Culture

For the first time, a team of astronomers has observed several pairs of galaxies in the final stages of merging together into single, larger galaxies. Peering through thick walls of gas and dust surrounding the merging galaxies' messy cores, the research team captured pairs of supermassive black holes--each of which once occupied the center of one of the two original smaller galaxies--drawing closer together before they coalescence into one giant black hole.

Led by University of Maryland alumnus Michael Koss (M.S. '07, Ph.D. '11, astronomy), a research scientist at Eureka Scientific, Inc., with contributions from UMD astronomers, the team surveyed hundreds of nearby galaxies using imagery from the W.M. Keck Observatory in Hawaii and NASA's Hubble Space Telescope. The Hubble observations represent more than 20 years' worth of images from the telescope's lengthy archive. The team described their findings in a research paper published on November 8, 2018, in the journal Nature.

"Seeing the pairs of merging galaxy nuclei associated with these huge black holes so close together was pretty amazing," Koss said. "In our study, we see two galaxy nuclei right when the images were taken. You can't argue with it; it's a very 'clean' result, which doesn't rely on interpretation."

The high-resolution images also provide a close-up preview of a phenomenon that astronomers suspect was more common in the early universe, when galaxy mergers were more frequent. When the black holes finally do collide, they will unleash powerful energy in the form of gravitational waves--ripples in space-time recently detected for the first time by the twin Laser Interferometer Gravitational-wave Observatory (LIGO) detectors.

The images also presage what will likely happen in a few billion years, when our Milky Way galaxy merges with the neighboring Andromeda galaxy. Both galaxies host supermassive black holes at their center, which will eventually smash together and merge into one larger black hole.

The team was inspired by a Hubble image of two interacting galaxies collectively called NGC 6240, which later served as a prototype for the study. The team first searched for visually obscured, active black holes by sifting through 10 years' worth of X-ray data from the Burst Alert Telescope (BAT) aboard NASA's Neil Gehrels Swift Observatory.

"The advantage to using Swift's BAT is that it observes high-energy, 'hard' X-rays," said study co-author Richard Mushotzky, a professor of astronomy at UMD and a fellow of the Joint Space-Science Institute (JSI). "These X-rays penetrate through the thick clouds of dust and gas that surround active galaxies, allowing the BAT to see things that are literally invisible in other wavelengths."

The researchers then combed through the Hubble archive, zeroing in on the merging galaxies they spotted in the X-ray data. They then used the Keck telescope's super-sharp, near-infrared vision to observe a larger sample of the X-ray-producing black holes not found in the Hubble archive.

The team targeted galaxies located an average of 330 million light-years from Earth--relatively close by in cosmic terms. Many of the galaxies are similar in size to the Milky Way and Andromeda galaxies. In total, the team analyzed 96 galaxies observed with the Keck telescope and 385 galaxies from the Hubble archive.

Their results suggest that more than 17 percent of these galaxies host a pair of black holes at their center, which are locked in the late stages of spiraling ever closer together before merging into a single, ultra-massive black hole. The researchers were surprised to find such a high fraction of late-stage mergers, because most simulations suggest that black hole pairs spend very little time in this phase.

To check their results, the researchers compared the survey galaxies with a control group of 176 other galaxies from the Hubble archive that lack actively growing black holes. In this group, only about one percent of the surveyed galaxies were suspected to host pairs of black holes in the later stages of merging together.

This last step helped the researchers confirm that the luminous galactic cores found in their census of dusty interacting galaxies are indeed a signature of rapidly-growing black hole pairs headed for a collision. According to the researchers, this finding is consistent with theoretical predictions, but until now, had not been verified by direct observations.

"People had conducted studies to look for these close interacting black holes before, but what really enabled this particular study were the X-rays that can break through the cocoon of dust," explained Koss. "We also looked a bit farther in the universe so that we could survey a larger volume of space, giving us a greater chance of finding more luminous, rapidly-growing black holes."

It is not easy to find galactic nuclei so close together. Most prior observations of merging galaxies have caught the coalescing black holes at earlier stages, when they were about 10 times farther away. The late stage of the merger process is so elusive because the interacting galaxies are encased in dense dust and gas, requiring very high-resolution observations that can see through the clouds and pinpoint the two merging nuclei.

"Computer simulations of galaxy smashups show us that black holes grow fastest during the final stages of mergers, near the time when the black holes interact, and that's what we have found in our survey," said Laura Blecha, an assistant professor of physics at the University of Florida and a co-author of the study. Blecha was a JSI Prize Postdoctoral Fellow in the UMD Department of Astronomy prior to joining UF's faculty in 2017. "The fact that black holes grow faster and faster as mergers progress tells us galaxy encounters are really important for our understanding of how these objects got to be so monstrously big."

Future infrared telescopes such as NASA's highly anticipated James Webb Space Telescope (JWST), slated for launch in 2021, will provide an even better view of mergers in dusty, heavily obscured galaxies. For nearby black hole pairs, JWST should also be capable of measuring the masses, growth rates and other physical parameters for each black hole.

"There might be other objects that we missed. Even with Hubble, many nearby galaxies at low redshift cannot be resolved--the two nuclei just merge into one," said study co-author Sylvain Veilleux, a professor of astronomy at UMD and a JSI Fellow. "With JWST's higher angular resolution and sensitivity to the infrared, which can pass through the dusty cores of these galaxies, searches for these nearby objects should be easy to do. Also with JWST, we will be able to push toward larger distances, to see objects at higher redshift. With these observations, we can begin to explore the fraction of objects that are merging in the youngest, most distant regions of the universe--which should be fairly frequent."

