Culture

A new study from Tel Aviv University (TAU) presents an innovative treatment for deafness, based on the delivery of genetic material into the cells of the inner ear. The genetic material "replaces" the genetic defect and enables the cells to continue functioning normally.

The scientists were able to prevent the gradual deterioration of hearing in mice that had a genetic mutation for deafness. They maintain that this novel therapy could lead to a breakthrough in treating children born with various mutations that eventually cause deafness.

The study was led by Professor Karen Avraham of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience. The paper was published in EMBO Molecular Medicine on December 22, 2020.

Deafness is the most common sensory disability worldwide. According to the World Health Organization, there are about half a billion people with hearing loss around the world today, and this figure is expected to double in the coming decades. One in every 200 children is born with a hearing impairment, and one in every 1,000 is born deaf. In about half of these cases, deafness is caused by a genetic mutation. There are currently about 100 different genes associated with hereditary deafness.

"In this study we focused on genetic deafness caused by a mutation in the gene SYNE4 - a rare deafness discovered by our lab several years ago in two Israeli families, and since then identified in Turkey and the UK as well," Professor Avraham reports. "Children inheriting the defective gene from both parents are born with normal hearing, but they gradually lose their hearing during childhood. The mutation causes mislocalization of cell nuclei in the hair cells inside the cochlea of the inner ear, which serve as soundwave receptors and are essential for hearing. This defect leads to the degeneration and eventual death of hair cells."

"We implemented an innovative gene therapy technology: we created a harmless synthetic virus and used it to deliver genetic material - a normal version of the gene that is defective in both the mouse model and the affected human families," says Shahar Taiber, one of Professor Avraham's students on the combined MD-PhD track. "We injected the virus into the inner ear of the mice, so that it entered the hair cells and released its genetic payload. By so doing, we repaired the defect in the hair cells and enabled them to mature and function normally."

The treatment was administered soon after birth and the mice's hearing was then monitored using both physiological and behavioral tests. "The findings are most promising," says Professor Jeffrey Holt from Boston Children's Hospital and Harvard Medical School, a collaborator on the study. "Treated mice developed normal hearing, with sensitivity almost identical to that of healthy mice who do not have the mutation."

The scientists are now developing similar therapies for other mutations that cause deafness.

"This is an important study that shows that inner ear gene therapy can be effectively applied to a mouse model of SYNE4 deafness to rescue hearing," says Prof. Wade Chien, MD, from the NIDCD/NIH Inner Ear Gene Therapy Program and Johns Hopkins School of Medicine, who was not involved in the study. "The magnitude of hearing recovery is impressive. This study is a part of a growing body of literature showing that gene therapy can be successfully applied to mouse models of hereditary hearing loss, and it illustrates the enormous potential of gene therapy as a treatment for deafness."

As scientists around the globe wage war against a novel, deadly virus, one University of Colorado Boulder lab is working on new weapons to battle a different microbial threat: a rising tide of antibiotic-resistant bacteria which, if left unchecked, could kill an estimated 10 million people annually by 2050.

"The COVID-19 situation is definitely putting us at risk for increasing resistance to antibiotics, so it's more important now than ever that we come up with alternative treatments," said Corrie Detweiler, a professor of molecular, cellular and developmental biology who has spent her career seeking those alternatives.

In a paper published Friday in the journal PLOS Pathogens, Detweiler and her research team unveil their latest discovery--a chemical compound that works with a host's innate immune response to push past cellular barriers that help bacteria resist antibiotics.

Along with their other recently published discoveries, the authors say, the finding could lead to a new arsenal for fighting what could be the next big public health threat.

"If we don't solve the problem of finding new antibiotics or somehow making old antibiotics work again, we are going to see sharply increasing deaths from bacterial infections we thought we had beaten decades ago," said Detweiler. "This study offers a totally new approach and could point the way toward new drugs that work better and have fewer side effects."

In the United States alone, 35,000 people die annually from bacterial infections that could not be treated because they've grown resistant to existing drugs. Countless others suffer life-threatening bouts with once-easily treatable illnesses like strep throat, urinary tract infections and pneumonia. By 2050, the authors note, there could be more deaths from antibiotic resistance than from cancer.

"As our existing antibiotics adapt and work less, we risk essentially going back to a period 100 years ago, when even a minor infection could mean death," said Detweiler.

The pandemic has shone even more light on the problem, she notes, as many patients die not from the virus itself but from hard-to-treat secondary bacterial infections.

Meanwhile, she and other scholars worry that heightened use of antibiotics to prevent or treat those secondary infections, while at times necessary, may be exacerbating resistance.

Most antibiotics in use today were developed in the 1950s, and pharmaceutical companies have since scaled back on research in the field in favor of more profitable ventures.

To feed the pipeline, Detweiler's lab developed a technique called SAFIRE for screening for new small molecules which work differently than older drugs.

Of 14,400 candidates screened from a library of existing chemicals, SAFIRE identified 70 that hold promise.

The new paper centers around "JD1," which appears to be particularly effective at infiltrating what are known as "Gram-negative bacteria."

With a tough exterior membrane that prevents antibiotics from accessing the cell, and another interior membrane providing a buffer, these bacteria (including Salmonella and E. coli) are inherently difficult to treat.

But unlike other drugs, JD1 takes advantage of the host's initial immune assault on that outer bacterial membrane, then slips inside and goes after the inner membrane too.

"This is the first study to show that you can target a Gram-negative bacteria's inner membrane by exploiting the innate immune response of the host," Detweiler said.

In laboratory and rodent experiments, JD1 reduced survival and spread of Gram-negative bacteria called Salmonella enterica by 95%.

But while it damaged the bacterial cell membranes, it couldn't penetrate the fine layer of cholesterol that lined its mammalian host's cell membranes.

"Bacteria are vulnerable to JD1 in a way that our cells are not," said Detweiler, noting that for this reason, side-effects would likely be minimal.

