Culture

Exercise is known to reduce blood pressure - but the activity of bacteria in our mouths may determine whether we experience this benefit, according to new research.

An international team of scientists has shown that the blood pressure-lowering effect of exercise is significantly reduced when people rinse their mouths with antibacterial mouthwash, rather than water - showing the importance of oral bacteria in cardiovascular health.

The researchers now suggest that health professionals should pay attention to the oral environment when recommending interventions involving physical activity for high blood pressure.

The study was led by the University of Plymouth in collaboration with the Centre of Genomic Regulation in Barcelona (Gabaldon's lab), Spain, and was published in the journal Free Radical Biology and Medicine.

Why did the research take place?

Lead author Dr Raul Bescos, Lecturer in Dietetics and Physiology at the University of Plymouth, said: "Scientists already know that blood vessels open up during exercise, as the production of nitric oxide increases the diameter of the blood vessels (known as vasodilation), increasing blood flow circulation to active muscles.

"What has remained a mystery is how blood circulation remains higher after exercise, in turn triggering a blood-pressure lowering response known as post-exercise hypotension.

"Previous research has suggested that nitric oxide was not involved in this post-exercise response - and only involved during exercise - but the new study challenges these views.

"It's all to do with nitric oxide degrading into a compound called nitrate, which for years was thought to have no function in the body. But research over the last decade has shown that nitrate can be absorbed in the salivary glands and excreted with saliva in the mouth.

"Some species of bacteria in the mouth can use nitrate and convert into nitrite - a very important molecule that can enhance the production of nitric oxide in the body. And when nitrite in saliva is swallowed, part of this molecule is rapidly absorbed into the circulation and reduced back to nitric oxide. This helps to maintain a widening of blood vessels which leads to a sustained lowering of blood pressure after exercise.

"We wanted to see whether blocking nitrate's ability to convert into nitrite by inhibiting oral bacteria would have any effect on post-exercise hypotension."

What did the study involve?

Twenty-three healthy adults were asked to run on a treadmill for a total of 30 minutes on two separate occasions, after which they were monitored for two hours.

On each occasion at one, 30, 60 and 90 minutes after exercise they were asked to rinse their mouths with a liquid - either antibacterial mouthwash (0.2% chlorhexidine) or a placebo of mint-flavoured water. Neither the researchers nor the participants knew which liquid they were rinsing with.

Their blood pressure was measured and saliva and blood samples were taken before exercise and at 120 minutes after exercise. No food or drink except water was allowed during exercise and the recovery period, and none of the study participants had any oral health conditions.

What did the science show?

The study found that when participants rinsed with the placebo, the average reduction in systolic blood pressure was -5.2 mmHg at one hour after exercise. However when participants rinsed with the antibacterial mouthwash, the average systolic blood pressure was -2.0 mmHg at the same time point.

*Systolic blood pressure refers to the highest blood pressure level when the heart is squeezing and pushing the blood round the body.

These results show that the blood pressure-lowering effect of exercise was diminished by more than 60% over the first hour of recovery, and totally abolished two hours after exercise when participants were given the antibacterial mouthwash.

Previous views also suggested that the main source of nitrite in the circulation after exercise was nitric oxide formed during exercise in the endothelial cells (cells that line the blood vessels). However, the new study challenges this. When antibacterial mouthwash was given to the participants, their blood nitrite levels did not increase after exercise. It was only when participants used the placebo that nitrite levels in blood raised, indicating that oral bacteria are a key source of this molecule in the circulation at least over the first period of recovery after exercise.

What the authors say

Craig Cutler, study co-author who conducted the research as part of his PhD at the University of Plymouth, said: "These findings show that nitrite synthesis by oral bacteria is hugely important in kick-starting how our bodies react to exercise over the first period of recovery, promoting lower blood pressure and greater muscle oxygenation.

"In effect, it's like oral bacteria are the 'key' to opening up the blood vessels. If they are removed, nitrite can't be produced and the vessels remain in their current state.

"Existing studies show that, exercise aside, antibacterial mouthwash can actually raise blood pressure under resting conditions, so this study followed up and showed the mouthwash impact on the effects of exercise.

"The next step is to investigate in more detail the effect of exercise on the activity of oral bacteria and the composition of oral bacteria in individuals under high cardiovascular risk. Long-term, research in this area may improve our knowledge for treating hypertension - or high blood pressure - more efficiently."

Frostbite is an injury which usually affects the extremities, such as fingers and toes, and has the potential of causing irreversible tissue loss. The treatment of freezing cold injuries to the periphery has advanced substantially in the last 10 years. Optimal outcomes are only likely to be achieved if a multi-disciplinary team uses the full range of diagnostic and treatment approaches that are now available, said Chris Imray, CASE Medicine, presenting this week at the Extreme Environmental Physiology conference of The Physiological Society.

The internet, and satellite phones, with digital images allow immediate access by patients from remote geographical locations to hospital-based specialists who can assess cold injuries and advise on early field-care.

The severity of frostbite injuries can now be assessed with a bone scan called triple-phase, allowing early prediction of likely subsequent tissue loss. Newer thrombolytic therapies (which dissolve blood clots) such as iloprost have transformed treatment options when instigated at an early time-point.

Frostbite occurs when the fluid in our cells freezes, it swells and chemicals are produced. These two processes permanently damage the tissues in our bodies. Frostbite can vary in the depth and the extent of damage it causes.

If only superficial skin is damaged and it is rewarmed soon after injury it may recover completely, this is called frost-nip. Frostbite commonly occurs on the extremities such as fingers, toes, ears, penis and nose, but it can technically occur anywhere.

It obviously requires a cold, but not necessarily freezing, environment and wind-chill can add to the potential for damage. Frostbite is more likely at altitude (less oxygen is available for the tissues to recover) and in a hypothermic or injured person. It is more likely if circulation is restricted by tight fitting clothes, boots or jewellery.

Clients with pre-existing conditions which may predispose to poor circulation (e.g. diabetes, Raynaud's sufferers etc.) are more likely to suffer from frostbite. Certain drugs that effect peripheral circulation may also predispose people (e.g. beta blockers or nicotine in cigarettes).

