Culture

Altered blood flow resulting from heart injury switches on a communication cascade that reprograms heart cells and leads to heart regeneration in zebrafish, says a new study in eLife.

The findings reveal signalling pathways important for heart regeneration in zebrafish that are also present in mammals, providing insights that could help scientists find new ways to repair the organ after a heart attack in future.

Heart muscle cells called cardiomyocytes hold on to the capacity to reprogram themselves and alter their fate in response to heart damage. Although several signalling cues are known to be involved in this regeneration activity, it is not well understood how heart injury switches on these pathways to initiate heart cell reprogramming.

"Recent studies suggest that biomechanical forces generated by blood flow can contribute to heart development through modulating cell signalling," explains lead author Manuel Gálvez-Santisteban, a postdoctoral scientist at the University of California, San Diego (UC San Diego), US. "We wanted to explore this further by seeing whether mechanical forces caused by altered blood flow during heart injury also activate these signalling pathways to control heart cell reprogramming and regeneration."

The team first looked at how heart injury affects signalling of an important heart development molecule called Notch in zebrafish. They found that injury-induced Notch activity peaks at 24 hours after injury but diminishes as the heart regenerates, so that by 96 hours it has returned to normal. If Notch is blocked, however, this prevents heart cell growth and stops heart precursor cells from reprogramming and maturing into cells that can replace the damaged cells.

They next explored whether heart injury could alter blood flow forces and, in turn, control injury-induced Notch signalling. Klf2a is a molecule that responds to changes in blood flow and switches on certain genes in response. In regions of the injured heart where blood flow was most disrupted, they found that levels of Klf2a were increased. In addition, they found that levels of Klf2a overlapped with the levels of Notch.

Further experiments revealed that, when mutated, Trpv4 - a molecule that is known to 'sense' changes in blood flow and can switch on the gene for Klf2a - led to a reduced amount of genes that drive heart cell growth and fewer cells maturing to replace the damaged tissue. Additionally, the team found that changes in blood flow controls heart cell reprogramming and growth via another two molecules, BMP and Erbb2. As these molecules are important for heart regeneration in mammals, the changes observed in the zebrafish may also hold true for other organisms, including humans.

"Our findings show how the heart senses and adaptively responds to environmental changes caused by injury, and provide insight into how flow-mediated mechanisms may regulate heart cell reprogramming and heart regeneration," concludes senior author Neil Chi, Professor of Medicine at UC San Diego. "Future studies are now needed to explore whether blood flow forces may affect mammals such as mice and to reveal new mechanisms that could take us a step towards being able to regenerate the human heart."

BLOOMINGTON, Ind. -- Psychologists at Indiana University who study how people pick their spouses have turned their attention to another important relationship: choosing a canine companion.

Their work, published in the journal Behavior Research Methods, recently found that, when it comes to puppy love, the heart doesn't always know what it wants.

The results are based upon data from a working animal shelter and could help improve the pet adoption process.

"What we show in this study is that what people say they want in a dog isn't always in line with what they choose," said Samantha Cohen, who led the study as a Ph.D. student in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences. "By focusing on a subset of desired traits, rather than everything a visitor says, I believe we can make animal adoption more efficient and successful."

As a member of the lab of IU Provost Professor Peter Todd, Cohen conducted the study while also volunteering as an adoption counselor at an animal shelter. Todd is co-author on the study.

"It was my responsibility to match dogs to people based on their preferences, but I often noticed that visitors would ultimately adopt some other dog than my original suggestion," Cohen said. "This study provides a reason: Only some desired traits tend to be fulfilled above chance, which means they may have a larger impact on dog selection."

The researchers categorized dogs based upon 13 traits: age, sex, color, size, purebred status, previous training, nervousness, protectiveness, intelligence, excitability, energy level, playfulness and friendliness. They surveyed the preferences of 1,229 people who visited dogs at an animal shelter, including 145 who decided to make an adoption.

A similar disconnect has been found in research on speed dating led by Todd, who has shown that people's stated romantic preferences tend not to match the partners they choose.

Although most participants in the dog adoption study listed many traits they preferred -- with "friendliness" as the most popular -- they ultimately selected dogs most consistent with just a few preferences, like age and playfulness, suggesting that others, like color or purebred status, exerted less influence on decision-making.

There was also another parallel to the world of dating. In short: Looks matter.

"As multiple psychologists have shown in speed-dating experiments, physical attractiveness is very important," Cohen said. "Most people think they've got a handsome or good-looking dog."

In the article, Cohen outlines some challenges facing aspiring dog-owners:

Focusing on "the one": Although adopters often came to the shelter with a vision of the perfect pet, Cohen said many risked missing a good match due to overemphasis on specific physical and personality traits. For example, an adopter who wants an Irish wolfhound because they're large, loyal and light shedders might fail to consider a non-purebred with the same qualities.

Mismatched perceptions: Surprisingly, adopters and shelters often used different traits to describe the same dog. These included subjective traits, such as obedience and playfulness, as well as seemingly objective traits, such as color.

Missed signals: People who have never had a dog may not grasp the implications of certain behaviors. A dog seen as "playful" at the shelter may come across as "destructive" in a small home, for example.

