Culture

Stroke researchers at the University of Cincinnati have released a new report recommending the proper protocol for delivering lifesaving treatment to stroke patients during the COVID-19 pandemic.

The report, published in Stroke, a journal of the American Heart and American Stroke associations, is timely as more data emerges that patients with COVID-19, even young, otherwise healthy patients, are experiencing strokes. The authors emphasize that diagnosis with COVID-19 should not prevent patients from receiving this time-sensitive treatment.

"Endovascular treatment for stroke involves the use of small catheters inserted from the groin or the arm into the blood vessels of the brain to remove a clot and restore blood flow to the brain," says Dr. Aaron Grossman, assistant professor in the department of neurology and rehabilitative medicine and a UC Health physician who is also the corresponding author on the report. "Opening a brain artery can reverse the effects of the stroke, and for some patients, leads to a quicker recovery time. In this current climate, the treatment presents challenges that doctors never previously needed to consider."

"We needed to find a process for treating patients using endovascular therapy in the COVID-19 era that would keep our staff safe while we cared for these patients as quickly as possible," says Dr. Matthew Smith, a neurocritical care fellow and UC Health physician who is the first author on the report.

Researchers reviewed published and real-time anecdotal experiences of providers caring for COVID-19 patients nationally and internationally. As the first patients with COVID-19 were arriving to UC's Comprehensive Stroke Center, members of every team who cared for these patients met via video to establish recommendations for care.

"We highlighted three populations of potential patients: patients with suspected COVID-19 who come into the emergency department; patients with COVID-19 who are already in the hospital and then develop stroke; and stroke patients without COVID-19 who are cared for at a hospital with constrained resources due to COVID-19, including access to [personal protective equipment], ventilators, ICU beds and staff, " Grossman explains. "Our proposed algorithm helped us decide recommended points of care. It considers the American Heart/American Stroke associations endovascular treatment guidelines, the safety of patients and staff, predictors of death in COVID-19 patients and the appropriate use of scarce resources."

The working group concluded that a COVID-19 diagnosis should not prevent doctors from using endovascular therapy to treat a patient's severe stroke.

"However, we have to use extreme caution when preparing the patient, to keep staff safe," Smith adds, "and during this time of extreme resource limitation, we have to be prepared to modify our current protocols to provide the best stroke care possible for all patients in the Tristate."

In publishing these recommendations, Grossman says the UC/UC Health Stroke Team researchers demonstrate how "adapting an existing and evolving workflow requires input, coordination and engagement across hospital units and disciplines and believe a multidisciplinary approach that is proactive rather than reactive will best serve patients with stroke during the COVID-19 pandemic."

When kidney transplants first came into practice in the 1950s, patients with chronic kidney disease (CKD) could finally picture freedom from the unrelenting routine of blood-cleansing dialysis treatments. Just over a half-century later, demand has completely outstripped supply. The critically ill languish for years on waiting lists, while doctors have little choice but to accept donations of damaged kidneys in a desperate attempt to save lives.

Transplant outcomes are so hard to predict that Dr. Darren Yuen, a nephrologist at St. Michael’s Hospital and scientist in the Keenan Research Centre for Biomedical Science in Toronto, compares it to “spinning a roulette wheel”. But recently published findings in JCI Insight are laying the groundwork to potentially revolutionize this dynamic – and empower physicians to eventually reset the gold standard in transplantation protocol.

The research is an integration of Yuen’s clinical insights on kidney disease with the medical physics expertise of Ryerson University’s Dr. Michael Kolios and PhD candidate Eno Hysi, and their respective teams. Both Yuen and Kolios have labs at the Institute for Biomedical Engineering, Science, and Technology (iBEST), a unique collaboration between the hospital and university, bringing together experts from diverse and traditionally siloed research fields.

The team’s new method is a world-first in applying photoacoustic (PA) imaging to visualize scarring in kidneys, also known as fibrosis, a common form of damage in donor kidneys. Their results produced clear images of kidney scarring just hours before surgery. During this window of opportunity, an accurate assessment could mean the difference between implanting an organ with decades-long durability – or one that quickly fails, sending a patient right back to dialysis and the years-long waitlist.

Accurate, non-invasive kidney screening
Needle biopsy – a painful procedure fraught with bleeding risk – is currently the only method to assess the amount of kidney scarring in prospective donors. But its reliability is hampered by potentially inaccurate estimates based on a tissue sample size of only 1% of the kidney.

The current research takes a quicker, non-invasive and more comprehensive route to quantify kidney damage, using PA imaging instead. The novel technology combines laser and ultrasound – a sequence that Hysi likens to lightning and thunder. “We shine light on kidney tissue, which creates a pressure wave that can be heard using an ultrasound probe.”

The sound data is then run through a proprietary algorithm based on a technique called spectral unmixing.

Each kind of body tissue absorbs coloured laser light in its own unique way. Collagen – one of the main components in kidney scarring – absorbs colour in a manner that is distinct from other components in the kidney. Spectral unmixing teases out the differences. Maps generated by the technology show the amount and distribution of collagen, blood or other tissue – thus allowing physicians to ‘see’ the quality of donated kidneys.

“It wasn’t at all obvious that it would work”
When Hysi first proposed using spectral unmixing to hone in on collagen, nothing in prior medical physics knowledge hinted that the application was even possible. “Typically, for the technique to work, you need to see large peaks and valleys in how components absorb light,” says Kolios. “But collagen is flat, so it wasn’t at all obvious that it would work.”

Hysi persisted with a counterintuitive approach. With so many other biological substances exhibiting peaks and valleys once spectral unmixing is applied, collagen might stand out conspicuously by virtue of its own flatness.

