Brain

In an article published in the April 8 issue of Nature, the National Institutes of Health's Somatic Cell Gene Editing Consortium provided a detailed update on the progress of their nationwide effort to develop safer and more effective methods to edit the genomes of disease-relevant somatic cells and reduce the burden of disease caused by genetic changes.

Gene editing allows scientists to modify sections of an organism's DNA and is considered a promising treatment for a number of genetic diseases. There have been numerous advances in the laboratory over the last few decades, but there are still many challenges to overcome before gene editing can be widely used in the patient population. Launched in 2018, the Somatic Cell Gene Editing Consortium (SCGE) has brought together some of the leading researchers in the field to advance discovery and accelerate the translation of somatic gene editing advances in the lab to the clinical setting.

Over six years, the NIH will allocate approximately $190 million to SCGE to realize gene editing's potential. The end result will be a freely available toolkit that will provide the biomedical research community with rigorously evaluated information about genome editors and methods for delivering and tracking gene editing molecules.

"NIH realized it was important for all of us who are investigating gene editing to work together toward a common goal," said Carnegie Mellon University Professor of Chemistry Danith Ly who joined the consortium in 2019. "We're designing molecules that can go into the cell and we're cataloging each and every one. What we'll end up with is a very valuable, rigorously evaluated resource for those who want to bring gene editing to patients."

While much of the consortium's work focuses on CRISPER-Cas related systems, the SCGE points out that it's important to continue to develop other systems. They specifically single out the peptide nucleic acid-based gene editing technique developed by Carnegie Mellon's Ly and Yale University's Peter Glazer.

"Although there is a significant focus on CRISPR-Cas related systems within the SCGE, it is crucial to continue to explore alternate systems, in part because they may differ in both their potential for delivery and their biological or immunological responses," the consortium wrote in Nature.

While CRISPR-Cas edits genes in cells that have been removed from the body, Ly and Glazer's peptide nucleic acid (PNA) system is administered intravenously and edits cells in vivo. Using nanoparticles, a PNA molecule paired with a donor strand of DNA is delivered directly to a malfunctioning gene. Ly, a leading researcher in synthetic nucleic acid technology, has programmed PNA molecules to open double stranded DNA at the site of a targeted mutation. The donor DNA from the complex binds to the cell's faulty DNA and triggers the DNA's innate repair mechanisms to edit the gene. The team has used the technique to cure beta thalassemia in adult mice and in fetal mice in utero.

The PNA gene editing system doesn't have the high-yield of CRISPER-Cas systems, but it does have the advantage of being less likely to make off-target modifications. According to Ly, that means their technique might be better for genetic diseases that only need to have a small percentage of cells corrected to make a therapeutic difference. For example, in the beta thalassemia studies, Ly and Glazer found that editing only six to seven percent of cells was curative.

Ly and Glazer plan to further refine and improve their technique through their participation in SCGE, and they look forward to sharing their results with the consortium and the greater biomedical community.

Cancer doctors may soon have a new tool for treating melanoma and other types of cancer, thanks to work being done by researchers at the University of Colorado Cancer Center.

In a paper published in the journal PNAS last month, CU Cancer Center members Mayumi Fujita, MD, PhD, Angelo D'Alessandro, PhD, Morkos Henen, PhD, MS, Beat Vogeli, PhD, Eric Pietras, PhD, James DeGregori, PhD, Carlo Marchetti, PhD, and Charles Dinarello, MD, along with Isak Tengesdal, MS, a graduate student in the Division of Infectious Diseases at the University of Colorado School of Medicine, detail their work on NLRP3, an intracellular complex that has been found to participate in melanoma-mediated inflammation, leading to tumor growth and progression. By inhibiting NLRP3, the researchers found, they can reduce inflammation and the resultant tumor expansion.

Specifically, NLRP3 promotes inflammation by inducing the maturation and release of interleukin-1-beta, a cytokine that causes inflammation as part of the normal immune response to infection. In cancer, however, inflammation can cause tumors to grow and spread.

"NLRP3 is a member of a larger family that is involved in sensing danger signals," Marchetti says. "It is a receptor that surveils the intercellular compartment of a cell, looking for danger molecules or pathogens. When NLRP3 recognizes these signals, it leads to the activation of caspase-1, a protein involved in the processing and maturation of interleukin-1-beta into its biological active form, causing an intense inflammatory response. We found that in melanoma, this process is dysregulated, resulting in tumor growth."

The oral NLRP3 inhibitor used in their study (Dapansutrile) has already shown to be effective in clinical trials to treat gout and heart disease, and it is currently being tested in COVID-19 as well. The CU cancer researchers are now trying to find out if this NLRP3 inhibitor can be successfully used in melanoma patients who are resistant to checkpoint inhibitors.

"Checkpoint inhibitors increase the efficacy of the immune system to kill tumors, but sometimes tumors become resistant to this treatment," Marchetti says. "A big part of cancer research now is to find therapies that can be combined with checkpoint inhibitors to improve their efficacy."

With the hypothesis that an NLRP3 inhibitor is one of those therapies, CU Cancer Center researchers are studying the drug's effects on melanoma, as well as other major cancers. In addition to improving the immune response, the NLRP3 inhibitor can also help reduce the side effects of checkpoint inhibitors. Marchetti says this research can make a big difference for melanoma patients who don't respond to checkpoint inhibitors alone.

"This was a very collaborative project that involved a lot of members of the university, and we are very excited about it," he says. This project is important because it further shows that NLRP3-mediated inflammation plays a critical role in the progression of melanoma, and it opens new strategies to improve patient care."

In a survey-based study of 105 graduate-level counseling students who identified as Black, Indigenous, or people of color (BIPOC), investigators found that experiences of discrimination can negatively affect student overall wellbeing and lead to burnout.

The authors of the study, which is published in the Journal of Multicultural Counseling and Development, stress the importance of addressing the unique needs and experiences of BIPOC students who are striving to become counselors, not only to help individual students but also to ensure the field is meeting the representative needs of a continuously diversifying client population.