Performance anxiety: Shelters are high-stress environments for dogs, whose personalities may shift when they're more relaxed at home. Picking a dog based upon personality at the shelter is akin to choosing a date based on how well they perform while public speaking, Cohen said.

To improve pet adoptions, Cohen said animal shelters need to know that people tend to rely on certain traits more strongly when choosing a dog, which might make it easier to match adopters to dogs. She also suggested shelters consider interventions, such as temporary placement in a calmer environment, to help stressed or under-socialized dogs put their best paw forward, showing their typical level of desirable traits, such as friendliness.

Finally, Cohen advises caution about online adoption, since adopters are dependent upon someone else's description of the dogs. She suggests users limit their search criteria to their most desired traits to avoid filtering out a good match based upon less important preferences.

The study was supported in part by an IU Graduate and Professional Student Government Research Award.

Journal

Behavior Research Methods

DOI

10.3758/s13428-019-01253-x

Main Findings:

Universal college admission testing in the state of Virginia could increase the number of high school graduates with test scores competitive for admission at universities in the state by as much as 40 percent--and at the most selective institutions, nearly 20 percent--with larger increases for low-income students.

In addition, policies that specifically target students with relatively high demonstrated academic performance have the potential to achieve many of the gains of universal testing in Virginia--capturing 89 percent of those non-takers predicted to achieve competitive test scores--at a lower cost.

The findings are consistent with results from other recent studies of policy changes in states like Colorado, Illinois, Kentucky, Tennessee, Maine, and Michigan, which find that universal college admission test mandates increase the pool of students scoring at a level consistent with college-readiness.

Details:

Using data from the Virginia Longitudinal Data System, researchers at the University of Virginia examined how the number of students scoring at different levels on college admission tests would change under different policies, including a statewide mandatory college admission testing policy, as well as initiatives that encourage test-taking among targeted groups of students with relatively strong academic achievement.

While 25 states have adopted agreements with test providers to offer either the ACT or the SAT to all students, states like Virginia leave decisions about student participation in college testing to district policy and parental discretion. Missed college admission tests produce a substantial reduction in the pool of students positioned to apply to four-year postsecondary institutions.

In 2014, 56 percent of Virginia high school graduates took the SAT, but under a universal testing mandate, the authors found that approximately 32,900 additional students would have taken the SAT that year. While many of the additional test-takers under universal test-taking are unlikely to score at a level consistent with readiness for a four-year college, 24 percent of those test takers are predicted to have a combined score at or above 1000 on the math and verbal sections.

The study authors explain that potentially high-scoring non-takers are disproportionately economically disadvantaged. They predict that a universal testing mandate would increase the number of low-income non-black students scoring above 1000 on the SAT by over 80 percent, while the corresponding number of low-income black students is just over 40 percent, and for all other students, approximately 30 percent. Potentially high-scoring non-takers are also disproportionately likely to reside in small districts.

"Our work reinforces the work of other studies which show that there are a substantial number of students well-positioned to enroll in college who miss the key step of taking a college admission test," said study coauthor Sarah E. Turner, a professor of economics and education at the University of Virginia's Curry School of Education. "Students from low-income families and those in relatively small districts are most likely to be absent from college admission testing."

The authors also found that it may be possible to achieve significant gains in college admission test-taking among college-ready students without incurring the full costs of universal testing at the state or district level. Had all students in the state who scored at or above the 40th percentile on Virginia's state 8th-grade Standards of Learning exams taken the SAT, the authors estimate that the tested population would have included about 89 percent of the observed non-takers predicted to score 1000 or higher.

"Mandatory testing is not free; costs include fees, time loss, and distraction for those students who are unlikely to gain from the additional testing, and the increased burden of administering tests for school counselors and administrators," said Turner. "Evidence-based targeted outreach efforts, combined with interventions designed to reduce financial and administrative barriers for students and schools, may generate a significant increase in test-taking among the college-ready without incurring the financial and administrative burden of statewide testing mandates."

While a number of universities across the country have adopted "test-optional" admission policies, the authors note that universal testing would still be of value to students, teachers, administrators, and policymakers because most four-year colleges require admission testing, test-optional schools tend to be small, and the exams relay important information to students.

"Admission tests provide critical information to students in two ways: first, the score can help a student create a well-matched application portfolio, and second, by taking an admission test, the student can participant in programs such as the College Board's Student Search Service, which help colleges, scholarship programs, and other parties identify and reach out to students," said Emily Cook, a coauthor and Ph.D. candidate at the University of Virginia.

The authors addressed whether higher education institutions would be able to accommodate a substantial increase in the pool of students. They note that the most selective universities in Virginia are engaged in proactive efforts to increase the representation of low-income students. While these institutions might not increase total capacity in response, one would expect that the representation of low-income students would increase, making the institutions more meritocratic. Other public universities in the state have demonstrated considerable elasticity in enrollment over time, while small private colleges would welcome increased enrollment.

The authors emphasize that admission tests are incomplete indicators of "college readiness" or of whether a student is "well-matched" or "admission-eligible" at a particular college.

