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ROCHESTER, Minn. ? Researchers at Mayo Clinic have combined results from a functional test measuring the effect of inherited variants in the BRCA2 breast and ovarian cancer gene with clinical information from women who received genetic testing to determine the clinical importance of many BRCA2 variants of uncertain significance (VUS). The findings were published today in a study in the American Journal of Human Genetics.

"There are 4,565 different VUS in the BRCA2 gene listed in the National Institutes for Health (NIH) Clinical Variant Database," says Fergus Couch, Ph.D., a breast cancer researcher at Mayo Clinic. The database lists variants submitted by genetic testing laboratories and research groups.

Dr. Couch says the 4,565 variants represent about 50% of all reported BRCA2 variants in the NIH database. He says many thousands of individuals tested around the world have these variants, but they have no way to know the clinical significance of their particular variants. And their doctors have no way to use this information to select methods for preventing breast or ovarian cancer, or to select targeted treatment approaches for tumors with BRCA2 alterations.

"The current method for attempting to determine the clinical relevance of BRCA2 variants of uncertain significance relies on a series of rules from the American College of Medical Genetics and Genomics ACMG/AMP that use genetic information about the variants and information from patients and patients' families," says Dr. Couch.

Dr. Couch and his team used a functional test to determine the influence of many VUS on BRCA2 DNA damage repair activity. They first showed that the functional test was able to clearly discriminate between known pathogenic cancer-causing variants and known benign BRCA2 variants that do not increase risk of cancer. Next, they applied the test to the VUS and combined the results with other ACMG/AMP rules-based information.

"We found that 86% of the VUS we studied were reclassified as benign or pathogenic, which is a major step forward from the 10% or so missense variants in the DNA binding domain that have previously been classified," says Dr. Couch. "This is the first time that a functional test has been combined with ACMG/AMP information in this way, and the results show that it is highly effective."

Dr. Couch says the results will have a positive effect on patient care because patients will know whether breast cancer VUS are benign or pathogenic.

"Patients whose VUS are benign will now be evaluated based on their personal and family history of breast and ovarian cancer, and not on the basis of the genetic testing result," says Dr. Couch. "And patients who are classified as having pathogenic variants will be able to benefit from more frequent cancer screening or prophylactic mastectomy to reduce risk of developing breast cancer."

The findings also mean that women with ovarian cancer now may know if they would qualify for targeted therapy with PARP inhibitors.

A new study published in The British Medical Journal by researchers including SFU health sciences professor Scott Lear found consuming a high number of refined grains, such as croissants and white bread, is associated with a higher risk of major cardiovascular disease, stroke and death.

The Prospective Urban Rural Epidemiology (PURE) study has been examining diets from diverse populations in low-, middle- and high-income countries around the world. Over 16 years of analysis of 137,130 participants in 21 countries, including Canada, the researchers found the intake of refined grains and added sugars have greatly increased over the years.

Grains were categorized into three groups: refined grains, whole grains and white rice. Refined grains included goods made with refined (e.g. white) flour, including white bread, pasta/noodles, breakfast cereals, crackers, and bakery products/desserts containing refined grains. Whole grains included whole grain flours (e.g. buckwheat) and intact or cracked whole grains (eg. steel cut oats).

The study found that having more than seven servings of refined grains per day was associated with a 27 per cent greater risk for early death, 33 percent greater risk for heart disease and 47 per cent greater risk for stroke.

"This study re-affirms previous work indicating a healthy diet includes limiting overly processed and refined foods," says Lear.

No significant adverse health effects were found with consuming whole grains or white rice.

The study suggests eating whole grain foods like brown rice and barley, and having fewer cereal grains and refined wheat products. Reducing one's overall consumption of refined grains and having better quality carbohydrates is essential for optimal health outcomes.

Microorganisms possess natural product biosynthetic gene clusters (BGCs) that may harbor unique bioactivities for use in drug development and agricultural applications. However, many uncharacterized microbial BGCs remain inaccessible. Researchers at University of Illinois Urbana-Champaign previously demonstrated a technique using transcription factor decoys to activate large, silent BGCs in bacteria to aid in natural product discovery.

Now, they have developed a direct cloning method that aims to accelerate large-scale discovery of novel natural products. Their findings are reported in the journal Nature Communications.

Named Cas12a assisted precise targeted cloning using in vivo Cre-lox recombination (CAPTURE), the method allows for direct cloning of large genomic fragments, including those with high-GC content or sequence repeats. Where existing direct cloning methods fail to effectively clone natural product BGCs of this nature, CAPTURE excels.

"Using CAPTURE, microbial natural product BGCs can be directly cloned and heterologously expressed at an unprecedented rate," said study leader and Steven L. Miller Chair professor of chemical and biomolecular engineering Huimin Zhao, also a member of the Carl R. Woese Institute for Genomic Biology at Illinois. "As a result, CAPTURE allows large-scale cloning of natural product BGCs from various organisms, which can lead to discovery of numerous novel natural products."