"This emphasizes the need for counseling programs in particular to be proactive and inclusive in their integration of wellness, to name the barriers that exist for BIPOC students, and to identify concrete ways to attend to those barriers," said lead author Dareen Basma, PhD, of Carnegie Mellon University. "In doing so, we can also begin to work towards increasing recruitment and retention of BIPOC students in our programs, and ultimately diversifying our profession."

New research led by the universities of Kent and Warwick has found that, contrary to previous beliefs, adolescents born preterm have the same levels of self-esteem and overall wellbeing as those born full-term.

Preterm birth, defined as birth before 37 weeks of gestation, has been previously found to be associated with an increased risk for lower academic achievement, higher mental health problems and increased difficulties in social relationships compared to those born full-term. This new study, co-led by Dr Ayten Bilgin (Kent) alongside colleagues from Warwick, demonstrates that in contrast, preterm birth does not affect the development of subjective wellbeing and self-esteem, which are personal evaluations and thus different from school grades or psychiatric diagnoses.

The research paper, published by the Journal of Developmental & Behavioral Pediatrics, reveals how adolescents born very preterm (28 to 32 weeks) or moderate-to-late preterm (32 to 37 weeks) are no different from those born full-term regarding general subjective wellbeing, and family, school and physical appearance related wellbeing, and global self-esteem.

However, the study found that adolescents born very preterm perceive their peer relationships as poorer than those born full-term. This would indicate that interventions to enhance wellbeing in very preterm adolescents may be focused around improving peer relationships in childhood and adolescence.

Dr Bilgin said: 'It is very encouraging to find that preterm born adolescents show the same levels of self-esteem and wellbeing as full-term born adolescents, despite the association between preterm birth and increased mental health problems. We hope our findings will impact the focus of future studies.'

Dieter Wolke, Professor of Developmental Psychology and Individual Differences at the University of Warwick's Department of Psychology, added: 'It is concerning that those born preterm perceive themselves to have poorer peer relationships. Together with our previous evidence that preterm children may be more often the subject of bullying, supporting friendships and peer relations in school and leisure activities should be a priority.'

Researchers at Tokyo Institute of Technology (Tokyo Tech) have experimentally demonstrated a novel cancer diagnosis technique based on the scattering of circularly polarized light. Computational studies revealed that this technique can detect the progression of precancerous lesions and early cancer. This method can be implemented using an endoscope equipped with spin-LEDs--devices that emit circularly polarized light.

Most cancers of the digestive system emerge in the surface layer first and then progress into deeper layers. While surface layer carcinomas can be readily treated using an endoscope, carcinomas that have advanced onto deeper layers need surgical intervention to prevent them from metastasizing to lymph nodes or other organs. Thus, accurate measurements of the depth of cancer progression without damaging tissues are important to obtain useful information for making treatment-related decisions.

Current endoscopic diagnosis techniques like narrow-band imaging can only confirm the presence of cancer and distinguish between tumorous and non-tumorous tissue. There are very few direct measurement techniques that can provide a quantitative diagnosis of the depth and area of a carcinoma.

To tackle the abovementioned issue, a multinational research team led by Dr. Nozomi Nishizawa of Tokyo Tech recently conducted a study to demonstrate a novel cancer diagnosis technique using circularly polarized light. Their findings have been published in the Journal of Biophotonics, and a scientific illustration of the study was selected as an inside cover in the journal (Figure 1).

Their approach relies on how circularly polarized light interacts with healthy and unhealthy cells. "The depolarization of circularly polarized light scattered from biological tissues depends on structural changes in cell nuclei, which can provide valuable information for detecting cancer concealed in healthy tissues," explains Dr. Nishizawa. The team experimentally demonstrated this fact by shining near-infrared circularly polarized light on sliced tissue samples of murine liver containing metastatic lesions derived from intrasplenically injected human pancreatic cancer cells. They observed clear differences in the degree of circular polarization of the light scattered from the samples depending on the state of the biotissue, showing that cancer identification is possible with this technique (Figure 2).

Moreover, through computational studies with numerical simulations incorporating the scattering phenomena of circularly polarized light, the team also demonstrated that the depth profile of biotissues can be obtained by manipulating the detection angle. In short, the sampling depth in the target biotissue becomes deeper as the emission angle of the scattered light becomes close to perpendicular. Therefore, this dependence on the emission angle provides information on the depth profile of tissues or, in other words, the cancer's progression toward the deeper layers.

However, one technical challenge had to be addressed to make this diagnosis method feasible: circularly polarized light cannot travel through optical fiber without losing its polarization. Therefore, the use of circularly polarized light in vivo requires a compact source of circularly polarized light. One promising candidate for such a source is spin-LEDs--devices developed by the researchers. In 2017, they succeeded in creating spin-LEDs capable of emitting almost pure circularly polarized light at room temperature. "By combining our novel technique based on circularly polarized light scattering and spin-LED devices, we will be able to determine the progression of precancerous lesions in vivo," remarks Dr. Nishizawa. To this end, in their latest study, the team designed the structure of an endoscope probe containing circularly-polarized LEDs, which can detect scattered light with various emission angles simultaneously (Figure 3).

The researchers are hopeful that the proposed technique will find application in the diagnosis of ulcerative colitis and alcoholic cirrhosis in future. Moreover, it could also be applied for the observation of engraftments in regenerative medicine and transplant surgery.

At a cost of $38 billion a year, an estimated 5.3 million people are living with a permanent disability related to traumatic brain injury in the United States today, according to the Centers for Disease Control and Prevention. The physical, mental and financial toll of a TBI can be enormous, but new research from the University of Georgia provides promise.

In a new study, researchers at UGA's Regenerative Biosciences Center have demonstrated the long-term benefits of a hydrogel, which they call "brain glue," for the treatment of traumatic brain injury. The new study provides evidence that not only does the gel protect against loss of brain tissue after a severe injury, but it also might aid in functional neural repair.