Further studies are underway to explore JD1 and other compounds like it.

Meanwhile, Detweiler has formed a spin-off company to help commercialize other compounds which work by inhibiting pumps, called "efflux pumps," that bacteria use to pump out antibiotics.

"The reality is, evolution is way smarter than all of the scientists put together and these bacteria will continue to evolve to resist what we throw at them," she said. "We cannot rest on our laurels. We have to keep feeding the pipeline."

DALLAS - Dec. 22, 2020 - UT Southwestern scientists have adapted a classic research technique called forward genetics to identify new genes involved in autism spectrum disorder (ASD). In a study published this week in eLife, the researchers used this approach in mice to find one such gene called KDM5A.

Approximately 1 in 54 children in the U.S. is diagnosed with ASD, a neurodevelopmental disorder that causes disrupted communication, difficulties with social skills, and repetitive behaviors. As a disease with a strong genetic component, it is hypothesized that thousands of genetic mutations may contribute to ASD. But to date, only about 30 percent of cases can be explained by known genetic mutations.

For decades, forward genetics has been used to find mutations that cause disease. It involves inducing genetic mutations in mice, screening for certain phenotypes, and then identifying the causative mutation through sequencing of all genetic material of an organism, or its genome.

"The difficult part in the beginning was finding the mutations. It had to be done by laborious cloning," says Nobel Laureate Bruce Beutler, M.D., director of the Center for the Genetics of Host Defense at UTSW and study co-author. "We developed a platform wherein when you see a phenotype you know the mutational cause at the same time." So, when a mouse displays a certain phenotype or trait of interest, the researchers would know almost instantly what genetic mutation was causing it. This technique, combined with a screen developed to ascertain ASD-like behaviors in mice, made it possible to use forward genetics for the first time to identify new genetic mutations in ASD.

Beutler won the 2011 Nobel Prize in Physiology or Medicine for his discovery of a family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response.

In this study, the research team documented the quality and number of vocalizations in young mice carrying induced genetic mutations. Given that one of the common characteristics seen in autism is disrupted communication, the researchers were on the lookout for mice that had changes in these vocalizations.

"Initially we found that the quality of these vocalizations was different in mice with KDM5A mutations. Looking more closely, we found that mice completely lacking KDM5A have a severe deficit in the number of these vocalizations," says Maria Chahrour, Ph.D., who led the study. Chahrour is assistant professor of neuroscience, psychiatry, and in both the Eugene McDermott Center for Human Growth and Development and Center for the Genetics of Host Defense.

In addition to loss of vocalizations, mice lacking KDM5A also displayed repetitive behaviors and deficits in social interaction, learning, and memory - all hallmarks of ASD.

Because this was the first time that KDM5A had been implicated in ASD, the researchers looked into whether KDM5A mutations could be found in patients with autism as well. Through international collaborative efforts, the group was able to identify nine patients with ASD and causative KDM5A mutations. Strikingly, eight out of nine patients also had a complete lack of speech.

Though one broad term is used for ASD, Chahrour likens autism to cancer in that it is a collection of individually rare forms of autism with hundreds of different genetic causes. Mutations in KDM5A appear to be one of those forms.

"We've identified a new genetic subtype of autism, and we're going to look for more patients with mutations in KDM5A," explains Chahrour. "This has a direct impact on diagnosis too. When a clinician gets a clinical sequencing result that reports a KDM5A mutation, it's now a known autism gene."

Aside from the impact on diagnosis, the researchers are interested in further characterizing this gene's role in the brain. With a better understanding of what KDM5A is doing in the brain, scientists might be able to find a target to aid in future studies investigating possible treatments.

This work will expand beyond KDM5A as researchers search for more genes involved in ASD, a subject of research for which the simplicity and efficiency of forward genetics comes in handy.

"The wonderful thing about forward genetics is that we can grind away at the genome. We know progressively how much of the genome we've saturated," says Beutler, who estimates that his group has already mutated about half of the mouse genome with this approach.

Chahrour, also a member of UT Southwestern's Peter O'Donnell Jr. Brain Institute, looks forward to continuing to screen these animals for ASD genes, adding, "At some point we'll get to a stage where we can saturate the genome with mutations and theoretically find every gene that functions in social behavior and cognition. That's the ultimate goal."

Retinal ganglion cells (RGCs) are the bottleneck through which all visual impressions flow from the retina to the brain. A team from the Max Planck Institute of Neurobiology, University of California Berkeley and Harvard University created a molecular catalog that describes the different types of these neurons. In this way, individual RGC types could be systematically studied and linked to a specific connection, function and behavioral response.

When zebrafish see light, they often swim towards it. Same with prey, although the signals are entirely different. A predator, on the other hand, prompts the fish to escape. That's good, because a mix-up would have fatal consequences. But how does the brain manage to react to a visual stimulus with the proper behavior?

Optical signals are generated by photons that bombard the retina of the eye. Neurons in the retina collect and process these impressions. While doing so, the retina focuses on the important details: Is there contrast or color? Are there small or large objects? Is something moving? Once these details are filtered out, retinal ganglion cells (RGCs) send them to the brain, where they are translated into a specific behavior.

As the only connection between the retina and the brain, RGCs play a central role in the visual system. We already knew that specific RGC types sends different details to different regions of the brain. However, it has been unclear how RGC types differ on the molecular level, what their respective functions are, and how they help to regulate context-dependent behavior.

To begin to solve this puzzle, a team led by Yvonne Kölsch from Herwig Baier's laboratory analyzed the genetic diversity of RGCs. Collaborating with the groups of Joshua Sanes (Harvard University) and Karthik Shekhar (UC Berkeley), they determined the transcriptomes, i. e., the patterns of all active genes, in RGCs and thereby assigned each cell its own unique molecular fingerprint. A computational analysis of the large scale dataset comprising >30,000 RGCs identified at least 32 different RGC types based on similarities.

