Culture

An international team of researchers led by the University of Adelaide has developed a new method to better understand the drivers of water theft, a significant worldwide phenomenon, and deterrents to help protect this essential resource.

In a paper published in Nature Sustainability, researchers developed a novel framework and model, which they applied to three case studies: in Australia, the US and Spain.

Lead author, Dr Adam Loch, Senior Lecturer at the University of Adelaide's Centre for Global Food and Resources, said that water theft is a research topic that has not received a lot of coverage due to a lack of data and because often those stealing water are poor, vulnerable and at risk in developing countries.

"But theft also occurs in the developed world, especially in agricultural settings," said Dr Loch.

"According to Interpol, thieves steal as much as 30-50 per cent of the world's water supply annually - a big number.

"Compounding this problem is the fact that, as the scarcity of our most precious resource increases due to climate and other challenges, so too do the drivers for water theft."

Drivers to water theft include social attitudes, institutions and future supply uncertainty.

With the novel framework and model, water managers can test the impact of changes to detection, prosecution and conviction systems, and accurately measure the effectiveness of current penalties which may not provide an effective deterrent.

"If users are motivated to steal water because it is scarce, and they need it to keep a crop alive, then the opportunity cost of that water may far exceed the penalty, and theft will occur," said Dr Loch.

The case studies also provide evidence that where authorities fail to support detection and prosecution theft will increase, and stronger deterrents may be needed to dissuade users from stealing water to maximise profits.

"In Spain regulators were assaulted by users when they tried to stop them from stealing water; in the US marijuana growers stole water from fire hydrants and the police felt powerless to do anything about it," said Dr Loch.

Researchers said there are many cases of water theft that could be studied using the framework and model - and they encourage institutions to use the free tools located within the paper's supplementary materials.

"Much of the world's focus right now is on water efficiency investments, which might achieve (at best) between 10-20 per cent savings for water managers. But if we can recover 30-50% of 'lost' water, targeting those who steal for profit making, then that would be good for our water supply, and good for us," said Dr Loch.

A recent study published in Neuron described in greater detail than ever before the anatomical embodiment of color sensations in the cerebral cortex, linking brain structure to perceptual function.

This discovery was the fruit of cooperative work between researchers in Dr. WANG Wei's lab at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences, State Key Laboratory of Neuroscience, and Dr. TANG Shiming's lab at Peking University.

Color is often found at the center of philosophical debates about the nature of conscious experience, mainly because color, more than any other sensation, illustrates that all perception is a mental creation. As realised early in the 18th century by Isaac Newton, visible wavelengths of electromagnetic radiation are not intrinsically colored; all the thousands of different hues we can recognize are simply arbitrary tags devised by the brain to represent various spectral compositions of light across the retinal image.

More technically, the outputs of retinal photoreceptors that discriminate wavelengths are combined and processed to eventually generate a perceptual color space. Color signals are processed through multiple neural stages in the deep brain; however, how our brains transform quantum-level events in photoreceptors to yield the many thousands of different hues we see every day is poorly understood.

To address this question, researchers in Drs. WANG and TANG's labs applied multiple techniques capable of imaging macaque brain activity at different scales and levels of resolution across successive processing stations in the cortex known as areas V1, V2 and V4. The aim of their study was to examine hierarchical changes in the patterns of activity when these areas process exactly the same color pattern.

The imaging methods reveal "hue maps," i.e., color palettes in the brain, spectrally organized arrangements of multiple hue responses. Figuratively, they can be thought of as rainbows of various conformations that are scattered across the brain surface.

The novel findings of this study arise from the fine structure of these hue maps. In V1, red and blue hues predominate, but this pattern of so-called "endspectral" dominance recedes in V2 and is nearly absent in V4. Essentially, the brain's hue maps develop hierarchically toward the uniformity of the perceptual hue map.

Computationally, the brain appears to be progressively integrating two distinct classes of cone-opponent signals originating in the retina. The information defining the precise hue of any given light is thus present in V1, coded by the ratio of activity between cone-opponent inputs - but it is not perceptible until it undergoes combinatorial processing by single neurons in area V4 and higher processing stations.

In summary, this comparative study reveals a progressive integration from cone-activation signals to isotropic hue representation along the visual hierarchy upon which our perceptual color space is built.

Osaka, Japan - Plastics are ubiquitous in modern life; unfortunately, once they lose function, they pollute the environment. Now, researchers at Osaka University have developed polymer materials that combine self-healing with strength and recyclability that could extend the functional lifetimes of manufactured plastics, thus minimizing the surging problem of discarded remnants.

Polymers are versatile substances, composed of many repeating molecular subunits, with essential and diverse functions in biological processes and industry. Sadly, their durability is double-edged: waste plastics generate litter and can contaminate our environment for centuries. About 50 kg of plastics is produced annually for every human; this doubles every decade. By the year 2050, there may be more plastics in our oceans than fish. As plastics are indispensable, extending their functional life by enhancing durability, self-healing and recyclability can help reduce waste.

Host-guest interactions, a fascinating branch of supramolecular chemistry, describes molecular complexes held in unique structural relationships by non-covalent bonding. These physical linkages allow molecular recognition and are ideal for preparing materials with rapidly reversible properties.

"We prepared supramolecular materials by mixing host and guest polymers of acetylated β-cyclodextrin and adamantane," explains Junsu Park, lead author. "We compared three mixing methods: conventional casting, planetary kneading and ball-milling. Ball-milling employs zirconia balls in a zirconia grinding jar on a sun-wheel revolving eccentrically in reverse. The additional rotational forces on the grinding surfaces and the interplay between impact and friction cause nanoscale mixing."

