Culture

Several countries have combated low organ donor counts by implementing a priority rule that pushes registered donors to the front of the line if they ever need a transplant. However, according to a study from the McCombs School of Business at The University of Texas at Austin just published in Management Science, this model has drawbacks.

McCombs accounting professor Ronghuo Zheng, along with Tinglong Dai of Johns Hopkins University and Katia Sycara of Carnegie Mellon University, saw a flaw with the priority rule that others, such as Nobel Prize-winning economist Alvin Roth, have advocated for the United States. Although the program incentivizes more donors and increases the supply of organs, there is the potential risk that the quality of donated organs will decline. Individuals who are more likely to become sick have the highest incentive to donate, because they are most likely to need a transplant in the near future.

"A person might feel pressured to become a donor, even though they don't want to because if they don't register, they might not have the opportunity to get a transplant," Zheng said.

The study, "Jumping the Line, Charitably: Analysis and Remedy of Donor-Priority Rule," examines this problem and proposes a solution of a "freeze period" for each pledge for a specified length of time during which donors are not given priority for a transplant until the waiting period expires.

"It ensures the organ supply is higher without compromising the quality of the organs," Zheng said.

In the study, researchers created a simulated organ market and placed a dollar value factor using data from the U.S. Organ Procurement and Transplantation Network. They found that running the model without a freeze period would have a net cost to society of $76 million a year due to setbacks from having more lower quality organs, while using a three-year freeze period could potentially boost social welfare by $235 million a year.

"When used in conjunction with the donor-priority rule, this remedy can ensure social-welfare improvement by expanding the size of the donor registry without reducing the average quality of donated organs or inducing unnecessarily high psychological costs of donating," Zheng said.

Scientists have succeeded in reducing levels of the bovine leukemia virus (BLV) in cows with severe infections by combining an immune checkpoint inhibitor and an enzyme inhibitor. The finding could be utilized to control other diseases in cattle, and perhaps in humans someday.

The BLV infection is a chronic viral infection affecting cows that is endemic in Japan and many other countries. At present, there is no effective vaccine or treatment. A total of 3,859 cases of bovine leukemia were reported among cattle in Japan in 2018, a 38-fold increase over 1998, posing a serious economic threat to cattle farmers.

In previous studies, the team led by Satoru Konnai of Hokkaido University demonstrated that the progression of bovine leukemia is closely related to immune suppression induced by immune checkpoint proteins such as PD-L1, and that an anti-PD-L1 antibody could effectively treat BLV-infected cows. However, the antibody alone was not effective in advanced cases with high BLV counts. Therefore, the researchers focused on prostaglandin E2 (PGE2), a bioactive substance which they discovered acted as an immune suppressor by upregulating PD-L1 in cows with a chronic bacterial disease called Johne's disease.

In the present study published in The Journal of Immunology, the team first showed that blood PGE2 levels increased in BLV-infected cows as the disease progressed. They also found that a COX-2 inhibitor, which blocks the production of PGE2, activated immune response against BLV in cultured immune cells, and that combining this with the anti-PD-L1 antibody boosted the immune activation effect. Most importantly, cows administered the COX-2 inhibitor showed reduced viral loads, demonstrating its antiviral effect in the animals themselves. Administering both drugs, the COX-2 inhibitor and anti-PD-L1 antibody in combination, led to reduced viral loads in advanced stage cows.

"Our study showed that the drug combination has an antiviral effect in BLV-infected animals with high viral levels, which are a major source of infection on farms," says Satoru Konnai of Hokkaido University. The researchers plan to conduct a larger verification experiment on BLV-infected cows and also study whether the drugs have any antibacterial and antiviral effects on other bovine diseases.

A team of neurobiologists from Peter the Great St. Petersburg Polytechnic University (SPbPU) published an article on their study of the causes of Alzheimer's disease and suggested therapy methods. The scientists believe the disease is associated with the genes that code the formation of contacts between neurons. The team also discovered a substance that could considerably reduce the negative effect of mutations in these genes. The work was published in Neuroscience.

Alzheimer's disease is one of the most widely-spread neurodegenerative diseases that manifests itself in elderly patients. At first the patients experience short- and then long-term memory impairment leading to dementia. Exact causes and main physiological pathways that lead to Alzheimer's disease remain unknown, therefore there is no effective therapy. Currently available therapeutic drugs are only able to slow down the symptoms. Another issue with this disease is that it is difficult to diagnose on early stages.

Memory loss is believed to be caused by the dysfunction of synapses in the brain. A neuronal synapse is a place of contact between distinct neuronal cells (neurons). Any abnormalities in this contact negatively affect many brain functions including memory.

