Culture

Early in human development, during the first trimester of gestation, a fetus may have XX or XY chromosomes that indicate its sex. Yet at this stage a mass of cells known as the bipotential gonad that ultimately develops into either ovaries or testes has yet to commit to its final destiny.

While researchers had studied the steps that go into the later stages of this process, little has been known about the precursors of the bipotential gonad. In a new study published in Cell Reports and co-led by Kotaro Sasaki of Penn's School of Veterinary Medicine, an international team lays out the detailed development of this key facet of sexual determination in two mammalian models.

"Using single-cell transcriptome data, we can get a lot of information about gene expression at each developmental stage," says Sasaki. "We can define what the default process is and how it might go awry in some cases. This has never been done in traditional developmental biology. Now we can understand development in molecular terms."

Disorders of sex development (DSD) occur when internal and external reproductive structures develop differently from what would be expected based on an individuals' genetics. For example someone with XY chromosomes might develop ovaries. These conditions often affect fertility and are associated with an increased risk of germ cell tumors.

"These disorders oftentimes create psychological and physical distress for patients," Sasaki says. "That's why understanding gonadal development is important."

To understand atypical development, Sasaki and colleagues in the current study sought to layout the steps of typical development, working with a mouse model and a monkey model.

The researchers began by examining mouse embryos throughout embryonic development, using molecular markers to track the location of different proteins suspected to be involved in the formation of reproductive structures. They noticed that by day nine of a mouse's embryonic development, a structure called the posterior intermediate mesoderm (PIM) lit up brightly with the marker for a gene critical to the development of gonads, kidneys, and the hormone-producing adrenal glands, which are located adjacent to the kidneys.

Zeroing in on the PIM and its progeny cells, the team found that, by day 10.5, these also expressed a marker known to be associated with the bipotential gonad.

"People have previously studied the origin of the urogenital organs and the kidney and based on that believed that their origins were very close," Sasaki says. "So our hypothesis was that the PIM was the origin of the gonads as well as the kidneys."

To identify the origin of the gonad, they performed lineage tracing, in which scientists label cells in order to track their descendents, which indeed supported the connection between the PIM and the gonads.

To further confirm that the PIM played a similar role in an organism closer to humans in reproductive biology, the researchers made similar observations in embryos from cynomolgus monkeys. Though the developmental timing was different from the mouse, as was expected, the PIM again appeared to give rise to the bipotential gonad.

Digging even deeper into the molecular mechanism of the transition between the PIM and bipotential gonad, the researchers used a cutting-edge technique: single-cell sequencing analysis, whereby they can identify which genes are being turned on during each developmental stage.

Not only were they able to identify genes that were turned on--many of which had never before been associated with reproductive development--but they observed a transition state between the PIM and bipotential gonad, called the coelomic epithelium. Comparing the mice and monkey embryos, the researchers came up with a group of genes that were conserved, or shared between the species. "Some of these genes are already known to be important for the development of mouse and human ovaries and testes," Sasaki says, "and some have been implicated in the development of DSDs."

He notes that in roughly half of patients with DSDs, however, the genetic cause is unknown. "So this database we're assembling may now be used to predict some additional genes that are important in DSD and could be used for screening and diagnosis of DSDs, or even treatment and prevention."

The study also illuminated the relationship between the origin of the kidneys, adrenal glands, and gonads. "They all originate from the PIM, but the timing and positioning is different," Sasaki says.

The adrenal glands, he says, develop from the anterior portion of the PIM, or that section closer to the head and arise early, while the kidney arises later from the posterior portion of the PIM. The gonadal glands span the PIM, with some regions developing earlier and others later.

In future studies, Sasaki and colleagues would like to continue teasing out the details and stages of gonadal development. Sasaki's ultimate goal is to coax a patient's own stem cells to grow into reproductive organs in the lab.

"Some patients with DSDs don't have ovaries and testes, and some cancer patients undergo chemotherapy and completely lose their ovary function," Sasaki says. "If you could induce a stem cell to grow into an ovary in the lab, you could provide a replacement therapy for these patients, allowing them to regain normal hormone levels and even fertility. With a precise molecular map to the developing gonad in hand, we are now one step closer to the this goal."

Although the fairy tale of the wicked stepmother is a tale as old as time, the effects of blending children with their new stepfamilies may not be as grim as once thought.

In fact, new research shows that stepchildren are not at a disadvantage compared to their peers from single-parent households and actually experience better outcomes than their halfsiblings -- good news for the more than 113 million Americans that are part of a steprelationship.

Led by East Carolina University anthropologist Ryan Schacht and researchers from the University of Utah, the study, "Was Cinderella just a fairy tale? Survival differences between stepchildren and their half-siblings," is available in the May edition of the Philosophical Transactions of the Royal Society B.

The study challenges the "Cinderella effect" theory. The effect contends that conflict within stepfamilies over physical, financial and emotional resources leads to higher mortality risks for stepchildren, and is a main factor in higher rates of abuse and neglect. The phenomenon suggests that stepparents play a major role in this abuse, hoarding resources for their biological children and leading to negative outcomes for stepchildren.