Researchers first characterized the efficiency and robustness of CAPTURE by cloning 47 natural product BGCs from both Actinomycetes and Bacilli. After demonstrating nearly 100% efficiency of CAPTURE, 43 uncharacterized natural product BGCs from 14 Streptomyces and three Bacillus species were cloned and heterologously expressed by researchers. The produced compounds were purified and determined as 15 novel natural products, including six unprecedented compounds designated as bipentaromycins. Four of the bipentaromycins exhibited antimicrobial activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and Bacillus anthracis.

"Addressing the current antimicrobial resistance crisis requires discovery of novel molecules capable of treating drug-resistant infections," said Zhao. "Discovery of bipentaromycins not only demonstrates the possibility of discovering novel antimicrobials, but it also provides an example on how this strategy can be applied for discovery of unique bioactive compounds for use in drug development and agricultural applications."

The researchers plan next to characterize these compounds for other bioactivities such as anticancer, antiparasitic and anticancer properties. Preliminary results are already showing anticancer properties for some of the compounds.

"Due to its exceptional robustness and efficiency, CAPTURE will likely become the method of choice for direct cloning of large DNA molecules such as natural product BGCs from genomic or metagenomic DNA for various basic and applied biological applications," said Zhao.

The Biden administration is revising the social cost of carbon (SCC), a decade-old cost-benefit metric used to inform climate policy by placing a monetary value on the impact of climate change. In a newly published analysis in the journal Nature, a team of researchers lists a series of measures the administration should consider in recalculating the SCC.

"President Biden signed a Day One executive order to create an interim SCC within a month and setting up a process to produce a final, updated SCC within a year," explains Gernot Wagner, a climate economist at New York University's Department of Environmental Studies and NYU's Robert F. Wagner Graduate School of Public Service and the paper's lead author. "Our work outlines how the administration can use the latest research in ways that take into account storms, wildfires, and other phenomena that are more devastating today than they were when the SCC was first created."

"Economic analysis is at the heart of the regulatory process in the U.S. and will therefore play a major role in shaping and informing the ambitious climate goals from the new administration," adds David Anthoff, co-author and assistant professor of Energy and Resources at UC Berkeley. "Our recommendations offer a roadmap for how this can be done in a way that is both scientifically rigorous and transparent."

"The damage and loss of life caused by the severe weather in Texas is only the latest example of how climate change can upend our well-being in ways not imagined only 10 years ago," observes Wagner.

The revised SCC will be created by the federal government's Interagency Working Group (IWG), which includes the Council of Economic Advisors, the Office of Management and Budget, and the Office of Science and Technology Policy.

In the Nature "Comment," the authors, who also include researchers from the University of Maryland, the London School of Economics and Political Science, Yale University, the University of Exeter, the University of Wisconsin-Madison, and Harvard University, list several recommendations for the IWG to consider in devising the new SCC. Among them are the following:

Reinstating the estimated economic cost of CO2 emitted to $50 a ton, which the Trump administration lowered to $1-7 a ton

Updating the damage functions that tally how climate change affects human welfare, from crop losses to heat impacting student learning and worker productivity

Incorporating the inequitable effects of climate change within and across countries

Reviewing discount rates--the ways in which the cost of future climate-related damages are priced in today's dollars--in order to better inform today's budgetary processes

Updating forecasts for both economic and population growth--both of which affect predictions of emissions and related environmental impact

"Climate science and economics have advanced since 2010," write the authors. "Devastating storms and wildfires are now more common, and costs are mounting. Advances in science mean that researchers can now link many more extreme weather events directly to climate change, and new econometric techniques help to quantify dollar impacts."

Photo and map

Robotic laboratories on the bottom of Lake Erie have revealed that the muddy sediments there release nearly as much of the nutrient phosphorus into the surrounding waters as enters the lake's central basin each year from rivers and their tributaries.

Excessive phosphorus, largely from agricultural sources, contributes to the annual summer cyanobacteria bloom that plagues Lake Erie's western basin and the central basin's annual "dead zone," an oxygen-starved region that blankets several thousand square miles of lake bottom and that reduces habitat for fish and other organisms.

The release of phosphorus from Lake Erie sediments during periods of low oxygen--a phenomenon known as self-fertilization or internal loading--has been acknowledged since the 1970s. But the new University of Michigan-led study marks the first time the process has been monitored step by step for an entire season using lake-bottom sensors.

The authors of the new study, published online Feb. 18 in the journal Environmental Science & Technology Water, say self-fertilization is likely increasing the severity of Lake Erie's central-basin dead zone and could make it harder to control in the future, as the climate continues to warm.

"Until now, we lacked evidence to pinpoint when and where this phenomenon occurs in Lake Erie and how much it contributes to nutrients in the lake," said study lead author Hanna Anderson, a research technician at U-M's Cooperative Institute for Great Lakes Research who did the work for a master's thesis at the School for Environment and Sustainability.

