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Researchers from the Moscow Institute of Physics and Technology have teamed up with colleagues in Russia and Saudi Arabia and proposed an efficient method for obtaining fundamental data necessary for understanding chemical and physical processes involving substances in the gaseous state. The proposed numerical protocol predicts the thermal effect of gas-phase formation of silver compounds and their absolute entropy. This includes first-ever such data for over 90 compounds. Published in the journal Inorganic Chemistry, the findings are important for the practical applications of substances containing silver: in water and wound disinfection, photography, rainmaking via cloud seeding, etc.

The team derived the precise values of two key characteristics -- the enthalpy of formation and the entropy -- of numerous silver compounds. The enthalpy (from Greek "thalpein," meaning "to heat") of a system describes its state in terms of the energy of the constituent particles, pressure, and volume. According to Hess' law, by multiplying stoichiometric coefficients and the difference between the formation enthalpies of the reactants and those of the products, one gets the amount of heat generated or consumed in a chemical reaction. Entropy is a measure of how disordered a system is. The second law of thermodynamics states that a system can spontaneously adopt a less organized state, so entropy grows with time.

Knowing the values of enthalpy and entropy is crucial for predicting whether a reaction will ever occur at given conditions. These characteristics also indicate how reaction yield and selectivity -- the ratio between products -- vary with temperature and pressure, allowing for optimization. The findings enable researchers to make predictions concerning chemical processes occurring in the gas phase. The data will also help manage the processes involved in thin film and pure sample deposition from the gas phase.

There are basically two ways for determining enthalpy and entropy changes: either through complex and costly experiments or by using the data from reference books and doing some arithmetic based on Hess' law.

"The choice seems to be obvious, more so considering that you cannot experimentally measure the heat of some reactions," said Yury Minenkov, senior researcher at the Laboratory of Supercomputing Methods in Condensed Matter Physics. "For example, incomplete graphite combustion always yields both carbon monoxide and carbon dioxide. So even by measuring the thermal effect of the reaction we could not determine carbon monoxide formation enthalpy.

"But the computational approach faces some problems," Minenkov went on. "First, the enthalpies of formation and entropies are not known for every compound. Second, even if the data are available, no one can guarantee their accuracy. The values vary widely between reference books. At times, the measurement errors may be quite large."

Luckily, quantum chemistry helps obtain the entropy and, to some extent, the enthalpy data. Each constituent molecule of a gaseous substance can be viewed as a system of positively charged nuclei and negatively charged electrons. Researchers can then apply electronic structure calculation methods to solve the molecular Schrödinger equation. This reveals the total electronic energy of the molecule, its wave function, and the spatial configuration of nuclei -- that is, its 3D geometric structure. Physicists can then calculate the entropy and enthalpy of an ideal gas composed of such molecules. The entropy values obtained in this way are then introduced into reference books and used in thermodynamic calculations.

The problem with enthalpy is that, not being a fundamental value at this point, it significantly depends on the chosen method for Schrödinger equation calculation.

Atomization reactions are usually employed to calculate the enthalpy of formation. In such reactions, the compound of interest breaks down into individual atoms. For example, silver sulfide -- Ag2S -- yields one sulfur and two silver atoms. Since the enthalpies of formation of atomic substances are well-known and reported in reference books, it is possible to calculate the enthalpy of formation of the initial substance -- in this case, silver sulfide -- by finding the enthalpy change in the reaction via quantum chemistry methods.

However, when molecules composed of many atoms undergo atomization, this affects the electronic structure to such an extent that enthalpy, too, is significantly changed. The currently available methods of theoretical chemistry cannot account for these effects with enough accuracy.

The team of researchers from MIPT, the Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Sciences, Ivanovo State University of Chemistry and Technology, and Saudi Arabia's King Abdullah University of Science and Technology has published a series of papers proposing a way to calculate the thermodynamic characteristics of organic and inorganic compounds with more accuracy.

In the case of silver sulfide, the researchers found its enthalpy of formation from the reaction with hydrochloric acid, which yields silver chloride and hydrogen sulfide (fig. 2). Since the number of bonds in the top row is the same as in the bottom row, the change in energy can be calculated with the least error.

The heats of formation for silver chloride, hydrogen sulfide, and hydrochloric acid are known with a high accuracy, and computer modeling reveals the thermal effect of the reaction. From these data, one can derive the heat of formation of silver sulfide using Hess' law.

"The classic coupled-cluster approach, known as CCSD(T), is the gold standard for solving the electronic Schrödinger equation in modern quantum chemistry," Minenkov explained. "We replaced it with the local version called DLPNO-CCSD(T), which was developed not long ago at Max Planck Institute. This shrank the required computing power by an order of magnitude. Under the conventional CCSD(T), the computation time varies with the size N of the molecule as N7, so it is not an option for large molecules. The local version is much less time- and resource consuming."

The team began by checking how well the results of their quantum chemical calculations agreed with the experimental thermodynamic and structural data. Reference books reported the values for 10 silver compounds, and they were a good match. Having thus ensured that their model is adequate, the researchers calculated the thermodynamic characteristics for 90 silver compounds missing in the books. The data are of use to both scientists working in the field of silver chemistry and for testing and calibrating new methods of electronic structure calculation.

Toronto - Credit default swaps (CDS) were heavily criticized for being a major contributor to the 2008/09 financial crisis.

But a new study shows that these market-based insurance tools have also served as a stabilizing force, protecting against stock price plunges and higher borrowing costs in the event a firm receives a downgrade from a credit rating agency. CDS are typically bought by lenders to hedge against a borrowing company's potential default on its loans.