The researchers analyzed the polymers by wounding, re-joining, as coating of a glass substrate and after repeated ball-milling. Using dynamic mechanical analysis, thermal property measurements, small angle X-ray scattering measurements, and confocal laser scanning microscopy, etc they assessed scratch resistance, deformability and tensile strength.

The results were remarkable. Planetary mixing efficiently produced tough, self-healable, and recyclable supramolecular materials. Surface scratches disappeared in seconds and fractured fragments united in minutes. Moreover, mechanical properties were preserved even after repeated milling. "Ball-milling disentangles the polymer chains in the materials and increases their mobility while facilitating their re-formation," Park explains. "This maintains the number of host-guest interactions, ensuring both self-healing and toughness."

Senior author Yoshinori Takashima describes the potential of these discoveries: "We can develop tough materials capable of self-repair that retain these properties even when recycled. Prolonging their functional lifespan is key to saving the environment as they are being increasingly deployed in manufacture. Additionally, their unique biomimetic properties open up avenues of application in fields such as artificial skin for prostheses, robots and even vehicles."

A team of scientists from ASU's School of Molecular Sciences and the Biodesign Institute have recently published a study in Nature Communications that helps clarify the contributions to an ion channel's temperature - dependent activation. This in turn should aid in the development of new types of non-addictive pain therapies.

The ability to sense and respond to temperature is fundamental in biology. Ion channels are formed by membrane proteins that allow ions to pass through the otherwise impermeable lipid cell membrane, where they are used as a communication network.

"TRPV1 is an ion channel that is widely expressed in various tissues and plays a variety of roles in biology," explains SMS professor Wade Van Horn, senior author of the current research. "It is best known for its role as the primary hot sensor in humans; it is the main way that we sense heat in our environment."

Although important contributions have been made in the investigation of TRPV1 thermosensing, its mechanism has remained elusive.

TRPV1 is also a common taste and pain sensor, think spicy foods and pepper spray. Beyond these roles, it has been implicated in longevity, inflammation, obesity, and cancer. For decades it has been a target in the search for new types of pain medication, ones that are not addictive.

"However, to date, a common feature is that while TRPV1 targeting compounds can relieve pain, they also cause off-target effects, especially causing changes in body temperature, which has limited their utility. These off-target effects happen because TRPV1 is activated by many distinct stimuli, including ligands (i.e., capsaicin - the main ingredient in pepper spray), heat, and protons (acidic pH)," says Van Horn.

Also particularly limiting, is the uncertainty about the mechanisms that underlie temperature-sensing and how the different activation mechanisms are linked together.

This study used a variety of techniques, from cellular to atomic in nature, to investigate the domain of TRPV1 that is key to its ligand activation.

The techniques included Nuclear Magnetic Resonance spectroscopy experiments (like an MRI) aided by Brian Cherry (Associate Research Professional in the Magnetic Resonance Research Center), intrinsic fluorescence carried out in SMS associate professor Marcia Levitus' lab. Levitus is also part of the Biodesign Center for Single Molecule Biophysics. Other techniques included far ultraviolet circular dichroism and temperature dependent electrophysiology.

Van Horn explains that this work identifies for the first time, both functionally and thermodynamically, that a particular region (of TRPV1) is crucial to heat activation. The team proposes, and provides experimental validation for, the heat activation mechanism and details a number of structural changes that happen as the temperature is changed.

This study provides a framework that the team anticipates will be foundational for future studies to further refine how we sense high temperatures and, importantly, how we can distinguish and target specific activation mechanisms that should promote the development of new types of non-addictive pain therapies.

All the interdisciplinary studies were completed at ASU. The team also included: Minjoo Kim, Nicholas Sisco and Jacob Hilton who are currently postdoctoral researchers at Columbia University, Barrow Neurological Institute and NIH respectively. Camila Montano and Wade Van Horn, are also part of the Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics and Manuel (Mac) Castro is currently a doctoral student at Vanderbilt University.

A joint research team led by Dr. MAO Fangyuan from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences and Prof. MENG Jin from the American Museum of Natural History has reported a new multituberculate mammal, Sinobaatar pani, with well-preserved middle ear bones.

The new mammal comes from the Early Cretaceous Jehol Biota in Northeast China. Comparing three types of fossils with extant mammals at different embryological stages, the researchers identified various evolutionary stages and ancestral phenotypes of the mammalian middle ear.

Their findings were published in National Science Review on Aug. 25.

For mammals, the external ear (the pinna) collects airborne sounds that vibrate the eardrums, and the middle ear bones on the inner side of the eardrum function as a delivery system that transmits sound vibrations to the inner ear.

According to previous studies, we know that the extra mammalian ear bones actually originated from the jawbones of reptiles. However, few studies have actually looked at the detailed morphologies of ear bones that are the ancestral phenotypes for the middle ear of modern mammals.

Multituberculates are an extinct group of mammals that lived from the Middle Jurassic (about 165 million years ago) to the Eocene (about 35 million years ago). The most exciting discovery about the new animal is its middle ear bones, which are the first unequivocal evidence of the five auditory bones from this extinct mammalian group.

These miniscule bones are still embedded in rock and not visible. Using computerized tomography (CT), MAO and her colleagues were able to digitally "extract" the ear bones from the rock and reconstruct them in three-dimensional form so that their morphology could be observed in detail.

The data provided by MAO and her colleagues are by far the best evidence of middle ear morphology in known Mesozoic mammals. For comparison, the data also included similar CT reconstructions of the middle ear of extant monotremes, marsupials and placentals.