"College admission test-taking is but one gateway step in the process of college choice. Guidance about whether and when to take college admission tests ideally would be situated in comprehensive and personalized interventions to help high school students make better informed postsecondary choices," said Turner. "Nevertheless, our findings provide further evidence that increasing the number of students taking admission tests can be beneficial."

SAN ANTONIO -- June 25, 2019 -- Inspired by movie streaming services such as Netflix or Hulu, a Southwest Research Institute scientist developed a technique to look for stars likely to host giant, Jupiter-sized planets outside of our solar system. She developed an algorithm to identify stars likely to host giant exoplanets, based on the composition of stars known to have planets.

"My viewing habits have trained Netflix to recommend sci-fi movies I might like -- based on what I've already watched. These watched movies are like the known star-exoplanet systems," said Dr. Natalie Hinkel, a planetary astrophysicist at SwRI. "Then, the algorithm looks for stars with yet-undetected planets -- which are comparable to movies I haven't watched -- and predicts the likelihood that those stars have planets."

Just as a cake recipe includes some basic ingredients, stars need certain elements to make giant planets. Scientists can use spectroscopy, or the way that light interacts with atoms in the star's upper layers, to measure a star's composition, which includes materials such as carbon, magnesium and silicon. These elements are the ingredients for making a planet, because stars and planets are made at the same time and from the same materials. However, while there are a lot of ingredients in your kitchen, not all of them belong in a cake. This is where the movie-streaming algorithm comes in, predicting planets based on the elements in stars.

"We found that the most influential elements in predicting planet-hosting stars are carbon, oxygen, iron and sodium," Hinkel said. "The funny thing was that we were not expecting sodium to be a key ingredient for predicting a planet. But it must be an important link between stars and planets, because it kept popping up, even when looking at different combinations of elements."

Hinkel used the Hypatia Catalog, a publicly available stellar database she developed, to train and test the algorithm. It's the largest database of stars and their elements for the population within 500 light years of our Sun. At last count, Hypatia had stellar element data for 6,193 stars, 401 of which are known to host planets. The database also catalogs 73 stellar elements from hydrogen to lead.

The algorithm, which will be publicly available, has looked at more than 4,200 stars and assessed their likelihood of hosting planets, based solely on the elements, or ingredients, within the star. In addition, Hinkel looked at different combinations of those ingredients to see how they influenced the algorithm.

Hinkel's team identified around 360 potential giant planet host stars that have more than a 90 percent probability of hosting a giant exoplanet. "We were excited, so we used archival telescope data to search for any signs of planets around these likely host stars," Hinkel said. "We identified possible Jupiter-sized planets around three stars predicted by the algorithm!"

When asked about how reliable her algorithm is, she explained that "we don't have any true-negatives in our data -- that is, stars that we know don't have planets -- so we 'hid' some known planet-hosting stars in the data to see what their prediction score would be like. On average they scored more than 75 percent, which is great! That's probably a higher average than me liking the sci-fi movies Netflix picks for me."

Moving forward, these findings could revolutionize target star selections for future research and clinch the role elements play in giant planet detection and formation. Hinkel is the lead author of the paper "A recommendation algorithm to predict giant exoplanet host stars using stellar elemental abundances" that will be published in an upcoming issue of the Astrophysical Journal.

For more information, see https://www.swri.org/astrophysics.

New Rochelle, NY, June 25, 2019--Researchers have shown that higher intelligence and younger age are predictors of greater cognitive recovery 2-5 years post-mild to severe traumatic brain injury (TBI). In contrast, injury severity, as measured by the duration of post-traumatic amnesia, was not associated with greater or worse long-term cognitive recovery, as supported by a study published in Journal of Neurotrauma, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here (https://www.liebertpub.com/doi/full/10.1089/neu.2019.6430) to read the full-text article on the Journal of Neurotrauma website through July 25, 2019.

"Cognitive Reserve and Age Predict Cognitive Recovery Following Mild to Severe Traumatic Brain Injury" is the title of the study written by Jennie Ponsford, Monash University-Melbourne and coauthors from Monash University and Epworth HealthCare, Melbourne, Australia. In this longitudinal study, the researchers were not surprised to find that all of the TBI patients performed significantly worse on initial measures of intelligence (IQ tests, including assessments of reading, attention, memory, and executive function) after the injury compared to a healthy control group. Within the TBI group, shorter duration of post-traumatic amnesia, younger age, and higher IQ were associated with better initial cognitive performance.

John Povlishock, PhD, Editor-in-Chief of Journal of Neurotrauma, notes that: "This is an extremely important study in that it confirms the long-held clinical impression that age and premorbid IQ are important factors in determining outcome from traumatic brain injury. As noted by the authors, these findings strongly endorse the role of cognitive reserve and age in the cognitive recovery seen following traumatic brain injury which, as such, should help inform prognostication and rehabilitation."

Columbia researchers have created a way to grow human hair in a dish, which could open up hair restoration surgery to more people, including women, and improve the way pharmaceutical companies search for new hair growth drugs.

It is the first time that human hair follicles have been entirely generated in a dish, without the need for implantation into skin.

Using 3D-Printing to Stop Hair Loss

For years it's been possible to grow mouse or rat hairs in the lab by culturing cells taken from the base of existing follicles.

