Culture

At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected to such food preference decisions.

Researchers, working with rats, found robust neural activity related to food choice in a previously overlooked part of the brain. The finding suggests this brain area could be key to developing therapies and treatments to encourage healthy eating. The findings are set for publication in the journal Nature Communications.

"We found a region in the brain that reflects our perception of food in a strikingly dominant way," said lead author David Ottenheimer, a Johns Hopkins University graduate student studying neuroscience. "The level of brain activity we saw exceeded our expectations by far."

The research team wanted to know how the brain determines what and how much to eat when someone has several good food options. It's a situation people face daily, if not at buffets or potlucks, then when looking over restaurant menus or at what's in the refrigerator.

This might seem automatic as you move down a buffet line, but when someone is considering either mac and cheese or mashed potatoes, the brain must quickly determine which of those quite similar choices -- both tasty, both treats, both carbs -- would be most rewarding. Even if we can have both, Ottenheimer says, the dish that's the favorite will likely be eaten faster and with bigger bites.

To study this question, researchers gave rats two similar sugary drinks. The rats preferred the one made with sucrose over the one with maltodextrin, and when they received sucrose, they'd lick it faster.

Over several days, the rats were given either one drink or the other. Meanwhile, the team mapped the rats' brain activity precisely at the moment the animals realized which drink they'd gotten, pinpointing the neurons that registered the excitement for sucrose, and the disappointment for maltodextrin.

The activated neurons were in an area called the ventral pallidum, a spot long associated with reward and pleasure perception, but thought to be in more of a secondary role.

Next, the team presented rats with a different set of options--either the maltodextrin drink or plain water. In this scenario, when rats got maltodextrin, ventral pallidum neurons fired liked they had for sucrose. This suggests the brain area is making context-dependent decisions, zeroing in on the best food option at any given time.

"Because the signaling by ventral pallidum neurons changes immediately when the rat changes his ranking of which flavor is his favorite, we see this response as providing a real-time readout of what you like best from currently available options," said senior author Patricia Janak, a Bloomberg Distinguished Professor of Psychological and Brain Sciences and Neuroscience.

The next step is to figure what the signaling in this part of the brain means. Is it used to reinforce prior food-seeking actions and make them more likely to occur again? Or is it used to inform future decisions and bias them towards one food reward over the other next time someone is presented with a food choice?

"Our data suggest that further investigation of ventral pallidum will be critical for understanding how we make decisions about eating," Ottenheimer said. "If we want to figure out why a food can be exciting in one scenario and disappointing in another, ventral pallidum could be the key."

Many important natural products such as antibiotics, immunosuppressants, or cancer drugs are derived from microorganisms. These natural products are often small proteins or peptides which are generated in the cell by NRPS enzymes similar to a modern automobile factory: at each station additional parts are added to the basic structure until finally a completed automobile leaves the factory. With regard to the NRPS, a specific amino acid is incorporated and processed at each station (module), so that in the end peptides emerge that can be linear, cyclic or otherwise modified including unusual amino acids.

If larger peptides are generated by these systems, often several NRPS enzymes - or assembly lines - operate successively. The order in which this happens is determined by docking domains. These are small regions at the end of the assembly lines that fit with the next NRPS enzyme in line like a key in a lock. Although the basic principles of these NRPS interactions have been known for a long time, the structure of the docking domains was unknown until now. The research groups led by Professor Jens Wöhnert form the Institute of Molecular Biosciences and Professor Helge Bode from Molecular Biotechnology at Goethe University have now been able to successfully explain this.

"We were able to determine the structures of individual docking domains and, for the first time, an NRPS docking domain pair as well," explains Carolin Hacker, who is a PhD student in Jens Wöhnert's group. "This made it possible to clarify the rules for the interaction of the docking domains and to change them in such a way that new natural products will be generated," adds Xiaofeng Cai, postdoctoral researcher in Helge Bode's group.

"We are only at the beginning of our research: We need structures of additional and structurally diverse docking domains so that in the end we can utilise them like building blocks. Our goal is to connect various biosynthesis pathways and create totally new substances" Wöhnert explains. "Nature has been quite inventive in this area, and there are apparently numerous different ways to mediate the interaction of these complexes," adds Bode.

Research in this area continues in both groups as part of the LOEWE research cluster MegaSyn. The first results on the structures of additional docking domains are quite promising.

Oct. 19, 2018--How long a person with obstructive sleep apnea (OSA) stops breathing may be a better predictor of mortality risk from OSA than the number of times they stop breathing, according to new research published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

In "Apnea-hypopnea Event Duration Predicts Mortality in Men and Women in the Sleep Heart Health Study," lead study author Matthew P. Butler, PhD, and colleagues report that participants who had short apneas and hypopneas (stopped breaths and shallow breaths, respectively) were at greater risk of dying over a decade of follow up.

"This result seems counter-intuitive because you might expect longer periods of not breathing to be more severe," said Dr. Butler, assistant professor in the Oregon Institute of Occupational Health Sciences at Oregon Health & Science University. "On the other hand, shorter periods of disturbed breathing indicate a low arousal threshold, which would associate with sleep fragmentation, elevated sympathetic tone and greater risk for hypertension."

Previous studies have shown that the apnea-hypopnea index (AHI), the most widely used measure of sleep apnea severity, is linked to mortality and heart disease. However, according Dr. Butler, AHI remains a coarse measure of sleep apnea severity and is not a good risk predictor for women.

The current study found that the duration of abnormal breathing events may be a better predictor of mortality risk in both women and men. The duration of these events, the authors wrote, is easily determined from the same polysomnography studies that patients now undergo to measure AHI.

The researchers analyzed the records of 5,712 adults (average age 63) who participated in the National Heart, Lung, and Blood Institute (NHLBI)'s Sleep Heart Health Study made available through the Institute's National Sleep Research Resource.

This community-based study enrolled an approximately equal number of men and women and followed them for up to 11 years.

