatic food chains.

One reason for the disregard of aquatic fungi in risk assessments is the lack of standardized bioassays using aquatic fungi as test species. "As the cultivation and identification of aquatic fungi in scientific labs is continuously improving, risk evaluations should consider the impact of fungicides on aquatic fungi", says IGB researcher Prof. Dr. Justyna Wolinska, head of the working group Disease Evolutionary Ecology.

When it comes to feeding, corals have a few tricks up their sleeve. Most of their nutrients come from microscopic algae living inside of them, but if those algae aren't creating enough sustenance, corals can use their tentacles to grab and eat tiny prey swimming nearby.

A new study from researchers at the Woods Hole Oceanographic Institution (WHOI), the University of New Mexico, and Scripps Institution of Oceanography is revealing that more of corals' nutrients come from this sort of hunting than previously expected, information that may help predict the fate of coral reefs as global ocean temperatures rise. The study published Sept. 17, 2019, in the journal Functional Ecology.

"When you have a heat wave, corals start bleaching. Symbiotic algae, which live inside corals and provide them with most of their nutrients, are expelled from their body. If corals stay bleached for too long they basically starve to death," says Michael Fox, a postdoctoral scholar at WHOI and lead author on the paper. "But if a coral has the opportunity to eat a lot before it bleaches or while it is bleached, it can survive off its fat stores long enough to regain those symbionts when water temperatures cool off. If we can better understand when, where, or why corals are eating, we may be able to understand why they survive better in some places than others during future bleaching events."

Fox and his colleagues conducted their study from samples they collected at Palmyra Atoll, a remote US national wildlife refuge in the central Pacific Ocean. After bringing them back into the lab, the researchers removed the coral polyps from their skeletons, and then separated the coral animals and their symbiotic algae in a centrifuge. The team then extracted essential amino acids from the corals, their symbionts, and the tiny zooplankton that corals often eat.

"Essential amino acids are required for an animal to survive, but most corals can't make them. They have to get them from either their symbionts or something they just ate," says Fox. "But each of those sources make amino acids in different ways, which gives the molecules distinct chemical signatures."

Those signatures can be used to "fingerprint" the source of the amino acid, he adds. By measuring chemical differences in six individual amino acids, the researchers were able to determine how much of a coral's nutrition was coming from symbionts, or from captured prey. This new method for measuring coral nutrition allows scientists to estimate the contributions of different food sources to coral diets, providing a more accurate view of their nutrition than previous methods. The technique was co-developed by animal ecologist Seth Newsome of the University of New Mexico, who is also a co-author on the study.

"To my knowledge, this has never been done with corals before. It really changed our perspective," says Fox. "Our findings suggest that some corals are eating a lot more than we previously thought, which has big implications for reef survival during climate change. We've also learned that individual corals of the same species can have very different diets--this may be an important source of variation that we'll have to take into account to understand how corals will respond to future changes."

A group of scientists studying the ways plant-associated bacteria interact were surprised to find that strains predicted to be more sensitive to bacteria were able to coexist with aggressor strains.

"Our findings are not consistent with a 'winner-take-all' result," says Jeff Chang, a scientist based at Oregon State University, " and may cause researchers to think differently about bacterial behaviors that are generally assumed to be hostile and open new directions to pursue on the role of microbe-microbe interactions in plant-microbe interactions."

This work is an international joint effort between Academia Sinica (Erh-Min Lai and Chih-Horng Kuo) and Oregon State University (Jeff Chang) led by 1st author Chih-Feng Wu. They used members of plant pathogenic Agrobacterium tumefaciens to examine how a type VI secretion system (T6SS), which is common among bacteria and used to deliver toxins into competing bacteria, affects competition between plant-associated bacteria. They competed different strains of these pathogens against each other to determine if aggressor strains could outcompete strains predicted to be sensitive to T6SS attack.

As stated above, the results were varied--sometimes the researchers were able to measure a significant decrease in the growth of sensitive strains. In other instances, sensitive strains were able to coexist with aggressor strains.

"These findings were consistent with computational simulations that suggested parameters, such as the number of bacteria and how they are structured in an environment, which affect the probability in which two competing strains are physically interacting, can impact the aggressiveness of bacteria," Chang explains. "Our findings additionally suggest that the genetics of the competing strains and also the environment in which they are competing can also impact aggressiveness."

Since T6SS is present in ~25% bacterial genomes sequenced to date, this work provides a foundation for future study in identifying genetic factors beyond T6SS anti-bacterial weapons in determining the competition outcomes.

