Culture

The Social Determinants of Health and Demographic Change (OPIK) research group of the UPV/EHU is a multidisciplinary team in the field of social and health sciences and is devoted, among other things, to research into the social factors influencing health and disease in the population, social inequalities in health and the policies having the potential to modify these social determinants to improve the health of the population. The study of socioeconomic inequalities in the Spanish sphere is a subject of growing interest, but most of the studies deal with the general population. Despite the existence of reviews on an international level and European studies that point to these inequalities in the elderly population in a range of health indicators, there are very few reviews about this population group in Spain.

In a study conducted in collaboration with Osakidetza (Basque Autonomous Community Health Service), the Biodonostia Institute of Healthcare Research and the Basque Government's Department of Health, a review has been made of the various pieces of research relating to socioeconomic inequalities in health in the over 65s in Spain in order to see "what type of indicators can be used in this case and to see what has been done in other contexts", explained the doctor in sociology Unai Martín, one of the authors of the work.

Educational attainment, ecological indices and past occupations

In the conclusion to the study the researchers confirm that there are socioeconomic inequalities in health among the elderly population and that their magnitude varies according to sex in some health indicators. Socioeconomic inequalities were in fact found across the health indicators analysed: functional state, sickness rate, perceived health, mental and emotional health, cognitive state, life quality, mortality and life expectancy. Educational attainment and ecological indices were the indicators that reflected the most inequalities in health. Martín added that "the occupation that a person had throughout his or her life also appears to mark his or her state of health; not only because of the characteristics of the job he or she had, but also because of the life conditions that ensue through having had one job or another". Another aspect they highlight in the study is that elderly women have a longer life expectancy but a worse state of health. The study also concludes that higher educational attainment and the maintaining of adequate pensions may be key policies that contribute towards reducing inequalities in this population group.

Gaining in-depth knowledge about the socioeconomic inequalities in health which affect the elderly population is an indispensable first step when it comes to designing suitable interventions and strategies aimed at reducing these inequalities. In Martín's view, "socioeconomic variables are very important in understanding people's health. Our health does not depend exclusively on our genetics or healthcare system, life conditions are very important to enjoy better health, healthier aging and a longer life expectancy. We sometimes believe that just by having a universal healthcare system we are already making everyone have better health, but health is not taken care of through healthcare policies alone, but also through urban, employment policies, etc.".

Researchers in China have discovered how a Zika virus protein reshapes its host cell to aid viral replication. The study, which will be published December 23 in the Journal of Cell Biology, reveals that the viral protein NS1 converts an interior cellular compartment called the endoplasmic reticulum (ER) into a protective region where the virus can survive and replicate. Blocking this process could be a novel therapeutic strategy to treat patients infected with Zika or similar viral pathogens, such as the yellow fever and dengue viruses.

The Zika virus causes relatively mild symptoms in most cases but can result in severe birth defects when pregnant women are infected. Once the virus enters a host cell, it reshapes the cell’s ER, causing this membrane-bound compartment to fold inward and form small pockets where the virus can replicate its genetic material, without being attacked by the host cell’s immune defenses.

“The architecture of this viral replication compartment is well known, but how the Zika virus remodels the ER is obscure,” says Lei Shi, a researcher at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, at Peking Union Medical College in Beijing.

In the new study, Shi and colleagues find that this remodeling process is carried out by a viral protein called NS1 that accumulates in the ER of infected cells. The researchers discovered that NS1 inserts itself into the ER membrane, causing it to fold inward and form viral replication compartments. When the researchers mutated NS1 to prevent it from inserting into the ER membrane, the protein was unable to remodel the ER and viral replication was inhibited.

“We conclude that NS1-induced ER remodeling is the basis of replication compartment biogenesis and that viral replication and production are abolished in the absence of this process,” says Shi, who co-led the study with Wei Yang, from the Institute of Pathogen Biology in Beijing, and Cheng-Feng Qin, from the Beijing Institute of Microbiology and Epidemiology.

The Zika virus is closely related to a number of other viruses, including the yellow fever virus, dengue virus, and West Nile virus, that also convert the ER of their host cells into specialized viral replication compartments. Shi and colleagues found that the dengue virus’s NS1 protein also induces ER remodeling, suggesting that all of these pathogenic viruses use similar mechanisms to generate their replication compartments and that blocking this process could be a new therapeutic strategy to treat Zika and other viral infections.

The Arlington Archosaur Site (AAS) of Texas preserves remnants of an ancient Late Cretaceous river delta that once existed in the Dallas-Fort Worth area. Known for discoveries of fossil crocodiles and dinosaurs, a multi-institution research team has described four extinct turtle species, including a new river turtle named after AAS paleontologist Dr. Derek Main and the oldest side-necked turtle in North America. These new turtles include an intriguing combination of native North American forms alongside Asian and Southern Hemisphere immigrants, suggesting extensive intercontinental migration of turtles during this time.

Originally discovered by amateur fossil hunter Art Sahlstein in 2003, the AAS is a prolific fossil locality found in the middle of a suburban subdivision. The AAS preserves remnants of an ancient Late Cretaceous river delta around 96 million years ago in what is today the Dallas-Fort Worth area. It preserves a record of a freshwater wetland that sat near the shore of a large peninsula, including a diverse assemblage of crocodile relatives, dinosaurs, amphibians, mammals, fish, invertebrates, and plants, several of which are also new species awaiting description. "Until this discovery, there were very few turtle fossils from this time period discovered in Appalachia," says Dr. Heather Smith, one of the authors of the paper. The research team describing these discoveries includes Brent Adrian, M.F.A., Heather F. Smith, Ph.D., and Ari Grossman, Ph.D., from Midwestern University in Glendale Arizona, and Christopher Noto, Ph.D., from University of Wisconsin-Parkside.

