Culture

There are no Food and Drug Administration (FDA)-approved treatments for COVID-19, the pandemic infection caused by a novel coronavirus. While several therapies are being tested in clinical trials, current standard of care involves providing patients with fluids and fever-reducing medications. To speed the search for new COVID-19 therapies, researchers are testing repurposed drugs -- medicines already known to be safe for human use because they are FDA-approved for other conditions -- for their abilities to mitigate the virus.

UC San Diego Health researchers recently reported that statins -- widely used cholesterol-lowering medications -- are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times. A second research team at UC San Diego School of Medicine has uncovered evidence that helps explains why: In short, removing cholesterol from cell membranes prevents the coronavirus from getting in.

The clinical study, published September 15, 2020 in American Journal of Cardiology, was led by Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Karen Messer, PhD, professor and chief of the Division of Biostatics and Bioinformatics in the Department of Family Medicine and Public Health.

The mechanistic study, published September 18, 2020 in The EMBO Journal, was led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center.

Patients with COVID-19 who took statins fared better

A molecule known as ACE2 sits like a doorknob on the outer surfaces of many human cells, where it helps regulate and lower blood pressure. ACE2 can be affected by prescription statins and other medications used for cardiovascular disease.

But, in January 2020, researchers discovered a new role for ACE2: SARS-CoV-2, the coronavirus that causes COVID-19, primarily uses the receptor to enter lung cells and establish respiratory infections.

"When faced with this novel virus at the beginning of the pandemic, there was a lot of speculation surrounding certain medications that affect ACE2, including statins, and if they may influence COVID-19 risk," Daniels said. "We needed to confirm whether or not the use of statins has an impact on a person's severity of SARS-CoV-2 infection and determine if it was safe for our patients to continue with their medications."

To do this, Daniels, Messer and team retrospectively analyzed the electronic medical records of 170 patients with COVID-19 and 5,281 COVID-negative control patients hospitalized at UC San Diego Health between February and June 2020. They collected anonymized data that included the patients' disease severity, length of hospital stay, outcome, and use of statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) within 30 days prior to hospital admission.

Among the patients with COVID-19, 27 percent were actively taking statins on admission, while 21 percent were on an ACE inhibitor and 12 percent on an ARB. The median length of hospital stay was 9.7 days for patients with COVID-19.

The researchers found that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster than those not taking the cholesterol-lowering medication.

"We found that statins are not only safe but potentially protective against a severe COVID-19 infection," said Daniels. "Statins specifically may inhibit SARS-CoV-2 infection through its known anti-inflammatory effects and binding capabilities as that could potentially stop progression of the virus."

This initial study was relatively small and focused on a single health system. Moving forward, Daniels is partnering with the American Heart Association to analyze thousands of patients all over the country to corroborate the data she's developed locally.

"I tell my patients who are on statins, ACE inhibitors or other ARBs to keep taking them," she said. "Fears of COVID-19 should not be a reason to stop, if anything our research findings should be incentive to continue with their medication."

Draining cholesterol from cell membranes blocks SARS-CoV-2 entry

Statins weren't yet on Rana's radar when they began their EMBO Journal study approximately six months ago. At first, his team was simply curious to see which genes are switched "on" in human lung cells in response to SARS-CoV-2 infection.

A gene called CH25H was "blazing hot," Rana said. CH25H encodes an enzyme that modifies cholesterol. "I got excited because with HIV, Zika, and a few others, we know that CH25H blocks the virus' ability to enter human cells."

Here's what's happening inside our cells: CH25H's enzymatic activity produces a modified form of cholesterol called 25-hydroxycholesterol (25HC). In turn, 25HC activates another enzyme called ACAT, found inside cells in the endoplasmic reticulum. ACAT then depletes accessible cholesterol on the cell's membrane. It's a normally occurring process that gets kicked into high gear during some viral infections.

The team quickly got to work examining 25HC in the context of SARS-CoV-2 from several angles. They explored what happens to human lung cells in the lab with and without 25HC treatment when they are exposed to first a noninfectious virus that carries the SARS-CoV-2 spike protein (its key to cell entry) or to live SARS-CoV-2 virus itself.

No matter which way they came at it, added 25HC inhibited the ability of the virus to enter cells -- blocking infection almost completely.

"The difference between untreated cells and those treated with 25HC was like day and night," Rana said.