The problem became so intriguing that Hysi decided to explore this possibility in parallel with his own doctoral research on cancer monitoring. Two years later, the findings validated his hypothesis, and the proprietary algorithms are now being patented.

In less than two minutes, the new technique can generate a 2D image with enough detail to quantify total scarring in a kidney. Within 15 minutes, 3D imaging allows visualization not only of overall scarring, but also its varied distribution throughout the kidney.

Potential for significant, widespread impact
As the research moves into clinical trials at St. Michael’s Hospital, Hysi and Yuen will assess how closely their predictions on kidney quality mirror actual outcomes in patients. If successful, their scoring method could have a significant impact on transplantation practice, and become the new gold standard in kidney assessment.

Healthcare systems could save the whopping $100,000 in direct, annual, per-patient costs to manage dialysis patients. But the greatest impact is in giving each patient the best possible kidney, keeping them off dialysis and giving them a new, durable lease on life.

Yuen sums up the two-year whirlwind of research: “I’ve never seen anything like this before. Clinicians and researchers working together, and discovering such great results in so short a time – it’s just amazing.”

BELLINGHAM, Washington, USA - A paper published in Advanced Photonics "Enhanced light–matter interactions in dielectric nanostructures via machine-learning approach," suggests that machine-learning techniques can be used to enhance metasurfaces, optimizing them for nonlinear optics and optomechanics. The discovery has promising possibilities for the development of a wide range of photonic devices and applications including those involved in optical sensing, optoacoustic vibrations, and narrowband filtering.

Metasurfaces are versatile platforms used to manipulate the scattering, color, phase, or intensity of light that can be used for light emission, detection, modulation, control and/or amplification at the nanoscale. In recent years, metasurfaces have been a subject of undergoing intense study as their optical properties can be adapted to a diverse set of applications, including superlenses, tunable images, and holograms.

According to Advanced Photonics Co-Editor-in-Chief, SPIE Fellow, and Head of Photonics & Nanotechnology Group at King's College London Anatoly Zayats, this work marks an exciting advancement in nanophotonics.

"Optimization of metasurfaces and metamaterials for particular applications is an important and time-consuming problem," said Zayats. "With traditional approaches, only few parameters can be optimised, so that the resulting performance is better than for some other designs but not necessarily the best. Using machine learning, one can search for the best design and cover the space of parameters not possible with traditional approaches."

Because customers who shop online cannot try on their purchases, a third of all Internet sales get returned. But handling these returns is costly, giving retailers that have both physical stores and digital sales a clear advantage over retailers that operate only online. A new study examined the decisions around the pricing and return policies of a retailer with both stores and online sales to help explain why some firms opt to fully refund customers for their returns while others charge a fee for online returns. The findings offer guidance to retailers about pricing and policies on returns and refunds.

Conducted by researchers at Carnegie Mellon University and the University of Washington, the study appears in Management Science.

"Our study can help firms with stores and online sales decide when to offer full refunds or charge a fee for online returns," says Soo-Haeng Cho, Associate Professor of Operations Management at Carnegie Mellon University's Tepper School of Business, who coauthored the study. "Our work shows that firms should consider offering full refunds whenever they can salvage online returns at mild discounts or if most of their customers choose to visit their stores before purchasing. They may also want to charge a fee for online returns to push customers toward using free in-store returns."

Researchers examined a retailer that sold a product through two channels--in stores and online--to customers who faced uncertainty about the valuation of the product--that is, they didn't know how much they would like the product. The customers differed in how they resolved that uncertainty--some evaluated the product in person at a store before deciding to purchase it while others bought the product online with the option of returning it if it did not fit. The cost of a product was the same whether it was purchased in the store or online, and the firm allowed free returns to its stores, but charged a fee for some products returned by mail (referred to as online returns).

The study found that when customers returned products online, the optimal refund given by a firm with both store and online sales was more generous than refunds given by firms that sell their products only online or only in a store. The refunds were often larger than the salvage value (how much the firm can get from the product after it is returned, either by selling it again or by recycling it) and may even have been a full refund. The findings help explain why some firms with both stores and online sales choose to offer full refunds while others charge a fee for online returns.

Specifically, the study found that firms with both physical stores and online sales that have good salvage partners (companies that will buy returned items for a reasonable price) for online returns (e.g., Nordstrom and firms like it that own their own outlet stores) and those with more customers who use their physical stores (e.g., Macy's) may offer full refunds. Similarly, the study found that firms have incentives to offer full refunds for products that customers are more likely to inspect in store (e.g., Express for footwear).

The authors suggest that firms with a significant network of stores and better in-store salvage opportunities (e.g., J.C. Penney) might be better off charging a fee for online returns to encourage customers to return items in stores. But they note that firms with both stores and online sales should be cautious in making the return process more convenient and improving accessibility to its stores because these seemingly beneficial policies, when combined with a policy offering partial refunds, could undermine firms' overall profit.

"Our work is a first step in capturing the complex dynamics that motivate different firms' choices surrounding return policies," explains Leela Nageswaran, Assistant Professor of Operations Management at the University of Washington, who coauthored the study (Nageswaran received her Ph.D. from the Tepper School of Business). "Return policies can be a valuable tool for firms with both stores and online sales, especially when firms use them to sway customers' choice of the way they return items as well as how they purchase products."

Older adults with depression may be at much higher risk of remaining depressed if they are experiencing persistent or worsening sleep problems, according to a study from researchers at Johns Hopkins Bloomberg School of Public Health.

The researchers, who published their findings online April 30 in the journal Sleep, analyzed data from almost 600 people over 60 years old who visited primary care centers in the Northeast U.S. All patients met clinical criteria for major or minor depression at the outset of the study.