"There are two basic patterns of the middle ear in living mammals, represented by monotremes and therians, respectively. In the former, the middle ear is characterized by an 'abutting contact' between the incus and malleus, which is distinct from the one in therian mammals where the incus-malleus articulation is saddle-shaped," said Dr. MAO.

The researchers recognized that the three main Mesozoic mammalian groups (i.e., multituberculates, eutriconodontans, and symmetrodontans) share a similar middle ear structure between the incus and malleus, which they termed the "braced hinge joint".

Although they acknowledged that the middle ear may have evolved independently in several mammalian groups, they proposed that the braced hinge joint could represent a critical feature of the ancestral phenotype of the mammalian middle ear.

The abutting pattern in monotremes and the saddle-shaped joint in therians may well be derived from the braced hinge joint linking the incus and malleus as observed in Mesozoic mammals. At the least, these fossil forms have narrowed the morphological gap between the middle ear of mammal-like reptiles, formed by the postdentary bones lodged in the lower jaw, to the middle ear of extant mammals.

The researchers proposed that the surangular bone, which is another postdentary bone in mammal-like reptiles, persisted in Mesozoic mammals; its fate in living mammals remains uncertain.

They further showed that middle ear morphologies in Mesozoic mammals represent different evolutionary stages, with that of Liaocodondon being the most primitive, Origolestes the intermediate, and Sinobaatar the most advanced.

Developmental features observed in extant mammals and evolution of the mammalian middle ear in fossil records are correlated, said MAO.

DARIEN, IL - A new study found a surprising association between frequent and severe nightmares and cardiovascular disease in veterans, even after controlling for post-traumatic stress disorder.

Preliminary results show that 32% of veterans reported having frequent nightmares and 35% reported severe nightmares over the past week. Frequent and severe nightmares were associated with heart problems, high blood pressure, and heart attack after adjusting for age, sex and race. Associations between nightmares and high blood pressure and heart problems remained significant after controlling for PTSD diagnosis, depression diagnosis and status as a smoker.

"Our cross-sectional findings set the stage for future research examining the possibility that nightmares may confer cardiovascular disease risks beyond those conferred by PTSD diagnosis alone," said principal investigator Christi Ulmer, who has a doctorate in clinical psychology and is a clinical research psychologist at the Durham VA Health Services Research and Development ADAPT Center and assistant professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center. "If longitudinal research demonstrates a causal role for nightmares in cardiovascular disease risk, nightmare treatment could be a strategy for improving cardiovascular health."

The study involved 3,468 veterans with an average age of 38 years. Nightmare frequency and severity was assessed using the Davidson Trauma Scale, with nightmares classified as "frequent" if they occurred at least 2 to 3 times per week and severe if they were at least moderately distressing. Medical problems were assessed using a medical questionnaire, and PTSD and depression diagnoses were established using a clinical interview. Thirty percent of participants met criteria for current PTSD.

The research was supported by the VISN 6 Mental Illness Research, Education and Clinical Center (MIRECC) and the Department of Veterans Affairs HSR&D ADAPT Center at the Durham VA Health Care System.

The research abstract was published recently in an online supplement of the journal Sleep and will be presented as a poster Aug. 28-30 during Virtual SLEEP 2020. SLEEP is the annual meeting of the Associated Professional Sleep Societies, a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

People with HIV from BAME communities, women and heterosexual men are underrepresented in HIV studies - according to new research from the University of East Anglia and Western Sydney University.

Medication to manage HIV is now very effective at keeping people well. But over half of people living with HIV do not take their medication as prescribed.

We are yet to find solutions that are routinely used by healthcare teams to successfully support people to take their medication as prescribed - despite many studies designed to investigate the problem.

New research published today reveals that the problem could be in the way that studies are designed in the first place - with BAME communities, women and straight men under-represented.

The research team say that this imbalance of representation needs to be fixed, in order to design solutions that suit the needs of a diverse population and keep people with HIV living longer, healthier lives.

Lead researcher Prof Debi Bhattacharya from UEA's School of Pharmacy said: "It's really important that people with HIV start taking medication as soon as possible and continue taking it as prescribed for life. While medication can't cure HIV, taking it correctly helps people live longer, healthier lives. Medication can also reduce the risk of HIV transmission.

The research team reviewed 80 studies designed to evaluate different approaches for supporting people to take their HIV medication correctly.

They found that people from ethnic minorities, women and heterosexual men were underrepresented for the country in which the study was taking place.

Prof Bhattacharya said: "We found that none of the 80 studies had a trial population that reflected the actual population of people living with HIV.

"For example in many cases, gay men were over-represented in studies, compared with the amount of gay men living with HIV.

"In one American study not a single woman was included even though women represent around one in five people with HIV."

"This is a problem because we know that in several countries including America, HIV rates in men are falling more than they are for women."

"As these patient groups are being significantly underrepresented in these types of trials, their needs, beliefs and attitudes to treatment are not fully understood. This potentially leaves these populations without the support they need to live well with HIV.

"We also know that language profoundly affects the way patients understand their treatment routines - which impacts on how they engage with their disease and medication. Failure to take this into account seriously hinders people from getting the best clinical outcomes.

"We found that none of the studies used research methods to encourage people with differing languages and culture to contribute in the ways that are needed for the research to be successful.

"This may explain why we have seen few of these solutions that are shown to work in the studies then go on to be routinely used in healthcare.

"Over the years we have seen greater scrutiny over how research is conducted to ensure that people invited to participate in research are fully informed before they decide to participate. These changes, like making sure that we have written consent, have been very important for protecting the public.

"But, the changes have led to new problems, such as people with limited literacy or those less fluent in the local language being excluded from studies. It is important that we continue to protect the public whilst also supporting people with differing needs to participate in research."