Alzheimer's disease can be inherited, and in this case patients are carriers of mutations. Some of them can be found in the genes that code amyloid precursor protein (APP). Cellular enzymes (secretases) cut the mutated protein, and amyloid beta peptide is formed. Other mutations may occur in the genes that code presenilins (proteins in the cellular membrane that are part of an secretase that cleaves APP to produce beta amyloid). All of them lead to the formation of amyloid plaques in the brain, and those break synaptic contacts and therefore cause the development of the disease.

A team from the Laboratory of molecular neurodegeneration SPbPU studied the PSEN1ΔE9 mutation that causes the removal of a certain gene region coding presenilin 1. This mutation was found in patients with inherited form of Alzheimer's disease in Finland. To study the properties of this mutation, the authors of the work added the mutated gene of presenilin 1 to the cultures of neurons along with a gene coding a fluorescent protein. The latter helped the scientists register the changes in the morphology of the synapses. The mutated gene and the gene of the fluorescent protein were added simultaneously, and therefore each fluorescent neuron expressed the mutated presenilin 1 gene. Dendrites have small protrusions (spines) on their surface, the shapes of which indicate the stage of a synapse's developments and its activity. In cells with the PSEN1ΔE9 mutation the number of mushroom-shaped spines was considerably reduced. This is a sign of reduced contact area between the neurons. Besides the changes in the shape of dendritic spines, the cells also experienced changes in their ability to transmit calcium ions that play an important role in the formation of a neural impulse.

Specifically, the neurons with the PSEN1ΔE9 mutation exhibited increase activity of store-operated calcium channels. After the EVP4593 compounds that blocks store-operated calcium channels was added, the negative effects of the mutation were considerably reduced and neural functions were almost back to normal. Therefore the team suggested that EVP4593 and compounds with similar activity may become promising prototypes of anti-Alzheimer's drugs.

However, the scientists emphasized that the Alzheimer's is a multifactor disease. This means that different patients can experience dysfunctions in different signalling pathways. Therefore, therapy should be selected individually for each patients. The authors of the work believe that EVP4593-based compounds may be used to treat the patients with increased activity of store-operated calcium channels.

Air pollution is made up of both gaseous and particulate matter (PM). Each year almost two million people die as a direct result of air pollution with many more experiencing impaired lung function, developing lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). However research, on the effects of low level air pollution, is often overlooked.

An international research team, led by the University of Technology Sydney (UTS) and the Woolcock Institute of Medical Research (WIMR) investigated whether a low level of exposure to PM10 was harmful. PM10 refers to particles equal or below 10 microns in size, they make up a large proportion of air pollution and can enter the lung.

The results of the study have been published in the American Journal of Physiology - Lung Cellular and Molecular Physiology (AJP-Lung).

Dr Yik Chan from UTS and WIMR, and co-lead author on the paper, said that low level air pollution was often mistakenly treated as "safe" and not harmful to health.

"In Sydney and other Australian capital cities the levels of traffic related air pollution (TRAP) are low by world standards and not often considered a problem in terms of developing chronic lung disease. However almost everyone living in an urban area is exposed to TRAP," Dr Chan said.

"Sydney has a lot of new construction taking place, as well as a growing population and increased traffic is inevitable," he said.

Researchers from the Kolling Institute, UNSW, Chinese University of Hong Kong, Chinese Academy of Sciences were also involved in the study that showed that, after three weeks, mice exposed to low levels of traffic related PM10 had an inflammatory response.

Chief Investigator Associate Professor Brian Oliver said that "these results have important implications for new [building] developments".

"For example, should schools or day care centres be built next to busy roads?

"Our results indicate that PM is a pro-inflammatory molecule, which exerts effects even at low concentrations. In our model we found strong, and statistically significant evidence of, lung inflammation and dysregulated mitochondrial activity. The mitochondria are the powerhouse of the cell, which means that any changes to the mitochondria effects energy production by the cell, and therefore how the cell divides and responds to external stimuli."

The researchers say that people living alongside major traffic corridors need to be aware of the potential adverse effects on their respiratory health.

Albinism is the best-known of a group of rare genetic disorders that can affect both eyes and skin. Some genes have been identified that are linked to these conditions, but many remain mysterious. Now a team led by UC Davis researchers has identified dozens of these genetic mutations in a screen of gene-targeted "knockout" mice. The authors hope the work, published Aug. 1 in Scientific Reports, will be a resource for clinicians specializing in genetic disorders.

"This mouse data may be of interest to clinicians, especially for patients with no known genetic cause for their condition," said Ala Moshiri, associate professor of ophthalmology in the UC Davis School of Medicine and corresponding author on the paper.

