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DNA from uterine cells of women with endometriosis has different chemical modifications, compared to the DNA of women who do not have the condition, according to researchers funded by the National Institutes of Health. The changes involve DNA methylation--the binding of compounds known as methyl groups to DNA--which can alter gene activity. Moreover, the methylated DNA regions varied according to the stage, or severity, of endometriosis and responded differently to hormones involved in the menstrual cycle. Uterine responses to hormones influence pregnancy and other functions of uterine tissue.

The study was conducted by Linda C. Giudice, M.D., Ph.D., and colleagues at the University of California, San Francisco. It appears in PLOS Genetics. The study was funded by NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

"The findings raise the possibility that differences in methylation patterns could one day be used to diagnose endometriosis and develop customized treatment plans for patients," said Stuart B. Moss, Ph.D., of NICHD's Fertility and Infertility Branch.

Endometriosis is a disease in which tissue similar to the lining of the uterus grows in other places in the body, such as on the ovaries, fallopian tubes or the bowels and bladder. It affects from 5 to 10% of women in the United States. Its main symptoms include pain, especially during menstrual periods, and infertility. Endometriosis is classified into four stages, ranging from minimal (stage I) to severe (stage IV). The only definitive way to diagnose endometriosis is with a surgical procedure called a laparoscopy.

The researchers analyzed a type of cell known as an endometrial stromal fibroblast, which regulates cells in the lining of the uterus. They compared methylation across DNA regions and differences in gene functioning in cells from women who did not have endometriosis or any other gynecological disorders to those of women with stage I endometriosis and of women with stage IV endometriosis. They also observed methylation patterns and gene functioning after the cells were exposed to estradiol (a form of estrogen) alone, progesterone alone, and to a combination of the two hormones to mimic changes in the levels of these hormones that occur during the menstrual cycle.

DNA methylation patterns and gene functioning differed among all groups of cells before exposure to the hormones, with exposure to each individual hormone, and to the combination of the two. The differences in methylation and gene functioning between stage I and stage IV endometrial cells could mean that the two may be distinct subtypes of endometriosis, rather than different degrees of the condition, Dr. Giudice added.

"The data indicate that the proper interactions of hormones and DNA methylation are critical in normal uterine function," said the study's lead author, Sahar Houshdaran, Ph.D., University of California, San Francisco. "The changes in these interactions that we've seen could play a role in the infertility that often accompanies endometriosis."

Simon Fraser University researchers are hoping their latest study on seniors will help to address one of their biggest physical challenges -- injury from falls.

Falls cause more than 95 per cent of hip fractures in older adults and recovery results can be grim. About 30,000 people experience a hip fracture each year in Canada. While most will face surgery, months of recovery time and reduced independence and physical activity, others may succumb to their injuries.

"About 25 per cent of older adults in long-term care who experience hip fracture die within six months, so it's really important that we direct efforts to prevent falls and also to prevent hip fracture in the event of a fall, especially in the high-risk, long-term care setting," says study lead, Steve Robinovitch, an SFU professor in the Department of Biomedical Physiology and Kinesiology.

While COVID-19 has highlighted the need to improve standards in long-term care facilities, the researchers say addressing issues related to safe mobility is also key to improving seniors' quality of life.

"We need to remember that it's not just infectious disease that strikes this population, it's also problems of mobility and injuries due to falls that are often on top of their list of challenges," says Robinovitch.

Since 2007, Robinovitch has partnered with two Lower Mainland long-term care homes to record and analyze video footage of falls in common areas.

For the most recent study, published in the Journal of Bone and Mineral Research, the team analyzed 2,377 falls experienced by 646 residents. Only 30 of the falls caused hip fracture, a little over one per cent of the total number of falls recorded.

"Only a small portion of falls caused hip fracture but the problem is that falls are so common, with the average resident in long-term care falling three times per year, that the cumulative toll is enormous," says Robinovitch.

The team found that all hip fractures were caused by falls from standing height that caused impact to the pelvis on the fracture side. While backward falls were safest, forward falls were just as likely as sideways falls to hip fracture, due to rotation during descent. Factors such as arresting the fall with outstretched hands, body weight or osteoporosis had no effect.

However, falling while wearing a hip protector reduced the risk of hip fracture by over twofold.

"Our study shows that older adults in long-term care in British Columbia are wearing and benefitting from hip protectors. Hip protectors were worn in over 70 per cent of falls, and halved the risk for hip fracture. But across Canada, there's evidence that only 10 to 20 per cent of people in long-term care are wearing hip protectors," Robinovitch explains.

"We're working with partners in Ontario to develop strategies to increase uptake of hip protectors in long-term care homes, and developing strategies to translate the successful B.C. model to other areas of Canada and internationally."

He says the team is continuing to analyze the data to gain a more precise understanding of the loads that are applied to bones during falls. These data can be used to help improve the design of hip protectors to provide more effective protection from the types of impacts that cause hip fractures.

The study also revealed that mobility aids reduce the likelihood of older adults fracturing a hip during a fall by over threefold. Robinovitch says families and care providers can encourage seniors to use their walkers to preserve mobility and maintain their independence while providing protection against injury.

Study co-author Fabio Feldman is the director of clinical quality and patient safety for Fraser Health. Feldman implemented a successful hip protector program in long-term care for Fraser Health, which is now being used across the province.

"This research is so important for us to better understand the characteristics of falls that result in hip fracture and shed a light on what are the possible interventions that we can have in place," he says.

Feldman, who is also an SFU alumnus, adds that he hopes their research leads to a shift from focusing on fall prevention to injury prevention.