"The AAS turtle assemblage informs a growing understanding of Appalachian ecosystems in the mid-Cretaceous, most of which were obscured by later erosion along coasts and extensive continental river drainages,'' said Brent Adrian, the lead author of the study, published in the current issue of the online journal Palaeontologia Electronica. One new species - "Trinitichelys" maini - is a baenid turtle, an extinct lineage of aquatic North American turtles that persisted from the Early Cretaceous through the Eocene. These turtles were medium-sized (about the size of a modern snapping turtle), had heavily fused bones and shells, and occupied freshwater river habitats. "Trinitichelys" maini is the oldest member of the group found in the eastern North American subcontinent of Appalachia, which at that time was separated from Laramidia, the western sub-continent of North America.

"T." maini honors the late Dr. Derek Main, the first director of the AAS project, who recognized the scientific potential of the site. "Derek's incredible work with the community led to the creation of one of the most extensive and diverse collections of mid-Cretaceous fossils known in Texas," says Dr. Chris Noto, who took over as director of the AAS in 2013, "He was an inspiration to all those who worked with him, and it is only fitting this new species is named after him."

Alongside T. maini, the study describes three more intriguing new turtles from the AAS. One species represents the oldest side-necked (pleurodire) turtle discovered in North America. Side-necked turtles originated in the Southern Hemisphere, and the AAS marks the first time they are found in North America. Yet another surprise is an early soft-shelled turtle (trionychid), which belongs to a lineage that immigrated from Asia. Adding to this unusual mix is Naomichelys sp., a large semi-aquatic turtle with unusual tubercles (raised bumps) on its shell that is a relict North American species typically found in much older rocks. This combination of turtle species in one location is unique, as it includes Asian, Southern Hemisphere, and native North American forms, and both young and older, relict taxa.

Unique Cancer Drug Discovered With Help From Advanced Light Source Begins Historical Clinical Trial

The first-of-its kind treatment showed promise in early studies

By Aliyah Kovner

An investigational cancer drug that targets tumors caused by mutations in the KRAS gene will be evaluated in phase 2 clinical trials, following promising safety and efficacy results in preliminary human studies and excellent results in animal studies. The drug, developed by Amgen and currently referred to as AMG 510, is the first therapy to reach clinical trials that inhibits a mutant KRAS protein. Errors in the KRAS gene, which encodes a crucial cell signaling protein, are one of the most common causes of cancer.

The particular mutant inhibited by AMG 510 - called KRAS(G12C) - is present in approximately 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors.

Despite its significant role in the pathogenesis of cancer, scientists have been unable to design KRAS-specific therapeutics due to the shape of the protein - it has an exceptionally smooth surface with no obvious regions for a drug molecule to bind. Seeking to develop a long-sought direct inhibitor, researchers at Amgen conducted X-ray crystallography of KRAS(G12C) proteins at Berkeley Lab's Advanced Light Source (ALS). The high-resolution structural maps generated using the data acquired at the beamlines helped Amgen make the breakthrough discovery of a small pocket on the molecule. In subsequent studies, the beamline data allowed scientists to investigate atomic-level molecular interactions between KRAS(G12C) and potential inhibiting compounds that bind in this pocket. AMG 510 emerged as a very promising candidate after a multiyear drug agent optimization program.

"It's rare that a compound gets all the way through the development process and becomes a drug. So, for the BCSB team, it feels great to see our (small) contribution finding its way to fight diseases," said Marc Allaire, one of the Berkeley Lab biophysicists who operate the BCSB beamlines.

Read more about the development of AMG 510 and its early clinical results.

These Artificial Proteins Have a Firm Grasp on Metal

Chelating peptoid library developed at Berkeley Lab could accelerate the design of new materials for a number of applications

By Theresa Duque

A team of scientists led by Berkeley Lab has developed a library of artificial proteins or "peptoids" that effectively "chelate" or bind to lanthanides and actinides, heavy metals that make up the so-called f-block elements at the bottom of the periodic table.

The new library offers researchers an automated, high-throughput method for precisely designing new peptoids - protein-like polymers with a precise sequence of monomer units - that chelate lanthanides such as gadolinium, a common ingredient in MRI contrast agents, and actinides such as plutonium.

As reported in the journal Chemical Science, the researchers incorporated custom-made monomers with f-block-binding properties onto peptoid scaffolds at Berkeley Lab's Molecular Foundry. In this initial study, the researchers assembled two bio-inspired hydroxypyridinone and catecholamide monomers onto molecular complexes called "tetramers," yielding a library of 16 chelating peptoids (also known as "ligands"). The researchers then used a luminescence-based technique to measure how well each chelating peptoid coordinated to the lanthanide cations (positively charged ions) europium and terbium.

The researchers discovered that the chelating systems featuring three and four hydroxypyridinone functional groups show a high affinity for lanthanide metals, and in particular europium, suggesting that these peptoid-based chelators could be used to design ligands tailor-made for a wide range of applications with f-block metals, such as chemical separation processes, optical device optimization, and pharmaceutical development. In addition, extending the researchers' technique to incorporate additional monomers could potentially lead to much larger libraries.