"These new measurements have allowed us to estimate that this self-fertilization process contributes up to 11,000 metric tons of phosphorus to the lake water each summer, an amount that is close to the total annual runoff of phosphorus from rivers and tributaries into the central part of the lake," said Casey Godwin, an assistant research scientist at the institute and a co-author of the paper.

Efforts to control Lake Erie nutrient pollution, or eutrophication, have focused on reducing the amount of phosphorus-rich runoff from farms and other sources that flows into the lake from rivers and their tributaries. In 2016, the U.S. and Canadian governments adopted a phosphorus-reduction target of 40%.

The authors of the new Environmental Science & Technology Water study say self-fertilization by phosphorus (P) released from lake-bottom sediments also needs to be considered.

"Environmental managers tasked with tributary load reduction must take internal loading estimates into account when determining how to balance the total P load," they wrote. "Historical and persistent sediment P loading represents a delayed lake response to eutrophication and prevents the successful management of a system when only external P loading is considered."

In addition to several U-M scientists, authors of the paper include researchers from the National Oceanic and Atmospheric Administration's Great Lakes Environmental Research Laboratory. U-M scientists and staff at CIGLR collaborate with NOAA GLERL on a number of projects such as this.

The researchers deployed two small autonomous laboratories at lake-bottom sites in Lake Erie's central basin--one at a depth of 67 feet and the other at a depth of 79 feet--in late July 2019 and left them there for more than two months.

The self-contained chemistry labs, manufactured by SeaBird Scientific and owned by the team's NOAA collaborators, are cylinders 22 inches long and 7 inches wide. The labs and their batteries were placed inside a protective steel framework that was lowered from the stern of a ship. The metal cage was attached to a 150-pound weight and two white floats that kept it off the bottom.

The autonomous analyzers were programmed to measure phosphorus concentrations in the water every six hours. They also monitored water temperature and dissolved-oxygen levels. More than 300 phosphorus measurements were made at each site before the devices were retrieved in early October.

This previously unobtainable dataset yielded some surprising findings.

For example, earlier studies had suggested that nutrients begin to flow out of lake-bottom sediments when dissolved-oxygen concentrations in the surrounding waters drop to very low levels, a condition called hypoxia.

But the chemistry robots showed that the flow of phosphorus did not begin during hypoxia--even when oxygen levels dropped below the point where fish can survive.

Instead, the "positive P flux" from the sediments began 12 to 24 hours after dissolved oxygen levels in the lake-bottom water dropped to zero, a condition called anoxia. At the two central-basin sites in Lake Erie, that period began in late summer and continued into early October.

"Within 24 hours of when the oxygen went away completely, we recorded a rapid increase of phosphorus in the water, and this continued until the concentration at the bottom of the lake was more than a hundred times higher than at the surface," said study senior author Thomas Johengen, director of U-M's Cooperative Institute for Great Lakes Research.

"Our findings about the timing of phosphorus release relative to oxygen levels in the water are the first of their kind for the Great Lakes and represent a novel application of this technology," Johengen said.

Knowing when the phosphorus release began, the rate of flow from the sediments, and the duration of the anoxic period enabled the researchers to estimate the total amount of phosphorus added to Lake Erie's central basin each year due to internal loading.

The researchers estimated that Erie's lake-bottom sediments annually release between 2,000 and 11,500 metric tons of phosphorus. The high end of this range equals the approximate annual inflow of phosphorus to Lake Erie's central basin from rivers and tributaries: 10,000 to 11,000 metric tons.

The released phosphorus is in a readily available form called soluble reactive phosphorus, or SRP, that likely fuels central-basin algal growth. When those algae die and sink, bacteria decompose the organic matter and consume oxygen in the process. The result: an oxygen-starved region in bottom and near-bottom waters of the central basin known as the dead zone.

"Internal loading of phosphorus from lake-bottom sediments can become a positive feedback loop: Hypoxia leads to the release of P from the sediments, which causes more algae growth, and the dead and dying algae consume the oxygen in the water and contribute to hypoxia the following summer," Godwin said.

"This type of feedback has been seen in lakes worldwide, and it interacts with ongoing efforts to reduce phosphorus loads from Lake Erie's tributaries," he said.

As the Great Lakes continue to warm in the years ahead due to human-caused climate change, Lake Erie's central-basin dead zone is expected to form earlier and last longer each year, resulting in a greater supply of phosphorus released from the sediments, according to the study authors.

The current study demonstrates the potential for using robotic laboratories to monitor those changes, as well as any changes that may occur due to the decreased flow of nutrients into Lake Erie from rivers and tributaries, according to the authors. Internal loading from central-basin sediments likely does not impact the severity of Lake Erie's western-basin algal blooms, according to the researchers.

"NOAA's mission in the Great Lakes includes observing, understanding and forecasting significant events such as internal loading. Very often, the development and application of advanced technology such as this can confirm a hypothesis or provide novel insight that was previously impossible," said study co-author Steve Ruberg, senior scientist at NOAA's Great Lakes Environmental Research Laboratory.