"There are many ways that you can reduce the risk of having a fall but in the senior population, especially long-term care, quality of life is important," Feldman says. "There are different ways to make people safe without restricting their activities."

The saying, "what doesn't kill you makes you stronger," doesn't necessarily hold up when it comes to military mental health. Michigan State University is the first to examine veterans' personalities before and after deployment to measure psychological changes resulting from combat.

The study, published in Journal of Personality, was born through a partnership between MSU and the United States Army because military leaders wanted a better understanding as to why some soldiers struggled with reintegration to civilian life while others did not.

"Veterans' substance abuse, domestic violence and suicide rates are higher than other populations; the Army knew it was time to more closely track psychological traits before and after they deployed," said William Chopik, associate professor of psychology at MSU and lead author. "Our research suggests that many mental health struggles existed before they were sent overseas."

As the largest study of its kind, more than 212,000 men and women Army active duty personnel completed a questionnaire that measured different psychological characteristics before deployment and after returning from combat.

"The questionnaire measured 24 'character strengths,' ranging from appreciation, courage and temperance to bravery, humor and love," Chopik said. "Having high character traits is something we associate with people who don't suffer from mental health conditions."

The researchers found that 60% of the soldiers scored highly in character strengths prior to deployment and changed little once they returned home. The other 40% started with lower character strengths and declined post-deployment - and they struggled significantly to recover.

"Our findings suggest that people who are stable with positive character strengths prior to deployment - which was the majority of soldiers - don't have high rates of substance abuse, depression or other struggles once they return from combat," Chopik said. "If someone from this group struggled once coming home, they were able to bounce back."

On the other hand, the 40% who went into the Army with lower character strengths experienced further declines, with only small improvements over time.

"If you're humble, forgiving and honest before deployment, you'll likely come home that way," Chopik said. "But if you're struggling before, you'll struggle later. Combat intensifies and exacerbates the low character strengths in nearly 85,000 soldiers - which is a substantial number of people who are at-risk for major mental health issues."

The Army is using the research findings to boost its efforts in developing resources that will help the 40% of its struggling veterans assimilate to civilian life, Chopik explained. He also said that the Army is taking a closer look at mental health before and after allowing soldiers to begin active duty.

"This is a scenario in which the effects of trauma are clearly pronounced," Chopik said. "Times have changed in our society, and we're paying much closer attention to military mental health than we did in the 20th century."

Chopik hopes that the public will be more sensitive to the fact that traumatic experiences - like serving in the military - are exposing people to experiences that can have long-lasting changes and effects on their personalities.

Root crops like cassava, carrots and potatoes are notoriously good at hiding disease or deficiencies which might affect their growth. While leaves may look green and healthy, farmers can face nasty surprises when they go to harvest their crops.

This also poses problems for plant breeders, who have to wait months or years before knowing how crops respond to drought or temperature changes. Not knowing what nutrients or growing conditions the crop needs early on also hinder crop productivity.

New research using machine learning and to help predict root growth and health with aboveground imagery was published June 14 in Plant Methods.

"One of the great mysteries for plant breeders is whether what is happening above the ground is the same as what's happening below," said Michael Selvaraj, a co-author from Alliance of Bioversity International and the CIAT.

"That poses a big problem for all scientists. You need a lot of data: plant canopy, height, other physical features that take a lot of time and energy, and multiple trials, to capture what is really going on beneath the ground and how healthy the crop really is," said Selvaraj, a crop physiologist.

While drones are getting cheaper, and hardware for capturing physical images through crop trials has become easier to use, a major bottleneck has been analyzing vast quantities of visual information and distilling it into useful data for plant breeders.

Using drone images, the Pheno-i platform can now merge data from thousands of high-resolution images, analyzing them through machine learning to produce a spreadsheet. This shows scientists exactly how plants are responding to stimuli in the field in real-time.

Using the technology, breeders can now respond immediately, applying fertilizer if a particular nutrient is lacking, or water. The data also allows scientists to quickly discover which crops are more resistant to climate shocks, so they can advise farmers to grow more drought or heat-resilient varieties.

"We're helping breeders to select the best root crop varieties more quickly, so they can breed higher-yielding, more climate-smart varieties for farmers," said Gomez Selvaraj.

"The drone is just the hardware device, but when linked with this precise and rapid analytics platform, we can provide useful and actionable data to accelerate crop productivity."

The technology holds promise for other crops.

"Automated image analytical software and machine learning models developed from this study is promising and could be applied to other crops than cassava to accelerate digital phenotyping work in the alliance research framework," said Joe Tohme, the Alliance research director for Crops for Nutrition and Health.

UCLA engineers have designed a thin adhesive film that could upgrade a consumer smartwatch into a powerful health-monitoring system. The system looks for chemical indicators found in sweat to give a real-time snapshot of what's happening inside the body. A study detailing the technology was published in the journal of Science Advances.

Smartwatches can already help keep track of how far you've walked, how much you've slept and your heart rate. Newer models even promise to monitor blood pressure. Working with a tethered smartphone or other devices, someone can use a smartwatch to keep track of those health indicators over a long period of time.

What these watches can't do, yet, is monitor your body chemistry. For that, they need to track biomarker molecules found in body fluids that are highly specific indicators of our health, such as glucose and lactate, which tell how well your body's metabolism is working.

To address that need, the researchers engineered a disposable, double-sided film that attaches to the underside of a smartwatch. The film can detect molecules such as metabolites and certain nutrients that are present in body sweat in very tiny amounts. They also built a custom smartwatch and an accompanying app to record data.