The study was led by Rebecca Abergel, a faculty scientist in Berkeley Lab's Chemical Sciences Division and assistant professor in UC Berkeley's Nuclear Engineering Department.

In Tooth Enamel, Slight Crystal Misorientations Stop Cracks in Their Tracks

Advanced imaging at Berkeley Lab shows nanoscale structure of tooth enamel

By Lori Tamura

Adult teeth can last a lifetime, withstanding enormous chewing pressures applied hundreds of times each day for decades. In a recent study published in Nature Communications, researchers discovered a natural toughening mechanism: small misorientations among the nanocrystal building blocks of human tooth enamel.

Enamel is composed of hydroxyapatite, a biomineral that forms long and thin 50-nanometer wide nanocrystals, bundled into rods like uncooked spaghetti in tubes. Previously, it was assumed that the nanocrystals' internal structures (their lattices) were oriented in the same direction as the long axes of the rods and "spaghetti."

But when the researchers studied enamel samples using X-rays produced by Berkeley Lab's Advanced Light Source, they detected slight differences in the lattice orientations. "While the spaghetti nanocrystals are aligned parallel to each other," said co-author and University of Wisconsin Professor of Physics Pupa Gilbert, "their crystal lattices are slightly misoriented from one nanocrystal to another."

Computer simulations confirmed that slight misorientations are effective at preventing nanoscale cracks from spreading, thus protecting the enamel from catastrophic failure. Not only do the results help explain how human tooth enamel can last a lifetime, they also provide insight into strategies for designing similarly tough bio-inspired synthetic materials.

Read the full story here.

DNA stores all of the information necessary for life phenomena, and a cell transmits its own genetic information to two daughter cells through DNA replication and cell division. Replication stress can be caused by extracellular and intracellular sources during DNA replication, which leads to slowed or stalled replication. If cells do not properly cope with such risks, chromosome break and rearrangement will occur, resulting in genomic instability. That helps explain why replication stress is one of the major contributors to cancer development.

Although many DNA repair proteins function to protect and restart stalled replication process under stress condition, it is still unclear how replisome proteins, which are real players in DNA replication, contribute and communicate with those proteins to ensure faithful DNA replication. Led by director Kyungjae Myung and Dr. Kyoo-young Lee, a research group at the Center for Genomic Integrity within the Institute for Basic Science (IBS) at the Ulsan National Institute of Science and Technology (UNIST), South Korea revealed that ATAD5 actively deals with replication stress, in addition to its known function to prevent such stressful situations. Though ATAD5 has been known as a tumor suppressor by maintaining genomic stability and suppressing tumorigenesis, it has been unclear whether the replication regulatory protein is also involved in the replication stress response. "We have identified the fundamental mechanism of replication stress control, which is a major cause of cancer. Hopefully our work will contribute to the development of cancer therapy," explains director Myung.

Director Kyungjae Myung group recently found that ATAD5 regulates the functions of PCNA, one of main replication proteins by removing the ring-shaped PCNA from DNA to ensure a complete end of its cycling. ATAD5-depleted cells show characteristic features of replication stress such as a slow replication rate. Although the PCNA-regulating activity of ATAD5 may be the cause of this cellular response to its depletion, the researchers hypothesized that ATAD5 may have an additional role in counteracting replication stress. ATAD5 proteins play an important role in the DNA replication process itself, so experimentally reducing the amount of ATAD5 in cells results in many abnormalities associated with normal DNA replication. Because replication stress, which is focused in this study, also occurs during the DNA replication, it is critical to separate the effects of ATAD5 deficiency on the replication stress and the general DNA replication process. To overcome this, the researchers devised an experimental method to induce ATAD5 deficiency at the beginning of replication stress.

Under these experimental conditions, they found that, when ATAD5 level is reduced, cells cannot resume DNA replication stalled by replication stress, but increases genome instability such as intracellular chromosome breakage and micronucleated reticulocytes in mouse blood. This means that ATAD5 contributes to maintaining genomic stability by restoring DNA replication under replication stress. Thereafter, they conducted experiments to elucidate the molecular mechanism for ATAD5 restarting DNA replication. RAD51 plays critical roles in structural changes and stability of stalled replication sites under replication stress. The researchers found that ATAD5 promotes RAD51 recruitment to stalled replication sites by direct protein-protein interaction.

In addition, they reported that PCNA unloading by ATAD5 is a prerequisite for efficient RAD51 recruitment. These suggest that a series of processes starting with RAD51 recruitment and leading to structural changes, breakage, and eventual replication restart are regulated by ATAD5. These findings highlight that the role of ATAD5 in maintaining genome stability extends beyond its roles in PCNA unloading during normal DNA replication. Dr. Su Hyung Park, the first author of this study notes, "Mutations in the ATAD5 gene are frequently found in many cancer cells. This study contributes to understating the cause of tumor formation by ATAD5 mutations."

Replication stress can be caused by extracellular sources such as oncogenes and chemicals. However, recent studies have shown that intracellular sources such as DNA-specific structures or the abnormal function of specific proteins can also provoke replication stress. In addition to enhancing our understanding of initial cellular responses to replication stress, this study provides us a novel conceptual advance that a protein can play dual roles in managing replication stress: the preemptive prevention and the resolution of replication stress. Dr. Kyoo-young Lee, the corresponding author of this study says, "In the future, we will examine how the internal factors cause replication stress and how the cells selectively recognize and cope with different stressor."

HAMILTON, ON (December 23, 2019) - A common cardiac blood test done before surgery can predict who will experience adverse outcomes after most types of surgery, says an international study led by Hamilton researchers.