The researchers found that those with a pattern of worsening insomnia symptoms over the following year had almost 30 times the odds of having a diagnosis of major depression at the end of that year, compared to patients whose sleep had improved during that year. The patients with worsening insomnia also were much more likely to have a diagnosis of minor depression. Additionally, they were more likely to report suicidal ideation at the end of the year.

Compared to patients whose sleep improved, the study found that those with insomnia symptoms that persisted but did not worsen also were more likely to have persistent major or minor depression, but their risk was not as high as patients with worsening sleep.

"These results suggest that, among older adults with depression, insomnia symptoms offer an important clue to their risks for persistent depression and suicidal ideation," says study senior author Adam Spira, PhD, professor in the Department of Mental Health at the Bloomberg School. The study's lead author was Joseph Gallo, MD, MPH, professor in the Bloomberg School's Department of Mental Health.

Sleep, or lack thereof, has long been considered a potential risk factor for mood disorders, and has more recently been studied in relation to suicidal thinking. In an earlier study of older adults living in low- and middle-income countries, Spira, Gallo, and colleagues found that older adults reporting insomnia symptoms and poor sleep quality were more likely to report having suicidal thoughts, and that those with insomnia symptoms were more likely to report a prior suicide attempt.

In their new analysis, the researchers examined data from a sleep and mental health study conducted from May 1999 to August 2001, covering older adults at 20 primary care centers in New York City, Philadelphia, and Pittsburgh.

"There otherwise hasn't been much research on insomnia and depression in older adults in primary care settings--even though primary care is where most people with depression are treated," Spira says.

The analysis covered 599 study patients, of whom 429 (71.6 percent) were women. At the outset of the study, the patients' average age was 70.3 years, and two-thirds met criteria for major depression, while the rest met criteria for minor depression.

The researchers examined the patients' reports of insomnia symptoms--chiefly difficulty falling asleep or waking without a full night's sleep--over 12 months, and sorted them into three groups based on their reports: 346 patients who started with fewer sleep problems and slept much better by the end of the study; 158 who started with more sleep problems and stayed the same or improved only slightly over the year; and 95 patients who at baseline had more sleep problems and worsened over the year.

The analysis revealed that, compared to the patients whose sleep had improved, those with worsening sleep disturbances had 28.6 times the odds of having a diagnosis of major depression at the end of the year--as opposed to no longer having a depression diagnosis.

The patients whose sleep worsened also had 11.9 times the odds of having a diagnosis of minor depression at the end of the year and were 10 percent more likely to report having suicidal thoughts at the end of the year.

"We can't say that the sleep disturbances we're seeing are necessarily causing the poor depression outcomes," Spira says. "But the results suggest that older adults who are being treated for depression and whose sleep problems are persistent or worsening need further clinical attention. They also suggest that treating sleep problems should be explored further as a potential means to improve depression outcomes in older people--as well as the poor cognitive and general health outcomes that have been tied to disturbed sleep in this population."

African naked mole-rats are sometimes referred to as animal superheroes. They resist cancer, tolerate pain, and live a remarkably long time. They're also known for their ability to handle high levels of carbon dioxide and can go for several minutes without oxygen. But researchers reporting in Current Biology on April 30 say they may have found the mole-rats' kryptonite: they need high levels of carbon dioxide to function.

"While they thrive in their cramped nest quarters, the air composition just above the surface of their burrows in East Africa makes them vulnerable to seizures," said Dan McCloskey of The City University of New York. "Because that's what happens when naked mole-rats lose carbon dioxide."

In other words, the mole-rats don't just tolerate high levels of carbon dioxide in their crowded nests; it appears that they actually require it. When they reach the hot surface and start heat-induced hyperventilation in the fresh air, it sends them into seizures. In the study now reported, the researchers found that this curious need for carbon dioxide is explained by the presence of a missense mutation in a gene that encodes the major neuronal chloride transporter known as KCC2.

The researchers came to this discovery in an unexpected way. Naked mole-rats have little control over their body temperature and also are prone to seizing in response to heat, they knew. McCloskey and first author of the new study Michael Zions had been exploring this susceptibility to fever-like conditions as a model for fever-induced (febrile) seizures in human children.

The team joined forces with Kai Kaila and Martin Puskarjov, University of Helsinki, Finland. Kaila, an expert in febrile seizures, and Puskarjov had earlier found a mutation affecting KCC2 in families of people prone to them. What they now know is that mole-rats and those families with a genetic predisposition for febrile seizures carry the very same genetic change.

"We knew there was some value in the line of inquiry, but we had no idea that the similarities would go all the way down to the genetic level," Kaila said.

"The identification of the genetic polymorphism in the naked mole-rat KCC2 was a surprise," Puskarjov added. "Aside from a small subset of humans, naked mole-rats are now the only other mammals known to harbor this variant."

Further study yielded more surprises. When the researchers gave a naked mole-rat the anti-seizure drug diazepam, the drug triggered a seizure rather than preventing one. While the result was unexpected, it helped them make sense of years of unusual behavioral and electrophysiological data: the naked mole-rats were relying on carbon dioxide to help them compensate for deficiencies in their brain's inhibitory GABAergic system.

KCC2 is a chloride transporter: its normal job is to control the amount of chloride inside of neurons. In a typical adult mammal, chloride levels in central neurons are kept low. When the neurotransmitter GABA binds to a neuron, chloride enters and blocks the activity of the neuron. This ability to reduce neural activity is essential for many thousands of neurons to work together in coordinated fashion and avoid becoming overexcited. In the naked mole-rat and people with the mutation, KCC2 doesn't clear chloride from neurons as effectively. As a result, this inhibitory cascade doesn't work as well.