The human genome has its own proofreaders and editors, and their handiwork is not as haphazard as once thought.

When DNA's double helix is broken after damage from, say, exposure to X-rays, molecular machines perform a kind of genetic "auto-correction" to put the genome back together -- but those repairs are often imperfect. Just as your smartphone might amend a misspelled text message into an incoherent phrase, the cell's natural DNA repair process can add or remove bits of DNA at the break site in a seemingly random and unpredictable manner. Editing genes with CRISPR-Cas9 allows scientists to break DNA at specific locations, but this can create "spelling errors" that alter the function of genes.

This response to CRISPR-induced damage, called "end joining," is useful for disabling a gene, but researchers have deemed it too error-prone to exploit for therapeutic purposes.

A new study upends this view. By creating a machine-learning algorithm that predicts how human and mouse cells respond to CRISPR-induced breaks in DNA, a team of researchers discovered that cells often repair broken genes in ways that are precise and predictable, sometimes even returning mutated genes back to their healthy version. In addition, the researchers put this predictive power to the test and successfully corrected mutations in cells taken from patients with one of two rare genetic disorders.

The work suggests that the cell's genetic auto-correction could one day be combined with CRISPR-based therapies that correct gene mutations by simply cutting DNA precisely and allowing the cell to naturally heal the damage.

The study, published this week in Nature, was led by David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, and vice chair of the faculty at the Broad Institute; David Gifford, professor of computer science and biological engineering at MIT; and Richard Sherwood, an assistant professor of medicine in the Division of Genetics at Brigham and Women's Hospital.

"Machine learning offers new horizons for the development of human therapeutics", said Gifford, "This study is an example of how combining computational experiment design and analysis with therapeutic goals can produce an unexpected therapeutic modality."

"We don't currently have an efficient way to precisely correct many human disease mutations," said Liu. "Using machine learning, we've shown we can often correct those mutations predictably, by simply letting the cell repair itself."

Many disease-associated mutations involve extra or missing DNA, known as insertions and deletions. Researchers have tried to correct those mutations with CRISPR-based gene editing. To do this, they cut the double helix with an enzyme and insert missing DNA, or remove extra DNA, using a template of genetic material that serves as a blueprint. The approach, however, only works in rapidly dividing cells like blood stem cells and even then it is only partly effective, making it a poor choice for therapeutics aimed at the majority of cell types in the body. To restore gene function without templated repair requires knowing how the cell will fix CRISPR-induced DNA breaks--knowledge that did not exist until now.

Evidence of a pattern to CRISPR repair outcomes had been noted previously, and Gifford's lab began to think that such outcomes might be predictable enough to model accurately; however, they needed much more data to turn those patterns into an accurate predictive understanding.

Led by MIT graduate student Max Shen and Broad Institute postdoctoral researcher Mandana Arbab, the researchers developed a strategy to observe how cells repaired a library of 2,000 sites targeted by CRISPR in the mouse and human genomes. After observing how the cell repaired those cuts, they poured the resulting data into a machine-learning model, inDelphi, prompting the algorithm to learn how the cell responded to cuts at each site -- that is, which bits of DNA the cell added to or removed from each damaged gene.

They found that inDelphi could discern patterns at cut sites that predicted what insertions and deletions were made in the corrected gene. At many sites, the set of corrected genes did not contain a huge mixture of variations, but rather a single outcome, such as correction of a pathogenic gene.

Indeed, after querying inDelphi for disease-relevant genes that could be corrected by cutting in just the right place, the researchers found nearly two hundred pathogenic genetic variants that were mostly corrected to their normal, healthy versions after being cut with CRISPR-associated enzymes. They were also able to correct mutations in cells from patients with two rare genetic disorders, Hermansky-Pudlak syndrome and Menkes disease.

"We show that the same CRISPR enzyme that has been used primarily as a sledgehammer can also act as a chisel," said Sherwood. "The ability to know the most likely outcome of your experiment before you do it will be a real advance for the many researchers using CRISPR."

"We had hoped that we would be able to repair disease-associated genes to their native forms, and it was quite rewarding to see that our hypothesis was correct," said Gifford.

A University of Kent study into post partum depression found the odds of developing this condition increased by 79% when mothers had baby boys compared to baby girls.

Overall the researchers identified that women who give birth to males are 71-79% more likely to develop post partum depression. Furthermore, women whose births had complications were 174% more likely to experience post partum compared to those women who had no complications.

As a result of their findings, Dr Sarah Johns and Dr Sarah Myers in the University's School of Anthropology and Conservation (SAC), conclude that recognising that both male infants and birth complications are post partum risk factors should help health professionals in identifying and supporting women who may by more likely to develop this condition.

Their research also showed that while women with a tendency towards symptoms of depression, anxiety, and stress were always at increased risk of post partum, they had reduced odds of developing post partum after experiencing birth complications. This is likely because these women may receive greater post-birth support because their mental health concerns were previously recognised. This finding suggests interventions to support women can be effective in preventing post partum developing.

Dr Johns said: 'Post partum is a condition that is avoidable, and it has been shown that giving women at risk extra help and support can make it less likely to develop. The finding that having a baby boy or a difficult birth increases a woman's risk gives health practitioners two new and easy ways to identify women who would particularly benefit from additional support in the first few weeks and months'

Dr Johns and Dr Myers decided to assess whether there was a relationship between the sex of infants and post partum because of the known link between inflammatory immune response and the development of depressive symptoms.