While SARS-CoV-2 uses the ACE2 receptor to initially dock on a cell, Rana's study suggests that the virus also needs cholesterol (normally found in cell membranes) in order to fuse with and enter the cell. 25HC takes away a lot of that membrane cholesterol, preventing viral entry.

In a similar way, statins are likely beneficial in preventing or reducing the severity of SARS-CoV-2 infection because, while intended to remove cholesterol from blood vessels, they are also removing cholesterol from cell membranes. As a result, the coronavirus can't get in.

"This is already happening in our bodies on a regular basis, so perhaps we just need to give it a boost, with statins or by other means, to better resist some viruses," Rana said. "It's not unlike cancer immunotherapy -- the idea that sometimes instead of attacking a tumor directly, it's better to arm a patient's immune system to do a better job of clearing away tumors on its own."

If it can be developed into a therapeutic, 25HC might work even better as an antiviral than statins, Rana said. That's because it works specifically on cholesterol in cell membranes, rather than cholesterol throughout the body. Like all medications, statins can cause negative side effects, including digestive problems and muscle pains, and may not be an option for many people with COVID-19. What's more, while some previous studies suggested statins may also elevate ACE2 levels, which could allow more viral entry, Rana's team did not see an increase in the receptor in response to 25HC.

Statins are FDA-approved for human use, but 25HC is a natural product currently available only for laboratory work. Rana and team plan to continue optimizing 25HC as a potential antiviral agent. Many steps remain before it might be tested in human clinical trials.

AMHERST, Mass. - In a new climate modeling study that looked at the impacts of accelerated ice melt from the Antarctic Ice Sheet (AIS) on future climate, a team of climate scientists reports that future ice-sheet melt is expected to have significant effects on global climate.

First author and graduate student Shaina Sadai at the University of Massachusetts Amherst, with Alan Condron of the Woods Hole Oceanographic Institution, Rob DeConto at UMass Amherst and David Pollard at Pennsylvania State University, present details this week in Science Advances.

Their study predicts how future climate conditions could change under high- and low-greenhouse gas emissions scenarios, while accounting for accelerated melting of the AIS.

Scientists have long recognized that future meltwater input from the Antarctic will affect the Southern Ocean and global climate, but ice-sheet processes are not now included in most state-of-the-art climate prediction simulations, Sadai says. She and colleagues report that their modeling with the added ice melt information reveals interacting processes.

For this work, Sadai's task was to add accelerated AIS melting and icebergs into simulations of Earth's future climate. One important step was to include the details of where and when the meltwater will go into the ocean.

She says, "We found that future melt water coming off Antarctica leads to huge amounts of thick sea ice around the continent. With higher greenhouse gas emissions, the ice sheet melts faster, which in turn leads to more freshwater flowing into the ocean and more sea ice production."

All this additional meltwater and sea ice production dramatically slows the pace of future warming around Antarctica, the researchers report - seemingly welcome news. And remarkably, the climate impacts are not just restricted to the Antarctic. Condron, previously at UMass Amherst, points out that the cooling effects are felt worldwide.

But ,he adds, "All that said, it's important to note that this is not a global 'cooling' scenario - average global temperatures would still be roughly 3 degrees Celsius warmer than today due to human greenhouse gas emissions, even with the cooling effects of this melt water on climate."

That is not the end of the story. Even though atmospheric warming slows, the deep sea waters around Antarctica actually warm faster in their model. This is because, Condron explains, the new sea ice stops heat from escaping from the deeper waters to the atmosphere. "The subsurface ocean waters warm by as much as one degree Celsius, which can increase melting below parts of the ice sheet. This could make the ice sheet more unstable and accelerate rates of sea level rise beyond current projections."

Overall, Sadai says, "Our results demonstrate a need to accurately account for meltwater input from ice sheets if we are to make confident climate predictions." She emphasizes that the delayed future warming they found in the new simulations may sound like good news, but it is important to keep in mind that serious warming and sea level rise will still occur with unabated greenhouse gas emissions, which will affect coastal communities and ecosystems worldwide.

DeConto and Pollard add that the future stability of the AIS and future sea-level rise will be governed by which process wins out - ocean warming or atmospheric cooling. Answering this question is the target of the team's ongoing research.

During pregnancy in mice, the billions of bacteria and other microbes that live in a mother's intestines regulate key metabolites, small molecules that are important for healthy fetal brain development, UCLA biologists report Sept. 23 in the journal Nature.