"The inspiration for this work came from recognizing that we already have more than 100 million smartwatches and other wearable tech sold worldwide that have powerful data-collection, computation and transmission capabilities," said study leader Sam Emaminejad, an assistant professor of electrical and computer engineering at the UCLA Samueli School of Engineering. "Now we have come up with a solution to upgrade these wearables into health-monitoring platforms, enabling them to measure molecular-level information so that they give us a much deeper understanding of what's happening inside our body in real time."

The skin-touching side of the adhesive film collects and analyzes the chemical makeup of droplets of sweat. The watch-facing side turns those chemical signals into electrical ones that can be read, processed and then displayed on the smartwatch.

The co-lead authors on the paper are graduate student Yichao Zhao and postdoctoral scholar Bo Wang. Both are members of Emaminejad's Interconnected and Integrated Bioelectronics Lab at UCLA.

"By making our sensors on a double-sided adhesive and vertically conductive film, we eliminated the need for the external connectors," Zhao said. "In this way, not only have we made it easier to integrate sensors with consumer electronics, but we've also eliminated the effect of a user's motion that can interfere with the chemical data collection."

"By incorporating appropriate enzymatic-sensing layers in the film, we specifically targeted glucose and lactate, which indicate body metabolism levels, and nutrients such as choline," Wang said.

While the team designed a custom smartwatch and app to work with the system, Wang said the concept could someday be applied to popular models of smartwatches.

The researchers tested the film on someone who was sedentary, someone doing office work and people engaged in vigorous activity, such as boxing, and found the system was effective in a wide variety of scenarios. They also noted that the stickiness of the film was sufficient for it to stay on the skin and on the watch without the need for a wrist strap for an entire day.

Over the past few years, Emaminejad has led research on using wearable technology to detect indicator molecules through sweat. This latest study shows a new way that such technologies could be widely adopted.

"We are particularly excited about our technology because by transforming our smartwatches and wearable tech into biomonitoring platforms, we could capture multidimensional, longitudinal and physiologically relevant datasets at an unprecedented scale, basically across hundreds of millions of people," Emaminejad said. "This thin sensing film that works with a watch shows such a path forward."

A COVID-19 outbreak in a refugee settlement will likely overwhelm the available healthcare capacity and infrastructure and spread through nearly the entire settlement population if left unchecked, according to a new study published June 16 in PLOS Medicine by Paul Spiegel of Johns Hopkins University, United States, and colleagues.

Forcibly displaced populations, especially those who reside in settlements with high density, poor access to water and sanitation, and limited health services, are especially vulnerable to COVID-19. Spiegel and colleagues used a dynamic model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission to simulate how a COVID-19 outbreak could spread through a such a setting, the Kutupalong-Balukhali Expansion Site in the Cox's Bazar district of Bangladesh. Approximately 600,000 Rohingya refugees from Myanmar reside at the settlement, where at least one refugee has died of COVID-19 and 29 have tested positive for the virus since the first case was detected on May 14 in the camps.

The researchers simulated high, moderate, and low transmission scenarios and estimated the hospitalizations, deaths, and healthcare needs expected, adjusting for the age distribution of the population at the Kutupalong-Balukhali. The model predicts the number of people infected in the first year will reach 421,500 (95% PI, 376,300-463,500), 546,800 (95% PI, 499,300-567,000), and 589,800 (95% PI, 578,800-595,600) in the low, moderate, and high transmission scenarios, respectively, should no effective interventions to prevent spread of the virus be put into place. Spiegel and colleagues estimate the hospitalization needs would exceed the current capacity 55-136 days after introduction, and the outbreak would lead to 2,040 (95% PI, 1,660-2,500), 2,650 (95% PI, 2,030-3,380), and 2,880 (95% PI, 2,090-3,830) deaths in the three scenarios.

The authors note that the known epidemiological properties of COVID-19 are based on the transmission of SARS-CoV-2 virus in non-displaced populations, and even in these populations the parameters are poorly defined. However, the spread of disease through the densely populated refugee settlement is likely to be faster, not slower, than in populations with easier access to the tools (social distancing, basic hygiene, contact tracing and isolation) used to limit spread of disease. The authors emphasize that in this setting, innovative responses and intervention from health agencies and local governments will be necessary to quell the spread and treat the infected population.

From Academic Editor, Parveen Parmar:
"The work by Spiegel and colleagues highlights the significant vulnerability of displaced populations in the time of COVID-19, both in the Rohingya refugee camps and beyond. Health systems that are already overstretched will require significant additional support from the global community to meet new needs. It is critical that we continue to bring the needs of the most vulnerable among us to the forefront in this manner. Indeed, if we are ever to be successful in this battle against COVID-19, no one can be left behind--no matter what their age, ethnicity, gender, sexuality, or legal status, and no matter what side of a border they find themselves on."

As cancer survivor rates increase with modern treatments, cardiovascular disease (CVD) rates are rising in cancer patients and survivors and CVD has emerged as a leading cause of long-term preventable death in this population. Even though cardioprotective medications--including statins, ACE inhibitors and antiplatelet therapies--are frontline primary and secondary CVD prevention, patients with a prior or current history of cancer had lower rates of utilization compared to those without cancer, according to a research letter published in JACC: CardioOncology.

"A history of cancer and cancer treatment are associated with an increased risk of cardiovascular disease and is an issue of substantial public health importance," said Doan TM Ngo, BPharm, B.Health Sc (Hons), PhD, of the School of Biomedical Sciences and Pharmacy at the University of Newcastle in Australia and senior author of the study. "It is clear there are practice and policy gaps regarding the treatment of these patients and it is vital to develop strategies to improve guideline-directed cardioprotective therapies in cardio-oncology."