"We're trying to shed a different light, showing that CDS is not such a bad thing. It can have a positive outcome for capital markets," says Chayawat Ornthanalai, an associate professor of finance at the University of Toronto's Rotman School of Management who co-authored the study with two other researchers.

The researchers looked at the experience of 644 companies between 1996 and 2010. Some 283 of them saw the introduction of CDS contracts on their debt during that period. Those companies covered by CDS saw a 44 to 52 percent reduction in drops to their stock prices after a credit downgrade, compared to companies with an identical downgrade but with no CDS.

And while they still absorbed some impact, having their debt covered by CDS meant downgraded companies did not take as heavy a hit to their operations, with fewer reductions in their debt and investments and less significant increases to their borrowing costs, compared to companies not covered by CDS. Firms with the greatest drop in stock price, despite having CDS, tended to be those in the "speculative grade" category - with ratings in the lower grade strata -- or with more conditions attached to their loans that were linked to their credit rating.

The researchers caution that CDS contracts aren't a replacement for the information provided by credit ratings, but their results suggest that CDS can act as a complement, using a market-based indicator of a firm's default risk instead of an analyst's opinion.

Prof. Ornthanalai says people shouldn't confuse the positive uses of CDS highlighted in his research with the situation leading to the financial crisis.

"CDS was not the main issue," he says. In some cases, CDS got "tied into pools of badness," created by the abuse of collateralized debt obligations (CDOs), where debt from multiple sources was repackaged into a single product and sold by banks and corporations to buyers.

As well, some investors engaged in highly speculative and predatory trading against the potential default of a company in which they had no other direct interest, a situation Prof. Ornthanalai compares to "insuring your relatives and then murdering them for the insurance money."

Cigarette smoke can make MRSA bacterial strains more resistant to antibiotics, new research from the University of Bath has shown.

In addition cigarette smoke exposure can make some strains of Staphylococcus aureus - a microbe present in 30-60% of the global population and responsible for many diseases, some fatal - more invasive and persistent, although the effect is not universal across all strains tested.

The researchers believe the stress cigarette smoke causes to S. aureus sparks an emergency 'SOS' response, which increases the rate of mutation in microbial DNA, resulting in hardy and persistent variants better able to resist antibiotics.

Previous studies had attributed smokers' increased susceptibility to infection to the damaging effects of smoke on our immune system, but this study shows that it may also be changing the DNA and characteristics of pathogenic microbes as well.

In a series of lab-based experiments the researchers from Bath, working with colleagues from Imperial College London, University of Oxford and Institut d'Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona and CIBER Enfermedades Respiratorias, Spain, exposed six reference strains of the most important 'superbug' Methicillin- Resistant S. aureus (MRSA) clones to cigarette smoke.

The strains were known to cause conditions ranging from skin infections to pneumonia and endocarditis and were chosen for their clinical relevance and genetic diversity. Although not all responded to cigarette smoke in the same way some, including those known to cause invasive infections, showed increased resistance to the antibiotic rifampicin and increased invasiveness and persistence. Resistance to other antibiotics is also likely to be affected.

The study links these changes to the emergence of Small Colony Variants (SCVs) - hardy sub-populations that are adapted to harsh conditions. SCVs have been linked to chronic infections in smokers in previous research.

The study is published in the journal Scientific Reports.

Lead author Dr Maisem Laabei, from the University of Bath's Department of Biology & Biochemistry, said: "We expected some effects but we didn't anticipate smoke would affect drug-resistance to this degree. We recognise that exposure in a lab is different to inhaled smoke over a long time, but it seems reasonable to hypothesise, based on our research and others' that stressful conditions imposed by smoking induce responses in microbial cells leading to adaptation to harsh conditions, with the net effect of increasing virulence and/or potential for infection.

"Smoking is the leading cause of preventable death worldwide, and cigarette smoke has over 4,800 compounds within it.

"We wanted to study S. aureus because it's so common in humans and it can cause a range of diseases, so we wanted to see what happened when we exposed it to smoke.

"These Small Colony Variants are highly adhesive, invasive and persistent. They can sit around for a long time, are difficult to kick out, and are linked to chronic infections. We hope that our work provides another reason for people not to smoke and for current smokers to quit."

The scientists are now interested in studying how air pollution, from diesel exhaust fumes and other sources, might affect the microbes in our nasal passages as many of the pollution compounds are the same as in cigarette smoke.

Neuroscientists at the University of Sussex have revealed that complex movements, such as those that maintain our posture, can be controlled by a simple genetic system, providing a framework to better understand the molecular basis of diseases that affect motor control, like Huntington's and Parkinson's.

Claudio Alonso, Professor of Developmental Neurobiology and Wellcome Trust Investigator at the University of Sussex, and colleagues studied a motor sequence in fruit flies called 'self-righting', which sees a change in posture involving the rotation of the body so as to maintain a constant position in respect to the ground.

Such movements are also seen in humans; rolling in babies represents one of the milestones to monitor motor development during infancy, and can form part of the repertoire of core motor sequences that control "body posture" providing the basis to all movements such as lifting an arm.

In Professor Alonso's new research paper, published in the journal Current Biology, he shows that, in fruit flies, these movements are controlled by a simple genetic system where one gene, called miR-iab4, represses another, a Hox gene, to enable 'self-righting' behaviour. Similarly, in mammals, a parallel gene to miR-iab4, is also able to repress Hox gene expression, demonstrating the common genetic circuitry present in flies and mammals.