"This important observational result will contribute to NOAA's collaboration with the EPA's Great Lakes National Program Office under the Great Lakes Water Quality Agreement, significantly improving our understanding of hypoxic zone phosphorus loading and the subsequent impact on the Lake Erie ecosystem," Ruberg said.

A highly porous metal organic framework, assembled from molecular building blocks designed to lock together in a specific orientation, has been developed by researchers at KAUST.

Metal organic frameworks (MOFs) are crystalline materials made from metal ions connected by organic linkers. Their internal structure is like a repeating array of tiny identical cages, which are ideal for hosting various molecules. MOFs have found potential uses from gas sensing to molecular separations to storage, depending on the dimensions and structure of their pores.

One family of MOFs has been inspired by inorganic porous materials called zeolites. Zeolites are a special class of porous material with myriad applications, explains Norah Alsadun, a Ph.D. student in Mohamed Eddaoudi's lab, who led the research. "However, the ability to fine-tune the pore-aperture size and pore system of a given zeolite, based on a given topology, is extremely challenging," she says.

By mimicking the zeolite structure with a MOF, however, the pore structure can be readily adjusted by changing the metal and the organic linker. "Our group introduced the use of single-metal-based tetrahedral building units for zeolite-like MOF (ZMOF) construction," Alsadun says. The basis of the tetrahedron-based ZMOF structure is a pair of triangular pyramids, attached tip-to-tip via a single bond.

The free rotation of the two triangles around the single bond typically leads to the formation of a diamond-like structure. However, the assembly of tetrahedral building units in MOF chemistry can lead to the simultaneous formation of multiple diamond networks, all penetrating each other, thus blocking the pores. "So, we developed a new concept for ZMOF assembly using polynuclear clusters as rigid, directional and locked-in building units," Eddaoudi says.

Rather than simple single-metal tetrahedra as the main building block, the team used expanded polynuclear clusters in which each edge and corner of the original tetrahedron is replaced by a new face -- a geometric concept known as cantellation. As a result, the single bond linking the two tetrahedrons together in the original structure is replaced by three bonds, locking the structure into a specific orientation.

As the team had planned, the locked building blocks generated a ZMOF with a "sodalite", rather than a diamond-like, structure. "The sodalite topology has no room for interpenetration," says Vincent Guillerm, a senior research scientist in the team. The resultant sod-ZMOF pores measured up to 43 angstroms in diameter, the largest yet reported for a ZMOF.

"Our work proves that these challenging structures can be accessed through our novel design," Eddaoudi says. "Applying this strategy to construct other ZMOFs is now in progress."

Sample pretreatment processes such as concentration or classification are essential to finding trace substances present in a fluid. In scientific communities recently, prolific research is being conducted on sample pretreatment techniques utilizing electrokinetics.1 However, due to the lack of commercial anion-permselective material - an essential component - its potential application is limited to only negatively charged particles. To this, a research team at POSTECH has found a way to isolate and concentrate only the cationic samples.

A POSTECH research team led by Professor Geunbae Lim, Ph.D. candidate Minsoo Lee, and Dr. Hyukjin J. Kwon of the Department of Mechanical Engineering developed a novel type of multiscale-porous anion exchange membrane (MP-AEM) and successfully fabricated a convenient cation-permselective electrokinetic concentrator. Recognized for their excellence, these research findings were recently published as the cover paper in Advanced Functional Materials.

The ion exchange material serves to induce a strong electric field region in the channel through which the fluid flows by selectively passing ions of a specific polarity. Through this, charged particles present in the fluid are continuously concentrated by receiving electric repulsion force. In general, the polarity of the ion exchange material required differs depending on the polarity of the charged particles to be concentrated. A cation exchange material is required for negatively charged species, and an anion exchange material is required for positively charged species. However, unlike the cation exchange material that currently exists, there is no material that can be easily applied to the anion exchange material, complicating the fabrication of a cation concentrator.

To this, the research team successfully produced an anion exchange material that has a MP-AEM structure with excellent mechanical strength, ion exchange capacity, and fluid transport capacity through the simple casting and salt leaching method2 using the conventional anionic exchange materials.

The MP-AEM can be easily inserted into the electrokinetic concentrator using its peculiar property that allows simultaneous ion and fluid transport, successfully fulfilling the role of an anion exchange material. Accordingly, the research team was able to fabricate the cation-selective electrokinetic concentrator through a simple insertion and assembly method, which greatly streamlines the manufacturing process compared to the conventional method.

"The MP-AEM will play a major role in the vitalization and advancement of research fields involving cationic species," commented Professor Geunbae Lim. He excitedly added, "Considering the high scalability of the novel exchange membrane, it will be applicable to the areas of pollution control, resource recovery, and semiconductor cleaning as well as in the fields of diagnosis and detection of diseases."

Genetic variation is like money in the bank: the more you have, the better your chances of survival in the future. Population bottlenecks decrease genetic variation, especially in endangered species. An individual's genome comprises the events that have impacted genetic variation over time, and relatively recent sequencing technologies allow us to read and interpret genetic variation across the genome. Although tigers have received significant conservation attention, little is known about their evolutionary history and genomic variation. This is especially true for Indian tigers, and with 70% of the world's tigers living in India, such understanding is critical to tiger conservation.

