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Monday, 13 July 2020

Why is CBD so popular among athletes and sportspeople?


Cannabidiol is a cannabinoid found in cannabis, more commonly known as "CBD". The latter has greatly increased in popularity in recent years. Indeed, CBD has been adopted by people of all ages looking for relief from a variety of symptoms. But the substance has also gained particular appeal among sportspeople and athletes.



Why are so many athletes and sportspeople so interested in CBD? Be aware that there is a huge amount of anecdotal evidence, and a growing body of clinical research suggesting that this cannabis compound may be beneficial for symptoms such as pain and anxiety. Today, a growing number of athletes are using and approving CBD products for this reason.

What is CBD?

CBD is one of the cannabinoids: these are the 144 active molecules found in hemp (known as cannabis), one of the oldest plants domesticated by humans. Hemp has been exploited for millennia for its industrial use (paper, plastic, building, etc.), but also for its beneficial food intake. Unlike its cousin, delta-9-tetrahydrocannabinol (THC), which is the main active ingredient in cannabis, CBD is not psychoactive.

It has been discovered that the cannabinoids in the cannabis plant can interact with receptors in our body, which are naturally reserved for endogenous cannabinoids (or endocannabinoids). Together, these are known as the endocannabinoid system and are believed to modulate a number of physiological and neurological processes such as pain management, mood control, appetite, and immune system functions.

For which health problems can CBD be useful?

Although research in this area is still limited, there are a number of clinical trials and reviews that have shown that CBD can be useful in the treatment of a variety of symptoms and ailments. Among these are pain, stress and anxiety.

Anxiety: This is one of the most common "mental health" problems facing modern society, and scientists have found that CBD interacts with the CB1 and serotonin receptors, causing an increase in development of natural substances, anandamide and serotonin. These naturally occurring compounds are known to regulate feelings of anxiety and depression.

Pain: caused by a number of different illnesses or health conditions, it is also often cited as a reason for using CBD. At this level, the scientists discovered that the interaction of the compound with the endocannabinoid system interferes with the reception of pain. Indeed, the anti-inflammatory properties of CBD mean that the substance can be added to topical treatments for example.



What is the link between athletes and CBD?

Today, more and more athletes and athletes are talking openly about using CBD. Many have even approved specific CBD brands, including professional golfer Gerry Lester Watson Jr (nicknamed "Bubba"), and MMA fighter Jessica-Rose Clark. This is also the case for other professionals in the field of BMX, FMX, surfing, skateboarding and many other sports. "I have personally experienced the benefits of CBD products," said Watson, who is partnering with a brand of CBD.

Indeed, be aware that the analgesic potential of CBD can be used locally through topical lotions for muscle pain. And some users also report pain relief after taking cannabinoids sublingually in the form of oil drops or orally via capsules and edibles.

But being an athlete at a professional level can undoubtedly also be very anxiety-provoking: many high-level athletes can therefore also take advantage of the anti-stress potential of the compound.

What about CBD and sports regulations?

Recently, sports regulators have also become more liberal with regard to CBD. For example, in 2017, the World Anti-Doping Agency removed CBD from its list of prohibited substances. Then, other sports decision-making bodies quickly followed suit. However, some continue to advise against the use of CBD products.

While this remains an important issue in a large number of countries, given the emerging CBD market, it has apparently not turned off many athletes, as they maintain their confidence in the brands they support.



Sources: USADA, Canex

Sunday, 12 July 2020

Food Poisoning Bacteria Causes Autoimmunity and May Be Linked to Alzheimer’s and Parkinson’s


Salmonella was previously thought to only form biofilms in the environment, such as on food processing surfaces. Biofilms are dense collections of bacteria that stick together on surfaces to protect the bacteria from harsh conditions, including antibiotics and disinfectants. Detecting biofilms in an animal during an infection was a surprise.



In research published today in PLoS Pathogens, a VIDO-InterVac team led by Dr. Aaron White (PhD) discovered that salmonella biofilms were formed in the intestines of infected mice. For the study, the team used a mouse model to replicate human food-borne illness and showed that a biofilm protein called curli—that grows on the surface of bacteria—was connected to negative health outcomes.

Curli are a special type of protein called amyloids. Similar human proteins have been associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Scientists don't know how these diseases start, but have speculated that something must trigger the accumulation of amyloids.

“We are the first to show that a food-borne pathogen can make these types of proteins in the gut,” said White, a leading expert on salmonella biofilms and curli amyloids.

“There has been speculation that bacteria can stimulate amyloid plaque formation in Alzheimer’s, Parkinson’s and ALS and contribute to disease progression. The discovery of curli in the gut could represent an important link, pointing to a potentially infectious cause for these diseases.”



Collaborator Dr. Çagla Tükel (PhD) and her team from Temple University determined that the presence of curli led to autoimmunity and arthritis—two conditions that are known complications of salmonella infections in humans.

“In mice, these reactions were triggered within six weeks of infection, demonstrating that curli can be a major driver of autoimmune responses,” said Tükel.

The next step in the research is to confirm that this also occurs in humans, and test if other food-borne pathogens related to salmonella can cause similar autoimmune reactions.

“This important discovery suggests that food-borne pathogens could initiate or worsen autoimmunity and have the potential to contribute to amyloid disorders such as Alzheimer’s and Parkinson’s disease,” said VIDO-InterVac Director Dr. Volker Gerdts (DVM).



Reference

In vivo synthesis of bacterial amyloid curli contributes to joint inflammation during S. Typhimurium infection. Amanda L. Miller et al. PLOS Pathogens, July 9, 2020, https://doi.org/10.1371/journal.ppat.1008591.

Saturday, 11 July 2020

Purifying water with the help of wood, bacteria and the sun


According to the United Nations, about one-fifth of the world's population lives in areas where water is scarce. Therefore, technologies to produce clean water from undrinkable sources, such as seawater, river or lake water, and contaminated water, are urgently needed. Now, researchers reporting in Nano Letters have developed a wood-based steam generator that, with the help of bacterial-produced nanomaterials, harnesses solar energy to purify water.