The researchers examined the records of 320 patients admitted to the cardiology unit at John Hunter Hospital between July 2018 and January 2019. Patients were divided into two groups: those with a prior or current history of cancer and those without. Of the 69 cancer patients, 36% had established CVD prior to their cancer diagnosis, while 64% developed CVD after their cancer diagnosis.

There were no significant differences in age, body mass index, gender, hypertension, diabetes, high cholesterol or atrial fibrillation between the cancer and non-cancer patients. The two groups also had similar cardiovascular risk factors when compared to one another. Cancer patients had lower utilization rates of antiplatelet therapies and statins compared to non-cancer patients. Cancer patients were also more likely to have been admitted to the hospital for heart failure.

When researchers evaluated the prescription of cardioprotective medications at admission, cancer patients' statins and antiplatelet prescriptions were also lower. According to the researchers, the results suggest that "the management of modifiable cardiovascular risk factors in patients with cancer is suboptimal compared to those without a history of cancer."

Study limitations include the risk of confounding, as well as the study being conducted in a single center.

While many people put off their regular trips to the dentist, recent research has shown that the consequences of doing so may go beyond cavities and root canals. From heart disease to diabetes, poor oral health is often a reflection of a person's overall health and may even be the cause of systemic disease.

A new collaborative study from the U-M Medical and Dental Schools reveals that inflammatory bowel disease (IBD), which included Crohn's disease and ulcerative colitis and afflicts an estimated 3 million adults in the U.S., may be the latest condition made worse by poor oral health.

Nobuhiko Kamada, Ph.D., assistant professor of internal medicine in the division of gastroenterology, has been studying the gut microbiome--the collection of bacteria that are normally present in the gut-- for years. He noted an emerging link in research literature between an overgrowth of foreign bacterial species in the guts of people with IBD--bacteria that are normally found in the mouth. "I decided to approach the dental school to ask the question, does oral disease affect the severity of gastrointestinal diseases?" says Kamada.

The new mouse study, published in Cell, shows two pathways by which oral bacteria appear to worsen gut inflammation.

In the first pathway, periodontitis, the scientific name for gum disease, leads to an imbalance in the normal healthy microbiome found in the mouth, with an increase of bacteria that cause inflammation. These disease-causing bacteria then travel to the gut.

However, this alone may not be enough to set off gut inflammation. The team demonstrated that oral bacteria may aggravate gut inflammation by looking at microbiome changes in mice with inflamed colons.

"The normal gut microbiome resists colonization by exogenous, or foreign, bacteria," says Kamada. "However, in mice with IBD, the healthy gut bacteria are disrupted, weakening their ability to resist disease-causing bacteria from the mouth." The team found that mice with both oral and gut inflammation had significantly increased weight loss and more disease activity.

In the second proposed pathway, periodontitis activates the immune system's T cells in the mouth. These mouth T cells travel to the gut where they, too, exacerbate inflammation. The gut's normal microbiome is held in balance by the action of inflammatory and regulatory T cells that are fine-tuned to tolerate the resident bacteria. But, says Kamada, oral inflammation generates mostly inflammatory T cells that migrate to the gut, where they, removed from their normal environment, end up triggering the gut's immune response, worsening disease.

"This exacerbation of gut inflammation driven by oral organisms that migrate to the gut has important ramifications in emphasizing to patients the critical need to promote oral health as a part of total body health and wellbeing," says co-author William Giannobile, DDS, the William K and Mary Anne Najjar professor of dentistry and chair of the department of periodontics and oral medicine at the U-M School of Dentistry.

The study has implications for novel treatments for IBD, necessary because "far too many patients still fail medications, leading to reduced quality of life and eventual surgery," says study co-author Shrinivas Bishu, M.D., assistant professor of gastroenterology. "This study importantly implies that clinical outcomes in IBD may be improved by monitoring oral inflammation - an intriguing concept."

Kansas City, MO--Scientists at the Stowers Institute for Medical Research have shown that a dysfunctional placenta can play a previously unrecognized role during the earliest stages of development in mouse models of Cornelia de Lange syndrome. People with this rare genetic disorder often harbor mutations in cohesins, ring-like proteins that help DNA organize and repair itself.

The researchers found that mice with cohesin mutations had placentas that accumulated damage to their DNA, entered a permanent growth-arrested state known as senescence, and churned out pro-inflammatory cytokines that affected embryonic growth.

The findings, which appear online June 16, 2020, in the journal Developmental Cell, suggest that targeting cytokine signaling may be a way to protect the health of the placenta and promote healthy pregnancies.

"The discovery that DNA damage activates senescence in the placenta has huge implications," says Jennifer L. Gerton, PhD, an Investigator at the Stowers Institute and lead author of the study. "In terms of potential relevance to human health, our research suggests that this could be one mechanism through which things like smoking, which can cause DNA damage and intrauterine growth restriction, might be acting."

An estimated one in 20 newborns are affected by intrauterine growth restriction, in which a baby is smaller than expected because it is not growing at a normal rate inside the womb. One of the most striking examples of this stunted growth is Cornelia de Lange syndrome, a rare condition that affects one in 10,000 newborns. People born with this disorder can have short stature, intellectual disability, and abnormalities of bones in the arms, hands, and fingers.

Cornelia de Lange syndrome is caused by mutations in genes that affect a complex of proteins called cohesins that encircle DNA and fold it into loops. Scientists have long believed that the syndrome occurs when defects in cohesin complexes throw the organization of DNA into disarray, disrupting the way genes are turned on and off during development. However, Gerton and her team suspected that was only part of the story.