"The guidelines for carrying out research need to recognise that research methods must be adapted to support the wide range of people with differing needs that make up the diversity of people with a specific disease.

"The guidelines also need to communicate more strongly, the importance of properly involving people for whom the research is intended to help, at the earliest possible stage of the research otherwise these health inequalities may continue."

A new meta-analysis of published studies into the drug hydroxychloroquine shows that it does not lower mortality in COVID-19 patients, and using it combined with the antibiotic azithromycin is associated with a 27% increased mortality. The study is published in Clinical Microbiology and Infection, the official journal of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

"This meta-analysis shows that hydroxychloroquine alone is not effective for the treatment of COVID-19 patients and that the combination of hydroxychloroquine and azithromycin increases the risk of mortality," say the authors who include Thibault Fiolet, Center for Research in Epidemiology and Population Health, INSERM, Institut Gustave Roussy and Paris-Sud 11 University/Paris-Saclay University, Paris, France. "These data support current clinical recommendations such as those of the US National Institutes of Health (NIH) which do not recommend the use of hydroxychloroquine alone or in combination with azithromycin for COVID-19 patients."

Chloroquine is used to prevent and treat malaria, while hydroxychloroquine is a less toxic metabolite of chloroquine and is used to treat rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and Sjogren's syndrome. Hydroxychloroquine in particular has received extensive media coverage since the outbreak of the SARS-CoV-2 pandemic as a potential treatment for COVID-19. Azithromycin is used to treat a wide range of bacterial infections, but has also been promoted as a potential treatment for COVID-19 due to its alleged antiviral or anti-inflammatory properties.

In this new analysis, the authors searched for studies that assessed chloroquine or hydroxychloroquine with or without the antibiotic azithromycin. The authors found 29 articles that met their criteria, all except one of which were conducted on hospitalised patients and evaluated the effects of hydroxychloroquine with or without azithromycin.

Among the 29 articles, 3 were randomised controlled trials, one was a non-randomised trial and 25 were observational studies, including 11 with a 'critical' risk of bias and 14 with a 'serious or moderate' risk of bias*. After excluding studies with a critical risk of bias, the meta-analysis included 11,932 patients in the hydroxychloroquine group, 8,081 in the hydroxychloroquine with azithromycin group and 12,930 in the control group (who received neither drug).

The results showed that hydroxychloroquine was not associated with mortality, either in all trials combined, or in separate analyses of randomised controlled trials or observational studies. The relative risk of death for use of hydroxychloroquine was 17% lower than controls for all studies combined, but 9% higher in randomised controlled trials. In both cases, these results were not statistically significant.

However, the combination of hydroxychloroquine and azithromycin in patients with COVID-19 was associated with a statistically significant 27% increase in mortality compared with controls. The authors say: "These results confirm the preliminary findings of several observational studies which have shown that the combination of hydroxychloroquine and azithromycin might increase the risk of acute, life-threatening cardiovascular events."

The authors discuss limitations of their work which include the differing levels of COVID-19 disease severity across patients and also the actual definition of severity. Furthermore, most of the studies included were observational studies (not designed to find a causal relationship). Finally, this meta-analysis did not include results from the European DisCoVeRy trial and the WHO Solidarity trial that are not yet published or communicated (but both have already discontinued their hydroxychloroquine arms).

The authors conclude: "There is already a great number of studies that have evaluated hydroxychloroquine alone or in combination and it seems unlikely at this stage that any efficacy will ever emerge. Our results suggest that there is no need for further studies evaluating these molecules, and the European DisCoveRy and WHO international Solidarity clinical trials have already discontinued treatment arms using hydroxychloroquine."

Vitamin C could be the key to better muscles in later life - according to new research from the University of East Anglia (UEA).

A study published today shows that older people who eat plenty of vitamin C - commonly found in citrus fruits, berries and vegetables - have the best skeletal muscle mass.

This is important because people tend to lose skeletal muscle mass as they get older - leading to sarcopenia (a condition characterised by loss of skeletal muscle mass and function), frailty and reduced quality of life.

Lead researcher Prof Ailsa Welch, from UEA's Norwich Medical School said: "As people age, they lose skeletal muscle mass and strength.

"People over 50 lose up to one per cent of their skeletal muscle mass each year, and this loss is thought to affect more than 50 million people worldwide."

"It's a big problem, because it can lead to frailty and other poor outcomes such as sarcopenia, physical disability, type-2 diabetes, reduced quality of life and death."

"We know that Vitamin C consumption is linked with skeletal muscle mass. It helps defend the cells and tissues that make up the body from potentially harmful free radical substances. Unopposed these free radicals can contribute to the destruction of muscle, thus speeding up age-related decline."

"But until now, few studies have investigated the importance of Vitamin C intake for older people. We wanted to find out whether people eating more Vitamin C had more muscle mass than other people."

The research team studied data from more than 13,000 people aged between 42-82 years, who are taking part in the EPIC (European Prospective Investigation into Cancer and Nutrition) Norfolk Study.

They calculated their skeletal muscle mass and analysed their vitamin C intakes from a seven-day food diary. They also examined the amount of vitamin C in their blood.

Dr Richard Hayhoe, also from UEA's Norwich Medical School, said: "We studied a large sample of older Norfolk residents and found that people with the highest amounts of vitamin C in their diet or blood had the greatest estimated skeletal muscle mass, compared to those with the lowest amounts.

"We are very excited by our findings as they suggest that dietary vitamin C is important for muscle health in older men and women and may be useful for preventing age-related muscle loss.