A solar steam generator is a device that uses the abundant energy of the sun to separate pure water from its contaminants by evaporation. Many different versions of these devices have been developed, with varying efficiencies. To design better solar steam generators, researchers must find ways to improve light absorption, heat management, water transport and evaporation. Shu-Hong Yu and colleagues at the University of Science and Technology of China wanted to combine all four improvements in a single device. They chose wood as the basis of their generator because of its sustainability and porous structure, which allows rapid water transport.

The researchers made their device with the help of bacteria that produced long cellulose nanofibers, which bound the layers of the device together. The team added bacteria to the surface of a block of wood and allowed them to ferment. Then, they sprayed an aerosol of glass bubbles—tiny hollow spheres that provide excellent thermal insulation—onto the surface. The glass bubbles became embedded in the cellulose nanofibers produced by the bacteria, forming a hydrogel.

Finally, the researchers added carbon nanotubes, which tangled with the cellulose nanofibers to form a light-absorbing, water-evaporating top layer. The device works by transporting water upward through the wood to the light-absorbing layer, which is heated by the sun. The water evaporates, and the steam is collected and condensed to produce pure water. The insulating layer of glass bubbles keeps heat from being transferred downward through the device and lost, and the nanoscale structures lower the energy required for water vaporization. As a result, the new device has a higher evaporation rate and efficiency than most existing solar steam generators.



More information: 

"Sustainable Wood-Based Hierarchical Solar Steam Generator: A Biomimetic Design with Reduced Vaporization Enthalpy of Water" Nano Letters (2020). pubs.acs.org/doi/abs/10.1021/acs.nanolett.0c01088

Mom and baby share 'good bacteria' through breast milk


A new study by researchers at the University of British Columbia and the University of Manitoba has found that bacteria are shared and possibly transferred from a mother's milk to her infant's gut, and that breastfeeding directly at the breast best supports this process.



The research, published today in Cell Host & Microbe, found that certain bacteria, including Streptococcus and Veillonella, co-occur in mothers' milk and their infants' stool, and this co-occurrence is higher when infants nurse directly at the breast.

"Our study confirms that breast milk is a major driver of infant gut microbiota development," said the study's senior co-author Dr. Stuart Turvey, a professor in UBC's department of pediatrics and investigator at BC Children's Hospital. "We found that breastfeeding exclusivity and duration was strongly associated with a baby's overall gut microbiota composition and that breast milk bacteria shape a baby's gut microbiome to a similar degree as other known modifiers of the gut microbiota such as birth mode—meaning a cesarean-section or vaginal delivery."

According to the researchers, this is the first study to evaluate the association of multiple breast milk feeding practices (mode, exclusivity, and duration), milk bacteria, and milk components with infant gut microbiota composition at multiple time points in a baby's first year.

The researchers analyzed the microbiome of infants' stool and their mothers' breastmilk using 16S rRNA sequencing, a technique used to identify, classify and determine the abundance of microbes.

The 1,249 mother-baby pairs involved in the research are participating in the CHILD Cohort Study (CHILD), a world-leading birth cohort study in maternal, newborn and child health research. The findings build upon previous CHILD research that showed pumping breast milk is associated with differences in both milk microbiota composition and infant health.

"Uniquely, our study showed that while breast milk and the infant gut have distinct microbiota compositions, there are a few commonly shared bacteria that were more prevalent and abundant in breast milk of mothers who only nursed directly at the breast, while other bacteria showed dose-dependent associations with exclusive breastfeeding," said the study's senior co-author Brett Finlay, professor in the departments of biochemistry and molecular biology, and microbiology and immunology at UBC.

"These results advance the hypothesis that breast milk may act as an incubator that enriches, protects and transports certain bacteria to a baby's intestinal tract and this may give us clues about which bacteria could make good probiotics since they appear to withstand the trip to the baby's gut," Finlay added.



More information: 

Kelsey Fehr et al, Breastmilk Feeding Practices Are Associated with the Co-Occurrence of Bacteria in Mothers' Milk and the Infant Gut: the CHILD Cohort Study, Cell Host & Microbe (2020). DOI: 10.1016/j.chom.2020.06.009

By 2025, carbon dioxide levels in Earth's atmosphere will be higher than at any time in the last 3.3 million years


By 2025, atmospheric carbon dioxide (CO2) levels will very likely be higher than they were during the warmest period of the last 3.3 million years, according to new research by a team from the University of Southampton published today in Nature Scientific Reports.



The team studied the chemical composition of tiny fossils, about the size of a pin head collected from deep ocean sediments of the Caribbean Sea. They used this data to reconstruct the concentration of CO2 in Earth's atmosphere during the Pliocene epoch, around 3 million years ago when our planet was more than 3°C warmer than today with smaller polar ice caps and higher global sea-levels.

Dr. Elwyn de la Vega, who led the study, said: "Knowledge of CO2 during the geological past is of great interest because it tells us how the climate system, ice sheets and sea-level previously responded to the elevated CO2 levels. We studied this particular interval in unprecedented detail because it provides great contextual information for our current climate state."

To determine atmospheric CO2, the team has used the isotopic composition of the element boron, naturally present as an impurity in the shells of zooplankton called foraminifera or 'forams' for short. These organisms are around half a millimeter in size and gradually accumulate in huge quantities on the seabed, forming a treasure trove of information on Earth's past climate. The isotopic composition of the boron in their shells is dependent on the acidity (the pH) of the seawater in which the forams lived. There is a close relationship between atmospheric CO2 and seawater pH, meaning past CO2 can be calculated from careful measurement of the boron in ancient shells.



Dr. Thomas Chalk, a co-author of the study, added: "Focussing on a past warm interval when the incoming insolation from the Sun was the same as today gives us a way to study how Earth responds to CO2 forcing. A striking result we've found is that the warmest part of the Pliocene had between 380 and 420 parts per million CO2 in the atmosphere. This is similar to today's value of around 415 parts per million, showing that we are already at levels that in the past were associated with temperature and sea-level significantly higher than today. Currently, our CO2 levels are rising at about 2.5 ppm per year, meaning that by 2025 we will have exceeded anything seen in the last 3.3 million years."