Until now, scientists thought that the Hox genes were just developmental, involved in the formation of body structures and the brain, but Professor Alonso and colleagues at the Champalimaud Institute in Lisbon, now show that these genes are also able to control neural physiology and behaviour.

The findings could help to provide a framework to better understand the molecular basis of motor diseases like Huntington's and Parkinson's.

Professor Alonso, Subject Chair for Neuroscience at the School of Life Sciences and a member of the internationally-leading research centre of Sussex Neuroscience, said: "Although our work is focused on deducing fundamental biological principles - what you may call "basic science" - there are several possible biomedical projections of this study.

"For example, ageing, as well as various forms of neural disease including motor neurone disease, Parkinson's and Huntingdon's disease, can degrade posture and motor control, leading to a deterioration of health and quality of life.

"In order to understand more about these conditions and to be able to map the anomalies caused by disease or advanced age, we need a deeper understanding of the genetic and physiological factors that underlie normal posture control and movement.

"While we knew that deregulation of the Hox genes can cause several types of disease and disorders, including cancer, as far as we know our results are the first to report Hox-dependent roles in neurophysiological and behavioural control in the fully formed organism (once development has concluded)."

A new study led by the Neuropharmacology Laboratory -NeuroPhar at UPF shows that increasing endocannabinoids in the brain may cause inflammation in specific brain areas such as the cerebellum, which is associated with problems of fine motor coordination. The results of the study in mice are contrary to what had been observed to date in other areas of the brain where endocannabinoids play an anti-inflammatory role. The article has been published in Brain Behavior and Immunity.

The endocannabinoid system is involved in many physiological brain functions, including motor coordination. This system is modulated by cannabinoid acquired both externally, as would be tetrahydrocannabinol (THC) from the plant Cannabis sativa, and endogenously, naturally produced by the body and known as endocannabinoids.

One of the beneficial effects of cannabinoids are their anti-inflammatory properties, which can be useful for treating inflammatory diseases that develop in the brain. To date an increase in the main endocannabinoids --2-arachidonoylglycerol (2AG) and anandamide-- had been seen to have an anti-inflammatory role in the brain in general, and the same results have also been observed by focusing the experiments in specific areas such as the hippocampus.

In this new study, the team of researchers led by Andrés Ozaita wondered what happens in the cerebellum, a brain area that has a very important role in coordinating chained and successive movements and motor learning. Their results show that in the cerebellum the opposite occurs from in the rest of the brain because increasing endocannabinoids increases inflammation, and this leads to motor coordination problems in the rodents.

To modulate the levels of endocannabinoids in the mice, the scientists use degradation inhibitors thus causing the latter to accumulate. They specifically inhibited the enzyme monoacylglycerol lipase (MAGL), which is responsible for degrading endocannabinoid 2AG.

"Our experiments show that the pharmacological or genetic inhibition of MAGL results in significant deficits in motor coordination and increases inflammation", explains Sara Martínez-Torres, first author of the article. "We have seen that this inflammation in the cerebellum is caused by an increase in the COX2 enzyme, which is induced during inflammatory processes and produces proinflammatory mediators", she adds.

The molecular alterations were not observed in the hippocampus, which points to a particular sensitivity of the cerebellum. In the words of Andrés Ozaita: "the differential response between the cerebellum and the hippocampus may arise from the alternative metabolism of 2-AG accumulated in the two brain areas".

"We focus specifically on the cerebellum because in a previous study we had seen that THC produced inflammation in this area, leading to deficits in motor coordination, and we wanted to find out if it also occurred by endogenously increasing the endocannabinoids", states Laura Cutando, co-author of the article.

Overall, the present study reveals the sensitivity of the cerebellum to changes in the signalling of the endocannabinoid system, compared with other areas of the brain like the hippocampus. It also highlights a possible disadvantage of strategies aimed at inhibiting MAGL activity for treating inflammatory disorders. "Increased endocannabinoids to reduce inflammatory processes should probably be supplemented by other conventional anti-inflammatories which, acting synergistically, may prevent inflammation in the cerebellum", concludes Andrés Ozaita.

Legal status is no guarantee that migrants will find more security in the workplace, according to a new study published in the journal Migration Letters.

Researchers interviewed around 200 migrants across Europe in a bid to find out whether regularisation - the process by which an immigrant obtains legal right to work - affects work conditions and opportunities.

It was found that although around 90% of the documented migrants surveyed worked in the primary sector, many reported issues such as employers not declaring their hours of work to the authorities in order to avoid contributing to tax or social insurance pay-outs. These issues were particularly prevalent in areas like cleaning, construction and agriculture.

Few regularised migrants chose to work in the informal sector because their employers preferred to offer work to those presenting themselves as undocumented, as they avoided having to comply with employment laws. Others chose informal work because they saw it as offering more freedom and, additionally, their earnings were not subject to taxation.

The research also found that because regularisation often depends on an endorsement from an employer, it often means workers feel unable to challenge employers who ignore labour laws.

In some cases, interviewees found that employers were less willing to employ them when they had legal status. In the case of those participants from the UK, only a minority found that a change in legal status resulted in improved employment conditions.

Co-author Dr Anna Paraskevopoulou, Senior Lecturer in Human Resource Management and Leadership at Anglia Ruskin University (ARU), said: "Around 40 regularisation programmes have been implemented in Europe and the United States, and more than five million people have been regularised since the 1980s.