A team of researchers from the National Centre for Biological Sciences (NCBS), Stanford University, and zoological parks and NGOs across the world recently completed a three-year project to gain insights into genomic variation in tigers and the processes that have sculpted it. The work, just published in Molecular Biology and Evolution, reiterates that tiger subspecies are genetically distinct and reveals that although Indian tigers have the highest total genetic variation, some individuals are inbred. Simulations based on the genomic data suggest relatively recent divergences between subspecies, and intense population bottlenecks. Analyses also indicate adaptation to cold environments in Russian far east tigers, and potential selection on body size in Sumatran tigers.

The team sequenced whole genomes from 65 individual tigers from four subspecies, with a specific aim to enhance genomes from wild tigers in different habitats in India. They used these data to conduct a variety of population genomic analyses that quantify genetic variability, and investigate the partitioning of genetic variation, possible impacts of inbreeding and founder events, demographic history (including population divergence) and possible signatures of local adaptation.

They found that total genomic variation in Indian tigers was higher than in other subspecies. However, several individual tigers in India had low variation, suggesting possible inbreeding and founding bottlenecks. Tigers from northeast India were the most divergent/different from other populations in India. "Given our results, it is important to understand why some Bengal tigers appear inbred and what the consequences of this are," says Anubhab Khan, co-first author, NCBS.

The history of tiger populations from across their current range shows recent divergences between tiger subspecies, within the last 20,000 years, which is concordant with a transition from glacial to interglacial climate change and increasing human impacts across Asia. These findings are in sharp contrast to an earlier study by ShuJin Luo and others in 2018 that suggested much older divergence times. The recent divergence between populations will need to be investigated further with expanded datasets and analyses of more tiger genomes.

The data and analyses also suggest strong bottlenecks in all tiger populations, highlighting the importance of population size decline on the erosion of genetic variation. "Most studies focusing on species of conservation concern use limited numbers of specimens to try to gain understanding into how genomic variation is partitioned. It is clear from our work here, and a growing number of other studies, that it is crucial to increase our sampling efforts and use caution when interpreting results from limited sample sizes," comments Ellie Armstrong, co-first and co-corresponding author, Stanford University.

Genomes of tigers in the Russian far east suggest adaptation to the cold, while those of Sumatran tigers suggest selection based on body size. Co-senior author Elizabeth Hadly of Stanford University says, "The tiger is an excellent example of the myriad historic events that sculpt species' genomic diversity and points to the importance of understanding this diversity as we attempt to stave off extinction of our most precious species on Earth. While some populations demonstrate the importance of adaptation to local conditions, other evidence suggests that particular populations may suffer the effects of climatic change in the Anthropocene." Such information will be critical to the success of genetic rescue efforts, which should take local adaptation into consideration.

'I have worked on Indian tiger genetic variation for over a decade and always wondered how they compared to other wild tigers. Our study reveals that while the total variation in Indian tiger genomes is high, they have also been dramatically shaped by population bottlenecks. The genomic variation of Indian tigers continues to be shaped by the ongoing loss of connectivity. Population management and conservation action must incorporate information on genetic variation. I hope doing so will help India maintain the gains in tiger conservation achieved so far,' says Uma Ramakrishnan, co-senior and co-corresponding author, NCBS.

Working with colleagues from Germany and the US, researchers at Leipzig University have achieved a breakthrough in research into how cancer cells spread. In experiments, the team of biophysicists led by Professor Josef Alfons Käs, Steffen Grosser and Jürgen Lippoldt demonstrated for the first time how cells deform in order to move in dense tumour tissues and squeeze past neighbouring cells. The researchers found that motile cells work together to fluidise tumour tissue.

Käs led the research project in cooperation with Professor Lisa Manning from Syracuse University (US) and Professor Bahriye Aktas from Leipzig University Hospital. They have now published their findings in "Physical Review X", a leading journal that primarily publishes groundbreaking research results.

"These first observations of a phase transition in human tumours change our basic concepts of tumour progression and could improve cancer diagnosis and therapy," said Käs, who has been studying the physical properties of cancer cells for years. He said the research showed that human tumours contain solid and fluid cell clusters, which would be a breakthrough in scientists' understanding of tumour mechanics. He added that the results form the basis for the first procedure with which metastatic cancer cells can already be detected in the tumour.

In tumour samples from patients at Leipzig University Hospital, the researchers found regions with motile cells as well as stable, solid-like regions with no cell movement. From a physical point of view, cells should not be able to move in the dense tumour mass - tumours are so densely crowded with cells that motion would be inhibited in any typical material.

The researchers therefore developed a new approach to live tumour microscopy by fluorescently staining human tumour samples immediately after surgery, allowing them to observe cell movement live. This led them to discover that, contrary to all previous findings, this cell motility does indeed take place and is associated with strong nuclear deformation. They observed how cells and their nuclei literally squeeze through the tissue by becoming severely deformed.