Schacht proposes that previous studies have placed blame for the negative outcomes associated with parental loss on stepparents yet have done so through an an "apples-to-oranges comparison." Specifically, they compare of the long-term outcomes of children who have suffered trauma like parental loss versus children from stable households. When the team compared stepchild outcomes more appropriately among those children who too have experienced the economic and emotional hardships associated with parental loss, they found no difference. Specifically, the introduction stepparenents did not increase stepchild mortality.

"The idea of a stepparent, especially the stepmother, as being an agent of evil seems to be a story as old as time," Schacht said. "It's easy to sell the Cinderella effect's result because we've been told these stories about the problems that stepfamilies experience for hundreds of years.

"We're not denying that some stepchildren suffer," he said. "However, if we truly believe it is the stepparent that is the source of negative outcomes for a stepchild, then we need to compare similar environments and experiences. A child that hasn't lost a parent through death or divorce hasn't experienced the same trauma that a stepchild has; comparing those two experiences and blaming the stepparent for diverging outcomes isn't a fair comparison."

The study compared the mortality of stepchildren whose parents remarried after the death of a spouse to children whose parents did not remarry and found three key findings:

* Parental mortality has a negative effect on children under 18 years old, especially for infants losing a mother;

* Children whose parents remarried after the loss of a spouse did not suffer a mortality rate any greater than children whose parents did not remarry; and

* Stepchildren received a protective effect when a halfsibling was introduced to their new family.

"The metrics of what makes a family successful -- household stability, relationship stability and economic stability -- are achieved by stepparents investing in their stepchildren to make that a reality. Coming in with an antagonistic approach doesn't make sense if stepparents want their relationship to succeed."

The research team analyzed a data set of more than 400,000 children from Utah from 1847-1940. Schacht said the time period provided an opportunity to analyze stepchild mortality rates in families during a natural fertility period where families were larger in size and most stepfamilies were formed due to the death of a parent.

The study adds that children who have suffered parental loss have more in common with their peers from single-parent households, facing many of the same educational, economic and health care disparities.

Schacht hopes the study will shed a light on public policy funding for interventions for families that have suffered parental loss.

Cells of all life forms are surrounded by a membrane that is made of phospholipids. One of these are the cardiolipins, which form a separate class due to their unique structure. When studying the enzyme that is responsible for producing cardiolipins in archaea (single-cell organisms that constitute a separate domain of life), biochemists at the University of Groningen made a surprising discovery. A single archaeal enzyme can produce a spectacular range of natural and non-natural cardiolipins, as well as other phospholipids. The results, which show potential for biotechnological applications, were published in the Journal of Biological Chemistry.

The phospholipids that are most abundant in cell membranes contain a hydrophilic head to which two hydrophobic tails are connected. Cardiolipins - so-called because they were first identified in heart cells - are slightly different since they are made up of a single head group that is attached to four lipid tails. 'We know which enzymes are responsible for cardiolipin production in bacteria and eukaryotes, but not in archaea,' says Marten Exterkate, who is the first author of the JBC paper.

Odd head group

His interest in these cardiolipins stems from his work on a synthetic minimal cell. 'Our group at the University of Groningen focuses on cell membrane growth, based on the enzymatic production of new phospholipids from basic building blocks.' Since cardiolipins are present in cell membranes of organisms from all domains of life, they are desired components of the synthetic cell. Exterkate wanted to know which enzymes are responsible for cardiolipin production in archaea. 'The lipids that form the cell membrane of archaea are structurally different from those in the other two domains of life,' Exterkate explains. 'Furthermore, while the other domains have one dominant type of cardiolipin, archaea appear to produce different kinds of cardiolipins, with head groups that contain, for example, only a single negative charge or different kinds of sugars or sulphate groups. Currently, we know next to nothing about how they are synthesized.'

By searching the genomes of archaeal species, Exterkate found several gene candidates for cardiolipin synthase. The most promising one from the archaea Methanospirillum hungatei was expressed in a standard laboratory strain of the E. coli bacterium, and the resulting enzyme was isolated and characterized. 'When we mixed the enzyme with potential building blocks, it produced the expected cardiolipin species. But then we noticed something really surprising: another cardiolipin with a very odd head group.' This turned out to be a molecule from the buffer solution in which the reaction took place.

Alarm bells

'All the alarm bells started ringing,' Exterkate recalls. 'If the enzyme can incorporate this buffer molecule as a lipid head group, what else could it do?' As it turned out, the enzyme was able to produce all kinds of variant cardiolipins and other phospholipids, containing both natural and non-natural head groups. 'Some enzymes are promiscuous; they can use slightly different variants of their normal substrates. But this enzyme is promiscuous in the extreme.' It can produce lipids that, in bacterial cells, for example, require many different enzymes.

This is the first identified enzyme with the ability to produce an entire range of different cardiolipins. Exterkate: 'Other archaea have similar genes, which are probably also suited to producing different cardiolipins, indicating that the variety in archaeal cardiolipins could be synthesized by the same enzyme.' Apart from being a surprising discovery, the new enzyme could be interesting for the production of self-designed membranes. This is useful because head groups in membrane phospholipids affect the overall properties of the membrane and the function of enzymes that are incorporated in it. 'The biotechnology industry could perhaps use this enzyme to artificially engineer membranes for specific purposes,' says Exterkate.