The study found:

Participants with the shortest duration of breathing events were 31 percent more likely to die.

This association was strongest in participants with moderate sleep apnea as measured by AHI. In this group, participants with the shortest duration of breathing events had a 59 percent increased risk of dying.

"This study shows the power of 'big data' analysis to identify novel predictors of disease outcomes," said senior study author Susan Redline, MD, senior physician, Division of Sleep and Circadian Disorders at Brigham and Women's Hospital in Massachusetts. "The findings indicate that there may be several mechanisms by which sleep apnea leads to increased mortality and a need to measure several features associated with apnea occurrence. In particular, apneas of different types and event durations may result in adverse health outcomes."

According to the researchers, these findings suggest a phenotype of OSA that may be genetically encoded. They add that other studies have shown that the duration of breathing events is highly heritable and that shorter abnormal breathing events are more common in women and in African Americans.

The study has an important limitation. Because it was not a randomized controlled trial, the study could not determine causality between shorter events and death. Shorter events, the authors explained, may be a marker for underlying problems that result in increased deaths, rather than the cause itself.

"This study shows that a readily available trait that is usually not analyzed--the duration of respiratory disturbances--predicts mortality over and beyond that predicted by AHI in both women and men," Dr. Butler said. "Further research is needed to determine how OSA and a low arousal threshold interact as a health risk."

Michael Twery, PhD, director of the National Center on Sleep Disorders Research at NHLBI, part of the National Institutes of Health, said, "Discovering new ways to measure the connection between abnormal breathing during sleep and risks to health is a great example of how NIH-supported research sets the stage for future medical advances."

A newly discovered toxin that some bacteria deploy to fend off competing bacteria stands out from others in the battle for microbial domination. While many deadly substances have been identified among bacteria, this previously unknown toxin behaves in a familiar way.

"What is special about this toxin," noted UW Medicine microbiologist Brook Peterson, "is that it acts by the same biochemical mechanism as some infamous toxins employed by human pathogens, which evolved much later than the toxins bacteria use against each other."

These include the diphtheria, pertussis and cholera toxins. These toxins use similar biochemical mechanisms to impair vital proteins inside host cells For example, the profuse diarrhea that occurs in cholera is a direct result of how its toxin forces cells in the gut to expel too much water and salt by interfering with internal signals. Although bacteria don't get diarrhea, a look under the microscope shows that they do get visibly sick while they are succumbing to the recently identified toxin, named Tre1.

Peterson is a research scientist in the laboratory of Joseph Mougous, professor of microbiology and biochemistry at the University of Washington School of Medicine in Seattle.

For this work on bacterial skirmishes, they studied Serratia proteamaculans. Some strains of this ubiquitous bacteria promote plant growth or live inside tree roots. Some strains inhabit the digestive tract of insects and other animals, and others spoil meat or seafood.

Peterson was one of the senior researchers on the project team that uncovered the new toxin and outlined how bacteria deploy this weapon.

The group also found out how some of the bacteria were protected from poisoning themselves. The findings are published today in the journal Cell.

Far from being a calm collection of one-cell organisms, bacterial struggle with each other for life-sustaining resources, and avail themselves of a variety of powerful antagonists. One survival method is to reduce overcrowding in their microbial colonies.

"The toxin we have discovered targets a protein, called FtsZ, that is essential for cells to divide," Peterson explained. When this protein is blocked, the intoxicated cells grow longer and longer, she said, and eventually split open.

How do some of the bacterial save themselves from their own deadly intentions? The researchers observed that they have an unusual safeguard. These bacteria produce a protein that acts as an enzyme to reverse, almost like an antidote, the modifications that the toxin had instigated.

"This protein protects the bacterium from both the toxin it produces itself," Peterson noted, "and from toxins that function by the same mechanism but made by other species."

"Our findings," the team wrote in the Cell paper, "reveal how an interbacterial arms race has produced a unique solution for safeguarding the integrity of the bacterial cell division machinery..." This protective mechanism confers broad immunity to a variety of toxins.

This inside look at the chemical warfare and biodefense strategies among bacteria in their own communities also provides new insights into the infections that trouble multicellular organisms, including people.

Interbacterial fighting might also be responsible for encouraging the formation of new, more effective toxins and thereby contribute to the emergence of bacterial diseases.

"Research such as this can offer clues to the evolutionary origins of the potent toxins that bacterial pathogens use to cause disease," Peterson observed. "It also provides a fascinating example of the complex strategies bacteria employ in their constant battle for survival with their microbial neighbors." The hostile encounters between bacterial, and their ancestral antibacterial toxins, predate the appearance on the Earth of more complex life forms

ESMO 2018 abstract 619PD_PR - Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric (OG cancer): a pooled analysis of 4 randomised trials.

Women may experience certain chemotherapy side-effects including nausea, vomiting, diarrhoea, mouth ulceration and hair loss more frequently than men, according to a new analysis of oesophageal and stomach cancer patients.

The study, led by The Royal Marsden NHS Foundation Trust and presented today (Friday 19 October 2018) at the European Society for Medical Oncology (ESMO) Congress 2018, analysed data from four randomised trials carried out in the UK and Australasia. All four studies looked at commonly used first-line chemotherapy combinations in advanced oesophageal and stomach cancer.

Drawing on data from 1,654 patients (1,328 men and 326 women), the researchers found that women experienced significantly higher rates of nausea and vomiting (89 per cent for women versus 78 per cent for men), diarrhoea (54 per cent vs 47 per cent), mouth ulceration (50 per cent vs 41 per cent) and hair loss (81 per cent vs 74 per cent). There was also a trend towards more infections in women as a result of low white blood cell counts, although this did not reach statistical significance.

The occurrence of 'serious adverse events' during treatment - potentially serious treatment complications which often require hospital admission - was also higher in women. When looking at chemotherapy effectiveness, there was no difference in survival between men and women, although overall response rate to chemotherapy - the proportion of patients experiencing a reduction in tumour size - was higher in men.