"Cells from rats and mice grow beautiful hairs," Christiano says. "But for reasons we don't totally understand, human cells are resistant."

To break the resistance of human hair cells, Christiano has been trying to create conditions that mimic the 3D environment human hair cells normally inhabit. The lab first tried creating little spheres of cells inside hanging drops of liquid. But when the spheres were implanted in mice, the results were unpredictable: The cells from some people created new hair while others didn't.

3D Printing Creates Patterned Hair Follicles

In the new study, Christiano's team exploited the unique capability of 3D printers to create a more natural microenvironment for hair follicle growth.

The researchers used 3D printing to create plastic molds with long, thin extensions only half a millimeter wide. "Previous fabrication techniques have been unable to create such thin projections, so this work was greatly facilitated by innovations in 3D printing technology," says Erbil Abaci, PhD, first author of this study.

After human skin was engineered to grow around the mold, hair follicle cells from human volunteers were placed into the deep wells and topped by cells that produce keratin. The cells were fed a cocktail of growth factors spiked with ingredients, including JAK inhibitors, that the lab has found stimulates hair growth.

After three weeks, human hair follicles appeared and started creating hair.

Hair Farms Could Expand Availability of Hair Restoration

Though the method needs to be optimized, engineered human hair follicles created in this way could generate an unlimited source of new hair follicles for patients undergoing robotic hair restoration surgery.

Hair restoration surgery requires the transfer of approximately 2,000 hair follicles from the back of the head to the front and top. It is usually reserved for male patients whose hair loss has stabilized and who have enough hair to donate.

"What we've shown is that we can basically create a hair farm: a grid of hairs that are patterned correctly and engineered so they can be transplanted back into that same patient's scalp," Christiano says.

"That expands the availability of hair restoration to all patients--including the 30 million women in the United States who experience hair thinning and young men whose hairlines are still receding. Hair restoration surgery would no longer be limited by the number of donor hairs."

The engineered follicles also could be used by the pharmaceutical industry to screen for new hair growth drugs. Currently, high throughput screening for new hair drugs has been hampered by the inability to grow human hair follicles in a lab dish. No drugs have been found by screening; the only two approved for the treatment of pattern hair loss--finasteride and minoxidil--were initially investigated as treatments for other conditions.

The team hopes that cultured hair farms will open up the ability to perform high throughput drug screens to identify new pathways that influence hair growth.

Research into the hearts of zebrafish, a pet shop staple marked by their eponymous stripes, has shed light on ways the human heart muscle could be healed following damage.

A team of researchers led by Neil Chi, MD, PhD, professor of medicine at University of California San Diego School of Medicine, and Manuel Galvez-Santisteban, PhD, a postdoctoral scientist working alongside him, have pinpointed a signaling pathway in zebrafish heart cells that leads to the regeneration of damaged tissue. The findings are published in the June 25, 2019 issue of eLife.

When the hearts of zebrafish are injured, altered blood flow sends a signal to reprogram the muscle and regenerate their cells. "Our findings show how the heart senses and adaptively responds to environmental changes caused by injury," said Chi, "and provide insight into how flow-mediated mechanisms may regulate heart cell reprograming and heart regeneration."

These same signaling pathways also exist in mammals, suggesting the findings could provide insights and perhaps ways to repair damaged tissue in humans after a heart attack or similar catastrophic cardiac events.

Researchers commonly use zebrafish -- a small tropical minnow fish -- to study blood and muscle development because they employ many of the same mechanisms to make cells that humans do, but they are translucent as they develop, which makes it much easier to chronicle cell development and function.

Chi and colleagues focused on cardiomyocytes, cardiac muscle cells that possess the ability to contract and maintain the pump function of the heart. However, in order for cardiomyocytes to reprogram and regenerate the heart after injury, cardiomyocytes rely upon signaling cues activated by changes in blood flow.

Researchers monitored a specific heart development molecule called Notch in zebrafish to see how it reacted after injury to a fish's heart. They found that Notch activity peaked one day after injury, but then dipped as the heart muscle regenerated. Within four days, damaged fish hearts were back to normal. When researchers blocked Notch, however, heart cell growth in the fish was also blocked, cells were unable to reprogram themselves and the damage was not repaired.

The scientists then looked at blood flow after a heart injury to see if injury had a direct effect on that blood flow and, in turn, activation of Notch. Their focus this time was on Klf2a, a molecule that activates certain genes when blood flow changes. The more blood flow was disrupted, the researchers found, the higher the levels of Klf2a.

The scientists also identified three other molecules -- Trpv4, BMP and Erbb2 -- that appeared connected to heart reprogramming and blood flow shifts. Levels and activity in all three changed in response to heart injury.

Chi said the next step is to take their investigation out of the water and onto land.

"Future studies are now needed to explore whether blood flow forces may affect mammals, such as mice, and to reveal new mechanisms that could take us closer to one day being able to regenerate the human heart," said Chi.