"Our study found that while immigration policy does play a part in determining the rights of an individual, the labour markets themselves play a crucial role in creating spaces for undocumented workers to live and work in a country.

"In speaking to these migrants, an alarming finding emerged that even though some had secured legal status, they remained trapped somewhere between formal and informal labour markets, working for employers who would not pay them for their actual hours, or failing to make necessary social security contributions.

"Regulation in itself cannot eliminate inequality - we cannot underestimate the roles played by weak trade unions, glass ceilings, and a weakening of employment law."

People are more likely to judge the performance of a group based on member's that are labelled as first or number one than they are on any other member, according to new research led by Cass Business School academic Dr Janina Steinmetz.

Dr Steinmetz and her colleagues, Maferima Touré-Tillery of Northwestern University and Ayelet Fishbach from the University of Chicago, used seven separate studies to confirm that the performance of a group's first member can significantly influence people's decisions about the rest of the group.

One implication from this research can be found in supermarkets or retailers where numbered cash registers are in use - specifically on registers labelled with the numeral one.

Because the number one on a register labels its cashier as the group's first member, even though in reality it is an arbitrary number, a person who has a bad experience with the cashier at register number one will judge the whole store more harshly than if they had a bad experience at cashier number three, five or any other number.

Conversely, a pleasant experience at register number one will result in greater positivity about the store than it would at any other register.

"If the first group member to do something is bad then the whole group is seen as bad, if the first group member to do something is great then the whole group is seen as great, and this is much less the case if the middle or the last member does something," Dr Steinmetz said.

This is because, in people's experience, the first group member is often influential for the group -- a company's first employee shapes its culture much more than later employees, for example -- and people then apply this logic to first members in general.

In one research study, participants were presented with a scenario where five international cancer researchers are granted temporary work visas with a potential for extension.

When the participants were told that the scientist whose visa was approved first made a grave mistake they were more likely to judge the whole group of scientists as incompetent and less likely to support extending their work visas.

"When the first one makes the big mistake, people are more likely to say that all these scientists are terrible and we don't want them in the country," Dr Steinmetz said.

"People are more forgiving when the mistake is made by the scientist who receives their visa in the middle or last in the group and don't make such a harsh judgment."

This effect occurred although there was no reason to believe that the first researcher was special in any way, or that the group was actually incompetent. Instead, people were ready to deport the scientists because the bad apple in their group happened to be first in some arbitrary way when receiving the visa.

Other studies conducted during the research found the effect is replicated in judging students, athletes, and even racehorses.

"If the first horse of a group that are trained together runs very slowly in its race then other members of its group are expected to be slow as well and people would be less likely to bet on them," Dr Steinmetz said.

With multi-resistant germs becoming more and more of a threat, we are in need of new antibiotics now more than ever. Unfortunately, antibiotics cannot distinguish between pathogens and beneficial microbes. They can destroy the delicate balance of the microbiome - resulting in permanent damages. The research team around chemist Dr Thomas Boettcher has now made a significant step towards solving these problems. In collaboration with the team around biologist Professor Christof Hauck, also from Konstanz, the researchers discovered antibiotic properties of a natural product that so far had been considered merely a bacterial signal molecule. The team, including the doctoral researchers Dávid Szamosvári and Tamara Schuhmacher, developed and investigated synthetic derivatives of the natural substance that proved surprisingly efficient against the pathogen Moraxella catarrhalis. In the process only the growth of these pathogens was inhibited, not the growth of other bacteria. In a further project, the researchers succeed in developing another selective agent to combat the malaria parasite. These results might lead to a new basis for novel precision antibiotics. The research results are published in the current editions of the journals Chemical Science and Chemical Communications.

As important as antibiotics are to treat infectious diseases, they leave a trail of destruction in the human microbiome. Gastrointestinal disorders following antibiotic treatments are one of the slightest problems in this context. Quite often, resistant pathogens replace beneficial microbes. Later on, these can cause severe infectious diseases or chronic illnesses. However, not all microbes are dangerous. On the contrary, many microorganisms live in peaceful coexistence with us, and are even vital for human health. We humans are true microcosms and host more microbes than human cells. Yet this ecosystem, the human microbiome, is fragile. Allergies, overweight, chronic inflammatory bowel diseases and even psychiatric disorders may be the result of a damaged microbiome. The question is how can we maintain this ecological diversity in case of a microbial infection?

The research team originally studied the signals of the bacterium Pseudomonas aeruginosa. A compound aroused their interest as it was highly selectively inhibiting the growth of the pathogen Moraxella catarrhalis. This pathogen causes, for example, otitis media in children as well as infections in patients with chronically obstructive pulmonary diseases. The synthetic scaffold engineering of this natural product resulted in a new compound class with enormous antibiotic efficiency. What was really surprising was the substance's selectivity: Only the growth of Moraxella catarrhalis was inhibited, not that of other bacteria. Even closely related bacteria from the same species remained completely unaffected.

Currently, Thomas Boettcher and Christof Hauck are investigating the mechanism of action of this highly selective antibiotic against the pathogen Moraxella catarrhalis. Antibiotics with such selectivity would make precision treatment possible and specifically eliminate pathogens while preserving the diversity of beneficial microbes.

