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Showing posts with label Medical Science. Show all posts
Showing posts with label Medical Science. Show all posts

Saturday, 23 May 2020

Detecting Red Blood Cell Damage in Real-time


According to the National Kidney Foundation, more than 37 million people are living with kidney disease.

The kidneys play an important role in the body, from removing waste products to filtering the blood. For people with kidney disease, dialysis can help the body perform these essential functions when the kidneys aren't working at full capacity.

However, red blood cells sometimes rupture when blood is sent through faulty equipment that is supposed to clean the blood, such as a dialysis machine. This is called hemolysis. Hemolysis also can occur during blood work when blood is drawn too quickly through a needle, leading to defective laboratory samples.

There is no reliable indicator that red blood cells are being damaged in a clinical setting until an individual begins showing symptoms, such as fever, weakness, dizziness or confusion.



University of Delaware mechanical engineer Tyler Van Buren and collaborating colleagues at Princeton University have developed a method to monitor blood damage in real-time.

"Our goal was to find a method that could detect red blood cell damage without the need for lab sample testing," said Van Buren, an assistant professor of mechanical engineering with expertise in fluid dynamics.

Detecting blood cell damage

In the body, red blood cells float in plasma alongside white blood cells and platelets. The plasma is naturally conductive and is efficient at passing an electric charge. Red blood cells are chock-full of hemoglobin, an oxygen-transporting protein, that also is conductive.

This hemoglobin is typically insulated from the body by the cell lining. But as red blood cells rupture, hemoglobin is released into the bloodstream, causing the blood to become more conductive.

"Think of the blood like a river and red blood cells like water balloons in that river," said Van Buren, who joined UD in 2019. "If you have electrons (negatively charged particles) waiting to cross the river, it is more difficult when there are a lot of water balloons present. This is because the rubber is insulated, so the blood will be less conductive. As the water balloons (or blood cells) break, there are fewer barriers and the blood becomes more conductive, making it easier for electrons to move from one side to the other."

This diagram depicts the way conductivity will change as blood cells break. The yellow dots represent electrons. The red circles represent blood cells. Viewing the graphic from left to right, one can see that when more blood cells are present, fewer electrons are able to get across. As blood cells break, there are fewer barriers and the blood becomes more conductive, making it easier for electrons to move from one side to the other.


In dialysis, a patient's blood is removed from the body, cleaned, then recirculated into the body. The researchers developed a simple experiment to see if they could measure the blood's mechanical resistance outside of the body.

To test their technique, the researchers circulated healthy blood through the laboratory system and gradually introduced mechanically damaged blood to see if it would change the conductive nature of the fluid in the system.

It did. The researchers saw a direct correlation between the conductivity of the fluid in the system and the amount of damaged blood included in the sample.

While this issue of damaged blood is very rare, the research team's method does introduce one potential way to indirectly monitor blood damage in the body during dialysis. The researchers theorize that if clinicians were able to monitor the resistance of a patient's blood going into a dialysis machine and coming out, and they saw a major change in resistance -- or conductivity -- there is good reason to believe the blood is being damaged.

"We are not doctors, we're mechanical engineers," said Van Buren. "This technique would need a lot more vetting before being applied in a clinical setting."

For example, Van Buren said the method wouldn't necessarily work across patient populations because an individual's blood conductivity is just that, individual.



In the future, Van Buren said it would be interesting to evaluate whether conductivity also could be used in place of lab sampling for applications outside of dialysis. For example, this might be useful in research aimed at understanding how blood cells may be damaged, both inside and outside of the body, and possible methods for prevention.

He also is curious whether this method could be used to evaluate and identify compromised blood samples on-site, saving time and money for hospitals or diagnostic laboratories, while eliminating the need for patients to make multiple trips to have blood drawn if there is a problem.


Bibliography:

A simple method to monitor hemolysis in real time

Tyler Van Buren, Gilad Arwatz & Alexander J. Smits

Scientific Reports volume 10, Article number: 5101

doi: 10.1038/s41598-020-62041-8

Wednesday, 20 May 2020

Small Study Shows Antiviral Drug May Speed Up COVID-19 Recovery


An international team of researchers led by Dr. Eleanor Fish, emerita scientist at the Toronto General Hospital Research Institute, University Health Network, and professor in the University of Toronto's Department of Immunology, has shown for the first time that an antiviral drug can help speed up the recovery of COVID-19 patients.

According to the new study, published today in Frontiers in Immunology, treatment with interferon(IFN)- α2b may significantly accelerate virus clearance and reduce levels of inflammatory proteins in COVID-19 patients.

The research team found that treatment with this drug, which has been used clinically for many years, significantly reduced the duration of detectable virus in the upper respiratory tract, on average by about 7 days. It also reduced blood levels of interleukin(IL)-6 and C-reactive protein (CRP), two inflammatory proteins found in COVID-19 patients.



Dr. Fish says that the research team considered IFN-α therapy for COVID-19 after they demonstrated interferon provided therapeutic benefit during the SARS outbreak of 2002 and 2003.

"Rather than developing a virus-specific antiviral for each new virus outbreak, I would argue that we should consider interferons as the 'first responders' in terms of treatment," says Dr. Fish.

"Interferons have been approved for clinical use for many years, so the strategy would be to 'repurpose' them for severe acute virus infections."

Boosting a natural defense mechanism

Interferons are a group of signaling proteins released by the human body in response to all viruses. As Dr. Fish explains, they are a "first line of defense."

They target different stages of a virus's life cycle, inhibiting them from multiplying. They also boost an immune response by activating different immune cells to clear an infection. Some viruses, however, can block this natural defense mechanism.

"But it is possible to override this block. If a virus blocks interferon production, then treating with interferon can offset this."



Study details

The researchers conducted this exploratory study on a group of 77 patients with COVID-19 in Wuhan, China. These patients were admitted to Union Hospital, Tongii Medical College, between January 16 and February 20, 2020. They represented moderate cases of the disease as none of the patients required intensive care or prolonged oxygen supplementation or intubation.

Despite the study's limitations of a small, non-randomized group of patients, the work provides several important and novel insights into COVID-19 disease, notably that treatment with IFN-α2b can accelerate viral clearance from the upper respiratory tract and also reduce circulating levels of inflammatory factors that are associated with severe COVID-19.

Dr. Fish says a randomized clinical trial is a crucial next step. According to her, a clinical trial with a larger group of infected patients who are randomized to treatment or placebo would further this research.



In the meantime, the findings from this study are the first to suggest therapeutic efficacy of IFN-α2b as an available antiviral intervention for COVID-19, which may also benefit public health measures by shortening the duration of viral clearance and therefore slowing the tide of the pandemic.


Bibliography:

Qiong Zhou, Virginia Chen, Casey P. Shannon, Xiao-Shan Wei, Xuan Xiang, Xu Wang, Zi-Hao Wang, Scott J. Tebbutt, Tobias R. Kollmann and Eleanor N. Fish

Interferon-α2b Treatment for COVID-19.

Front. Immunol.