Globally, of the 200 million adults who undergo major surgery, 18 percent will experience serious cardiac and vascular complications including death within 30 days following their intervention, such as hip and knee replacements, bowel resections and abdominal aortic aneurysm repair.

"Any type of surgery has the potential to cause damage to heart tissue, through blood clot formation, long periods of inflammation, or bleeding," said study lead, Dr. PJ Deveraux, professor of medicine, cardiologist at Hamilton Health Sciences (HHS) and scientific lead for perioperative research at McMaster University and HHS' Population Health Research Institute (PHRI).

The VISION study looked at whether levels of a cardiac blood test, NT-proBNP, measured before surgery can predict cardiac and vascular complications. Higher levels of NT-proBNP, which can be caused by various anomalies in the cardiac muscle, such as stress, inflammation or overstretch, can help identify which patients are at greatest risk of cardiac complications after surgery.

The study included 10,402 patients aged 45 years or older having non-cardiac surgery with overnight stay from 16 hospitals in nine countries.

"As a result of these findings, doctors can predict who is at greater risk of heart attacks and other negative vascular events after surgery," said Dr. Devereaux.

This phase of the VISION study builds upon six years of research studies to understand pre- and post-operative factors that lead to cardiac complications.

"This simple blood test can be done quickly and easily as part of patient's pre-operative evaluation and can help patients better understand their risk of post-operative complications and make informed decisions about their surgery," said first author of the publication, Dr. Emmanuelle Duceppe, internist and researcher at the Centre Hospitalier de l'Universite de Montreal (CHUM), PhD candidate in clinical epidemiology at McMaster University, and associate researcher at PHRI. "This blood test is twenty times cheaper than more time-consuming tests such as cardiac stress tests and diagnostic imaging."

Results of this simple blood test may inform the type of surgery the patient will undergo, such as laparoscopic or open surgery, the type of anesthesia used during surgery and who will require more intense monitoring post-operatively.

Blood test results can also reduce the need for pre-surgical medical consultations for patients that show no risk for cardiac complications.

"Heart injury after non-cardiac surgery is emerging as an important health issue requiring attention. Using CIHR funding, the research group led by PHRI and Dr. Devereaux, has clarified the association between an elevation of a common biomarker and the risk of per-operative morbidity and mortality," said Dr. Brian H. Rowe, Scientific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes for Health Research.

Study data was published today in Annals of Internal Medicine.

Make some room in the garden, you storied three sisters: the winter squash, climbing beans and the vegetable we know as corn. Grown together, newly examined "lost crops" could have produced enough seed to feed as many indigenous people as traditionally grown maize, according to new research from Washington University in St. Louis.

But there are no written or oral histories to describe them. The domesticated forms of the lost crops are thought to be extinct.

Writing in the Journal of Ethnobiology, Natalie Muellert, assistant professor of archaeology in Arts & Sciences, describes how she painstakingly grew and calculated yield estimates for two annual plants that were cultivated in eastern North America for thousands of years -- and then abandoned.

Growing goosefoot (Chenopodium, sp.) and erect knotweed (Polygonum erectum) together is more productive than growing either one alone, Mueller discovered. Planted in tandem, along with the other known lost crops, they could have fed thousands.

Archaeologists found the first evidence of the lost crops in rock shelters in Kentucky and Arkansas in the 1930s. Seed caches and dried leaves were their only clues. Over the past 25 years, pioneering research by Gayle Fritz, professor emerita of archaeology at Washington University, helped to establish the fact that a previously unknown crop complex had supported local societies for millennia before maize -- a.k.a. corn -- was adopted as a staple crop.

But how, exactly, to grow them?

The lost crops include a small but diverse group of native grasses, seed plants, squashes and sunflowers -- of which only the squashes and sunflowers are still cultivated. For the rest, there is plenty of evidence that the lost crops were purposefully tended -- not just harvested from free-living stands in the wild -- but there are no instructions left.

"There are many Native American practitioners of ethnobotanical knowledge: farmers and people who know about medicinal plants, and people who know about wild foods. Their knowledge is really important," Mueller said. "But as far as we know, there aren't any people who hold knowledge about the lost crops and how they were grown.

"It's possible that there are communities or individuals who have knowledge about these plants, and it just isn't published or known by the academic community," she said. "But the way that I look at it, we can't talk to the people who grew these crops.

"So our group of people who are working with the living plants is trying to participate in the same kind of ecosystem that they participated in -- and trying to reconstruct their experience that way."

That means no greenhouse, no pesticides and no special fertilizers.

"You have not just the plants but also everything else that comes along with them, like the bugs that are pollinating them and the pests that are eating them. The diseases that affect them. The animals that they attract, and the seed dispersers," Mueller said. "There are all of these different kinds of ecological elements to the system, and we can interact with all of them."

Her new paper reported on two experiments designed to investigate germination requirements and yields for the lost crops.

Mueller discovered that a polyculture of goosefoot and erect knotweed is more productive than either grown separately as a monoculture. Grown together, the two plants have higher yields than global averages for closely related domesticated crops (think: quinoa and buckwheat), and they are within the range of those for traditionally grown maize.

"The main reason that I'm really interested in yield is because there's a debate within archeology about why these plants were abandoned," Mueller said. "We haven't had a lot of evidence about it one way or the other. But a lot of people have just kind of assumed that maize would be a lot more productive because we grow maize now, and it's known to be one of the most productive crops in the world per unit area."