Brain damage following significant TBI commonly results in extensive tissue loss and long-term disability. There currently are no clinical treatments to prevent the resulting cognitive impairments or tissue loss.

Reported on March 5 in Sciences Advances, the new finding is the first to provide visual and functional evidence of the repair of brain neural circuits involved in reach-to-grasp movement in brain glue-implanted animals following severe TBI.

"Our work provides a holistic view of what's going on in the recovery of the damaged region while the animal is accomplishing a specific reach-and-grasp task," said lead investigator Lohitash Karumbaiah, an associate professor in the University of Georgia's College of Agricultural and Environmental Sciences.

Created by Karumbaiah in 2017, brain glue was designed to mimic the structure and function of the meshwork of sugars that support brain cells. The gel contains key structures that bind to basic fibroblast growth factor and brain-derived neurotrophic factor, two protective protein factors that can enhance the survival and regrowth of brain cells after severe TBI.

In a prior short-term study, Karumbaiah and his team showed that brain glue significantly protected brain tissue from severe TBI damage. In this new research, to harness the neuroprotective capacity of the original, they further engineered the delivery surface of protective factors to help accelerate the regeneration and functional activity of brain cells. After 10 weeks, the results were apparent.

"Animal subjects that were implanted with the brain glue actually showed repair of severely damaged tissue of the brain," said Karumbaiah. "The animals also elicited a quicker recovery time compared to subjects without these materials."

To measure the glue's effectiveness, the team used a tissue-clearing method to make brain tissue optically transparent, which allowed them to visually capture the immediate response of cells in the reach-to-grasp circuit using a 3D imaging technique.

"Because of the tissue-clearing method, we were able to obtain a deeper view of the complex circuitry and recovery supported by brain glue," said Karumbaiah. "Using these methods along with conventional electrophysiological recordings, we were able to validate that brain glue supported the regeneration of functional neurons in the lesion cavity."

Karumbaiah pointed out that the RTG circuit is evolutionarily similar in rats and humans. "The modulation of this circuit in the rat could help speed up clinical translation of brain glue for humans," he said.

With support from UGA's Innovation Gateway, Karumbaiah has filed for a patent on the brain glue. He is also partnering with Parastoo Azadi, technical director of analytical services at the UGA Complex Carbohydrate Research Center, and GlycoMIP, a $23 million, National Science Foundation-funded Materials Innovation Platform, created to advance the field of glycomaterials through research and education.

"Doing the behavioral studies, the animal work and the molecular work sometimes takes a village," said Karumbaiah. "This research involved a whole cross-section of RBC undergraduate and graduate students, as well as faculty members from both UGA and Duke University."

The collaborative research effort provided five UGA RBC fellow undergraduates with an experiential learning opportunity and to publish their first paper. This is the first publication for Rameen Forghani, an aspiring M.D.-Ph.D. undergraduate working in the Karumbaiah lab.

Forghani said the undergraduate team "learned how to collaborate on this project" and about the impact of moving lab research to patients who need treatment.

"My fellow undergraduates and I were empowered to take ownership of a piece of the project and see it through from the planning stages of data analysis to writing and being published," said Forghani. "As an aspiring, early-career physician-scientist, working on a project that has translational impact and directly addresses a very relevant clinical problem is very exciting to me."

Charles Latchoumane, research scientist in the Karumbaiah lab and first author on the study, divides his time between UGA and Lausanne, Switzerland, where he works at NeurRestore, a research center aimed at restoring lost neurological function for people suffering from Parkinson's disease or from neurological disorders following a head injury or stroke.

"This study has been four to five years in the making," said Latchoumane. "Our collaborative research is so painstakingly documented that, after you read about it, you have to believe there is new hope for severe victims of brain injury."

CHAPEL HILL, NC - A team led by scientists at the UNC School of Medicine identified a molecule called microRNA-29 as a powerful controller of brain maturation in mammals. Deleting microRNA-29 in mice caused problems very similar to those seen in autism, epilepsy, and other neurodevelopmental conditions.

The results, published in Cell Reports, illuminate an important process in the normal maturation of the brain and point to the possibility that disrupting this process could contribute to multiple human brain diseases.

"We think abnormalities in microRNA-29 activity are likely to be a common theme in neurodevelopmental disorders and even in ordinary behavioral differences in individuals," said senior author Mohanish Deshmukh, PhD, professor in the UNC Department of Cell Biology & Physiology and member of the UNC Neuroscience Center. "Our work suggests that boosting levels of miR-29, perhaps even by delivering it directly, could lead to a therapeutic strategy for neurodevelopmental disorders such as autism."

miR-29 and brain maturation

MicroRNAs are short stretches of ribonucleic acid inside cells that regulate gene expression. Each microRNA, or miR, can bind directly to an RNA transcript from certain other genes, preventing it from being translated into a protein. MiRNAs thus effectively serve as inhibitors of gene activity, and the typical microRNA regulates multiple genes in this way so that genetic information is not overexpressed. These essential regulators have been intensively researched only in the past two decades. Therefore, much remains to be discovered about their roles in health and disease.

Deshmukh and colleagues set out to find microRNAs involved in the maturation of the brain after birth, a phase that in humans includes approximately the first 20 years of life. When the scientists looked for microRNAs with more activity in the adult mouse brain than the young mouse brain, one set of miRNA stuck way out from the rest. Levels of the miR-29 family were 50 to 70 times higher in the adult mouse brains than in young mouse brains.

The researchers examined a mouse model in which the genes for the miR-29 family were deleted just in the brain. They observed that although the mice were born normally, they soon developed a mix of problems, including repetitive behaviors, hyperactivity, and other abnormalities typically seen in mouse models of autism and other neurodevelopmental disorders. Many developed severe epileptic seizures.

To get a sense of what caused these abnormalities, the researchers examined gene activity in the brains of the mice, comparing it to activity in mouse brains that had miR-29. As expected, many genes were much more active when miR-29 was no longer there to block their activity. But the scientists unexpectedly found a large set of genes - associated with brain cells - that were less active in miR-29's absence.