"Cells in biological tissues behave much like people in a bar. At low densities, they can move freely. However, movement becomes difficult when things get very crowded. But even in a crowded bar, you can still squeeze past if you turn sideways. This is exactly the effect we see in tumour tissues," said Käs. The researchers believe this phase transition explains how cells can move and multiply in a tumour, eventually leading to metastasis. The fluid tissues showed elongated, deformed cells and nuclei. Static images of elongated cell and nuclear shapes could thus serve as a fingerprint for the metastatic aggressiveness of a tumour.

"These are spectacular results from the field of cancer physics. We now need to investigate whether the fluid regions can predict tumour aggressiveness. Here we have found a cancer marker that indicates active, motile regions and that is based on a simple physical mechanism," said Steffen Grosser. Professor Käs is currently embarking on a clinical trial to investigate the potential of cell and nuclear shape as a new tumour marker that could be used to examine and treat patients in a much more targeted way than before.

Hip dysplasia is a developmental disorder common in most dog breeds, and its onset is affected by both hereditary and environmental factors.

Prior studies have identified dozens of genetic loci associated with hip dysplasia in various breeds. The relevance of the loci to disease susceptibility remains an open question. The previously identified loci were reinvestigated at the University of Helsinki, Finland, using a large independent cohort of 1,600 dogs representing ten breeds.

The individual genetic variants at the target loci were determined from blood samples. The standardized radiographic hip phenotypes as assessed by expert veterinarians were obtained from the Finnish Kennel Club.

"Key to the study was the opportunity to utilize the world's largest canine DNA bank maintained by Professor Hannes Lohi's research group. We validated the disease association of 21 loci from 14 chromosomes," says Professor Antti Iivanainen from Faculty of Veterinary Medicine, University of Helsinki, and continues: "Genes related to a protein modification process known as neddylation were overrepresented among the genes residing in the validated loci. This was an interesting new find."

Lea Mikkola, PhD, who wrote her doctoral thesis on the topic at the University of Helsinki, emphasizes that, genetically, hip dysplasia is a highly complex disease.

"A multitude of genes affect the development of the disease. There are marked differences in the genetic background of the disease between breeds, even if certain gene loci associated with it are the same."

In the future, the researchers want to pay closer attention to the loci now identified as relevant to uncover the actual genes underlying hip dysplasia and their variants.

"The findings do not boost disease diagnostics or dog breeding as such, but they can likely be used as part of broader risk profiles in the future. The identified loci also contain new candidate genes associated with hereditary hip dysplasia in humans, which may eventually improve humans' care. More hip dysplasia studies should be conducted, through increased international collaboration, with different dog breeds," notes Professor Hannes Lohi from the Faculty of Veterinary Medicine and the Faculty of Medicine.

As investors set their sights on the mineral resources of the deep seabed, the International Seabed Authority (ISA) is developing regulations that will govern their future exploration and possible exploitation. A new IASS Policy Brief, published in cooperation with the Federal Environment Agency (UBA), presents three recommendations to ensure that future deep seabed mining would be to the common benefit all humankind, as required by international law.

The ecosystems of the deep ocean are complex and provide a wide range of benefits to humankind. Oceans soak up carbon dioxide and act as a natural buffer to global warming in addition to regulating the climate and serving as an important source of food. Yet our knowledge of these vast and remote regions is limited. The authors of this new IASS Policy Brief call on policymakers to adopt a highly cautious and considered approach before approving potentially harmful activities such as deep seabed mining. All potential costs and risks to living and future generations must be considered, the authors argue.

The International Seabed Authority is currently developing regulations to govern the exploration and exploitation of the mineral resources of the international seabed (known as "the Area"). This governance framework will include a so-called 'financial mechanism' for the distribution of any benefits that might arise from seafloor mineral exploitation, as required by the UN Convention of the Law of the Sea (UNCLOS). The current proposal for this mechanism focuses substantially on the financial burden facing contractors and fails to adequately consider the potential environmental and socio-economic harms.

The IASS Policy Brief "A Comprehensive Approach to the Payment Mechanism for Deep Seabed Mining" offers three messages to guide the development of the financial mechanism towards a more sustainable outcome and ensure that any revenues from deep-sea mining are managed on behalf of humankind as a whole:

1) Reflect the risks to the deep-sea environment

The deep ocean is a complex environment that provides numerous ecosystem services. A holistic accounting system based on true cost and natural wealth is needed to capture impacts on ecosystem resilience and identify any potential financial benefits. The financial mechanism should reflect all costs and risks associated with mining in the Area.

2) Be inclusive of stakeholder interests

The payment regime must be designed with foresight and be sufficiently responsive to the concerns and priorities of diverse stakeholders, including indigenous and civil society actors as well as future generations.

3) Deliver optimal returns to Humankind

The payment regime needs to be designed with the interests of Humankind, and in particular of developing countries rather than contractors at its centre. Ensuring optimal returns requires a financial model that delivers best possible cost structures and timing.