While the maternal gut microbiota has been associated with abnormalities in the brain function and behavior of offspring -- often in response to factors like infection, a high-fat diet or stress during pregnancy -- scientists had not known until now whether it influenced brain development during critical prenatal periods and in the absence of such environmental challenges.

To test the impact the gut microbiata has on the metabolites and other biochemicals that circulate in maternal blood and nurture the rapidly developing fetal brain, the researchers raised mice that were treated with antibiotics to kill gut bacteria, as well as mice that were bred microbe-free in a laboratory.

"Depleting the maternal gut microbiota, using both methods, similarly disrupted fetal brain development," said the study's lead author, Helen Vuong, a postdoctoral scholar in laboratory of UCLA's Elaine Hsiao.

Depleting the maternal gut microbiota altered which genes were turned on in the brains of developing offspring, including many genes involved in forming new axons within neurons, Vuong said. Axons are tiny fibers that link brain cells and enable them to communicate.

In particular, axons that connect the brain's thalamus to its cortex were reduced in number and in length, the researchers found.

"These axons are particularly important for the ability to sense the environment," Vuong said. "Consistent with this, offspring from mothers lacking a gut microbiota had impairments in particular sensory behaviors."

The findings indicate that the maternal gut microbiota can promote healthy fetal brain development by regulating metabolites that enter the fetal brain itself, Vuong said.

"When we measured the types and levels of molecules in the maternal blood, fetal blood and fetal brain, we found that particular metabolites were commonly decreased or missing when the mother was lacking a gut microbiota during pregnancy," she said.

The biologists then grew neurons in the presence of these key metabolites. They also introduced these metabolites into the microbiata-depleted pregnant mice.

"When we grew neurons in the presence of these metabolites, they developed longer axons and greater numbers of axons," Vuong said. "And when we supplemented the pregnant mice with key metabolites that were decreased or missing when the microbiata was depleted, levels of those metabolites were restored in the fetal brain and the impairments in axon development and in offspring behavior were prevented.

"The gut microbiota has the incredible capability to regulate many biochemicals not only in the pregnant mother but also in the developing fetus and fetal brains," Vuong said. "Our findings also pinpoint select metabolites that promote axon growth."

The results suggest that interactions between the microbiota and nervous system begin prenatally through the influence of the maternal gut microbiota on the fetal brain, at least in mice.

The applicability of the findings to humans is still unclear, said the study's senior author, Elaine Hsiao, a UCLA associate professor of integrative biology and physiology, and of microbiology, immunology and molecular genetics in the UCLA College.

"We don't know whether and how the findings may apply to humans," said Hsiao, who is also an associate professor of digestive diseases at the David Geffen School of Medicine at UCLA. "However, there are many neurodevelopmental disorders that are believed to be caused by both genetic and environmental risk factors experienced during pregnancy. Our study suggests that maternal gut microbiota during pregnancy should also be considered and further studied as a factor that could potentially influence not only the health of the mother but the health of the developing offspring as well."

Hsiao, Vuong and colleagues reported in 2019 that serotonin and drugs that target serotonin, such as antidepressants, can have a major effect on the gut's microbiota. In 2018, Hsiao and her team established a causal link between seizure susceptibility and gut microbiota and identified specific gut bacteria that play an essential role in the anti-seizure effects of the ketogenic diet.

A neighborhood's overall socioeconomic status, including income and education level, may influence its residents' risk of chronic kidney disease, according to a study recently published in SSM Population Health by researchers from Drexel University's Dornsife School of Public Health.

Although previous studies have shown an association between individual socioeconomic status and chronic kidney disease, less is known about how the characteristics of an individual's neighborhood, such as overall socioeconomic status, walkability, violent crime and availability of healthy food, may influence the risk of chronic kidney disease, poor blood sugar control (A1c over or equal to 6.5 percent) and uncontrolled high blood pressure (at least one instance of systolic blood pressure greater than 140 mm Hg and/or diastolic blood pressure greater than 90 mm Hg), especially in urban areas.

In a study of 23,692 adult Philadelphians, all seen in a primary care practice in 2016 or 2017, the authors found that those living in low socioeconomic status neighborhoods (factoring in neighborhood income, educational attainment and occupation), were more likely to have kidney disease than those living in higher socioeconomic status neighborhoods. Also, poor neighborhood walkability, as measured by Walkscore®, was associated with poor blood sugar control in chronic kidney disease patients and poor blood pressure control in those without chronic kidney disease. The authors adjusted for individual age, race, sex and insurance type.