Mueller wanted to quantify yield in this experiment so that she could directly compare yield for these plants to maize for the first time.

But it didn't work out perfectly. She was only able to obtain yield estimates for two of the five lost crops that she tried to grow -- but not for the plants known as maygrass, little barley and sumpweed.

Reporting on the partial batch was still important to her.

"My colleagues and I, we're motivated from the standpoint of wanting to see more diverse agricultural systems, wanting to see the knowledge and management of indigenous people recognized and curiosity about what the ecosystems of North America were like before we had this industrial agricultural system," Mueller said.

The diverse colours, shapes and patterns of fish are captivating. Despite such diversity, a general feature that we can observe in fish such as salmon or tuna once they are served in a dish like sushi, is the distinct 'V' patterns in their meat. While this appears to be genetically observed in the muscle arrangement of most fish species, how such a generic 'V' pattern arises is puzzling.

A team of researchers from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) investigated the science behind the formation of the 'V' patterns - also known as chevron patterns - in the swimming muscles of fish. The study focused on the myotome (a group of muscles served by a spinal nerve root) that makes up most of the fish body. These fish muscles power the fish's side-to-side swimming motion and the chevron pattern is thought to increase swimming efficiency. The research team found that these patterns do not simply arise from genetic instruction or biochemical pathways but actually require physical forces to correctly develop. The findings of the study were published in the journal Proceedings of the National Academy of Sciences of the United States of America on 26 November 2019.

Friction and stress combine to shape patterns in fish muscle

The chevron pattern is not unique to salmon and tuna; it is also present in other fish species such as the zebrafish, as well as in some amphibian species like salamanders and frogs during development. The 'V' shape first appears in the somites - the precursor building blocks of the myotome, which forms the skeletal muscles. The somites typically form during the first few days of fish development or morphogenesis.

A team of scientists led by MBI Postdoctoral Fellow Dr Sham Tlili and Principal Investigator Assistant Professor Timothy Saunders studied chevron formation in the myotome of zebrafish embryos. Initially, each future developing myotome segment is cuboidal in shape. However, over the course of five hours, it deforms into a pointed 'V' shape. To find out how this deformation actually takes place, the team adopted a combination of different techniques - imaging of the developing zebrafish myotome at single cell resolution; quantitative analysis of the imaging data; and fitting the quantitative data into biophysical models.

Based on findings from their experimental as well as theoretical studies, the MBI scientists identified certain physical mechanisms that they thought might be guiding chevron formation during fish development.

Firstly, the developing myotomes are physically connected to other embryonic tissues such as the neural tube, notochord, skin and ventral tissues. The strength of their connection to these different tissues varies at different time points of myotome formation, and accordingly, different amounts of friction are generated across the tissue. Effectively, the side regions of the developing myotome are under greater friction than the central region. As new segments push the myotome forward, this leads to the formation of a shallow 'U' shape in the myotome tissue.

Secondly, cells within the future myotome begin to elongate as they form muscle fibres. The research team revealed that this transformation process generates an active, non-uniform force along certain directions within the somite tissue, which results in the 'U' shape sharpening into the characteristic 'V'-shaped chevron. Lastly, orientated cell rearrangements within the future myotome help to stabilise the newly acquired chevron shape.

Deciphering the patterns guiding organ formation

Asst Prof Saunders, a theoretical physicist who applies physical principles to characterise biological processes that take place during development, said, "This work reveals how a carefully balanced interplay between cell morphology and mechanical interactions can drive the emergence of complex shapes during development. We are excited to see if the principles we have revealed are also acting in the shaping of other organs."

It is common to attribute anything 'appearance-related' to the genetics of an organism. Through this study, the MBI scientists show how temporally and spatially varying biophysical forces play a role in determining the form of an organism.

Neurochemicals such as serotonin and dopamine play crucial roles in cognitive and emotional functions of our brain. Vesicular monoamine transporter 1 (VMAT1) is one of the genes responsible for transporting neurotransmitters and regulating neuronal signaling. A research team led by Tohoku University has reconstructed ancestral VMAT1 proteins, revealing the functional changes in neurotransmitter uptake of VMAT1 throughout the course of human evolution.

Human bodies are made up of millions of cells. Each individual contains a specific set of instruction of codes that make up all of a living thing's genetic material. These instructions are known as genomes. PhD candidate Daiki Sato and Professor Masakado Kawata of the Graduate School of Life Sciences at Tohoku University, and two of the authors involved in the current study, previously discovered VMAT1 to be one of the genes that had evolved throughout human lineage.

VMAT 1 contains two human-specific mutations, or where the genomes changed, with the change being represented as 130Glu to 130Gly and from 136Asn to 136Thr. Previous studies have shown that having the new 130Gly/136Thr variant decreases the uptake of neurotransmitters and is associated with higher depression and/or anxiety.

In this study, Sato, Kawata and their colleagues revealed the evolutionary changes in neurotransmitter uptake of VMAT1 by reconstructing ancestral VMAT1 proteins. First they applied a fluorescent substrate to visualize and quantify the neurotransmitter uptake of each genotype. The ancestral (130Glu/136Asn) VMAT1 protein exhibited an increased uptake of neurotransmitters compared to a derived (130Gly/136Thr) genotype. Given that the derived (130Gly/136Thr) genotype is shown to be associated with depression and/or anxiety in modern human populations. "This results of our study reveal that our ancestors may have been able to withstand higher levels of anxiety or depression," noted the authors.