"Naked mole-rat brains lack some of the inhibition that a mammal needs. Instead, they're using the carbon dioxide to get back to where they have to be," Zions said. "They prefer CO2 levels that would panic a person, but are troubled by fresh air. They've leveraged a liability to literally dig themselves a niche."

As the researchers explain, an inhibition-impaired brain would normally be a handicap as it is in people prone to febrile seizures. It works for naked mole-rats because they rely on their carbon dioxide-rich environments to help keep their brain within normal parameters. "We believe they are utilizing nest carbon dioxide to offset their impoverished GABA system," Kaila said.

The researchers think the findings may provide an essential clue as to why the naked mole-rats are one of only two mammalian species to evolve eusociality, living together in highly cooperative colonies.

"Low carbon dioxide areas may cause hyperexcitability and overstimulation or anxiety. Their brain physiology urges them to go back to the nest rather than set out on their own," McCloskey said. Support for this idea comes from the researchers' discovery that the only other eusocial mammal, the Damaraland mole-rat, has a slightly different mutation in the exact same location on the KCC2 gene as the naked mole-rat.

In addition to the insights into mole-rat evolution, the findings may also have implications for people who carry the KCC2 variant, including those prone to febrile seizures and people with idiopathic generalized epilepsy, schizophrenia, or autism who in some cases also have the variant, according to the researchers. "The breathing patterns and carbon dioxide needs of these individuals is something to consider," Kaila said.

Despite the infamy of the transatlantic slave trade, scientific research has yet to fully explore the history of the enslaved Africans brought into Latin America. In a study appearing April 30th in the journal Current Biology, scientists tell the story of three 16th century African slaves identified from a mass burial site in Mexico City. Using a combination of genetic, osteological, and isotope analyses, the scientists determined from where in Africa they were likely captured, the physical hardships they experienced as slaves, and what novel pathogens they may have carried with them across the Atlantic. This study paints a rare picture of the lives of African slaves during early Spanish colonization and how their presence may have shaped disease dynamics in the New World.

"Using a cross-disciplinary approach, we unravel the life history of three otherwise voiceless individuals who belonged to one of the most oppressed groups in the history of the Americas," says senior author Johannes Krause, an archaeogeneticist and professor at the Max-Planck Institute for the Science of Human History.

The three individuals were found within a mass grave at San José de los Naturales Royal Hospital in Mexico City, an ancient hospital site largely devoted to servicing the indigenous community. "Having Africans in central Mexico so early during the colonial period tells us a lot about the dynamics of that time," says first author Rodrigo Barquera (@jrockdrigo), a graduate student at the Max-Planck Institute for the Science of Human History. "And since they were found in this mass burial site, these individuals likely died in one of the first epidemic events in Mexico City."

Researchers extracted genetic and isotope data from the individuals' teeth, piecing together their lives before enslavement. "Their genetics suggest they were born in Africa, where they spent all of their youth. Our evidence points to either a Southern or Western African origin before being transported to the Americas," says Barquera.

A close look at their bones revealed a life of severe hardship once they arrived in the Americas. Anthropologists found large muscle insertions in the upper body of one skeleton, likely pointing to continuous physical labor. Another individual had the remnants of gunshot wounds from copper bullets, while the third had a series of skull and leg fractures. The team could also tell, however, that the abuse did not end their lives. "Within our osteobiographies we can tell they survived the maltreatment that they received. Their story is one of difficulty but also strength, because although they suffered a lot, they persevered and were resistant to the changes forced upon them," Barquera says.

From the remains, researchers also recovered the genetic material of two pathogens that infected two of the individuals while they were alive. "We found that one individual was infected with hepatitis B virus (HBV), while another was infected with the bacterium that causes yaws--a disease similar to syphilis," says co-senior author Denise Kühnert, a mathematician working on the phylogeny of disease, from the Max-Planck Institute for the Science of Human History. "Our phylogenetic analyses suggest that both individuals contracted their infections before they were likely forcibly brought to Mexico."

These are the earliest human remains in Americas in which HBV and yaws have been identified, suggesting that the slave trade may have introduced these diseases into Latin America very early into the colonial period. This is particularly meaningful for yaws, as it was rather common in Mexican people during the colonial period. "It is plausible that yaws was not only brought into the Americas through the transatlantic slave trade but may subsequently have had a considerable impact on the disease dynamics in Latin America," says Kühnert.

By conducting science in this interdisciplinary manner, researchers are now able to answer deep questions about the roots of Mexican culture. "We want to get insights into how pathogens emerged and spread during the colonial period in the New Spain, but we also want to continue to explore the life stories of the Africans brought here and other parts of the Americas. That way they can take a more visible place in Latin American history," says Barquera.

Five centuries after Charles I of Spain authorized the transport of the first African slaves to the Viceroyalty of New Spain, the ancestry of the hundreds of thousands of abducted and enslaved people forms an integral part of the genetic and cultural heritage of the Americas. The origins and experiences of those enslaved individuals, however, remains largely unknown.

This study, published in Current Biology, applies an interdisciplinary approach to explore the backgrounds and living conditions of three African individuals recovered from a mass grave on the grounds of Hospital Real de San José de los Naturales, an early colonial period hospital in Mexico City officially devoted to the indigenous population. Dated to the 16th century, these individuals tell the stories of some of the earliest people forcefully relocated to the Americas in the early years of European colonialism.

Multidisciplinary study reconstructs the lives of early enslaved Africans

The three individuals in the study first caught the attention of the team with their distinct dental modifications, a filing of the upper front teeth consistent with cultural practices recorded for African slaves which can still be observed in some groups living in western Africa today.