Skin, eyes and nerve tissue are linked because they all develop from the same early embryonic tissue. Another group of rare eye and skin disorders distinct from albinism, called phakomatoses, are also caused by genetic alterations inherited from parents or that occur by accident early in embryo development.

Albino people and animals lack pigment in their hair, skin and eyes. The degree of pigment loss varies, depending probably on the genetic change responsible. Some albinos are entirely lacking in pigment; at the other end of the scale, some people with "blonde" coloration may have a mild form of albinism.

There are known genes linked to albinism in humans, but not all cases have a clear genetic cause.

Lab mouse a model for human genetics

Moshiri, Bret Moore, resident at the UC Davis Veterinary Medical Teaching Hospital and an international team of colleagues searched the public database of gene knockout mice created by the International Mouse Phenotyping Consortium (IMPC) for animals with skin, hair or pigmentation abnormalities. Then they cross-checked for those which also had eye defects. That produced a list of 52 genes affecting both skin and eye organ systems, 35 of which were previously unknown.

"I expect the majority of these genes will cause similar problems in humans," Moshiri said.

The IMPC is an international effort including the Mouse Biology Program at UC Davis. The IMPC collaborators create mice with targeted deletions of a single gene ("knockout" mice) and examine the effects. So far, the consortium has produced lines of knockout mice for about 6,000 genes, of which more than 5,000 have been characterized, or phenotyped, across 11 body systems.

Identifying mouse genes related to a specific disorder can help identify the equivalent genes in humans. Sequencing an entire human genome is relatively easy in 2019, but working out which genetic change is tied to a specific disease or disorder is much harder because humans are so genetically variable. Laboratory mice, on the other hand, are inbred on a consistent genetic background, making it much easier to link traits to a single genetic change. Armed with a list of candidate genes from mice, clinicians could home in on specific genes in human patients.

BOSTON, Aug. 1, 2019 -- Use of the illegal stimulant methamphetamine causes build-up of tough protein fibers in heart muscle, which may help explain the development of enlarged hearts and heart failure in users, according to preliminary research presented at the American Heart Association's Basic Cardiovascular Sciences 2019 Scientific Sessions.

Methamphetamine, also known as meth, is an extremely addictive and commonly abused stimulant drug, with 1.6 million Americans reporting using the drug in 2017.

Previous autopsy reports of some meth users have documented injury to heart cells, scarring of heart muscle and enlargement of the heart. The current studies were designed to systematically compare autopsy results in meth users and non-users and look for the mechanisms by which the drug might create heart problems.

"Our goal is to discover a fundamental mechanism of methamphetamine toxicity in order to find a way to treat heart muscle diseases associated with illicit methamphetamine use," said Md. Shenuarin Bhuiyan, Ph.D., senior author of the study and assistant professor in the department of pathology and translational pathobiology at the Louisiana State University Health Sciences Center-Shreveport.

Researchers used heart samples obtained at autopsy from 32 chronic meth users (mostly Caucasian men, average age 38 years) who died from meth overdose or from gunshot wounds, hanging, blunt force injury, stab wounds or sudden heart or lung problems. These were compared with samples from five non-substance users who also died suddenly from gunshot, hanging, blunt force injury or blood clots in the lungs. Meth used was established by medical history and the results of toxicology reports.

In comparison to samples from non-users, samples from the heart's main pumping chamber (left ventricle) in meth users showed:

Increased deposits of collagen (stiff protein fibers) around the blood vessels.

Accumulation of collagen throughout the spaces between heart muscle cells.
"Regardless of the cause of death, we found methamphetamine has profound harmful effects on the cardiovascular system and results in irreversible damage to the heart, raising the risk of a heart attack, sudden cardiac arrest and heart failure," said Chowdhury S. Abdullah, Ph.D., co-lead author of the study and a postdoctoral fellow in Dr. Bhuiyan's laboratory. "Rehabilitation centers for methamphetamine users should routinely monitor heart function and look for signs of heart failure, since early detection of heart problems could prevent further deterioration of the heart muscle. Monitoring should continue even after people have quit using the drug."

The researchers found similarly increased collagen deposits in mice exposed to meth compared to those who were not. The studies on mice also indicated that methamphetamine may lead to structural changes in heart muscle by inhibiting a specific receptor in the heart, suggesting a possible mechanism to prevent meth-induced heart damage in the future.

The study is limited by using only autopsy samples, so researchers could not determine how the structural differences they documented in methamphetamine users might specifically affect blood tests and heart function.

"We need to further study cardiac function and biochemical blood parameters in methamphetamine users and compare them to those in other substance users and in non-substance users," Bhuiyan said.

New Haven, Conn. -- Yale investigators have shown that the combination of a vaccine and a medicated cream is a promising strategy to dramatically reduce the recurrence of genital herpes. Their study, co-led by researchers at the University of Pennsylvania and University of Cincinnati Children's Hospital Medical Center, was published in the journal npj Vaccines.