Professor Gavin Foster, who was also involved in the study, continued: "The reason we don't see Pliocene-like temperatures and sea-levels yet today is because it takes a while for Earth's climate to fully equilibrate (catch up) to higher CO2 levels and, because of human emissions, CO2 levels are still climbing. Our results give us an idea of what is likely in store once the system has reached equilibrium."

Concluded Dr. de la Vega, "Having surpassed Pliocene levels of CO2 by 2025, future levels of CO2 are not likely to have been experienced on Earth at any time for the last 15 millions years, since the Middle Miocene Climatic Optimum, a time of even greater warmth than the Pliocene."

The paper, "Atmospheric CO2 during the Mid-Piacenzian Warm Period and the M2 glaciation," is published in Nature Scientific Reports.



More information: 

Elwyn de la Vega et al. Atmospheric CO2 during the Mid-Piacenzian Warm Period and the M2 glaciation, Scientific Reports (2020). DOI: 10.1038/s41598-020-67154-8

Physicians give first comprehensive review of COVID-19's effects outside the lung


After only a few days caring for critically ill COVID-19 patients at the start of the outbreak in New York City, Aakriti Gupta, MD, realized that this was much more than a respiratory disease.



"I was on the front lines right from the beginning. I observed that patients were clotting a lot, they had high blood sugars even if they did not have diabetes, and many were experiencing injury to their hearts and kidneys," says Gupta, one of the first Columbia cardiology fellows to be deployed to the COVID intensive care units at Columbia University Irving Medical Center.

In early March, there wasn't much clinical guidance on the non-respiratory effects of COVID-19, so Gupta decided to coalesce findings from studies that were just beginning to appear in the literature with what the physicians were learning from experience.

Gupta, along with senior author Donald Landry, MD, Ph.D., chair of medicine at Columbia University Vagelos College of Physicians and Surgeons, organized senior co-authors, and Gupta, along with two other colleagues, Mahesh Madhavan, MD, a cardiology fellow at CUIMC, and Kartik Sehgal, MD, a hematology/oncology fellow at Beth Israel Deaconess Medical Center/Harvard Medical School, mobilized clinicians at Columbia, Harvard, Yale, and Mount Sinai Hospital, among other institutions, to review the latest findings on COVID-19's effect on organ systems outside the lungs and provide clinical guidance for physicians.

Their review—the first extensive review of COVID-19's effects on all affected organs outside the lungs—was published today in Nature Medicine.

"Physicians need to think of COVID-19 as a multisystem disease," Gupta says. "There's a lot of news about clotting but it's also important to understand that a substantial proportion of these patients suffer kidney, heart, and brain damage, and physicians need to treat those conditions along with the respiratory disease."



Blood Clots, Inflammation, and an Immune System in Overdrive

"In just the first few weeks of the pandemic, we were seeing a lot of thrombotic complications, more than what we would have anticipated from experience with other viral illnesses," says Sehgal, "and they can have profound consequences on the patient."

Scientists think these clotting complications may stem from the virus's attack on cells that line the blood vessels. When the virus attacks blood vessel cells, inflammation increases, and blood begins to form clots, big and small. These blood clots can travel all over the body and wreak havoc on organs, perpetuating a vicious cycle of thromboinflammation.

To combat clotting and its damaging effects, clinicians at Columbia, many of whom are co-authors on this review, are conducting a randomized clinical trial to investigate the optimal dose and timing of anticoagulation drugs in critically ill patients with COVID-19.

The untempered inflammation can also overstimulate the immune system, and though doctors initially shied away from using steroids to globally suppress the immune system, a recent clinical trial has found that at least one steroid, dexamethasone, reduced deaths in ventilated patients by one-third. Randomized clinical trials are underway to target specific components of thromboinflammation and the immune system, such as interleukin-6 signaling.

"Scientists all over the world are working at an unprecedented rate towards understanding how this virus specifically hijacks the normally protective biological mechanisms. We hope that this would help in the development of more effective, precise, and safer treatments for COVID-19 in the near future," says Sehgal.



Straight to the Heart

Clots can cause heart attacks, but the virus attacks the heart in other ways, one author says.

"The mechanism of heart damage is currently unclear, as the virus has not been frequently isolated from the heart tissue in autopsy cases," says Gupta.

The heart muscle may be damaged by systemic inflammation and the accompanying cytokine release, a flood of immune cells that normally clears up infected cells but can spiral out of control in severe COVID-19 cases.

Despite the degree of heart damage, physicians were not able to utilize the diagnostic and therapeutic strategies, including heart biopsies and cardiac catheterizations, that they would normally use during the early stages of the pandemic given the need to protect personnel and patients from viral transmission. This has changed as the disease prevalence has gone down in New York CIty.



Kidney Failure

Another surprising finding was the high proportion of COVID-19 patients in the ICU with acute kidney damage.

The ACE2 receptor used by the virus to gain entry into the cells is found in high concentrations in the kidney and could likely be responsible for the renal damage. Studies in China reported renal complications, but in New York City, clinicians saw renal failure in up to 50% of patients in the ICU.

"About 5 to 10% of patients needed dialysis. That's a very high number," Gupta says.

Data regarding long-term renal damage are currently lacking, but a significant proportion of patients will likely go on to require permanent dialysis.

"Future studies following patients who experienced complications during hospitalizations for COVID-19 will be crucial," notes Madhavan.



Neurological Effects

Neurological symptoms, including headache, dizziness, fatigue, and loss of smell, may occur in about a third of patients.

More concerning, strokes caused by blood clots occur in up to 6% of severe cases and delirium in 8% to 9%.

"COVID-19 patients can be intubated for two to three weeks; a quarter require ventilators for 30 or more days," Gupta says.

"These are very prolonged intubations, and patients need a lot of sedation. 'ICU delirium' was a well known condition before COVID, and the hallucinations may be less an effect of the virus and more an effect of the prolonged sedation."

"This virus is unusual and it's hard not to take a step back and not be impressed by how many manifestations it has on the human body," says Madhavan.

"Despite subspecialty training as internists, it's our job to keep all organ systems in mind when caring for the patients in front of us. We hope that our review, observations, and recommendations can help other clinicians where cases are now surging."