A mysterious methylator

With key assistance from co-author Michael Greenberg, PhD, a professor of neuroscience at Harvard University, the researchers eventually found the explanation for this mysterious reduction in gene activity.

One of the target genes that miR-29 normally blocks is a gene that encodes for an enzyme called DNMT3A. This enzyme places special chemical modifications called CH-methylations onto DNA, to silence genes in the vicinity. In mice brains, the activity of the gene for DNMT3A normally rises at birth and then sharply declines several weeks later. The scientists found that miR-29, which blocks DNMT3A, is what normally forces this sharp decline.

Thus, in the mice whose brains lack miR-29, DNMT3A is not suppressed and the CH-methylation process continues abnormally - and many brain cell genes that should become active continue to be suppressed instead. Some of these genes, and the gene for DNMT3A itself, have been found to be missing or mutated in individuals with neurodevelopmental disorders such as autism, epilepsy, and schizophrenia.

To confirm DNMT3A's role, the scientists created a unique mouse model that prevents miR-29 from suppressing DNMT3A, but leaves miR-29's other targets untouched. They showed that this unleashing of DNMT3A on its own results in many of the same problems such as seizures and early death, as seen in the mice without miR-29.

The findings highlight and clarify what seems likely to be a crucial process in shaping the brain late in its development: the switching-off of DNMT3A to free up many genes that are meant to be more active in the adult brain.

"These results are the first to identify miR-29 as an essential regulator of CH methylation, and to show why restricting CH methylation to a critical period is important for normal brain maturation," Deshmukh said.

Deshmukh and colleagues are now following up by studying in more detail how the lack of miR-29 in different sets of brain cells might give rise to such disorders, and more generally they are studying how miR-29's activity is regulated in childhood to fine-tune brain functions, thereby giving humans the traits that make them unique individuals.

DURHAM, N.C. -- Integrating the American classroom has long been a goal of many who seek to eradicate racial discrimination. But a new paper from four economists, including Duke University's William A. "Sandy" Darity Jr., suggests that Black students do not always benefit from attending racially balanced schools.

Instead, Black adults who attended racially balanced high schools in the mid-20th century completed significantly less schooling than those who attended either predominantly black or predominantly white schools, the authors found.

"Standard wisdom has it that school desegregation paves the way to racial nirvana in the United States," says Darity, director of Duke's Samuel DuBois Cook Center on Social Equity and a professor of public policy, African and African American Studies and economics. "Our study suggests that the effects have been more muted than typically claimed in other studies and in the popular media."

"Of course, school desegregation is desirable to produce a better America, but we must be far more cautious about the benefits we ascribe to it."

The authors analyzed data from the National Survey of Black Americans, a nationally representative survey of Black Americans age 18 or older who attended school in the period from the 1930s through the early 1970s. Initial interviews for the survey were conducted in 1979 and 1980, with follow-up interviews conducted eight, nine and 12 years later.

The authors looked at the experience of Black students who attended three types of schools: "mostly or almost all white," "mostly or all black" schools and "mixed-race" schools, where the student population was racially balanced.

Based on data from 1,121 respondents, the authors found that Black students fared worse in mixed-race schools, where the student population was about half black and half white.

Black students attending racially balanced high schools -- schools that were about equally divided between black and white students -- completed a half year less of school, on average, than Black students in predominantly black high schools. Moreover, Black students attending racially balanced high schools earned three-quarters of a year less education than Black students at predominantly white high schools.

Black students who attended racially mixed high schools were also less likely to graduate, when compared with Black students who attended either predominantly white or predominantly black schools. Black students who attended predominantly white high schools had higher graduation rates than their Black peers in either mixed-race or predominantly black schools.

The study appears online in RSF: The Russell Sage Foundation Journal of the Social Sciences.

Previous research by Darity and Darrick Hamilton, a co-author of this paper, suggests a possible explanation for why Black students fared less well in racially mixed schools. In other studies, the authors have found that discrimination arises and intensifies when the dominant group's position is threatened.

In racially balanced schools, competition over resources is highest, and discrimination is thus most likely to arise and intensify, the authors write. In these roughly half-white, half-Black schools, "Black students are perceived as more of a competitive threat to white students for preferred resources," such as attention from teachers, placement in desirable classes, and positions of status in co-curricular activities, the authors write.

"The potential for greater resources available in racially integrated schools does not necessarily offset adverse effects in a school with a negative racial climate," said Timothy M. Diette of Washington and Lee University, the paper's lead author.

Some financial outcomes were also worse for Black students who attended racially balanced schools. Compared to their peers at mostly white or mostly black schools, Black men and women who attended racially balanced schools were less likely to go on to own homes, with the result for Black women being statistically significant.

Employment outcomes were roughly equivalent for Black students regardless of the racial composition of the school they attended.

These findings are consequential for education policy, the authors note. Integration in the 21st century has typically resulted in shifts from predominantly Black schools to mixed-race schools. Yet simply increasing the number of mixed-race schools, without eliminating discriminatory treatment and tracking of Black students, may not improve Black students' performance--and may in fact hinder it, the new research suggests.

Nineteen years before Brown v. Board of Education, W.E.B Du Bois sounded a cautionary note about school integration as a potential cure-all for Black students: "(T)heoretically, the Negro needs neither segregated schools nor mixed schools. What he needs is Education," Du Bois wrote in 1935. Du Bois' comments still resonate today, Diette said.

"If the goal is to ensure black students are well educated, then focusing exclusively on school integration is misguided," said Diette. "Resources and school environments matter."

High levels of biodiversity in aquatic settings offers a wide range of vitamins, minerals, and fatty acids crucial for human health, a range of nutrients that are lacking in ecosystems where the number of species have been reduced by overfishing, pollution, or climate change, researchers report April 5 in the journal Proceedings of the National Academy of Sciences.