"Combining molecular biology, isotopic data and bioinformatic tools with classical historical, anthropological and archaeological evidence allowed us to gain insights into the life history of some of the earliest African slaves in the Americas," says Johannes Krause, director of the Department of Archaeogenetics at the Max Planck Institute for the Science of Human History (MPI SHH).

Genetic analysis showed that all three individuals shared a Y-chromosome lineage that is highly prevalent in Sub-Saharan Africa, and which is now the most common lineage among African Americans. Combined with isotopic data showing that all three individuals were born outside of Mexico and osteobiographies showing years of physical abuse before premature death, the findings suggest that these individuals may be among the first Africans to reach the Americas after being abducted in their homelands in Sub-Saharan Africa.

"Modern lab techniques allow us to gather incredible amounts of data from very little biological material. The amount of information we can give back to archaeologists, anthropologists and society today using only one tooth from each individual is something we could only dream about just ten years ago," says Rodrigo Barquera, the study's lead author.

The spread of pathogens across the Atlantic

Researchers from all three departments and one independent group of the MPI SHH and two laboratories from the ENAH combined their expertise to tell the story of these individuals, examining not only their ancestry and origins, but also their health status and life experiences. The team was able to reconstruct two full pathogen genomes from tooth samples. One individual was infected with a strain of the Hepatitis B virus (HBV) typically found in western Africa today.

"Although we have no indication that the HBV lineage we found established itself in Mexico, this is the first direct evidence of HBV introduction as the result of the transatlantic slave trade," says Denise Kühnert, leader of the tide research group at MPI SHH. "This provides novel insight into the phylogeographic history of the pathogen."

Another individual was infected with Treponema pallidum pertenue which causes yaws, a painful infection of the bones similar to syphilis that affects joints and skin. The same strain of yaws has been previously identified in a 17th century colonist of European descent, suggesting the establishment of this disease lineage of African origin in the early colonial population of Mexico.

"This study sheds light into early cases of yaws after the European colonization of the Americas," says Aditya Kumar Lankapalli of MPI SHH. "Future studies should focus on understanding the transmission and introduction of this pathogen to the Americas. More high-coverage ancient Treponema genomes will allow us to get a better understanding of the coevolution and adaptation of this pathogen to humans."

"Interdisciplinary studies like this will make the study of the past a much more personal matter in the future," adds Thiseas C. Lamnidis. The authors hope that future interdisciplinary endeavors will continue to provide insights into the lives, deaths and legacies of historically oppressed groups whose stories have been buried, often in mass graves.

WASHINGTON--Older men who have lower lean body mass as they age are more prone to developing diabetes, while similar findings were not found in older women, according to a new study published in the Journal of the Endocrine Society.

One in four adults aged 65 and older has diabetes, making them the group with the greatest burden of diabetes. Skeletal muscle is the largest insulin-sensitive tissue in the body and plays an essential role in blood sugar regulation. Age-related muscle loss, called sarcopenia, may contribute to the development of diabetes in older adults.

"Age-related muscle loss may be an under-recognized target for interventions to prevent the development of diabetes in older adults," said the study's first author, Rita R. Kalyani, M.D., of the Johns Hopkins University in Baltimore, Md. "We found that relatively lower lean body mass with aging was related to a higher incidence of diabetes in men but not women, and partially related to body size."

The researchers studied 871 men and 984 women, with an average age of 60 years at the initial visit, from the Baltimore Longitudinal Study of Aging, who were followed up to 15 years. They used Dual X-ray Absorptiometry and found that lower lean body mass with aging is associated with incident diabetes in men but not women.

"Future studies that use more direct methods to assess skeletal muscle mass may give further insights into these relationships and the sex differences that we observed," Kalyani said.

Osaka, Japan - Homologous recombination is an essential process of DNA repair to maintain genomic integrity of the organism. Now, researchers from Japan have identified mechanisms that choose between alternate pathways of DNA repair to limit anomalous and deleterious chromosomal combinations that may be predisposed to cancer and genetic diseases.

In a recent study, researchers from Osaka University show that Rad52-dependent single-strand annealing (SSA) is the mechanism of homologous pairing that leads to gross chromosomal rearrangements (GCRs) at the centromere. They also identify mutations that allow this pathway to predominate in preference to the error-free Rad51 pathway.

Cells are under constant genotoxic pressure from exogenous and endogenous factors. Genome instability underlies several diseases including cancer. Consequently, DNA repair necessarily occurs thousands of times per day in each human cell to correct detrimental mutations, blockage of replication and transcription, and chromosomal breakage. Paradoxically, this recombination may occasionally cause dysfunctional GCRs.

The centromere of a chromosome is the specialized DNA sequence that links a pair of sister chromatids. Many organisms, including humans and fission yeast (Schizosaccharomyces pombe), have repetitive sequences at centromeres. This renders them vulnerable to isochromosome formation —dysfunctional mirror-images—due to a specific type of recombination between inverted repeats. In experiments conducted on fission yeast, the researchers demonstrated that DNA replication mechanisms reduce the occurrence of GCRs by inhibiting SSA activity at centromeres.

"At centromeres, Rad51-dependent recombination predominates and other recombination pathways appear to be inhibited," explains Atsushi T. Onaka, lead author. "As Rad51 promotes conservative non-crossover recombination, the choice of recombination pathways is important for suppressing GCRs. This recombination predominantly occurs between inverted repeats, thereby suppressing formation of isochromosomes. However, how Rad51-dependent recombination predominates at centromeres is unknown."

Jie Su, co-lead author, explains further. "We showed that Rad52-dependent SSA is the mechanism of homologous pairing that leads to centromeric GCRs. The rad52-R45K mutation impairs SSA activity of the Rad52 protein and reduces isochromosome formation in rad51 mutant cells. To better understand how Rad52-dependent SSA is suppressed at centromeres, we performed a genetic screen and found that specific mutations in replication fork proteins and a fork protection complex increase Rad52-dependent SSA at centromeres and isochromosome formation."