Cell type specific genes

In this new catalog of neuronal cell types, the scientists found genes that are only active in certain RGC types. With the help of these genes and targeted genome editing, they gained genetic access to selected RGC types - the prerequisite for studying their structure and function.

In the almost transparent zebrafish, it was thus possible to fluorescently label RGC types and to record in which brain regions their axonal projections end. It was also possible to determine which visual detail a RGC type prefers. To do this, the researchers showed fish larvae various visual stimuli and investigated which of them activate a particular cell type. For example, one RGC type reacted to light, but not to the simulation of an attacking predator.

What does it mean for the fish's behavior if this cell type no longer functions? Normally, fish larvae prefer a bright environment in which they can perceive their surroundings and easily find food. When the scientists inactivated the above cell type measuring light conditions, the fish lost their ability to navigate to their favorable environment - a clear sign that the RGC type is especially important for approaching light.

Highly specialized genes

The analysis links a molecularly described RGC type to a specific structure, function and behavioral response. It also shows how specialized individual RGC types are - from the brain regions they contact to their role in behavior. This finding supports the theory that highly specialized neuronal circuits are the brain's secret to translating diverse visual stimuli into proper behavior.

In the future, the molecular catalog will allow to systematically investigate other RGC types. The study thus takes us a decisive step forward in gaining a comprehensive understanding of the functional architecture of the visual system.

SETD2 is a protein well known as a chromatin remodeler, one that helps turn genes on or off by modifying histone proteins in the nucleus of the cell. When researchers discovered that SETD2 is mutated or lost in several cancer types, most commonly a type of kidney cancer called clear-cell renal cell carcinoma, all eyes turned toward SETD2 function in the nucleus of the cell to explain these cancers.

In 2016, the lab of Dr. Cheryl Walker, director of the Center for Precision Environmental Health at Baylor College of Medicine, made the unexpected discovery that SETD2 not only remodels chromosomes in the nucleus, but also microtubules of the cytoskeleton outside the nucleus. The cytoskeleton is a dynamic network of interlinking protein thread-like structures, including filaments and microtubules that extend throughout the cell. It gives a cell its shape and internal organization and provides mechanical support that enables cells to carry out essential functions like division and movement.

The Walker team found that SETD2 tags cytoskeleton microtubules with a methyl group. Loss of SETD2 resulted in defective delivery of chromosomes and problems with the separation of daughter cells during cell division.

"Our findings suggested that defects in SETD2 could not only affect gene expression but also functions controlled by the cytoskeleton, such as movement, metastasis and migration, which are very important for cancer cells," Walker said. "We wondered whether SETD2 might target other cytoskeletal proteins."

SETD2 works with Huntingtin and actin to regulate cell migration

Actin proteins, which form the filaments of the cytoskeleton, stood out as a prime target for SETD2. Two recent papers from the Walker lab have now revealed the role of SETD2 in modifying the actin cytoskeleton and its implications for two important functions of cancer cells, cell migration and autophagy.

One of the first findings was that SETD2 interacts with the actin cytoskeleton and is able to modify actin in cells or in reactions using purified proteins. SETD2 adds three methyl groups to actin at a location called lysine-68. Interestingly, they found that SETD2 interacted with two other proteins to methylate actin in cells: Huntingtin (HTT) and the actin-binding adapter HIP1R.

Trimethylated lysine-68 regulates the normal dynamics of actin, including polymerization and depolymerization. Disrupting the SETD2-HTT-HIP1R association inhibited actin methylation, caused defects in actin dynamics and impaired cell migration, an important function of cancer cells.

"These findings were very exciting because, to our knowledge, nobody had investigated the significance of the SETD2-Huntingtin interaction that had been known for over two decades," said first and co-corresponding author Riyad Navroz Seervai, an M.D./Ph.D. student in the Medical Scientist Training Program who completed his Ph.D. thesis in the Walker lab. "There was a limited list of papers about Huntingtin involvement in actin dynamics and cell migration, but enough to pursue the SETD2-Huntingtin-actin connection."

Together, these data provided a new understanding of how defects in SETD2 and HTT can drive disease via disrupting cytoskeletal methylation and defects in cell migration. The researchers also were able to manipulate the SETD2-HTT-actin axis to show that changes in cell migration are specific to this new target of SETD2 (actin) rather than to chromatin or microtubules.

Read all about this work in the journal Science Advances.

A role for SETD2 in autophagy

The group also explored the influence of SETD2 on autophagy, a mechanism cells use to remove unnecessary or dysfunctional components.

"Dr. Walker's lab has an extensive background and expertise in studying autophagy," Seervai said. "There was always a suspicion that SETD2 might be involved in this process, but it had not been tested. This project got off the ground once we performed the initial experiments looking at autophagy markers and found differences between cells with functional SETD2 and those without it."

As they had found when studying cell migration, disrupting SETD2's ability to methylate actin at lysine-68 caused defects in actin polymerization. In autophagy, disrupted actin polymerization altered actin's interaction with another protein called WHAMM. As a result, the cells had autophagy defects. Significantly, there were no changes in the expression of any autophagy-related genes, further suggesting a role for SETD2 cytoskeleton modification rather than its chromatin function.

Find all the details of this work in the journal Biochemical and Biophysical Research Communications.

A rapidly growing field of cell biology

"Actin modifications, such as the addition of methyl groups described here, have been aptly dubbed the 'Cinderella of the cytoskeleton' and are only now being recognized as key regulators of cytoskeleton dynamics," Seervai said. "But our findings and those of other groups are changing this perspective. More researchers are expressing interest in this new aspect of cytoskeleton regulation and we anticipate new discoveries pointing at potential new therapies for conditions involving cytoskeleton defects."

Seervai was also involved in organizing a special interest subgroup at the ASCB/EMBO Cell Bio 2020 virtual meeting on post-translational modifications of the cytoskeleton, including actin and tubulin. "We had nearly 300 people, including the ASCB president, at our session this year. From what I've heard, this is a sign that things have turned a corner for the field since such a session was first organized several years ago."