Osmoregulation

The discovery of this promiscuous enzyme also raises the question of why archaeal cells need all these different cardiolipins. So far, the textbooks refer to cardiolipins as one particular molecule. It is becoming clear, though, that cardiolipins form a class of molecules. Exterkate and his colleagues suspect that the enzyme is involved in osmoregulation. 'Depending on the environment, the enzyme can switch the production towards different phospholipids and in doing so, alter the functionality of the membrane.'

The enzyme could also turn out to be a bonus for the synthetic cell that Exterkate and his colleagues are working on. 'We planned to produce a membrane with a minimalistic phospholipid composition, so we wouldn't need to add lots of genes for different enzymes. Now, we can potentially produce lots of different phospholipids using only a single enzyme.'

Reference: Marten Exterkate, Niels A.W. de Kok, Ruben L.H. Andringa, Niels H.J. Wolbert, Adriaan J. Minnaard, Arnold J.M. Driessen: A promiscuous archaeal cardiolipin synthase enables construction of diverse natural and unnatural phospholipids. Journal of Biological Chemistry, first online as accepted 20 April

Lessons Learned from India's Polio Vaccination Program Provide Valuable Insights for Future Mass Vaccination Initiatives.

Toronto - As India urgently scales up its vaccination campaign for the COVID-19 virus, a new study which examined the country's successful program to eliminate polio provides guidance on how this and future mass immunization campaigns can be successful, especially in vaccinating hard to reach groups.

The study, conducted by students and faculty with the Reach Alliance, a research initiative based at the University of Toronto's Munk School of Global Affairs & Public Policy, says that medicine alone is insufficient for the elimination of disease.

The World Health Organization declared India polio-free in 2014. While the country had the medical ability to eliminate polio for decades, new managerial strategies were necessary to achieve polio elimination among India's hardest to reach, including within religious minorities and impoverished communities.

"We found that the barriers to vaccination were deeply rooted in larger issues of social trust and political vulnerability," says, Anita M. McGahan, University Professor and the George E. Connell Chair in Organizations & Society at the University's Rotman School of Management and Munk School. "Many of these same issues will need to be dealt with by governments and health agencies globally in order to vaccinate the most vulnerable today against COVID-19."

The study found that managerial strategies were necessary to achieve polio elimination among India's hardest to reach. Namely, these strategies were the bundling of basic healthcare services when marketing the vaccine, which tackled existing essential healthcare concerns in the communities; engaging stakeholders in vulnerable communities including religious leaders, local media outlets, employers of migrant workers, and private health providers; and, implementing accountability mechanisms among healthcare workers which improved the accuracy of both polio surveillance and vaccination data.

May 6, 2021 -- A significant level of symptoms of depression, anxiety and post-traumatic stress may follow COVID-19 independent of any previous psychiatric diagnoses, according to new research by Columbia University Mailman School of Public Health with colleagues at Universidade Municipal de São Caetano do Sul in Brazil. Exposure to increased symptomatic levels of COVID-19 may be associated with psychiatric symptoms after the acute phase of the disease. This is the largest study to evaluate depressive, anxiety, and post-traumatic stress symptoms in tandem among patients who had mild COVID-19 disease. The findings published online in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry shed light on a significant subpopulation at risk for mental symptoms.

"These results are important because the vast majority of COVID-19 patients are classified as mild cases, facing long periods of at-home isolation," said João Mauricio Castaldelli-Maia, MD, PhD, NIDA-INVEST Postdoctoral Fellow in the Department of Epidemiology at Columbia Mailman School. "It is probable that the increased prevalence of psychiatric symptoms post-COVID-19 is a consequence of the psychological context of the disease, and patients should be closely monitored for the development of psychiatric symptoms after COVID-19 treatment discharge."

Nasal swabs were collected from residents within a section of Sao Paulo, Brazil, 18 years of age or older with suspected COVID-19 symptoms. Patients were tested at their homes under the supervision of trained healthcare personnel. Those who tested positive for COVID-19 -- with at least two of the following symptoms: fever, cough, sore throat, change in/loss of smell -- and were classified as mild cases -- were further assessed for the presence of psychiatric symptoms approximately two months later.

Significant levels of depressive, anxiety and post-traumatic stress symptoms were reported by 26 percent, 22 percent, and 17 percent, respectively. For comparison purposes, previous estimates of post-traumatic stress levels within Brazil were 8.5% demonstrating that the prevalence within individuals presenting with mild COVID-19 increased versus past estimates.

In general, survivors of critical illnesses have a high level of mental symptoms after the condition improves. Depression, anxiety and post-traumatic stress disorder are among the most reported psychiatric events in patients with these conditions, according to the researchers. The ongoing COVID-19 pandemic has disrupted the lives of many across the globe, resulting in an increased burden of physical and mental health consequences. Brazil, to date, is one of the most affected countries, reaching around 412,000 deaths by early May 2021.