"What we found is that biodiversity is crucial to human health," said Yale's Joey Bernhardt, a G. Evelyn Hutchinson Postdoctoral Fellow in the Department of Ecology and Evolutionary Biology and co-author of the paper.

While humans can achieve their protein requirements even with seafood from less-diverse systems, meeting their need for key micronutrients such as calcium, iron, and zinc requires high levels of biodiversity. Seafood sourced from biodiverse ecosystems can help combat a phenomenon known as "hidden hunger," in which people have access to enough calories, but not enough micronutrients, Bernhardt said.

The effects of aquatic biodiversity change on human health are particularly acute in coastal areas of the world where populations are heavily dependent on seafood in their diets.

For the study, Bernhardt and co-author Mary I. O'Connor of the University of British Columbia, analyzed 7,245 nutrient samples from 801 marine and freshwater finfish and invertebrates. They found that different species have distinct and complementary nutrient profiles. While they detected little difference in the protein content among the aquatic species, they found that concentrations of micronutrients -- including calcium and iron -- and essential fatty acids varied significantly.

The results illustrate the importance of monitoring and preserving biodiversity in changing aquatic ecosystems across the globe, the authors say.

"While we have known that biodiversity on land is important for benefits such as forest production, this study provides new evidence that the benefits of biodiversity in oceans and freshwaters are as great as on land," Bernhardt said. "Ecological concepts of biodiversity can deepen our understanding of nature's benefits to people and unite sustainability goals for biodiversity and human well-being."

A new Veterans Affairs study finds that combat experience is associated with a higher risk of alcohol use to cope with PTSD symptoms. But the connection is weaker when accounting for the severity of the PTSD.

The findings appeared online in the Journal of Dual Diagnosis in March 2021.

In an observational study of more than 11,000 men with at least one traumatic experience, the researchers found that those with combat experience were much more likely than those without to report drinking alcohol to cope with PTSD. The diversity of traumatic experiences, the severity of PTSD, and diagnoses of alcohol abuse or dependence were significantly tied to drinking to cope with PTSD.

However, combat experience was not strongly linked to drinking to cope when the researchers adjusted for a person's total number of PTSD symptoms.

The researchers write: "Our findings suggest that although men with combat experience may be more prone to use alcohol to cope with PTSD symptoms and associated distress than trauma-exposed men without military combat experience, this may be partially due to greater overall posttraumatic stress severity among men who experienced military combat.

"This interpretation is supported by higher rates of PTSD and greater PTSD symptom totals among men with [combat experience] versus those without in our sample, as well as with prior research linking PTSD severity to both combat exposure and hazardous alcohol use. Alcohol use may be perceived by military combat Veterans as an effective, socially acceptable strategy for coping with PTSD symptoms and associated distress, perhaps due to certain personality factors, masculinity-related gender norms, or general attitudes toward alcohol common in the military. These and other possible interpretations warrant additional research attention."

Dr. Shannon Blakey, a postdoctoral fellow at the Mid-Atlantic Mental Illness, Research, Education and Clinical Center at the Durham VA Health Care System in North Carolina, led the study. Dr. Jack Tsai and Dr. Eric Elbogen, both of the VA National Center on Homelessness Among Veterans, were the co-authors.

Blakey was most surprised by two of the findings.

"First, the association between combat experience and drinking to cope was statistically significant when adjusting for the presence versus absence of a PTSD diagnosis, but not when adjusting for the number of PTSD symptoms," she says. "This suggests that drinking to cope among trauma-exposed men is more strongly associated with PTSD severity than the mere presence of PTSD."

"Second, our analyses showed that trauma-exposed men without combat experience were more likely than men with combat experience to report an alcohol use disorder," she adds. "That's not entirely consistent with previous research and highlights the complexity of associations between trauma exposure, posttraumatic experiences, drinking to cope, and drinking severity among trauma survivors."

Understanding the complicated nature of PTSD is one of VA's most pressing challenges. Large percentages of Veterans who fought in Vietnam, the Gulf War, and Iraq and Afghanistan have had PTSD sometime in their lives. Symptoms include flashbacks, nightmares, hypervigilance, aggressive behavior, and anxiety.

Studies have shown that PTSD increases the risk for drinking problems. But research has been scant on whether combat experience is linked to alcohol use to cope with PTSD.

Blakey's team used data from men who took part in the National Epidemiologic Survey on Alcohol and Related Conditions. The survey recruited a nationally representative sample of U.S. adults between 2004 and 2005, including Veterans and non-Veterans.

The researchers focused mostly on the responses to the yes-no question, "Did you ever drink alcohol to improve your mood or to make yourself feel better when you were [experiencing PTSD symptoms]?" They adjusted for whether the men met the criteria for alcohol use disorder. They were thus able to capture both drinking severity and drinking to cope with PTSD symptoms in their analyses.

The survey also asked participants if they were ever in combat. Nearly 1,400 said they had combat experience, and more than 10,000 said they did not. It's possible that some in the latter group were non-combat Veterans. An analysis showed that drinking to cope with PTSD symptoms was more than twice as common among men with combat experience than those without (6.46% versus 2.37%).

Blakey says the findings raise questions that can be explored in future studies.

"Is there something unique about combat trauma, relative to other types of trauma, that increases the chances men will use substances like alcohol to ease their PTSD symptoms. Are men who experience combat more likely than men without combat experience to hold positive sociocultural beliefs about the acceptability and helpfulness of alcohol to cope with PTSD symptoms? Are men who assume combat roles at greater risk of drinking to cope due to some other pre-existing risk factor?"

Although a large sample size was a strength of Blakey's study, the research had limitations. One of them was that the participants were specifically asked about their combat experience, not about their overall military service history. Therefore, it was unknown how many of the men without combat experience were Veterans. The study also did not include women.

"Future research can hopefully compare PTSD-related alcohol use risk factors and outcomes among combat Veterans, non-combat Veterans, and non-Veterans," Blakey said. "It would also be important for future studies to recruit enough women Veterans to examine the potential influence of sex and gender on these relationships."