Both the gestation of male foetuses and the experience of birth complications have documented associations with increased inflammation, yet, until this study, their relationships with post partum were unclear.

Many known risk factors for depressive symptoms are associated with activation of inflammatory pathways, opening up the potential for identifying new risk factors based on their inflammation causing effects - an idea supported by this study.

The study used complete reproductive histories of 296 women from contemporary, low fertility populations.

Observations by ALMA and data from the MUSE spectrograph on ESO's VLT have revealed a colossal fountain of molecular gas powered by a black hole in the brightest galaxy of the Abell 2597 cluster -- the full galactic cycle of inflow and outflow powering this vast cosmic fountain has never before been observed in one system.

A mere one billion light-years away in the nearby galaxy cluster known as Abell 2597, there lies a gargantuan galactic fountain. A massive black hole at the heart of a distant galaxy has been observed pumping a vast spout of cold molecular gas into space, which then rains back onto the black hole as an intergalactic deluge.The in- and outflow of such a vast cosmic fountain has never before been observed in combination, and has its origin in the innermost 100 000 light-years of the brightest galaxy in the Abell 2597 cluster.

"This is possibly the first system in which we find clear evidence for both cold molecular gas inflow toward the black hole and outflow or uplift from the jets that the black hole launches," explained Grant Tremblay of the Harvard-Smithsonian Center for Astrophysics and former ESO Fellow, who led this study. "The supermassive black hole at the centre of this giant galaxy acts like a mechanical pump in a fountain."

Tremblay and his team used ALMA to track the position and motion of molecules of carbon monoxide within the nebula. These cold molecules, with temperatures as low as minus 250-260°C, were found to be falling inwards to the black hole. The team also used data from the MUSE instrument on ESO's Very Large Telescope to track warmer gas -- which is being launched out of the black hole in the form of jets.

"The unique aspect here is a very detailed coupled analysis of the source using data from ALMA and MUSE," Tremblay explained. "The two facilities make for an incredibly powerful combination."

Together these two sets of data form a complete picture of the process; cold gas falls towards the black hole, igniting the black hole and causing it to launch fast-moving jets of incandescent plasma into the void. These jets then spout from the black hole in a spectacular galactic fountain. With no hope of escaping the galaxy's gravitational clutches, the plasma cools off, slows down, and eventually rains back down on the black hole, where the cycle begins anew.

This unprecedented observation could shed light on the life cycle of galaxies. The team speculates that this process may be not only common, but also essential to understanding galaxy formation. While the inflow and outflow of cold molecular gas have both previously been detected, this is the first time both have been detected within one system, and hence the first evidence that the two make up part of the same vast process.

What started as Ninad Oak's side project turned out into something much larger, his doctorate thesis.

"The project started as my qualifying exam that I proposed at the end of my first year of graduate school," said Oak, a graduate student in molecular and human genetics in Dr. Sharon E. Plon's lab. "This was an off topic qualifying exam at the time, meaning the lab had not worked on this topic before."

One of the main interests of the Plon lab is cancer predisposition, in particular looking at protein coding regions of gene variants that may be responsible for susceptibility to childhood cancers.

"I started the project thinking that we had focused on protein coding regions for a long time. But they only represent 1 percent of the genome, so I thought that by looking at the remaining 99 percent we might find variations we have been missing that might explain some undiagnosed patient cases," Oak said.

In his qualifying exam, Oak proposed to look at variations on microRNA.

"Although the amount of microRNA that is found in the cell is often studied in human disease, microRNA variations that are associated with disease are understudied," Oak said.

MicroRNAs are small non-coding RNAs that are only about 18 to 25 nucleotides long; they are much smaller than genes that code for proteins, which are thousands of nucleotides long. MicroRNAs upregulate or downregulate the expression of more than 60 percent of genes by binding to matching sequences in other's genes' RNA. One microRNA might change the level of expression of up to 200 genes at a time, therefore affecting a number of different pathways.

Disturbing the normal function of microRNAs can lead to altered expression of their target genes, and this has been associated with a wide variety of human diseases, such as cancer, cardiovascular and developmental diseases.

"When he presented this proposal, I thought it was a good idea," said Plon, who is professor of pediatrics - oncology and molecular and human genetics at Baylor and director of the Cancer Genetics Clinical and Research Programs at Texas Children's Hospital.

ADmiRE helps prioritize microRNA variation linked to disease

Oak developed a novel computational tool called ADmiRE, which stands for Annotative Database for miRNA Elements. ADmiRE extensively annotates human microRNA variants to determine which ones are likely to contribute to or cause diseases.

"There were multiple challenges when I started working on this project," Oak said. "Most datasets of genomic sequencing are of whole exome sequencing (WES), which captures only protein coding regions. So first, I looked at how well WES datasets captured microRNAs and found that they captured about 50 percent."

The second challenge was to determine how well were microRNA mutations annotated by different annotation tools that already were available. These annotation tools allow researchers to add notes of explanation or comments that provide more information about each microRNA.

"There are various annotation tools that identify where a mutation is in general in the genome, not exclusively in microRNA. I found that these tools didn't annotate microRNA accurately; they tended to favor the potential change to a protein coding gene and not the impact on microRNAs. These tools also didn't include comprehensive information that would help us interpret and prioritize the potential role of that microRNA in disease," Oak said.

Oak worked on a microRNA annotation tool that would correctly annotate all microRNA variants and then used it to analyze one of the largest publicly available WES datasets of adults (gnomAD) to establish a baseline of microRNA variation in normal human populations.