Dr Michael Davidson, Clinical Research Fellow at The Royal Marsden NHS Foundation Trust, said: "Our findings show that women seem to experience higher rates of certain chemotherapy side effects than men in this cancer type, particularly those related to gastro-intestinal function.

"We have known for a long time in oncology that there are differences between males and females in the incidence and prognosis of many non gender-specific cancers. However, we are only just beginning to understand how genetic and biological differences between men and women influence cancer development and response to treatment. There is also on-going research looking at differences in how men and women respond to newer anti-cancer treatments such as immunotherapy, and it is an area that is likely to become increasingly important in the future."

Professor David Cunningham, Director of the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research, London, said: "This work adds to the growing body of evidence that gender can be an important factor in cancer treatment, and that clinicians need to be aware of such differences. For example, knowing female patients are more likely to experience side effects such as nausea and vomiting or diarrhoea may allow for more tailored chemotherapy education and support to be given in order to optimise the management of these common problems."

Philadelphia, October 17, 2018--A new study by researchers at Children's Hospital of Philadelphia (CHOP), the University of Pennsylvania and six other centers reveals that children with developmental delays, including autism spectrum disorder (ASD), are up to 50 percent more likely to be overweight or obese compared with the general population.

The findings were published online by The Journal of Pediatrics.

This is the first large study to demonstrate that young children with ASD or developmental delays are at an equally high risk of developing obesity. Among children with ASD, those with a higher degree of impairment and more severe symptoms were found to be at even greater risk of developing obesity by age five.

The study included nearly 2,500 children between the ages of two and five years old. This age group is especially relevant, since it is an important window for early obesity prevention.

The research was conducted as part of the Study to Explore Early Development (SEED). The multisite study analyzed 668 children with ASD, 914 children with developmental delays or disorders and 884 children from the general population who served as controls. Children's heights and weights were measured during clinical visits, and ASD severity was measured using the Ohio State University Global Severity Scale for Autism.

The study showed that children with ASD were 1.57 times more likely to be overweight or obese than the general population. Children with developmental delays were 1.38 times more likely to be overweight or obese. The risk for obesity was even more pronounced in children with severe ASD symptoms, as they were 1.7 times more likely to be classified as overweight or obese than children with mild ASD symptoms.

"These findings make it clear that monitoring these children for excess weight gain at an early age is critical, and that prevention efforts should be expanded to include not just children with ASD, but those with other developmental diagnoses, as well," said Susan E. Levy, MD, MPH, the study's lead author and medical director of the Center for Autism Research at CHOP.

Although increased obesity in children with ASD has been reported in other studies, this study is the first to examine if children with other developmental disabilities are also at increased risk for developing obesity. Also, the researchers examined connections between excess weight gain and the presence of other medical, behavioral, developmental, or psychiatric conditions.

"We need more research to understand why these children are more likely to develop obesity, and which children are at the highest risk," said Levy. Other medical conditions are especially common among children with ASD, and the authors note that these may play a role in excess weight gain. Possible factors include endocrine disorders, genetic disorders, gastrointestinal symptoms, medication-associated side effects, sleep disturbances, or rigid food choices, among others.

The research findings may shed light into possible mechanisms underlying the increased obesity risk in children with ASD, which may offer targets for early intervention. The authors suggest that clinicians monitor children who receive a diagnosis of ASD or developmental delays/disorders for signs of excess weight gain, and that they provide specific guidance for their parents in an effort to prevent obesity. Parents should discuss with their medical caregiver any concerns they have about their child who may be showing signs of obesity.

Teenage girls who were maltreated as children are more likely to entertain suicidal thoughts if the relationship with their mother is poor and the degree of conflict between the two of them high.

Researchers at the University of Rochester's Mt. Hope Family Center found that the quality of the mother-daughter relationship and their level of conflict are two direct mechanisms underlying the association between child maltreatment and suicidal thoughts during adolescence.

Their study, published in the journal Suicide and Life Threatening Behavior, included 164 socio-economically disadvantaged, depressed, adolescent girls (average age 14) and their mothers. Of the adolescents, 66.3 percent were African-American, 21.3 percent white, and 14 percent Latina.

The team, led by Mt. Hope research assistant professor Elizabeth Handley, used structural equation modeling to test three distinct mediating pathways that linked earlier maltreatment in childhood to suicidal thoughts for adolescent girls: 1) mother-daughter relationship quality, 2) mother-daughter conflict, and 3) adolescent depressive symptoms.

"Our findings suggest that disruptions to a positive mother-teen relationship are one reason why children who experienced abuse or neglect are at risk for suicide as teens," says lead author Handley.

According to Handley, the findings highlight how important relationship-based interventions are for vulnerable youths.

The researchers assessed child maltreatment and mother-daughter relationship quality by looking at the teens' responses to a series of questions. Mother-daughter conflict was measured by using their mothers' answers to another questionnaire.

"We know from decades of research that a warm, nurturing, and consistent relationship between mothers and their children is critical for many aspects of healthy development. This continues to be true even in adolescence, when teens spend more time with their friends and less time at home with family," says Handley.

Maltreatment includes emotional, physical, and sexual abuse, and emotional and physical neglect. Among the study participants 51.8% of adolescents indicated a history of at least one form of maltreatment.

As expected, the researchers found that rates of suicidal thoughts and recurrent thoughts of death were higher among teenage girls with a history of maltreatment than those without: 11.7 percent of non-maltreated, depressed adolescents indicated suicidal ideation, compared to 26.8 percent of maltreated, depressed adolescents.

Child maltreatment is associated with poorer mother-daughter relationship quality and increased mother-daughter conflict, both of which are linked with higher levels of suicidal thoughts among teenagers.

According to the Centers for Disease Control and Prevention (CDC), suicide is the second leading cause of death among adolescents aged 10 to 24 in the United States (accidental death is the leading cause). Adolescent girls in general are more likely than their male counterparts to have suicidal thoughts.