Herpes simplex virus (HSV) type 2, which causes genital herpes, is very common, affecting more than 400 million people worldwide. There's no cure and efforts to develop a vaccine have had limited success.

The research team tested a novel vaccine strategy, known as prime and pull, in guinea pigs infected with genital herpes. The "prime" involves a vaccine that generates a response to the virus from T cells, highly specialized immune cells. The "pull" consists of a cream containing imiquimod, a medication commonly used to treat genital warts. Applied to the affected area, the cream attracts key immune cells to the site of infection where they can block the virus from spreading and causing herpes lesions.

The study showed that the effect of the combination therapy was far greater than either the vaccine or cream alone. "It's the first time that a study has shown that prime-and-pull strategy can block existing recurrent disease," said co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale School of Medicine.

"Development of a therapeutic HSV vaccine is a high priority. Our exciting results have encouraged us and, hopefully others, to pursue this strategy with more vaccines," said co-corresponding author David Bernstein, professor of pediatrics and former director of the Division of Infectious Diseases at Cincinnati Children's Hospital.

The study team gave three rounds of treatment to the animals, noting that the strategy worked rapidly and beginning with the first round.

This strategy, if developed into a therapy for humans, could be a game changer for individuals with recurrent infections or resistance to standard antiviral treatment, said Iwasaki. Active herpes infection causes painful lesions that are physically and emotionally harmful to affected people, she noted.

Japanese researchers were able to rapidly and accurately predict the microstructure of Nickel - Aluminum (Ni-Al) alloys that are commonly used in the design of jet engine turbine parts. Predictions of the microstructure of these alloys have so far been time-consuming and expensive. The findings have the potential to greatly advance the design of materials - made up of a range of different alloys - that are used to make products in several different industry sectors.

Alloys are durable materials made up of two or more metals. The current high cost and design limitations of traditional alloy manufacturing processes have driven the need to create more efficient design methods. One key challenge has been how to accurately predict an alloy's microstructure (the very small-scale structure that is only visible by microscope) which can greatly influence physical properties such as strength, toughness, resistance to corrosion, hardness and/or wear and tear resistance.

The authors were able to predict alloy microstructures by using the "first-principle phase field method." This procedure predicts the microstructure of alloys based on the fundamental laws of physics alone (first principles) and then uses those parameters to model microstructure formations (phase field). This is contrary to empirical modeling, or predictions based on experiments or previous observations alone. Furthermore, the researchers conducted their modelling experiments under high temperatures that mimic those of jet engine turbines (~1027oC).

The research was published in Nature Communications on Aug 1, 2019.

The quest of new materials with desirable properties requires microstructure engineering of materials based on changing several variables, such as composition, morphology, pressure, temperature, doping, casting and forging.

A reliable simulation technique that can help with the design and production of new materials based on a theoretical principle alone could make production faster and cheaper. However, most of the current theories of material design are phenomenological and derived from experimental observations and empirical experiences. These are both time-consuming and expensive.

What makes the first-principles phase field method so advantageous, according to the authors, is that it bridges the accurate small-scale (first principles) calculations and large-scale (phase field) model by renormalization theory, a concept in physics that essentially makes infinite degrees of freedom finite, or continuous variables discrete. In other words, by using their method, they were able to overcome time-consuming and expensive experimental procedures and still produce materials that were in agreement with experimental methods.

"First-principles phase field method was invented as the world's first innovative multiscale simulation technique. Using this method, we were able to successfully predict complex microstructures of any compositions of Ni-Al alloys from first-principles (basic laws of physics) without using any empirical parameter, and our results agree quite well with experiments," says Kaoru Ohno, corresponding author and professor at Yokohama National University.

Ohno and co-authors from the National Institute for Materials Science in Japan say the method can be used to predict mechanical strength of alloys because the local force distributions as well as the microstructures can be easily calculated.

The method that the authors present can also be used to predict microstructures of multicomponent alloys, or alloys that are made up of more than two metals. "These studies highlight the fundamental nature of steels and other alloys that have so far only been demonstrated based on empirical observations. As such, the proposed method is a powerful theoretical tool to quickly predict the most suitable alloy that can realize the desired strength, toughness, ductility, plasticity, lightness, etc. as much as possible," adds Ohno.

In the future, the authors plan to apply the method to various steel materials and other multicomponent alloys in order to predict the dependence of microstructures and local stress distributions on their initial compositions and better understand their characteristics.

Hip fractures are a major cause of death and disability among older people worldwide, with 70,000 cases every year in the UK, which cost the NHS around £2 billion.