"These findings echo warnings from the previous SARS outbreak, when survivors of SARS infections experienced increased psychological distress, persisting one year or more subsequent to the outbreak, and similar findings were observed following the occurrence of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2015," observed Silvia Martins, MD, PhD, associate professor of Epidemiology at Columbia Mailman School.

"Early mental health intervention such as psychotherapy and supportive groups could play an important role in preventing incident mental health problems for post-COVID sufferers," said Castaldelli-Maia. "While further investigations for the possible neurobiological mechanisms linking COVID-19 and mental health conditions are warranted, healthcare systems must prepare for an influx of individuals experiencing psychological distress as a result of the COVID-19 pandemic."

The Marburg virus, a relative of the Ebola virus, causes a serious, often-fatal hemorrhagic fever. Transmitted by the African fruit bat and by direct human-to-human contact, Marburg virus disease currently has no approved vaccine or antivirals to prevent or treat it.

A team of researchers is working to change that. In a new paper in the journal Antimicrobial Agents and Chemotherapy, investigators from Penn's School of Veterinary Medicine, working together with scientists from the Fox Chase Chemical Diversity Center and the Texas Biomedical Research Institute, report encouraging results from tests of an experimental antiviral targeting Marburg virus. The compound blocks the virus from departing infected cells, thus putting the brakes on the spread of infection. Their findings are the first to show that this novel class of inhibitors can be effective against the infection in an animal model.

In addition, due to possible similarities in virus-host interactions between Marburg and SARS-CoV-2, the team has conducted experiments on the culprit behind the coronavirus pandemic. While preliminary and thus-far-unpublished, their initial tests show signs of promise.

"It really is exciting," says Ronald Harty, a co-corresponding author of the research and a professor at Penn Vet. "These viruses are quite different but may be interacting with the same host proteins to control efficient egress and spread, so our inhibitors may be able to block them both."

While many antivirals target the virus itself, the drug candidates that Harty and colleagues have been developing for years are known as "host-oriented." They prevent virus-host interactions by blocking the proteins in host cells that viruses hijack during late stages of infection.

Not only does this approach help avoid the likelihood that a virus would evolve to resist such a therapy, but it also increases the chance that a drug could be used against multiple viruses, as many rely on the same host cell machinery to reproduce and spread.

The Marburg and Ebola viruses use the VP40 protein to interact with a host protein called Nedd4 to complete the process of "budding" off a host cell. This stage of infection, which is key to viral spread, is the one the research team has targeted.

In previous studies, they had tested a variety of small molecule inhibitors of this process using laboratory tests that relied on non-infectious and more-benign viral models. Those assays helped them land on a leading candidate, FC-10696, for further study.

In the current work, they zeroed in on this candidate with rigorous evaluations. First, they tested the inhibitor to ensure it would be safe and retained long enough in the body to have an effect. Next, because the live Marburg virus is too dangerous to study safely in anything but a Biosafety Level 4 (BSL-4) laboratory, they used an assay to look at what are known as virus-like particles, or VLPs, which can bud off of a host cell like the live virus but are not infectious.

Using the Biosafety Level 2 laboratory at Penn, "it's a very quick way we can test these inhibitors," Harty says.

After seeing a dose-dependent response to FC-10696 on VLP budding in cells in a cell-culture dish, the researchers tested the compound using the real Marburg virus. These studies were done in a BSL-4 lab at Texas Biomedical Research Institute and found the compound inhibited the budding and spread of live Marburg virus in two human cell types, including in macrophages, an immune cell type commonly infected by the virus.

Finally, they evaluated the compound in mice that had been exposed to Marburg virus. Those mice treated with FC-10696 took longer to display disease symptoms and had a reduced viral load.

"These are the first promising in vivo data for our compounds," Harty says. "Whereas the control group all became sick very quickly and died, with the treated animals there was one survivor and others showed delayed onset of clinical symptoms. It's showing that our inhibitors are having an effect."

A portion of the VP40 protein in Marburg and Ebola viruses that enables budding is known as a PPxY motif. SARS-CoV-2 also happens to have this motif on its Spike (S) protein, which it uses to infect human cells. In a follow-up experiment that is not yet published, the researchers found evidence that FC-10696 was able to inhibit budding of the SARS-CoV-2 coronavirus in human lung epithelial cells.

"The SARS-CoV-2 studies are ongoing, and they're very exciting," Harty says.

New research published in Experimental Physiology highlight the possible long term health impacts of COVID-19 on young, relatively healthy adults who were not hospitalized and who only had minor symptoms due to the virus.

Increased stiffness of arteries in particular was found in young adults, which may impact heart health, and can also be important for other populations who may have had severe cases of the virus. This means that young, healthy adults with mild COVID-19 symptoms may increase their risk of cardiovascular complications which may continue for some time after COVID-19 infection.

While SARS-CoV-2, the virus known for causing the COIVD-19 pandemic, is mainly characterized by respiratory symptoms, other studies have recently shown changes to blood vessel function among young adults 3-4 weeks after being infected with SARS-CoV-2 (Ratchford et al., 2021).

This has also been observed months after infection in older adults as well (Riou et al. J Clin Med. 2021).