Given the scientific evidence that the more severe and pervasive the suicidal thoughts, the greater the likelihood of suicide attempt, understanding the cause of suicidal thoughts is critical for effective youth suicide prevention and intervention design.

According to the Rochester researchers, relationship-based interventions are a promising approach to depression treatment for maltreated youth, such as interpersonal psychotherapy for adolescents, which focuses on the interpersonal context of depression. Attachment-based family therapy has also proven useful in reducing suicidal thoughts among teenagers by strengthening the functioning of the family and the parent-adolescent attachment relationship.

The Mt. Hope study, which received funding from the National Institute on Mental Health (NIMH), was conducted by researchers at the University of Rochester's Mt. Hope Family Center and the University of Minnesota: lead author Handley was joined by Mt. Hope's Tangeria Adams, Jody Todd Manly, and Sheree Toth, and Minnesota's Dante Cicchetti.

What do watermelons and bacteria have in common? Just like the tasty fruit, microbes can be molded into unusual shapes, a study in Nature Communications has shown. The paper, produced by researchers at the Okinawa Institute of Science and Technology Graduate University (OIST), has modified the structure of bacterial cells from simple rods into elaborate shapes not seen in nature, showing just how robust these life forms can be.

The study centers around the FtsZ protein, a main regulator of cell division in bacteria. Early in the division process, FtsZ acts as a scaffolding protein around which other cell division proteins assemble. During the process, thousands of FtsZ molecules come together in the middle of the cell and form multiple complexes in a circle-like structure known as the Z-Ring.

In the model bacterium Escherichia coli, Z-rings are produced at the site of cell division. But Dr. Bill Söderström of the Structural Cellular Biology Unit wondered if that would always be the case under all circumstances: "This ring forms along the circumference at the midcell, but I wanted to know how important cell shape itself is in creating that. If the cell wasn't rod-shaped, would the Z-ring still be round?"

In essence, Dr. Söderström wondered if he could square a circle. Inspired by seeing watermelons grow into box shapes, his first step was to see if he could get rod-shaped bacterial cells to grow into cubes. The technology already existed: previous studies conducted at OIST had utilized a micro-scale frame that had successfully been used to place bacterial cells upright, instead of flat against the surface of an agarose pad - similar to the way eggs sit upright in an egg box.

These frames were constructed by Dr. Alexander Badrutdinov in OIST's Microfabrication lab, so Dr. Söderström asked if the design could be modified to use a square shape. One simple modification later, the team introduced the growing bacterial cells to their new boxy homes. The team then added chemicals that lowered the structural integrity of the cells, easing them into the irregular shape of the molds.

Just like the watermelons, the bacteria adapted to their new environment and grew into box shapes - and the Z-rings were now Z-squares. From there, the possibilities opened up: what other shapes could the rings be molded into? New nanofabricated frames were constructed. Hearts, triangles, pentagons, crosses, half-moons and even star shapes were produced, and the bacteria set in each. Every shape successfully molded the bacteria and their Z-rings.

"Really, we ended up doing these extra shapes for fun," laughed Dr. Söderström, "yet there's very fundamental science at the heart of it."

The simplicity is deceptive. Dr. Söderström's observations tell us about very basic biology that is fundamental to how these cellular structures are formed. The study demonstrates that these cells can cope with growing and forming division rings in very restrictive conditions. It's a simple piece of science, but it could have bigger ramifications for future research.

Many antibiotics target cellular functions closely related to cell division and the FtsZ-maintained scaffold. When looking for approaches for developing new antibiotics, one would need to look elsewhere than at cell shape. "Our study shows that the Z-ring is incredibly robust - geometry isn't an obstacle to ring formation," said Dr. Söderström.

While the shapes the bacteria can take on might be surprising, it's no shock to see just how adaptable this form of micro-life is - and in an age of antibiotic resistance, it's a timely reminder of the resilience scientists face in finding ways to combat them.

Scientists at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and the Stein Eye Institute have been awarded a $5.1 million grant from the California Institute for Regenerative Medicine to advance the development of a novel therapy for blinding retinal conditions.

The award by the California Institute for Regenerative Medicine, or CIRM, will support the development of a treatment that will use patients' own skin cells to generate autologous induced pluripotent stem cells to derive retinal pigment epithelium cells, which are lost in many blinding eye conditions. The team, led by Dr. Steven Schwartz, will use the grant to drive the promising therapy to the next critical step toward a clinical trial in humans, submitting an investigational new drug application to the Food and Drug Administration.

"We're grateful to CIRM and the people of California for this grant, which will allow our team to translate our research into a treatment for major causes of untreatable blindness such as macular degeneration," said Schwartz, Ahmanson professor of ophthalmology and chief of the retina division at the UCLA Stein Eye Institute. "This pivotal investment brings hope to countless patients and families suffering with blinding eye disease."

Retinal diseases affecting the center of vision, also called maculopathies, are the leading cause of blindness in the developed world and affect more than 10 percent of the U.S. population over 65. The number of people affected by this untreatable group of disorders, such as age related and myopic macular degeneration, and Stargardt's macular dystrophy, is expected to increase to nearly 20 million in the nation by 2020.

Although disorders in this group can have varied underlying causes, they are all linked to the deterioration of the layer of retinal pigment epithelium cells beneath the retina, which lines the inner surface of the back of the eye. These cells are critical to vision; they maintain function of light-sensitive cells called photoreceptors, or rods and cones. Without the retinal pigment epithelium cells, the rods and cones cannot survive. Ultimately, the deterioration of these cells leads to the loss of photoreceptors and eventually to blindness.

The induced pluripotent stem cells maintain the genetic code of the individual from whom they originated. The cells also bear none of the hallmarks of age and instead appear much like very young cells. In the research, these induced pluripotent stem cells will be differentiated into a large volume of the patient's own retinal pigment epithelium cells -- between 50,000 and 500,000 -- which will then be surgically transplanted into their own retinas. Pre-clinical research suggests these new cells will integrate with the patients' remaining retinal pigment epithelium cells, rescue related eye tissue and spur regeneration of the surrounding tissue. Thus, these transplants may preserve or restore vision.