"Our finding, that people who are living in neighborhoods with the fewest resources are at highest risk for kidney disease, should be a call to health providers to integrate knowledge about their patients' environments in their care processes, and to policymakers to allocate resources to at-risk communities that will promote health," said senior author Meera Harhay, MD, an associate professor of Medicine at Drexel's College of Medicine and Dornsife School of Public Health. "Our results also show that neighborhood environments that promote physical activity are protective when it comes to blood pressure and blood sugar management, whereas less walkable neighborhoods might exacerbate conditions that are risk factors for kidney disease."

Chronic kidney disease is characterized by damaged kidneys that are unable to adequately filter waste and excess fluids out of blood. Without early detection and management of blood pressure and blood glucose, this damage can lead to kidney failure and dialysis or a kidney transplant as the remaining options. An estimated 37 million -- 15% -- of U.S. adults are estimated to suffer from chronic kidney disease, and nine out of 10 of those cases go undiagnosed. The findings of this research are valuable to the U.S. Department of Health and Human Services' Advancing American Kidney Health Initiative, whose goals include reducing the number of Americans in end-stage renal disease by 25% by 2030.

"This study offers tools to help identify communities at higher risk of kidney disease at earlier stages so their condition can be managed to prevent end-stage kidney disease from developing," Harhay said. "Health providers should consider incorporating knowledge about neighborhood-level social determinants of health when they are assessing their patients."

The authors note that future studies should look at what neighborhood characteristics might contribute to progression of chronic kidney disease, and whether socioeconomic status might be a marker for lower access to health-promoting resources, such as information on self-care and chronic disease management, that might help prevent chronic kidney disease.

Researchers at the University of Alberta have discovered a novel, second mechanism of action by the antiviral drug remdesivir against SARS-CoV-2, according to findings published today in the Journal of Biological Chemistry.

The research team previously demonstrated how remdesivir inhibits the COVID-19 virus’s polymerase or replication machinery in a test tube. 

Matthias Götte, chair of medical microbiology and immunology in the Faculty of Medicine & Dentistry, likened the polymerase to the engine of the virus. He said the first mechanism the team identified is like putting diesel fuel into an engine that needs regular gasoline. 

“You can imagine that if you give it more and more diesel, you will go slower and slower and slower,” he said.

The newly identified mechanism is more like a roadblock, “so if you want to go from A to B with the wrong fuel and terrible road conditions, you either never reach B or you arrive extremely late,” Götte said.

“Remdesivir stops or heavily delays replication of the virus, which in turn reduces propagation and spread.”

Benchmark drug against COVID-19

Götte said it is not common for antiviral drugs to have more than one mechanism of action. The first mechanism his team uncovered affects what is known as the “primer strand” of RNA or the first copy the virus makes of the viral genome as it infects a cell. The second mechanism affects the “template strand” which is repeated over and over as the virus spreads.

Clinical trials of remdesivir in COVID-19 patients are underway around the world, including one run by the U.S. National Institutes of Health which reported preliminary results showing the average recovery time for treated patients was shortened to 11 days compared with 15 days for the placebo group. 

Götte said it is important to know how remdesivir works because it is the only direct-acting antiviral currently approved for conditional and/or emergency use as a COVID-19 treatment in several countries, including Canada and the U.S. 

“That means remdesivir is a benchmark that we need to understand in great detail in order to build on it and to improve therapies in the future,” Götte said.

Next steps for human trials and laboratory studies

Götte said that while remdesivir looks promising in laboratory tests and in cell cultures, he is anxious to see more results from human clinical trials, in particular how remdesivir affects the “viral load” or amount of virus in patients. 

“Is there a difference as to whether somebody has a low viral load from the beginning or a high viral load? We don’t know that yet,” he pointed out.

He said laboratory results can differ from human trials because there could be reservoirs of the virus in the human body that the drug does not reach. SARS-CoV-2 may also develop resistance to the drug, although he thinks this will be difficult based on what is known about how remdesivir interacts with other coronaviruses.

“We need these data to help us to better understand which patients will benefit from remdesivir,” he said. 