Addressing the importance of the issue, Chris Imray said:
"Awareness and experience is the key to prevention, and prevention is the key to treatment. The adage that "prevention is better than treatment" is especially true for frostbite, which is typically preventable but very difficult to treat."

People who suffered a financial, housing-related, or job-related hardship as a result of the Great Recession were more likely to show increases in symptoms of depression, anxiety, and problematic drug use, research shows. The research findings, published in Clinical Psychological Science, a journal of the Association for Psychological Science, reveal declines in mental health that were still evident several years after the official end of the recession, but were obscured when examining trends in population-level data (e.g., the number of people overall with each mental health outcome).

"Our study provides a new perspective on the impact of The Great Recession, showing that population-level analyses likely miss important patterns in the data," says lead researcher Miriam K. Forbes, who began the research at the University of Minnesota and now works at Macquarie University in Sydney, Australia. "By looking at individuals' mental health and experiences of the recession, we could see a different picture."

"Individuals who experienced even a single recession impact still had higher odds of nearly all of the adverse mental health outcomes we examined - including clinically significant symptoms of depression, generalized anxiety, panic, and problems with drug use - three years after the recession," Forbes explains. "And these odds were higher still in specific sociodemographic groups who suffered marked losses during the recession or without a strong safety net."

Forbes and University of Minnesota colleague Robert F. Krueger examined data collected as part of the longitudinal Midlife in the United States study of adults aged 25 to 75. To investigate the impacts of the Great Recession, which officially lasted from December 2007 to June 2009, the researchers focused on data collected in the 2003-2004 wave, three years before the recession began, and the 2012-2013 wave, three years after the recession ended.

Forbes and Krueger examined participants' symptoms of depression, anxiety, and panic disorder and their symptoms of problematic alcohol and drug use. In the 2012-2013 wave, participants also reported whether they had experienced a variety of recession-related impacts, including financial impacts (e.g., missed mortgage or credit card payments, declared bankruptcy), job-related impacts (e.g, took on an additional job, lost a job), and housing impacts (e.g., moved in with family/friends, threatened with foreclosure).

As observed in previous studies, the prevalence of each mental-health outcome in the full sample remained stable or decreased slightly from 2003-2004 to 2012-2013. But when the researchers looked at mental-health outcomes in relation to the hardships individuals experienced as a result of the Great Recession, the analyses told a different story. Specifically, each hardship experienced was associated with an increased likelihood of having symptoms of depression, generalized anxiety, panic, or problems with drug use. This pattern held even when Forbes and Krueger accounted for participants' previous symptoms and their sociodemographic characteristics.

The researchers also found that individuals who did not have a college education were more likely to show increased anxiety in relation to job-related hardships. And people not living with a spouse or partner were more likely to have problems with drug use associated with housing-related hardships. These associations may reflect the relative lack of safety net available to people in the job market who have fewer qualifications, or who rely on a single income.

The analyses also showed that people with greater financial advantage were particularly affected by some hardships. Compared with their less-advantaged peers, participants who were well off were more likely to have anxiety symptoms associated with housing-related hardships and were also more likely to have drug use problems associated with financial hardships. These associations may reflect that fact that experiences such as "moving in with friends or family to save money" or "selling possessions to make ends meet" likely signal a substantial loss of assets and a considerable level of hardship for people who were previously living comfortably.

The researchers note that the observational nature of the MIDUS data does not allow them to conclude that recession hardships caused an increase in participants' symptoms. However, the findings do reveal the limited perspective afforded by aggregate-level analyses - understanding people's actual lived experiences requires analyses that examine individual-level outcomes and changes over time.

The Great Recession of 2007 to 2009 resulted in huge losses to employment, earnings, assets, and income in the United States and this research shows that those losses were associated with lasting negative mental health outcomes for many individuals.

"These findings suggest the adverse effects of the Great Recession on individuals' mental health likely compounded and prolonged its economic costs, highlighting that government-funded mental health support following financial recessions may not only ease individuals' burdens, but could be a sound financial investment that may act to stimulate faster economic recovery following future recessions," says Forbes.

"These findings may be particularly pertinent given some indications that the next period of economic contraction might begin as early as 2020," she adds.

[Background]

For proper and healthy metabolism of bone, appropriate stimuli are necessary. In outer space with microgravity, calcium is lost from bone and bone mass is reduced. Measurement of the bone density of astronauts before and after a long stay in outer space indicates bone mass loss. At the dawn of an era where astronauts are to stay for a long period of time in an international space station, it is an urgent task to elucidate changes of osteoblasts and osteoclasts under microgravity conditions and to perform research on potential drugs as remedies. Since it is difficult in outer space to use a cell culture system that meets in vivo conditions, other experimental models are necessary.

The present research group, consisting of 53 scientists from 33 institutions, led by scientists of Kanazawa University, Tokyo Medical and Dental University, Okayama University and University of Toyama, used cultured goldfish scales to investigate the mechanism of bone loss in space. A scale contains hydroxyapatite, a fundamental element of bone, and its bone matrix of two layers (osseous layer: a thin, well-calcified external layer; a fibrillary layer: a thick, partially calcified layer). A scale also has cells corresponding to osteoblasts and osteoclasts (Figure 1). Scales protect the surface of the fish body and play a role as a reservoir of calcium. With freshwater fish, the latter function is noteworthy; when salmon swim upstream to lay eggs, it is known that their scales get smaller in order to supply calcium to the eggs. To achieve this, osteoclasts release calcium from the scales. In addition, ground-basis experiments reveal that the responses of scales to hormones and extra-gravity due to centrifugation are very similar to those of mammalian bones. Furthermore, cultured scales may be considered to be an excellent experimental model for research of bone metabolism in outer space since scales are readily available and they can be used for experiments for about 10 days at a low temperature (4ºC) without exchanging culture media.

[Results]

Upon removal of a scale from fish skin, a new scale is regenerated. In this study, regenerated scales were used since their osteoblast and osteoclast activities are high. First it was shown that melatonin*1) was produced in scale osteoblasts and that melatonin synthesis decreased in space due to reduced expression of acetylserotonin O-methyltransferase, an enzyme important in melatonin synthesis (Figure 2a).