DOI: https://doi.org/10.3389/fimmu.2020.01061

Monday, 18 May 2020

Our Ability To Focus May Be Impacted After Eating a High-fat Meal


Fatty food may feel like a friend during these troubled times, but new research suggests that eating just one meal high in saturated fat can hinder our ability to concentrate – not great news for people whose diets have gone south while they’re working at home during the COVID-19 pandemic.

The study compared how 51 women performed on a test of their attention after they ate either a meal high in saturated fat or the same meal made with sunflower oil, which is high in unsaturated fat.

Their performance on the test was worse after eating the high-saturated-fat meal than after they ate the meal containing a healthier fat, signaling a link between that fatty food and the brain.

Researchers were also looking at whether a condition called leaky gut, which allows intestinal bacteria to enter the bloodstream, had any effect on concentration. Participants with leakier guts performed worse on the attention assessment no matter which meal they had eaten.

The loss of focus after a single meal was eye-opening for the researchers.



“Most prior work looking at the causative effect of the diet has looked over a period of time. And this was just one meal – it’s pretty remarkable that we saw a difference,” said Annelise Madison, lead author of the study and a graduate student in in clinical psychology at The Ohio State University.

Madison also noted that the meal made with sunflower oil, while low in saturated fat, still contained a lot of dietary fat.

“Because both meals were high-fat and potentially problematic, the high-saturated-fat meal’s cognitive effect could be even greater if it were compared to a lower-fat meal,” she said.

Madison works in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research at Ohio State. For this work, Madison conducted a secondary analysis of data from Kiecolt-Glaser’s study assessing whether high-fat meals increased fatigue and inflammation among cancer survivors.

Women in the study completed a baseline assessment of their attention during a morning visit to the lab. The tool, called a continuous performance test, is a measure of sustained attention, concentration and reaction time based on 10 minutes of computer-based activities.

The high-fat meal followed: eggs, biscuits, turkey sausage and gravy containing 60 grams of fat, either a palmitic acid-based oil high in saturated fat or the lower-saturated-fat sunflower oil. Both meals totaled 930 calories and were designed to mimic the contents of various fast-food meals such as a Burger King double whopper with cheese or a McDonald’s Big Mac and medium fries.

Five hours later, the women took the continuous performance test again. Between one and four weeks later, they repeated these steps, eating the opposite meal of what they had eaten on the first visit.

Researchers also analyzed participants’ fasting baseline blood samples to determine whether they contained an inflammatory molecule that signals the presence of endotoxemia – the toxin that escapes from the intestines and enters the bloodstream when the gut barrier is compromised.

After eating the meal high in saturated fat, all of the participating women were, on average, 11 percent less able to detect target stimuli in the attention assessment. Concentration lapses were also apparent in the women with signs of leaky gut: Their response times were more erratic and they were less able to sustain their attention during the 10-minute test.

“If the women had high levels of endotoxemia, it also wiped out the between-meal differences. They were performing poorly no matter what type of fat they ate,” Madison said.

Though the study didn’t determine what was going on in the brain, Madison said previous research has suggested that food high in saturated fat can drive up inflammation throughout the body, and possibly the brain. Fatty acids also can cross the blood-brain barrier.



“It could be that fatty acids are interacting with the brain directly. What it does show is the power of gut-related dysregulation,” she said.

The statistical analysis accounted for other potential influences on cognition, including depressive symptoms and the participants’ average dietary saturated fat consumption. The women in the study ate three standardized meals and fasted for 12 hours before each lab visit to reduce diet variations that could affect their physiological response to the high-fat meals.

The findings suggest concentration could be even more impaired in people stressed by the pandemic who are turning to fatty foods for comfort, Kiecolt-Glaser said.

“What we know is that when people are more anxious, a good subset of us will find high-saturated-fat food more enticing than broccoli,” she said. “We know from other research that depression and anxiety can interfere with concentration and attention as well. When we add that on top of the high-fat meal, we could expect the real-world effects to be even larger.”


Bibliography:

Afternoon distraction: a high-saturated-fat meal and endotoxemia impact postmeal attention in a randomized crossover trial

Annelise A Madison, Martha A Belury, Rebecca Andridge, M Rosie Shrout, Megan E Renna, William B Malarkey, Michael T Bailey, Janice K Kiecolt-Glaser


The American Journal of Clinical Nutrition, nqaa085,

DOI: https://doi.org/10.1093/ajcn/nqaa085

Saturday, 16 May 2020

Blind Adults Were Able To "See" Letters Traced on Their Brain Using Electrical Stimulation


For most adults who lose their vision, blindness results from damage to the eyes or optic nerve while the brain remains intact. For decades, researchers have proposed developing a device that could restore sight by bypassing damaged eyes and delivering visual information from a camera directly to the brain. In a paper publishing in the journal Cell on May 14, a team of investigators at Baylor College of Medicine in Houston report that they are one step closer to this goal. They describe an approach in which implanted electrodes are stimulated in a dynamic sequence, essentially "tracing" shapes on the surface of the visual cortex that participants were able to "see."



"When we used electrical stimulation to dynamically trace letters directly on patients' brains, they were able to 'see' the intended letter shapes and could correctly identify different letters," senior author Daniel Yoshor says. "They described seeing glowing spots or lines forming the letters, like skywriting."

Previous attempts to stimulate the visual cortex have been less successful. Earlier methods treated each electrode like a pixel in a visual display, stimulating many of them at the same time. Participants could detect spots of light but found it hard to discern visual objects or forms. "Rather than trying to build shapes from multiple spots of light, we traced outlines," says first author Michael Beauchamp. "Our inspiration for this was the idea of tracing a letter in the palm of someone's hand."

The investigators tested the approach in four sighted people who had electrodes implanted in their brains to monitor epilepsy and two blind people who had electrodes implanted over their visual cortex as part of a study of a visual cortical prosthetic device. Stimulation of multiple electrodes in sequences produced perceptions of shapes that subjects were able to correctly identify as specific letters.

This image shows different letter-like shapes (W and Z) created by different dynamic stimulation patterns, with the stimulation pattern on the left and the participant drawings on the right. Credit: Beauchamp et al./Cell

The approach, the researchers say, demonstrates that it could be possible for blind people to regain the ability to detect and recognize visual forms by using technology that inputs visual information directly into the brain, should they wish to. The researchers note, however, that several obstacles must be overcome before this technology could be implemented in clinical practice.



"The primary visual cortex, where the electrodes were implanted, contains half a billion neurons. In this study we stimulated only a small fraction of these neurons with a handful of electrodes," Beauchamp says. "An important next step will be to work with neuroengineers to develop electrode arrays with thousands of electrodes, allowing us to stimulate more precisely. Together with new hardware, improved stimulation algorithms will help realize the dream of delivering useful visual information to blind people."


Bibliography:

Beauchamp, M. S., Oswalt, D., Sun, P., Foster, B. L., Magnotti, J. F., Niketeghad, S., Pouratian, N., Bosking, W. H., & Yoshor, D. (2020).