The paper is titled, "Extrapulmonary manifestations of COVID-19."



More information: 

Aakriti Gupta et al, Extrapulmonary manifestations of COVID-19, Nature Medicine (2020). DOI: 10.1038/s41591-020-0968-3

Friday, 10 July 2020

Scientists have pointed to the possibility of extending human life


Scientists at USC Dornsife College of Letters, Arts and Sciences may have found the beginnings of a path toward increasing human lifespan.

The research, published July 10 in the Journal of Gerontology: Biological Sciences, shows the drug mifepristone can extend the lives of two very different species used in laboratory studies, suggesting the findings may apply to other species, including human beings.



Countering wear and tear inflicted by males

Studying one of the most common laboratory models used in genetic research — the fruit fly Drosophila — John Tower, professor of biological sciences, and his team found that the drug mifepristone extends the lives of female flies that have mated.

Mifepristone, also known as RU-486, is used by clinicians to end early pregnancies as well as to treat cancer and Cushing disease.

During mating, female fruit flies receive a molecule called sex peptide from the male. Previous research has shown that sex peptide causes inflammation and reduces the health and lifespan of female flies.

Tower and his team, including Senior Research Associate Gary Landis, lead researcher on the study, found that feeding mifepristone to the fruit flies that have mated blocks the effects of sex peptide, reducing inflammation and keeping the female flies healthier, leading to longer lifespans than their counterparts who did not receive the drug.

The drug’s effects in Drosophila appear similar to those seen in women who take it.

“In the fly, mifepristone decreases reproduction, alters innate immune response and increases life span,” Tower explained. “In the human, we know that mifepristone decreases reproduction and alters innate immune response, so might it also increase life span?”



Overcoming juvenile hormone effects

Seeking a better understanding of how mifepristone works to increase lifespan, Tower and his team looked at the genes, molecules and metabolic processes that changed when flies consumed the drug. They found that a molecule called juvenile hormone plays a central role.

Juvenile hormone regulates the development of fruit flies throughout their life, from egg to larvae to adult.

Sex peptide appears to escalate the effects of juvenile hormone, shifting the mated flies’ metabolism from healthier processes to metabolic pathways that require more energy to maintain. Further, the metabolic shift promotes harmful inflammation, and it appears to make the flies more sensitive to toxic molecules produced by bacteria in their microbiome.

Mifepristone changes all of that.

When the mated flies ate the drug, their metabolism stuck with the healthier pathways, and they lived longer than their mated sisters who did not get mifepristone. Notably, these metabolic pathways are conserved in humans, and are associated with health and longevity, said Tower.



Hope for humans?

In a scientific first, Tower and collaborators Chia-An Yen, who obtained her Ph.D. last spring from USC Dornsife, and Sean Curran, associate professor of gerontology and biological sciences at USC Leonard Davis School of Gerontology and USC Dornsife, also gave mifepristone to another common laboratory model, a small roundworm called C. elegans. They found the drug had the same life-extending effect on the mated worm.

Because Drosophila fruit flies and C. elegans worms sit on relatively distant branches of the evolutionary tree, Tower believes the similar results in such different species suggest other organisms, including humans, might see comparable benefits to lifespan.

“In terms of evolution, Drosophila and C. elegans are equally as distant from each other as either one is distant from humans,” he said, and the fact that mifepristone can increase lifespan in both species suggests the mechanism is important to many species.

Tower emphasizes that a clearer understanding of the intricacies of mifepristone’s actions is needed before drawing any firm conclusions.

“Our data show that in Drosophila, mifepristone either directly or indirectly counteracts juvenile hormone signaling, but the exact target of mifepristone remains elusive.”

Revealing that target may give scientists critical insight needed to extend lifespan in people.



More information: 

Gary N Landis et al, Metabolic Signatures of Life Span Regulated by Mating, Sex Peptide and Mifepristone/RU486 in Female Drosophila melanogaster, The Journals of Gerontology: Series A (2020). DOI: 10.1093/gerona/glaa164

Researchers solve a 50-year-old enzyme mystery


Advanced herbicides and treatments for infection may result from the unravelling of a 50-year-old mystery by University of Queensland researchers.

The research team, led by UQ’s Professor Luke Guddat, revealed the complete three-dimensional structure of an enzyme, providing the first step in the biosynthesis of three essential amino acids – leucine, valine and isoleucine.



“This is a major scientific advance, which has been pursued globally by chemists for half a century,” Professor Guddat said.

“This information provides new insights into an important enzyme – acetohydroxyacid synthase – a target for more than 50 commercial herbicides.

“It’s also a potential target for new drugs to treat infections such as tuberculosis and invasive Candida infections.”

Using advanced techniques such as cryo-electron microscopy and X-ray crystallography, the team deciphered the structure of the plant and fungal versions of the enzyme.

“We identified how this highly complex structure is assembled, which is the highly unusual shape of a Maltese Cross,” Professor Guddat said.

“Coincidently, the Maltese Cross also features as a part of UQ’s logo.”

Professor Guddat said the discovery could have big implications for global agriculture.



“Sulfometuron is a herbicide that targets this enzyme, and was widely used in the 1990s for wheat crop protection throughout Australia,” he said.

“But today it is completely ineffective due to the development of resistance.

“With this new insight, we will be able to make changes to existing herbicides, restoring options for future herbicide application.”

Professor Guddat said the enzyme was only found in plants and microbes, not in humans.

“For this reason, the herbicides and drugs that it targets are likely to be safe and non-toxic to all mammals,” he said.

“And another surprising finding of the research was the role that the molecule known as ATP plays in the regulation of the enzyme.

“Normally ATP plays a role in providing energy to all living cells,” Professor Guddat said.

“However, here it is acting like a piece of glue to hold the structure together.”

“They’re fascinating findings for us, and we’re excited for new opportunities for targeted design of next-gen herbicides and antimicrobial agents.”



More information: 

Thierry Lonhienne et al, Structures of fungal and plant acetohydroxyacid synthases, Nature (2020). DOI: 10.1038/s41586-020-2514-3

No NELL2, no Sperm motility. Novel protein is essential for male fertility


Newly produced spermatozoa within the testis are not fully functional until they mature in the epididymis, a duct that helps to transport and store sperm. Male infertility may arise from lack of communication between the testis and the epididymis and new research has uncovered a mechanism of this communication.