The research team at Appalachian State University found that the virus may have detrimental effects to arteries throughout the body, including in the carotid artery which supplies the brain with blood.

This draws comparisons between SARS-CoV-2 and other acute bacterial and viral infections which alter arterial stiffness such as rheumatic fever, Kawasaki disease, pneumonia, H. Pylori, and lupus, all of which may persist long after symptoms have resolved.

The researchers tested young adults 3-4 weeks after being infected with SARS-CoV-2. They used an ultrasound on the carotid artery and took recordings of that image for 10-15 heart beats.

These recordings were analyzed on a computer software to find measures of carotid stiffness. For the control group, they used data from young healthy adults who were studied prior to the COVID-19 pandemic.

As far as limitations of this study goes, the researchers do not know if the SARS-CoV-2 group had any innate decrements in arterial stiffness prior to contracting the virus.

They also did not control for menstrual cycle or variations in contraceptive use in either group. However, previous research has indicated that contraceptive use and menstrual cycle fluctuations among young healthy females may not influence the outcome measures they were studying.

The researchers are following these young adults for 6 months after initial infection with SARS-CoV-2 to observe if and when the arterial health of these individuals is improving.

The results of the longitudinal study will be interesting, as these adults' symptomology may improve, yet their arterial health may not be recovering as quickly, which may have significance for their heart health.

Further investigations should aim to study a more diverse patient population over time, especially older adults who are more susceptible to the virus and who may have underlying conditions such as heart disease, diabetes, and hypertension.

Dr. Steve Ratchford, the senior author on the paper said: "These findings suggest a potential long-term impact of COVID-19 on young, relatively healthy adults who may otherwise think the virus may not be affecting them."

Just as people keep their houses clean and clutter under control, a crew of cells in the body is in charge of clearing the waste the body generates, including dying cells. The housekeeping cells remove unwanted material by a process called phagocytosis, which literally means 'eating cells.' The housekeepers engulf and ingest the dying cells and break them down to effectively eliminate them.

"Phagocytosis is very important for the body's health," said Dr. Zheng Zhou, whose lab at Baylor College of Medicine has been studying phagocytosis for many years and provided key new insights into this essential process. "When this cell-eat-cell process fails, the dying cells will lose their integrity, break down and release their content into the surrounding tissues. Dumping the cell content would cause direct tissue damage and trigger inflammatory and autoimmune responses. If the dying cells are infected by a virus, releasing the cellular content would spread the infection."

In the current study, Zhou, professor in the Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor, and her colleagues focused on necrosis, the type of cell death caused by injury or disease. Necrosis is mostly associated with stroke, cancer, neurodegenerative diseases and heart conditions. The team investigated in more detail the signal necrotic cells display that cues the 'eating' or phagocytic cells to engulf and eliminate the dying cell.

"In previous work, the Zhou lab showed that the signal in necrotic cells is phosphatidylserine, which is a type of lipid," said Yoshitaka Furuta, first author of the current study on which he worked while he was an undergraduate student intern in the Zhou lab. Furuta currently is a student in Baylor's Development, Disease Models and Therapeutics Graduate Program.

The team found that necrotic cells, but not living cells, expose phosphatidylserine on their outer surfaces and when phagocytes detect it, they ingest and destroy the dying cells."

Healthy cells keep phosphatidylserine in their inside, but when they are injured, for instance by lack of oxygen during a stroke when neurons are over excited due to constant entry of calcium ions, or during neurodegeneration, a process begins that ultimately flips phosphatidylserine to the outside of the cell. "We wanted to know what activates the flipping of phosphatidylserine," Furuta said.

Following the process of necrosis in the transparent worm C. elegans

The researchers worked with the model organism C. elegans, a worm that is as long as a credit card is thick. C. elegans is transparent, which allows the researchers to visually identify necrotic neurons, which look swelled when compared to living cells, and follow changes in the dynamics of cellular components using a time-lapse recording approach they developed.

Previous work in C. elegans neurons had shown that certain mutations in ion channel proteins, which regulate the flow of ions like calcium2+ in and out of the cell, induced necrosis that was accompanied by an increase of calcium ion levels inside the cell. To investigate whether changes in calcium ion levels were linked to the triggering of the eat-me signal, the team introduced some of the ion channel mutant genes in neurons of their C. elegans model and monitored both calcium levels and phosphatidylserine over time.

"We discovered in our model of necrosis that a robust and transient increase in calcium ions inside the cell preceded phosphatidylserine exposure in necrotic neurons," said Zhou, a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "Further experiments showed that necrotic neurons first had a small increase of calcium ions, which prompted the release of more calcium ions from an intracellular structure called the endoplasmic reticulum (ER), a larger source of calcium. Having larger than normal calcium levels inside the cell triggered phosphatidylserine exposure."

Supporting the role of calcium ions as a trigger of the 'eat-cell' signal, the researchers found that artificially increasing the level of calcium ions inside living cells also resulted in phosphatidylserine exposure and that suppressing calcium release from the ER prevented exposure of the signal.

The team also zoomed in into the process leading to the flipping of phosphatidylserine and found another piece of the puzzle. They discovered that a calcium increase inside the cells activates ANOH-1, an enzyme known to promote phosphatidylserine exposure.