Replacing retinal pigment epithelium cells lost to disease with the stem cell-based cells has already been tested in a first-of-its-kind clinical trial led by Schwartz. That trial showed that retinal pigment epithelium cell replacement strategies are safe and possibly effective in addressing retinal blindness. However, these earlier trials used cells created from human embryonic stem cells, which require that patients take drugs that suppress the immune system longer term so that their bodies do not reject the foreign cells. These immunosuppressive drugs carry substantial health risks, particularly for the elderly.

By creating retinal pigment epithelium cells from patient-derived induced pluripotent stem cells, the new method developed by Schwartz and his team should not pose a risk that the cell therapy will be rejected by the patient's immune system, thus likely eliminating the need for immune suppression. Because many maculopathies are age-related, this key improvement may make Schwartz's novel treatment more accessible to the individuals who need it most.

Another difference between Schwartz's method and previously studied treatments is that the new retinal pigment epithelium cells will be delivered to patients suspended in liquid rather than on a scaffold. This makes it possible for the treatment to be administered in a minimally invasive transplant surgery, which reduces risks and provides faster recovery time.

These two advantages open up the possibility of administering the cell therapy earlier in the course of macular diseases, when some functional tissue remains. Early intervention could be critical to the success of treatments for maculopathies because when diseased retinal pigment epithelium cells are lost, neighboring and essential tissues such as photoreceptors are compromised or disappear completely.

"We hope this research will improve upon the methods studied in previous trials, which showed promise but came with drawbacks and risks," Schwartz said. "The project holds the possibility of developing a treatment that will preserve vision in patients with an early diagnosis, restore vision in patients with end-stage loss of vision, and carry fewer risks."

Schwartz is developing this treatment in collaboration with a multi-disciplinary team comprised of stem cell biologists, ophthalmologists, retinal biologists, immunologists, transplant surgeons, bioengineers and regulatory experts. This group includes co-investigators Dr. Donald Kohn, professor of microbiology, immunology and molecular genetics, pediatrics and molecular and medical pharmacology; William Lowry, professor of molecular, cell and developmental biology; Jerome Zack, professor and chair of microbiology, immunology and molecular genetics; David Williams, professor of ophthalmology and neurobiology; Saravanan Karumbayaram, adjunct professor of microbiology, immunology and molecular genetics; and Zoran Galic, an associate professor of medicine, all members of the UCLA Broad Stem Cell Research Center; as well as Xiaoyang Wang, assistant professor of medicine and health services research.

This research is supported by the California Institute for Regenerative Medicine-funded UCLA-UCI Alpha Stem Cell Clinic and the UCLA Broad Stem Cell Research Center. This includes previous support from the Esther B. O'Keeffe Foundation, the Jean Perkins Foundation and the UCLA department of ophthalmology, which has support from Research to Prevent Blindness Inc., Louis & Harold Price Foundation, Lavery Foundation, and the Smidt Family Foundation.

The potential cell-based treatment for blinding retinal conditions is used in pre-clinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans.

In January the technology world was rattled by the discovery of Meltdown and Spectre, two major security vulnerabilities in the processors that can be found in virtually every computer on the planet.

Perhaps the most alarming thing about these vulnerabilities is that they didn't stem from normal software bugs or physical CPU problems. Instead, they arose from the architecture of the processors themselves - that is, the millions of transistors that work together to execute operations.

"These attacks fundamentally changed our understanding of what's trustworthy in a system, and force us to re-examine where we devote security resources," says Ilia Lebedev, a PhD student at MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL). "They've shown that we need to be paying much more attention to the microarchitecture of systems."

Lebedev and his colleagues believe that they've made an important new breakthrough in this field, with an approach that makes it much harder for hackers to cash in on such vulnerabilities. Their method could have immediate applications in cloud computing, especially for fields like medicine and finance that currently limit their cloud-based features because of security concerns.

With Meltdown and Spectre, hackers exploited the fact that operations all take slightly different amounts of time to execute. To use a simplified example, someone who's guessing a PIN might first try combinations "1111" through "9111." If the first eight guesses take the same amount of time, and "9111" takes a nanosecond longer, then that one most likely has at least the "9" right, and the attacker can then start guessing "9111" through "9911", and so on and so forth.

An operation that's especially vulnerable to these so-called "timing attacks" is accessing memory. If systems always had to wait for memory before doing the next step of an action, they'd spend much of their time sitting idle.

To keep performance up, engineers employ a trick: they give the processor the power to execute multiple instructions while it waits for memory - and then, once memory is ready, discards the ones that weren't needed. This is called "speculative execution."

While it pays off in performance speed, it also creates new security issues. Specifically, the attacker could make the processor speculatively execute some code to read a part of memory it shouldn't be able to. Even if the code fails, it could still leak data that the attacker can then access.

A common way to try to prevent such attacks is to split up memory so that it's not all stored in one area. Imagine an industrial kitchen shared by chefs who all want to keep their recipes secret. One approach would be to have the chefs set up their work on different sides - that's essentially what happens with the "Cache Allocation Technology" (CAT) that Intel started using in 2016. But such a system is still quite insecure, since one chef can get a pretty good idea of others' recipes by seeing which pots and pans they take from the common area.

In contrast, the MIT CSAIL team's approach is the equivalent of building walls to split the kitchen into separate spaces, and ensuring that everyone only knows their own ingredients and appliances. (This approach is a form of so-called "secure way partitioning"; the "chefs", in the case of cache memory, are referred to as "protection domains.")

As a playful counterpoint to Intel's CAT system, the researchers dubbed their method "DAWG", which stands for "Dynamically Allocated Way Guard." (The "dynamic" part means that DAWG can split the cache into multiple buckets whose size can vary over time.)