"This is particularly significant as Vitamin C is readily available in fruits and vegetables, or supplements, so improving intake of this vitamin is relatively straightforward.

"We found that nearly 60 per cent of men and 50 per cent of women participants were not consuming as much Vitamin C as they should, according to the European Food Safety Agency recommendations.

"We're not talking about people needing mega-doses. Eating a citrus fruit, such as an orange, each day and having a vegetable side to a meal will be sufficient for most people."

MSA toolkits first appear some 300 thousand years ago, at the same time as the earliest fossils of Homo sapiens, and are still in use 30 thousand years ago. However, from 67 thousand years ago, changes in stone tool production indicate a marked shift in behaviour; the new toolkits that emerge are labelled LSA and remained in use into the recent past. A growing body of evidence suggests that the transition from MSA to LSA was not a linear process, but occurred at different times in different places. Understanding this process is important to examine what drives cultural innovation and creativity, and what explains this critical behavioural change. Defining differences between the MSA and LSA is an important step towards this goal.

"Eastern Africa is a key region to examine this major cultural change, not only because it hosts some of the youngest MSA sites and some of the oldest LSA sites, but also because the large number of well excavated and dated sites make it ideal for research using quantitative methods," says Dr. Jimbob Blinkhorn, an archaeologist from the Pan African Evolution Research Group, Max Planck Institute for the Science of Human History and the Centre for Quaternary Research, Department of Geography, Royal Holloway. "This enabled us to pull together a substantial database of changing patterns of stone tool production and use, spanning 130 to 12 thousand years ago, to examine the MSA-LSA transition."

The study examines the presence or absence of 16 alternate tool types across 92 stone tool assemblages, but rather than focusing on them individually, emphasis is placed on the constellations of tool forms that frequently occur together.

"We've employed an Artificial Neural Network (ANN) approach to train and test models that differentiate LSA assemblages from MSA assemblages, as well as examining chronological differences between older (130-71 thousand years ago) and younger (71-28 thousand years ago) MSA assemblages with a 94% success rate," says Dr. Matt Grove, an archaeologist at the University of Liverpool.

Artificial Neural Networks (ANNs) are computer models intended to mimic the salient features of information processing in the brain. Like the brain, their considerable processing power arises not from the complexity of any single unit but from the action of many simple units acting in parallel. Despite the widespread use of ANNs today, applications in archaeological research remain limited.

"ANNs have sometimes been described as a 'black box' approach, as even when they are highly successful, it may not always be clear exactly why," says Grove. "We employed a simulation approach that breaks open this black box to understand which inputs have a significant impact on the results. This enabled us to identify how patterns of stone tool assemblage composition vary between the MSA and LSA, and we hope this demonstrates how such methods can be used more widely in archaeological research in the future."

"The results of our study show that MSA and LSA assemblages can be differentiated based on the constellation of artefact types found within an assemblage alone," Blinkhorn adds. "The combined occurrence of backed pieces, blade and bipolar technologies together with the combined absence of core tools, Levallois flake technology, point technology and scrapers robustly identifies LSA assemblages, with the opposite pattern identifying MSA assemblages. Significantly, this provides quantified support to qualitative differences noted by earlier researchers that key typological changes do occur with this cultural transition."

The team plans to expand the use of these methods to dig deeper into different regional trajectories of cultural change in the African Stone Age. "The approach we've employed offers a powerful toolkit to examine the categories we use to describe the archaeological record and to help us examine and explain cultural change amongst our ancestors," says Blinkhorn.

In a development that may finally offer hope to children with Dravet syndrome and their parents, a promising investigational new therapeutic appears to alter the destructive course of the deadly disease in a mouse model.

Lori Isom, Ph.D., Chair of the U-M Department of Pharmacology and Professor of Molecular & Integrative Physiology, and Neurology and her team have spent several years tracing the developmental pathway of Dravet syndrome, a debilitating genetic disease that causes intractable seizures and can lead to sudden death. Dravet syndrome variants lead to a decrease in the level of a crucial protein that normal brain cells use to control the flow of sodium ions into cells. Neurons use these sodium channels to transmit signals back and forth.

Patients with Dravet syndrome have variants in a sodium channel gene, SCN1A, that in general result in there being only half the amount of the corresponding functional protein, Nav1.1, expressed in the brain. "With only 50 percent SCN1A expression in the brain, you have a severe epileptic disease with a high risk of sudden death," Isom says.

The team's goal was to increase the gene's expression back up to 100 percent in neurons using an antisense oligonucleotide (ASO) that was developed by Stoke Therapeutics, a biotechnology company. In collaboration with Stoke, Dr. Isom and her team tested the ASO called STK-001 in a Dravet syndrome mouse model.

"The brain normally uses sections of genes called poison exons to dial up or down the expression of a particular gene, as an internal regulatory mechanism," explains Isom. "We are taking advantage of a poison exon in SCN1A to increase its expression." Unlike using CRISPR, viruses, or other forms of gene editing, ASOs are reversible. "The problem with gene therapy is you are changing something forever, which is risky especially with the brain. If you make a mistake, there's no going back."

Injecting the ASO into the brains of mice that carry only one healthy copy of the SCN1A gene two days after they were born led to 97 percent survival out to 90 days, while just 23 percent of the untreated mice survived during the same time range. "Our thought is that early intervention with an ASO in mice may be able to change brain excitability," says Isom, "And if that's also true for kids with Dravet...that would be incredible." The results are published in the journal Science Translational Medicine.

Based on the encouraging findings of the mouse study, Stoke has recently launched a clinical study to begin evaluating STK-001 in children and adolescents with Dravet syndrome.