"It was interesting to me that calcium can be good and bad for living cells," Furuta said. "Too much calcium is toxic to cells and induces necrosis, but at the same time calcium is necessary for dying cells to expose phosphatidylserine, the eat-me signal that promotes their clearance."

"Necrosis is a universal phenomenon that is present in many types of diseases and the clearance of necrotic cells is very important for keeping our bodies healthy," Zhou said.

Our findings provide new insight into the process of necrosis that can potentially lead to the development of therapeutic strategies, maybe along the lines of promoting clearance of necrotic cells by modulating phosphatidylserine exposure, which may help reduce the toxic effects of necrosis and improve cellular housekeeping."

Retinoblastoma starts in the retina, the thin membrane at the back of the eye. Most patients are infants or toddlers when their cancer is found. Without treatment, the cancer spreads. Thanks to chemotherapy, surgery and other treatments, 96% of patients survive.

St. Jude researchers studied how survivors fared years later at home and at school. A previous St. Jude study of 98 retinoblastoma survivors found that their early learning and life skills declined from diagnosis to age 5.

Researchers tested 78 of the same survivors five years later. The results were more upbeat. By age 10, almost all the children functioned within the normal range in those areas. That included children who had one eye removed, although they did not make up quite as much ground in the areas of learning, thinking and memory.

"The good news is that as a group the children did improve over time, but not everyone is recovering at the same rate," said Victoria Willard, PhD, of St. Jude Psychology. "The findings show we all need to be aware of factors that put children at risk for difficulties later. It highlights that all young children with retinoblastoma may benefit from early intervention to promote growth and development."

The Journal of Clinical Oncology published a report on this work.

Recently published research from the University of Arizona Health Sciences shows that advanced-stage kidney cancer is more common in Hispanic Americans and Native Americans than in non-Hispanic whites, and that both Hispanic Americans and Native Americans in Arizona have an increased risk of mortality from the disease.

"We knew from our past research that Hispanic Americans and Native Americans have a heavier burden of kidney cancer than non-Hispanic whites," said Ken Batai, PhD, a Cancer Prevention and Control Program research member at the UArizona Cancer Center and research assistant professor of urology in the College of Medicine - Tucson. "But we also know that around 90% of the Hispanic population in Arizona is Mexican American - either U.S.-born or Mexican-born - and we do not think this subgroup is well-represented in the national data."

With funding from the National Cancer Institute, Dr. Batai led a team of UArizona Cancer Center researchers that examined data from the National Cancer Database and the Arizona Cancer Registry to look for disparities in surgical treatment of kidney cancer. They also investigated the possibility that delayed treatments may result in advanced-stage kidney cancer, which has been associated with high mortality rates in Hispanic Americans and Native Americans.

The paper, "Renal Cell Carcinoma Health Disparities in Stage and Mortality among American Indians/Alaska Natives and Hispanic Americans: Comparison of National Cancer Database and Arizona Cancer Registry Data," was published in the journal Cancers.

The study found that Arizona's Hispanic Americans are about two times more likely than non-Hispanic white people to have advanced-stage kidney cancer and have nearly a two times higher risk of mortality from early-stage kidney cancer. Similarly, Native Americans are about 30% more likely to have advanced-stage kidney cancer and face a 30% increased risk of mortality from early-stage kidney cancer.

These findings suggest that observed disparities in kidney cancer mortality risk cannot be explained by delays in treatment.

The researchers utilized state data to organize Hispanic Americans into various subgroups, including U.S.-born Mexican Americans. They determined this group to have a three times higher risk of mortality compared with non-Hispanic white Americans. National cancer statistics do not break down subgroups within the general Hispanic population, thus risks to U.S.-born Mexican Americans living in Arizona may be understated in national reporting.

Dr. Batai attributes the discrepancy in national versus state data to the data-collection process. The National Cancer Database relies on hospital-based reporting, whereas the state registry is population-based. Many small hospitals and clinics in rural settings may not report to the National Cancer Database, which could explain the misrepresentation of Hispanic Americans in Arizona.

"To this point, there has been no research documenting this disparity in Hispanic Americans," Dr. Batai said. "This can be very useful information to share with primary care providers and urologists who may not yet be aware."

"Carefully documenting these disparities is something that distinguishes us as a comprehensive cancer center," said Joann Sweasy, PhD, Cancer Center director and inaugural holder of the Nancy C. and Craig M. Berge Endowed Chair. "Dr. Batai is embedded in our center not only in prevention, but he is also a part of our genitourinary clinical research team. This research benefits both perspectives, which are critical for us to meet the needs of our patients."

The research could drive further investigation into why Arizona's Hispanic and Native American populations face increased risks from kidney cancer.

"We know these populations also have higher prevalence of diabetes and blood pressure, both of which are risk factors for kidney cancer," Dr. Batai said. "While we continue to explore differences in kidney cancer surgical treatment across these groups, we are investigating if there are biologic bases in kidney cancer disparities."

New research from Simon Fraser University suggests that students learning remotely become night owls but do not sleep more despite the time saved commuting, working or attending social events.