Dynamic Stimulation of Visual Cortex Produces Form Vision in Sighted and Blind Humans.

Cell, 181(4), 774-783.e5.

https://doi.org/10.1016/j.cell.2020.04.033

A Neural Basis for Longing: Absence Makes the Heart Grow Fonder and the Nucleus Accumbens Activate


When it comes to forming a lasting bond, our longing for a partner may be as important as--if not more important than--how we react when we're with them, suggests a surprising new brain imaging study published in the Proceedings of the National Academy of Sciences this week.

"In order to maintain relationships over time, there has to be some motivation to be with that person when you are away from them," said lead author Zoe Donaldson, an assistant professor of behavioral neuroscience at the University of Colorado Boulder. "Ours is the first paper to pinpoint the potential neural basis for that motivation to reunite."



The paper marks the latest discovery in Donaldson's years-long study of prairie voles, one of only about 3% to 5% of mammalian species (including humans) that tend to mate for life. By observing the behavior and brain activity of the monogamous rodents, she seeks to better understand what brain regions--down to the cellular level--drive the instinct to form lasting bonds.

Ultimately, the findings could be used to develop therapies for those with autism, severe depression and other disorders that make such emotional connections hard to come by. But right now, she said, the research also lends insight into why social distancing is so tough.

Why social distancing is so hard

"We are uniquely hardwired to seek out close relationships as a source of comfort, and that often comes through physical acts of touch," she said.

For the study, Donaldson used tiny cameras and a cutting-edge technology called in-vivo-calcium imaging to spy on the brains of dozens of voles at three time points: when they were just meeting another vole; three days after they had mated; and 20 days after they had essentially moved in together. Researchers also observed the animals interacting with voles who were not their mates.

Previous brain imaging research in humans has shown altered brain activity in a region called the nucleus accumbens, the same reward center that lights up during heroin or cocaine use, when the research subjects held the hand of a romantic partner versus a stranger. So, at first, Donaldson's team assumed the voles' brain activity would be markedly different when they were huddling with their mate versus a random vole.

"Surprisingly, that is not what we found," she said.

Stranger or lover, the voles' brains looked basically the same when they were together.

It was only when the voles were away from their partner and running to meet them--imagine the classic romantic reunion-scene at the airport or the theme of any number of love poems--that a unique cluster of cells in the nucleus accumbens consistently fired up.

The longer the animals had been paired, the closer their bond became and the larger the glowing cluster of cells--dubbed the "partner approach ensemble"--on image screens.

Notably, a completely different cluster of cells lit up when the vole approached a stranger.

"This suggests that maybe the recruitment of these cells for this new purpose is important for forming and maintaining a bond," Donaldson said.

She suspects that brain chemicals like oxytocin, dopamine and vasopressin, which have been shown in both animal and human studies to play a role in fostering trust and closeness, are involved in the process. But she doesn't know for sure what that cluster of cells does.



It's also not clear whether the specific "neuronal code" associated with a desire to reunite in voles inspires the same emotion in people. More research is underway.

What the study does confirm is that monogamous mammals are uniquely hard-wired to be with others.

"These negative feelings so many of us are experiencing right now may result from a mismatch: we have a neuronal signal telling us that being with loved ones will make us feel better, while practical restrictions mean this need is going unmet," Donaldson said. "It's the emotional equivalent of not eating when we are hungry, except now instead of skipping a meal, we are slowly starving."


Bibliography:

Scribner, J. L., Vance, E. A., Protter, D. S. W., Sheeran, W. M., Saslow, E., Cameron, R. T., Klein, E. M., Jimenez, J. C., Kheirbek, M. A., & Donaldson, Z. R. (2020).

A neuronal signature for monogamous reunion.

Proceedings of the National Academy of Sciences.

https://doi.org/10.1073/pnas.1917287117

Thursday, 14 May 2020

Researchers Create "Assassin" Cells Armed With Anticancer Drugs to Kill Cancer Masses


There are immune cells in our bodies that directly destroy infected or cancer cells - they are called natural killer cells. Recently, a POSTECH research team has developed an integrative cancer therapy using adoptive natural killer cell therapy and chemotherapy.

A research team led by Professor Won Jong Kim of POSTECH's Department of Chemistry developed a treatment for solid cancers using the formation of natural killer-tumor cell immunological synapse through a joint research with GI Cell. The research findings were published as a front cover for the latest online edition of Advanced Materials, a leading academic journal in the field of material science.



To date, three methods including surgery, radiation therapy, and chemotherapy are implemented to treat cancer. While surgery and radiation therapy are helpful in reducing the size of tumors in treating solid cancer, there is a high risk of recurrence due to residual or metastatic cells. The residual cells and metastatic cells are treated by administering chemotherapy to patients, but their use is limited due to serious side effects in all parts of the body.

However, there is an immune system in the human body that can distinguish cancer cells from normal cells and selectively induce their death, and using this mechanism in anticancer immunotherapy not only has fewer side effects but also a higher survival rate for patients compared to chemotherapy.

In particular, treatments using natural killer cells during chemotherapy have low side effects and are more effective in treating leukemia. However, unlike leukemia cells where individual cells float in blood, in solid cancers, the extracellular layer surrounding the cancer tissues reduces the penetration rate of the natural killer cells, thus lowering their efficacy. Studies are being conducted to overcome this issue.

Schematic illustration of the reinforced natural killer cell (ReNK) system and its anti?cancer effect upon encountering cancer cells. NK cells reinforced with doxorubicin (DOX)?loaded, acid?responsive micelles, home onto the tumor site. When an NK cell engages a cancer cell, an immunological synapse is formed, and acidic granules are released by the former into the synapse. Acidification of the synapse induces the release of DOX from the micelles and its diffusion into the tumor site. Credit: Won Jong Kim (POSTECH)


The research team hypothesized that the acidity would decrease rapidly near the immunological synapses based on the fact that the natural killer cells form immunological synapses and secrete low acidic granules at the boundary of natural killer-tumor cells in order to induce the death of cancer cells.

Based on this hypothesis, if the surface of natural killer cells is equipped with polymeric micelles*1, which can respond to low acidity and release anticancer drugs, it may provide a pragmatic platform that allows natural killer cells to selectively release anticancer drugs in tumor cells.

It was also anticipated that cancer drugs could induce the death of cancer cells in the deep parts of the tumor as their size is small enough to penetrate the dense extracellular layer around the tumor tissues. In the treatment of solid cancer, the team fused the adoptive natural killer cell therapy and chemotherapy to overcome the low therapeutic effects and high side effects. They implemented a system that can release anticancer drugs only when natural killer cells recognize the cancer cells and induce their death.

In addition, video footages filmed using a confocal scanning fluorescence microscope confirmed that acidity was reduced in the immunological synapses formed between natural killer and cancer cells and that the ReNK*2 system selectively released anticancer drugs.



It also confirmed that the delivery efficiency to cancer tissues increased significantly when anticancer drugs were delivered using ReNK in animal models with solid cancer.