Lebedev co-wrote a new paper about the project with lead author Vladimir Kiriansky and MIT professors Saman Amarasinghe, Srini Devadas and Joel Emer. They will present their findings next week at the annual IEEE/ACM International Symposium on Microarchitecture (MICRO) in Fukuoka City, Japan.

"This paper dives into how to fully isolate one program's side-effects from percolating through to another program through the cache," says Mohit Tiwari, an assistant professor at the University of Texas at Austin who was not involved in the project. "This work secures a channel that's one of the most popular to use for attacks."

In tests, the team also found that the system was comparable with CAT on performance. They say that DAWG requires very minimal modifications to modern operating systems.

"We think this is an important step forward in giving computer architects, cloud providers and other IT professionals a better way to efficiently and dynamically allocate resources," says Kiriansky, a PhD student at CSAIL. "It establishes clear boundaries for where sharing should and should not happen, so that programs with sensitive information can keep that data reasonably secure."

The team is quick to caution that DAWG can't yet defend against all speculative attacks. However, they have experimentally demonstrated that it is a foolproof solution to a broad range of non-speculative attacks against cryptographic software.

Lebedev says that the growing prevalence of these types of attacks demonstrates that, contrary to popular tech-CEO wisdom, more information-sharing isn't always a good thing.

"There's a tension between performance and security that's come to a head for a community of architecture designers that have always tried to share as much as possible in as many places as possible," he says. "On the other hand, if security was the only priority, we'd have separate computers for every program we want to run so that no information could ever leak, which obviously isn't practical. DAWG is part of a growing body of work trying to reconcile these two opposing forces."

It's worth recognizing that the sudden attention on timing attacks reflects the paradoxical fact that computer security has actually gotten a lot better in the last 20 years.

"A decade ago software wasn't written as well as it is today, which means that other attacks were a lot easier to perform," says Kiriansky. "As other aspects of security have become harder to carry out, these microarchitectural attacks have become more appealing, though they're still fortunately just a small piece in an arsenal of actions that an attacker would have to take to actually do damage."

The team is now working to improve DAWG so that it can stop all currently known speculative-execution attacks. In the meantime, they're hopeful that companies such as Intel will be interested in adopting their idea - or others like it - to minimize the chance of future data breaches.

"These kinds of attacks have become a lot easier thanks to these vulnerabilities," says Kiriansky. "With all the negative PR that's come up, companies like Intel have the incentives to get this right. The stars are aligned to make an approach like this happen."

Ecosystems have a variety of benefits: They provide us with food, water and other resources, as well as recreational space. It is therefore even more important that these systems remain functional and stable - especially in view of climate change or environmental pollution. Ecologists at the University of Zurich and the Swiss Federal Institute of Aquatic Science and Technology (Eawag) have now examined the factors that influence this stability in a unique and comprehensive experiment.

Mini-ecosystems with ciliates

The scientists specifically researched how biodiversity affects the stability of ecosystems. As model organisms, they used six species of ciliates - tiny protozoans that live in water. The researchers put varying numbers and combinations of these ciliates in sample vials, thereby creating miniature ecosystems that they then let thrive at temperatures between 15 and 25 degrees Celsius. The increased temperatures simulated a climatic change, as the ciliates used in the experiment previously lived at a temperature of 15 degrees Celsius.

The researchers then used novel video evaluation techniques to analyze how stable the biomass production in these small ecosystems was. An algorithm developed by the team made it possible to identify the ciliate species in about 20,000 video sequences of the numerous samples recorded under a microscope.

Contrary results

At first glance, the results of the experiment seem contradictory: High biodiversity simultaneously furthers and hinders the stability of an ecosystem. "Ecological stability is complex and consists of various components," says Frank Pennekamp, first author of the study. "The experiment shows how biodiversity affects the individual stability components in different ways." In other words, the more diverse the species community in the miniature ecosystems was, the less the biomass production fluctuated - regardless of temperature. At higher temperatures, however, the researchers found that protozoans produced less biomass the more species were bustling about the system.

"The fact that various components react differently should be taken into consideration in the management of ecosystems, as non-linear connections may occur between diversity and the overall stability of the ecosystem depending on the weighting of the components," says Pennekamp.

Similar effects observed in other ecosystems

Literature research showed that other scientists also observe the contrary connection between biodiversity and stability in other ecosystems, such as grassland or algae communities. "The results make it clear that more species alone is not enough to ensure the overall stability of an ecosystem," says Florian Altermatt, professor of aquatic ecology at Eawag. "In addition to a diversity of species, the species themselves must be able to react to environmental changes in a variety of ways."

Bottom Line: A statistical method could fill the gaps in the U.S. cancer registry data to estimate the short- and long-term risk of recurrence of hormone receptor (HR)-positive and HR-negative breast cancers.

The study found that while women diagnosed with HR-positive breast cancer have lower risk of progression to metastatic disease soon after the diagnosis, their risk persists for several years. In contrast, for women diagnosed with HR-negative disease, the risk of progression to metastatic disease is high soon after the diagnosis, but the long-term risk is lower than that for HR-positive disease.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research

Author: Angela Mariotto, PhD, chief of Data Analytics Branch at the National Cancer Institute, Bethesda, Maryland

Background: "Progression to metastatic breast cancer is probably the most important concern women have when they are diagnosed with early-stage breast cancer," said Mariotto. "Knowing the risks of progressing to metastatic breast cancer is important for patients making decisions about their treatment as well as for cancer control experts identifying research priorities and health services planning."

Currently there are no reliable data on the risk of metastatic breast cancer recurrence after a non-metastatic breast cancer diagnosis, because registries do not routinely collect information on cancer progression or recurrence, Mariotto explained.

How the Study Was Conducted: To estimate the risk of recurrence, Mariotto and colleagues used data from a cohort of 381,430 women, ages 15-84, diagnosed with breast cancer from 1992-2013, from the Surveillance, Epidemiology, and End Results Program (SEER) database.