"Our research implicates DNA replication machinery in the recombination pathway choice at centromeres, preventing Rad52-dependent SSA that results in GCRs," explains senior author Takuro Nakagawa. "This knowledge identifies Rad52 as a promising target in treating cancer."

Durham, NC - A new study released today in STEM CELLS suggests for the first time that regulatory T-cells (Treg) induced by mesenchymal stromal cells can yield an abundant replacement for naturally occurring T-cells, which are vital in protecting the body from infection. Led by Rita I. Azevedo, Ph.D., at the Instituto de Medicina Molecular in Lisbon, Portugal, this study could yield new treatments for a long list of chronic inflammatory diseases that includes everything from cancer and asthma to inflammatory bowel disease, rheumatoid arthritis and more.

"Treg play a critical role in immune tolerance," Dr. Azevedo said. "In stem cell transplantation to treat leukemia and other blood diseases, for example, lower Treg counts are associated with the development of chronic graft-versus-host disease. However, Treg are very scarce. Finding alternative sources of stable Treg induction might produce a large enough number for effective treatment uses."

Mesenchymal stromal cells (MSCs) have been suggested as one way to achieve this. These multipotent progenitor cells, which can be isolated from a wide range of adult and postnatal tissues, are able to differentiate into diverse cell types. And like Treg, MSCs constitute an important immunoregulatory population by inhibiting both innate and adaptive immune responses.

"But thus far, the potential of MSC to recruit Treg has been poorly understood," Dr. Azevedo said.

Previous studies suggest that MSC-mediated immunomodulation may be partly driven by Treg induction and/or expansion. However, these reports have not assessed Treg yield in terms of absolute counts, nor characterized the resulting Treg-like cells in detail. In the present study, Dr. Azevedo's team sought to determine whether MSC are able to induce and/or expand Treg in vitro, as well as the mechanisms of Treg enrichment by MSC.

To conduct the study, they collected human peripheral blood mononuclear cells - including T-cells - from healthy donors and co-cultured them with allogeneic bone marrow-derived MSC. Fourteen days later, the results showed an increase in the count and frequency of Treg cells -- four- and six-fold, respectively.

The MSC-induced Treg-like cells resemble Treg functionally, and importantly, their DNA methylation profile closely resembles that of natural Treg, indicating that this population is stable. DNA methylation is an important component in numerous cellular processes, including embryonic development. Errors in the methylation have been linked to several human diseases.

"Our data sheds new light into the origin, functional potential and stability of MSC-induced Treg-like cells, which are key features for their potential applicability in the clinical setting." Dr. Azevedo concluded. "The co-administration of MSC and Treg might have the potential to constitute a more effective cellular therapy approach by harnessing the suppressive capacity of both these immunomodulatory populations."

"This is an exciting advance", said Dr. Jan Nolta, Editor-in-Chief of STEM CELLS. "Dr. Azevedo and her team have defined important MSC-based mechanisms to induce and enrich Treg cells, which could have important future implications for the treatment of chronic diseases."

April 29, 2020 - Early reports of COVID-19 symptoms and the compelling need to quickly identify treatment options and curb the growing number of critically ill patients have led to erroneous and potentially dangerous comparisons between COVID-19 and other respiratory diseases like high altitude pulmonary edema, or HAPE.

In "COVID-19 Lung Injury and High Altitude Pulmonary Edema: A False Equation with Dangerous Implications," the authors urge clinicians to rely on scientific evidence to guide treatment. The paper was posted early online in the Annals of the American Thoracic Society.

There are some similarities between COVID-19 and HAPE as there are similarities between COVID-19 and other respiratory illnesses that cause respiratory failure: very low oxygen levels in the blood, significant difficulty breathing, the degree to which there is stiffness in the lungs, and abnormal findings on chest CT scans. However, there are fundamental differences between COVID-19 and HAPE.

"HAPE develops when people ascend to high altitude. The low oxygen levels in the atmosphere cause low oxygen levels in the air sacs of the lungs," said Andrew Luks, MD, professor of medicine in the Division of Pulmonary, Critical Care and Sleep Medicine at Harborview Medical Center and the University of Washington. "In all people, this leads the blood vessels in the lungs to constrict and raises the blood pressure in the lungs (pulmonary artery pressure). In people who develop HAPE, this response is excessive.

There is far too much vasoconstriction and far too great a rise in pulmonary artery pressure, all of which lead fluid to leak out of the blood vessels into the lung tissue, but this occurs with no inflammation."

"In lung injury due to COVID-19, the virus attacks the cells that make up the air sacs of the lungs. This leads to a big inflammatory response that damages the air sacs (alveoli), leading fluid to leak out of the blood vessels even under much lower pressures, causes the alveoli to collapse, interferes with gas exchange and makes the lungs stiffer and harder to expand than normal. "

These fundamental differences necessitate different treatment approaches. While treatment with oxygen can resolve HAPE symptoms, oxygen alone is ineffective for the lung injury associated with COVID-19. Nifedpine and acetazolamide, two medications used to treat altitude sickness, can have dangerous consequences in COVID-19 patients.

"If given to a patient with lung injury due to COVID-19, it [nifedpine] has the potential to actually worsen oxygen levels in the blood and to lower systemic or whole body blood pressure," said Dr. Luks.

Treating with acetazolamide can cause a host of problems, among them "fatigue of the diaphragm, causing the blood to become more acidic, and at high enough concentrations in the blood, impairing the transport and elimination of carbon dioxide, all of which will make patients even more short of breath."