Previous studies revealed that women who were carrying babies with Cornelia de Lange syndrome had lower levels of a protein called pregnancy associated plasma protein-A (PAPP-A). Because this protein is secreted by the placenta, the finding suggested that something might also be wrong with this vital and yet understudied organ.

Vijay Pratap Singh, PhD, a postdoc in the Gerton lab, decided to look at what was happening to the placenta in mouse models of Cornelia de Lange syndrome. He found persistent damage to their genomes, underscoring an important but understudied function of cohesins in repairing DNA damage. These maintenance issues sent the placenta into a premature state of senescence, where its cells stopped dividing.

Singh showed that as the cells of the placenta shifted into senescence, they began secreting chemicals known as cytokines that initiate the inflammatory response, like flares to signal danger. These cytokines accumulated in the embryonic mice, affecting their growth and health.

"There is an old saying that during pregnancy, any kind of stress can affect the baby's growth. Here, using mouse models, we have shown on a molecular level how DNA damage can affect embryonic growth through cytokine signaling," says Singh, who was first author of the report.

To further explore the role of the placenta in Cornelia de Lange syndrome, Singh tested whether a normal mouse placenta could reduce the growth defects of a Cornelia de Lange mouse model embryo. Remarkably, he found that Cornelia de Lange mouse model embryos supported by normal mouse placentas survived better and were healthier than those fed by affected placentas.

In the future, the researchers plan to test whether they can also generate better outcomes in mouse models of the syndrome with small-molecule drugs that block pro-inflammatory cytokines in the placenta. Gerton says it is possible that such anti-inflammatory drugs could one day improve pregnancy outcomes, but more research is needed.

Sean McKinney, PhD, head of the Stowers Microscopy Center was also a co-author on the study. The work was funded by the Stowers Institute for Medical Research and the March of Dimes.

Lay Summary of Findings

Cohesins are ring-like proteins that are essential for chromosome segregation, gene expression, and repair of DNA damage. Mutations that affect these proteins cause the human developmental disorder Cornelia de Lange syndrome. In a report published online June 16, 2020, in the journal Developmental Cell, Stowers Institute scientists from the laboratory of Jennifer L. Gerton, PhD, describe a detailed study of the placentas of mouse models of the syndrome.

The researchers discovered that the Cornelia de Lange mouse model placentas accumulated damage to their DNA, entered a permanent growth-arrested state known as senescence, and churned out pro-inflammatory cytokines that affected the growth of the embryonic mice. These findings have important implications for understanding the crucial role that the placenta plays in mammalian development.

A new method of screening thousands of drugs in freshly collected human tumor cells can help identify which of the drugs are most likely to be effective against those cancers, Dana-Farber Cancer Institute researchers report today in a study published in Science Signaling.

Because the technique uses tumor cells that less than a day earlier were in patients' bodies, it may well prove more accurate than traditional drug-screening approaches, which use laboratory cell models that may be weeks or even years removed from their origin in patients, the study authors say. Its use could improve physicians' ability to personalize treatment to individual patients and help scientists uncover vulnerabilities in cancer cells that can be targeted by new drugs.

"Cancer cells that are cultured for extended periods of time can undergo a variety of changes and may not be representative of the tumor cells that are actually in a mouse or human," says study first author Patrick Bhola, PhD, of Dana-Farber. "The challenge has been to create a drug-screening technique that shrinks the gap between tumor cells in the body and the cells we do the screening on. The technique we've developed helps to accomplish that."

The technique, known as high-throughput dynamic BH3 profiling (HT-DBP) is a scaled-up version of a test created by Dana-Farber researchers that gauges how close tumor cells are to death after treatment with cancer drugs. Death in this case is defined as apoptosis - the self-destruct mechanism that cells initiate in response to DNA damage and many cancer therapies.

When many chemotherapies are applied to cancer cells, they change the balance of pro-death and anti-death molecules at mitochondria - structures best known for providing energy to the cell. Once the activity of pro-death molecules outweighs the activity of anti-death molecules, mitochondria release toxic substances that destroy the cancer cell. To determine how close the cell is to the brink of apoptosis, a property scientists have dubbed "apoptotic priming," researchers add segments of pro-death proteins to mitochondria and directly measure the release of toxic proteins. The segments are known as BH3 domains, hence the name "dynamic BH3 profiling" or DBP.

When a drug is put on a patient's cancer cells, DBP indicates whether, and how fully, the drug switches on the pro-death program. Tumor cells that show a significant increase in apoptotic priming after being treated with a particular drug are likely to respond to that drug in the lab as well as in patients.

One of the virtues of the first version of DBP was that it generated results quickly - less than a day in many cases. But it was limited by its ability to screen only 10-20 drugs at a time - a significant constraint given the myriad drugs now available to treat many kinds of cancer. Dana-Farber researchers joined colleagues at the Broad Institute of MIT and Harvard and the Laboratory of Systems Pharmacology at Harvard Medical School to miniaturize and automate DBP so it could screen hundreds or thousands of drugs, creating a high-throughput (HT) model of the technique.

The increased capacity meant investigators could conduct "unbiased" screenings drugs in patient or mouse tumor cells - screenings not influenced by any preconceptions of which agents might perform best, and therefore completely objective.

HT-DBP can be used as both a scientific tool and a means of rapidly matching patients with the drugs best able to corral their cancer. In the Science Signaling study, researchers used HT-DBP to screen 1,650 drugs in fresh samples of breast cancer tissue from mice. They selected six of the drugs - three that showed activity in DBP and three that did not - to test in the mice. They found that the three that had been flagged as active caused the animals' tumors to shrink or delayed tumor growth. The three that had shown no signs of activity on DBP, by contrast, had no discernible effect on the tumors. The researchers also performed similar screens on mouse avatars of colorectal cancer and identified a drug combination that delayed tumor growth in one of the mouse models.