The study, led by psychology professor Ralph Mistlberger, Andrea Smit and Myriam Juda, at SFU's Circadian Rhythms and Sleep Lab, compared self-reported data on sleep habits from 80 students enrolled in a 2020 summer session course at SFU with data collected from 450 students enrolled in the same course during previous summer semesters. The study results were recently published in the journal PLOS ONE.

"There is a widespread belief among sleep researchers that many people, especially young adults, regularly obtain insufficient sleep due to work, school, and social activities," says Mistlberger. "The move toward remote work and school during COVID-19 has provided a novel opportunity to test this belief."

The student participants kept daily sleep diaries over a period of two-to-eight weeks, completed questionnaires and provided written reports. Fitbit sleep tracker data was collected from a subsample of participants.

The team found that students learning remotely in the summer 2020 session went to bed an average of 30 minutes later than pre-pandemic students. They slept less efficiently, less at night and more during the day, but did not sleep more overall despite having no early classes and 44 per cent fewer work days compared to students in previous semesters.

"One very consistent finding is a collective delay of sleep timing - people go to bed and wake up later," says Mistlberger. "Not surprisingly, there is also a marked reduction in natural light exposure, especially early in the day. The lack of change in sleep duration was a bit of a surprise, as it goes against the assumption that young adults would sleep more if they had the time."

Self-described night owls were more likely to report a greater positive impact on their sleep, getting to sleep in, instead of waking up early for that morning class, while morning types were more likely to report a negative response to sleeping later than usual.

Sleep plays an important role in immune functioning and mental health, which is why good sleep habits are crucial.

"My advice for students and anybody working from home is to try to get outside and be active early in the day because the morning light helps stabilize your circadian sleep-wake cycle - this should improve your sleep, and allow you to feel more rested and energized during the day," says Mistlberger.

Loneliness and social isolation have been significant problems for the general population during the COVID-19 pandemic, but for cancer patients these issues were particularly acute, likely due to isolation and social distancing, according to a new UCSF study.

The study, which is the first to evaluate loneliness, anxiety, depression, fatigue and other symptoms in a single group of patients, is published in Cancer, a peer-reviewed journal of the American Cancer Society.

"We found that oncology patients were experiencing a deep sense of loneliness," said first author Christine Miaskowski, RN, PhD, a professor in the UCSF School of Nursing.

"For these patients, the burden of their symptoms is extremely high, and oncology clinicians can suggest a number of strategies to help them," she said. "Patients should be encouraged to maintain contact with family and friends, and structure their daily routines when possible, through outdoor activities for example, as well as to maintain a healthy diet and sufficient sleep. These suggestions might mitigate some of the negative effects of loneliness."

The COVID-19 pandemic brought to the forefront a pervasive sense of loneliness in the lay population, but the effects have not been well-studied in oncology patients. The new survey, administered in late May 2020, evaluated the severity of loneliness, social isolation and related symptoms - such as anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction and pain - in a sample of 606 oncology patients.

Altogether, 53 percent were found to be in the lonely group, which was higher than the range reported prior to the pandemic (32 percent - 47 percent). About a third had moderately high degrees of loneliness, and 5.3 percent reported high levels of depression.

The lonely group was significantly more likely to be younger than the non-lonely group and less likely to be married or partnered. They also had a higher number of comorbidities and were more likely to report a diagnosis of depression and back pain.

Older cancer patients reported lower levels of loneliness, while patients 50 to 59 reported higher levels. The researchers believe older adults adapted their need for social contact to available opportunities.

Lower levels of household income were associated with higher levels of loneliness. The authors suggest that people at higher incomes have "more opportunities to engage in social activities and reciprocate in social relationships."

Nearly 83 percent of the patients in the lonely group suffered from breast cancer, a third were currently in cancer treatment and a quarter had metastatic disease. Nearly 92 percent of the participants were female - as a result, no conclusions could be drawn about sex differences, the authors said.

Primarily, the participants were White, well-educated, and had an annual income exceeding $60,000. As such, the authors said, their findings may not fit all patients with cancer, and symptoms could be higher in patients who are socioeconomically disadvantaged.

Researchers at North Carolina State University and the University of North Carolina Greensboro made a surprising finding while examining areas where sand flies rear their young: a new species of bacteria that is highly attractive to pregnant, or gravid, sand flies. The findings could advance the production of ecologically safe baits or traps to reduce sand fly populations.

Sand flies are vectors for important parasitic diseases affecting people in tropical and subtropical regions in Asia, Africa and the Middle East. One of those diseases is Leishmaniasis, which generally causes sores and skin ulcers but in some cases can detrimentally affect internal organs.

"Sand flies live in sheltered places such as animal burrows, caves, and rock or tree crevices, so it's difficult to reach them with insecticides," said Loganathan Ponnusamy, principal research scholar in NC State's Department of Entomology and Plant Pathology and the corresponding author of a paper describing the research. "If you're able to attract sand flies with a chemical that attracts them in nature, you're better able to target and kill them."