In another current project, described in the journal Chemical Communications, the research team around Thomas Boettcher and doctoral researcher Dávid Szamosvári, in collaboration with researchers from Duke University (USA), succeeded in developing highly selective agents against the malaria parasite. These also were inspired by Nature's example and the team created novel, previously undescribed quinolone ring systems. One compound proved to be extremely specific to a critical stadium in the life cycle of the malaria parasite. At first, this parasite settles in the liver before invading blood cells. The researchers were able to target and eliminate the parasite at this stage of malaria. The new findings can now be used for targeted research and the development of selective therapies to combat malaria based on new chemical compound classes.

The discovery of a new target for the blood-pressure medication propranolol may lead to the development of new and safer therapies for vascular diseases, according to new findings published in eLife.

The study also helps explain how propranolol is able to shrink benign tumours in infants called hemangiomas and relieve symptoms in some individuals born with a rare condition called hypotrichosis-lymphedema-telangiectasia and renal syndrome (HLTRS), which causes an overgrowth of blood vessels.

Propranolol's ability to block adrenaline receptors has made it a mainstay of treatment for hypertension and other heart-related conditions for decades. More recently, the drug has been repurposed to treat hemangiomas, although it was not clear how it is able to shrink the tumours. But then an adolescent patient with unusually mild symptoms of HLTRS, which is caused by mutations in a gene called SOX18, was found. The patient had been taking high doses of propranolol since a young age to control high blood pressure.

"The milder symptoms seen in this HLTRS patient taking propranolol raised the possibility that the drug has a SOX18-dependent molecular mode of action in addition to its beta-blocking activity," says co-lead author Jeroen Overman, a PhD student at the Institute for Molecular Bioscience, The University of Queensland, Australia.

When a 17-month-old patient in Dubai with HLTRS and a mutation in SOX18 developed heart problems, his physicians and parents chose to try propranolol. This treatment rapidly resolved the child's heart problem, further bolstering the idea that the drug targeted SOX18.

The team conducted experiments in cells grown in the laboratory, and confirmed that propranolol directly interferes with SOX18 activity by preventing it from binding with other SOX18 proteins. Later studies in mice, whereby the researchers treated eight-day-old mice that had SOX18 mutations with propranolol, revealed that the drug eliminated the HLTRS-like overgrowth of blood vessels in the cornea usually seen in mice with these mutations.

Finally, a collaborative team at Boston Children's Hospital, led by co-senior author Joyce Bischoff, treated hemangioma cells collected from patients and grown in the laboratory with propranolol. They found that the drug's SOX18-blocking action stopped the differentiation of the tumour cells. Specifically, they showed that one component of propranolol, called the R(+) enantiomer, is responsible for the SOX18-blocking effect, while its mirror image, S(-) enantiomer, had only a weak effect.

"This discovery suggests that it might be possible to treat hemangiomas or HLTRS using only the R(+) enantiomer of propranolol," says co-senior author Mathias Francois, PhD, Associate Professor at the Institute for Molecular Bioscience at The University of Queensland. "This would allow for lower doses of the medication or a shorter duration of therapy, and sparing patients from potential side effects related to beta-blockers."

In addition to opening the door for improved treatment for hemangioma or HLTRS, the discovery may lead to the development of new therapies for other conditions that involve excessive growth of blood-vessel cells. "Our work may enable the repurposing of the R(+) enantiomer of propranolol as a treatment for a broad range of conditions which include vascular disorders," concludes Joyce Bischoff, PhD, Principal Investigator in the Vascular Biology Program and Professor in the Department of Surgery at Boston Children's Hospital and Harvard Medical School, Boston, US.

Philadelphia, July 30, 2019 - Building on a track record of developing adeno-associated viral (AAV) vectors as a groundbreaking clinical tool for gene therapy and gene editing, Children's Hospital of Philadelphia (CHOP) researchers report a more sensitive method for capturing the footprint of AAV vectors--a broad range of sites where the vectors transfer genetic material.

By capturing the full range of gene expression patterns caused by AAV vectors, the technique is expected to significantly advance the already rapidly developing field of gene therapy. The innovative results appeared today in the journal Nature Communications.

AAV vectors are bioengineered tools that use a harmless virus to transport modified genetic material safely into tissues and cells impacted by otherwise difficult-to-treat conditions. These vectors deliver their "genetic cargo" into tissues, after which the modified genes will create new instructions for those tissues and help treat disease. Vector technology that was pioneered at CHOP led to the development of the first FDA-approved gene therapies, including Kymriah for B-cell acute lymphoblastic leukemia and Luxturna for inherited retinal disease.

For safe and effective application of these vectors, researchers must have a complete picture of where the virus delivers its genetic cargo in the body. Conventional methods to define gene transfer rely on fluorescent reporter genes that glow under a microscope, highlighting cells that take up and express the delivered genetic material. However, these methods reveal only cells with stable, high levels of the cargo. The new technology described in this study allows researchers to better detect where the cargo is expressed, even if it is expressed at extremely low levels, or only for a very short time.

"Conventional screening methods miss transient or very low levels of expression from AAV viral vectors," said study leader Beverly L. Davidson, PhD, Chief Scientific Strategy Officer at CHOP and Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics. "What this study shows is that AAV vectors lead to gene transfer in many more places than we and other groups initially realized."

Gaining a complete picture of the reach of this genetic cargo is particularly relevant following the discovery of the CRISPR/Cas9 system, which has revolutionized genome editing - removing, adding or altering sections of DNA - and opens the door to a new degree of precision medicine. CRISPR/Cas9 gene editing machinery, when expressed in cells even for a short time or at low levels, permits targeted DNA editing.