COVID-19 has affected how the medical community shares information and what the community is learning about the disease can change quickly. Clinicians and families are looking for data to help care for patients. Dr. Luks and his co-authors warn that without careful scrutiny, misinformation can quickly spread. Now more than ever, it is critical that clinicians rely on the data accumulated over time and scientific evidence related to treating acute lung injury.

While the capability for organisms to work together is by no means novel, humans possess an unparalleled capacity for cooperation that seems to contradict Darwinian evolutionary principles. Humans often exhibit traits--such as sympathy, loyalty, courage, and patriotism--that prioritize collective well-being over individual fitness, and often cooperation occurs among individuals with no shared biological relation. This behavior, likewise, adapts in response to changing conditions, demonstrating the flexible nature of human cooperation.

In "Identity, Kinship, and the Evolution of Cooperation," published in Current Anthropology, Burton Voorhees, Dwight Read, and Liane Gabora argue that humans' tendency toward these cooperative traits--or ultrasociality--sets them apart. Voorhees, Read, and Gabora assert that components of human cooperation--especially cooperative behavior between unrelated individuals--are unique, and the authors suggest that existing theories lack explanations for how this distinctly human shift to cooperative behavior arose and how cooperation is maintained within a population.

Expanding upon the current literature, Voorhees, Read and Gabora present a theory that attributes unique elements of human cooperation to the cultivation of a shared social identity among members of a group. The authors propose that evolutionary developments in the brain enabled the acquisition of this shared identity by providing humans with the capability for reflective self-consciousness. Reflective self-consciousness allows an individual to fully recognize their own personhood and point of view. In turn, recognition of their own experiences aided humans in identifying similar mental states in others, allowing humans to view themselves as part of a collective unit.

The authors argue that cultural idea systems such as kinship systems, provided the necessary framework for cultivating this unique degree of cooperation among humanity. Unlike culture-gene theories where group characteristics develop from individual traits, cultural idea systems provide a top-down, organizational structure that establishes expectations of behavior among individuals in a group and leads individuals to view other members as kin. As individuals are indoctrinated, or enculturated, in these systems, their worldviews are shaped. They develop an understanding of accepted cultural norms, how to interpret their environment and their experiences, and how to interact with one another. In particular, the authors assert that enculturation fosters feelings of obligation toward cultural kin.

Emphasizing linkages between psychology and behavior, the authors suggest this obligation deterred individuals from deviating from accepted behaviors and in turn, sustained cooperative behavior within the group. A shared social identity provided beneficial advantages. As a result, the authors propose that an association developed between an individual's social identity and their survival instincts. In kinship systems, emotions are experienced within a specific cultural context, resulting in culture-laden mental feelings that prompt behavior. Voorhees, Read, and Gabora likewise argue that external cues contradicting existing culture-laden mental feelings can result in emotional reactions. Any behavior that diverges from cultural norms and threatens an individual's identity could be physiologically perceived as endangering their survival. Group members will feel driven to punish defectors in response. This theory can thus explain why failure to meet group obligations may evoke guilt in those who deviate from cultural expectations.

As retrenchments continue to cloud the foreseeable future of businesses worldwide, new research from the University of South Australia, the University of Melbourne and RMIT indicates that some businesses will fare better than others - and it's all dependent on their type of human resource management system.

In a new study published in the Human Resource Management Journal this week, researchers found that the ability of an organisation to recover after layoffs is directly connected to their HRM system: those that encourage participative, motivation practices will recover more quickly than those that emphasise financial incentives.

Layoffs are a dire reality, occurring recently across many industries including travel, hospitality, entertainment and retail, as well as professional services, but as UniSA researcher, Professor Carol Kulik says, HRM research delivers important insights for organisational resilience in times of hardship.

"In recent weeks we've seen many organisations tighten their belts to stay afloat, with some resorting to layoffs in the hope that a 'leaner and meaner' structure will help them retain or restore a competitive edge," Prof Kulik says.

"But the challenge is, the success of a layoff depends on the surviving staff, who inevitably must work harder as the workforce shrinks and, as a result, organisational performance drops.

"Our research shows that businesses with strategic HRM systems focussed on participation and collaborative communication practices are far stronger in times of adversity. This is because the nature of these HRM practices have developed a culture of trust. As a result, employees are more likely to feel that they share the responsibility and step up to help management move the organisation forward.

"On the other hand, organisations that place a heavy emphasis on financial incentives ¬- that is pay for performance - create a culture of risk¬. Here, businesses align workers' financial interests with those of the company, encouraging employers to 'take a risk' that their investment (in working hard) will pay off and they will share in the company's profits.

"Layoffs in these situations tell employees that their risks will not pay off, so when incentives drop, so too does performance."

Drawing from five years of WERS data (Britain's flagship survey of employment relations) which included 745 workplaces, the team used cluster analysis to identify workplaces with high-performance workplace systems (HPWS) - systems that use integrated HRM practices such as rigorous selection, training, and teamwork to motivate and maintain high performance - and regression analyses to compare the performance effects of different employment systems.

The researchers found that 60 per cent of workplaces had HPWS and that these outperformed businesses with less-strategic HRM practices. Additionally, it highlighted the benefit of collaborative HRM practices as opposed to financially driven HRM practices.

"High-performance workplace systems send clear messages to employees about what the employer values, motivating employees to focus on those particular parts of their performance, so these produced higher performance than those without such clarity," Prof Kulik says.

"But, when we assessed the impact of these systems after significant layoffs, we found that businesses that emphasised financial incentives experienced bigger drops in performance, and even five years later, hadn't yet recovered.