Professor Won Jong Kim, who led the study as a corresponding author, stated, "This study is significant in that it has developed a strategy to enhance the effectiveness of cell therapy using natural killer cells in treating solid cancers." He added, "This method can be applied to any cell with a simple process, so we expect to apply it to treatments currently on the market or in clinical trials."


Bibliography:

Sooseok Im, Donghyun Jang, Gurusamy Saravanakumar,  Junseok Lee, Yeoul Kang, Yeong Mi Lee, Jaehyun Lee, Junsang Doh,  Zung Yoon Yang,  Myoung Ho Jang, & Won Jong Kim

Harnessing the Formation of Natural Killer–Tumor Cell Immunological Synapses for Enhanced Therapeutic Effect in Solid Tumors.

Advanced Materials.

DOI: https://doi.org/10.1002/adma.202000020

Wednesday, 13 May 2020

Little Skates Could Hold the Key to Cartilage Therapy in Humans


Nearly a quarter of Americans suffer from arthritis, most commonly due to the wear and tear of the cartilage that protects the joints. As we age, or get injured, we have no way to grow new cartilage. Unlike humans and other mammals, the skeletons of sharks, skates, and rays are made entirely of cartilage and they continue to grow that cartilage throughout adulthood.

And new research published this week in eLife finds that adult skates go one step further than cartilage growth: They can also spontaneously repair injured cartilage. This is the first known example of adult cartilage repair in a research organism. The team also found that newly healed skate cartilage did not form scar tissue.



"Skates and humans use a lot of the same genes to make cartilage. Conceivably, if skates are able to make cartilage as adults, we should be able to also," says Andrew Gillis, senior author on the study and a Marine Biological Laboratory Whitman Center Scientist from the University of Cambridge, U.K.

The researchers carried out a series of experiments on little skates (Leucoraja erinacea) and found that adult skates have a specialized type of progenitor cell to create new cartilage. They were able to label these cells, trace their descendants, and show that they give rise to new cartilage in an adult skeleton.

Why is this important? There are few therapies for repairing cartilage in humans and those that exist have severe limitations. As humans develop, almost all of our cartilage eventually turns into bone. The stem cell therapies used in cartilage repair face the same issue--the cells often continue to differentiate until they become bone. They do not stop as cartilage. But in skates, the stem cells do not create cartilage as a steppingstone; it is the end result.

"We're looking at the genetics of how they make cartilage, not as an intermediate point on the way to bone, but as a final product," says Gillis.



The research is in its early stages, but Gillis and his team hope that by understanding what genes are active in adult skates during cartilage repair, they could better understand how to stop human stem-cell therapies from differentiating to bone.

Note: There is no scientific evidence that "shark cartilage tablets" currently marketed as supplements confer any health benefits, including relief of joint pain.


Bibliography:

Aleksandra Marconi, Amy Hancock-Ronemus and J. Andrew Gillis (2020)

Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea.

eLife, DOI: https://doi.org/10.7554/eLife.53414

Saturday, 9 May 2020

Vitamin D levels appear to play role in COVID-19 mortality rates


After studying global data from the novel coronavirus (COVID-19) pandemic, researchers have discovered a strong correlation between severe vitamin D deficiency and mortality rates.

Led by Northwestern University, the research team conducted a statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States.

The researchers noted that patients from countries with high COVID-19 mortality rates, such as Italy, Spain and the UK, had lower levels of vitamin D compared to patients in countries that were not as severely affected.

This does not mean that everyone -- especially those without a known deficiency -- needs to start hoarding supplements, the researchers caution.

"While I think it is important for people to know that vitamin D deficiency might play a role in mortality, we don't need to push vitamin D on everybody," said Northwestern's Vadim Backman, who led the research. "This needs further study, and I hope our work will stimulate interest in this area. The data also may illuminate the mechanism of mortality, which, if proven, could lead to new therapeutic targets."

The research is available on medRxiv, a preprint server for health sciences.



Backman is the Walter Dill Scott Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. Ali Daneshkhah, a postdoctoral research associate in Backman's laboratory, is the paper's first author.

Backman and his team were inspired to examine vitamin D levels after noticing unexplained differences in COVID-19 mortality rates from country to country. Some people hypothesized that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained skeptical.

"None of these factors appears to play a significant role," Backman said. "The healthcare system in northern Italy is one of the best in the world. Differences in mortality exist even if one looks across the same age group. And, while the restrictions on testing do indeed vary, the disparities in mortality still exist even when we looked at countries or populations for which similar testing rates apply.

"Instead, we saw a significant correlation with vitamin D deficiency," he said.

By analyzing publicly available patient data from around the globe, Backman and his team discovered a strong correlation between vitamin D levels and cytokine storm -- a hyperinflammatory condition caused by an overactive immune system -- as well as a correlation between vitamin D deficiency and mortality.

"Cytokine storm can severely damage lungs and lead to acute respiratory distress syndrome and death in patients," Daneshkhah said. "This is what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system."

This is exactly where Backman believes vitamin D plays a major role. Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive. This means that having healthy levels of vitamin D could protect patients against severe complications, including death, from COVID-19.



"Our analysis shows that it might be as high as cutting the mortality rate in half," Backman said. "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected."

Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system's second line of defense and more likely to overreact.

"Children primarily rely on their innate immune system," Backman said. "This may explain why their mortality rate is lower."

Backman is careful to note that people should not take excessive doses of vitamin D, which might come with negative side effects. He said the subject needs much more research to know how vitamin D could be used most effectively to protect against COVID-19 complications.

"It is hard to say which dose is most beneficial for COVID-19," Backman said. "However, it is clear that vitamin D deficiency is harmful, and it can be easily addressed with appropriate supplementation. This might be another key to helping protect vulnerable populations, such as African-American and elderly patients, who have a prevalence of vitamin D deficiency."


Bibliography:

Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv, Posted April 30, 2020; [link]

Friday, 8 May 2020

Coronavirus found in patients' semen in small Chinese study


The virus that causes COVID-19 can be found in semen, Chinese researchers report in a small study that doesn't address whether sexual transmission is possible.

Doctors detected the virus in semen from six of 38 men hospitalized with laboratory-confirmed COVID-19. Four were still very sick with the disease while two were recovering.

The report from Shangqiu Municipal Hospital in China was published Thursday in JAMA Network Open.

There was no long-term follow-up so it is not known how long the virus may remain in semen or if men can spread it to their partners during sex.



The results contrast with a study of 34 Chinese men with COVID-19 published last month in the journal Fertility and Sterility. U.S. and Chinese researchers found no evidence of virus in semen tested between eight days and almost three months after diagnosis.

Dr. John Hotaling of the University of Utah, co-author of that report, said the new study involved much sicker men, most with active disease.

Authorities believe the coronavirus mainly spreads from droplets produced when infected people cough, which are inhaled by people nearby.

Some studies have reported finding the virus in blood, feces and tears or other fluid from COVID-19 patients with inflammation in their eyes.

Evidence suggesting that other infectious viruses including Zika and Ebola may be sexually transmitted has prompted questions about the coronavirus.