(Boston)--The COVID-19 pandemic has continued to cause dramatic shifts in the practice of otolaryngology. Even with standard precautions such as physical distancing and wearing personal protective equipment, aerosol-generating procedures such as nasolaryngoscopy (a commonly performed in-office procedure in which a soft, flexible fiber-scope is passed through the nose and into the throat) and intranasal instrumentation were determined to carry a risk of potential transmission if not adequately protected.

In an effort to mitigate exposure to these airborne particles, researchers from Boston University School of Medicine (BUSM) designed and tested a prototype nasolaryngoscopy hood, worn by the patient that offers safe and effective protection in reducing aerosols exposures.

In order to test the efficacy of the hood, a particle counter was used to calculate the average number of 0.3-mm particles/L detected during various clinical scenarios that included sneezing, nasolaryngoscopy, sneezing during nasolaryngoscopy and topical lidocaine spray administration. Experiments were repeated to compare the effectiveness of the hood versus no protection.

When no patient barrier (hood or mask) was used, a significant increase in aerosols was detected during sneezing, sneezing during nasolaryngoscopy and topical spray administration. With the hood was in place, the level of aerosols returned to baseline levels in each scenario.

"This simple intervention allows patients to undergo routine flexible nasal laryngoscopy, even with topical lidocaine spray administration, with less risk to the provider," explained corresponding author Christopher Brook, MD, assistant professor of otolaryngology--head and neck surgery at BUSM. "If a patient begins to sneeze during the examination, our data suggest that providers will remain protected through the use of the hood," he added.

While this study evaluated the efficacy of the hood in the setting of a routine nasolaryngoscopy in reducing aerosol spread, there are other possible applications but also one major barrier to overcome. "For clinical use, either the hood would need to be mass produced to allow for single use, or a safe and effective protocol of cleaning and reusing each hood would need to be established," said Brook who also is an otolaryngologist at Boston Medical Center.

The most-visited news release on EurekAlert! in 2020 racked up just under 1 million hits - the most in the site's near 25-year history.

The University of California, Riverside release is one of three about brain health on the 2020 Trending list in a year when COVID-19 dominated headlines across the globe. It described a mouse study that showed soybean oil induced negative changes to genes affecting neurological conditions like autism and Alzheimer's disease. The news release registered an unprecedented 987,050 visits, surpassing the previous record set in 2017 for yearly total views of a single release by almost 10%.

EurekAlert! is an editorially independent, nonprofit news release distribution platform operated by the American Association for the Advancement of Science (AAAS) as a free resource to journalists and the public. News releases hosted on EurekAlert! are produced and submitted by research institutions and journal publishers and must meet eligibility guidelines for acceptance.

In the fourth most-visited release, Swiss and Italian scientists proved a link between low gut microbial diversity and Alzheimer's disease. Researchers from Tokyo Metropolitan University found a new enzyme mutation that impacts how proteins cluster in the brain and cause Alzheimer's disease in the ninth most popular release.

Three COVID-19-related news releases appear on the list, starting with the second trending release. It described a research review that pointed to a relationship between cardio exercise and protection against COVID-19 respiratory symptoms. Potential coronavirus mitigation strategies also featured in the third and seventh news releases, in the form of an anti-parasitic drug and vitamin supplements, respectively. Overall, approximately 13% of news releases accepted by EurekAlert! in 2020 were COVID-related.

Half of the 2020 Trending releases originated outside the United States and, for the first time, a news release from China, by the Chinese Academy of Sciences, made the top 10. It describes the bones of a small prehistoric rodent, unearthed in northeast China, that clarified the evolution of mammalian ear bone structure. Another paleontology release detailed a specimen of the carnivorous Allosaurus, discovered in Utah, that became the oldest known of its species in North America.

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VIDEO: The fifth most-visited release in 2020 included a video showing a wolf pup playing fetch with a handler. The study showed this behavior in wolf pups who had not had previous exposure to it.

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Mussels, oysters and scallops have the highest levels of microplastic contamination among seafood, a new study reveals.

The research - led by researchers at Hull York Medical School and the University of Hull - looked at more than 50 studies between 2014 and 2020 to investigate the levels of microplastic contamination globally in fish and shellfish.

Scientists are still trying to understand the health implications for humans consuming fish and shellfish contaminated with these tiny particles of waste plastic, which finds its ways into waterways and oceans through waste mismanagement.

Study author, Evangelos Danopoulos, a postgraduate student at Hull York Medical School said: "No-one yet fully understands the full impact of microplastics on the human body, but early evidence from other studies suggest they do cause harm.

"A critical step in understanding the full impact on human consumption is in first fully establishing what levels of microplastics humans are ingesting. We can start to do this by looking at how much seafood and fish is eaten and measuring the amount of MPs in these creatures."

The study shows microplastic content was 0-10.5 microplastics per gram (MPs/g) in molluscs, 0.1-8.6 MPs/g in crustaceans, 0-2.9 MPs/g in fish.

The latest consumption data in the research shows China, Australia, Canada, Japan and the US are amongst the largest consumers of molluscs, followed by Europe and the UK.

Molluscs collected off the coasts of Asia were the most heavily contaminated with researchers suggesting that these areas are more heavily polluted by plastic.

Evangelos Danopoulos added: "Microplastics have been found in various parts of organisms such as the intestines and the liver. Seafood species like oysters, mussels and scallops are consumed whole whereas in larger fish and mammals only parts are consumed. Therefore, understanding the microplastic contamination of specific body parts, and their consumption by humans, is key."

Plastic waste generated worldwide is expected to triple to 155-265 million metric tonnes per year by 2060. Once the plastic finds its way into oceans, lakes and rivers it has the potential to end up as microplastic inside shellfish, fish and marine mammals.