"This approach allowed us to draw conclusions about how frequently microRNAs are variable in normal datasets," Oak said. "Knowing the background variation would help us identify potential microRNA variants in disease states."

To identify microRNAs that could be associated with disease, Oak developed a metric called allele frequency percentile score that shows how frequently a microRNA varies when compared to other microRNAs in these large datasets. He then selected a group of microRNAs that were in the lower quartile, essentially highlighting those with little variation. The reasoning is that microRNAs that are highly conserved in the adult population are so because otherwise disease may follow. Those highly conserved microRNAs would be candidates for being associated with disease.

The researchers then applied this new tool to analyze mutations across 10,000 cancer cases that included 32 cancer types in the Cancer Genome Atlas PanCancerAtlas WES dataset.

"We found miR-142 mutations linked to hematologic cancers, confirming the finding made a few years ago. Also, we found microRNA mutations in miR-21, which had not been previously associated with cancer. Our analysis with ADmiRE suggests that these mutations may contribute to mechanisms involved in esophageal cancer.

"At a personal level, I found this work very satisfying because I think it contributes a new technique to our lab that fills a gap in the field," Oak said. "From the scientific point of view, ADmiRE offers a new resource for researchers who have not found a genetic cause for a disease in protein coding genes. We have made this tool publicly available, and researchers can apply it to determine whether there is a signal in miRNA sequences. Maybe down the line this tool could be used by clinical laboratories."

"I think it is an important tool," Plon said. "Mutations in microRNA have been missed for many years, but I think ADmiRE will now allow labs that have mutation data to see if these mutations that we know are important play a role in the biology of human health."

Hypotrichosis simplex leads to progressive hair loss already in childhood. A team of researchers led by human geneticists at the University Hospital of Bonn has now deciphered a new gene that is responsible for this rare form of hair loss. Changes in the LSS gene lead to impairment of an important enzyme that has a crucial function in cholesterol metabolism. The scientists now present their findings in the renowned journal the American Journal of Human Genetics.

In infancy, fine hair tends to sprout sparsely. With increasing age, hair loss progresses. Ultimately, only a few hairs are left on the head and body. Hypotrichosis simplex is a rare form of hair loss (alopecia). The condition is limited to a few hundred families worldwide. So far, only a few genes are known that are causally related to the disease. Under the leadership of the Institute of Human Genetics at the University Hospital of Bonn, a team of researchers from Germany and Switzerland has now deciphered mutations in another gene that are responsible for hair loss.

The scientists examined the coding genes of three families that are not related to each other and are of different ancestry. A total of eight relatives showed the typical symptoms of hair loss. All those affected had mutations in the LSS gene. "This gene encodes lanosterol synthase - LSS for short," said Prof. Dr. Regina C. Betz from the Institute of Human Genetics at the University Hospital of Bonn. "The enzyme plays a key role in cholesterol metabolism." However, the cholesterol blood values of those affected are not changed. Betz: "There is an alternative metabolic pathway for cholesterol, which plays an important role in the hair follicle and is not related to blood cholesterol levels."

Mutation leads to displacement of lanosterol synthase

Using tissue samples, the scientists tried to find out exactly where the lanosterol synthase is located in the hair follicle cells. The hair roots are formed in the follicle. If the LSS gene is not mutated, the associated enzyme is located in a system of very fine channels in the follicle cells, the endoplasmic reticulum. If a mutation is present, the lanosterol synthase also spreads outside these channels into the adjacent substance, the cytosol. "We are not yet able to say why the hair is falling out," says lead author Maria-Teresa Romano, a doctoral student in Prof. Betz's team. "It is likely that the displacement of LSS from the endoplasmic reticulum results in a malfunction."

Prof. Dr. Matthias Geyer from the Department of Structural Immunology at the University of Bonn investigated the consequences of mutations for the structure of the enzyme lanosterol synthase. With him and Prof. Betz, there are now two principal investigators from the Cluster of Excellence ImmunoSensation of the University of Bonn, which was impressively endorsed in the latest round of the Excellence Competition and will receive further funding.

Improved diagnosis

For the scientists, the current study result is an important finding: Each further gene decoded is yet another part of the jigsaw and helps to complete the picture of the biological basis of the disease. "A better understanding of the causes of the disease may in future enable new approaches to the treatment of hair loss," said the human geneticist. But there is still a long way to go. However, the discovery of the gene already contributes to an improved diagnosis of the rare disease. Betz: "Those affected by hypotrichosis simplex only have to deal with hair loss. This is upsetting, but other organs are not affected."

EUGENE, Ore. -- Nov. 6, 2018 -- Researchers at the University of Oregon have identified a novel protein secreted by a common gut bacterium in zebrafish that reduces inflammation in the gut and delays death by septic shock.

By examining how the protein, Aeromonas immune modulator (AimA), mutually benefits both the bacteria and their larval zebrafish hosts, the research team's experiments shed light on how animals and their resident microbes negotiate a moderated level of inflammatory response.

A paper on the study, "A bacterial immunomodulatory protein with lipocalin-like domains facilitates host-bacteria mutualism," appeared in a special edition of the journal eLife devoted to mechanistic microbiome studies.

"One of the major questions about how we coexist with our microbial inhabitants is why we don't have a massive inflammatory response to the trillions of the bacteria inhabiting our guts," said study co-author Karen Guillemin, a professor of biology and member of the Institute of Molecular Biology.

"We set out to test whether gut bacteria actively secrete factors that prevent an excessive inflammatory response, which would be detrimental not only to the host but also to the bacterial residents," she said. "We used zebrafish as a model host because we could perform many tests and search in an unbiased way for new anti-inflammatory factors."