Many groups are seeking to use AAV vectors to deliver CRISPR/Cas9 due to its track record as a safe vehicle for gene transfer. Due to methodological limitations, many sites of low-level gene transfer have been missed. Combining AAV with gene editing machinery requires a more sensitive method for safe and effective applications.

To address this crucial gap in knowledge, Davidson and her lab developed a new AAV screening method that uses sensitive editing-reporter transgenic mice that are marked even with a short burst of expression or very low expression. In side-by-side comparisons with conventional screening methods, the new method radically redefines the true extent of AAV-mediated gene transfer.

According to the authors, this novel screening method will help improve the safety of AAV-gene editing approaches because it better defines sites where the vector expresses the modified gene. Importantly, because high and stable expression levels are not required for effective editing, dose levels that would not be ideal for more stable expression might work very well for genome editing. Additionally, this method expands the utility of the AAV platform by revealing new, never-before-described sites of gene transfer. It also offers an opportunity to better understand the basic biology of AAV vectors and what is required for them to effectively deliver their genetic payload.

LA JOLLA--(July 30, 2019) Neurodevelopmental disorders arising from rare genetic mutations can cause atypical cognitive function, intellectual disability, and developmental delays, yet it is unclear why and how this happens. Scientists suspected a mutation in a complex of proteins could be the culprit for a group of rare genetic disorders and, now, Salk Institute researchers have identified the molecular mechanism linking this mutation with abnormal nervous system development. The team's findings, published in Molecular Cell on July 30, 2019, bring researchers one step closer to understanding neurodevelopmental disorders, such as Nicolaides-Baraitser syndrome and others.

"For the first time, we have been able to characterize the mechanism of a known gene mutation implicated in neurodevelopmental disorders," says Assistant Professor Diana Hargreaves, senior author and holder of the Richard Heyman and Anne Daigle Endowed Developmental Chair.

The root cause has to do with a complex of proteins called the SWI/SNF complex, which is involved in DNA regulation, and, when mutated, is associated with Nicolaides-Baraitser syndrome, Coffin-Siris syndrome, autism and even some cancers. These complexes repackage and reshape the DNA in the nucleus to either enable or prevent access to genes. And yet, scientists do not know how mutations in individual subunits of the SWI/SNF complex affect its function.

"We sought to understand how a single mutation in the SMARCA2 subunit affected brain development," says Fangjian Gao, the paper's first author and a postdoctoral fellow at Salk. "We expected to see some effect on the neurodevelopmental pathways, but we were not sure how, specifically."

The scientists turned to cell cultures in a dish to model growth patterns in afflicted brain cells versus normal brain cells. They used the gene-editing technique CRISPR to mimic the SMARCA2 mutation observed in Nicolaides-Baraitser syndrome. Notably, the researchers found that healthy cells had minimal SMARCA2 activity. The cells with the mutation, however, had a dramatic increase in SMARCA2 activity and a significantly impaired ability to generate precursors to neurons, called neural progenitor cells. In this highly activated state, SMARCA2 affected the function of the normal SWI/SNF complex. This led to a domino effect with changes in gene expression resulting in abnormal brain development.

"By better understanding this mutation in SMARCA2, we have tapped into what looks like a core developmental process that could be perturbed in disease states such as autism or even cancer," says Hargreaves.

Savvy business leaders understand that when companies give back, they can attract better employees and win customers. But a new study shows they're not only doing it to impress workers and consumers: they're also doing it to boost their bottom line.

Corporate social responsibility, or CSR, is defined as actions that promote social good beyond the immediate interest of a company and its shareholders, and also beyond what is required by law. This can include things like sponsoring a new city park, launching green initiatives, setting up an employee assistance program, seconding an employee to a charitable organization, or making improvements to safety and working conditions that are far greater than what regulations demand.

New research from the UBC Sauder School of Business found that when public interest in corporate social responsibility is high, investors place a premium on companies that get involved in CSR activities. In other words, when companies do good, investors perceive greater value -- even if the fundamentals aren't especially impressive.

"Back in the late '90s there was similar investor sentiment for dot-com companies. Companies changed their names to dot-com and they saw their stock prices increase," says UBC Sauder assistant professor Ira Yeung, who co-authored the study.

"Recently it was the same thing with blockchain companies: we saw companies that added blockchain to their corporate name and their stock price jumped," he says. "We wanted to look at investor sentiment -- not for dot-com companies or for blockchain, but for CSR activity."

Analyzing information from the Thomson Reuters ASSET4 databases as well as thousands of corporate press releases that announced CSR initiatives, the researchers tracked the link between CSR activities and stock market performance, and found that when consumer interest in CSR is high, stock prices jump.

The researchers also noted that businesses respond to that sentiment-driven investing by upping their CSR activities -- especially when they're looking for a short-term stock market boost. This is especially true for firms that are inherently difficult to value, or that have more transient investors and higher share turnover.

The findings have significant implications both for businesses and for investors. Yeung says companies that aren't involved in corporate social responsibility might want to consider the significant role CSR can play in investor sentiment. "The value of the company is not just purely the future cash flows or future profits," he explains. "Clearly investors value companies more than just future profits, and CSR activities play a role in that."

Conversely, companies that are too heavily involved in CSR activities should also be mindful that, as was the case with the dot-com bust, consumer sentiment can shift, and the premium people place on those CSR projects in theory could diminish -- even though interest in CSR has been on a steady incline for years. "If they are doing CSR to boost the short-term stock price, they may want to be very careful about that," cautions Yeung.

For the same reason, investors should be careful not to overpay for companies whose stock prices are high because of CSR-driven sentiment.