The researchers applied a statistical technique called the "mixture-cure model" to the survival data to identify the "cure" fraction (fraction of women whose cancer did not progress). Then, they used two pieces of information that are available in the SEER database and published studies to estimate the time to metastasis for women in the "non-cured" fraction (fraction of women whose cancer progressed).

"For the mathematically minded, if we know that A=B+C, and if we know C and A, then we can estimate B," explained Mariotto. "A is the time from diagnosis to death, B is the time from diagnosis to metastasis, and C is the time from metastasis to death. We estimated B using published studies on cohorts of patients diagnosed with recurrent metastatic breast cancer (A and C)."

Results: "We were surprised by the insights the estimates provided into how the risk of recurrence for women diagnosed with early breast cancer in the United States varies with stage, HR status, age, year of diagnosis, and time since diagnosis," Mariotto said. "We found that the risks of progressing to metastasis were lower for women diagnosed with breast cancer more recently, at younger ages, at early stage, and with HR-positive disease."

Mariotto added that for women who survived five or more years after diagnosis, their chances of progressing to metastatic breast cancer within the next five years were lower if they were diagnosed with HR-negative breast cancer compared with women diagnosed with similar stage but with HR-positive breast cancer.

For example, among women diagnosed with stage 3 breast cancer at ages 60-74, the percent progressing to metastasis within five years from diagnosis is lower (34.5 percent) if their breast cancer is HR-positive and higher (48.5 percent) if their breast cancer is HR-negative. However, if they are still metastasis-free five years from diagnosis, the percent progressing to metastasis within the next five years is higher for HR-positive breast cancer (16.8 percent) versus HR-negative breast cancer (6.4 percent).

WHAT: 11th World Stroke Congress brings together leading international stroke experts and an unparalleled scientific program covering epidemiology, prevention, acute care, rehabilitation and recovery in 100s of sessions and oral posters. Congress is attended by close to 2500 stroke professionals, researchers, policy makers, survivors and caregivers from around the world. #worldstroke2018

WHERE: Montreal, Canada, Palais des Congrès

WHEN: October 17 - 20, 2018

MEDIA OPPORTUNTIES: Stroke experts and people with lived experience of stroke will be available for interviews.

TODAY'S CONGRESS HIGHLIGHTS

Late Breaking trials:

VERSE: Very Early Rehabilitation in SpEech (VERSE): A prospective, multicentre randomised, controlled, open-label, blinded-endpoint trial in patients with aphasia following acute stroke. Results will be presented by Dr. Erin Godecke of Australia (6:10 p.m., Hall A)

FIND-AF: The final 3-year results of the FIND-AF Randomized Trial (6:50 p.m., Hall A). Results will be presented by Dr. Rolf Wachter of Germany.

Time course of risk versus benefit of clopidogrel and aspirin in acute ischemic stroke and high-risk TIA: a planned secondary analysis from the POINT Trial, presented by Dr. Jordan Elm of the U.S.A. (6:30 p.m., Hall A)

The first of two presentations of results of studies evaluating the use of the drug dabigatran will be presented. Today's (7:30 p.m., Hall A) will examine the use of dabigatran against acetylsalicylic acid (ASA) to prevent secondary stroke in patients with embolic stroke of undetermined source (ESUS) while on Saturday, Oct. 20, results will be presented evaluating dabigatran versus dose-adjusted warfarin in patients with cerebral venous thrombosis (11:30 a.m., Hall B).

HOT TOPIC: Access to stroke rehabilitation in Canada

A Canadian study, conducted by Dr. Anita Mountain of Dalhousie University in Halifax and Dr. Patrice Lindsay of Heart & Stroke, found that while overall access to and efficiency of stroke rehabilitation in Canada improved from 2008 to 2017, significant provincial and regional differences exist.

Access to and efficiency of stroke rehabilitation is an important subject given that there are about 62,000 strokes in Canada every year and more than 400,000 people are living with long-term disability from stroke - a number that is expected to double in the next 20 years.

The study looked at data from 188 inpatient stroke rehabilitation facilities across Canada, of which 99 report statistics to the Canadian Institute for Health Information. Between 2008 and 2015, the number of stroke rehab admissions rose from 5,969 to 9,025.

The study also found that while 93 per cent of Canadians live less than one hour from an inpatient stroke rehabilitation facility, bed capacity continues to hamper prompt access. However, from 2013 to 2017 there was improved access to a dedicated stroke rehabilitation unit, interdisciplinary teams and specialized equipment.

"Canadian Stroke Best Practice Recommendations help guide the delivery of effective evidence-based stroke rehabilitation across Canada," said Dr. Mountain. "We know what needs to be done and have seen improvements in the access and efficiency of stroke rehabilitation over the past decade. However, the degree of improvement is not consistent across Canada. We need to ensure there is access to the same quality and intensity of stroke rehabilitation services for all Canadians regardless of what province or region they live in."

Rehabilitation needs to begin early after stroke when the brain is most amenable to recovery. More than 80 per cent of people now survive a stroke but more than 60 per cent are left with long-term disability, a figure that could be improved with broad and timely access to appropriate services.

HOT TOPIC: Gender differences in accessing stroke care

Another Canadian study, led by Dr. Noreen Kamal of the University of Calgary, looks at differences between women and men in access to a key type of acute stroke care in Canada, endovascular thrombectomy (EVT). With EVT, a person with an ischemic stroke has the clot physically removed as soon as possible after symptoms start. The process involves threading a thin tube through an artery, and guiding it with X-ray imaging through blood vessels to the brain. A retrievable stent is used to remove the clot. The procedure has shown remarkable results in studies, reducing the overall death rate by 50 per cent and greatly diminishing the lasting effects of stroke in many patients.

The study analyzed Canadian hospital data over five years from 2011 to 2016. It found that more men presenting with ischemic stroke were transferred to a comprehensive stroke centre, compared to women. It also found that 17 per cent of patients were transferred to a comprehensive stroke centre to receive a clot-busting drug treatment. Among patients transferred, only 40.4 per cent were women. Additionally, the study found that men had a slightly shorter median time than women from when they first arrived to when they were transferred, 1.37 hours versus 1.50 hours. Researchers say that further investigation is needed to understand the results and determine what may be causing the gap in efficient stroke treatment for women.