Ion channels are pores in the membrane of cells or cell organelles. They allow positively or negatively charged particles, so-called ions, to be transported across the membrane. Biochemists at Johannes Gutenberg University Mainz (JGU) have now succeeded in imaging an important regulatory region of the human TRPML2 calcium ion channel at high resolution, an area of the channel shaped like a large ring on one side of the membrane. This ring acts like a doorman, deciding whether ions can move through the channel. "Our study has revealed the structure of the ring, which is also called the extracytosolic/lumenal domain (ELD), in human TRPML2 channels, and also that it is this domain that is responsible for the channel's interaction with calcium," said Professor Ute Hellmich of the JGU Institute of Pharmacy and Biochemistry - Therapeutical Life Sciences. Depending on the pH value, the calcium ions can open or block the channel, and therefore control their transport across cellular membranes.

Hellmich's research group investigated which structural properties of the ion channel ring are responsible for allowing calcium ions to pass. "Calcium is an important cellular messenger that also plays a role in many diseases," explained Hellmich. The element performs numerous tasks in the body, including regulating enzymes and helping with membrane fusion.

TRPML2, short for transient receptor potential mucolipin 2, is an ion channel of the mucolipin subfamily of TRP channels involved in sensory perception in humans. TRPML2 plays a role in the immune response to infections and increases the infectivity of Zika and dengue viruses. In addition, mutations in TRPML ion channels can result in blindness, deafness, and neurological damage in humans.

The pH value is crucial for ion channel activity

As Hellmich makes clear, ion channels are not simple holes. They can be actively opened and closed. This, in turn, activates and controls cellular pathways. "We have now discovered that binding of calcium to the TRPML2 extracytosolic/lumenal domain on top of the channel is dependent on pH," stated Kerstin Viet, first author of the paper in the scientific journal Structure. This research was part of her Master's thesis and resulted in her being awarded the Adolf Todt Foundation Prize.

At a higher pH value of around 7, found at the outside of the cell, the calcium ions can bind to the ring and thus block it. Conversely, the calcium ions are no longer able to block the opening at a lower pH typical of certain intracellular compartments. "The ring acts like a gatekeeper for the rest of the ion channel," said Viet.

This therefore regulates the activity of the channel: It is important that the ion channel is only activated within the cell, where the pH is generally low; in effect the channel is only opened when a particular cellular mechanism signals that it requires calcium. Unprompted activation on the cell surface could well result in damage to the cell. "The regulation mechanism is clever. It is also relevant, for example, to how the cell reacts to a viral infection," said Hellmich, adding that the entire process just when and how an ion channel is opened or closed is not yet fully understood. The other two ion channels of the human mucolipin subfamily, TRPML1 and TRPML3, also have a similar doorkeeper ring. The study's results therefore make it possible for the first time to compare all three subtypes.

This first identification of the structure of the ion channel TRPML2 was achieved by the Membrane Biochemistry group of Professor Ute Hellmich working in close cooperation with the JGU Pharmacy group of Professor Tanja Schirmeister. They also collaborated with scientists from the European Synchrotron Radiation Facility (ESRF) in Grenoble, and the working groups of Professor Nina Morgner of Goethe University Frankfurt and Professor Hermann Schindelin of Julius-Maximilians-Universität Würzburg.

The identification of specific neural signatures can help develop specific biomarkers and personalized treatments for Huntington's disease.

Research results underscore the value of multimodal approaches in the characterization of heterogeneous patterns of neurodegeneration

Researchers from the Cognition and Brain plasticity group of Bellvitge Biomedical Research Institute (IDIBELL) and the Institute of Neurosciences of the University of Barcelona (UBNeuro), with the collaboration of Radboud University in the Netherlands, have identified two specific patterns of cerebral disorders underlying two clinical profiles of Huntington's disease. The study, published in "Neuroimage: Clinical", can help develop specific biomarkers and personalized treatments for each profile of this rare disease.

The research, led by doctors Estela Càmara and Ruth de Diego, with predoctoral researcher Clara García Gorro as first author, widens the current knowledge about Huntington's disease. This neurodegenerative genetic disease is characterized by associated motor, cognitive and psychiatric deficits, but there is "large symptomatic heterogeneity among patients, so we decided to investigate the neurobiological basis of these differences to see if we could link it to the clinical profiles", Dr de Diego, ICREA researcher, explains.

For the study, researchers used a multimodal fusion analysis technique that combines different types of magnetic resonance imaging modalities. "This type of analysis allows us to integrate the information of the different modalities and thus study the brain and the pattern of neurodegeneration in a more global way, making the identification of more subtle cerebral alterations possible", Dr Càmara explains.

The analysis of the relationship between the symptoms of the disease and the measures of the structural alterations of the white and gray matter allowed the researchers to establish that the cognitive and motor symptoms shared a common neurobiological basis while the psychiatric domain had a differentiated neural signature.

"Cognitive and motor symptoms were associated together with a pattern of reduction in gray matter, cortical thickness and the integrity of the white substance in brain regions responsible for the execution of movements and the processing of different cognitive functions, such as memory, planning or visual-spatial processing. Depressive symptoms, on the other hand, were associated with a very different pattern, characterized by a lower thickness in the cerebral cortex in regions responsible for the emotional processing typically associated with psychiatric alterations", Dr García Gorro adds.