HERSHEY, PA - Can a computer be used to explain why an environmental toxin might lead to neurodegenerative disease? According to Penn State College of Medicine researchers, a computer generated-simulation allowed them to see how a toxin produced by algal blooms in saltwater might cause Amyotrophic Lateral Sclerosis (ALS).

The researchers investigated an environmental toxin called β-Methylamino-L-alanine (BMAA) that has been linked to significantly increased occurrence of sporadic ALS in populations with frequent dietary consumption of food sources containing high levels of BMAA -- including the Chamorro population of Guam where ALS incidence is approximately 100 times greater than other populations.

The toxin is produced by cyanobacteria, a blue-green algae, and can occur in marine ecosystems. According to the researchers, BMAA accumulates in sharks, shellfish and bottom feeders -- so populations relying mainly on these food sources may be at risk.

Elizabeth Proctor, assistant professor of neurosurgery, and Nikolay Dokholyan, professor of pharmacology, used a computer to investigate why exposure to the toxin may lead to the development of diseases like ALS.

According to the researchers, if BMAA becomes part of a protein called copper-zinc superoxide dismutase (SOD1), the protein may adopt a form that is toxic to neurons.

Proctor, who holds a doctorate in bioinformatics and computational biology, said the study may be a model for investigating non-genetic cases of ALS, which account for 90% of all diagnoses.

"Our results suggest a need for further investigation of SOD1 modification patterns in ALS patients," Proctor said. "If we can determine the molecular patterns of disease onset and progression, it may aid in the development of lifestyle and preventative interventions for sporadic ALS."

What eluded researchers was an explanation for why BMAA led to the development of ALS and other neurodegenerative diseases.

In their study, published in PLOS Computational Biology, Proctor and Dokholyan proposed that BMAA causes the protein SOD1 to fold into a form that is toxic to neurons.

Proteins are built using 20 amino acids according to specific "recipes" coded in DNA. Slight changes to the "ingredients" can result in proteins that aren't able to function the way they are supposed to. Proctor said if enough BMAA is present in a motor neuron that is building SOD1, it may be mistaken for the amino acid L-serine, which has similar properties.

According to the researchers, who used computer modeling to see what the protein would look like with BMAA instead of serine, this substitution critically alters the structure and stability of the protein.

More than 150 mutations of SOD1 have been associated with ALS, but the structural changes from those mutations aren't enough to affect the stability of the protein according to Nikolay Dokholyan, professor of pharmacology and co-author of the study.

"SOD1 has a higher level of stability compared to most normal proteins," said Dokholyan, who has a doctorate in physics. "Although many mutations in this protein are associated with ALS, the resulting changes to its structure are not strong enough to cause significant destabilization."

Serine, the amino acid that BMAA competes with, occurs ten times in the "recipe" for SOD1. The researchers tested their theory by substituting BMAA for serine in each of those ten occurrences using a computer program developed by Dokholyan. They observed that BMAA incorporation had detrimental effects to the structure and stability of the protein and caused it to fold, or adopt its shape, incorrectly.

According to the researchers, studying patterns of SOD1 modifications in patients may be useful in developing potential interventions for sporadic ALS. One example of a possible intervention is L-serine supplementation for people exposed to a high amount of BMAA.

Although the study suggestions a connection between two pieces of ALS evidence, Dokholyan says many molecular factors contribute to the presentation of symptoms that doctors see.

"A variety of gene mutations and external factors, like BMAA exposure, are associated with ALS," Dokholyan said. "If we can figure out one pattern out, it may give clues for how to unlock others."

Scientists have demonstrated a way for police to quickly and safely test whether a baggie or other package contains illegal drugs without having to handle any suspicious contents directly. The new technique can limit the risk of accidental exposure to fentanyl and other highly potent drugs that can be dangerous if a small amount is accidentally inhaled.

The proposed method involves swiping the outside of a baggie then analyzing the swipe for drugs in the same way that airport security officers swipe carry-on luggage to detect explosives. Researchers at the National Institute of Standards and Technology (NIST) and state forensic laboratories in Maryland and Vermont have demonstrated that this approach can reliably predict whether a package contains fentanyl, even if mixed with cocaine, heroin or other substances. Their research was published this week in Forensic Science International.

"What's needed is a fast and safe way to screen drug evidence so that it can be handled appropriately," said Ed Sisco, a research chemist at NIST and the lead author of the study. For instance, hazardous packages can be flagged so they are opened only under a laboratory fume hood.