The research points to the need to standardise methods of measuring microplastic contamination so that different measurements can be more readily compared. Researchers said more data is needed from different parts of the world to understand how the issue varies between different oceans, seas and waterways.

Chestnut Hill, Mass. (12/22/2020) - Air pollution in India resulted 1.67 million deaths in 2019 - the largest pollution-related death toll in any country in the world - and also accounted for $36.8 billion (US) in economic losses, according to a new study led by researchers from the Global Observatory on Pollution and Health at Boston College, the Indian Council of Medical Research, and the Public Health Foundation of India.

The 2019 death toll attributed to air pollution in India accounted for 17.8 percent of all deaths in the country in 2019, according to the study's findings, published today in the journal Lancet Planetary Health.

The $36.8 billion in economic loss was 1.36 percent of the country's gross domestic product, according to the report, titled "The health and economic impact of air pollution in the states of India."

Pollution-related losses "could impede India's aspiration to be a $5-trillion economy by 2024," the researchers concluded. "Successful reduction of air pollution in India would lead to substantial benefits for both the health of the population and the economy."

"Pollution takes an enormous human toll in India," said lead researcher Boston College Professor of Biology Philip J. Landrigan, MD, director of the Global Observatory on Pollution and Health. "It is causing 1.67 million premature deaths per year - many more than from COVID-19."

The consequences will be long-lasting without efforts to reduce air pollution in the nation of 1.35 billion people, according to Landrigan, whose research was funded in part by UN Environment Programme.

"It is also having a profound effect on the next generation of Indians," said Landrigan. "It increases future risk for heart disease, diabetes, and respiratory disease for today's children when they become adults. It is reducing children's IQ. It will be very difficult for India to move forward socially or economically if they don't do something about the problem."

Researchers also found rapidly changing patterns of air pollution and pollution-related disease in India, according to the report. The death rate from indoor air pollution, which is caused mainly by poorly ventilated home cook stoves, has decreased by 64.2 percent since 1990.

In the same time period, the death rate due to ambient (outdoor) particulate matter pollution increased by 115.3 percent and that due to ambient ozone pollution increased by 139.2 percent. These increases in deaths from ambient air pollution reflect increasing emissions from cars, trucks, and buses, as well as the widespread use of coal to generate electricity in India.

Among the many costs associated with increased mortality and illness caused by air pollutants, the researchers estimate the air pollution-related costs to India's health care system at nearly $12 billion in 2019.

Climate change exacerbates pollution, the researchers noted, through atmospheric stagnation, temperature-driven increases in particulate matter, and ground-level ozone formation, which are likely to be particularly severe in India.

State-by-state analysis showed a more than three-fold variation in air pollution death rates across the states of India. Southern Indian states have put policies in place to reduce air pollution when compared to states in the north, where pollution and its consequences showed a greater impact in mortality and economic costs, said Landrigan.

Landrigan said there are ample solutions and examples of successful pollution reduction policies that can be developed to meet the specific needs of the country and its states. China, a country with a similar size population and equally ambitious economic goals, adopted pollution control targets in its most recent five-year plan and is making progress on pollution control, he said.

"We point to countries like the United States where we reduced air pollution by 70 percent since passage of the Clean Air Act in the 1970s," said Landrigan. "At the same time, US GDP grew by 250 percent. There are similar statistics from Europe, Australia, and Japan. Pollution control does not stifle economic growth."

While researchers report a decline in indoor air pollution produced primarily by cook stoves used in millions of homes throughout the country, further reductions will require additional strategies that address poverty as well as energy needs, said co-author Gautam Yadama, dean of the School of Social Work at Boston College.

"One of our challenges is to provide the poor with greater access to devices and clean fuels that can be sustainably used in a variety of real-world conditions," said Yadama. "The more these are developed and tested in collaboration with communities -- particularly the women, the devices' end users -- the more likely their uptake."

Lifestyle, or put another way 'bad habits', is one of the textbook explanations for why some people are at higher risk for cancer. We often hear that smoking increases our risk of developing lung cancer or that a high-fat diet increases our risk of developing bowel cancer, but not all smokers get lung cancer and not all people who eat cheeseburgers get bowel cancer. 'Other factors' must be at play.

Now, new research from University of Calgary scientist Dr. Edwin Wang, PhD, is shedding light on those 'other factors'. Wang has discovered seven DNA fingerprints or patterns that define cancer risk. The research is published in Science Advances.

"This discovery rewrites the textbook explanation that cancer occurs because of human behaviour combined with some bad luck to include one's genetic make-up," says Wang. "We believe that a baby is born with a germline genomic pattern and it will not change, and that pattern is associated with a lower or higher cancer risk."

The research offers new insight into multi-generational disease risk as the germline represents the cells that determine our children and the DNA that is passed from parent to children. It is the first time scientists have described these highly-specialized biological patterns applicable to cancer risk.

Wang, a cancer systems biologist and big data scientist, holds the Alberta Innovates Translational Chair in Cancer Genomics. He hypothesizes that everyone fits into these risk categories making them more-or-less predisposed to cancer, much like a sliding scale. A member of the Alberta Children's Hospital Research Institute (ACHRI) and Arnie Charbonneau Cancer Institute at the Cumming School of Medicine, Wang found that the DNA fingerprints could be classified into subgroups with distinct survival rates. One of the seven germlines offers protection from developing cancer, and the other six germlines present a greater risk for cancer.

"It is interesting that one of these germlines is protective against developing cancer and it appeared frequently in our analysis of genomes," says Wang, a professor in the CSM's Department of Biochemistry and Molecular Biology. "We know there are individuals who can smoke and have an unhealthy lifestyle but never get cancer, and this discovery may explain that phenomena."

For this research, Wang conducted a massive systematic analysis of more than 26,000 germline genomes of individuals, about 10,000 people who had cancer, and the rest without. His team analyzed computer files from cancer patients at the National Cancer Institute - data collected by the National Institute of Health for the Cancer Genome Atlas, part of the National Institutes of Health in the U.S. The samples include 22 distinct cancers, including lung, pancreatic, bladder, breast, brain, stomach, thyroid, and bone and a dozen more. The control group of people without cancer included genomic-sequenced groups from Sweden, England and Canada.