The mechanism that keeps arterial blood pressure stable in black and white tegu lizards (Salvator merianae) even as their body temperature varies substantially is more efficient at lower than higher external temperatures, contrary to what has always been believed, and vascular regulation plays a key role in pressure adjustments, according to an article published in PLOS ONE by researchers at the Federal University of São Carlos (UFSCar) in the state of São Paulo, Brazil. The research was supported by FAPESP.

The findings pave the way for more investigation of the physiology of ectothermic animals, which rely on external environmental factors to regulate body temperature, and of novel applications for the method used in the study.

“At some time, practically everyone feels dizzy on getting out of bed too quickly. The baroreflex is the mechanism that compensates for the sudden change in arterial pressure as blood in the lower part of the body, which flows at the same height as the heart while the person is lying down, suddenly has to flow against gravity when they get up. This kind of reflex is a feature of all vertebrates and is affected by temperature. It used to be thought that the increase in metabolism at higher temperatures enhanced the efficiency of the mechanism, but that’s not what we found in our study,” said Renato Filogonio, first author of the article and a researcher in the Department of Physiology at UFSCar’s School of Biological and Health Sciences (CCBS) with a postdoctoral scholarship from FAPESP.

The research was part of a project funded by FAPESP and with Cléo Alcantara Costa Leite, a professor at CCBS-UFSCar, as principal investigator.

“The baroreflex is an important mechanism that keeps pressure stable at the start of the circulatory circuit,” Leite said. “Blood pressure must be high at the start and low at the end of the system because the pressure difference is what drives the blood flow. Without blood flow, there’s no perfusion, which is the passage of blood through the tissues. The baroreflex is an adjustment mechanism, a reflex produced by the autonomic nervous system in all vertebrates to maintain homeostasis in the cardiovascular system.”

No drugs

Previous research showed that the efficiency of the baroreflex in reptiles and amphibians increases as the temperature rises, but heart rate alterations were measured after the use of drugs to raise or lower blood pressure in the studies in question. Here the animals were evaluated without the stress of pharmacological manipulation.

Furthermore, previous studies focused on compensatory baroreflex-related heart rate modulation, known as the cardiac branch, as this can be measured using the pharmacological method. The CCBS-UFSCar researchers analyzed the vascular branch, i.e. vascular resistance and compliance when aortic valves close, to find out if it helped the cardiac branch sustain cardiovascular homeostasis at low temperatures.

“It’s counterintuitive to observe that the cardiac branch of the baroreflex is less efficient at low temperatures because animals lower their heart rate as they cool down and fewer events are therefore needed to regulate blood pressure,” Filogonio said. “In this situation, the cardiac branch should be more efficient, not less, so we assumed there must be other mechanisms besides the cardiac branch that assisted pressure regulation at low temperatures and decided to investigate the vascular branch, which is ignored by most research in this field.”

Diastolic and systolic arterial blood pressure, heart rate, and pulse interval were measured via catheters implanted in 11 tegus and connected to pressure transducers. Measurements were taken at three temperatures: 15 °C, corresponding to mean nocturnal temperature; 35 °C, preferred for daytime activities; and 25 °C, corresponding to the midpoint between these two extremes.

“The results showed that in practice the baroreflex acts more efficiently when the temperature is falling, which is the opposite of what was previously believed. When the temperature is lower, heart rate is lower and compensations can’t rely only on this regulatory branch. That’s what happens in this case. The mechanism is made more efficient by vascular adjustments,” Leite said.

“The study is a good starting point for further research on the vascular branch of the baroreflex, focusing on comparative physiology, evolution or medical aspects, given that the method can easily be implemented in other animals,” Filogonio said.

ORLANDO, Feb. 18, 2021 - University of Central Florida researchers are homing in on the cause of a major disease of sea turtles, with some of their latest findings implicating saltwater leeches as a possible factor.

The disease, known as fibropapillomatosis, or FP, causes sea turtles to develop tumors on their bodies, which can limit their mobility and also their health by interfering with their ability to catch and eat prey.

While the cause of FP isn't known, saltwater leeches have been suspected to play a role due to their frequent presence on areas of sea turtles where FP tumors often develop, such as on their eyes, mouths and flippers.

The results, which were published recently in the journal Diseases of Aquatic Organisms, are the first evidence of a significant association between leeches and the disease in sea turtles, according to the researchers.

"Florida is one of the areas most heavily impacted by FP," says Anna Savage, an associate professor in UCF's Department of Biology and study co-author. "Over the past three decades, approximately half of the green turtle juveniles encountered in the Indian River Lagoon have FP tumors, which is one of the highest rates documented," she says.

Sea turtle health is important because the ancient marine reptiles contribute to healthy oceans and coastlines by grazing and maintaining sea grass beds.

All sea turtles are categorized as threatened or endangered because of threats from pollution, coastal development and fishing, in addition to infectious diseases.

Central Florida's Atlantic coastline hosts about one-third of all green turtle nests in the state and is one of the most important nesting areas in the world for loggerheads.