The paper - led by Annah Rolig, a former UO postdoctoral fellow and now a research scientist at the Cancer Immunobiology Laboratory at Providence Portland Medical Center - details how the protein was discovered in the common zebrafish gut bacterium Aeromonas and how the researchers narrowed in on a better understanding of its structure and function.

When they first discovered the AimA protein, Guillemin and her team were baffled because the array of amino acids making up the protein chain looked like no other protein that had ever been described.

Using protein crystallography, co-author and UO research associate Emily Goers Sweeney was able to determine the 3D structure of the protein. When viewed in 3D, AimA showed a striking similarity to a class of proteins called lipocalins, which include members that modulate inflammation in humans.

"That structural similarity suggested to us that the bacterial protein may function like the human protein" Guillemin said. "In particular, rather than doing something specific to counteract inflammation caused by one kind of bacteria, maybe it was doing something more generally to temper the host's immune response."

To test this idea in zebrafish the researchers induced inflammation in several different ways. In all cases, they found that the AimA protein could reduce inflammation. Even when they induced a lethal inflammatory response, called septic shock, they found that the protein could counteract this and extended the lifespan of zebrafish.

In probing the question as to why bacteria make this protein, researchers delivered an AimA-deficient version of the Aeromonas bacterium to zebrafish. They found that host animals fared worse than when they were colonized with normal Aeromonas and suffered more intestinal inflammation. The bacteria also did worse, Guillemin said.

"The bacteria were experiencing this inflammation, which is detrimental to them," she said. "Inflammation involves the production of antimicrobial compounds like reactive oxygen species that are designed for clearing bacteria, so, now, a beneficial bacterium is going to be at a disadvantage if it's experiencing too much of this inflammatory response."

When AimA protein was delivered back to the fish, its presence benefitted both partners. The intestinal inflammation went away and Aeromonas returned to normal numbers. When the researchers did the same experiment in immunocompromised fish that couldn't mount an inflammatory response, Aeromonas bacteria didn't need the protein. This showed that the primary reason why the bacteria make AimA is to prevent inflammation.

As a protein that benefits both bacterial and animal partners, AimA represents a new class of bacterial effector proteins, which Guillemin calls mutualism factors.

Unlike virulence factors that promote the fitness of pathogens to the detriment of their hosts, a mutualism factor like AimA confers mutual benefits, and both host and bacterium suffer when it is removed from the host-microbe equation. AimA proteins, she said, act to promote both bacterial colonization and host survival.

"Most studies of beneficial microbes have focused exclusively on the benefits to the host and have tended to find very generic microbial molecules, such as metabolic byproducts, as the mediators," she said. "The discovery of AimA is exciting because it is a very specific specialized product that a mutualist is making for maintaining that mutualism. I suspect there are many more of these mutualism factors to be found."

The findings have potential applications for a range of human diseases associated with excessive inflammation. It could someday be useful in treating intestinal inflammation, including inflammatory bowel diseases, or in preventing chronic inflammation associated with metabolic syndrome and sepsis.

Additionally, Guillemin said, the study suggests that other bacteria that live inside humans are a potential rich source of novel anti-inflammatory molecules.

"These resident gut microbes are motivated to inhibit inflammation," she said, "and they probably have lots of creative ways of dampening down our immune system. We can learn a lot from them about how to design novel anti-inflammatory therapies."

People are more prejudiced against women leaders than the statistics might indicate. This could be because participants in surveys investigating attitudes towards men and women in leadership positions may not answer honestly unless they are guaranteed confidentiality of their answers. These are the findings of a new study by Adrian Hoffmann and Jochen Musch of the Heinrich-Heine-University Düsseldorf in Germany, which is published in Springer's journal Sex Roles.

Hoffmann and Musch used an indirect questioning technique to gather information on people's true feelings about women leaders. The technique showed that people are not always honest when directly asked their opinion on socially sensitive questions because they prefer to give answers that they think will be accepted by others.

Gender stereotypes and gender-oriented prejudice pose a serious threat to women's careers and facilitate gender bias in the workplace. According to theorists, prejudice against women leaders emerges from an incongruity between their gender role and the more masculine social role of a leader. Self-reports are often used to study people's prejudice against women leaders, and these have helped to gather important information about the form intolerance and stereotyping against women in power takes. Such methods may, however, be biased because of the unwillingness of some people to disclose information that could be viewed by others as violating social norms, and therefore reflect unfavourably on the respondent.

To counter this effect, Hoffmann and Musch collected responses from 1529 German students with either a conventional direct question, or an indirect question in the format of the so-called Crosswise Model. The randomization of individual answers which lies at the core of this advanced questioning technique grants full confidentially to respondents answering questions of a sensitive nature. It therefore allows respondents more freedom to answer honestly without feeling the need to provide answers that would put themselves in a better light. Estimates of the prevalence of prejudice obtained using the Crosswise Model were further compared with ones obtained using a conventional direct question.

Results from the Crosswise Model show that people are significantly more prejudiced against women (37 per cent) than results from direct questions indicate (23 per cent). This could be because more participants were willing to admit to being prejudiced against women leaders if they were granted full confidentiality in their answers.

When granted full confidentiality, 28 per cent of women and 45 per cent of men in the sample indicated that they considered women to be less qualified for leadership positions than men. Across the two study methods, men showed more prejudice than women. However, the increase in the estimated prevalence of prejudice from a conventional direct question to the Crosswise Model was higher in women (from 10 per cent to 28 per cent) than in men (from 36 per cent to 45 per cent), indicating that women responded more strongly to being granted full confidentiality of their answers.