The research team, which included researchers from Gideon Wasserberg's lab at the University of North Carolina Greensboro, cultured a number of different bacterial species from the sand fly larval rearing area and found one that hadn't yet been identified: Sphingobacterium phlebotomi, a new member of the family of bacteria known as Sphingobacteriaceae.

To prove that the bacterium hadn't already been identified, Madhavi Kakumanu, an NC State research scholar, performed a number of tests - including scanning electron microscopy, chemical analysis and whole genome sequencing - and showed the bacterium's novelty.

"We were culturing and isolating a lot of different bacteria and found this new one almost by accident," Kakumanu, the paper's first author, said.

Bahjat Fadi Marayati, a graduate student in Wasserberg's lab, conducted attraction tests and demonstrated that this new bacteria species produces volatile chemicals that were attractive to pregnant sand flies.

Pregnant sand flies preferred the smell of the new bacterium over other chemical compounds presented during testing, Ponnusamy said, showing that the bacterium acted as a beacon for an appropriate place for females to lay eggs.

Ponnusamy says further testing will be done to narrow down even further the chemical compounds that attract sand flies.

HOUSTON - (May 6, 2021) - A Rice University laboratory has adapted its laser-induced graphene technique to make high-resolution, micron-scale patterns of the conductive material for consumer electronics and other applications.

Laser-induced graphene (LIG), introduced in 2014 by Rice chemist James Tour, involves burning away everything that isn't carbon from polymers or other materials, leaving the carbon atoms to reconfigure themselves into films of characteristic hexagonal graphene.

The process employs a commercial laser that "writes" graphene patterns into surfaces that to date have included wood, paper and even food.

The new iteration writes fine patterns of graphene into photoresist polymers, light-sensitive materials used in photolithography and photoengraving.

Baking the film increases its carbon content, and subsequent lasing solidifies the robust graphene pattern, after which unlased photoresist is washed away.

Details of the PR-LIG process appear in the American Chemical Society journal ACS Nano.

"This process permits the use of graphene wires and devices in a more conventional silicon-like process technology," Tour said. "It should allow a transition into mainline electronics platforms."

The Rice lab produced lines of LIG about 10 microns wide and hundreds of nanometers thick, comparable to that now achieved by more cumbersome processes that involve lasers attached to scanning electron microscopes, according to the researchers.

Achieving lines of LIG small enough for circuitry prompted the lab to optimize its process, according to graduate student Jacob Beckham, lead author of the paper.

"The breakthrough was a careful control of the process parameters," Beckham said. "Small lines of photoresist absorb laser light depending on their geometry and thickness, so optimizing the laser power and other parameters allowed us to get good conversion at very high resolution."

Because the positive photoresist is a liquid before being spun onto a substrate for lasing, it's a simple matter to dope the raw material with metals or other additives to customize it for applications, Tour said.

Potential applications include on-chip microsupercapacitors, functional nanocomposites and microfluidic arrays.

As the human body's largest organ, the skin is responsible for protecting against a wide range of possible infections on all fleshy surfaces, from head to toe. So how exactly does the skin organize its defenses against such an array of threats?

A new Yale study shows that the epidermis, the outermost layer of skin, is comprised of an army of immune cells that station themselves at regular intervals across the skin's vast expanse to resist infection. When necessary, the researchers found, these immune system soldiers are able to reposition themselves to protect vulnerable areas.

The study, published in the journal Nature Cell Biology, was conducted by the lab of Valentina Greco, the Carolyn Walch Slayman Professor of Genetics, at Yale School of Medicine.

"It's a surveillance system with two separate roles," said Catherine Matte-Martone, manager of the Greco lab manager and co-first author of the study. "The skin controls the sentinels by mediating their numbers based on its own density, while they in turn provide dynamic coverage to prevent cracks in the skin's defenses."

The epidermis contains two main types of immune system cells, Langerhans cells (LCs) and dendritic epidermal T cells (DETCs). In the study, the research team led by Matte-Martone and Sangbum Park, a researcher from Michigan State University (MSU), captured images of these immune system cells interacting with epithelial cells, the closely packed skin cells that comprise most of the epidermis.

They found that the immune system cells are distributed in a distinct pattern, maintaining a minimum distance between the individual cells. According to the researchers, these immune cells seem to have the ability to avoid each other, preventing clusters in any locations and maintaining a consistent distribution.

The phenomenon is similar to a property observed in neurons, in which scientists have observed a tendency of neurons from a single branch to avoid each other.

"Our study suggests that LCs and DETCs appear to have a mechanism of 'self-avoidance,', similar to neuronal cells," said Park, an assistant professor at MSU and former postdoctoral fellow in the Greco lab at Yale.

When the team removed some immune cells in one area, they observed that the remaining cells were able to reposition across the skin tissue to defend the gaps in coverage. They also found that they could disrupt the normal distribution of those cells by knocking out a gene known as Rac1 (Ras-related C3 botulinum toxin substrate 1), which regulates projections on immune cells called dendrites. This process, they hypothesize, helps maintain the distance between immune cells.

The findings illustrate how specialized cell types can cooperate to carry out a larger role within the body.

"It is fascinating to observe how these different cell types co-exist and interact together in a developmental context rather than an immunological one," Martone said.