Isom notes that the mouse study could have even wider implications for treating the genetic cause of generalized epilepsy, especially for the third of patients whose epilepsy is not controlled with traditional drugs. "We just need to start over and think about epilepsy in a new light--to get at the genetic source, rather than being reactive and trying to treat something that has already happened."

BOSTON -Xu Yu, MD, Ragon group leader, recently published a study entitled "Distinct viral reservoirs in individuals with spontaneous control of HIV-1," in Nature. Yu's lab, in collaboration with Ragon group leaders Mathias Lichterfeld, MD, PhD, and Mary Carrington, PhD, and Ragon director, Bruce Walker, MD, sequenced billions of cells from 64 elite controllers, people living with HIV who suppress the virus naturally without the need for medication, and 41 individuals on antiretroviral drugs (ART). Unlike ART-treated individuals, elite controllers' viral reservoirs appear to be incapable of being reactivated. This likely helps the elite controllers maintain spontaneous, drug-free control of HIV and may represent a distinguishing feature for a functional cure of HIV infection.

HIV affects more than 35 million people worldwide and can be effectively controlled, but not cured, with a daily regimen of ART. Upon infection, retroviruses like HIV place copies of their viral genetic material into cells' genomes, creating viral reservoirs, sanctuaries where HIV persists despite ART, throughout the body. When a complete copy of the virus, or intact viral genome, is incorporated into a cell's genome, it can be used to create new copies of HIV. For people living with HIV, this means that if they stop taking ART, the intact viral genomes previously integrated into the cells' genomes start making new copies of the virus, leading to rapid viral rebound and disease progression. The HIV viral reservoir has remained a major obstacle to an HIV cure.

Elite controllers' immune systems use a T-cell mediated immune response to control the virus without medication, to the point that the virus is completely undetectable by standard assays. Understanding the interplay between their immune system and HIV may hold the key to helping the immune systems of people living with HIV to suppress the virus without daily treatment, achieving what is known as a functional cure.

Yu's group studied the viral reservoir in elite controllers, using next-generation sequencing techniques to precisely map the locations of intact HIV genomes in the human genome. They found that in elite controllers, HIV was often found in locations of the genome that researchers call gene deserts. In these inactive parts of the human genome, human DNA is never turned on, and HIV cannot be effectively expressed but remains in a "blocked and locked" state. This means that HIV is locked in the cell's genome, and the viral genome is blocked from being used to create more viruses and is therefore incapable of causing disease.

"This positioning of viral genomes in elite controllers," Yu, says, "is highly atypical, as in the vast majority of people living with HIV-1, HIV is located in the active human genes where viruses can be readily produced."

When the authors collected cells from elite controllers and infected them with HIV in the lab, they found the virus integrated into active sites in the cell genomes, not in the inactive gene deserts. This suggests that the elite controllers' unique viral reservoirs may be a result of their HIV-suppressing T cell response eliminating intact viral genomes from active sites.

If researchers are able to identify which viral reservoirs can make new copies of the virus after treatment stops, it may help them to target a treatment against the active, or rebound-competent, reservoirs. This study suggests that if researchers can activate the kind of T cell immunity that is present in elite controllers, they may be able to eliminate rebound-competent viral reservoirs in people living with HIV, achieving a functional cure. The remaining viral DNA, located in non-active parts of the human genome, could be allowed to exist without causing disease.

Yu's group had one more finding: one of their elite controller participants had no intact HIV found in over 1.5 billion cells analyzed. This raises the possibility that a "sterilizing cure" of HIV, in which the participant's immune system has removed all intact HIV genomes from the body, may be achieved naturally in extremely rare instances.

A new study says that many of the ice shelves ringing Antarctica could be vulnerable to quick destruction if rising temperatures drive melt water into the numerous fractures that currently penetrate their surfaces. The shelves help slow interior glaciers' slide toward the ocean, so if they were to fail, sea levels around the world could surge rapidly as a result. The study appears this week in the leading journal Nature.

Ice shelves are giant tongues of ice floating on the ocean around the edges of the continent. The vast land-bound glaciers behind them are constantly pushing seaward. But because many shelves are largely confined within expansive bays and gulfs, they are compressed from the sides and slow the glaciers' march--somewhat like a person in a narrow hallway bracing their arms against the walls to slow someone trying to push past them. But ice shelves experience a competing stress: they stretch out as they approach the ocean. Satellite observations show that, as a result, they rip apart; most are raked with numerous long fractures perpendicular to the direction of stretching. Fractures that form at the surface can be tens of meters deep; others, forming from the bottom, can penetrate the ice hundreds of meters upward. Some fractures are hundreds of meters wide.

Currently, most of the shelves are frozen year round, and stable. But scientists project that widespread warming could occur later in the century. And, existing research has shown that even subtle temperature swings can spur widespread melting. This could send melt water surging into the surface fractures. Such surges would potentially cause hydrofracturing-a process in which liquid water, heavier than ice, would violently force the fractures to zip open, and cause the shelf to rapidly disintegrate The new study estimates that 50 to 70 percent of the areas of the ice shelves buttressing the glaciers are vulnerable to such processes.

"It's not just about melting, but where it's melting," said lead author Ching-Yao Lai, a postdoctoral researcher at Columbia University's Lamont-Doherty Earth Observatory.

"The ice shelves-that's the weak spot, where the atmosphere, the ice and ocean interact," said study coauthor Jonathan Kingslake, a glaciologist at Lamont-Doherty. "If they fill up with melt water, things can happen very quickly after that, and there could be major consequences for sea levels."