These results provide a new vision of a disease traditionally considered as a uniform entity and promote new lines of research that take into account these individual qualitative differences. "Our results are especially relevant in the context of clinical trials, as they could be used to define specific biomarkers for each symptomatological profile, even before clinical signs appea","says Dr. Càmara, adding that "besides, we are opening a door to personalized medicine in Huntington's disease, as findings increase the likelihood of finding individualized treatments aimed at specific cognitive, motor, and psychiatric disorders."

Vienna, 25 June 2019: Ovarian reserve, a term widely adopted to reflect the number of resting follicles in the ovary and thus a marker of potential female fertility, has been found in a large-scale study to be adversely affected by high levels of air pollution.

Results from the Ovarian Reserve and Exposure to Environmental Pollutants (ORExPo study), a 'real-world data' study using hormone measurements taken from more than 1300 Italian women, are presented today at the Annual Meeting of ESHRE by first investigator Professor Antonio La Marca from the University of Modena and Reggio Emilia, Italy.

Behind the study lay emerging evidence that many environmental chemicals, as well as natural and artificial components of everyday diet, have the potential to disturb the physiological role of hormones, interfering with their biosynthesis, signaling or metabolism. The hormone in this case, anti- Müllerian hormone or AMH, is secreted by cells in the ovary and is now widely recognised as a reliable circulating marker of ovarian reserve.(1)

'The influence of age and smoking on AMH serum levels is now largely accepted,' explains Professor La Marca, 'but a clear effect of environmental factors has not been demonstrated so far.'

The ORExPo study was in effect an analysis of all AMH measurements taken from women living in the Modena area between 2007 and 2017 and assembled in a large database. These measurements were extended to a computing data warehouse in which AMH levels were linked to patients' age and residential address. The analysis was completed with environmental data and a 'geo-localisation' estimate based on each patient's residence. The assessment of environmental exposure considered daily particulate matter (PM) and values of nitrogen dioxide (NO2), a polluting gas which gets into the air from burning fuel.

Results from the 1463 AMH measurements collected from 1318 women firstly showed - as expected - that serum AMH levels after the age of 25 were inversely and significantly related to the women's age. However, it was also found that AMH levels were inversely and significantly related to environmental pollutants defined as PM10, PM2.5 and NO2. This association was age-independent.

These results were determined by dividing the full dataset into quartiles reflecting PM10, PM2.5 and NO2 concentrations. The analysis found significantly lower levels of AMH in the fourth quartile than in the lowest quartiles, which, said Professor La Marca, 'again confirms that independently of age the higher the level of particulate matter and NO2, the lower the serum concentration of AMH'. The lowest concentration of AMH - reflecting 'severe ovarian reserve reduction' - was measured in subjects who were exposed to levels of PM10, PM2.5 and NO2 above 29.5, 22 and 26 mcg/m3 respectively. Nevertheless, these were values well below the upper limits recommended by the EU and local authorities (ie, 40, 25 and 40 mcg /m3 respectively).

Severe ovarian reserve reduction, as reflected in a serum AMH concentration below 1 ng/ml, was significantly more frequent in the fourth quartile than in the first three quartiles for PM10 (62% vs 38%), for PM2.5, and for NO2. 'This means by our calculations,' said Professor La Marca, 'exposure to high levels of PM10, PM2.5 and NO2 increases the risk of having a severely reduced ovarian reserve by a factor between 2 and 3.'

While noting that this study again confirms that age is the most important determinant of AMH concentration in women, Professor La Marca emphasised that other factors such as smoking, body weight and long-term hormonal contraception are already recognised as having an impact on AMH. Similarly, he said, environmental pollutants may also have a significant effect in determining circulating levels of AMH. 'Living in an area associated with high levels of air pollutants in our study increased the risk of severely reduced ovarian reserve by a factor of 2 or 3,' he said.

The thymus is the powerhouse producing the immune system's T cells, which combat infection in our body. Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.

Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in motion this loss and the mechanisms behind this.

Their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.

Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus - a small organ located below the collarbone - degenerated from puberty onwards. However, the mechanisms underlying this were unclear.

"Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function. As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections," she said.

"It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells."

The study showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.

"This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells. This leads to a reduced capacity to support the production of T cells," Associate Professor Chidgey said.

"This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing. By doing this we can now focus on how to reverse that and 'switch on' the thymus again, even just transiently, to replenish our T cell diversity," she said.

"We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration."

Researchers from the University of Seville, the Seville Biomedicine Institute and Lund University (Sweden) have been able to describe how the body responds to a component present in the brain in Alzheimer's patients. This discovery opens new pharmacological possibilities for the control of brain inflammation and its harmful effects.

Specifically, the researchers have revealed the fundamental role that the protein Galectin-3 plays in the regulation of immune response associated with the peptide Amyloid beta, which is responsible for the amyloid and senile plaques that are present in the brains of Alzheimer's sufferers. For that reason, they have analysed both post-mortem samples from patients diagnosed with Alzheimer's and samples from transgenic rats that emulate the disease. In both cases, they have shown that the microglia that are activated (set of cells that measure immune response in the brain) show high levels of galectin-3.

The researchers have carried out genetic studies that show that certain mutations of the gene of Galectin-3 are associated with a higher risk of suffering from Alzheimer's. In their work, they have shown how the activated microglia release galectin-3 in response to the fibrous form of the Amyloid beta peptide, so playing an essential regulatory role in the activation of the microglia.