Niigata, Japan - Cancer is the world's second deadliest disease which contributes towards the fatality of over 10 million people per year. Oncologists adopt a variety of treatment procedures to treat cancer cells. Among the different methods used to fight cancer, chemotherapeutic treatment is a prominent and well-adopted technique. It is a drug based method, wherein powerful chemical compounds are injected into the body to annihilate the malignant cells. Although these chemicals support the destruction of the cancerous cells, optimizing their dosage has always been a challenge to the medical specialists.

Cisplatin is a chemotherapy medication which is used to treat a number of cancers such as lung cancer, brain tumor, breast cancer, liver cancer etc. This platinum-metal based chemotherapy drug is highly powerful and is instituted by the intravenous route into the body. Although it is renowned for effective destruction of cancerous cells for the past 4 decades, its alarming side effects is of serious concern to the medical community. Researchers have reported that administration of high dosage of the chemical is not only ineffective on the tumor cells but is also responsible for adverse side effects which may even lead to the sudden demise of the patient. The control on the level of the cisplatin drug has been a matter of persisting concern for medical practitioners. A recent study on monitoring the cisplatin level in liver cancer cells reported by researchers from the Graduate School of Medical and Dental Sciences at Niigata University, Japan and their collaborators from Niigata Medical Center, Uonuma Institute of Community Medicine Niigata University Hospital, Niigata City General Hospital, Saiseikai Niigata Hospital and, Kashiwazaki General Hospital and Medical Center provides a ray of hope to the health professionals. The findings were published recently in the prestigious Scientific Reports journal from Nature publishing house. The multi-disciplinary research team has identified adipose most abundant 2 protein (APM2) as a potential marker to indicate the permissible level of the drug. They have experimentally investigated the liver and gastro cancer cells and have compared the variation in the protein concentration in the presence and absence of the chemo drug.

"Our results demonstrate a significant relationship between the high level of APM2 expression in serum, cancerous cells in the liver, the surrounding liver tissue and cisplatin resistance. The study reveals that APM2 expression is related to cisplatin sensitivity" explains Professor Kenya Kamimura of the Division of Gastroenterology and Hepatology, the Graduate School of Medical and Dental Sciences, Niigata University. The research study paves way for effective monitoring of chemotherapeutic drug level and their safe administration. Professor Kenya Kamimura states with confidence that, "The serum APM2 can be an effective biomarker of the liver and gastric cancer cells for determining the sensitivity to cisplatin. The results of the study would provide an advantage for the technicians, allowing easy adaption in small local clinics."

The research group has noticed that APM2 concentration favours the development of ERCC6L gene card. This is manifested by the growth of the cancerous cells and marks the resistance to the chemo drug. The valuable findings offers the potential to control the cisplatin dosage level and avoid cytotoxicity. Such a study is essential in today's context as research groups across the globe strive to develop new methodologies to optimize the dosage and control the severe side-effects induced by the concentration of chemo drugs. The research team has also utilized bioinformatics based tools to complement the experimentally obtained results.

"To the best of our knowledge, this is the first report to demonstrate that the serum level of APM2 can be the predictor of the CDDP chemosensitivity. This study thus represents a milestone for detecting CDDP sensitivity, and further studies will help modify APM2 expression, which could contribute to the chemosensitization of the tumor" describes Professor Kenya Kamimura.

The interesting results of the research study has laid a foundation to track the chemo drug level. Future studies will explore the mechanism and relation between APM2 and ERCC6L. Such studies are on the cutting edge research areas of oncological sciences and hold immense potential in further extending the results to other types of cancers.

Nanographene is flexible, yet stronger than steel. With unique physical and electronic properties, the material consists of carbon molecules only one atom thick arranged in a honeycomb shape. Still early in technological development, current fabrication methods require the addition of substituents to obtain a uniform material. Additive-free methods result in flimsy, breakable fibers--until now.

An international team of researchers has developed self-assembling, stable and strong nanographene wires. The results were published on March 24 in Journal of the American Chemical Society.

The team, led by Yasutomo Segawa, associate professor at the Institute for Molecular Science, part of the National Institutes of Natural Science in Japan, set out to synthesize curved, infinitely stacking nanographenes -- like potato chips in a cardboard can -- that can assemble into nanowires.

"Effectively stacked hydrocarbon wires have the potential to be used as a variety of nano-semiconductor materials," Segawa said. "Previously, it has been necessary to introduce substituents that are not related to or inhibit the desired electronic function in order to control the assembly of the wires."

By removing substituents, or additives, from the fabrication process, researchers can develop molecular materials that have a specific, desired electronic function, according to Segawa. With this goal in mind, the team developed a molecule called 'bitten' warped nanographene (bWNG), with 68 carbon atoms and 28 hydrogen atoms forming a 'bitten apple' shape. Created as a solution, when left to evaporate over 24 hours in the presence of hexane -- an ingredient in gasoline with six carbon atoms -- bWNG becomes a gel.

The researchers attempted to recrystallize the molecules of the original solution to examine the specific structure of the bWNG gel through X-ray crystallography. This technique can reveal the atomic and molecular structure of a crystal by irradiating the structure with X-rays and observing how they diffract.

"We attempted recrystallizing many times to determine the structure, but it grew to only a few hundred nanometers," Segawa said, noting that this size is much too small for X-ray crystallography. "It was only by electron diffraction, a new method for determining the structure of organic materials, that we were able to analyze the structure."

Electron diffraction is similar to X-ray crystallography, but it uses electrons instead of X-rays, resulting in a pattern of interference with the sample material that indicates the internal structure.

They found that the bWNG gel consisted of double-stranded, double-helix nanofibers that assembled themselves from curved, stackable nanographenes.

"The structure of the nanofibers is a double-stranded double helix, which is very stable and, therefore, strong," Segawa said. "Next, we would like to realize a semiconductor wire made entirely of carbon atoms."