Dr. Martin Matzuk at Baylor College of Medicine, Dr. Masahito Ikawa with Osaka University and their colleagues have discovered a novel testicular luminal protein, NELL2, that triggers in the epididymis a chain of events that matures the sperm and enables each one to be motile in females.

Sperm production

Sperm are produced in the seminiferous tubules of the testis and move through the epididymis, a long, convoluted tube linked to the vas deferens, the duct that moves sperm from the testicle to the urethra. When the sperm enter the epididymis, they are not motile and are incapable of fertilization. However, in their passage through the epididymis, the sperm are provided an appropriate environment for maturation and storage pending ejaculation.

It has been hypothesized that proteins released by the testis earlier in this process could act on the epididymis to mature the sperm as they arrive in the epididymis.

“Until now the proteins working through the lumicrine system of signaling have remained elusive. While it was known that the orphan receptor tyrosine kinase ROS1 expressed in the initial segment of the epididymis is necessary for its differentiation, neither the testicular factors that regulate initial segment differentiation nor the process of sperm maturation had been fully understood,” said Matzuk, professor and director of the Center for Drug Discovery at Baylor.



Identifying NELL2

The researchers zeroed in on NELL2, a protein factor secreted by testicular germ cells, as a possible lumicrine regulator of fertility.

“Using innovative genome editing technology, we generated knockout mice lacking the NELL2 gene and showed that these knockout males are sterile due to a defect in sperm motility,” explains lead author Dr. Daiji Kiyozum. “Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We also illustrated lumicrine signaling by demonstrating tagged NELL2 in the epididymal lumen.”

The research team observed that spermatogenesis proceeds normally in NELL2 knockout mouse testes but their epididymis was poorly differentiated, similar to Ros1 knockout mice. Following mating, neither NELL2 knockout nor Ros1 knockout spermatozoa can enter the uterine tubes or fertilize an egg. Further investigation showed that the Nell2 knockout epididymis is incapable of processing a specific sperm surface protein essential for male fertility.

Implications for male fertility?

Elaborating on their study, Ikawa and Matzuk, both senior authors, said, “We discovered a complicated cascade of events in which disruption of any point in this lumicrine pathway causes a male to be infertile."



Reference: 

Kiyozumi et al. (2020). NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility. Science. DOI: 10.1126/science.aay5134

Plant Proteins Less Effective at Supporting Aging Muscles Than Animal Protein


On a gram for gram basis, animal proteins are more effective than plant proteins in supporting the maintenance of skeletal muscle mass with advancing age, shows research presented this week at The Physiological Society's virtual early career conference Future Physiology 2020.



The number of vegans in the UK has quadrupled since 2006, meaning that there are around 600,000 vegans in Great Britain (1). While we know plant-based diets are beneficial for the environment, we don't actually know how healthy these diets are for keeping muscles strong in elderly people.

Scientists generally agree that the primary driver of muscle loss with age -- at least in healthy individuals -- is a reduction of muscle proteins being built from amino acids. These amino acids come from protein that we eat and are also formed when we exercise.

Oliver Witard of King's College London is presenting research at The Physiological Society's Future Physiology 2020 conference about soy and wheat proteins showing that a larger dose of these plant proteins is required to achieve a comparable response of building muscles.

Simply transitioning from an animal-based protein diet to a plant-based diet, without adjusting total protein intake, will likely to be detrimental to muscle health during ageing. A more balanced and less extreme approach to changing dietary behaviour, meaning eating both animal and plant-based proteins, is best.

Witard and his colleagues conducted carefully controlled laboratory studies in human volunteers that involve the ingestion of plant compared with animal-based protein sources. To test changes in participants' muscles, they use several techniques including stable isotope methodology, blood sampling, and skeletal muscle biopsies to see how quickly the muscles were building up from amino acids.

It's important to note that this research to date has only compared two plant-based protein sources, namely soy and wheat. The researchers in this field will be conducting further research on other promising plant proteins such as oat, quinoa and maize.

Commenting on the research, Oliver Witard said: "This research challenges the broad viewpoint that plant proteins don't help build muscles as much as animal protein by highlighting the potential of alternative plant-based protein sources to maintain the size and quality of ageing muscles."



Reference

Presented by Oliver Witard this week at The Physiological Society's virtual early career conference Future Physiology 2020.

COVID-19 Could Outwit Science Unless Knowledge Stays Current


The virus that causes COVID-19 has many variants, and if scientists don’t stay on top of how it is changing in different parts of the world, testing for it may produce false negative results.

The development of an effective vaccine could also be hampered if experts don’t constantly sequence samples of the virus to track its genetic diversity.



These insights arise from a study by researchers in the University of Manitoba’s Rady Faculty of Health Sciences in collaboration with a virology lab at Universidad de Concepción in Chile. The study was published online in May in PeerJ – the Journal of Life and Environmental Sciences.

The researchers used publicly available datasets to analyze whole genome sequencing samples from patients who were infected with SARS-CoV-2, the virus that causes COVID-19, before March 27, 2020.

Dr. Carlos Farkas, a postdoctoral researcher in pharmacology and therapeutics in the Max Rady College of Medicine and at the Research Institute in Oncology and Hematology, is the study’s lead author. He is at the forefront of using novel tools in bioinformatics (the science of using computers to analyze biological data) to track mutations of the coronavirus.

The UM team was the first to combine genomic sequencing data from two worldwide sources in order to detect variants by geographic region. They found 146 different variants, or genetic “footprints” left by the virus, in the patient data.

“One of our key findings was that samples from Washington, one of the U.S. states where the virus was first detected, had quite a distinctive footprint of specific viral sequence changes,” said co-author Dr. Jody Haigh, associate professor of pharmacology and therapeutics and senior scientist at the Research Institute in Oncology and Hematology.

“About 39 per cent of Washington State samples had this footprint. Asian and European samples were more diverse in terms of changes in viral sequence, but their footprints were clearly different from those in the U.S. samples.”