In 2010, a Best Practice Tariff (BPT) was launched across England, which promised extra payments to hospitals for each hip fracture patient whose care satisfied six clinical standards, such as surgery within 36 hours.

Researchers from the University of Oxford and Yale University compared the data from England with that in Scotland, which does not provide BPT payments to hospitals. They found that the BPT scheme saved up to 7,600 lives in England between 2010 and 2016.

David Metcalfe of Oxford's Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, said: 'This is the first study to show that the Best Practice Tariff drove changes in practice that reduced mortality for older adults with a hip fracture in England.

'Our research also suggests that the BPT led to generally improved standards of care for hip fracture patients. It increased the proportion of patients receiving an operation within 36 hours, shortened the average length of stay in hospital and reduced the number of patients that had to be re-admitted to hospital.

'As it is possible that similar schemes could improve outcomes for patients and reduce costs for the NHS, we should support the controlled expansion of the BPT model to other clinical areas.'

A total of 1,037,860 adults aged over 60 were admitted to hospitals between 2000 and 2016 with a hip fracture in England, and 116,594 in Scotland. Before the BPT scheme was introduced, trends in 30-day mortality were the same in England and Scotland. However, the number of hip fracture deaths fell much more markedly in England after the BPT was introduced. A pre-existing trend towards increased numbers of patients requiring re-admission to hospital was halted after the introduction of the BPT scheme.

CLEVELAND -- In a perspective article appearing in the Aug. 1 issue of the New England Journal of Medicine, a group of prominent physician-scientist leaders, including senior pharmaceutical executives and Nobel laureates, proposes a plan for increasing the number of physicians who conduct research looking for tomorrow's breakthroughs and cures.

They write, "Revitalizing the physician-scientist pipeline is of critical importance to overcoming current and future health challenges."

As part of that effort, they announce the establishment of a nonprofit foundation, the Physician-Scientist Support Foundation, which has a mission to build a sustainable and diverse physician-scientist workforce by supporting the development of investigators who will make fundamental discoveries that improve human health.

Lead author Mukesh K. Jain, MD, Chief Academic Officer at University Hospitals Cleveland Medical Center and Vice Dean of University Hospitals Affairs at Case Western Reserve University School of Medicine, said, "Physician-scientists have been a driving force in biomedical research and have made major contributions to medical breakthroughs. However, in the past 40 years, the proportion of U.S. doctors engaged in research has dwindled from a peak of 4.7 percent of the overall physician workforce in the 1980s to about 1.5 percent today

"The need to take action is now. This decrease comes at a time when we crucially need innovations in medicine, as the population ages and communicable diseases spread more rapidly and widely around the world," he said.

The authors enumerate a diverse set of challenges that have resulted in the decline of physician-scientists. They propose solutions to augment entry of medical trainees into research, reduce attrition, and increase support for this career path both through institutional and national efforts. They also advocate for the creation of a national network of academic institutions committed to supporting physician-scientists.

For their foundation, they seek partners who share their sense of urgency about refilling the pipeline of physician-scientists.

"Together, we can catalyze a new golden age by cultivating and supporting the next generation of talented physician-scientists," said Dr. Jain.

Nearly 80 percent of radiation oncology studies funded by the National Institutes of Health involve investigating the effects that radiation has on tumor cells and healthy tissue in pre-clinical settings, such as experiments done in cell cultures or mice. A majority of these radiation biology studies, however, have serious flaws in how their irradiation methodology is described, which makes them very difficult to replicate, according to a new finding from the University of Maryland School of Medicine (UMSOM).

Important details in the irradiation protocol and the experimental setup are routinely not included in most of these journal articles, which could lead to dose variations or other errors when other researchers try to repeat the experiments in their own laboratories.

"Glaring omissions or errors in the methodology sections of radiation biology journal articles make the studies very difficult to reproduce, interpret, and compare with other research," said study principal investigator Yannick Poirier, PhD, Assistant Professor in the Department of Radiation Oncology at UMSOM.

In the new study published this month in the International Journal of Radiation Oncology Biology and Physics, Dr. Poirier and his colleagues from UMSOM and the University of Washington, Seattle, reviewed 1,758 peer-reviewed studies from 469 journals that were used in pre-clinical studies to evaluate the effects of radiation therapy to treat malignant tumors and other conditions. Specifically, they examined the journal article's "methods" section that described the radiation protocol used.

The researchers found that the source of radiation used in the study (such as low vs high energy X-rays or gamma rays) was unclear or ambiguous in nearly 14 percent of the studies they reviewed. They also found that only 1 percent of studies listed the protocol the researchers used to calibrate the machines, and only 16 percent named the equipment used to measure the absorbed radiation dose.