"Some of these companies might be responding too much to CSR sentiment, or they might be quite overpriced relative to companies that are not doing CSR, so the future returns of these high CSR firms could be lower," explains Yeung. "They should be a little wary about investing in some of these companies, especially when investor sentiment for CSR is high."

If somebody asks me "are you a coffee addict?" I may say, "Yeah it seems like, but on the one condition, only in my office." I don't have that much craving for coffee at home, but just being in the office, where I used to drink coffee all the time seeking to get caffeine jitters, seems to trigger my caffeine-addicted brain. It is often said that breaking bad habits or additions is all about a person's willpower. However, as a behavior study researcher Bruce Alexander put it, "Addiction is an adaption. It's not you--it's the cage you live in." (Source: Chasing the Scream (audiobook): The First and Last Days of the War on Drugs). Studies have revealed that environmental stimuli such as places are the strong force behind our addiction. For example, the studies into the heroin-addicted Vietnam war veterans found that changes in their living place - returning home from the battlefield were the hidden force to break their drug addictions so effectively.

When you feel happy or pleasant, several areas of the brain take part to feel, remember, and repeat the action. Specifically, the hippocampus is responsible for spatial memory acquisition. People may remember where such feeling-good experience takes place and revisit the place to remind such pleasant experience. However, things could get quite problematic if the experience involves drug abuse. The Conditioned Place Preference (CPP) is an experimental paradigm to study the mechanism of addictive behaviors associated pleasant experience. It was long believed until recently that the release of the hormone dopamine in the mesolimbic pathway of the brain is the key to CPP. However as dopamine-deficient mice were found to exhibit CPP, the brain's CPP pathways have remained elusive. Meanwhile, the hippocampus, the brain region responsible for spatial memory, has not been considered to be involved in CPP.

Led by Dr. C. Justin Lee, researchers at the Center for Cognition and Sociality within the Institute for Basic Science (IBS) in Daejeon, South Korea have identified a new mechanistic element of CPP, mu-opioid receptors (MORs) expressed in astrocytes of the hippocampus. Opioids include endorphins (our brain's feel-good transmitters) or morphine (a major painkiller) that can make people feel relaxed or happy, and can be addictive. Much has been studied on neuronal MORs, but failed to form a comprehensive understanding of the CPP mechanism. The research team looked at a seemingly unlikely cells that had been deemed to only provide support and protection for neurons, astrocytes (i.e. a cell type of non-neuron cells) in the brain. They narrowed their target range to the astrocytic MORs in the hippocampus as it is the place where spatial memory is formed.

In their mice experiments, the researchers placed mice in two separate spaces with one door in the middle. One compartment was black with a stainless steel grid rod floor and another one was striped with black and white. At first, they let mice to move around the two spaces through the door in order to find their preferred place and non-preferred one. Then they gave mice DAMGO or morphine in their non-preferred spaces to condition only opioids controls the mice's CPP. After this conditioning, the researchers again let the mice freely explore the two separate spaces, and observed which room the mice prefer. (See Figure 2.) The experiments demonstrated the injection of exogenous opiod (DAMGO) or morphine activates astrocytic MORs in the hippocampus to release glutamates. These excitatory neurotransmitters increase the synaptic transmissions at Schaffer collateral-CA1 synapse in the hippocampus, which is responsible for the acquisition of spatial memory to induce CPP. The increased synaptic activities is technically called the long-term potentiation (LTP). (See Figure 3.)

To see whether the astrocytic MORs are the essential component to initiate opioid-induced CPP, the researchers performed astrocyte-specific gene-silencing of MORs in the hippocampus and see if CPP is induced by DAMGO treatment. The researchers found that CPP was not induced by DAMGO treatment without hippocampal astrocytic MORs. These findings indicate that hippocampal astrocytic MORs are critical for CPP induction, in addition to mesolimbic neuronal MORs. The first author of this study, Dr. Min-Ho Nam says, "There have been long-believed dogma about conditioned place preference (CPP): Interneuronal MOR in mesolimbic dopamine system is the only key for CPP. To overcome this dogma, we adopt multidisciplinary strategies including genetics, histology, electrophysiology, and behavioral assays."

Notably, this study verified that the astrocytic MORs in the hippocampus is where both artificial (morphine) and biological opioids (endorphin replaced by DAMGO) begin to induce the acquisition of contextual memory associated with pleasure. "Astrocyte is the most abundant cell type in the brain. This astrocyte-oriented study allows to step forward in understanding how humans prefer a certain place where a happy memory is associated with. We expect this study fuel the move from neuro-centric to glio-centric view in the brain science field," explains the corresponding author of this study Dr. Lee.

The current leading method to assess the presence of viruses and other biological markers of disease is effective but large and expensive. It is prohibitively difficult for use in many situations, especially due to certain economic and geographic factors. So researchers created and tested an alternative miniaturized system that makes use of low-cost components and a smartphone. Researchers hope the system could aid those who tackle the spread of diseases.

A virus scanner for a smartphone might not sound too exciting at first, but this virus scanner doesn't search for the latest malware; it scans biological samples for real viruses. It is a portable, low-cost, battery-powered device and is the brainchild of Yoshihiro Minagawa from the University of Tokyo. It was tested with viruses but could also detect other biological markers.

"I wanted to produce a useful tool for inaccessible or less-affluent communities that can help in the fight against diseases such as influenza," said Minagawa. "Diagnosis is a critical factor of disease prevention. Our device paves the way for better access to essential diagnostic tools."