The massive quantities of data could only be processed with machine learning. Wang's lab is equipped to deal with data through ultra high-speed networks at UCalgary. This research requires a colossal amount of computer storage: 10 million terabytes. To help understand this volume, one terabyte can store 250 movies.

"Even at high-speed, with two streams running 24/7, it took our lab three straight months just to download the biological information containing billions and billions of nucleotides in each individual genome," says Wang.

Wang notes that between five to 10 per cent of cancers are caused by specific gene mutations. Think of breast cancer and the inherited gene BRCA1 and BRCA2, a gene mutation made widely known by actor Angelina Jolie. Wang has always suspected these inherited cancers only represent a handful of associations and undertook a deeper investigation with advanced genomic capabilities to yield more associations.

"We wanted to investigate whether a genomic pattern or a substantial, repeatedly occurring sequential profile in genomes could serve as a promising measurement for genetic predisposition to cancer," says Wang.

"We found that one DNA-fingerprint was enriched tens to hundreds of times in germline genomes of cancer patients, suggesting that it is a universal inheritable trait encoding cancer risk." The research also uncovered that another DNA-fingerprint was highly enriched in cancer patients who were also tobacco smokers, indicating that smokers bearing such a DNA-fingerprint have a higher risk of cancer.

Genomic medicine makes diagnosis of disease more efficient, cost-effective, and can help people make health decisions throughout their life. Wang's research lays the groundwork for tools that could help cancer specialists and family physicians guide patients. "I hope that further studies are carried out to expand upon this work, so that it may eventually be put into practice allowing clinicians to inform patients of their cancer risk and how to take precautions to ensure a healthy life."

Researchers at the Kobe University Graduate School of Medicine have revealed that alterations in fetal microglia (*1) resulting from maternal inflammation could contribute towards the onset of developmental and psychiatric disorders. The research team including PhD student OZAKI Kana and Professor YAMADA Hideto et al. from the Department of Obstetrics and Gynecology observed that infant mice that were exposed to maternal immune activation (MIA mice) displayed changes in microglial process motility during gestation and development. These changes remained after birth and were linked to social behavior deficits, such as those that are found in autism spectrum disorders.

Microglia, the brain's immune cells, monitor the parenchyma of the brain by extending and retracting their processes. In recent years, controlling the number of neurons and synapses using this movement has received attention.

Therefore, process motility is thought to play a vital role in the microglia's physiological functions. This research sought to investigate how microglial process motility changes in developmental disorders and schizophrenia. The researchers succeeded in illuminating part of the role that these microglial changes play.

The research group compared and analyzed microglial process movements in MIA mice during the gestational, developmental and adolescent stages using two-photon microscopy (*2). They discovered that changes in microglial process motility were present at all stages, revealing that these alterations were related to social behavioral patterns akin to those characteristic of developmental disorders and schizophrenia.

This research was conducted in collaboration with Professor WAKE Hiroaki and Associate Professor KATO Daisuke of Nagoya University, and Dr. Andrew J. Moorhouse of The University of New South Wales. The results were published in Scientific Reports on December 7.

Main Points

The researchers revealed that in MIA model mice, microglial process movements changed during gestation and that these alterations persisted in the developmental and adolescent stages.

There was a recognizable connection found between sustained changes in microglial process motility and abnormal social behavior in adolescence, which was akin to that seen in developmental disorders and schizophrenia.

Research Background

Research published in recent years has suggested that maternal inflammation caused by infection and auto-immune diseases during pregnancy increases the risk of developmental disorders or schizophrenia occurring in the offspring. However, few studies on the mechanism by which maternal inflammation increases the risk of these disorders have focused on clarifying the role of the brain's immune cell microglia in this mechanism.

Microglia are the only immune cells in the brain. They originate in the yolk sac and permeate the brain during early embryonic stage. Microglia function as tissue macrophages and distribute themselves inside the brain via repeated division.

Up until now, scientists have focused on finding out how microglia contribute towards the formation of the neural network. In recent years, research has clarified that microglia monitor the brain parenchyma via repeatedly extending and retracting their processes, and this is how they perform their functions on neurons and synapses. As microglia are immune cells, they can also change in response to maternal inflammation.

The current research team revealed that changes to microglial process motility resulting from maternal inflammation during gestation remained after birth. They discovered this by comparing the motility of normal microglia with the microglia from MIA mice. The researchers also illuminated that in adolescence this altered process motility was linked to deficits in social behavior that are characteristic of developmental disorders and schizophrenia.

Research Findings

First, the researchers created MIA mice, which are mice exposed to maternal immune activation in the womb. This was achieved by injecting pregnant mice during the second or third trimesters with a substance to cause inflammation that resembled that which results from a viral infection. They subsequently compared the expression of microglial inflammatory agents (cytokines (*3)) during the embryonic and post-natal developmental stages. In both Group 1 (exposed to MIA in the second trimester) and Group 2 (exposed to MIA in the third trimester), there was an increase in microglial inflammatory cytokines in the brains of the fetal mice. In addition, the post-natal development stage changes in the expression of microglia-specific genes were also found in MIA mice.

Observation of microglia in MIA mice under a two-photon microscope showed that there was an increase in microglial process velocity at 18 days gestation for both the second and third trimester groups. However, in both groups microglial process velocity declined at 10 days after birth (i.e. during the developmental stage). Furthermore, the MIA mice that were induced with maternal inflammation during the second trimester demonstrated a tendency towards increasingly polarized microglial process motility. These results suggest the possibility that changes in microglial process motility affect the formation of the neural network during developmental stages.