"For organisations, this research shows how important it is to send clear, strategic messages to employees as these will guide and increase performance.

"Yet for those who link HRM practices with financial incentives, there's an extra warning: while financial incentives work when it's business as usual, in times of hardship the short- and long-term performance of those organisations is likely to suffer."

Understanding the principles of cancer evolution is important in designing a therapeutic strategy. A research group at The Institute of Medical Science, The University of Tokyo (IMSUT) announced a new simulation model that describes various modes of cancer evolution in a unified manner.

"We clarified the conditions under which each of the evolutionary modes is realized by performing simulation analysis using a supercomputer. Our findings have allowed us to explain the underlying principles of the evolutionary diversity of cancer." said lead scientist Atsushi Niida, Senior Assistant Professor, Laboratory of Molecular Medicine, Human Genome Center of IMSUT.

To build a unified evolutionary simulation model

Cancer can be regarded as a disease of evolution, which results from natural selection of cells with high proliferative and malignant potential, following the accumulation of mutations in their genomes. Moreover, because cancer has a high evolutionary potential, it easily adapts to treatment-related changes in its environment and acquires therapeutic resistance (*1),

Previous genomic studies have shown that cancer evolution can be roughly divided into four modes of evolution. However, it has remained unclear what conditions give rise to each mode. Therefore, the research group have built a unified evolutionary simulation model that can recapitulate a variety of evolutionary modes.

By performing massively parallel simulation(*2) with various conditions on SHIROKANE, a supercomputer at IMSUT, the research group determined the conditions under which each evolution mode is generated. By providing a mathematical basis for understanding cancer evolution, this study is expected to contribute to the understanding of therapeutic resistance in cancer and the development of novel therapeutic strategies.

Various mathematical principles that explain the evolution of cancer

Classically, cancer evolution has been regarded as a process of evolution, in which normal cells evolve step-wise into a homogeneous cell population with high malignancy by serially acquiring driver mutations(*3) that favor cell growth and survival while undergoing natural selection (Figure 1A).

However, in recent years, multi-region sequencing(*4), which analyzes DNA samples obtained from multiple regions of a tumor, has demonstrated intratumor heterogeneity (ITH)(*5); that is, multiple clones with different mutations are generated during the course of cancer evolution and coexist in a single tumor. Also, depending on the types of cancers, driver mutations present only in a fraction of cells contribute to ITH; that is, natural selection appears to shape ITH (FIG. 1B).

On the other hand, it has been found that ITH can be shaped by the accumulation of neutral mutations(*6) that do not affect the growth and survival of cells; that is, ITH can be generated by neutral evolution (FIG. 1C). The evolutionary principle underlying ITH has not only varied among cancer types, but Niida and colleagues have also found that a temporal shift occurs during colorectal tumorigenesis (Saito et al.,2018); that is, it has been found that, in early lesions, ITH is shaped by natural selection while in advanced cancer, ITH is shaped by neutral evolution. Also, in contrast to the gradual evolution that results from the stepwise accumulation of single nucleotide mutations as assumed above, punctuated evolution has attracted attention. This is an evolutionary mode in which large changes occur over a short time at the chromosomal and genomic levels, such as copy number changes and structural abnormalities, explosively expanding from a few initial cells (Fig. 1D).

Thus far, four evolutionary modes have been proposed, but there are many unclear points concerning under what conditions these modes occur. Simulation using an agent-based model is considered to be a useful tool for understanding the principle of cancer evolution. The agent-based model assumes the components of a system called an agent, and specifies rules for the autonomous behavior of the agent itself and the interactions between agents and the environment.

Viewing each cell as an agent, ITH can be easily represented by the difference in the internal state of each agent. Niida and colleagues have recently developed MASSIVE, a new methodology of parameter sensitivity analysis(*7), which examines the dynamics of agent-based simulations (Niida et al., 2019). MASSIVE takes an approach completely different from conventional parameter sensitivity analysis methods; it makes it possible to intuitively search a large parameter space by combining massively parallel computing with interactive data visualization.

Based on the above, in order to clarify the conditions under which the above-mentioned four different evolution modes are realized, we have constructed a unified evolution simulation model that can recapitulate various evolution modes using an agent-based model. Parameter sensitivity analysis utilizing MASSIVE was performed on SHIROKANE, a supercomputer of IMSUT. They found that linear evolution occurs when strong driver mutations are assumed, while ITH is generated by natural selection when the driver mutations are weak. Moreover, the simulation revealed that the generation of ITH by neutral evolution requires a high neutral mutation rate, and the presence of cancer stem cells also contributes to neutral evolution by promoting the accumulation of neutral mutations.

Punctuated evolution could also be reproduced by assuming an explosive driver gene that enables cells to overcome the resource limitation required for cell proliferation. Furthermore, it was shown by simulation that punctuated evolution triggers the above-described temporal shift of the principle underlying ITH from natural selection to neutral evolution in colorectal tumorigenesis (Fig. 1E). This result also helps us understand that each mode works not as discrete, exclusive modes but rather blend continuously as a series of phases of cancer evolution.

The results of all the simulation analyses in this research can be searched interactively at https://www.hgc.jp/~aniida/canevosim/index.html.

Contributing toward a deeper understanding of therapeutic resistance in cancer

"In this study, we clarified the principle underlying the diversity of cancer evolution by simulation analysis using a supercomputer. Since cancer has a high evolutionary potential, it adapts to the environment changed by therapy and easily acquires therapeutic resistance, so understanding the evolutionary principle of cancer is an important problem for designing therapeutic strategies." Niida emphasized

By providing a mathematical basis for understanding cancer evolution, this study is expected to contribute to the understanding of therapeutic resistance in cancer and the development of novel therapeutic strategies.