The researchers have shown that transgenic rats with Alzheimer's that have been genetically modified so that they are not able to synthesize galectin-3 demonstrate diminished inflammatory response and preserved cognitive response. The researchers have shown for the first time that Galectin-3 has the capacity to join to the microglial receptor TREM2, which has recently been shown to play an important role in the pathology of Alzheimer's given that the appearance of certain mutations associated with this gene significantly increase the risk of suffering the illness.

OAK BROOK, Ill. - When used with a common heart scan, machine learning (ML), a type of artificial intelligence, does better than conventional risk models at predicting heart attacks and other cardiac events, according to a study published in the journal Radiology.

Heart disease is the leading cause of death for both men and women in the United States. Accurate risk assessment is crucial for early interventions including diet, exercise and drugs like cholesterol-lowering statins. However, risk determination is an imperfect science, and popular existing models like the Framingham Risk Score have limitations, as they don't directly consider the condition of the coronary arteries.

Coronary computed tomography arteriography (CCTA), a kind of CT that gives highly detailed images of the heart vessels, is a promising tool for refining risk assessment--so promising that a multidisciplinary working group recently introduced a scoring system for summarizing CCTA results. The decision-making tool, known as the coronary artery disease reporting and data system (CAD-RADS), emphasizes stenoses, or blockages and narrowing in the coronary arteries. While CAD-RADS is an important and useful development in the management of cardiac patients, its focus on stenoses may leave out important information about the arteries, according to study lead author Kevin M. Johnson, M.D., associate professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Conn.

Noting that CCTA shows more than just stenoses, Dr. Johnson recently investigated an ML system capable of mining the myriad details in these images for a more comprehensive prognostic picture.

"Starting from the ground up, I took imaging features from the coronary CT," he said. "Each patient had 64 of these features and I fed them into a machine learning algorithm. The algorithm is able to pull out the patterns in the data and predict that patients with certain patterns are more likely to have an adverse event like a heart attack than patients with other patterns."

For the study, Dr. Johnson and colleagues compared the ML approach with CAD-RADS and other vessel scoring systems in 6,892 patients. They followed the patients for an average of nine years after CCTA. There were 380 deaths from all causes, including 70 from coronary artery disease. In addition, 43 patients reported heart attacks.

Compared to CAD-RADS and other scores, the ML approach better discriminated which patients would have a cardiac event from those who would not. When deciding whether to start statins, the ML score ensured that 93 percent of patients with events would receive the drug, compared with only 69 percent if CAD-RADS were relied on.

"The risk estimate that you get from doing the machine learning version of the model is more accurate than the risk estimate you're going to get if you rely on CAD-RADS," Dr. Johnson said. "Both methods perform better than just using the Framingham risk estimate. This shows the value of looking at the coronary arteries to better estimate people's risk."

If machine learning can improve vessel scoring, it would enhance the contribution of noninvasive imaging to cardiovascular risk assessment. Additionally, the ML-derived vessel scores could be combined with non-imaging risk factors such as age, gender, hypertension and smoking to develop more comprehensive risk models. This would benefit both physicians and patients.

"Once you use a tool like this to help see that someone's at risk, then you can get the person on statins or get their glucose under control, get them off smoking, get their hypertension controlled, because those are the big, modifiable risk factors," he said.

Dr. Johnson is currently working on a paper that takes results from this study and folds them into the bigger picture with non-imaging risk factors.

"If you add people's ages and particulars like smoking, diabetes and hypertension, that should increase the overall power of the method and improve the overall results," he said.

Memory impairment and mood changes are typically observed in patients with Alzheimer's disease but what disturbs these neuronal functions is unclear. Some researchers have proposed that alterations in the production of new neurons in the brain, or neurogenesis, may be involved; however, whether neurogenesis happens in humans, much less those with Alzheimer's disease, has been debated. A discovery published today in the journal Cell Reports provides a possible explanation for this debate and may shed light on what happens in Alzheimer's disease.

Working with animal models of Alzheimer's disease, a team led by researchers at Baylor College of Medicine discovered that seizures that are associated with the disease both in animal models and humans alter the normal dynamics of neurogenesis in adult brains. Administering anti-seizure medication restored neurogenesis and improved performance in a spatial discrimination task.

"Whether neurogenesis is altered at all in patients with Alzheimer's disease is a controversial topic in the field. While some groups present evidence supporting a decrease in neurogenesis, others claim that it increases or that there is no change," said corresponding author Dr. Jeannie Chin, associate professor of neuroscience at Baylor College of Medicine. "Working with mouse models of the disease we have identified a mechanism that we propose may integrate all of these various findings."

Neurogenesis is altered in animal models of Alzheimer's disease

Scientists have found that in normal mice neurogenesis occurs throughout life and decreases as the animals age. Neurogenesis is a multistep process that begins with the proliferation of neural stem cells, continues with the production of intermediary cells such as progenitor cells, and ends with new neurons being born. Findings from Chin's collaborators demonstrated that the pool of neural stem cells in the brain is finite. After a certain number of cell divisions, a neural stem cell stops being a stem cell, and is not replaced. Consequently, throughout the life of normal mice, the number of neural stem cells progressively decreases.