These results point to the advantages of performing direct functional drug testing on freshly isolated tumor tissue, the study authors say. "Laboratory specimens of tumor tissue are widely used to extract information on the molecular makeup of tumors - the DNA, RNA, proteins, and other components of cells," says Dana-Farber's Anthony Letai, MD, PhD, the new study's senior author. "While these studies have had a major impact on cancer treatment, they provide a static picture of the tumor cell, rather than the kind of functional information we need to understand how tumor cells actually interact with drugs. Our approach involves putting living cancer cells in contact with drugs to assess their potential."

The investigators also explored whether tumor cells grown in culture conditions for an extended period of time differed from fresh cells in their vulnerability to specific cancer drugs. To evaluate the effect of extended culture on tumor cells, the investigators performed HT-DBP on freshly collected tumor cells from breast cancer tissue from mice, and on tumor cells from the animals that had been grown in a lab for a month. They found that while some drug vulnerabilities were preserved during the extended culture, other vulnerabilities were artificially lost or gained. Importantly, a drug vulnerability that was lost during extended culture was able to delay tumor growth in mice, whereas a vulnerability that was gained during extended cultured had no effect on the tumors. These results suggest that performing drug screens on extended cultures of cancer cells may miss potentially useful therapies.

The technique, when applied to patient tissue, could be used to personalize therapy and improve the translation of therapies from the bench to the bedside. "With HT-DBP, the drug could be screened on a tumor sample only recently removed from a patient," Letai says. "By using tissue samples with greater fidelity to tissue within the body, this technique provides a more accurate representation of what actually happens when a drug meets a tumor."

To evaluate its potential in customizing treatment, investigators performed HT-DBP on colon cancers directly removed from patients, rather than ones that had first been cultured in a lab or modeled in a mouse. The test identified several agents that increased apoptotic signaling in human colon cancer cells, making them potential candidates as treatments for the cancer.

The technique could be used in clinical trials to identify patients most likely to benefit from investigational therapies, researchers say. It can also be used in the lab to gain insights into the molecular workings of cancer cells. If HT-DBP reveals that a drug targeting a particular signaling pathway that pushes a set of tumor cells toward apoptosis, it's a sign that the cells are depending on that pathway for their growth and survival.

The 10-year plan for conserving biodiversity adopted as part of the International Convention on Biological Diversity (CBD) failed to reach its targets for 2020. A scientist from Karlsruhe Institute of Technology (KIT) proposes therefore a prominent political target to give discussions of species conservation more vigor. Together with a group of experts from other research institutions, he proposes to limit species extinctions to 20 per year. This is reported in Science. (DOI: 10.1126/science.aba6592).

The 2-degree target of the Paris Agreement aims to make climate policy focus on the measures needed to stop climate change. But such a target does not exist for species conservation. "Humankind depends on biodiversity," says Professor Mark Rounsevell, Head of the Land Use Change and Climate Research Group of the Atmospheric Environmental Research Division of KIT's Institute of Meteorology and Climate Research. "Without the services provided by ecosystems, such as crop pollination by insects, we lack the fundamental basis of our life support system. Politics needs a clear target to conserve biological diversity in order to maintain the supply of ecosytem services." In the opinion of Rounsevell and a group of other researchers, their demand to lower species extinctions to 20 per year over the next 100 years is easy to communicate and measure. The scientists would like to see this target included in the CBD that will be newly negotiated next year. The last 20 so-called Aichi biodiversity targets agreed upon by the CBD signatories covered worldwide protection of ecosystems and support of sustainability, among others.

The proposal of Rounsevell and other experts is based on existing studies of the stress limit of our planet. In addition to ocean acidification, air pollution, or freshwater consumption, loss of biodiversity is a major factor that might irrevocably endanger the stability of worldwide ecosystems. When exceeding a certain threshold value, researchers expect long-term negative impacts on the environment. To prevent these, species extinction should not exceed more than ten times the background (i.e. prehistorical) rates. "With presently about two million species described, this corresponds to about 20 extinct species per year," Rounsevell says. "This includes all fungi, plants, invertebrates, and vertebrates as well as all ecosystem types, whether terrestrial, freshwater, or marine." In the longer term (beyond 100 years) the ambition should be to return extinctions to background rates.

Necessary Measures Will Improve the Overall State

As the species extinction rate has increased continuously to date, far-reaching political measures would be required to reach the target of the biodiversity researchers. This would positively affect the overall state of ecosystems. The 2-degree target in climate protection works in a similar way. Although temperature is just one of several factors used to represent the complex climate system, the measures required to reach this target will improve climate protection in general. A reduced temperature increase will indirectly affect the rise of the sea level or the occurrence of weather extremes, such as storms or strong rainfall.

Potential action options proposed by Rounsevell and the group of researchers based on recommendations by the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) include extension of nature protection areas, increased funding of species protection, further development of ecolabels, or strict prosecution of wildlife trade. As biodiversity varies greatly at the regional level, Rounsevell considers it important to adapt political measures to local and regional conditions. "Each country has to develop its own catalog of measures and to take responsibility for reaching the target," the environmental researcher says. Success of the new approach to species protection should be monitored continuously. "To find out how the rate of species extinction will develop, large-scale monitoring projects will be required," Rounsevell says. If the efforts to protect biodiversity are successful, then the the number of extinct species per year can be reduced to lower values later on.