The swipe method works because opening a bag contaminates its outside surface. "If you've ever opened a bag of flour, you know that some of it poofs into the air," said NIST co-author Elizabeth Robinson. "That's just the way lightweight powders behave."

Before fentanyl became a common street drug, police often field-tested evidence by scooping a bit of powder into a solution that would change color depending on what type of drug was present, if any. But many police departments now discourage or prohibit such "color tests" in the field for safety reasons. Instead, officers must send the suspected drugs to a crime lab, then wait for a result before getting a search warrant or making an arrest.

Amber Burns, manager of the Maryland State Police forensic chemistry lab and a co-author of the study, said that she gets a lot of rush requests, and each request currently requires a full work-up of the evidence. Her lab plans to install an instrument called a Direct Analysis in Real Time Mass Spectrometer (DART-MS) to do the quick screening, which should speed up the process considerably. "They just need to bring me the swipe, and they can be on their way in two minutes," she said.

Alternately, departments can purchase instruments that fit in a police vehicle. Wherever the screening is done, it provides only a preliminary identification. To bring a criminal case to court, a complete work-up using standard laboratory equipment would still be necessary.

To conduct this study, the NIST scientists teamed up with Burns and her counterpart at the Vermont Forensic Laboratory, Rebecca Mead, who was also an author of the study. When suspected drug evidence arrived at their labs, Burns and Mead swiped the outside of the packages. Most were plastic baggies, though they also included envelopes, tinfoil and pill bottles. The chemists also dissolved a small amount of the suspicious material in alcohol and put a drop of the resulting solution onto a second swipe for comparison. They then sent the pair of swipes to NIST for analysis.

The NIST authors received swipes from 191 suspicious packages, which they analyzed using DART-MS and another technique called liquid chromatography-mass spectrometry (LC/MS). Those swipes contained a panoply of contemporary street drugs, including several types of fentanyl as well as heroin, cocaine, methamphetamines, ketamine and others. Many of the cocaine and heroin samples were mixed with fentanyl. The swiped packages also contained plant material sprayed with synthetic cannabinoids, which are often marketed as K2 or Spice.

Two of the packages contained carfentanil, a super-potent form of fentanyl, sometimes used as a large animal tranquilizer, which can be particularly dangerous for police and first responders. Carfentanil is roughly 5,000 times as potent as heroin.

The authors found that swiping the outside of a package correctly predicted its contents 92% of the time. In cases involving fentanyl and other opioids, the outside of the package predicted the contents 100% of the time. In other words, if the goal is to flag fentanyl-containing packages for special handling, the technique worked every time.

The 8% of non-matches involved cases where several bags of different material were placed together by police into a single evidence bag, allowing for cross-contamination. Also, the technique did not work in most cases involving plant material in heat-sealed bags.

This swipe technique will do more than help police get faster answers when investigating drug crimes. It will also help at crime labs. At the Maryland lab, Burns said that upon receiving evidence they use color tests -- the same tests that officers once used in the field -- to quickly get an idea of what's in the bag so they can line up the right types of laboratory analysis. But those color tests don't detect many of the new designer drugs that make up an increasing fraction of the caseload.

The swipe test will work for this, however. "We plan to use this to optimize our whole workflow," Burns said.

When bidding in a competitive market, our brains use a special type of heuristic to adjust the price depending on the success of previous attempts to buy goods. Moreover, this learning mechanism involves not only the cerebral cortex, but the evolutionary ancient brain area of the striatum. This was the conclusion reached by neuroscientists from the HSE University and the Research Center of Neurology in a study that was published in the European Journal of Neuroscience.

The supply and demand of a certain product affects the price at which we are willing to buy or sell that product. Interestingly market competition influences the exchange of services and resources not only among humans, but among monkeys and even fish. However, the fundamental mechanisms by which we learn to set an appropriate price depending on changes in supply and demand have not yet been fully studied by scientists. In order to learn exactly which processes in our brain are activated when we agree to pay one price or another, scientists from the HSE Institute of Cognitive Neuroscience and the Centre for Neurology conducted a brainimaging experiment.

During the study, subjects participated in an economic game by playing the role of buyers in a double auction. In total, 27 people took part in the experiment. The game simulated three types of double auctions: in the first type, two sellers and one buyer traded in a market with a high supply of goods (with sellers competing); in the second type, one seller and one buyer bargained in a 'noncompetitive' market; and in the third type, two buys bid for a product with one seller in a market with high demand (with buyers competing). In all types of markets, the outcome of the transaction was determined by comparing the highest purchase price with the lowest sale price. During the game, brain activity of subjects (buyers only) was recorded using magnetic resonance imaging (MRI).