It is known that inflammation, such as fever, can result in improved social ability in patients with autism. To investigate this, the researchers induced systemic inflammation in normal mice and MIA mice at 42 days after birth (adolescence) and compared the reactions of their microglia to this inflammation. They also evaluated changes in the mice's social behavior before and after the systemic inflammation was induced. From the results of this experiment, they found that microglial process velocity increased in response to systemic inflammation, and this was the case in both Group 1 and Group 2 MIA mice and in normal mice. However, polarized microglial process motility was seen only in Group 1 MIA mice (Figure 1). Furthermore, this revealed that the increased polarization of process motility is connected to social behavior.

The above findings showed that maternal inflammation affects the fetal microglia during the embryonic stage, resulting in alterations in microglial process motility that begin at the embryonic stage and remain in the developmental stage, or even the adolescent stage. Moreover, these research results demonstrate the possibility of a connection between changes in microglial process motility and deficits in social behavior that are characteristic of developmental disorders and schizophrenia.

Further Developments

This research has revealed that changes in microglial process motility are the key physiological parameter for the effects of maternal inflammation, and that these alterations persist from the embryonic stage up until the developmental or even adolescent stages, which suggests that these alterations affect neuronal network formation. Furthermore, they indicate a possible connection between these changes and social behavioral deficits found in developmental disorders and schizophrenia.

These results can help clarify how changes in microglial process motility affect the development of the neural network, thus contributing towards the treatment of developmental disorders and schizophrenia.

Dr. J. James Frost and The International Journal of Unconventional Computing will soon be publishing "Cancer's Intelligence" which reports that Cancer can be analyzed as an intelligent system of collaborating and computing cells. The limitations of the current regime of cancer research and treatment are addressed, and the resultant need for new paradigmatic thinking is presented. Features of intelligence pervade the natural world from humans to animals of all sizes and complexity to microorganisms. Yet, cancer has hitherto not been investigated as acting with intelligence as it evades the body and the oncologist's failed attempts to eradicate it.

In this analysis, concepts of computation, including self computation and the limits of computation; game playing; ε-machine analysis; self-aware systems; P and NP-hard problems; and Boolean networks are addressed and related to features of cancer that can be described as intelligent.

Dr. J. James Frost a retired Johns Hopkins University Professor said, "The grim plight of cancer continues to endure in the face of legions of targeted drugs, reams of cancer gene data, and multitudes of physicists and mathematicians on the attack."

A few of the many examples are the National Cancer Intelligence Network; "intelligent drug delivery"; Watson's Artificial Intelligence System for Cancer Care; artificial intelligence in image analysis; the "intelligent knife" for cancer surgery; and - last but not least - the intelligent mind of the oncologist.

Rather, this article addresses the obverse problem: cancer's own intelligence.

From currently available game-theoretical approaches for understanding and treating cancer to computation on Boolean networks as a mechanism for measuring the computation capability of cancer and its pathways, Dr. J. James Frost expands the discussion of intelligence as applied to cancer; computation and its limits and develops a new approach to advanced personalized oncology where elucidation of the patient's intrinsic cancer computational machine and its gameplay strategies, coupled to recent developments in AI human gameplay, including bluffing and deception, can lead to vastly improved strategies for the oncologist to defeat the patient's cancer.

Dr. Frost concludes in their OCP Research Paper, "The concepts summarized in this article squarely juxtapose the current cancer paradigm and the conditions for progress to a foundational level of understanding cancer and its intelligence. This new knowledge would necessarily lead to the development of novel measures to disrupt or reverse the cancer process. The road will be long and broad, requiring many disciplines to seamlessly stream together. It cannot be bypassed. The stakes are too high."

For more information on cancer, intelligence, computation, game theory, Boolean network, please view the FULL TEXT HERE

CHAMPAIGN, Ill. -- By drawing from decades of studies, scientists created a timeline marking the arrival of black-legged ticks, also known as deer ticks, in hundreds of counties across 10 Midwestern states. They used these data - along with an analysis of county-level landscape features associated with the spread of ticks - to build a model that can predict where ticks are likely to appear in future years.

Black-legged ticks can carry the bacterium that causes Lyme disease, an infection that can affect the nervous system, heart and joints. The new model will help local authorities prepare for the onset of Lyme disease in their counties before the first cases appear, researchers say. They report their findings in the Proceedings of the Royal Society B.

Black-legged ticks were first found in the Midwest in the 1960s in a few counties in Wisconsin and Minnesota. The first known case of what was later named Lyme disease occurred in the Midwest in 1969. Since then, black-legged ticks have expanded into numerous counties across those states and into Illinois, Indiana, Iowa, Michigan, Ohio, Nebraska, North Dakota and South Dakota. The first Lyme disease cases in those counties track closely with the first reports of ticks.

Understanding that local health departments report new Lyme disease cases in their counties to federal officials and that the National Land Cover Database includes information about landscape features of each county, the researchers chose to use county-level data in their model. Their goal was to identify factors associated with the spread of ticks and Lyme disease to new counties.

"We used historical information to build a model that forecasts the future spread of Lyme disease in the Midwest," said Brian Allan, an entomology professor at the University of Illinois Urbana-Champaign who led the research with former doctoral student Allison Gardner, a professor of biology and ecology at the University of Maine.

"Our model was based on a few landscape factors that were highly predictive of the spread of ticks and Lyme disease and could be used as an early warning system to forecast areas likely to undergo invasion next," Gardner said.

The researchers observed "a wavelike pattern of spread, where counties that get invaded with black-legged ticks tend to be adjacent to a county that has already been invaded," Allan said. "And in some Midwestern states, we see that areas adjacent to major rivers are invaded in sequence. In Illinois, for example, the ticks first arrived along the Illinois River and then spread up and down the river quite quickly."

The percentage of forest cover in a county also was important in predicting whether black-legged ticks would occur there. These three factors - proximity to a county where ticks had been detected, the presence of a river and the percentage of forest cover - together can predict the future occurrence of ticks in counties where none had been previously reported, the researchers found.