Few compounds are as important to industry and medicine today as titanium dioxide. Despite the variety and popularity of its applications, many issues related to the surface structure of materials made of this compound and the processes taking place therein remain unclear. Some of these secrets have just been revealed to scientists from the Institute of Nuclear Physics of the Polish Academy of Sciences. It was the first time they had used the SOLARIS synchrotron in their research.

It is found in many chemical reactions as a catalyst, as a pigment in plastics, paints or cosmetics and in medical implants it guarantees their high biocompatibility. Titanium dioxide (TiO2) is practically ubiquitous today, which does not mean that all its properties are already known to humanity. A group of scientists from the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Cracow, led by Dr. Jakub Szlachetko, working on the Solaris synchrotron, has managed to shed some light on the details of the oxidation processes of the outer layers of titanium samples and the related changes in the electronic structure of the material. The research on titanium dioxide inaugurated the presence of IFJ PAN scientists in the research programs carried out on the SOLARIS synchrotron. The device, operating as part of the National Synchrotron Radiation Centre, is situated in Cracow on the campus of the 600th anniversary of the Jagiellonian University.

Synchrotron radiation was discovered in 1947, when General Electric launched an accelerator that curved the path of accelerated electrons with the use of magnets. The particles would then start emitting light randomly, so they lost energy - whereas they were supposed to gain it! Synchrotron radiation was therefore considered an undesirable effect. Only thanks to successive generations of synchrotron radiation sources were light beams with higher intensities and better quality of emitted light achieved, including high repeatability of pulses with practically always the same characteristics.

The SOLARIS synchrotron, the largest and most modern device of this type in Central Europe, consists of two main parts. The first is a 40 m long linear electron accelerator. Particles gain energies of 600 megaelectronvolts here, after which they reach the second part of the apparatus - the interior of an accumulation ring with a circumference of 96 m, where curving magnets, wigglers and undulators are placed in their path. These are sets of alternately oriented magnets, inside which the shape of the electron path begins to resemble a sinusoid. It is then that the "wobbling" electrons emit synchrotron radiation, directed to the appropriate end stations with measuring equipment. The electromagnetic waves produced by SOLARIS are classified as soft X-rays.

The unique features of synchrotron radiation have many applications: they assist in the development of new materials, track the course of chemical reactions and make it possible to conduct experiments useful for the development of nanotechnology, microbiology, medicine, pharmacology and many other fields of science and technology.

"Research on the SOLARIS synchrotron opens up entirely new possibilities, so it is no wonder that many research groups from Poland and throughout the world apply for beamtime here. Although our Institute - just like the SOLARIS synchrotron - is located in Cracow, like everyone we competed in terms of research quality for beamtime at the appropriate measurement station," says Prof. Wojciech M. Kwiatek, head of the Division of Interdisciplinary Research at the IFJ PAN and President of the Polish Synchrotron Radiation Society. Prof. Kwiatek notes that in an era of travel restrictions caused by the development of the pandemic, the possibility of conducting advanced physical examinations practically on site is a huge advantage.

Researchers from the IFJ PAN conducted their latest measurements, co-financed by the Polish National Science Centre, at the XAS experimental station. It records how X-rays are absorbed by the surface layers of titanium samples previously produced at the Institute under carefully controlled conditions.

"We focused on observations of the changes in the electronic structure of the surface layers of samples depending on changes in temperature and progress of the oxidation process. For this purpose, we heated titanium discs at different temperatures and ambient atmospheres. After being transported to the synchrotron experimental station, the samples were illuminated with synchrotron radiation, i.e. X-rays. Since the properties of synchrotron radiation are well known, we were able to use it to precisely determine the structure of unoccupied electronic states of titanium atoms and on this basis make conclusions about changes in the structure of the material," says PhD student Klaudia Wojtaszek (IFJ PAN), the first author of the article published in the Journal of Physical Chemistry A.

Titanium dioxide occurs in three polymorphic forms, characterized by different crystallographic structures. The most popular is rutile, a mineral that is common in many rocks (the other varieties are anatase and brookite). Research on the SOLARIS synchrotron allowed the physicists from Cracow to precisely recreate the process of forming the rutile phase. It turned out that it is formed at lower temperatures than previously thought.

"Our research provides fundamental knowledge about the structure of the material. However, this structure is closely related to the physico-chemical properties of the titanium dioxide surface. Potentially, our results can therefore be used, for example, to optimize the surface characteristics of medical implants," concludes Dr. Anna Wach, who was responsible for the conduction of experiment at SOLARIS synchrotron.

UConn researcher Paulo Verardi, associate professor of pathobiology and veterinary science in the College of Agriculture, Health and Natural Resources, has demonstrated the success of a vaccine against Zika virus and recently published his findings in Scientific Reports, a Nature Research publication.
He has also filed provisional patent for the novel vaccine platform technology used to generate the vaccine, as well as genetic modifications made to the vaccine that significantly enhance expression of the vaccine antigen.

Verardi, a Brazilian native, was in Brazil visiting family in the summer of 2015 when the Zika outbreak first began to make waves and soon reached epidemic status.

Back in the United States, Verardi kept tabs on the Zika epidemic and its emerging connection to microcephaly, a serious birth defect that causes babies to be born with small heads and underdeveloped brains.

In October of that year, Verardi called then-Ph.D.-student Brittany Jasperse (CAHNR '19) into his office and told her he wanted to apply their newly developed vaccine platform and start developing a vaccine for Zika virus.

Verardi and Jasperse were among the first researchers in the US to receive NIH funding to generate a vaccine against Zika virus, thanks to Verardi recognizing the significance of Zika virus early.

Modern advancements in genomic technology have expediated the vaccine development process. In the past, researchers needed to have access to the actual virus. Now just obtaining the genetic sequence of the virus can be sufficient to develop a vaccine, as was the case for the Zika vaccine Verardi and Jasperse developed, and the COVID-19 vaccines currently approved for emergency use in the United States and abroad.