It turned out that when setting the price, a simple model-based algorithm was used: buyers increased or decreased the price depending on whether this amount was accepted or rejected by sellers at the previous stage of the game. So, if sellers at the previous stage rejected a certain price, then the player reduced it. Such a strategy is called directional learning. Unlike classical value-based reinforcement learning, directional learning presupposes the existence of a priori knowledge of the structure of the problem - this means that people automatically differentiate types of markets and ways to purposefully change prices in a specific market.

An MRI scan of the brain showed that a learning brain signal leading to a price change while bidding occurs in the striatum, an evolutionarily ancient part of the brain involved in the learning process. The results suggest that the brain automatically learn to adjust the price that we are willing to pay for the goods, depending on the behavior of other buyers and sellers.

In addition, the MRI showed that the activity of our parietal cortex encodes the current value of the goods, while the prefrontal cortex 'monitors' the level of competition between sellers and buyers and calculates the preferred price.

For the first time, this study provides insight into the brain mechanisms at work when we determine prices while bidding in competitive market conditions.

London, September 17, 2019 - According to a new study in the journal Heliyon, published by Elsevier, dysfunctional eating patterns and habits in overweight and obese adults can be triggered by early life experiences that are deeply rooted within patients' personality features. As a result, weight loss interventions like surgery and cognitive-behavior therapy might not be sufficient to guarantee long-term success. Cognitive psychologists used the Schema Therapy (ST) model to gain a deeper understanding of the emotional and psychological functioning of these individuals with a view towards developing more effective treatment options.

"While the biological and environmental causes of obesity are well known, psychological determinants that might indicate chronic predispositions are less clear," explained lead investigator Barbara Basile, PhD, Association of Cognitive Psychology (APC), School of Cognitive Psychotherapy (SPC), Rome, Italy. "The results of our study suggest that dysfunctional eating patterns and habits associated with overweight and obesity are deeply rooted within patients' personality features and current interventions are not enough to guarantee a long-lasting effect."

The key concepts within the ST approach include Early Maladaptive Schemas, Schema Modes and dysfunctional Coping strategies. All of these develop across the life span and originated in early childhood and adolescence, where emotional core needs, such as love and nurturance, safety, acceptance, autonomy, limits setting, etc., might not have been adequately satisfied by caregivers and significant others.

Using an ST framework, investigators assessed early maladaptive schema and coping modes in 75 normal, overweight, and obese patients. Overweight and obese adults reported more maladaptive schemas and dysfunctional coping strategies when compared to normal-weight individuals. Moreover, investigators found that stressors trigger shifts from one coping mode to another, some predictive of frequent binge and bulimic behaviors.

Maladaptive schemas encapsulate dysfunctional thoughts and behaviors and map out patterns of perception, emotion, and physical sensation rooted in early life experiences that subsequently shape individuals' beliefs about themselves and the world. The dysfunctional schemas observed in obesity are linked to coping mechanisms resulting in self-defeating thoughts and emotion-avoidant food attitudes and behaviors.

"Our findings highlight the role of the Insufficient Self-Control schema among overweight and obese individuals, which manifests as difficulties in tolerating distress and restraining impulses. We also documented that overeating and bingeing behaviors serve as self-soothing strategies that help individuals to cut off their feelings and quiet their internalized 'Punitive Parent'," noted Professor Basile.

Among study participants, overeating and bingeing behaviors served as self-soothing strategies when they experienced feelings of abandonment (the belief others will be unavailable or unpredictable in their support or connection); dependence/incompetence (the belief that one has failed, or will fail in important life areas of achievement); and subjugation (the belief that one must surrender control to others), as well as to quiet internalized Punitive Parent voices (inner dialogue that is self-blaming, punishing, and abusive that causes one to detach emotionally and reject help). Frequent bingeing was associated with belief patterns of abandonment, enmeshment (being excessively emotionally involved and connected with others at the expense of full individuation or normal social development); and failure (the belief that one always fails in important life areas of achievement) schemas, as well as by those who react impulsively with anger and frustration (Impulsive/Undisciplined Child) and by those with a Punitive Parent inner dialogue.

Professor Basile and her co-investigators believe that this deeper understanding of the emotional and psychological functioning of obese patients, recognizing the impact of early life experiences, might help clinicians promote the long-term efficacy of psychological interventions in overeating related pathologies.