Hotaling said it's an important public health concern but that more research is needed to provide a definitive answer.

The American Society for Reproductive Medicine said the new study shouldn't be cause for alarm. To be safe, though, "it may be wise to avoid sexual contact with men until they are 14 days without symptoms," Dr. Peter Schlegel, the group's immediate past president, said in a statement.


Bibliography:

Diangeng Li et al. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019, 

JAMA Network Open (2020).

DOI: 10.1001/jamanetworkopen.2020.8292

Wednesday, 6 May 2020

Abnormally Small Red Blood Cells Could Indicate Cancer


Having abnormally small red blood cells - a condition known as microcytosis - could indicate cancer, according to new research led by a University of Exeter student working with a world-leading team.

Medical Sciences student Rhain Hopkins was lead author of the study of more than 12,000 UK patients aged over 40, which found that the cancer risk in males was 6.2 per cent, compared to 2.7 per cent in those without microcytosis.



The research, funded by Cancer Research UK and NIHR and published in BJGP, found that in females, the risk of cancer was 2.7 per cent in those with microcytosis, compared to 1.4 per cent without.

Of more than 108,000 followed within the Clinical Practice Research Datalink records, 12,289 patients with microcytosis were followed up. Of those, 497 developed cancer within a year.

Microcytosis is related to iron deficiency and with genetic conditions which affect haemaglobn in the blood. Similarly, iron deficiency has been identified as a feature of some cancers, particularly colorectal. Microcytosis is easily identified in a routine blood test.

Rhian Hopkins was working with Exeter's cancer diagnosis team as part of her Professional Training Year, which gives Medical Sciences students practical experience of research. As lead author of the paper, she said: "Research targeted at diagnosing cancer earlier is so important in reducing the burden of this devastating disease. The identification of risk markers, such as microcytosis, that are relevant to a range of cancers, can have a real impact in primary care. Being part of this research has been a very rewarding experience and getting my first paper published is such a massive achievement."

Professor Willie Hamilton, at the University of Exeter Medical School, who oversaw the research, said: "Overall, the risk of cancer in patients with microcytosis was still low, however our research indicates a need to investigate cancer. In two patients with cancer out of three the possibility of cancer is fairly easy to identify. For the other third, symptoms are often vague, and don't clearly point to cancer. For these patients GPs have to use more subtle clues to recognise that cancer may be present. Small red cells have long been recognised with colon cancer, but this study shows that they are a much broader clue, alerting the doctor to the small possibility of one of several possible cancers."



Dr Elizabeth Shephard, who supervised Rhian, said: "Rhian was a dedicated, proactive and enthusiastic student and an absolute pleasure to work with. As part of her Professional Training Year (PTY), Rhian undertook this standalone project of investigating the role of microcytosis as a possible early marker of cancer. She taught herself to use Stata statistical analysis software, and with guidance learned how to build the database from which to run the analyses. She also analysed the data and wrote up the paper for publication, making a meaningful contribution to the potentially life-saving area of cancer diagnosis.

"The PTY placement is a fantastic opportunity for undergraduates to gain valuable research work experience - and for academics to work with bright students. I wouldn't hesitate to recommend the programme."


Bibliography:

Hopkins, R., Bailey, S. E., Hamilton, W. T., & Shephard, E. A. (2020).

Microcytosis as a risk marker of cancer in primary care: A cohort study using electronic patient records.

 British Journal of General Practice.

doi: 10.3399/bjgp20x709577

Tuesday, 5 May 2020

New Test Detects Glaucoma Progression Earlier


A new test can detect glaucoma progression 18 months earlier than the current gold standard method, according to results from a UCL-sponsored clinical trial.

The technology, supported by an artificial intelligence (AI) algorithm, could help accelerate clinical trials, and eventually may be used in detection and diagnostics, according to the Wellcome-funded study published in Expert Review of Molecular Diagnostics.

Lead researcher Professor Francesca Cordeiro (UCL Institute of Ophthalmology, Imperial College London, and Western Eye Hospital Imperial College Healthcare NHS Trust) said: "We have developed a quick, automated and highly sensitive way to identify which people with glaucoma are at risk of rapid progression to blindness."

Glaucoma, the leading global cause of irreversible blindness, affects over 60 million people, which is predicted to double by 2040 as the global population ages. Loss of sight in glaucoma is caused by the death of cells in the retina, at the back of the eye.



The test, called DARC (Detection of Apoptosing Retinal Cells), involves injecting into the bloodstream (via the arm) a fluorescent dye that attaches to retinal cells, and illuminates those that are in the process of apoptosis, a form of programmed cell death. The damaged cells appear bright white when viewed in eye examinations - the more damaged cells detected, the higher the DARC count.

One challenge with evaluating eye diseases is that specialists often disagree when viewing the same scans, so the researchers have incorporated an AI algorithm into their method.

In the Phase II clinical trial of DARC, the AI was used to assess 60 of the study participants (20 with glaucoma and 40 healthy control subjects). The AI was initially trained by analysing the retinal scans (after injection of the dye) of the healthy control subjects. The AI was then tested on the glaucoma patients.

Those taking part in the AI study were followed up 18 months after the main trial period to see whether their eye health had deteriorated.

The researchers were able to accurately predict progressive glaucomatous damage 18 months before that seen with the current gold standard OCT retinal imaging technology, as every patient with a DARC count over a certain threshold was found to have progressive glaucoma at follow-up.

"These results are very promising as they show DARC could be used as a biomarker when combined with the AI-aided algorithm," said Professor Cordeiro, adding that biomarkers - measurable biological indicators of disease state or severity - are urgently needed for glaucoma, to speed up clinical trials as the disease progresses slowly so it can take years for symptoms to change.

"What is really exciting, and actually unusual when looking at biological markers, is that there was a clear DARC count threshold above which all glaucoma eyes went on to progress," she added.

First author Dr Eduardo Normando (Imperial College London and Western Eye Hospital Imperial College Healthcare NHS Trust) said: "Being able to diagnose glaucoma at an earlier stage, and predict its course of progression, could help people to maintain their sight, as treatment is most successful if provided at an early stage of the disease. After further research in longitudinal studies, we hope that our test could have widespread clinical applications for glaucoma and other conditions."



The team is also applying the test to rapidly detect cell damage caused by numerous conditions other than glaucoma, such as other neurodegenerative conditions that involve the loss of nerve cells, including age-related macular degeneration, multiple sclerosis, and dementia.

The AI-supported technology has recently been approved by both the UK's Medicines and Healthcare products Regulatory Agency and the USA's Food and Drug Administration as an exploratory endpoint for testing a new glaucoma drug in a clinical trial.

The researchers are also assessing the DARC test in people with lung disease, and hope that by the end of this year, the test may help to assess people with breathing difficulties from Covid-19.


Bibliography:

Normando, E. M., Yap, T. E., Maddison, J., Miodragovic, S., Bonetti, P., Almonte, M., . . . Cordeiro, M. F. (2020).