Hydrofracturing has already occurred in a few places. Parts of the Larsen Ice Shelf, which had been stable for at least 10,000 years, disintegrated within just days in 1995 and 2002. This was followed by the partial breakup of the Wilkins Ice Shelf in 2008 and 2009. The main agreed-upon causes: hydrofracturing. The Larsen and Wilkins comprise some of the northernmost ice on the continent, and so have been the first to suffer under rising temperatures and seasonal melting.

The new study follows a 2017 paper led by Kingslake showing that seasonal ponds and streams on the ice surface are far more common across Antarctica than previously believed; some reach within 375 miles of the South Pole. But most cataloged features are in places not subject to hydrofracturing. The new study shows that, so far, only about 0.6 percent of East Antarctic ice shelves that provide buttressing experience melt-water ponding, making them vulnerable. A much larger percentage would potentially be endangered, if warming takes hold.

In collaboration with Cameron Chen, a researcher from Google, Lai trained a machine-learning model to identify ice-shelf fracture locations across Antarctica, to produce the first continent-wide map of such features. Although most fractures now contain no liquid water, the scientists considered future cases in which melt water might fully fill the surface fractures. This allowed them to predict which parts of the shelves would be vulnerable to hydrofracturing, when factoring in the competing forces of compression from the sides, and stretching of the ice from back to front.

They calculated that inflow of liquid into the existing fractures could potentially exert enough force to cause widespread hydrofracturing across 50 to 70 percent of the ice-shelf areas that provide buttressing. The main exceptions were smaller, solider areas of ice closest to land, which experience less stress from stretching. The end portions of the shelves, mostly surrounded by open ocean, are also vulnerable, but floating freely as they do, those do not help hold back the glaciers.

While the study flashes a warning, the researchers say they cannot predict the ice shelves' behavior with any exactitude. "How fast melt water would form and fill in those cracks is the first question," said Kingslake. He said the worst-case scenario would be that "lots of places will be covered by lots and lots of water by the end of the century." But projections vary widely, depending on which models scientists use, and how vigorously humanity cuts greenhouse gases, or not. The second question is whether particular locations will undergo hydrofracturing, he said. The third question: whether the process would run away, causing the shelf to undergo explosive Larsen-type disintegration.

Theodore Scambos, a leading Antarctic glaciologist and the National Snow and Ice Data Center, said the paper "does a great job of pointing to areas where one can say, 'If it floods with melt here, it's likely to break up the shelf." He added that it "has huge implications for sea level" if summer temperatures along the coasts rise.

"Eventually, all the ice shelves could be covered by melt water," said Lai. "But we don't have a time frame, and there are a lot of big questions left."

BOSTON - Inhaled nitric oxide (NO) can be a valuable adjunct respiratory therapy for pregnant women with severe and critical COVID-19, a team of researchers from Massachusetts General Hospital (MGH) has found. The delivery of the therapeutic gas to six COVID-19 pregnant patients admitted to MGH, as described in a paper in Obstetrics & Gynecology, resulted in a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. The resolution of viral infection within 22 days was observed in five of the six patients, findings that could have important implications for treating viruses like Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

"We noted rapid relief from breathlessness in these patients, with lower respiratory rate and better oxygenation after mask administration of high concentration nitric oxide, with no adverse side effects," says Lorenzo Berra, MD, investigator in the Department of Anaesthesia, Critical Care and Pain Medicine at MGH, and the corresponding author of the study. "In addition, inflammatory markers showed a rapid decrease after breathing nitric oxide and five of the six patients in our study showed viral clearance from nasopharyngeal swabs by 22 days after COVID-19 diagnosis. All patients were discharged in stable condition from the hospital. We found these results to be very encouraging."

Inhaled nitric oxide acts as a selective pulmonary vasodilator, increasing oxygenation by dilating or opening constricted blood vessels, especially in more well-ventilated areas of the lung, thereby improving intrapulmonary shunt fraction. Nitric oxide was approved by the U.S. Food and Drug Administration (FDA) in 1999 for the treatment of persistent pulmonary hypertension in newborns. Since then, NO has also been used off-label for many pediatric and adult clinical applications, including pulmonary hypertension in pregnancy, post-cardiac surgery, lung transplantation and acute respiratory distress syndrome (ARDS). The MGH study is the first to investigate the role of inhaled NO in pregnant people with COVID-19.

A recent report from the Centers for Disease Control and Prevention (CDC) suggests that pregnant women with COVID-19 are more likely to be hospitalized, are at increased risk of being admitted to the intensive care unit, and more often require mechanical ventilation compared to nonpregnant women. The lack of effective treatments for patients with severe or critical COVID-19 respiratory symptoms prompted a group of physicians from MGH to form an interdisciplinary team to offer pregnant women a novel treatment with inhaled NO to prevent progressive respiratory failure. Between April and June 2020, six hospitalized pregnant COVID-19 patients were given NO therapy. Each treatment was started within 48 hours of admission at a high but still safe dosage of 160 to 200 parts per million (ppm) of inhaled NO for 30 to 60 minutes twice-a-day.

"Even at that dosage, nitric oxide is easy to use and appears well tolerated," says Bijan Safaee Fakhr, MD, an investigator in the Department of Anaesthesia, Critical Care and Pain Medicine at MGH and lead author of the article. "We found that nitric oxide inhalation therapy provided rapid relief of shortness of breath in these patients and that their respiratory rates decreased." Moreover, he notes that three of the six women delivered four babies, including a set of twins, while in the hospital, and that each infant tested negative for COVID-19 and remained in good condition 28 days after maternal admission. These findings suggested to Safaee Fakhr that inhaled NO could result in improved placental oxygenation by improving maternal oxygenation.