Knowing if leeches play a role in the disease transmission can help researchers better understand and predict its spread, as well as inform conservation actions, such as leech removal in sea turtle rehabilitation centers.

The Process

The study's lead author and a recent undergraduate alumna of UCF's Biology Department, Leah Rittenburg, spearheaded the research and was responsible for the genetic analyses.

To find out a possible connection between leeches and FP, the researchers documented the presence of leeches on green and loggerhead turtles captured from the Indian River Lagoon and also used genetic analyses to determine if leeches collected from the turtles contained chelonid alphaherpesvirus 5, or ChHV5, the virus most likely responsible for disease development in an individual turtle.

"Our historical data, collected by the UCF Marine Turtle Research Group between 2006 and 2018, revealed that leech parasitism was significantly associated with FP in green turtles but not in loggerhead turtles," Rittenburg says.

"For the genetic analysis, about one-fifth of the leeches we collected were positive for ChHV5, and one leech species trended towards coming from FP-positive turtles, further supporting the hypothesis that leeches may act as ChHV5 transmitters," she says.

Now that the researchers have demonstrated a relationship between FP and leeches, they want to evaluate more specifically if leeches transmit the turtle herpesvirus, which would provide stronger evidence that the virus in an underlying cause of FP.

As climate change takes hold across the Americas, some areas will get wetter, and others will get hotter and drier. A new study of the yellow warbler, a widespread migratory songbird, shows that individuals have the same climatic preferences across their migratory range. The work is published Feb. 17 in Ecology Letters.

"What's amazing is that the birds track similar climates despite the fact that they have migrated thousands of miles," said Rachael Bay, assistant professor in the Department of Evolution and Ecology, College of Biological Sciences at the University of California, Davis. "It seems that individual birds may be adapted to particular climate regimes."

Yellow warblers (Setophagia petechia) breed throughout North America and fly south to Central and South America to spend the winter. A previous study by Bay and colleagues found links between genetic variation and precipitation across North America, suggesting that certain individuals might be adapted to dry conditions while others thrive in wet conditions. In the current study, the authors were able to use genetics to predict where birds captured on their wintering grounds in Central and South America would end up breeding and compare climate patterns in their winter and summer areas.

Individual birds showed preferences for drier or wetter areas, but not for warmer or cooler areas. In other words, birds that bred in relatively dry parts of North America -- such as California's Central Valley -- overwintered in dry parts of South or Central America.

"This is the first demonstration of using individual genetic tracking to link climates across the migratory cycle within a bird species," Bay said.

Impact of climate change

This range of climatic preferences could have consequences for how the birds respond to climate change. Bay speculates that the variation she and her colleagues found might provide the raw material for the species to adapt to changing climate conditions. For example, populations that are adapted to drier conditions might displace those adapted to wetter ones. In fact, Bay and colleagues have already found that population sizes of yellow warblers changed with precipitation across years.

Bay collected data for the study during her postdoctoral research, in collaboration with banding stations and collecting sites in North and South America. Bay and her colleagues are now eager to see whether individuals of other bird species also track climate during migration.

NEW YORK, NY (Feb. 18, 2021)--A new study from Columbia University Vagelos College of Physicians and Surgeons has found that suicide mortality can be reduced by a Federally coordinated approach employing scientifically proven options.

Columbia researchers J. John Mann, MD, Christina A. Michel, MA, and Randy P. Auerbach, PhD, conducted a systematic review, determining which suicide prevention strategies work and are scalable to national levels.

The study, "Improving Suicide Prevention Through Evidence-Based
Strategies: A Systematic Review," was published online in the American Journal of Psychiatry.

The researchers found that screening school children or the general population for those at risk for suicide--the tenth leading cause of death in the U.S. with 48,344 suicide deaths in 2018--have generally not reduced suicide rates.

The outstanding exception is training primary care physicians in depression recognition and medication treatment. That approach prevents suicide, often halving the risk.

While educating the public about depression and suicidal behavior has not been shown to prevent suicidal behavior in adults, educating high school students prevents suicidal behavior, though educating their teachers or parents does not.

"Timing is everything," said Dr. Mann. "Active outreach to psychiatric patients after discharge or following a suicidal crisis both prevent suicidal behavior."

Although medication treatment of depression is subject to a black box warning by the FDA, meta-analyses of FDA and NIMH-funded study data find antidepressants prevent suicide attempts. But standard antidepressants take weeks to work, which has led to increased interest in intravenously administered ketamine, a promising treatment to reduce suicidal ideation in hours that is untested for suicidal behavior prevention.

The study found that the final line of defense in suicide prevention is reducing access to the most lethal methods for suicide. Half of all suicides in the United States involve a firearm that was mostly purchased years earlier, suggesting that improved gun safety in the home should be a national priority.

Combinations of these approaches in health care systems show promise in reducing suicide rates in the U.K., Denmark, and even parts of the U.S.

"It is time to use this knowledge and implement a national suicide prevention plan, " said Dr. Mann.