A CNN-aided method to predict glaucoma progression using DARC (Detection of Apoptosing Retinal Cells).

Expert Review of Molecular Diagnostics, 1-12.

doi: 10.1080/14737159.2020.1758067

Monday, 4 May 2020

Parkinson’s Dyskinesia Mechanism Identified


Many people with Parkinson’s disease eventually develop debilitating movements called dyskinesia, a side effect of their much-needed dopamine replacement medication. The mechanism underlying this unwanted side effect has been unknown, until now. An international collaboration led by Scripps Research, Florida has found a key cause, and with it, potentially, a new route to providing relief.

Dopamine replacement therapy makes Parkinson’s symptoms much better at first, but eventually treatment gives way to uncontrollable, jerky body movements. But why? New research shows that underlying this development is the therapy’s unintended boost of a protein with the unwieldy name Ras-guanine nucleotide-releasing factor 1, or RasGRP1 for short. This boost in RasGRP1 produces a cascade of effects which lead to abnormal, involuntary movements known as LID, or L-DOPA-induced dyskinesia, says co-lead author Srinivasa Subramaniam, PhD, associate professor of neuroscience at Scripps Research, Florida.

Encouragingly, the collaboration found that in dopamine-depleted mice and other animal models, inhibiting production of RasGRP1 in the brain during dopamine replacement diminished the involuntary movements without negating the useful effects of the dopamine therapy.



Taken together, the research offers a new path to easing Parkinson’s dyskinesia while allowing maintenance of dopamine replacement therapy, Subramaniam says.

Subramaniam’s group has long been interested in cellular signaling in the brain underlying motor movements, and how it is affected by brain diseases, including Huntington’s and Parkinson’s.

“Parkinson’s patients describe treatment-induced dyskinesia as one of the most debilitating features of their illness,” Subramaniam says. “These studies show that if we can down-regulate RasGRP1 signaling before dopamine replacement, we have an opportunity to greatly improve their quality of life.”

The study was published in the journal Science Advances. In addition to Subramaniam, the co-lead author is Alessandro Usiello, PhD, of the University of Campania Luigi Vanvitelli, Caserta, Italy, and the Behavioural Neuroscience Laboratory at Ceinge Biotecnologie Avanzate, Naples, Italy.

Dopamine is a neurotransmitter and hormone that plays a key role in movement, learning, memory, motivation, and emotion. Parkinson’s develops when dopamine-producing neurons in a region of the mid-brain called the substantia nigra stop working or die. It’s a brain region associated with both movement initiation and reward, so its impairment causes a wide variety of symptoms, including stiffness, balance problems, walking difficulty, tremor, depression and memory issues.

Doctors treat Parkinson’s with dopamine replacement therapy, often a medicine called levodopa. The brain converts levodopa into dopamine, and at proper doses, this leads to resolution of symptoms. But as dose and duration grow, a side effect called dyskinesia can develop. After a decade, about 95 percent of Parkinson’s patients will experience some degree of involuntary dyskinesia, Subramaniam says.

Dyskinesia is different than tremor, according to the Michael J. Fox Foundation.

“It can look like fidgeting, writhing, wriggling, head bobbing or body swaying,” the foundation explains. “Many people say they prefer dyskinesia to stiffness or decreased mobility. Others, though, have painful dyskinesia or movements that interfere with exercise or social or daily activities.”

The reason for its development has eluded scientists. Subramaniam and his team had studied the problem over the past decade, leading them eventually to the discovery that RasGRP1 signaling was a main culprit.

“There is an immediate need for new therapeutic targets to stop LID, or L-DOPA-induced dyskinesia in Parkinson’s disease,” Subramaniam says. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”



The next steps in the research will be discovering the best route to selectively reducing expression of RasGRP1 in the striatum while not affecting its expression in other areas of the body, Subramaniam says.

“The good news is that in mice, a total lack of RasGRP1 is not lethal, so we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” Subramaniam says.

“It’s rare for a nonprofit institution to possess the medicinal chemistry and drug development expertise needed to identify and develop such a therapy, but we have that at Scripps Research,” Subramaniam says. “Our next task is to develop suitable compounds capable of blocking RasGRP1 in the striatum.”


Bibliography:

Eshraghi et al. (2020).

RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease.

Science Advances.

DOI: https://doi.org/10.1126/sciadv.aaz7001

Sunday, 3 May 2020

Scientists Regenerate Neurons in Mice with Spinal Cord Injury and Optic Nerve Damage


Like power lines in an electrical grid, long wiry projections that grow outward from neurons -- structures known as axons -- form interconnected communication networks that run from the brain to all parts of the body. But unlike an outage in a power line, which can be fixed, a break in an axon is permanent. Each year thousands of patients confront this reality, facing life-long losses in sensation and motor function from spinal cord injury and related conditions in which axons are badly damaged or severed.

New research by scientists at the Lewis Katz School of Medicine Temple University (LKSOM) shows, however, that gains in functional recovery from these injuries may be possible, thanks to a molecule known as Lin28, which regulates cell growth. In a study published online in the journal Molecular Therapy, the Temple researchers describe the ability of Lin28 -- when expressed above its usual levels -- to fuel axon regrowth in mice with spinal cord injury or optic nerve injury, enabling repair of the body's communication grid.



"Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries," explained Shuxin Li, MD, PhD, Professor of Anatomy and Cell Biology and in the Shriners Hospitals Pediatric Research Center at the Lewis Katz School of Medicine at Temple University and senior investigator on the new study. The research is the first to demonstrate the regenerative ability of Lin28 upregulation in the injured spinal cord of animals.

"We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity," said Dr. Li. "It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration."

To explore the effects of Lin28 on axon regrowth, Dr. Li and colleagues developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye.

Injured CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Dr. Li’s group demonstrates that upregulating Lin28 gene in mature neurons induces significant long distance regeneration of both spinal cord axons and optic nerve in adult mice.


Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector (a type of carrier) for Lin28 to examine the molecule's direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimeters beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

"We observed a lot of axon regrowth, which could be very significant clinically, since there currently are no regenerative treatments for spinal cord injury or optic nerve injury," Dr. Li explained.

One of his goals in the near-term is to identify a safe and effective means of getting Lin28 to injured tissues in human patients. To do so, his team of researchers will need to develop a vector, or carrier system for Lin28, that can be injected systemically and then hone in on injured axons to deliver the therapy directly to multiple populations of damaged neurons.



Dr. Li further wants to decipher the molecular details of the Lin28 signaling pathway. "Lin28 associates closely with other growth signaling molecules, and we suspect it uses multiple pathways to regulate cell growth," he explained. These other molecules could potentially be packaged along with Lin28 to aid neuron repair.


Bibliography:

Fatima M. Nathan, Yosuke Ohtake, Shuo Wang, Xinpei Jiang, Armin Sami, Hua Guo, Feng-Quan Zhou, Shuxin Li.

Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury.