The modern photonics industry is constantly working on making its devices more compact, be it computing systems or sensors and lidars. For this, it is necessary to make lasers, transistors and other elements smaller. A team of scientists led by ITMO researchers proposed a quick and affordable method to create optical chips right in a Petri dish. The research was published in ACS Nano.

Nowadays, using devices that are based on microscopic lasers and optical chips is becoming more and more common. They are used in the production of lidars, in the development of new biosensors, and in the future, they can become the foundation for new optical computers that will use photons rather than electrons to transfer and process information. Today's optical chips operate in the infrared (IR) range, i.e. the lasers they use emit at the wavelengths that's invisible to the human eye.

"But to make the devices even more compact, we need to work in the visible range," says Sergey Makarov, chief researcher at ITMO's Department of Physics and Engineering, "as the size of a chip depends on the wavelength of its emission."

An optical chip consists of such components as lasers and waveguides. While creating a source that would emit in the green or red part of the spectrum is quite easy, waveguides for these wavelengths can be an issue.

"A microlaser is a source of emission that you need to guide somewhere," comments Ivan Sinev, senior researcher at ITMO's Department of Physics and Engineering, "and this is what waveguides are for. But the standard silicon waveguides that are used in IR optics do not work in the visible range. They transmit the signal no further than several micrometers. For an optical chip, we need to transmit along tens of micrometers with a high localization, so that the waveguide would have a very small diameter and the light would go sufficiently far through it."

Scientists made attempts to replace silicon waveguides with silver ones, but the transmission distance in such systems was also insufficient. In the end, a team of scientists that included specialists from ITMO University used gallium phosphide as a material for the waveguides, as it has very low losses in the visible band. But the most important thing is that both the light source can be grown directly on a waveguide in a Petri dish using solution chemistry methods, which is way cheaper than the commonly used nanolithography.

The size of the new chip's elements is about three times smaller than that of its counterparts that work in the IR spectral range.

"The chip's important property is its ability to tune the emission color from green to red by using a very simple procedure: an anionic exchange between perovskite and hydrogen halides vapor," notes Anatoly Pushkarev, senior researcher at ITMO's Department of Physics and Engineering. "Importantly, you can change the emission color after the chip's production, and this process is reversible. This could be useful for the devices that have to transmit many optical signals at different wavelengths. For example, you can create several lasers for such a device, connect them to a single waveguide, and use it for transmitting several signals of different colors at once."

The scientists also equipped the newly created chip with an optical nanoantenna made of perovskite that receives the signal travelling along the waveguide and allows uniting two chips in a single system.

"We added a nanoantenna at the other end of our waveguide," explains Pavel Trofimov, PhD student at ITMO's Department of Physics and Engineering, "so now we have a light source, a waveguide, and a nanoantenna that emits light when pumped by the microlaser's emission. We added another waveguide to it: as a result, the emission from a single laser went into two waveguides. At the same time, the nanoantenna did not just connect these elements into a single system, but also converted part of the green light into the red spectrum."

Prehistoric pioneers could have relied on shellfish to sustain them as they followed migratory routes out of Africa during times of drought, a new study suggests.

The study examined fossil reefs near to the now-submerged Red Sea shorelines that marked prehistoric migratory routes from Africa to Arabia. The findings suggest this coast offered the resources necessary to act as a gateway out of Africa during periods of little rainfall when other food sources were scarce.

The research team, led by the University of York, focused on the remains of 15,000 shells dating back 5,000 years to an arid period in the region. With the coastline of original migratory routes submerged by sea-level rise after the last Ice Age, the shells came from the nearby Farasan Islands in Saudi Arabia.

The researchers found that populations of marine mollusks were plentiful enough to allow continuous harvests without any major ecological impacts and their plentiful availability would have enabled people to live through times of drought.

Lead author, Dr Niklas Hausmann, Associate Researcher at the Department of Archaeology at the University of York, said: "The availability of food resources plays an important role in understanding the feasibility of past human migrations - hunter-gatherer migrations would have required local food sources and periods of aridity could therefore have restricted these movements.

"Our study suggests that Red Sea shorelines had the resources necessary to provide a passage for prehistoric people."

The study also confirms that communities settled on the shorelines of the Red Sea could have relied on shellfish as a sustainable food resource all year round.

Dr Hausmann added: "Our data shows that at a time when many other resources on land were scarce, people could rely on their locally available shellfish. Previous studies have shown that people of the southern Red Sea ate shellfish year-round and over periods of thousands of years. We now also know that this resource was not depleted by them, but shellfish continued to maintain a healthy population."

The shellfish species found in the archaeological sites on the Farasan Islands were also found in abundance in fossil reefs dating to over 100 thousand years ago, indicating that these shellfish have been an available resource over longer periods than archaeological sites previously suggested.

Co-author of the study, Matthew Meredith-Williams, from La Trobe University, said: "We know that modelling past climates to learn about food resources is extremely helpful, but we need to differentiate between what is happening on land and what is happening in the water. In our study we show that marine foods were abundant and resilient and being gathered by people when they couldn't rely on terrestrial food."

MOSS LANDING, CA--For 30 years, MBARI ecologist Ken Smith and his colleagues have studied deep-sea communities at a research site called Station M, located 4,000 meters (2.5 miles) below the ocean's surface and 290 kilometers (180 miles) off the coast of Central California. A recent special issue of the journal Deep-Sea Research features 16 new papers about research at Station M by scientists from around the world. These papers cover a wide range of topics, from satellite observations of the sea surface to the behavior and genetics of deep-sea life.