Using the genetic sequence of Zika virus, Verardi and Jasperse developed and tested multiple vaccine candidates that would create virus-like particles (VLPs). VLPs are an appealing vaccine approach because they resemble native virus particles to the immune system and therefore trigger the immune system to mount a defense comparable to a natural infection. Critically, VLPs lack genetic material and are unable to replicate.

The vaccine Verardi and Jasperse developed is based on a viral vector, vaccinia virus, which they modified to express a portion of Zika virus' genetic sequence to produce Zika VLPs. Their vaccine has an added safety feature that it is replication-defective when given as a vaccine but replicates normally in cell culture in the lab.

"Essentially, we have included an on/off switch," Jasperse says. "We can turn the viral vector on in the lab when we're producing it by simply adding a chemical inducer, and we can turn it off when it's being delivered as a vaccine to enhance safety."

The team developed five vaccine candidates in the lab with different mutations in a genetic sequence that acts as a signal to secrete proteins. They evaluated how these mutations affected the expression and formation of Zika VLPs and then selected the vaccine candidate that had the highest expression of VLPs to test in a mouse model of Zika virus pathogenesis. This model was developed by Helen Lazear of University of North Carolina at Chapel Hill, whose lab Jasperse now works in as a postdoctoral research associate.

Verardi and Jasperse found that mice who received just a single dose of the vaccine mounted a strong immune response and were completely protected from Zika virus infection. They did not find any evidence of Zika virus in the blood of challenged mice who were exposed to the virus after vaccination.

Zika virus is part of a group of viruses known as flaviviruses which include dengue virus, yellow fever virus, and West Nile virus. Verardi and Jasperse's findings, particularly the mutations they identified that enhanced expression of Zika VLPs, could be useful for improving production of vaccines against diseases caused by other related flaviviruses.

Ongoing work in the Verardi lab incorporates these novel mutations into vaccine candidates against other viruses, including Powassan virus, a tick-borne flavivirus that can cause fatal encephalitis.

Verardi emphasizes that developing vaccines for viruses, in this case Zika, help the world be better prepared for outbreaks of novel and emerging viruses by having vaccine development frameworks in place.

"Emerging viruses are not going to stop popping up any time soon, so we need to be prepared," Verardi says. "Part of being prepared is to continue the development of these platforms."

The nucleus is the headquarters of a cell and molecules constantly move across the nuclear membrane through pores. The transport of these molecules is both selective and fast; some 1,000 molecules per second can move in or out. Scientists from the University of Groningen and Delft University of Technology, both in the Netherlands, and a colleague from the Swedish Chalmers University of Technology, have developed an artificial model of these pores using simple design rules, which enabled them to study how this feat is accomplished. Their results were published on 31 March in Nature Communications.

Nuclear pores are extremely complicated structures. The pore itself is a big protein complex and the opening of the pore is filled with a dense network of disordered proteins called nucleoporins. These proteins regulate selective transport, but exactly how they do this is still unclear. 'The nuclear pore complex is one of the biggest protein structures in the cell,' explains Patrick Onck, professor of Micromechanics at the University of Groningen. 'We previously studied the pores in all their complexity, but for this study, we created a drastically simplified 'designer' pore to investigate the essential physical mechanisms of transport.'

Nanopore

First, the team analysed the composition of the nucleoporins to design a simplified, 'average' version, which they termed nucleoporin X, or NupX for short. These proteins are made up of domains comprising phenylalanine (F) and glycine (G) amino acids in tandem, and these play an essential role in transport. These FG repeats are separated by 'spacers' of other amino acids. In addition to the FG repeats, some nucleoporins also contain domains of glycine, leucine, phenylalanine and glycine, or GLFG repeats. The team designed proteins that contain both domains, separated by spacers of ten amino acids.

NupX was tested in two different systems: it was studied experimentally, attached to a surface and added to artificial nanopores that were 'drilled' in a 'membrane' of silicon nitride, and through molecular dynamics simulations. The experiments were performed at Delft University of Technology, while the simulations were prepared and executed in Groningen, mostly by Henry de Vries, a PhD student in Onck's laboratory.

Transport ticket

The nucleoporins were tested for interactions with non-specific proteins and with chaperones, which are proteins that act as transport tickets through the pore. In the cell, large molecules that must be transported into or out of the nucleus can only do so when they are attached to such a chaperone. The artificial nucleoporins selectively interacted with the chaperones but not with the non-specific proteins. This demonstrated that the NupX pores are fully functional: they are able to facilitate selective transport. De Vries: 'However, the experiments showed that transport through the artificial pores occurs but not what happens inside the pore. With our simulations, we showed what exactly happens inside the pore as the chaperones translocate, while the non-specific proteins do not interact with the pore at all.'

The simulations also revealed how the FG and the GLFG nucleoporins were distributed inside the pore. 'Recent studies suggested that they would be in different places in nuclear pores and that this might help to create selectivity,' says De Vries. 'However, we found that they were homogenously distributed and yet we still saw selectivity.' Another suggestion was that the amino acids that make up the spacers are important for the selectivity. 'Our results showed that the specific sequence of amino acids in the spacer doesn't matter since we used random sequences. The only important part is the ratio of charged amino acids to hydrophobic amino acids within the spacers, which determines the stickiness of the proteins.'

Redundancy

The final conclusion of the study is that a very simple system in nucleoporins that has limited variation still produces a selective pore. 'What is needed is a certain density of these FG nucleoporins,' says Onck. 'These form a barrier, which can only be breached by the chaperones.' This begs the question of why the pores contain a very large number of different nucleoporins in nature. Onck: 'We know that nature doesn't always come up with optimized solutions. However, their redundancy could very well have a function in natural pores.'

The fact that the very simple artificial system already reproduces selective transport mechanisms means that the scientists now have an excellent tool to study the physical principles that regulate nuclear pore function. Onck: 'This could lead to new fundamental insights but also to new applications, for example in creating filtration systems, or in the design of artificial cells.'

Simple Science Summary