Several publications were found to contain outright errors where a quantity of radiation dose was misreported. In a few cases, researchers found descriptions of "unachievable" experiments including irradiation produced by a linear accelerator at energy levels that would have been impossible for the named device to produce.

The authors graded the level of physics reporting necessary to successfully reproduce the experiment on a scale of 1(worst) to 10 (best) and found that only 3 percent of the journal articles would receive a score of 8 or above. "Disturbingly, articles published in higher impact journals -- and, consequently, those that are higher cited -- scored the poorest. This means that these studies with poor-quality physics are being propagated and are amplifying the reproducibility problem," said study co-author Amit Sawant, PhD, Associate Professor and Chief of the Division of Physics in the Department of Radiation Oncology at UMSOM.

The UMSOM researchers stipulate that their findings are limited to the physics and irradiation aspects of these radiation biology studies. The quality of the science, hypotheses, or non-physics aspects of the experimental design were not reviewed by the UMSOM researchers.

"This inability to reproduce scientific findings could profoundly impact the translation of preclinical research results into clinical practice," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "The UMSOM researchers highlight a crucial issue that should be addressed by the radiation oncology research community."

The failure to report or reproduce radiation absorbed dose in radiation biology journal articles is likely due to a lack of consultation between the radiation biologists performing the study and radiation physicists who have the expertise to design, document and validate the radiation delivery protocol, according to the UMSOM researchers.

"We are raising awareness of this issue because the problem can be fixed by involving more properly trained physicists in these studies," said Dr. Poirier. "That is because radiation delivery follows well-understood radiation physics principles that lend themselves to high accuracy, precision, and reproducibility."

Efforts are already underway to address the problem: NIH's National Cancer Institute and National Institute on Allergy and Infectious Diseases recently formed a program to standardize and monitor the radiation dosimetry delivery among the entirety of their preclinical research program funded by the radiation countermeasures program. The American Association of Physicists also established a task force last year to create guidelines for accurate dosimetry in radiobiology experiments.

DALLAS - July 31, 2019 - UT Southwestern researchers have shown that precision editing of the bacterial populations in the gut reduces inflammation-associated colorectal cancer in mice.

The study published this week by the Journal of Experimental Medicine could lay the groundwork for novel cancer prevention strategies for individuals with chronic intestinal inflammation. Inflammatory bowel disease (IBD) affects more than 1.6 million people in the United States, about equally divided between those with ulcerative colitis and Crohn's disease, said co-corresponding author Dr. Ezra Burstein, Professor of Internal Medicine and Molecular Biology and Chief of UT Southwestern's Division of Digestive and Liver Diseases.

People living with IBD have a higher risk of developing colon cancer, which can be a source of significant health consequences for these patients, he said. The World Health Organization lists colorectal cancer as the third most-common cancer worldwide and the second highest cause of malignancy-related death.

IBD increases the risk of colorectal cancer by three- to sevenfold. Because of that association, patients with persistent bowel inflammation should get intestinal screening, called colonoscopy, three to 10 times more often than healthy people who have no family history of such cancer: every one to three years vs. every 10, Dr. Burstein said.

"The most significant finding in this study is that manipulating the intestinal microbiome is sufficient to affect the development of tumors. One could envision a time in which medications that change the behavior and composition of the bacteria that live in the gut will be part of the treatment for IBD," he added.

In addition to colorectal cancer, long-standing IBD is associated with imbalances in the bacterial species that line the gut, explained co-corresponding author Dr. Sebastian Winter, Assistant Professor of Microbiology and Immunology and a W.W. Caruth, Jr. Scholar in Biomedical Research. The study's first author is Dr. Wenhan Zhu, a postdoctoral researcher in the Winter laboratory.

"Our intestinal tract is teeming with microbes, many of which are beneficial and contribute to our overall health. Yet, under certain conditions, the normal function of these microbial communities can be disturbed. An overabundance of certain microbes is associated with increased risk for the development of diseases, including certain cancers," Dr. Winter said.

The strategy used in the study targets metabolic pathways that are only active during intestinal inflammation and only in some forms of bacteria, providing an Achilles' heel for reducing their abundance. The current study builds on work the researchers published last year in Nature that found the approach prevented or reduced inflammation in a mouse model of colitis, while having no obvious effect on healthy control animals with balanced bacterial populations in their guts.

"For example, most E. coli (Escherichia coli) bacteria are harmless and protect the human gut from other intestinal pathogens such as Salmonella, a common cause of food poisoning. However, a subset of E. coli bacteria produce a toxin that induces DNA damage and can cause colon cancer in research animals. We developed a simple approach - giving a water-soluble tungsten salt to mice genetically predisposed to develop inflammation - to change the way potentially harmful E. coli bacteria generate energy for growth. Restricting the growth of these bacteria decreased intestinal inflammation and reduced the incidence of tumors in two models of colorectal cancer," Dr. Winter said.