Identifying each patient's unique maladaptive schema and modes is the first step of ST intervention. To help the patient deal with their future needs and emotions in a healthier way, treatment might also include:

Addressing and satisfying the frustrated core emotional needs, embedded in the vulnerable child mode, in a safe therapeutic relationship.
De-potentiating the punitive parental mode and its destructive messages.
Reducing dysfunctional coping mechanisms, such as the detached protector self-soothing.
Expanding the healthy adult mode.

"Addressing actual schema modes and the connected early experiences within a caring and solid clinical setting, such as the one used within ST practice, might be of particular value for obese patients," concluded Professor Basile.

CLEMSON, South Carolina - A Clemson University professor's research has documented the movement of antibiotic resistance in humans into animal species.

College of Science researcher Vincent Richards recently published results that draw attention to reverse zoonosis, or pathogens moving from human populations to animals.

Every year, tens of thousands of Americans get sick from a variety of diseases contracted from animals. Known as zoonotic diseases, these infections are transmitted through food, water or direct contact with the animals. They include salmonella, E. coli, anthrax and cat scratch disease, to name a few.

While the U.S. Centers for Disease Control and other health agencies keep tabs on animal-to-human diseases, there's a dearth of knowledge about reverse zoonosis.

According to Richards, humans have acquired antibiotic-resistant genes, most likely through the overuse and abuse of prescription antibiotic drugs.

"I found actual cases of transmission of these antibiotic resistance genes from humans into livestock, companion animals and wildlife," said Richards, who speculates that the genetic material was transmitted via animal handling or through wastewater runoff.

Richards reported these findings in an article titled "Population gene introgression and high genome plasticity for the zoonotic pathogen Streptococcus agalactiae," which was recently published in Molecular Biology and Evolution.

In the study, he and his collaborators analyzed a global set of 901 genome sequences of the bacteria Streptococcus agalactiae (also known as group B Strep) from nine different host species - humans, cows, dogs, fish, frogs, gray seals, dolphins, goats and a camel - to better understand the transmission process. Streptococcus agalactiae can cause life-threatening illnesses like meningitis, pneumonia and sepsis in newborn babies. In addition, the bacterium is a leading cause of bovine mastitis, an inflammatory disease that limits milk production in dairy cows.

"One of the things that makes the bacteria so interesting is its wide host range," said Richards, an assistant professor in the department of biological sciences. "It doesn't just infect humans and cows, it infects a whole range of terrestrial and aquatic mammals, reptiles and amphibians, and fish. It has quite the taxonomic range for a bacteria."

As part of the analysis, Richards grouped the genes into core and dispensable categories. Core genes are shared by all the genomes, while dispensable genes only appear in some species' genomes. Together, the core and dispensable genes make up the pan-genome (the entire gene set of all strains of a species).

In classifying the genes as either core or dispensable, Richards was surprised to discover that only about 10 percent of the pan-genome was core while 90 percent was dispensable.

Significantly, the study showed how high bacterial genome plasticity can produce an expansive and yet highly partitioned pan-genome, which in turn facilitates further expansion of the pan-genome. Plasticity allows bacteria to adapt their DNA quickly so they can survive changes in their environment. As the pan-genome expands, continued adaptation to a diverse landscape of niches produces multiple biochemically diverse and divergent populations.

This population expansion can cause directionally biased spillover, demonstrating how genes selected in one niche or host can ultimately be transmitted into another.

"You have genes that are adapted to a particular population now being transferred into another population," Richards said. "A particular gene for antibiotic resistance that was selected in human populations is now being transmitted into animal populations."

In the future, Richards hopes to apply the genomic methods utilized in this study to his group's research on related strep bacteria found in the human mouth. Specifically, he'd like to examine the role that certain metatabolic genes have in tooth decay in children.

If a company wants a leader who is committed to corporate social responsibility, it would be wise to hire a married man. Married men in the top leadership jobs typically have greater concern for their employees' well-being, and are more accepting of diverse employees, than are their non-married peers.

Those are the findings of a study led by the University of Connecticut and University of Saskatchewan and published in the Journal of Corporate Finance.

"What we found was absolutely fascinating,'' says Shantaram Hegde, professor of finance at UConn, who co-authored the paper with UConn alum Dev R. Mishra '01, professor of finance at University of Saskatchewan. "The social benefits of the union appear to be a significant driver of corporate policy.''

Family Life Broadens Perspective 

Researchers analyzed 2,163 U.S. public corporations, from 1993 to 2008. Organizations with married CEOs accounted for about 86% of the those studied. The average age of the CEOs in the sample was about 55, with roughly six years of tenure with the company.