The lab test that is used to detect SARS-CoV-2, Farkas and Haigh said, uses small pieces of DNA, or primers, that bind to the viral sequence and amplify any viral RNA/DNA that is present in the patient sample.

“These primers need to match the viral sequence exactly in order to produce a robust positive result,” Farkas said. “If researchers design these primers to bind to regions of the virus that they don’t realize have changed in a particular population, there may be poor amplification and the result can be false negatives.”

The UM researchers found that some changes in viral sequence were indeed located in regions of the virus where primers were supposed to bind. “This may explain some of the false negative results in COVID-19 testing,” Haigh said.

“Because SARS-CoV-2 is changing rapidly, researchers should be aware of its current local viral footprints in order to design DNA primers that don’t bind to regions of the virus that have changed. Other regions of the virus that don’t show these changes should be used for designing primers.”

The researchers hope their results will influence COVID-19 testing and vaccine development and highlight the importance of frequent genetic sequencing of samples in every country of the world.

The study team, in collaboration with BioXplor, a data-driven drug discovery platform, has recently obtained funding from Mitacs to develop new online software tools. These tools will allow researchers to continuously track changes in viral sequence and to design primers that avoid viral change “hotspots.”



Reference: 

Farkas, C., Fuentes-Villalobos, F., Garrido, J. L., Haigh, J. J., & Barría, M. I. (2020). Insights on early mutational events in SARS-CoV-2 virus reveal founder effects across geographical regions. PeerJ – the Journal of Life and Environmental Sciences. doi: 10.1101/2020.04.09.034462

Thursday, 9 July 2020

Lung Cancer in Non-smokers May Respond Differently to Treatment



Lung cancer in non-smokers is a diverse and distinct disease from that in smokers, and is likely to respond differently to targeted treatments, a major new study shows.

Scientists studied a population in Taiwan with high rates of lung cancer among non-smokers – and found a range of genetic changes which varied depending on a patient’s age or sex.



Many non-smokers with lung cancer had signs of DNA damage from environmental carcinogens, with young women in particular having particular genetic changes which are known to drive cancer to evolve aggressively.

The study – which was co-led by scientists at The Institute of Cancer Research, London, alongside colleagues in Taiwan – could lead to new treatments for non-smokers with lung cancer tailored to the newly identified genetic changes.

The research, published in the prestigious journal Cell today (Thursday), is the most comprehensive ever study of the biology of lung cancer in non-smokers. It was funded by Cancer Research UK and various institutions in Taiwan including the Ministry of Science and Technology.

Scientists at The Institute of Cancer Research (ICR) worked with colleagues at the Academia Sinica and the National Taiwan University to analyse tumour samples from 103 lung cancer patients from Taiwan – the majority of whom were non-smokers.

Around 10-15 per cent of lung cancers in the UK occur in people who have never smoked – but in East Asia, the proportion of lung cancers that occur in non-smokers is much higher, especially among women.

The researchers conducted a detailed analysis of genetic changes, gene activation, protein activity and cellular ‘switches’ in lung cancer to develop the most comprehensive overview of the biology of disease in non-smokers to date.



Looking at the genetics and the related proteins produced by cancer cells in the tumour samples, scientists found that some early-stage lung tumours in non-smokers were biologically similar to more advanced disease in smokers.

Tumours in women often had a particular fault in the well-known lung cancer gene EGFR, whereas in men the most common faults were in the KRAS and APC genes. These differences could affect the response to targeted drugs in men and women.

Picking out people with ‘late-like’ early-stage lung tumours could help guide treatment decisions, and patients could be monitored more closely for signs of their disease progressing.

The study found a pattern of genetic changes involving the APOBEC gene family in three-quarters of tumours of female patients under the age of 60, and in all women without faults in the EGFR gene.

APOBEC proteins play an important role in the function of the immune system – but they can be hijacked by cancers, speeding up evolution and the emergence of drug resistance, a key area of study in the ICR’s new Centre for Cancer Drug Discovery.

Patients without EGFR faults tend to do better on immunotherapy, and so testing for APOBEC could help pick out women more likely to respond to this form of treatment.



The team also picked out groups of patients – particularly among older women – whose cancers had mutation patterns linked to cancer-causing substances in their environment such as pollutants.

Finally, the team identified 65 proteins that were overactive in lung tumours that matched with existing candidate drugs. They found that one protein that cuts away at the surrounding tissue, called MMP11, was linked to poorer survival – and could be explored as a marker for early detection.

While the new study looked at patients treated in Taiwan, the researchers believe that many of their findings could be applicable to UK patients. Next, they will be validating their findings in larger studies and beyond Asia.

Dr Jyoti Choudhary, Team Leader in Functional Proteomics at The Institute of Cancer Research, London, said:

“We carried out the most comprehensive study ever conducted into the biology of lung cancers in an East-Asian population with a high proportion of non-smokers, and found that their disease is molecularly diverse, and distinct from what we classically see in smokers.

“We found distinct patterns of genetic faults in non-smokers and between women and men, which suggest that a woman who has never smoked, for example, is likely to respond differently to treatment than a male smoker.



“Some early-stage lung tumours had molecular features that are much more like that typically seen in later-stage disease – which could help us more accurately diagnose patients with aggressive disease, and inform treatment strategies.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

“This new study offers a deep dive into the biology of lung cancer in people who have never smoked. It reveals new ways of telling apart patients with different tumour characteristics that could be exploited with tailored treatment strategies.

“Lung cancer is the biggest cancer killer in the UK, and much of what we know about the disease comes from studies in smokers. I’m hopeful that the new insights gleaned in this new study will really step up precision medicine in lung cancer for non-smokers, so they can be offered smarter, kinder treatment options.”

Dr Emily Armstrong, research information manager at Cancer Research UK, said:

“In order to beat cancer, we need to understand all the ways it can develop. This research highlights just how much cancers can vary between people depending on their lifestyle and environment. Understanding the difference between lung cancers in smokers and non-smokers could be vital for providing patients with the most appropriate treatment.”