Current state-of-the-art tools for detecting and counting viruses and other biomarkers, such as fluorescence microscopes, are generally large, expensive, slow and difficult to use. Although highly accurate at counting viruses, these tools are just too cumbersome for many situations, especially when rapid diagnosis is required.

"Given two equal samples containing influenza, our system detected about 60 percent of the number of viruses as the fluorescence microscope. But it's much faster at doing so and more than adequate to produce good estimates for accurate diagnoses," continued Minagawa. "What's really amazing is that our device is about 100 times more sensitive than a commercial rapid influenza test kit, and it's not just limited to that kind of virus."

The device is about the size of a brick with a slot on top in which you place a smartphone such that its camera looks through a small lens to the inside of the device. On the screen through a custom-made smartphone app you would see what may at first glance look like a starry night sky, except those stars would in fact be individual viruses.

Viruses are held in place on a clear surface in tiny cavities lit with an LED. The surface and fluid surrounding it were designed so that only when a cavity has a virus inside does incident light -- the light that directly hits the surface -- from the LED redirect up to the camera, manifesting in a bright pixel in an otherwise dark void. Each cavity is 48 femtoliters (quadrillionths of a liter) -- it would take over 10 million of these to hold a single human tear.

"This is now possible because smartphones and their embedded cameras have become sufficiently advanced and more affordable. I now hope to bring this technology to those who need it the most," concluded Minagawa. "We also wish to add other biomarkers such as nucleic acids -- like DNA -- to the options of things the device can detect. This way we can maximize its usefulness to those on the front line of disease prevention, helping to save lives."

Japanese scientists have developed an efficient method of successfully generating hair growth in nude mice. The new method can be scaled up and therefore shows great potential for clinical applications in human hair regenerative therapy.

Their findings were published on May 9, 2019 in Biomaterials.

Several factors contribute to human hair loss: It can be hereditary, or it can occur as a result of aging, hormonal imbalances or treatment with cancer fighting medications, all of which can lead to the loss of stem cells responsible for hair formation during development and the replacement of hairs that are shed during normal hair cycling.

Hair loss is currently treated with drugs and hair transplantation -- where hair follicles are removed from one part of the body (ex. the back of the head) to the site of hair loss. However, these treatment methods have their limitations; drugs are inefficient at stimulating hair regrowth to the extent necessary to counteract hair loss and hair transplantation doesn't increase hair numbers in the scalp.

Previous studies have shown improved results by transplanting, onto the backs of mice, a three-dimensional tissue culture called hair follicle germ (HFG). HFG is composed of hair follicle stem cells derived from both epithelial (outer layer of the skin) and mesenchymal tissue (connective tissue derived from the mesoderm). However, this approach requires manually merging the stem cells derived from these two different origins under a microscope, making it a challenge to produce the 5,000 or more hair follicle germs (HFGs) required per transplant patient.

To make the method scalable and therefore clinically viable, a team of scientists led by Dr. Tatsuto Kageyama and Prof. Junji Fukuda from Yokohama National University in Japan proposed a new approach to regenerate hair using mouse and human hair follicle stem cells.

The team fabricated hair beads (HBs) in u-shaped wells in a plate array using hair follicle stem cells encapsulated in collagen, a structural protein in skin believed to play an important role in hair follicle generation during embryonic development and hair regrowth throughout life. A suspension of mouse epithelial cells was then added into the wells containing the gel encapsulated hair beads. After 24 hours, the epithelial cells clumped together in a ball and adhered to the collagen gel. The collagen gel then contracted to form a "bead-based hair follicle germ" (bbHFG).

To test the efficiency of the hair bead approach, the scientists transplanted HBs and bbHFGs onto the backs of mice.

The team also transplanted hair follicle cell aggregates fabricated with two other methods onto the backs of nude mice as comparisons. In the first of these methods, mesenchymal and epithelial cells were mixed before being seeded in the wells. These cells initially aggregated, but spatially separated out from each after three days of culture to form a hair follicle germ (ssHFG), as reported by the same team. For the second method, they prepared a collagen solution containing a mixture of epithelial and mesenchymal cells and prepared droplets from this mixture. The microgel containing the cell aggregate contracted similar to that of the hair beads, but they did not separate and remained randomly mixed.

The results showed that compared to the other methods, the collagen-enriched hair bead (bbHFG) approach produced a high rate of hair generation four weeks after being transplanted onto the skin of the mice. After comparing gene expression of hair-producing gene markers in the three different methods, they found that gene expression for almost all the hair producing gene markers was greater in the bbHFGs, suggesting that collagen enrichment and cell aggregation play an important role in promoting hair follicle stem cell development.

The researchers also investigated whether this method could be automated to mass produce hair follicle germs on the scale needed to be clinically feasible for hair regenerative treatment of patients suffering hair loss.

"Using an automated spotter, this approach was scalable to prepare a large number of hair follicle germs, which is important for human treatment because thousands of tissue grafts are necessary for a single patient," said Prof. Fukuda.

As the ultimate goal of this research is to develop an efficient method of hair regenerative therapy that can be upscaled to make it clinically viable, the researchers next step "is to find a way to expand the number of hair follicle stem cells," said Prof Fukuda. "In this study, we worked on how to prepare tissue grafts. However, to deliver this approach to hair loss patients, we need a proper approach to obtain a sufficient number of hair follicle stem cells before preparing tissue grafts."

According to the authors, further studies that use hair follicle stem cells derived from patients suffering from hair loss are also required.