"This pattern suggests that women are much more reluctant than men to express their prejudice against women leaders. Perhaps because women feel obligated to solidarize with members of their in-group," explains Hoffmann.

"Given that even many women have reservations against women leaders, the societal and political promotion of gender equity has obviously not been successful at changing the attitudes of every potential future leader. It therefore does not seem unreasonable to expect the further persistence of workplace bias", adds Musch.

Adults who sleep just six hours per night -- as opposed to eight -- may have a higher chance of being dehydrated, according to a study by Penn State.

These findings suggest that those who don't feel well after a night of poor sleep may want to consider dehydration -- not simply poor sleep -- as a cause, and drink more water.

Results of the study are published in the journal SLEEP on Nov. 5.

Researchers looked at how sleep affected hydration status and risk of dehydration in U.S. and Chinese adults. In both populations, adults who reported sleeping six hours had significantly more concentrated urine and 16-59 percent higher odds of being inadequately hydrated compared to adults who slept eight hours on a regular basis at night.

The cause was linked to the way the body's hormonal system regulates hydration.

A hormone called vasopressin is released to help regulate the body's hydration status. It is released throughout the day, as well as during nighttime sleeping hours, which is what the researchers focused on for this study.

"Vasopressin is released both more quickly and later on in the sleep cycle," said lead author Asher Rosinger, assistant professor of biobehavioral health at Penn State. "So, if you're waking up earlier, you might miss that window in which more of the hormone is released, causing a disruption in the body's hydration."

Dehydration negatively affects many of the body's systems and functions, including cognition, mood, physical performance and others. Long term or chronic dehydration can lead to more serious problems, such as higher risk of urinary tract infections and kidney stones.

"If you are only getting six hours of sleep a night, it can affect your hydration status," Rosinger said. "This study suggests that if you're not getting enough sleep, and you feel bad or tired the next day, drink extra water."

Two samples of adults were analyzed through the National Health and Nutrition Examination Survey and one sample of adults was analyzed through the Chinese Kailuan Study. More than 20,000 adults were included across the three samples. Participants were surveyed about their sleeping habits, and also provided urine samples which were analyzed by researchers for biomarkers of hydration.

All data is observational and from cross-sectional studies or a cross-sectional wave of a cohort study; therefore, the association results should not be viewed as causal. Future studies should use the same methodology across sites and examine this relationship longitudinally over the course of a week to understand baseline sleep and hydration status, Rosinger said.

Scientists at Scripps Research have made a surprising discovery in their mission to understand how cells stay healthy, uncovering an important connection between a cell's sugar metabolism and its antioxidant response, one of the cell's key mechanisms to protect itself from oxidative stress and other damaging agents.

Targeting this link, the researchers identified a small molecule capable of activating the antioxidant response, a potential therapy for a range of diseases involving oxidative stress such as chronic kidney disease, neurodegeneration, and autoimmune disease. They reported their discovery recently in Nature.

"This study demonstrates that there's clear cross-talk between central carbon metabolism and the antioxidant response and opens the door to develop these findings to target a range of diseases," says Luke Lairson, PhD, an assistant professor at Scripps Research and co-senior author of the study. "The small molecule we developed targets the glycolysis pathway in a reversible way to activate the antioxidant response, which could represent a new strategy for developing drugs to turn on this protective pathway."

The key player in this cross-talk is a protein called KEAP1, which acts as a sensor for potentially damaging reactive molecules in cells. When these reactive molecules build up, KEAP1 triggers the antioxidant stress response to clean them up.

Because reactive molecules are linked to the development of so many diseases--from cancers to autoimmune and neurological disorders--scientists are searching for a way to target KEAP1 and take control of the cell stress response. There has been good progress in finding a "covalent" mechanism to directly target KEAP1, but this approach has the downside of potentially affecting other proteins and causing side effects.

To discover alternative mechanisms to activate this pathway, the Scripps Research scientists decided to employ a chemical genetics-based approach to find non-covalent activators of KEAP1. "We identified a completely new mechanism by first searching for molecules that activate this pathway in an unbiased cell-based screen--and then retroactively looking for their targets and mechanisms of action," says Michael Bollong, PhD, a Scripps Fellow and first author of the new study.

This approach led the scientists to a molecule called CBR-470-1, which was then optimized by researchers at Calibr, a nonprofit drug discovery division of Scripps Research.

"This is a great example of how screening for active molecules at a cellular level that interrogates all molecules in cells in an unbiased way, rather than targeting a specific protein, can both provide new biological insights as well as lead to potential new drug development opportunities," says Peter Schultz, PhD, president of Scripps Research and president of Calibr, who serves as co-senior author of the study.

Experiments with CBR-470-1 and its analogue, CBR-470-2, led to the surprising conclusion that KEAP1 is modified through a mechanism that is part of a cell's response to glucose, called glycolysis, which breaks sugar molecules into energy.

"You could say these two pathways are communicating with each other," says Bollong. "That had never been shown before."

This understanding of the molecule's mechanism of action came from study collaborators at the University of Chicago, led by Raymond Moellering, PhD, who found that KEAP1 activation occurred through a previously unknown post-translational modification, a change made to a cellular protein after its initial production that changes its function

Molecules in the CBR-470 series inhibit a central carbon metabolism enzyme. Inhibiting that enzyme leads to the accumulation of an endogenous metabolite that modifies KEAP1.