Reference:

Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression
DOI: https://doi.org/10.1016/j.cell.2020.06.012

Researchers apply the anti-de Sitter/conformal field theory to cosmology


The anti-de Sitter/conformal field theory (AdS/CFT) correspondence, also referred to as gauge/gravity duality, hypothesizes the existence of a relationship between two types of physics theories, namely gravity theories in AdS spacetimes and CFTs. Over the past few decades, gauge/gravity duality constructs have been applied in a wide range of scientific research fields. For instance, some researchers tried to use AdS/CFT to advance the development of a full quantum theory of gravity.



A team of researchers at the University of Maryland has recently explored the potential of this theoretical construct in cosmology studies. In a paper published in Nature Physics, they showed how previously proposed cosmological models could be microscopically realized by incorporating elements of AdS/CFT.

"Our work is set up at the intersection of two ideas," Stefano Antonini, one of the researchers who carried out the study, told Phys.org. "The first is the AdS/CFT correspondence, one of the most studied frameworks for the formulation of a quantum gravity theory."

AdS/CFT essentially theorizes the relation of a gravitational theory in an asymptotically AdS spacetime to a CFT that does not account for gravity and has one less dimension. Antonini and his colleague Brian Swingle asked themselves whether it was possible to describe the evolution of a cosmological universe using this theoretical construct, which had so far primarily been applied to other research topics.

"When trying to answer this question, a second idea came into play: The Randall-Sundrum model and its generalizations propose that our 4-D universe could be a 4-D membrane embedded in a 5-D asymptotically AdS spacetime," Antonini explained.

The researchers' study builds on ideas proposed in a previous paper by Swingle and other researchers, published in Springer Link's Journal of High Energy Physics. This past study explored the possibility that certain high-energy holographic CFT states correspond to black hole microstates with a particular structure that terminated at an end-of-the-world (ETW) brane.

Wavefunction of a gravitational mode "trapped" on the brane, as a function of the tortoise coordinate. The sharp peak at the position of the brane (bottom-right inset) shows that gravity is well localized on the brane. The oscillatory behavior near the black hole horizon (top-left inset) reveals that gravity localization is only local, and the trapped mode has a finite lifetime. Credit: Antonini & Swingle.

In string theory and other related physics theories, a brane is a dynamical object that can propagate through spacetime in accordance with quantum mechanics laws. In their new paper, the researchers wanted to identify a way in which Randall-Sundrum braneworlds could be studied in AdS/CFT correspondence by showing the existence of particular CFT states that are dual to charged black hole geometries involving an "end-of-the-world" brane living in the second asymptotic region, which emerges from and falls back into the black hole horizon.



"It is well-known that the motion of a 4-D brane in a 5-D AdS black hole spacetime looks like the evolution of a 4-D FLRW universe to an observer 'living on the brane,' who, like us, is not aware of the existence of the fifth dimension," Antonini said. "For a brane-world model to be meaningful, however, such an observer must also perceive gravity to be effectively four-dimensional, as it is the case in the original Randall-Sundrum model. In the presence of a large black hole, however, this 'gravity localization' phenomenon is particularly troublesome to obtain."

The model proposed by Antonini and his colleagues suggests that under appropriate conditions and for part of its evolution process, a brane sits far away from a black hole horizon and moves slowly. The researchers showed that in this particular regime, a gravitational perturbation remains locally bound to the brane.

This is because the perturbation is 'trapped' by a negative delta potential, which arises from the Neumann boundary conditions in the place where the brane is positioned. In other words, in this regime a hypothetical 4-D observer would interpret gravity to be 4-dimensional, as long as they do not try to probe very large spatial scales.

"There are two main achievements of this work," Antonini said. "First, it showed the existence of charged black hole microstates, which allow a holographic dual description and involve at the same time an end-of-the-world brane sitting far enough from the black hole horizon to possibly support gravity localization. Secondly, we found that gravity is, indeed, locally localized on such brane-worlds."

The ideas presented by Antonini and Swingle could ultimately open up new possibilities for describing quantum cosmology phenomena and simulating these on quantum computers. While so far, the researchers have only produced a toy model of their theory and much progress needs to be done before it can be effectively applied to cosmology problems, their work introduces a new way of studying cosmology in AdS/CFT correspondence and thus of investigating quantum gravity in a cosmological universe.

"We are now exploring the possibility of explicitly realizing our construction in the context of the charged SYK model, which is dual to a simple 1+1 dimensional gravitational model," Antonini said.



More information: 

Stefano Antonini et al. Cosmology at the end of the world, Nature Physics (2020). DOI: 10.1038/s41567-020-0909-6

Study explains potential causes for 'happy hypoxia' condition in COVID-19 patients


A new research study provides possible explanations for COVID-19 patients who present with extremely low, otherwise life-threatening levels of oxygen, but no signs of dyspnea (difficulty breathing). This new understanding of the condition, known as silent hypoxemia or “happy hypoxia,” could prevent unnecessary intubation and ventilation in patients during the current and expected second wave of coronavirus.



The condition “is especially bewildering to physicians as it defies basic biology,” said Martin J. Tobin, MD, Loyola Medicine and Edward J. Hines Jr. VA Hospital pulmonologist and critical care specialist, and professor, Loyola University Chicago Stritch School of Medicine. Dr. Tobin is lead author of the study, “Why COVID-19 Silent Hypoxemia is Baffling to Physicians,” appearing recently in the online American Journal of Respiratory and Critical Care Medicine.

“In some instances, the patient is comfortable and using a phone at a point when the physician is about to insert a breathing (endotracheal) tube and connect the patient to a mechanical ventilator,” said Dr. Tobin, “which while potentially lifesaving carries its own set of risks.”

The study included 16 COVID-19 patients with very low levels of oxygen (as low as 50%; normal blood oxygen saturation is between 95 and 100%), without shortness of breath or dyspnea, and found that “several pathophysiological mechanisms account for most, if not all, cases of silent hypoxemia. This includes the initial assessment of a patient’s oxygen level with a pulse oximeter.

“While a pulse oximeter is remarkably accurate when oxygen readings are high, it markedly exaggerates the severity of low levels of oxygen when readings are low,” said Dr. Tobin. “Another factor is how the brain responds to low levels of oxygen. As oxygen levels drop in patients with COVID-19, the brain does not respond until oxygen falls to very low levels—at which point a patient typically becomes short of breath,” he said.