Corporate social responsibility is broadly defined as a firm's commitment to minimizing potential harmful effects of its operations on its stakeholders and maximizing its long-run beneficial impact on society.

Firms led by married CEOs were associated with significantly higher scores on a respected corporate social responsibility index, even after controlling for a wide range of variables such as age, tenure, gender, wealth, compensation and risk propensity. The findings were particularly clear when studying issues surrounding diversity and employee relations.

"We were able to build on social-science studies that found that married life is a catalyst for nourishing pro-social values and preferences among family members,'' Hegde said.

While unmarried CEOs do not ignore corporate social responsibility codes and standards, and may raise concerns about compliance with norms and laws, they seem to show less commitment to other corporate social responsibility programs, the authors found.

Meanwhile, married CEOs appear to embrace corporate social responsibility.

In particular, organizations led by married CEOs are more likely to support hiring and promotion of women, minorities, and disabled employees, as well as advancing gay and lesbian policies, the researchers say. They also scored well in affirmative action, employee benefits, labor relations, employee health and retirement benefits, safety and well-being, profit sharing and stock ownership.

And, while the number of women in the study was small -- less than 2% -- it appears that both spouses in a family are likely to have adopted pro-social preferences after marriage.

Corporate Leadership Transitions Prove It

To further scrutinize the findings, the researchers reviewed companies that had transitioned to new CEOs with a different marital status from their predecessors. The dataset of 3,466 firms indicated notable changes in corporate social responsibility following the transition.

"We found a significant drop in average corporate social responsibility results when a company transitioned from a married to an unmarried CEO,'' Hegde said. "Although based on a small number of observations, this test further isolates the influence of CEO marriage transitions from other types of CEO turnover, and helps strengthen our claim about a robust link between CEO marriage and corporate social responsibility.''

In addition to the family-induced effect, officers who choose marriage might have innate pro-social preferences because they agreed to pursue the tradition of marriage. However, the database that the researchers used to confirm marital status of CEOs only recorded marriage between opposite genders; another study would be needed to look at the impact of same-sex marriage.

Although businesses today are seeking leaders who are committed to their shareholders, they are increasingly concerned about the social impact of their businesses, ranging from the environment to employee relations, Hegde said. The modern-day CEO must balance the demands of profit maximization with social obligations, he said.

The #metoo movement, highlighting the abuse and harassment of employees, is just one of the revelations that quickly revised the qualifications of a leader-in-chief, he said. A year ago, Time magazine reported that more than 400 high-profile executives were accused of misconduct, and at least half were fired or resigned.

"With this emphasis on employee relations and welfare, the environment and sustainability, it is critical to have the right type of leader in the executive suite,'' Hegde said. "The right CEO can not only solve many problems but also contribute to a better society.''

"Obviously a company cannot discriminate based on marital status, when hiring a CEO or anyone else,'' Hegde continued. "But if you take the best leadership talent and select an unmarried CEO, executives and board members might consider a custom training program to better equip the top leader with a stronger, socially responsible perspective.''

DALLAS - Sept. 17, 2019 - In work suggesting new therapeutic targets to fight obesity, UT Southwestern researchers have identified a novel mechanism that regulates the creation of fat in mammals.

"Obesity is a global health problem that represents a major risk for several chronic diseases, including Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular disease, stroke, and cancer," said Dr. Joshua Mendell, Professor of Molecular Biology at UT Southwestern and an Investigator in the prestigious Howard Hughes Medical Institute. Dr. Mendell is corresponding author of the study appearing online in the journal Genes & Development.

Illustration of fat cells

Illustration of fat cells. Researchers found that loss of a family of microRNAs results in a dramatic increase in fat formation. In addition, the overexpression of the miR-26 family of miRNAs strongly protects against weight gain in mice.

The molecular mechanisms that regulate how and where fat tissue builds up in the body - or doesn't - are key to understanding the development of obesity. However, the genes and molecular pathways that influence the size and number of fat cells in the body are not completely understood.

"We found that loss of a family of microRNAs results in a dramatic increase in fat formation. In addition, we showed that overexpression of the miR-26 family of miRNAs strongly protects against weight gain in mice fed a high fat diet," said Dr. Asha Acharya, an Instructor of Molecular Biology and lead author of the study.

The researchers further found that the miR-26 family controls the levels of a protein called FBXL19 that is important for new fat cell production. "This protein had not been linked to fat formation or obesity in the past, so this result was unexpected," Dr. Mendell said.