The deep seafloor is one of the largest and least known habitats on this planet. The flat, muddy expanses of the deep ocean floor--known as the abyssal plain--cover more than 50 percent of Earth's surface and play a critical role in the Earth's carbon cycle. Scientists visit from time to time, but they rarely get to stay long. That's one reason why the long-term studies at Station M are so remarkable.

Animals on the deep seafloor get most of their food from the sunlit surface waters thousands of meters above. This food typically arrives in the form of marine snow--bits and pieces of dead algae or animals that sink to the muddy ocean bottom. This detritus carries carbon from the surface waters to the deep sea.

Because much of this carbon originates as carbon dioxide in the atmosphere, sinking marine snow indirectly reduces the amount of carbon dioxide in the atmosphere and sequesters organic carbon in the deep ocean over geologic timescales.

Station M is the only deep-sea site in the world where scientists have conducted long-term, continuous measurements of both the supply of carbon to the seafloor and the consumption of this organic carbon by deep-sea animals and microbes.

Over the past three decades, Smith and his colleagues have developed and used a whole suite of oceanographic tools to study Station M. These include satellites, research ships, bottom trawls, human-occupied vehicles such as Alvin, remotely operated vehicles (ROVs), a robotic seafloor rover, seafloor landers, coring devices, fish traps, sediment traps, respirometers (which measure oxygen consumption), current meters, and time-lapse cameras.

The underwater observatory at Station M includes instruments and robots that operate autonomously 24 hours a day, seven days a week. MBARI scientists only need to visit the site once a year to collect and download data, service instruments, and swap out batteries.

The results of this research have dramatically changed marine biologists' perceptions of life in the deep sea. For one thing, the data show that the deep seafloor is far from static--physical conditions and biological communities can change dramatically over time scales ranging from days to decades.

Research at Station M also confirmed that changes on the seafloor directly relate to conditions near the sea surface. For example, huge populations of algae or gelatinous animals such as salps may consume available nutrients and food in surface waters, then die and sink rapidly to the bottom. The resulting "blizzard" of detritus provides a feast for deep-seafloor organisms, allowing some species to reproduce and dominate seafloor communities--at least until most of the food is used up.

Such "feast and famine" cycles affect some seafloor animals more than others. For example, some species of sea cucumbers were rare at Station M in the 1990s, then became extremely abundant, and then disappeared entirely. Other sea cucumbers had relatively stable populations throughout the 30-year study.

The 16 research papers in the special edition of Deep-Sea Research cover these topics and many more. Two of the papers focus on connections between processes at the sea surface and the amount of carbon reaching the deep seafloor. Three papers examine the types and amounts of material sinking down through the water. Two other papers describe changes in the chemical and biological conditions on the seafloor. The remaining nine papers describe animals and microbes living on and near the seafloor and how these organisms respond to changes in their environment.

The papers in this volume provide an overview of ongoing research at Station M and show how this research has improved scientists' understanding of the biogeochemistry, biology, and ecosystems on the deep seafloor. As human impacts in the ocean become more pervasive, research at Station M and at similar sites around the world are essential to understanding this vast but little-studied environment. Long-term studies such as the Station M time series are also essential for understanding long-term changes in the ocean and in Earth's climate.

Smith and his research team hope to continue their work at Station M to find out if the surprising changes in seafloor communities will continue. They will also be developing new technologies that will allow researchers to monitor conditions at Station M from shore in real time.

(Boston, MA)--A new study led by the Department of Population Medicine finds that individuals with bipolar disorder who switched to high-deductible health plans (HDHPs) experienced a moderate decrease in nonpsychiatrist mental health outpatient visits, but rates of psychiatrist visits, medication use, emergency department visits, and hospitalizations did not change. The study, "Effect of High-deductible Insurance on Healthcare Use in Bipolar Disorder" appears in The American Journal of Managed Care on June 16.

Bipolar disorder is a serious mental illness characterized by acute episodes of mania, hypomania, and depression and has a lifetime prevalence of approximately 4% in the United States. People living with bipolar spectrum disorders often battle episodes of clinical instability and impairment, and require consistent access to medications and specialist care to reduce depressive symptoms or prevent future manic or depressive episodes. A small reduction in access could serve as a tipping point given that suboptimal adherence to bipolar medications can result in debilitating episodes. Considering these needs and the increasing prevalence of HDHPs with deductibles over $1,000 per year, the study team examined the impact of HDHPs on health care use among people with bipolar disorder.

"Early cost sharing research suggested that high out-of-pocket costs have a 'blunt instrument' effect, leading consumers to reduce all healthcare utilization," said Frank Wharam, MD, MPH, lead author and Associate Professor in the Department of Population Medicine at Harvard Medical School. "Our study demonstrates that high-deductible health plans do not appear to have this 'blunt instrument' effect on healthcare use among people with bipolar disorder who are covered through employer-sponsored plans. Rather, patients might make tradeoffs to preserve important care."

The study population, drawn from a large national health insurance plan, included members with bipolar disorder who were enrolled in low-deductible plans during a baseline year. Some experienced an employer-mandated switch to HDHPs and were followed for a subsequent year. Those remaining in low-deductible plans, as the only option offered by their employer, comprised the control group. Study findings show that HDHP members maintained stable overall mental health outpatient visits compared to members in low-deductible health plans. However, members with HDHPs experienced an 11% decrease in nonpsychiatrist mental health outpatient visits. Rates of psychiatrist visits, medication use, emergency department visits, and hospitalizations did not change.

Regarding next steps, Dr. Wharam adds, "Policy makers, employers, and health plans could use our findings to construct highly efficient value-based or tailored health insurance designs that optimize health care use and spending. For example, health insurers could reduce out-of-pocket costs for psychiatric counselling visits."