To test their model, Gardner used data gathered before 2012 to determine how ticks would spread into new areas in the Midwest from 2012 to 2016. The model predicted the appearance of ticks in new counties with greater than 90% accuracy.

"It was a little surprising to me that so few parameters could make these predictions with such high accuracy," Gardner said.

Looking forward, the researchers identified 42 additional counties in the Midwest where black-legged ticks are likely to be detected by the end of 2021. The evidence suggests those ticks will carry the Lyme disease bacterium.

Understanding where ticks may be present before they have been reported may prompt public health officials and clinicians to include Lyme disease as a possible diagnosis for patients appearing with symptoms consistent with the infection, Allan said.

"If they don't think the tick occurs in their area, doctors may be reluctant to diagnose a patient with Lyme disease," he said.

Military members who receive gun locks and lethal means counseling, which focuses on ways to limit a person's access to specific methods for suicide, are more likely to use a gun safe and unload firearms before they are stored, according to a Rutgers researcher.

The study was published in the American Journal of Public Health.

More than 60 percent of military suicides involve firearms. "Suicide mortality is higher in homes with a firearm and the majority of military personnel do not store their firearms safely or report suicidal thoughts," says Michael Anestis, executive director of the New Jersey Gun Violence Research Center based at Rutgers and an associate professor of Urban-Global Public Health in the Rutgers School of Public Health.

The researchers tracked 232 firearm-owning members of the Mississippi National Guard who were divided into four groups: those who received lethal means counseling or health and stress counseling only or a combination of both types of counseling in addition to being given cable gun locks. They followed up at three and six months to assess how safe firearm storage practices improved.

They found that the combination of lethal means counseling and cable locks resulted in greater adoption of safe storage methods, such as storing firearms in a gun safe, using a locking device when the firearm is not in use and storing firearms unloaded.

Participants who received cable locks were about twice as likely to use locking devices. Those who received lethal means counseling alone increased their use of gun safes and locking devices by 40 percent over six months.

"The findings show that service members may benefit from lethal means counseling and distribution of cable locks, perhaps at the point when a person enters the service," Anestis said.

New research shows that a majority of European anaesthesiologists and intensive care specialists believe that precious intensive care (ICU) capacity should be shared between nations during international emergencies such as the COVID-19 pandemic, allowing countries with excess capacity to help those that are being overwhelmed at any particular moment.

The study is published in the European Journal of Anaesthesiology (the official journal of the European Society of Anaesthesiology and Intensive Care [ESAIC]), and is co-authored by Dr Elisabeth Adam, University Hospital Frankfurt, Germany; Professor Kai Zacharowski, President of ESAIC and also of University Hospital Frankfurt, Germany; Professor Stefan De Hert, Immediate Past President of ESAIC and University Hospital Ghent, Belgium, and colleagues.

During the first wave of the pandemic, countries such as Germany, which experienced a relatively low case load and also have a higher number of ICU beds per head of population, were able to help other European nations that were temporarily or continuously overwhelmed with an excess of cases.

"Mass casualty events (MSE), such as the COVID-19 pandemic, can generate many critically ill patients that can overwhelm health care systems," explain the authors. "When there are limited medical resources, recommendations for the preparation and management of such MSEs have suggested the use of a triage system for the fair and adequate allocation of the available resources. However, these recommendations tend to be based on ethical triage systems and do not address mechanisms that might balance overcapacity and overload of health care systems in some countries with availability of ICU beds in others, as seen during this pandemic."

This new study assessed opinions on the acceptance of allocation strategies for managing patients and limited resources for critical care that are not based on ethical triage, but on existing international capacity.

The authors conducted a survey sent to the representative bodies (National Anaesthesiologists Societies Committee (NASC) and Council) of ESAIC, that includes experienced national key opinion leaders, anaesthesiologists and intensivists, across European borders. The objective was to provide expert opinions and guidance to facilitate the (ethical) burden currently facing these specialists on the front line of this pandemic.

A total of 74 responses were received from 42 countries representing ESAIC. The majority of the 74 respondents (84%) indicated that resources for COVID-19 were available at the time of the survey, taken during the first wave in April 2020. Of the representatives of the ESAIC governing bodies, 59% favoured an allocation of excess critical care capacity: of these, two thirds (69%) wished to make them available to patients from other countries, while one third (31%) preferred to keep the resources available for the local population of that country.

Regarding the type of distribution of resources, 35.3% preferred to make critical care available, 32.4% favoured the allocation of medical equipment and 32.4% wished to support both options (meaning in total some two thirds were in favour of making critical care available to other nations). In total, of all consulted members of ESAIC, around 60% were in favour of the implementation of a centralised European institution to distribute such resources.

The authors say: "Strategies to manage critical care capacity during the COVID-19 pandemic may be politically charged and ethically controversial. They pose tremendous challenges for both health care providers and policy makers. As critical care bed numbers vary considerably between countries in Europe, an international platform that provides a dialogue on free, available and restricted resources should facilitate the planning and use of critical care resources in the future."

They add: "The main finding of an emerging readiness to share critical care resources underscores the importance of establishing specific systems for further mass casualty events, such as further waves of the COVID-19 pandemic or other new, as yet unknown threats. The aim should be to assess and ultimately restructure inequalities of critical care supply resources to address shortages in the availability of critical care beds."

They say that the devastating experience in Italy, and other countries since, has clearly demonstrated the limitations that can exist on a national level, despite the greatest efforts of all concerned to effectively manage a new pandemic.

They conclude: "Europe needs a tool to match the supply and demand of ICU beds for COVID-19 patients of the local population, based on infection rates and length of stay. Where demand exceeds supply, patients should be re-allocated on an international basis in close collaboration with the specialties responsible for treating patients with COVID-19 who are citizens of the European Union...this would be appropriately organised by a suitable political and medical institution to be implemented in the event of future crises requiring medical treatment beyond locally available capacity."