The researcher's next step is to identify the neurological and behavioral consequences of the mutations in mice to clarify how the variants contributed to our brain evolution. "This would be the striking evidence that links evolution of our genome and brain," said the authors. The researchers hope that this finding provides insights into our diverse psychological traits including psychiatric disorders.

A diet low in fat and high in egg whites could be the key to boosting male fertility according to a new pilot study.

The research, by Dr Karma Pearce from the University of South Australia in collaboration with fertility specialist Prof Kelton Tremellen, Repromed, and Flinders University, presents a direct link between diet and testosterone - showing that what men eat could affect their fundamental male sex hormone.

The study is the first to identify that a diet high in any type of fat - including healthy mono-saturated fats such as olive oil - negatively impacts testosterone production over as little as five hours, yet one supplemented with egg whites, and to a lesser extent whey protein, can positively affect serum testosterone.

Globally, infertility affects 15 per cent of couples, with the World Health Organization estimating that up to 25 per cent of couples in developing countries are affected. While the causes are many and varied, 20-30 per cent of the problems are attributed to male factors alone.

Lead researcher, Dr Karma Pearce, says the preliminary findings present controversial insights over the shorter five-hour term about the link between testosterone and 'healthy' monounsaturated fat, which is popularly considered to be a component of a healthy diet, including the Mediterranean dietary pattern.

"There's an assumption that 'good' fats and 'bad' fats perform as they're described - but what's surprising, is that it wasn't the type of fat that mattered at all, as an equal amount of the good and bad fats significantly supressed testosterone production," Dr Pearce says.

While the researchers acknowledge they have tested individual nutrients and the effects may be different in the context of whole food dietary patterns, their earlier work has shown that 'Western diets' typified by fast food dietary pattern produced a 25 per cent decrease in serum testosterone within an hour of eating, with levels remaining suppressed below fasting baseline for up to four hours.

"In this study we also found that consuming albumen - the protein in egg whites - increased testosterone levels, and did so by four-fold relative to fasting, while albumin, combined with the bad saturated fat somewhat ameliorated the effect of the bad fats on testosterone levels, providing another diet-based influencer of testosterone levels."

The study tested eight diet protocols (meals comprising polyunsaturated fat; monounsaturated fat; refined carbohydrate (orange juice); whey; egg white; and mixed meals of polyunsaturated fat and refined carbohydrate; polyunsaturated fat and egg white; refined carbohydrate (orange juice) and egg white) with four blood tests/hormone analyses taken before eating and at every hour afterwards for five hours.

Dr Pearce says the study is one step in a series of work needed to support and enhance fertility.

While the study only analyses the impact of various dietary macronutrients on testosterone production, not sperm quality, the researchers believe the study results suggest at least the potential for diet to negatively impact on sperm production and fertility. The findings are extremely promising for couples trying to start a family.

"It's important to note that it's still early days and more research needs to be done, particularly at looking at the effect of these nutrients in the context of whole food dietary patterns over the longer-term," Dr Pearce says. "Over the Christmas period, for infertile men, and men with lower than normal testosterone levels, lowering the overall fat content and possibly increasing whey or adding egg whites may lead to improvements in testosterone levels over the shorter term."

The next step in their research is to evaluate the longer-term effect of these nutrients on testosterone levels in the context of whole food dietary patterns.

Roman emperors faced a high risk of violent death in their first year of rule, but the risk slowly declined over the next seven years, according to an article published in the open access journal Palgrave Communications. When statistically modelled, the length of time from the beginning of their reign until their death followed a set pattern, similar to that seen in reliability engineering, interdisciplinary research by Dr Joseph Saleh, an Aerospace Engineer from the Georgia Institute of Technology, US suggests.

Historical records show that of 69 rulers of the unified Roman Empire, 43 (62%) suffered violent deaths either by assassination, suicide or during combat. Historical accounts typically examine each death as a single, random event alongside individual contributing factors such as allegiances and wealth. It is not known whether there were any common, underlying patterns to how long each emperor's reign lasted before they died.

By applying statistical methods frequently used to test the reliability of components in engineering, Dr Joseph Saleh modelled the typical length of time between the beginning of an emperor's reign and their subsequent death. The author found parallels between the seemingly random failures of components in engineering and the seemingly random deaths of emperors.

Dr Saleh said: "In engineering, the reliability of a component or process is defined as the probability that it is still operational at a given time. The time it takes for a component or process to fail is referred to as its time-to-failure and this shows similarities to the time-to-violent-death of Roman emperors."

Dr Saleh found that Roman emperors faced a high risk of violent death during their first year of reign, a pattern also seen when engineering components fail early, often as a result of a failure to function as intended or, in the case of an emperor, meet the demands of their role. The risk of death stabilised by the eighth year but increased again after 12 years of rule, a pattern similar to the failure of components because of fatigue, corrosion or wear-out. When data points were aligned on a graph, the failure rate of Roman emperors displayed a bathtub-like curve, a model widely seen with mechanical and electrical components.

Dr Saleh said: "It's interesting that a seemingly random process as unconventional and perilous as the violent death of a Roman emperor--over a four-century period and across a vastly changed world--appears to have a systematic structure remarkably well captured by a statistical model widely used in engineering. Although they may appear as random events when taken singularly, these results indicate that there may have been underlying processes governing the length of each rule until death."