"In this study, we compared the process of neurogenesis in normal mice with that in our mouse model of Alzheimer's disease, and found that the processes are similar but, when seizures occur in mice with the disease, neurogenesis is acutely stimulated," said first author Chia-Hsuan Fu, neuroscience graduate student in the Chin lab.

The researchers observed that early in the disease when seizures begin, there is an increase in neurogenesis as neural stem cells are stimulated to divide. As the disease progresses and seizures recur stimulating more neural stem cells, the cell pool is depleted faster than in animals without the disease, and neurogenesis decreases. Later in the disease, when the pool of cells is exhausted, there is very little neurogenesis.

"These findings indicate that in the mouse model of the disease, seizures accelerate the normal process of neurogenesis. The pool of neural stem cells that generates new neurons is exhausted faster than in mice without the condition," Fu said.

"Although our study was conducted in mice, we suggest that the level of neurogenesis in a human brain with Alzheimer's disease may similarly depend on the stage of the disease, being higher at very early stages and then declining more rapidly than normal as disease continues," Chin said. "The level of neurogenesis would depend on when during the disease the samples were taken. These findings may explain the seemingly contradictory findings about whether and how neurogenesis is affected in Alzheimer's disease."

Chin also speculated that the mechanism they discovered may also help explain controversial studies regarding whether adult neurogenesis, which has primarily been studied in rodents, occurs at all in humans. "Depending on the medical history of the patients from whom the brain samples were obtained, they might have high, low or even nonexistent levels of neurogenesis at the time of death," Chin said.

Interestingly, when the researchers treated their mouse model with anti-seizure drugs they normalized the dynamics of neurogenesis. Further, animals treated with anti-seizure drugs improved their performance in a spatial discrimination task when compared with non-treated mice. Taken together, the findings suggest that the seizures are deeply connected to the alterations in neurogenesis and cognitive functions both in Alzheimer's disease and epilepsy.

They were expecting that accumulation of amyloid-beta in the brain, a major hallmark of the disease, would also affect neurogenesis as suggested by experiments in the labs of other groups, Chin said. However, the observations of Chin and her colleagues suggest that the effect of seizures on neurogenesis seems to be larger than that of amyloid-beta accumulation.

The finding that anti-seizure medications can normalize the process of neurogenesis in a model of the disease suggests that it also might be possible to do so in human patients.

"However," Chin remarks, "more work is needed and caution is necessary because the medication would have to be administered early in the disease, just as seizures are beginning to occur."

The Levänluhta water burial site, dating back to the Iron Age (300-800 CE), is one of Finland's most famous archaeological sites. Nearly one hundred individuals, mainly women or children, were buried in a lake located at Isokyrö in SW Finland, during the Iron Age. Some of the deceased were accompanied by arm rings and necklaces made out of copper alloy, bronze or brass.

Style of jewellery domestic but material from abroad

"The origin of the metals used in these pieces of jewellery was determined on the basis of the objects' geochemical and lead isotope compositions. The jewellery of the deceased is stylistically typical Finnish Iron Age jewellery, making it probable that they were cast in local workshops. However, the metals used to make these objects are unlikely to be originally from the region, since copper ores had not yet been discovered here during the Iron Age," says Elisabeth Holmqvist-Sipilä, a postdoctoral researcher.

Up to now, archaeologists have assumed that copper used in the Iron Age came mainly from the copper ores discovered in southern Scandinavia. However, this interpretation has in recent years been called into question, since the copper found in archaeological metal discoveries in Sweden has also been determined to be imported.

In a study conducted in collaboration between archaeologists at the University of Helsinki and the Geological Survey of Finland, the origin of the bronze and brass jewellery found at Levänluhta was investigated by comparing their geochemical composition and lead isotope ratios to known copper ores in Finland, Sweden and elsewhere in Europe. The study was published in the Journal of Archaeological Science: Reports.

Copper tracks lead to southern Europe

"The results demonstrate that the copper used in the objects was not from Finland or the nearby regions; rather, it has travelled to Finland along extensive exchange networks, most likely from southern Europe," says Holmqvist-Sipilä.

Based on the lead isotope ratios, the copper in the objects has its origins in the copper ores found in Greece and Bulgaria. These regions produced a large quantity of copper in the Bronze and Iron Age, which spread around Europe as various object forms, distributed as presents, loot and merchandise. Metals were also recycled by melting old objects into raw material for new casts. It may be possible that metals that ended up in Finland during the Bronze Age were recycled in the Levänluhta region.

The findings of this project, funded by the Emil Aaltonen Foundation, demonstrate that products of the copper exchange network of continental Europe also reached Finland across the Baltic Sea, thus making it possible to link the region with the extensive copper exchange system known to have extended throughout Europe. The results also illustrate the temporally and technologically multi-layered nature of prehistoric metal artefacts: raw materials found their way here through a number of hands, most likely over a long period of time and across very great distances. In domestic artisan workshops, these metals of international origin were manufactured into pieces of jewellery in domestic Iron Age fashion, perhaps embodying the local identity and place of residence of the bearer.