Further, melatonin functions in outer space were investigated by comparing scales cultured in a media supplemented with melatonin and those without. This experiment revealed that after a three-day culture in melatonin-free media, a number of osteoclasts fused together to form multinucleated, active osteoclasts. These active osteoclasts widened the grooves of a scale's osseous layer and enhanced bone resorption of scales. Moreover, the expression level of the Rankl*2) gene, a factor enhancing bone resorption, was elevated while the expression level of the Calcitonin*3) gene, a hormone suppressing bone resorption, was repressed. In contrast, in scales cultured in a media supplemented with melatonin, the expression level of Rankl was found to be repressed while Calcitonin expression was at a normal level, which coincided with suppressed gene expression levels for osteoclast functions (Figures 2b-e).

To our knowledge, no investigations have so far been performed on melatonin levels in outer space. We believe that one of the mechanisms of bone resorption under microgravity conditions could be a decrease of melatonin level to suppress CALCITONIN secretion (Figure 3). In fact, other research groups reported that the blood CALCITONIN level of a monkey decreased in outer space and that the CALCITONIN level in the blood of human subjects decreased after 120 days on a head-down tilt bed rest, a pseudo-microgravity experimental model.

The present research group confirmed in ground-basis experiments that scale osteoblasts produced CALCITONIN and that melatonin enhanced CALCITONIN secretion. Due to the limitation of rocket load, experiments on morphological changes of osteoclasts due to melatonin were not possible in outer space at this time; however, ground-basis experiments indicated suppression of morphological changes of activated osteoclasts by melatonin by using a three-dimensional clinostat, which produces pseudo-microgravity conditions. A research paper with these results was published in a high impact factor journal based on life science experiments performed in the Japanese Experiment Module for the first time.

As above, investigation of melatonin action on bones in outer space, which had been neglected so far, revealed that melatonin suppresses bone resorption by stimulating osteoblasts to secret CALCITONIN (Figure 3).

[Future prospects]

The present study indicates the possibility that melatonin could serve as a prophylactic drug to prevent bone loss of astronauts during their missions. Melatonin is expected to be used as a preventive and curative drug for loss of bones of astronauts in the future. The present research group performs in-space experiments on the functions of new melatonin derivatives on scales, which may lead to drug discovery of bone diseases.

WINSTON-SALEM, N.C. - Sept. 3, 2019 - Could following a certain type of diet affect the gut microbiome - the good and bad bacteria that live in the gastrointestinal tract - in ways that decrease the risk of Alzheimer's disease?

According to researchers at Wake Forest School of Medicine, that is a fair possibility.

In a small pilot study, the researchers identified several distinct gut microbiome signatures - the chemicals produced by bacteria - in study participants with mild cognitive impairment (MCI) but not in their counterparts with normal cognition, and found that these bacterial signatures correlated with higher levels of markers of Alzheimer's disease in the cerebrospinal fluid of the participants with MCI.

Through cross-group dietary intervention, the study also showed that a modified Mediterranean-ketogenic diet produced changes in the gut microbiome and its metabolites that correlated with reduced levels of Alzheimer's markers in the members of both study groups.

The study appears in the current issue of EBioMedicine, a journal published by The Lancet.

"The relationship of the gut microbiome and diet to neurodegenerative diseases has recently received considerable attention, and this study suggests that Alzheimer's disease is associated with specific changes in gut bacteria and that a type of ketogenic Mediterranean diet can affect the microbiome in ways that could impact the development od dementia," said Hariom Yadav, Ph.D., assistant professor of molecular medicine at Wake Forest School of Medicine, who co-authored the study with Suzanne Craft, Ph.D., professor gerontology and geriatric medicine at the medical school and director of Wake Forest Baptist Health's Alzheimer's Disease Research Center.

The randomized, double-blind, single-site study involved 17 older adults, 11 with diagnosed MCI and six with normal cognition. These participants were randomly assigned to follow either the low-carbohydrate modified Mediterranean-ketogenic diet or a low-fat, higher carbohydrate diet for six weeks then, after a six-week "washout" period, to switch to the other diet. Gut microbiome, fecal short-chain fatty acids and markers of Alzheimer's, including amyloid and tau proteins, in cerebrospinal fluid were measured before and after each dieting period.

The study's limitations include the subject group's size, which also accounts for the lack of diversity in terms of gender, ethnicity and age.

"Our findings provide important information that future interventional and clinical studies can be based on," Yadav said. "Determining the specific role these gut microbiome signatures have in the progression of Alzheimer's disease could lead to novel nutritional and therapeutic approaches that would be effective against the disease."

Corals are shown to recycle their own waste ammonium using a surprising source of glucose--a finding that reveals more about the relationship between corals and their symbiotic algae.

Symbiosis between corals and algae provides the backbone for building coral reefs, particularly in nutrient-poor waters like the Red Sea. Algae and corals cooperate to share nutrient resources, but the precise metabolic interactions at play are still unclear.

Now, KAUST researchers have shown that the coral host uses organic carbon--in glucose sourced from its symbiotic algae--to recycle its own waste ammonium. Previous research had suggested that the algae alone may be responsible for ammonium (nitrogen) recycling. The KAUST team believes that, by controlling this nitrogen recycling mechanism, the coral host can in turn control algal growth by restricting or enabling nitrogen flow.

"Molecular research on coral-algae symbiosis is relatively young. The first genetic sequencing study focusing on the coral model anemone Aiptasia was published in 2014," says Guoxin Cui at the Red Sea Research Center, who worked on the project under the supervision of Manuel Aranda. "To explore the molecular mechanisms underlying Aiptasia's symbiotic relationship with the algae Symbiodiniaceae, we first integrated all published RNA-sequencing data on this relationship and conducted a meta-analysis."

Meta-analysis is a statistical method originally developed for medical research, to calculate the precise effects of a specific medicine on patients with a specific disease by combining results from multiple trials.

"In our case, each gene could be seen as an individual 'medicine,' and we can calculate the effect of each gene on symbiosis by monitoring its expression changes across many experiments" says Cui. "Because we use large datasets compiled from multiple studies, we can be pretty confident of the effect size we calculate for each gene. By focusing on those genes that are definitely associated with symbiosis, we can eliminate noise from unwanted parameters."