Molecular Therapy, 2020;

DOI: 10.1016/j.ymthe.2020.04.010

Friday, 1 May 2020

The ova of obese women have lower levels of omega-3 fatty acids


A study conducted by researchers from the UPV/EHU, Cruces Hospital, the IVI Clinic Bilbao and Biocruces Bizkaia shows that the oocytes of obese or overweight women have a different composition of fatty acids. This difference in levels could be linked to poor IVF outcomes and could suggest that the offspring of overweight women have an unfavourable environment even before conception.

Researchers from the UPV/EHU, Cruces Hospital, the IVI Clinic Bilbao and Biocruces Bizkaia have discovered that the oocytes –immature ova- from obese and overweight women have lower concentrations of omega-3 fatty acids. A study of the lipid composition of 922 ova obtained during IVF treatment from 205 women of normal build and who were overweight or obese has found that the oocytes of both obese and overweight women have a very different lipid composition; the study was led by Roberto Matorras-Weinig, lecturer at the UPV/EHU’s Faculty of Medicine and Nursing, and was published in the journal Fertility and Sterility.

Omega-3 fatty acids are essential in the human diet, in other words, they have to be ingested because the body cannot synthesise them.  The intake of them tends to be low in the western diet. Moreover, as Dr Matorras of the Department of Medical and Surgical Specialties at the UPV/EHU points out, “omega-3 fatty acids compete metabolically with omega-6 ones, and the intake of the latter tends to be too high in the western diet. So the high intake of omega-6 fatty acids contributes towards low levels of omega-3 ones. Presumably this is the mechanism responsible for their low levels in the ova”.



Childhood obesity could kick in before conception

Obesity is a well-known public health problem with numerous repercussions on different organs. “One of its implications in pregnancy is the birth of macrosomic babies (with a high weight), and the subsequent risk of childhood and adult obesity. Until now, this had been attributed to the effect of maternal obesity during pregnancy as well as to unsuitable diets during childhood. But these findings raise the possibility that the problems of these children may start even before conception, due to the poorer lipid composition of the ova which have generated them,” said Matorras.

On another front, the researcher added that “obese patients tend to have poorer IVF outcomes, which have been attributed to a whole range of motives. This discovery highlights another possible cause of these poorer outcomes”.


Bibliography:

Roberto Matorras, Antonia Exposito, Marcos Ferrando, Rosario Mendoza, Zaloa Larreategui, Lucía Laínz, Larraitz Aranburu, Fernando Andrade, Luis Aldámiz-Echevarria, Maria Begoña Ruiz-Larrea, Jose Ignacio Ruiz-Sanz

Oocytes of women who are obese or overweight have lower levels of n-3 polyunsaturated fatty acids compared with oocytes of women with normal weight

Fertility and Sterility

DOI: 10.1016/j.fertnstert.2019.08.059

Wednesday, 29 April 2020

Scientists recreate DNA damage caused by toxins from smoking


The causes of bladder cancer remain largely unknown; however, smoking is seen as the main risk factor for the disease.

Researchers – led by Dr Simon Baker from the Department of Biology – grew human bladder tissues in the laboratory and exposed them to a common toxin from cigarette smoke. After the tissues were damaged by the smoke toxin, the team analyzed all three billion letters of the genetic code (DNA) to find a pattern of changes called a “mutational signature.”

Fingerprints

Dr Baker said: “Mutational signatures can be used like fingerprints at a crime scene. When we look at the DNA in a cancer we can see the fingerprints of all the criminals involved in causing the damage that led to cancer.

“The DNA damaging event might be exposure to cigarette smoke or UV from the sun but it might also be an unknown event that causes cancer.

“Our study found that the smoke toxin left its distinctive fingerprints on the DNA of bladder tissues grown in the laboratory. However, when we looked at the DNA of patients’ bladder cancers the mutational signature, of the smoke toxin, was only responsible for a small amount of the damage.

“So despite smoking being the key risk factor for bladder cancer, direct damage of the DNA by smoke toxins is unlikely to be the main reason for these cancers forming.”



Enzymes

It may be that the smoke toxins accelerate other DNA damaging events and attention is now focusing on a family of enzymes called "APOBEC”.

APOBEC enzymes destroy viruses by mutating their DNA as part of the body’s natural defenses against infection, but recent studies suggest they might mistakenly target our own DNA in a number of cancer types.  The next stage of the study will be to try and understand how and why APOBEC enzymes become activated in the cells of the bladder.


Bibliography:

Baker et al. (2020).

Procarcinogen Activation and Mutational Signatures Model the 4 Initiation of Carcinogenesis in Human Urothelial Tissues In Vitro.

European Urology.

DOI: https://doi.org/10.1016/j.eururo.2020.03.049

Force Fields Help Identify Promising Peptides To Disrupt COVID-19


Drug discovery is arduous, expensive, and often prone to failure, but computer-aided drug design and simulation can speed up and improve the development of treatments.

Thomas Cheatham -- a professor of medicinal chemistry and director of the Center for High Performance Computing at the University of Utah -- and Rodrigo Galindo -- a research professor in his group -- use powerful supercomputers to predict the characteristics of novel drugs.

Recently, they have been using Frontera, the fastest supercomputers at any university in the world, and Longhorn, an IBM/NVIDIA system at the Texas Advanced Computing Center (TACC), to rapidly generate molecular models of compounds relevant for COVID-19, in collaboration with medicinal chemists.



How molecules bend, bind or react with proteins in a cellular environment depends strongly on their molecular force fields (not in the Star Trek sense of the term, but rather the potential energy of a system of interacting atoms). However, force fields are extremely challenging to predict accurately.

One of the leading tools used to simulate force fields and their impacts on binding is Amber (Assisted Model Building with Energy Refinement), a molecular simulation suite of software and force fields, for which Cheatham is one of the main developers. Known as one of the first community codes, Amber has also been evolving since 1978; its simulations and force fields get more accurate with each passing year.

For relatively simple structures, Amber can match experimental results to within less than half an angstrom (Å) -- one hundred-millionth of a centimeter, 10-10 meter.

Cheatham and Galindo apply Amber to biomolecular simulations with applications in medicine. "The goal is to understand the structure, function, dynamics, and energetics of biomolecular systems in their native environment, with water and other ligands."

Using Longhorn, an IBM/NVIDIA system at the Texas Advanced Computing Center (TACC), University of Utah researchers rapidly generated molecular models of compounds relevant for COVID-19, in collaboration with medicinal chemists. [Credit: Cheatham Lab]


They were in the midst of two biomolecular studies -- exploring a promising class of cancer-fighting copper-compounds and investigating how experimental modifications to the backbone of DNA can resist degradation inside the body -- when the COVID-19 pandemic struck.

Cheatham and Galindo swiftly turned their attention to discovering drugs that could disrupt the coronavirus.

In 2015, supported by an NSF RAPID grant, Cheatham had developed an approach to rapidly identify molecules to stop the Ebola virus. The workflow, based on known crystal structures, uses the Rosetta software suite to select promising amino acid side chains on a fixed peptide backbone template and then performs molecular dynamics simulations with Amber to optimize the structures, which are then ranked based on free energetics estimates.