Dr. Thalia Field, a stroke neurologist and fellowship program director for the Vancouver Stroke Program, will present a study tomorrow that analyses gender differences in stroke care and outcomes among 257,582 Canadian stroke patients from 2009 to 2016, of whom 49 per cent were female. This study found that women were less likely to receive alteplase clot-busting medication for ischemic stroke (13.7 per cent vs. 14.2 per cent for men), had longer times from entering hospital to receiving treatment (average median time from arrival to treatment of 103 minutes vs. 89 for men) and were more likely to die within seven days of their stroke (8.5 per cent vs. 7.9 per cent).

HOT TOPICS: Other presentations of interest on the first day of the Congress:

A major study of the impact of the consolidation of acute stroke care from nine community hospitals in southeastern Ontario to three specialized stroke units resulted in a huge increase in stroke unit care and a five-per-cent drop in the stroke mortality rate. "More people are getting stroke unit care and fewer people are dying," says Cally Martin, regional director of the Stroke Network of Southeastern Ontario.

An Australian study found women died more often within the first year after a stroke compared to men, and the causes of death varied by sex. By observing the outcomes of almost 10,000 Australians who experienced a stroke, researchers from the Florey Institute of Neuroscience and Mental Health and the Menzies Institute for Medical Research have been able to rule out any systemic bias in the healthcare received by men and women. However, researchers were not sure whether men and women have different causes of death following a stroke. They also weren't sure if the higher long-term death rate following a stroke could be traced back to a specific cause or causes, and whether these might differ by sex.

An interactive platform discussion with world experts will examine shaping a future of integrated care for stroke and non-communicable diseases (NCDs). Stroke and other NCDs are collectively driven by the same risk factors and often present as co-morbidities. They are often chronic, complex, and related to persistent handicaps. As stroke survivors know well, a more integrated care with a life-course approach is required. Yet, health systems are ill-equipped to respond to this need, as they focus on single diseases with specific therapies. A new policy brief on stroke and NCDs with key messages and action points on these issues will be presented at a 12:40 pm session in the Exhibition Hall featuring Dr. Marc Fisher, Professor of Neurology, Harvard Medical School, Editor-in-Chief of Stroke (USA), Dr. Sheila Martins, Founder and President of Brazilian Stroke Network (Brazil), Dr. Bo Norrving, Professor of Neurology, Lund University (Sweden), and Yves Savoie, CEO, Heart & Stroke Foundation (Canada)

The 2.7 billion people who live in China and India -- more than a third of the world's population -- regularly breath some of the dirtiest air on the planet. Air pollution is one of the largest contributors to death in both countries, ranked 4th in China and 5th in India, and harmful emissions from coal-fire powerplants are a major contributing factor.

In a recent study, researchers from Harvard University wanted to know how replacing coal-fired powerplants in China and India with clean, renewable energy could benefit human health and save lives in the future.

The researchers found that eliminating harmful emissions from powerplants could save an estimated annual 15 million years of life in China and 11 million years of life in India.

The research was published in the journal Environment International.

Previous research has explored mortality from exposure to fine particulate matter (known as PM2.5) in India and China but few studies have quantified the impact of specific sources and regions of pollution and identified efficient mitigation strategies.

Using state-of-the-art atmospheric chemistry modeling, the researchers calculated province-specific annual changes in mortality and life expectancy due to power generation. Using the province-specific approach, the researchers were able to narrow down the areas of highest priority, recommending upgrades to the existing power generating technologies in Shandong, Henan, and Sichuan provinces in China, and Uttar Pradesh state in India due to their dominant contributions to the current health risks.

"This study shows how modeling advances and expanding monitoring networks are strengthening the scientific basis for setting environmental priorities to protect the health of ordinary Chinese and Indian citizens," said Chris Nielsen, executive director of the Harvard-China Project and a co-author of the paper. "It also drives home just how much middle-income countries could benefit by transitioning to non-fossil electricity sources as they grow."

MINNEAPOLIS - A simple test taken within a week of a stroke may help predict how well people will have recovered up to three years later, according to a study published in the October 17, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"We found that this test, which takes less than 10 minutes, can help predict whether people will have impaired thinking skills, problems that keep them from performing daily tasks such as bathing and dressing and even whether they will be more likely to die," said study author Martin Dichgans, MD, of Ludwig-Maximilians University in Munich, Germany. "This test should be used to screen people with stroke and to counsel them and their families about long-term prognosis and also to identify those who would most benefit from interventions that could improve their outcomes."

For the study, 274 people in Germany and France who had a stroke were given the test, called the Montreal Cognitive Assessment, within a week of the stroke. They were then divided into two groups: those with no problems with thinking and memory skills and those with cognitive impairment. The participants were tested for their thinking and memory skills, motor functioning and ability to complete daily living tasks six months later and then at one and three years after the stroke.

The study found that those who had thinking problems within one week of the stroke were seven times more likely to die during the three years of the study than those who did not have thinking problems. The survival rate for those with thinking problems after three years was 83 percent, while the rate was 97 percent for those with no thinking problems early on.

Those with thinking problems on the first test were also five times more likely to have problems with their motor skills than those who did not have thinking problems early on. By three years after the stroke, 29 percent of those with thinking problems on the first test had problems with their motor skills, compared to 5 percent of those who did not have thinking problems early on.

Those with cognitive impairment were more than twice as likely to have problems completing their daily activities such as bathing and dressing, with 42 percent having problems compared to 13 percent three years after the stroke.

Those with cognitive impairment were five times more likely to continue having thinking problems three years after the stroke than the other group.

Dichgans noted that the test helped predict outcomes even when other factors such as the severity of the stroke were taken into account.

A limitation of the study was that most of the people involved had relatively mild strokes, so more research is needed to determine whether the results apply to people with more severe strokes.