Once the team had identified a set of high-confidence genes, they set up a metabolomics experiment, with the help of their colleagues at KAUST's Core Labs, using symbiotic and nonsymbiotic (or bleached) Aiptasia. They placed the anemones in water and added bicarbonate containing labeled carbon-13 (13C) isotopes.

The symbiotic algae absorbed the bicarbonate during photosynthesis, transferring the 13C signal to the host's metabolites. The team could then follow the carbon isotope through the metabolic pathways of the anemones and determine which were enriched with 13C.

"Our results show that competition for nitrogen is a key mechanism within coral-algae symbiosis," says Cui. "These insights will help us understand what goes wrong when the relationship is placed under stress, for example, because of shifting climates."

BINGHAMTON, N.Y. -- Money can't buy you happiness, but it could motivate you to live a better life.

A new study featuring researchers at Binghamton University, State University of New York found that viewing wealth and material possessions as a sign of success yields significantly better results to life satisfaction than viewing wealth and possessions as a sign of happiness.

"People simply say 'money can't buy you happiness' and just assume that materialism has a negative influence on overall well-being," said Jenny Jiao, assistant professor of marketing at Binghamton University School of Management. "But it's not that simple. There is a real difference between success materialism and happiness materialism."

Jiao and her fellow researchers surveyed over 7,500 German adults to get their findings. They first determined if participants had either a happiness materialistic or success materialistic mindset, and then asked questions regarding current satisfaction of life, expected satisfaction of life in the future and economic motivations.

What they found:

Happiness materialism (wealth and material consumption is the sign of a happy life) can negatively influence life satisfaction in two different ways:

It can lead a person to be dissatisfied with their current standard of living, which in turn negatively influences overall life satisfaction.

This can lead a person to not find satisfaction from other important areas of life (family life, social life, health, etc.), which negatively influences overall life satisfaction.

Success materialism (wealth and material possessions are a sign of success in life) positively influences life satisfaction by boosting a person's economic motivation. This can lead to a rise in their future satisfaction with their standard of living, which positively influences overall life satisfaction.

"We work so hard over the course of our lives. We want to make money and we want to have a better life, but what actually gives us satisfaction with life? Is it wealth and material possessions, or is it what those things are a sign of?" said Jiao.

The researchers cross-checked their results with survey answers from other parts of the world, including the United States, to verify the universality of the findings.

Jiao recommends focusing on future goals in order to stay driven and motivated.

"Your happiness should never rely on money alone, but money can be a tool to motivate you to achieve major milestones in your life, which can make you feel happier in the long run," said Jiao.

She also cautions to forget about the other aspects of life that bring satisfaction.

"Never lose sight of the other things that provide happiness that don't necessarily have monetary value. These include family, friends, your health, continual learning and new experiences," she said.  

When bare skin is exposed to sunlight, it makes Vitamin D, which is needed by our bodies to absorb calcium and ensure strong, healthy bones. With bathing suit skin exposure, it only takes about 10-15 minutes of sun exposure during the summer to generate all the vitamin D your body needs for the day. Unfortunately, for Canadians, exposure to sunlight is diminished during the long winter months. This results in many turning to supplements to get the required vitamin D.

For normal, healthy adults, Health Canada recommends a total daily intake of 600 international units (IU) up to age 70, and 800 IU after age 70. Other sources, like Osteoporosis Canada, suggest adults at risk of osteoporosis, a condition characterized by bone loss, should take 400 - 2,000 IU of Vitamin D. However, some people may be taking up to 20 times the recommended daily dose to prevent or treat a variety of medical conditions that might be related to having not enough vitamin D. So, what is the correct dose? And, how much is too much?

"Although vitamin D may be involved in regulating many of the body's systems, it is the skeleton that is most clearly affected by vitamin D deficiency," says Dr. David Hanley, MD, an endocrinologist in the Cumming School of Medicine (CSM), and one of the principal investigators of the study. "Current Health Canada recommendations were set to prevent the bone diseases caused by vitamin D deficiency for the vast majority of healthy Canadians. But it has been more difficult to clearly establish the optimal dose of vitamin D. When we designed this study, there remained a question whether there's more benefit in taking a higher dose."

A three-year study by researchers at the Cumming School of Medicine's McCaig Institute for Bone and Joint Health published in the Journal of the American Medical Association (JAMA), showed there is no benefit in taking high doses of vitamin D. The study followed 300 volunteers between the ages of 55 and 70 in a double-blind, randomized clinical trial to test the hypothesis that with increasing doses of vitamin D, there would be a dose-related increase in bone density and bone strength. A third of the study participants received 400 IU of vitamin D per day, a third received 4,000 IU per day, and a third received 10,000 IU per day.

Volunteers had both their bone density and bone strength measured using a new, high-resolution computed tomography (CT) scan of bone at the wrist and ankle, called an XtremeCT, used only for research. The XtremeCT, located in the McCaig Institute's new Centre for Mobility and Joint Health, is the first of its kind in the world, and allows researchers to look at bone microarchitecture in detail never seen before. Standard dual-X-ray absorptiometry (DXA) bone density was also obtained. Participants received scans at the start of the study and at 6, 12, 24 and 36 months. To assess vitamin D and calcium levels, researchers also collected fasting blood samples at the beginning of the study and at 3, 6, 12, 18, 24, 30 and 36 months as well as urine collections annually.

Bone mineral density (BMD) is determined by measuring the amount of calcium and other minerals in a defined segment of bone. The lower the bone density, the greater the risk for bone fracture.

Adults slowly lose BMD as they age, and the DXA results showed a modest decrease in BMD over the duration of the study, with no differences detected between the three groups. However, the more sensitive measurement of BMD with high resolution XtremeCT showed significant differences in bone loss among the three dose levels.

Total BMD decreased over the three-year period by 1.4 per cent in the 400 IU group, 2.6 in the 4,000 IU group and 3.6 in the 10,000 IU group. The conclusion was that, contrary to what was predicted, vitamin D supplementation at doses higher than those recommended by Health Canada or Osteoporosis Canada were not associated with an increase in bone density or bone strength. Instead, the XtremeCT detected a dose-related decrease in bone density, with the largest decrease occurring in the 10,000 IU per day group. More research is required to determine if high doses may actually compromise bone health.