The researchers next tested an analogue of the compound in a mouse model of UV damage, a source of cell stress. The analogue CBR-470-2 had the advantage of being more bioavailable than the first two molecules in the series. The researchers found that the mechanism was relevant in the adult mouse, and it was not an artifact of tissue culture.

"The mechanism has the ability to beneficially impact disease progression following systemic delivery of the compound at well tolerated doses," says Lairson.

Currently, molecules in the CBR-470 series serve to show the "proof of concept" that KEAP1 can be activated by non-covalent drug-like molecules. Going forward, the Bollong lab is looking for new mechanisms and molecules targeting the antioxidant response that may serve as promising drug candidates.

"We're also testing this mechanism in other disease models to see where activating this response might be useful," says Bollong.

How did words or the rain sound inside the Mosque of Cordoba in the time of Abd al-Rahman I? Today, thanks to virtual simulation tools, it is possible to know the sound filed of spaces that no longer exist. This field of work is known as "Acoustic Archaeology" by some researchers. Working in this field, researchers from the Higher Technical School of Architecture at the University of Seville have carried out a study in which they have determined the variation of the acoustic parameters, such as reverberation, clarity or definition of the Mosque of Seville currently.

Faced with the visual homogeneity of the interior of the Islamic mosque, the results obtained in the acoustic study allow us to confirm that the sound perception varies by area. This is due to the successive expansions that the temple has experienced during its history.

"The mosque founded by Abd al-Rahman I responded acoustically to Muslim liturgical requirements, providing a living space that favoured their majesty. Later expansions gave a formal appearance of superposition on the pre-existing space. However, notable sound difference were produced in the interior space. This, united with the increase in depth caused by the expansion of Abd al-Rahman II, meant a reduction in the acoustic quality of the areas furthest away from the qibla wall", explains the University of Seville professor Juan José Sendra.

With the expansion of Al-Hakam II, two acoustically juxtaposed mosques were obtained. The last lateral expansion, by Al-Mansur, in which even the mihrab was decentred with respect to the new layout, was separated from the rest of the building, with a clear degradation in the quality of verbal communication.

The Christian era

The Christian transformations of the Mosque, to make it suitable for use as a cathedral, substantially modified the Muslim space. Therefore, the experts state that in the modern day space of the Mosque-Cathedral is a "complex architectural unit", with a multiplicity of sound spaces, the fruit of all the spatial transformations that have taken place, each different according to the spatial archetype, be it Muslim or Christian.

Sound spaces

The research group 'Architecture, Heritage and Sustainability: Acoustics, Lighting, Optics and Energy' ('Arquitectura, Patrimonio y Sostenibilidad: Acústica, Iluminación, Óptica y Energía') of the University of Seville has spent more than a decade working in this field of study. In recent years, two Plan Estatal I+D+I (State R+D and innovation) Projects on Spanish cathedrals, mainly Andalusian, stand out. Various articles have been published, from different perspectives, which analyse the sound in the cathedrals of Seville, Granada, Malaga, Cordoba and Jaen. Specifically, in the case of Seville Cathedral, articles have been published that have analysed both the acoustic-spatial variety of the cathedral space, as well as the influence certain special spatial configurations have had on its acoustics, for example, when there is a big concert, or of the temporary architectural features present for certain religious celebrations.

Currently, they are also working on publishing a book that intends to decodify the complex and fragmented space of the Mosque-Cathedral today, via analysis of its process of evolution from the first mosque of Abd al-Rahman I until the present day, with the aim of recovering a lost sound memory.

SAN DIEGO -- Studies that link breakdowns in the brain's blood vessels to Alzheimer's disease and vascular dementia were presented today at Neuroscience 2018, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health. Molecules that signal damage in these systems could aid in earlier detection of these diseases and inform more effective interventions.

Alzheimer's disease and vascular dementia cause impairments of memory, cognition, and learning. Although there are important genetic risk factors for these diseases, there is also strong evidence to suggest that vascular disorders such as high blood pressure and heart disease play a major role. The research presented today reveals new mechanisms for how damage to the brain's vascular system contributes to neurodegeneration and point towards potentially protective or therapeutic interventions, such as exercise.

Today's new findings show that:

Molecules called biomarkers, which signal brain vascular injury, could help identify dementia in its early stages and allow intervention and eventually treatment to improve patient outcomes (Berislav Zlokovic, abstract 469.10).
Cardiovascular exercise seems to improve blood flow to white matter and protects against vascular impairment in a mouse model of dementia (Lianne Trigiani, abstract 467.15).

A molecule that is depleted in vascular dementia patients could be used for early detection or for treatment of patients with this cognitive decline (Deron Herr, abstract 469.27).

Age-related loss of function in the brain's lymphatic system plays a role in neurodegeneration and improving it could help delay or prevent Alzheimer's disease (Jonathan Kipnis, abstract 267.02).

The blood brain barriers' effectiveness is reduced in mice engineered with the strongest genetic risk factor for Alzheimer's, leading to neuronal loss and cognitive decline (Berislav Zlokovic, abstract 540.04).

"The research presented today represents a growing understanding of two complex and related disorders," said moderator Richard Wainford, PhD, of Boston University School of Medicine. "Knowledge of the neurobiology and mechanisms involved open the door to being able to identify dementia early, which offers hope of potential new treatments and interventions that could help patients and their families around the world."