Data was obtained from the De Imperatoribus Romanis, a peer-reviewed online encyclopedia of Roman emperors. The author cautions that the limitations of the data should be acknowledged, as sources of ancient history are often inconsistent and the exact causes of death may differ between accounts. Further studies could explore why emperors repeatedly met a violent end and whether other historical events may be analysed in this way.

A new study by collaborators at Klein Buendel, Inc. and the Prevention Research Center finds that recreational cannabis stores in Colorado and Washington state, both of which legalized adult recreational use in 2012, show high levels of compliance with rules preventing underage purchase of cannabis. The study also shows that there is more than can be done to reach full compliance.

Between September 2016 and April 2017, 175 recreational cannabis stores in Colorado and Washington State were visited by "pseudo-buyers." The protocols were as follows:

Each store in each state was visited twice.

An observer entered the store first to scan the store's environment and observe the buyers' purchase behavior.

On each of these visits in Washington, a young-adult buyer attempted to enter the store and purchase cannabis without showing a state-approved ID (a valid driver's license).

The same protocol was used on the first visit in Colorado, while in a second Colorado visit, an 18-20 year old buyer showed an underage driver's license and attempted to enter the store to purchase cannabis.

The results show:

All stores across the two states requested an ID.

Stores refused buyers in 73.6% of visits at the entrance, 88.3% cumulative before the counter, and 92.6% by the time of a purchase attempt.

Refusal was lower in Washington State than in Colorado (at entry, 53.1%; before the counter, 80.5%; and at purchase attempt, 86.6%), but refusal did not differ by buyer protocol.

Says PIRE Co-Author Dr. Robert Saltz: "Compliance with laws restricting cannabis sales to individuals 21 or older with a valid ID was high and higher than we see for alcohol sales. Whether this reflects the newness of the industry or not will be determined by future compliance checks. Compliance in Washington state might be improved by having store personnel check IDs at the store entry."

Nearly one in six deaths from prostate cancer could be prevented if targeted screening was introduced for men at a higher genetic risk of the disease, according to a new UCL-led computer modelling study.

Prostate cancer is the most common form of cancer in men with around 130 new cases diagnosed in the UK every day and more than 10,000 men a year dying as a result of the disease. However, unlike breast and cervical cancer there is currently no national screening programme for this disease in the UK.

A blood test that detects raised levels of the prostate-specific antigen (PSA) can be used to screen for prostate cancer. However, this test is not a reliable indicator as it does not accurately distinguish between dangerous cancers from harmless ones - leading to both unnecessary operations and missed cancers that are harmful.

The study, published in PLOS Medicine, modelled the harms and benefits of introducing four-yearly PSA screening for all men aged 55 to 69 versus more targeted checks for those at higher risk of the disease.

The researchers concluded that the best approach would be to screen men at a slightly higher genetic risk - nearly half of men in that age group - as this would have the biggest health benefit, preventing deaths from prostate cancer while minimising unnecessary treatments for harmless tumours. This is because men with a higher genetic risk are more likely to benefit and less likely to be harmed by undertaking screening.

Professor Nora Pashayan (UCL Applied Health Research), senior author of the study, said: "Prostate cancer is a leading cause of death from cancer in men in the UK, but screening is not performed because the harm of overdiagnosis is thought to outweigh the benefits.

"Our study shows that targeted screening can reduce unnecessary diagnoses while helping to prevent people dying from the disease by enabling earlier detection."

Researchers created a hypothetical cohort of 4.5 million men, representing the number of men aged 55 to 69 in England, and simulated the outcomes of introducing screening into this population. Outcomes including prostate cancer deaths averted, unnecessary diagnoses and screening costs were compared for no screening, universal age-based screening and more targeted screening using a range of thresholds of genetic risk.

The optimal scenario, the researchers concluded, would be to screen men with a 4-7% risk of getting prostate cancer over the next 10 years - that is, between roughly half and a quarter of all men aged 55 to 69.

Screening all men in that age group would result in the most deaths averted (20%) but, along with the extra cost, would also lead to a large number of unnecessary diagnoses, with nearly one in three cancers detected by screening being harmless.

Screening at a threshold of 4% would prevent 15% of deaths from prostate cancer - nearly one in six deaths - while delivering the greatest gains in terms of quality adjusted life years, meaning more years of good health across the population. This would also reduce the number of unnecessary diagnoses of harmless cancers by about one third compared with screening all men aged 55 to 69.

Screening men with a 4-7% risk would also be much more cost effective than screening all men aged 55 to 69, saving between a fifth (for the 4% risk threshold) to nearly half of the cost (7% risk threshold), while maintaining the benefits of screening.

Under the scenarios simulated, men aged 55 to 69 would have four-yearly checks once they had reached the risk threshold. This would mean a widening proportion of men having checks the older they got, as older men are at greater risk of the disease.

Pioneering UCL-led research has already led to a change in the way prostate cancer is diagnosed. As of last December, MRI is now recommended as the first test for men suspected of having the cancer, after two clinical trials conducted with University College London Hospitals (UCLH) trust found MRI scans could markedly and safely reduce the numbers of men needing an invasive biopsy.

Professor Mark Emberton (UCL Medical Sciences) said: "I feel we now have the tools that help us identify men with clinically important disease - applying these tools to the right patient has to be the future. That is why this work is so important in helping us know who and when to screen."

Researchers said targeted screening based on genetic risk would require an evolution of screening services. They noted that inviting people for screening at different ages may affect screening delivery and that the broader impact of screening using genetic risk required further research.