"Tungsten is a heavy metal and should not be used by anyone due to its toxicity," he added. "As with our 2018 paper, this is a proof-of-concept study that will guide us in developing future drugs with similar activity and less toxicity."

Precision editing of the gut microbiome is a shift in strategy from current clinical treatments that target reducing inflammation in the patient during IBD flare-ups or using broad-spectrum antibiotics that kill both good and bad bacteria in order to reduce the risk of cancer, the researchers said.

"Here, we present evidence that targeting the gut microbiota can be sufficient to affect tumor formation in a significant and meaningful way," Dr. Winter said.

When it comes to choosing which other species to hang out with, wild animals quite literally change their minds with the weather, a new University of Liverpool study reveals.

The findings, which are published in the journal Philosophical Transactions of the Royal Society B, could help conservationists better predict the risk of extinction faced by endangered species.

"In the wild, a species always exists as part of a community of other species, which affect its survival. These interactions are crucial when it comes to predicting extinction risk: if we focus only on single species in isolation we may get it very wrong," explains the leader of the research team, Dr Jakob Bro-Jørgensen.

In this study the researchers aimed to uncover if species alter their preference for different social partners when their environment changes - a central question to forecast how current environmental changes caused by humans are likely to affect animal populations and communities.

Over a year, they followed the distribution in space and time of a dozen species inhabiting the Masai Mara plains in East Africa, including buffaloes, giraffes, zebras, antelopes, ostriches and warthogs, to see how the strength of social attraction within individual species pairs changed between the wet and dry season.

All of the savannah herbivore species underwent seasonal changes when it came to their social groupings, with rainfall affecting half of all the possible species pairs.

The researchers suggest that this could be due to a number of reasons, including species migration, climate adaption and feeding preferences. For example, the presence of migrating wildebeest during the dry season may provide a welcome social partner for some, like zebra, but be avoided by others, like buffalo, while arid-adapted species, such as gazelles, ostrich and warthog, may group together during the dry season but separate during the wet season.

"Our study shows that the dramatic changes that humans are causing to the environment at present, be it through climate change, overhunting or habitat fragmentation, will likely create indirect consequences by changing the dynamics of ecological communities," says Dr Bro-Jørgensen.

"This can cause unexpected declines in species if critical bonds with other species are broken. A particular concern is when animals find themselves in novel conditions outside the range which they have been shaped by evolution to cope with," he adds.

Following on from this study, the researchers now plan to investigate how predation and feeding strategies interact to drive the formation of mixed-species groups.

BIRMINGHAM, Ala. - Bone marrow contains biological factories, which pump out billions of new blood cells daily. The non-blood cells that maintain this production also have the potential to produce bone, fat and cartilage. This output all starts from stem cells that have the ability to differentiate into various types of cells.

Knowledge of the genes that control this differentiation and the paths that cells take to their final, differentiated forms is an important biological question because dysregulation of this process is linked to pathologies -- such as obesity, osteoporosis, cancer, tooth loss and aging. Knowledge of the mechanisms that regulate cell differentiation could lead to improved understanding of the pathogenesis of these disorders and eventually new treatments. But the search is challenging because bone marrow is a complex mix of cells in small niches and with largely unknown interactions and relationships.

Research led by Robert Welner, Ph.D., assistant professor in the University of Alabama at Birmingham Division of Hematology and Oncology, has now mapped distinct bone marrow niche populations and their differentiation paths for the bone marrow factory that starts from mesenchymal stromal cells and ends with three types of cells -- fat cells, bone-making cells and cartilage-making cells. Respectively, those cells are called adipocytes, osteoblasts and chondrocytes. This non-hematopoietic cell system is distinct from another production line in the bone marrow -- the hematopoietic system -- that makes red blood cells, blood-clotting cells and cells of the immune system.

Welner and colleagues at UAB, Harvard Medical School and Beth Deaconess Medical Center, Boston, have published their findings in Cell Reports. Their main research tool was single-cell RNA sequencing, which identified mRNA transcripts from genes in 2,847 individual bone marrow cells of the non-hematopoietic system. By sequencing these RNAs, researchers could tell which genes had been turned on or off at different steps on differentiation pathways.

"The single-cell RNA sequencing gene expression profiles generated permit a real-time depiction of dynamic processes associated with fate choices within the bone marrow microenvironment," said Welner, who is also an associate scientist with the O'Neal Comprehensive Cancer Center at UAB. "Our study provides a landscape for a better understanding of transcriptional networks regulating differentiation of bone marrow microenvironment cells."