"We weren't surprised that using DXA we found no difference among the treatment arms, whereas with XtremeCT, the latest in bone imaging technology, we were able to find dose-dependent changes over the three years. However, we were surprised to find that instead of bone gain with higher doses, the group with the highest dose lost bone the fastest," says Steve Boyd, a professor in the CSM and one of the principal investigators of the study. "That amount of bone loss with 10,000 IU daily is not enough to risk a fracture over a three-year period, but our findings suggest that for healthy adults, vitamin D doses at levels recommended by Osteoporosis Canada (400-2000 IU daily) are adequate for bone health."

A secondary outcome of the study indicated a potential safety concern with taking high levels of vitamin D. Although there were incidences in all three arms of the study, the investigators found that participants assigned to receive higher doses of daily vitamin D supplementation (4000 IU and 10,000 IU) over the three years were more likely to develop hypercalciuria (elevated levels of calcium in the urine), compared to those receiving a lower daily dose. Hypercalciuria is not uncommon in the general population, but is associated with increased risk of kidney stones and may contribute to impaired kidney function.

Hyperalciuria occurred in 87 participants. Incidence varied significantly between the 400 IU (17%) 4000 IU (22%) and 10,000 IU (31%) study groups. If hypercalciuria was detected in study participants, calcium intake was reduced. After repeat testing, the hypercalciuria usually resolved.

"What we can see in this study is that large doses of vitamin D don't come with a benefit to the skeleton," says Dr. Emma Billington, MD, one of the authors of the study. "For healthy adults, 400 IU daily is a reasonable dose. Doses of 4,000 IU or higher are not recommended for the majority of individuals."

A few years before NASA astronaut Jessica Meir began learning to fly a spacecraft for her upcoming trip to the International Space Station, she was in flight-training of a different kind: teaching bar-headed geese how to fly in a wind tunnel at the University of British Columbia.

The goal was to understand how the birds -- who are famed for their long migrations between Mongolia, China and India -- frequently fly in severely low oxygen at extreme altitudes between 5000 to 6000m, or even as high as the summits surrounding Mt. Everest, which are at roughly 8500m. The findings of the research were published today in eLife.

"Flapping wings in flight is very metabolically costly and requires an enormous amount of oxygen -- and to do that where the air is so thin is remarkable," said Meir, who led the study as a postdoctoral fellow at UBC zoology. "We found that the geese maintained flight in extremely low oxygen levels in the wind tunnel by reducing their metabolism compared to when flying in normal oxygen levels."

While previous research suggested the geese have adaptations that allow them to maximize oxygen use at high altitudes, this study is the first to comprehensively measure their physiology during flight at simulated altitudes in a wind tunnel and gauge the associated metabolic costs.

But gathering the data required a little ingenuity, so Meir and her former UBC colleague Julia York each became mother goose to a gaggle of little bar-headed goslings born and bred at sea level.

As the first living things the birds saw when they hatched, the geese "imprinted" on Meir and York, allowing the pair to train the birds to fly in a wind tunnel wearing a face mask and a tiny backpack containing measuring equipment.

The researchers found that six of the seven birds that could fly in the tunnel were willing to fly in moderately low-oxygen levels around 5500m. Three of the birds also flew in severely low-oxygen conditions comparable to roughly 9000m, the maximum altitude at which bar-headed geese have been anecdotally reported to fly in the Himalayas.

"We found that during flight, the metabolic rate of these birds increased 16-fold from rest, along with an increase in the amount of oxygen transported per heartbeat and a smaller increase in heart rate," said principal investigator Bill Milsom, a professor emeritus at UBC zoology who has studied the geese for over a decade. "In comparison, humans and most animals can at best increase their metabolism ten-fold, so this is a remarkable capacity."

And when the going got tough, it appeared the birds actually became more efficient.

"We measured a drop in the metabolic cost of birds flying at the equivalent of 5500m in the wind tunnel, compared to flying at sea level oxygen conditions," said Meir. "When we decreased the oxygen further to the equivalent of roughly 9000m, the drop was even more extreme."

Data on heart rate, the rate of oxygen consumption and carbon dioxide production and blood temperature provided insights into the physiology underlying this unique ability.

"We were surprised to find that their heart rate during flight in reduced oxygen was no higher than during flights in normal oxygen levels," said co-author York, an undergraduate student at UBC at the time of the study and currently a PhD candidate at the University of Texas at Austin. "We also saw that the temperature in their veins decreased during our simulated flights, which is hypothesized to significantly increase the amount of oxygen they can carry in their blood."

Determining how these results relate to longer migratory flights of bar-headed geese at high altitudes will require further work to measure the physiological variables in the wild, or during longer flights in normal, low-oxygen and low-pressure conditions.

"Our findings are also relevant to all physiological and biomedical fields involving animals and humans in low-oxygen environments, from medical conditions such as heart attacks and strokes to procedures like organ transplants," said Meir.

For Meir, who has spent a good chunk of her career studying the physiology of animals in extreme environments, her trip to space on Sept. 25 is a turning of the tables, of sorts. Among the scientific experiments she will be supporting during her six-month mission, Meir will study how her own body responds to the extremes of space.

"It only seems fitting that it's now my turn to serve as the subject for many human physiology research experiments aboard the International Space Station," she said.

September 3rd, 2019, London, UK: Deep Knowledge Analytics salutes its parent company, Deep Knowledge Ventures, in the landmark Nature Biotechnology publication of its portfolio company, Insilico Medicine, demonstrating the design, synthesis and preclinical validation of a novel drug candidate in just 46 days.

The many advances in deep learning reinforcement learning and generative adversarial learning made since 2014 are rapidly transforming multiple industries including search, translation, video games, retail, transportation, and many others. It is relatively easy to validate the performance of the AI systems in imaging, voice, text and other areas where human sensory systems can be used to rapidly verify the validity of the experimental results. However, in the pharmaceutical industry, the validation cycles take decades and cost billions of dollars. Most of the common questions asked by the pharmaceutical industry executives to all of the leading artificial intelligence groups worldwide deal with the novelty of the algorithms and experimental validation of the results in mice or even in humans. There is a grave disconnect between the leaders in AI focusing on the novelty of the algorithms and drug discovery and development experts focusing only on experimental data.