In mammals, including mice and humans, a diet loaded with calories - such as the high fat diet used in this study - can cause existing fat cells to expand. It can also result in the creation of new fat cells from a population of stem-like progenitor cells, he explained.

"Fat storage in adult mammals is a highly regulated process that involves mobilizing progenitor cells that differentiate into fat cells," said Dr. Mendell, a member of the Harold C. Simmons Comprehensive Cancer Center and the Hamon Center for Regenerative Science and Medicine at UTSW, as well as a CPRIT Scholar in Cancer Research.

A feature of obesity is the uncontrolled expansion of white fat tissue, which does more than store energy in times of caloric surplus. It also plays an important role in metabolic regulation by secreting signaling proteins and lipids that influence pathways controlling appetite, blood sugar balance, and immune responses.

While earlier studies indicated important roles for the miR-26 family as suppressors of cancer and regulators of insulin sensitivity, the broader functions of these miRNAs had remained a mystery. In part, that was due to the difficulty of knocking out, or removing, all three genes that produce miR-26 family members in mammals in order to study their functions.

To overcome this technical challenge, the researchers used the gene-editing technique called CRISPR/Cas9 to remove all miR-26-encoding genes from the mouse genome. They found that although mice lacking these miRNAs developed normally in early life, they had a two- to threefold increase in white fat tissue beginning in early adulthood, even while consuming a normal diet.

To further test the role of these miRNAs in regulating fat formation, the scientists used a different genetically engineered mouse line that produces excess miR-26. After being fed a high fat diet, normal mice exhibited dramatic weight gain and an increase in fat content to 40 percent of their overall body mass. Mice with increased miR-26, however, were strongly resistant to weight gain and, despite consuming an identical diet, produced very little additional fat. Mice with increased miR-26 also showed lower blood sugar and lipid levels compared with controls.

"This study reveals a new mechanism of controlling fat production in the body," Dr. Mendell said. "A deeper understanding of this mechanism could lead to new therapies to treat obesity, for example by revealing strategies to increase miR-26 activity or to inhibit the downstream targets of this microRNA."

DURHAM, N.C.-- Biomedical engineers at Duke University have developed a new platform to create biologic drugs using specially engineered bacteria that burst and release useful proteins when they sense that their capsule is becoming too crowded.

The platform relies on two main components: the engineered bacteria, called "swarmbots," that are programmed to sense the density of their peers within their container, and the biomaterial that confines the swarmbots, a porous capsule that can shrink in response to changes in the bacterial population. When it shrinks, the capsule squeezes out targeted proteins created by the captive bacteria.

This self-contained platform could make it easier for researchers to create, analyze and purify diverse biologics for use in small-scale biomanufacturing.

The research appeared online Sept. 16 in the journal Nature Chemical Biology.

Bacteria are commonly used to produce biologics, which are products like vaccines, gene therapies and proteins that are created or synthesized from biological sources. Currently, this process involves a series of sophisticated steps including cell culturing, protein isolation and protein purification, each of which requires delicate infrastructure to ensure efficiency and quality. For industrial operations, these steps are carried out on a large scale. While this helps produce large quantities of certain molecules, this setup is not flexible or financially viable when researchers need to produce small amounts of diverse biologics or work in resource-limited settings.

The new technology was developed by Lingchong You, a Professor of Biomedical Engineering at Duke University, and a former Duke postdoctoral researcher, Zhuojun Dai, now an Associate Professor at Shenzhen Institute of Advanced Technologies. In the new study, they show how their new platform uses communication between swarmbots and their capsule to achieve versatile production, analysis and purification of diverse proteins and protein complexes.

In an earlier proof of concept, You and his team engineered a non-pathogenic strain of E. coli bacteria to produce an antidote to antibiotics when the bacteria reached a certain density. These swarmbots were then confined to a capsule, which was bathed in antibiotics. If a bacterium left the capsule it was destroyed, but if it remained inside the container where the population density was high, it survived.

"Our first study essentially showed one-way communication, where the cells could sense the environment within the capsule but the environment didn't react to the cells," said You. "Now, we have two-way communication -- the engineered swarmbots can still sense their density and their confinement, but we have introduced a material that can respond when the bacterial population inside it changes. It's like the two components are talking to each other, and collectively they give you very dynamic behavior."

Once the population inside the capsule reaches a certain density, the bacteria start to 'pop,' releasing all of their cellular contents, including the protein product of interest. At the same time, this bacterial growth changes the chemical environment within the capsule, causing it to shrink. As it shrinks, it squeezes out the protein released from the bursting cells while the bacteria and cell debris are kept within the capsule.