Galindo rapidly generated more than 2,000 molecular models of compounds relevant for COVID-19 using this approach on the Longhorn and Frontera supercomputers at TACC. The success of the effort led Cheatham and Galindo to apply for, and obtain, 2.7 million node hours on Blue Waters, another GPU-based system located at the National Center for Supercomputing Applications (NCSA), to continue their efforts.

The award was granted through the COVID-19 HPC Consortium -- a public-private consortium working to match researchers with resources to accelerate virus research.

They are investigating the crystal structure of the COVID-19 main protease -- an enzyme which breaks down proteins and peptides -- in complex with a peptide inhibitor N3 that was recently published. They plan to apply the Ebola peptide design workflow to this system to explore the ability of the COVID-19 main protease to break down a series of similar, easy to detect probes, which have already been designed. This will serve as the basis for protease assays which test the efficacy of the inhibitors.

The peptide leads will later be transformed into circular modified peptides by the Schmidt lab in the Medical Chemistry department at the University of Utah, which has considerable experience in this area. Circular peptides are promising scaffolds for biopharmaceuticals that can be applied to the inhibition of protein-protein interactions, and protease inhibition.



Cheatham and his team were among the first to use the Longhorn and Frontera systems for COVID-19 research. That access is helping to fast-track treatment options.

"Our hope is that we find a new peptide inhibitor that can be experimentally verified in the next couple of weeks," Cheatham said. "And then, we will engage in further design to make the peptide cyclic to make it more stable as a potential drug. The hope is we can, in the next few months, find and experimentally verify a better peptide inhibitor for the COVID main protease."


Bibliography:

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Tuesday, 28 April 2020

Staining Technique Lets Researchers Visualize Whole Brains (and Bodies)


A RIKEN research team has established an optimized three-dimensional (3D) tissue-staining and observation technique based on existing tissue clearing technology. Published in Nature Communications, the study details how the new technique can be used to stain tissue and label cells in mouse brains, human brains, and whole marmoset bodies. This technique will allow detailed anatomical analysis and whole-organ comparisons between species at the cellular level.

Tissue clearing allows 3D observation of organs using an optical microscope. In 2014, a research team led by Etsuo Susaki and Hiroki Ueda at the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan developed a 3D tissue clearing technology called CUBIC, which can image the whole body at the single-cell level by making tissue transparent.



While tissue clearing can result in fantastical images, by itself it does not have much scientific value. In order for tissue clearing to be meaningful, scientists need to be able to stain and label specific tissues and cell types, which can then be studied. This requires a system that works with a wide range of staining agents and antibodies. Although several types of 3D staining and labeling methods have been attempted, none has been versatile enough.

Realizing that they needed a better understanding of body tissue, the team at BDR and their colleagues performed detailed physical and chemical analyses. They found that biological tissues can be defined as a type of electrolyte gel.

Based on the tissue properties they discovered, they constructed a screening system to examine a series of conditions using artificial gels that can mimic biological tissues. By analyzing the staining and antibody labeling of artificial gels with CUBIC, they were able to establish a fine-tuned, versatile 3D-staining/imaging method, which they named CUBIC-HistoVIsion. By using this optimized system with high-speed 3D microscopic imaging, they succeeded in staining and imaging the whole brain of a mouse, half a marmoset brain, and a square centimeter of human brain tissue. Whole-body 3D imaging of an infant marmoset was also successful. The system worked well with about 30 different antibodies and nuclear staining agents, making it useful for scientists in many different fields, from studying the brain to studying kidney function.

The system can be used for many purposes, one of which is to compare whole-organ anatomical features among species. CUBIC-HistoVIsion revealed that the overall distribution patterns of blood vessels in the brains of mice and marmosets are very similar and thus likely evolutionarily preserved. At the same time, they found that glia-cell distribution in the brain’s cerebellum differed between humans, mice, and marmosets. The authors speculate that these differences in glia patterning could lead to the well-known structural differences in the cerebellum among species.



“The 3D staining method developed in our study surpasses the performance of the typical staining methods published so far and is the best method in the world at present,” says Susaki. “It also provides a paradigm shift in the development of methods in tissue chemistry, such as the construction of staining protocols based on tissue properties. These results are expected to contribute to the understanding of biological systems at organ and organism scales, and to the improvement of the diagnostic accuracy and objectivity of 3D clinical pathology examination.”


Bibliography:

Susaki et al. (2020).

Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues.

Nature Communications.

DOI: https://doi.org/10.1038/s41467-020-15906-5

Monday, 27 April 2020

How the Immune System Responds to Hepatitis C Infection


If a virus penetrates a cell, the immune system reacts immediately and produces the signalling protein interferon. This protein activates hundreds of highly specialised defence mechanisms in all surrounding cells, which can inhibit various steps in the replication of the virus. Even though these so-called interferon-stimulated genes form the backbone of the innate immune system, the mechanisms of action of only a few of them are understood as yet.

The interferon-stimulated gene C19orf66 plays an important role in the defence against hepatitis C viruses. A research team at Ruhr-Universität Bochum (RUB) headed by Professor Eike Steinmann from the Department for Molecular and Medical Virology has now studied how C19orf66 works. The results show that C19orf66 disrupts the formation of the viral replication machinery.

The researchers published their study on 12 April 2020 in the Journal of Hepatology.



Hepatitis C patients produce more of the gene than healthy individuals

“In order to find out whether the gene is increasingly activated in samples from hepatitis C patients, we first examined liver tissue samples from infected and healthy people,” explains PhD student Volker Kinast. The analysis showed that the production of C19orf66 is increased in hepatitis C patients.

“In the next step, we checked whether the gene has an antiviral effect against hepatitis C viruses. We conducted experiments using cells that contained a lot of C19orf66 and cells that contained only a little of it. We then observed that the hepatitis C virus replicates much more slowly in cells that contain a lot of C19orf66 than in control cells,” says Kinast.

Virological and molecular biological analyses

Additional experiments with cells in which the gene was completely switched off confirmed: C19orf66 inhibits the replication of the hepatitis C virus. In order to understand how it does this, the researchers conducted numerous virological and molecular biological analyses.

The results show that the gene disrupts the formation of the viral replication machinery. The hepatitis C virus has the ability to manipulate liver cells in such a way that an accumulation of membrane vesicles occurs within the cell. The virus uses these membrane vesicles as a scaffold to replicate effectively. C19orf66 disrupts and alters the structure of the scaffold and thus inhibits the replication of the virus.



Many people don’t know that they are infected

An estimated 71 million people have a chronical hepatitis C infection, and a large percentage of them are not aware of this fact. Over the years, the virus damages the liver, resulting in severe liver disease that often requires liver transplantation.


Bibliography:

Volker Kinast et al.:

C19orf66 is an interferon-induced inhibitor of HCV replication that restricts formation of the viral replication organelle, in:

Journal of Hepatology, 2020,

DOI: 10.1016/j.jhep.2020.03.047

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