Gender-tailored methods to address the harmful mental health effects of childhood adversity may help alleviate the current opioid crisis and make treatment more effective, concludes University of Massachusetts Amherst epidemiology researcher Elizabeth Evans in her latest research about opioid use disorder (OUD).

Looking for new ways to address the public health emergency that the opioid crisis has created, Evans and colleagues examined gender differences in associations between mental health conditions and adverse childhood experiences (ACE) among adults with opioid use disorder.

The study, published in the international journal Addictive Behaviors, suggests that treatment for OUD and mental health conditions, especially in the case of women, should be integrated in settings that also provide child care and create a supportive environment to address stigma and shame. "Women are often treated for OUD in predominantly male settings," she says. "The care to address OUD and mental health conditions needs to be coordinated, and women's fears need to be addressed," such as concern over potential loss of parental rights if they seek treatment.

ACEs are potentially traumatic events - anything from experiencing or witnessing violence, abuse and neglect to household instability due to incarceration, illness, substance misuse and death, according to the Centers for Disease Control and Prevention. ACEs can be balanced by positive experiences, which act as protective factors, but they also are linked with risky health behaviors, chronic health conditions, low life potential and early death.

"The findings suggest ACE may cause or contribute to OUD differently for women and men," says Evans, assistant professor in the School of Public Health and Health Sciences. "We need to address these ACE issues, in addition to opioid use disorder and mental health problems, in order to resolve both of these conditions."

In an effort to fill some gender-based knowledge gaps about OUD, Evans and colleagues at UMass Amherst and the University of California, Los Angeles, analyzed nationally representative, 2012-2013 data from 388 women and 390 men with heroin or prescription opioid misuse who were part of the National Epidemiological Survey on Alcohol and Related Conditions-III.

"This survey is a powerful resource for understanding the causes and consequences of addiction in our country. It has a broader range of the continuum of addiction, including all those people who never access treatment. Another powerful advantage is that the survey measures childhood adversity, mental health, and opioid and other types of substance use disorders. Very few nationally representative surveys measure all of those risk factors and conditions," Evans explains.

The researchers examined factors associated with OUD, mental health conditions, ACE and gender, and calculated predicted probabilities. Among the findings:

Women with opioid use disorder are more likely than men to have mood and anxiety disorders, and less likely than men to have conduct disorders. "Women more than men internalize the effects of trauma, and the depression and anxiety become this persistent vulnerability, and they turn to opioids to relieve it," Evans says. "Men are more likely to externalize - become angry and aggressive. They turn to different ways of coping that lead to conduct disorders."

More than 80% of both men and women with OUD reported at least one adverse childhood experience, compared with an ACE prevalence of about 60% in those without OUD. Almost half reported more than three types of ACE, and as exposure to ACE increases, the risk for mood disorders is higher for women than men.

More women than men have prescription opioid disorder and fewer women have heroin use disorder.

Evans says addressing ACE and its impact needs to become a routine part of preventive healthcare.

"Opioid misuse is a form of childhood adversity. In other words, parents with OUD may transfer risk factors for mental health conditions and OUD to their children," she says. "So how do we break the cycle? Evaluating and assessing for ACE should be standard practice in the primary care and other health care settings as a way to prevent mental health conditions and opioid use disorder."

INDIANAPOLIS -- Researchers at Indiana University School of Medicine have made several novel discoveries in the field of spinal cord injuries (SCI). Most recently, the team led by Xiao-Ming Xu, PhD, has been working to determine how to activate movement after a spinal cord injury at the ninth thoracic level, where nerve fibers from the brain down to the spinal cord are interrupted. Instead of focusing on the injury site, researcher Qi Han and his colleagues modulated the spared lumbar circuits below the injury to improve recovery from SCI, using animal models. The team revealed that neuromodulation of interrupted lumbar motor circuits by neurotrophic therapy improved locomotor performance. These findings are being published in the December 20 issue of Nature Communications.
"There are no definitive treatments yet for SCI patients," said Han. "However, hope for restoring motor function continues to rise, for good reason. We find that, despite no direct damage from thoracic SCI, the lumbar circuit undergoes a profound neurodegeneration, which we have highlighted as a promising new therapeutic target for promoting neuroprotection."

SCI disrupts pathways at the injury site and affects MNs by causing their dendrites to withdraw or atrophy below the injury, which can lead to diminished movement or locomotor function. Previously, the research team was able to improve locomotor recovery and reduce MN dendritic atrophy after a moderate, contusive SCI at the ninth thoracic level, by transporting Neurotrophin-3 (NT-3) to lumbar MNs. NT-3 is known as a trophic factor that contributes neuronal survival and growth. These latest research findings extend the role of NT-3 to modulating propriospinal-MN circuit reorganization, which accounts for improvement of locomotor function after SCI.

Researchers were also able to determine that a moderate injury at the ninth thoracic level stops the corticospinal tract and rubrospinal tract projections down to the spinal cord, but maintains some neural transmissions which can be reinforced by the NT-3 therapy. Additionally, they discovered the spared pathway, made up of a collection of nerve fibers, namely, the descending propriospinal pathway, connecting to the lumbar spinal cord, is functionally associated with NT-3-mediated locomotor recovery after SCI. Their research also suggests that NT-3 supports MN recovery by promoting dendritic regrowth.

Xu says he hopes their research findings in animal models will lay the groundwork for more NT-3 therapy research to help patients with SCI in the future.

"Modulating propriospinal-MN circuitry with NT-3 gene therapy could be an attractive strategy to enable functional recovery after SCI." said Xu.