Once the proteins are collected, researchers can add a nutrient replenishment to the dish as a cue for the capsules to enlarge. This resets the interior environment and allows the bacteria to begin growing again, restarting the process. According to You, this cycle can be repeated for up to a week.

To make the approach useful for biomanufacturing, the team added the capsules to a microfluidic chip, which included a chamber for them to detect and quantify which proteins were released. This could be replaced with a purification chamber to prepare the proteins for use in biologics.

"It's a very compact process. You don't need electricity, and you don't need a centrifuge to produce and isolate these proteins," said You. "It makes this a good platform for biomanufacturing. You have the ability to produce a certain type of medicine in a very compact format at a low cost, and it's easy to deliver. On top of that, this platform offers an easy way to produce multiple proteins simultaneously."

According to You, this ease of use has enabled the team to produce, quantify and purify more than 50 different proteins in collaboration with the lab of Ashutoshi Chilkoti, Alan L. Kaganov Professor and Chair of the Department of Biomedical Engineering at Duke. They have also explored how their platform can simplify the creation of protein complexes, which are structures made from multiple proteins.

On a proof-of-concept experiment to produce a fatty acid synthesis pathway from multiple enzymes, "we were able to use seven versions of our microbial swarmbots, each of which was programmed to produce a different enzyme," said You. "Usually, to produce a metabolic pathway you'd need to balance the supply chain, which could involve upregulating the expression of one enzyme and downregulating the expression of another. With our platform you don't need to do that, you just need to set the correct ratio of swarmbots."

"This technology is incredibly versatile," he said. "That's a capability we want to take advantage of."

Two years after discovering a way to neutralize a rogue protein linked to Alzheimer's disease, University of Alberta Distinguished University Professor and neurologist Jack Jhamandas has found a new piece of the Alzheimer's puzzle, bringing him closer to a treatment for the disease.

In a study published in Scientific Reports, Jhamandas and his team found two short peptides, or strings of amino acids, that when injected into mice with Alzheimer's disease daily for five weeks, significantly improved the mice's memory. The treatment also reduced some of the harmful physical changes in the brain that are associated with the disease.

"In the mice that received the drugs, we found less amyloid plaque buildup and a reduction in brain inflammation," said Jhamandas, who is also a member of the Neuroscience and Mental Health Institute.

"So this was very interesting and exciting because it showed us that not only was memory being improved in the mice, but signs of brain pathology in Alzheimer's disease were also greatly improved. That was a bit of a surprise for us."

This discovery builds on previous findings of a compound called AC253 that can block the toxic effects of a protein called amyloid beta, which is believed to be a major contributor to Alzheimer's because it is often found in large quantities in the brains of patients with the disease. AC253 blocks amyloid beta from attaching to certain receptors in brain cells--a process Jhamandas likens to plugging a keyhole.

However, while AC253 was shown to prevent a buildup of amyloid beta, it isn't very effective at reaching the brain and is quickly metabolized in the bloodstream. As a result, treatment using AC253 requires large amounts of the compound to be effective, which is impractical and increases the chances of the body developing an immune reaction to treatment. Transforming AC253 from an injectable drug into a pill would address the metabolism issues and increase efficacy, but AC253 was too complex to be able to make an effective oral drug.

Jhamandas' solution was to chop AC253 into pieces to see whether he could create smaller peptide strings that blocked amyloid beta in the same way AC253 did. Through a series of tests using mice genetically modified to carry Alzheimer's disease, Jhamandas' team found two shorter pieces of AC253 that replicated the preventative and restorative abilities of the larger peptide.

With the short peptides identified, Jhamandas and his team, which includes renowned virologists Lorne Tyrell and Michael Houghton, used a process of computer modelling and artificial intelligence to discover a small-molecule drug--similar to medications used to treat high blood pressure or cholesterol--it's now developing.

The team is focused on manufacturing an optimized and oral version of the drug so human clinical trials can begin, said Jhamandas, who added small-molecule drugs are preferable for treatments, particularly for drug companies, because they are cheaper to make, can be taken orally and can more easily reach the brain through the blood, said Jhamandas.

While Jhamandas is optimistic about the potential of his new drug to change the way Alzheimer's is managed, he is quick to point out the years of research he and other researchers have done to get to this point.

"This has been 15, 20 years of painstaking and incremental work," he said. "And it's like building a house: you put one brick down, then you put another brick on top of that, and pretty soon you have a foundation and then you have a house.

"Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I'm very excited that we are really on to something here."