In addition, more than half of the patients had low levels of carbon dioxide, which may diminish the impact of an extremely low oxygen level.

“It is also possible that the coronavirus is exerting a peculiar action on how the body senses low levels of oxygen,” said Dr. Tobin, which could be linked to the lack of smell, experienced by two-thirds of COVID-19 patients.

While acknowledging that further research is needed, the study concludes that “features about COVID-19 that physicians find baffling become less strange when viewed in the light of long-established principles of respiratory physiology.”

“This new information may help to avoid unnecessary endotracheal intubation and mechanical ventilation, which presents risks, when the ongoing and much anticipated second wave of COVID-19 emerges,” said Dr. Tobin.



Reference:

Martin J. Tobin, Franco Laghi, Amal Jubran. Why COVID-19 Silent Hypoxemia is Baffling to Physicians. American Journal of Respiratory and Critical Care Medicine, 2020; DOI: 10.1164/rccm.202006-2157CP

Wednesday, 8 July 2020

The powerhouses inside cells have been gene-edited for the first time


The genome in mitochondria — the cell’s energy-producing organelles — is involved in disease and key biological functions, and the ability to precisely alter this DNA would allow scientists to learn more about the effects of these genes and mutations. But the precision editing technologies that have revolutionized DNA editing in the cell nucleus have been unable to reach the mitochondrial genome.



Now, a team at the Broad Institute of MIT and Harvard and the University of Washington School of Medicine has broken this barrier with a new type of molecular editor that can make precise C•G-to-T•A nucleotide changes in mitochondrial DNA. The editor, engineered from a bacterial toxin, enables modeling of disease-associated mitochondrial DNA mutations, opening the door to a better understanding of genetic changes associated with cancer, aging, and more.

The work is described in Nature, with co-first authors Beverly Mok, a graduate student from the Broad Institute and Harvard University, and Marcos de Moraes, a postdoctoral fellow at the University of Washington (UW).

The work was jointly supervised by Joseph Mougous, UW professor of microbiology and an investigator at the Howard Hughes Medical Institute (HHMI), and David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute, professor of chemistry and chemical biology at Harvard University, and HHMI investigator.

“The team has developed a new way of manipulating DNA and used it to precisely edit the human mitochondrial genome for the first time, to our knowledge — providing a solution to a long-standing challenge in molecular biology,” said Liu. “The work is a testament to collaboration in basic and applied research, and may have further applications beyond mitochondrial biology.”



AGENT OF BACTERIAL WARFARE

Most current approaches to studying specific variations in mitochondrial DNA involve using patient-derived cells, or a small number of animal models, in which mutations have occurred by chance. “But these methods pose major limitations, and creating new, defined models has been impossible,” said co-author Vamsi Mootha, institute member and co-director of the Metabolism Program at Broad. Mootha is also an HHMI investigator and professor of medicine at Massachusetts General Hospital.

While CRISPR-based technologies can rapidly and precisely edit DNA in the cell nucleus, greatly facilitating model creation for many diseases, these tools haven’t been able to edit mitochondrial DNA because they rely on a guide RNA to target a location in the genome. The mitochondrial membrane allows proteins to enter the organelle, but is not known to have accessible pathways for transporting RNA.

One piece of a potential solution arose when the Mougous lab identified a toxic protein made by the pathogen Burkholderia cenocepacia. This protein can kill other bacteria by directly changing cytosine (C) to uracil (U) in double-stranded DNA.

“What is special about this protein, and what suggested to us that it might have unique editing applications, is its ability to target double-stranded DNA. All previously described deaminases that target DNA work only on the single-stranded form, which limits how they can be used as genome editors,” said Mougous. His team determined the structure and biochemical characteristics of the toxin, called DddA.

“We realized that the properties of this 'bacterial warfare agent' could allow it to be paired with a non-CRISPR-based DNA-targeting system, raising the possibility of making base editors that do not rely on CRISPR or on guide RNAs,” explained Liu. “It could enable us to finally perform precision genome editing in one of the last corners of biology that has remained untouchable by such technology — mitochondrial DNA.”



“TAMING THE BEAST”

The team's first major challenge was to eliminate the toxicity of the bacterial agent — what Liu described to Mougous as “taming the beast” — so that it could edit DNA without damaging the cell. The researchers divided the protein into two inactive halves that could edit DNA only when they combined.

The researchers tethered the two halves of the tamed bacterial toxin to TALE DNA-binding proteins, which can locate and bind a target DNA sequence in both the nucleus and mitochondria without the use of a guide RNA. When these pieces bind DNA next to each other, the complex reassembles into its active form, and converts C to U at that location — ultimately resulting in a C•G-to-T•A base edit. The researchers called their tool a DddA-derived cytosine base editor (DdCBE).

The team tested DdCBE on five genes in the mitochondrial genome in human cells and found that DdCBE installed precise base edits in up to 50 percent of the mitochondrial DNA. They focused on the gene ND4, which encodes a subunit of the mitochondrial enzyme complex I, for further characterization. Mootha's lab analyzed the mitochondrial physiology and chemistry of the edited cells and showed that the changes affected mitochondria as intended.

“This is the first time in my career that we’ve been able to engineer a precise edit in mitochondrial DNA,” said Mootha. “It's a quantum leap forward — if we can make targeted mutations, we can develop models to study disease-associated variants, determine what role they actually play in disease, and screen the effects of drugs on the pathways involved.”

FUTURE DEVELOPMENTS

One goal for the field now will be to develop editors that can precisely make other types of genetic changes in mitochondrial DNA.

“A mitochondrial genome editor has the long-term potential to be developed into a therapeutic to treat mitochondrial-derived diseases, and it has more immediate value as a tool that scientists can use to better model mitochondrial diseases and explore fundamental questions pertaining to mitochondrial biology and genetics,” Mougous said.

The team added that some features of DdCBE, such as its lack of RNA, may also be attractive for other gene-editing applications beyond the mitochondria.



Reference:

Mok BY, de Moraes MH, et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature, 2020 DOI: 10.1038/s41586-020-2477-4

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