On Monday, September 2nd, a group of collaborators from Insilico Medicine and WuXi AppTec published irrefutable proof where cutting-edge work in artificial intelligence utilizing the next-generation generative tensorial and reinforcement learning was followed by experimental validation. The molecules "imagined" by the Generative Tensorial Reinforcement Learning (GENTRL) techniques were rapidly synthesized, tested in enzymatic, cell-based fibrosis, metabolic stability, microsomal stability assays, and in mice.

The paper Alex Zhavoronkov, et al, 2019, "Deep learning enables rapid identification of potent DDR1 kinase inhibitors", Nature Biotechnology, presents a substantial advance in artificial intelligence for drug discovery. The AI work presented in the paper was done in 2017 and the code is openly available. The company scientists believe that they can go after the many target classes and challenging targets with the universal generative pipeline that can account for cases where no crystal structure exists and one or even no template molecules are known while achieving respectable hit rates.

We sent the article to a number of thought leaders in the industry asking for their opinion:

"This is an important demonstration of the power of AI, using a GAN approach, to markedly accelerate the design and experimental validation of a new molecule, no less one targeting fibrosis, a major unmet medical need." said Dr. Eric Topol, Executive Vice-President of Scripps Research and Founder and Director of the Scripps Research Translational Institute (Eric Topol has no relationship with the company in question nor its authors).

"Zhavoronkov et al. show that AI techniques can be used to guide our search for good drug molecules in the the vastness of chemical space, one of the key challenges in drug discovery today. The work provides compelling evidence that AI can learn from historical datasets to generate novel molecular compounds with drug-like properties, and helps clarify how AI can be used to improve the speed of drug development." said Mark DePristo, former Head of Genomics at Google Brain, Co-founder and CEO, BigHat Biosciences.

"When Deep Knowledge Ventures chose to provide Insilico Medicine's initial funding round in 2014, we did so because we saw their potential to increase Quality-Adjusted Life Years (QALY) for the betterment of humanity as a whole. Since then they have been the first to use cutting edge deep learning techniques like Generative Adversarial Networks to design novel drug candidates from scratch with specified molecular properties in 2016, and in 2018 to succeed in designing, synthesizing and validating a new drug end to end in less than 2 months. I am also thrilled by the fact that this article visualizes what Insilico Medicine has been making in their R&D already back in 2017 and submitted for publication in 2018. I would not be surprised to find out that since then they have made even greater progress in applying next-generation AI techniques for drug design, which might be publicly disclosed in 2020" said Dmitry Kaminskiy, General Partner of Deep Knowledge Ventures.

"Using Advanced GANs in the discovery of drugs is a great example of cutting edge application of AI in the pharmaceutical industry - it speeds up a critical process from years to just weeks." said Christian Guttmann, Executive Director Nordic AI Institute, Professor AI at the University of New South Wales, and Senior AI Research Fellow AI at Karolinska Institute.

"Exhilarating news in Nature Biotechnology today, as scientists from Insilico Medicine (Hong Kong), report that an AI process called GENTRL, has facilitated the identification of new small molecule kinase inhibitors, DNA damage response (DDR1) inhibitors, in a two month time frame, reducing the current non-AI early 'research/preclinical development' time estimates for new drugs by approximately 94%. The cost savings for bio-marker drugs using AI processes is huge. Not only is the end-to-end development time reduced, but so too are the costs related to R&D scientific, professional and technical personnel, which account for approximately 29% of the total cost to develop a drug, according to Tufts CSDD. In addition to the reduced development time and costs, drugs potentially get to market sooner, generating revenues for the companies who developed the drugs. DDR inhibitors are being studied for the treatment of cancer. Since the FDA fast tracks many drugs for serious conditions, there is incredible potential to reduce overall developments costs while increase the speed which novel drugs can be approved for very sick patients waiting for them. This welcome news comes at a time when soaring costs for drug development, arguably are being recouped in high prices of novel innovative therapies hitting the market." said Barbara Gilmore, Senior Consultant on Transformational Health at Frost & Sullivan.

"It is extremely exciting seeing Deep Learning and other techniques being used to help pinpoint drug discovery in a matter of days. In particular, exploiting large, publicly-available data sets to accelerate this process can give huge benefits for low cost. The data-driven approach will give better and faster results than the traditional methods, leading to faster drug discovery and safer, more reliable results than clinical trials on their own. While it's unlikely that AI will replace the current methods overnight, it's obvious that organisations which add AI to their methods will quickly replace those who do not. It is vital these organisations 'Uber' themselves before they get Kodaked" said David Whewel, former Director of Architecture and Software Innovation at Merck Group.

"As far as I know, this marks the first ever demonstration that AI can generate entirely novel, synthesizable, active molecules against a specific pharmacological target. In my view, the fact that they were able to generate entirely novel, pharmacologically viable compounds using AI is the most amazing achievement here. Of course it's even more amazing that they established this ground-breaking proof of concept in just 46 days!" said Olivier Elemento, Director of the Englander Institute for Precision Medicine & Associate Director of the Institute for Computational Biomedicine at Weill Cornell Medicine.

AURORA, Colo. (Sept. 3, 2019) - Using advanced imaging techniques, researchers at the University of Colorado Anschutz Medical Campus have mapped a previously uncharted region of the human genome that gives rise to a variety of disease, setting the stage to potentially test for the conditions in the future.

The study, published Sept. 3 in the journal Genome Research, was conducted by scientists at CU Anschutz led by Tamim Shaikh, PhD, the University of California San Francisco (UCSF) led by Pui-Yan Kwok MD, PhD and KU Leuven in Belgium led by Joris Vermeesch, PhD.

The research upends the view of many that the human genome was fully mapped in 2001 with the completion of the Human Genome Project.

"We have realized over time that this is not entirely true, as there are numerous gaps that remain in the reference human genome sequence," said Shaikh, one of the senior authors of the study. Shaikh is a professor of pediatrics in the section of Genetics and Metabolism at University of Colorado School of Medicine. "These gaps are present in regions that are unmappable and often `invisible' to past and most current sequencing technologies."