The MGH physicians were further intrigued by the potential antiviral activity of inhaled NO in patients with COVID-19. Berra, who is also an associate professor of Anesthesia at Harvard Medical School cited a group of clinicians in China who, during the 2003-2004 SARS outbreak, administered inhaled NO to infected patients and reported that their chest x-ray findings cleared rapidly (Chen et al. Clin Infect Dis. 2004;39(10):1531-5). "Because of the genetic similarities between Coronavirus SARS-CoV-1 (SARS) and CoV-2 (COVID-19), we decided to use high-dose nitric oxide to prevent viral replication," Berra explains. What the physicians learned was that five of the six patients in their cohort who received inhaled NO but no other antiviral medication while in the hospital were clear of the virus, as shown by two negative nasopharyngeal swabs obtained after 9 to 22 days from treatment initiation.

"Additional randomized clinical trials are needed to confirm the antiviral effects and definitively determine the efficacy of inhaled nitric oxide on SARS-CoV-2," says Berra. "Irrespective of that, the cardiopulmonary, anti-inflammatory, and possible mild bronchodilatory effects of NO, coupled with its safety profile, offer clear evidence to support using high dose NO therapy for respiratory failure in pregnant women to combat a still unknown disease like COVID-19."

By making use of enzymes found in the digestive tract, MIT engineers have devised a way to apply a temporary synthetic coating to the lining of the small intestine. This coating could be adapted to deliver drugs, aid in digestion, or prevent nutrients such as glucose from being absorbed.

In a study conducted in pigs, the researchers demonstrated that they could use this approach to simplify the delivery of medications that normally have to be taken multiple times per day. They also modified the coatings to deliver the enzyme lactase, which helps people digest the milk sugar lactose, and to block glucose absorption, which could offer a new strategy to treat diabetes or obesity.

"These three applications are fairly distinct, but they offer a sense of the breadth of things that can be done with this approach," says Giovanni Traverso, an MIT assistant professor of mechanical engineering, a gastroenterologist at Brigham and Women's Hospital, and the senior author of the study.

The lining consists of a polymer made from dopamine molecules, which can be consumed as a liquid. Once the solution reaches the small intestine, the molecules are assembled into a polymer, in a reaction catalyzed by an enzyme found in the small intestine.

Junwei Li, a postdoc at MIT's Koch Institute for Integrative Cancer Research, is the lead author of the study, which appears in Science Translational Medicine.

Sticky polymers

The MIT team began working on this project with the goal of trying to develop liquid drug formulations that could offer an easier-to-swallow alternative to capsules, especially for children. Their idea was to create a polymer coating for the intestinal lining, which would form after being swallowed as a solution of monomers (the building blocks of polymers).

"Children often aren't able to take solid dosage forms like capsules and tablets," Traverso says. "We started to think about whether we could develop liquid formulations that could form a synthetic epithelial lining that could then be used for drug delivery, making it easier for the patient to receive the medication."

They took their inspiration from nature and began to experiment with a polymer called polydopamine (PDA), which is a component of the sticky substance that mussels secrete to help them cling to rocks. PDA is made from monomers of dopamine -- the same chemical that acts as a neurotransmitter in the brain.

The researchers discovered that an enzyme called catalase could help assemble molecules of dopamine into the PDA polymer. Catalase is found throughout the digestive tract, with especially high levels in the upper region of the small intestine.

In a study conducted in pigs, the researchers showed that if they deliver dopamine in a liquid solution, along with a tiny amount of hydrogen peroxide (at levels recognized to be safe), catalase in the small intestine breaks the hydrogen peroxide down into water and oxygen. That oxygen helps the dopamine molecules to join together into the PDA polymer. Within a few minutes, a thin film of PDA forms, coating the lining of the small intestine.

"These polymers have muco-adhesion properties, which means that after polymerization, the polymer can attach to the intestinal wall very strongly," Li says. "In this way, we can generate synthetic, epithelial-like coatings on the original intestinal surface."

Once the researchers developed the coating, they began experimenting with ways to modify it for a variety of applications. They showed that they could attach an enzyme called beta-galactosidase (lactase) to the film, and that this film could then help with lactose digestion. In pigs, this coating improved the efficiency of lactose digestion around 20-fold.

For another application, the researchers incorporated a drug called praziquantel, which is used to treat schistosomiasis, a tropical disease caused by parasitic worms. Usually this drug has to be given three times a day, but using this formulation, it could be given just once a day and gradually released throughout the day. This approach could also be useful for antibiotics that have to be given more than once a day, the researchers say.

Lastly, the researchers showed that they could embed the polymer with tiny crosslinkers that make the coating impenetrable to glucose (and potentially other molecules). This could help in the management of diabetes, obesity, or other metabolic disorders, the researchers say.

Temporary coating

In this study, the researchers showed that the coating lasts for about 24 hours, after which it is shed along with the cells that make up the intestinal lining, which is continually replaced. For their studies in pigs, the researchers delivered the solution by endoscopy, but they envision developing a drinkable formulation for human use. The researchers are also developing other alternative formulations, including capsules and pills.

The researchers performed some preliminary safety studies in rats and found that the dopamine solution had no harmful effects. Their studies also suggested that most or all of the dopamine molecules become part of the synthetic coating and do not make it into the tissue or the bloodstream, but the team plans to do additional safety studies to explore any possible effects the dopamine may have.

Moreover, the researchers investigated the nutrient absorption capacity of the intestine after 24 hours and showed no difference between animals that had received the gastrointestinal synthetic epithelial lining (GSEL) and those that hadn't received the GSEL.

Additionally, the team found that the coating was able to stick well to human GI tissue.