SAN DIEGO -- Neuroscientists are developing a clearer picture than ever before of how the animal brain processes social information, from status and competitive advantage in a group to the calls and vocalizations of peers. New studies in mice and marmosets help us understand a range of disorders defined by deficits in social function and identify mechanisms that could also operate in the human brain. The research is presented today at Neuroscience 2018, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

Using imaging to record activity from brain cells, neuronal viral tracing, and positron emission tomography (PET), it is possible to observe and track activity in the brain during experimental social interactions. Since many regions of the brain are common across mammals, being able to visualize a mouse brain reacting to a social interaction, or view the processing of vocalizations at a neurological level, could be relevant in understanding the human brain. These findings are of particular interest to researchers studying disorders of social learning, such as autism spectrum disorder.

Today's new research shows that:

Blocking or genetically turning off the receptors for a specific neuropeptide reduces aggressive behavior in mice, offering a promising route for treatment of people with social disorders that manifest themselves in aggression (Scott Russo, abstract 416.03).

A small subset of cells in the mouse brain determines their social rank and competitive success, offering a window into mechanisms underlying competitive behavior and social learning (Ziv Williams, abstract 110.01).

Marmosets can discriminate between their peers based on their vocalizations and show increased neural response to calls from single individuals compared to calls from multiple individuals. The underlying neural response suggests there is a shared neural mechanism for the perception of vocalizations in marmosets and humans (Atsushi Iriki, abstract 364.12).

Circuits controlling vocalizations in mice are both embedded in and recruited from brain networks that control social behavior, furthering our knowledge of the neural basis of social communication (Richard D. Mooney, abstract 407.10).

"The ability to zoom into areas of the brain and watch communication or interaction being processed in such detail provides fascinating information," said press conference moderator Kay Tye, PhD, of the Massachusetts Institute of Technology. "Whether for perception of vocalization and communication or a social rank in a competitive situation, we are beginning to build up a picture of normal brain processing of social interaction that opens opportunities for strategies to treat dysfunction and disorders that affect social function."

SAN DIEGO -- Excessive stress during fetal development or early childhood can have long-term consequences for the brain, from increasing the likelihood of brain disorders and affecting an individual's response to stress as an adult to changing the nutrients a mother may pass on to her babies in the womb. The new research suggests novel approaches to combat the effects of such stress, such as inhibiting stress hormone production or "resetting" populations of immune cells in the brain. The findings were presented at Neuroscience 2018, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

Childhood stress increases the chance of developing anxiety, depression, or drug addiction later in life by two to four times, while stress during pregnancy may increase the child's risk of developing autism spectrum disorder, as well as several other psychiatric illnesses. Scientists are discovering more about the mechanisms through which childhood or fetal stress disrupts brain development and leads to these disorders, which may help reveal new therapeutic strategies.

Today's new findings show that:

In a mouse model of autism spectrum disorder caused by maternal infection during pregnancy, renewing fetal brain immune cells alleviates symptoms of the disorder (Tsuneya Ikezu, abstract 030.09)

Stress before or during pregnancy can alter gut bacteria in women and mice, which in the mice reduces critical nutrients reaching fetuses' brains (Eldin Jašarevic, abstract 500.14)

Early life stress changes chromatin structure in a brain reward region in mice, making them more vulnerable to stress as adults (Catherine Pena, abstract 500.01)

In rat pups, stress-induced deficits in social behavior and amygdala development occur only when the mother is present (Regina Sullivan, abstract 783.14)

Early life stress accelerates the development of the fear response in young mice, but the effect can be prevented by blocking stress hormone production (Kevin Bath, abstract 499.01)

"The research presented today demonstrates the long-lasting and far reaching effects of stress during early development, from the populations of bacteria in the gut to the way DNA is folded in the nucleus," said press conference moderator Heather Brenhouse, PhD, of Northeastern University and an expert in the effects of early life trauma. "Understanding how stress impacts developing biological systems may lead to new, patient-specific approaches to treatment and better outcomes."

SAN DIEGO -- Promising findings from preclinical animal studies show the potential of gene therapy for treating incurable neurological disorders. In new research presented today, scientists successfully used gene therapy to slow the progression and improve symptoms of disorders such as amyotrophic lateral sclerosis and Parkinson's disease. The findings were presented at Neuroscience 2018, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

Gene therapy typically employs an inactivated virus to carry new genetic cargo into cells, altering specific genes to treat or prevent a disease. Researchers might replace a mutated gene with a healthy copy of the gene, turn off a disease-causing gene, or add a new gene to the body to help fight a disease.

Although gene therapy is a promising treatment option for a limited number of conditions, including certain cancers, the technique is still experimental for most diseases, with ongoing research to ensure they will be safe and effective in human patients. Animal studies are a key part of the process by which an experimental gene therapy treatment goes to clinical trial.

Today's new findings show that:

A new technique allows gene therapy to be delivered to the entire spinal cord in mice (M. Bravo Hernandez, abstract 208.10).

Gene therapy safely and effectively extends life and improves motor function in a mouse model of ALS (Gretchen Thomsen, abstract 208.16).

Gene therapy slows the progression of neuronal loss in a mouse model of inherited Parkinson's disease (Jose L. Lanciego, abstract 292.01).

Gene therapy shows promise in a mouse model of Batten disease, a childhood neurodegenerative disease (Shibi Likhite, abstract 355.01).

"Gene therapy holds the promise to transform the lives of patients with incurable neurological diseases," said press conference moderator Fredric Manfredsson, PhD, of Michigan State University. "The research presented today represents important and exciting steps toward being able to prevent and treat disorders that currently have no cure, such as Parkinson's disease and Alzheimer's disease."