The researchers focused on a region on Chromosome 22, known as 22q11. There were numerous gaps in the sequence of this chromosome due to unmappable genetic sequences known as low copy repeats or LCRs.

LCRs are a significant source of genetic instability and can break chromosomes. That leads to a loss or gain of large pieces of DNA which can cause serious diseases. The loss of DNA in 22q11 leads to the 22q11 deletion syndrome resulting in symptoms which may include intellectual disability, dysmorphic features, heart defects, seizures, Autism spectrum disorders and schizophrenia.

Using two state-of-the-art genome mapping technologies known as fiber FISH and Bionano optical mapping, the researchers were able to see long DNA molecules and discover an unprecedented and extreme level of variability between individuals and populations. These differences can be hundreds of thousands to over two million base pairs of DNA.

"The large differences between people cannot be assessed without the mapping technologies deployed in this study," said Dr. Pui-Yan Kwok, Henry Bachrach Distinguished Professor at UCSF, a collaborator of Dr. Shaikh who co-authored the paper. "Our approach brings clarity to the organization of the highly complex region studied."

Shaikh agreed.

"You are mapping these chromosomal fragments back to the genome to see what is different," Shaikh said. "We looked at over 150 apparently healthy people. We found the region in question was drastically different in each person."

Some people carried far less and some far more DNA in this part of the genome.

Children with the 22q11 deletion syndrome and their parents were also tested to determine if their 22q11 LCRs were different.

"Now we can start asking questions like, `Is someone with more or less DNA more disposed to have a child with disease?'" Shaikh asked. "If so, then it might be possible to genetically test parents before they have children."

Shaikh said this region of the genome is constantly evolving.

"If you look from one generation to the next you may see changes within the same family," he said. "That is pretty incredible."

In "Intra- and Interspecific Variation in Production of Bile Acids that Act As Sex Pheromones in Lampreys," published in Physiological and Biochemical Zoology, Tyler J. Buchinger and others find that sexual selection may play a role in the evolution of lamprey pheromones.

Although most existing pheromone research has focused on insects, lampreys have a relatively well-understood pheromone communication system that offers a useful opportunity to study pheromone evolution in a vertebrate. "Our results help address biases in the animal communication literature, in which research on the evolution of vertebrate pheromones remains relatively scarce."

The key to the research centers on bile acids produced in the livers of sea lamprey, as well as other lamprey species. Within the sea lamprey species, both larvae and sexually mature males synthesize many of the same bile acids. However, bile acids produced by larvae are involved with digestive processes, while those produced by sexually mature males--who do not feed and have a degenerate digestive system--act as pheromones. Since the same bile acids serve different purposes depending on life stage, sea lampreys offer a unique opportunity to compare the evolution of bile acids produced for sexual versus nonsexual functions, Buchinger writes.

Buchinger's study aimed to understand not only how current life stage affects the makeup of bile acids in sea lampreys, but also across other lamprey species. Buchinger conducted an experiment quantifying liver concentrations of eight pheromone-related bile acids in sea lamprey larvae and sexually mature males. In a second experiment, he determined the effect of life stage on the similarity of bile acid across several lamprey species, including the pouched lamprey, silver lamprey, and American brook lamprey.

Results showed that within the sea lamprey species, bile acid profiles were generally less varied among mature male sea lampreys than for larvae sea lamprey. However, in the experiment that included other species of lamprey, liver bile acids varied more for males than larvae. This result supports the argument that sexual selection influences the pheromone evolution. Buchinger suggests that within sea lamprey males strive to produce one particular pheromone mixture--that which females find most attractive. In contrast, bile acid mixtures may have diversified across species as each evolved slightly different mate preferences or needed to recognize the correct species when mating.

Buchinger stresses the need for further research, including studies that use a larger number of lamprey species, to further investigate his findings. Despite the results pointing to sexual selection's role in pheromone evolution, there are also many ecological factors that may be at play, he writes. For instance, whether a lamprey species is polygynous, polygynandrous, or monogamous, or what they feed on are just a couple of the possible contributing factors to bile evolution. "Although we hypothesize that female mate choice and male competition have some role in the diversification of lamprey pheromones, their effects are almost certainly intertwined with other aspects of lamprey ecology," Buchinger writes.

Physiological and Biochemical Zoology: Ecological and Evolutionary Approaches primarily publishes original research in animal physiology and biochemistry as considered from behavioral, ecological, and/or evolutionary perspectives. Studies at all levels of biological organization from the molecular to the whole organism are welcome, and work that integrates across levels of organization is particularly encouraged. Studies that focus on behavior or morphology are welcome, so long as they include ties to physiology or biochemistry, in addition to having an ecological or evolutionary context.

A new study using mass spectrometry is helping piece together what happens when DNA that has been sensitized by the oncology drug 5-fluorouracil is subjected to the ionising radiation used in radiotherapy.

The anti-cancer drug 5-fluorouracil (5FU) acts as a radiosensitizer: it is rapidly taken up into the DNA of cancer cells, making the cells more sensitive to radiotherapy. However, little is known about the precise mechanism through which radiation damages cells. A team of scientists led by Peter van der Burgt at the National University of Ireland in Maynooth, Ireland have now used mass spectrometry to shed some light on this process; their work was recently published in EPJ D. A full understanding of this process could ultimately lead to new ways of protecting normal tissues from the radiation damage caused by essential cancer treatments.

Radiotherapy involves delivering radiation, in the form of X-rays, to the cancer site. The X-rays or other high-energy particles collide with the molecules they encounter, knocking off electrons to form positively-charged ions, and these ions and electrons in turn react with other molecules in the cells: this can kill cancer cells, but can also cause short- and long-term damage to others.

5-fluorouracil resembles the bases in normal DNA but is more sensitive to radiation, both on its own and when incorporated into DNA. Van der Burgt and his colleagues investigated this sensitivity by producing a stream of 5FU particles in a mass spectrometer and colliding them with a beam of radiation. The spectrometer was then used to determine which ions were formed in the collisions by measuring their mass-to-charge ratio. Two sets of experiments were carried out: one using electrons as the radiation source, and the other using high-intensity photons.