A major finding was a detailed characterization of three distinct paths in a simple, branching hierarchy of differentiation, starting from mesenchymal stem cells, or MSCs, and ending with pre-adipocytes, pro-osteoblasts and pro-chondrocytes. In all, they identified seven distinct cell states in two branching pathways. One branch was MSCs to adipocyte progenitors to pre-adipocytes. The other was from MSCs to osteoblast/chondrocyte progenitors to pre-osteoblasts/chondrocytes, and finally a split to either pro-osteoblasts or pro-chondrocytes.

For each of these unique subpopulations, they identified gene signatures, and they demonstrated how several transcription factors -- gene control proteins that alter the rate of transcription from DNA to mRNA -- influence fate decisions to specific bone marrow lineages. The dataset the researchers created and the analysis tools they used are publicly available and will serve as a resource for future studies investigating stromal cell differentiation.

An important control in the research, Welner says, and one that should be used in all single-cell RNA sequencing research, was validation studies. These included fate-marked reporters and knockdowns of transcription factors previously reported to govern bone and fat differentiation. The knockdowns allowed researchers to assay differentiation potential in cell culture for the lineages they identified through single-cell RNA sequencing. The validation studies by Welner and colleagues all supported the findings from their single-cell RNA sequencing.

INDIANAPOLIS--New research from the Alzheimer's Disease Metabolomics Consortium (ADMC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) has uncovered novel connections between liver dysfunction and Alzheimer's disease (AD), paving a new path toward a systems level view of Alzheimer's relevant for early detection and ultimately for prevention.

The study, published today in JAMA Network Open [insert link], was led by IU School of Medicine radiology professor Kwangsik Nho, PhD and explores the relationship between blood-based biochemical markers of liver function and established Alzheimer's disease biomarkers including multi-modal neuroimaging. With increasing evidence linking Alzheimer's disease to diabetes or high cholesterol and other systemic illnesses, Nho and colleagues discovered an association between liver function and Alzheimer's, which adds to the understanding of metabolic dysfunction in the disease.

Researchers evaluated more than 1,500 participants from the National Institute of Aging (NIA)-sponsored ADNI over two years using five serum-based liver function assays, which measure enzymes predominantly found in the liver. By using the peripheral biochemical markers, the team was able to uncover evidence of metabolic disturbance and gain a new perspective on altered liver enzymes association with both cognitive impairment and AD pathophysiology including amyloid-β and phosphorylated tau in cerebrospinal fluid (CSF) and reduced brain glucose metabolism on PET scans.

"This study was a combined effort of the ADNI, a 60-site study, and the ADMC. It represents the new wave of Alzheimer's research, employing a broader systems approach that integrates central and peripheral biology," said Andrew J. Saykin, PsyD, director of the Indiana Alzheimer Disease Center at IU School of Medicine and site principal investigator for the Alzheimer's Disease Metabolomics Consortium. "In this study, blood biomarkers reflecting liver function were related to brain imaging and CSF markers associated with Alzheimer's," Saykin said. "No stone can be left unturned in our attempt to understand the disease and to identify viable therapeutic targets."

Funded by the NIA under its Accelerating Medicine Partnership for Alzheimer's Disease program, this research is a result of international collaboration, led by Rima Kaddurah-Daouk, PhD, of Duke University, that attempts to connect the dots in the body's "gut-liver-brain" communication pathway and relate this to AD. "This is a new paradigm for Alzheimer's research," Nho said. "Until now, we only focused on the brain. Our research shows that by using blood biomarkers, we can still focus on the brain but also find evidence of Alzheimer's and improve our understanding of the body's internal signaling."

"While we have focused for too long on studying the brain in isolation, we now have to study the brain as an organ that is communicating with and connected to other organs that support its function and that can contribute to its dysfunction. The concept emerges that Alzheimer's disease might be a systemic disease that affects several organs including the liver," said Kaddurah-Daouk. The study's focus outside the brain aligns with known risk factors for Alzheimer's disease, including metabolic disorders. According to Nho, looking elsewhere in the body for signals correlated with the disease can provide important clues toward detection and ultimately prevention.

Not only does this research shed light on the connection between the liver and brain, but this line of research is expected to ultimately enable physicians to provide more personalized patient care. Through IU's Grand Challenge Precision Health Initiative and the ADMC precision medicine approach, researchers and physicians can focus on how a patient's environment, genes and lifestyle impact their overall health. Instead of a one-size-fits-all tactic, precision medicine allows researchers and physicians to more accurately predict and prevent devastating diseases, like Alzheimer's. The NIA-ADMC research program opens the door for physicians treating patients with liver dysfunction to ensure they aren't also exhibiting early-stage Alzheimer's disease.