Increasing the energy of the radiation increased the number and type of ions that were formed; the researchers identified many different fragment ions and determined the radiation level at which each was first formed. These included some ions that were absent from the spectrum of the natural base, uracil, and some that had not been observed in this type of experiment before. Undoubtedly, similar processes take place in the tissues of patients undergoing radiotherapy.

HERSHEY, Pa. -- While there are several effective options for treating non-melanoma skin cancers, some may result in better cosmetic appearance after treatment, according to researchers.

In a meta-analysis of 58 studies, a study led by Penn State compared four types of skin cancer treatments and found that while all four had similar recurrence rates a year after treatment, a form of radiation called brachytherapy and a type of surgery called Mohs micrographic surgery had better cosmetic results.

Nicholas Zaorsky, assistant professor in radiation oncology and public health sciences, said the findings suggest that when surgery is not an option, types of radiation therapy can also be a good option for treating skin cancers like basal and squamous cell carcinomas.

"Based on our analysis, it appears that radiation can be a good alternative treatment to surgery," Zaorsky said. "It shouldn't necessarily be thought of as something that's an antiquated treatment that will result in a high chance of the cancer coming back or having unfavorable cosmetic outcomes."

Zaorsky said skin cancer is relatively common in the United States, with approximately one in five people being diagnosed with at least one skin cancer in their lifetime. The American Cancer Society estimates that 5.4 million cases of basal and squamous cell carcinomas are diagnosed each year, and while these cancers are rarely fatal, they do require treatment.

The four treatments analyzed included two types of surgery. Conventional excision involves removing the entire site of the cancer and then suturing the skin closed, while Mohs surgery is more detailed. For Mohs surgery, a surgeon removes the cancer layer by layer, testing the tissue between each layer until the cancer is completely removed.

The study also looked at two types of radiation therapy, including external beam radiation therapy (EBRT) and brachytherapy. EBRT is the most common form of radiation, involving a machine that directs beams from outside the body toward the cancer. But with brachytherapy, the beams are more closely targeted to the cancer.

"'Brachy' means short, as in a short distance," Zaorsky said. "With this type of therapy, the radiation doesn't penetrate to a deep location in the body. It may only go through a few millimeters or a centimeter, versus other forms of radiation that may go much deeper."

According to the researchers, radiation was once thought of as an inferior treatment for treating skin cancer when compared to surgery. But, Zaorsky said there was a lack of modern research to support this belief. Furthermore, while surgery is a common option, it might not be the best option for certain patients.

"Older patients, for example, may not be able to have surgery for a variety of reasons, or it could be the case that the cancer is near a major organ like the nose or eye," Zaorksy said. "There's been a concern from physicians wondering if radiation is a good option in these cases or if it may not be as effective or have worse side effects."

For the meta-analysis, the researchers analyzed the results of 58 studies that included 21,371 patients with non-melanoma skin cancer. Data included information about the type of cancer, form of treatment the patient received, recurrence rate after one year, and a rating of the cosmetic appearance of the site of the cancer after treatment. The treatments were given a cosmetic rating of "good," "fair" or "poor."

After analyzing the data, the researchers found that a "good" cosmetic rating was achieved 81 percent, 75 percent, 98 percent, and 96 percent of the time for conventional excision, EBRT, brachytherapy, and Mohs surgery respectively. Brachytherapy and Mohs surgery had more "good" and "fair" ratings than the other two treatments.

Zaorsky said the findings -- recently published in the journal Cancer -- could potentially be used to update industry guidelines for skin cancer treatment.

Toyohashi University of Technology has developed a novel liquid process for fabrication of an affordable multiferroic nanocomposite film in collaboration with Japan Fine Ceramics Center, National Institute of Technology Ibaraki College, International Iberian nanotechnology Laboratory, Chang'an university and University of Erlangen-Nuremberg. The multiferroic material obtained by the novel process possesses strong correlation between the electric and the magnetic properties, thus various applications such as low-power-consumption large-volume memory, spatial light modulator, and unique sensors, etc. are expected in the future.

Multiferroic materials combine electrical (ferroelectric) and magnetic (ferromagnetic) properties and have a strong correlation between these properties (exhibit a magnetoelectric effect), and their development is expected to realize more versatile and higher performance next-generation electrical and magnetic devices. In recent years, several methods of production of multiferroic films exhibiting large magnetoelectric properties have been reported. However, these processes require large and extraordinary expensive vacuum devices, making them impractical for fabricating materials with a large area in particular. As a result, multiferroic materials have only been used in a very limited range of applications.

With this background, the research team developed a process for producing a material with advanced multiferroic properties by combining several liquid-phase methods that are relatively inexpensive and simple.

The lead author, Associate Professor Go Kawamura of Toyohashi University of Technology explained, "In order to fabricate a material that exhibits advanced multiferroic properties, it is necessary to combine ferroelectric and ferromagnetic materials appropriately and periodically on the nanometer scale. In the past, nanopillar array structures were fabricated in a self-organized manner using gas-phase methods, and a large magnetoelectric effect was observed in such materials. However, the gas-phase methods required the use of large and expensive equipment, and it was practically impossible to increase the area of the sample. Therefore, we worked on the fabrication of nanopillar array-like composite films using only affordable and simple liquid-phase methods. In the multiferroic composite film obtained by the process we developed, it is clarified that there is a local epitaxial relationship at the interface between the ferroelectric and the ferromagnetic materials, thereby producing a large magnetoelectric effect. Compared to conventional gas-phase processes, multiferroic composite films can be produced at a much lower cost and can be used for larger areas."

This study was interdisciplinary, requiring a variety of specialties. Therefore, the research team collaborated with specialists in dielectric materials and magnetic materials, specialists in observation of nanostructures using electron microscopes, and specialists in liquid-phase synthesis, among others, from various institutions in Japan and overseas. The novel process was developed by combining these advanced specialties.

The research team believes that more precise creation of controlled nanostructures can further improve the magnetoelectric effect, and will continue to optimize the process. Ultimately, the team plans to produce large area materials, which is also a feature of the process that was developed, and apply them to a spatial light modulator to develop applications such as spatial displays that can build huge three-dimensional images.