Götte’s lab will continue trying to understand more about how remdesivir and other polymerase inhibitors work against SARS-CoV-2 to aid drug discovery and development. 

University of Houston researchers have found that during early pregnancy, the mix of alcohol and nicotine significantly alters the gene regulatory pathways of the developing fetus, which can lead to major deficiencies in brain development. Metin Akay, founding chair and John S. Dunn Endowed Chair Professor of biomedical engineering is reporting the findings, the first study of its kind, in the Nature journal Scientific Reports.

"The alterations of these pathways are crucial since they are involved in neural network formation, cell development and communication," reports Akay. "Among pathways in which many genes and miRNAs were significantly altered in response to perinatal nicotine/alcohol co-exposure are dopamine cell growth, neuronal migration, neuronal axon guidance, neurotrophin signaling and glutamatergic synapse."

Addictive substances act on the brain's reward system by triggering the release of the dopamine hormone through the activation of the mesocorticolimbic DA system, also known as the reward circuitry in the brain.

"A characteristic structure of dopamine neurons are the long axons that project to different regions of the brain to build functional networks, which results in pathways such as the mesocorticolimbic DA system," said Akay. "It is highly likely that axon guidance is modulated in the newborn after perinatal substance abuse and may cause faulty assembly of the network."

The alterations in this pathway cause interruptions in cellular communication and development, and finally, lead to synaptic rearrangements in the plasticity and neurological disorders.

It's no small problem.

Maternal substance abuse (drinking and smoking) during pregnancy increases health risks, including cognitive impairments, lower academic achievement, attention deficit hyperactivity disorder (ADHD), the likelihood of substance abuse in newborns, and may even lead sudden infant death syndrome (SIDS). Despite these harmful effects, more than 10% of pregnant women drink and smoke, according to the Centers for Disease Control.

Following alcohol treatment, 1,257 unique genes were found to be differentially upregulated and 330 were differentially downregulated. Following perinatal nicotine-alcohol treatment contrasted against the alcohol group, 2,113 genes were upregulated and 1,836 were downregulated.

"A more comprehensive treatment needs to be developed for the perinatal co-exposure since more pathways and gene expressions were significantly altered, suggesting the involvement of several addiction pathways in newborns," said Akay.

"Until now, the influence of maternal alcohol and nicotine co-exposure on the brain development of newborns has not been investigated at the multi scale from molecular, to cellular and to systemic levels," said Yasemin Akay, instructional associate professor of biomedical engineering and the co-lead investigator on the project. "Our group has focused on the integration of molecular, cellular and systemic data - using a custom-made implantable dopamine probe and artificial intelligence - to better understand the addiction mechanism and develop effective therapeutics," she said.

PHILADELPHIA -- A recent study published in the journal Nature Medicine, led by researchers James Riley, PhD, a professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, and Todd Allen, PhD, a professor of Medicine at Harvard Medical School and Group Leader at the Ragon Institute of MGH, MIT and Harvard, describes a new Dual CAR T cell immunotherapy that can help fight HIV infection. The paper's first authors are Colby Maldini, a graduate student at the University of Pennsylvania and Daniel Claiborne, PhD, a research fellow at the Ragon Institute.

"This study highlights how relatively straightforward alterations to the way T cells are engineered can lead to dramatic changes in their potency and durability," Riley said. "This finding has significant implications for using engineered T cells to fight both HIV and cancer."

The global HIV epidemic impacts more than 35 million people around the world. Antiretroviral therapy (ART) is a daily treatment that can control, but not cure, HIV infection. However, access and lifelong adherence to a daily regimen is a significant barrier for many people living with HIV. A major hurdle to HIV cure is the viral reservoir, copies of HIV hidden away in the genome of infected cells. If ART treatment is stopped, the virus is able to rapidly make new copies of itself, ultimately leading to the development of AIDS.

CAR T cells are a powerful immunotherapy, currently used in cancer treatments, in which a patient's own immune T cells are engineered to express Chimeric Antigen Receptors (CARs). These CARs re-program the T cells to recognize and eliminate specific diseased or infected cells, such as cancer cells or, potentially, HIV-infected cells.

Allen's and Riley's research groups worked together to design a new HIV-specific CAR T cell. They needed to design a CAR T cell that would be able to target and quickly eliminate HIV-infected cells, survive and reproduce once in the body, and resist infection by HIV itself, since HIV's primary target is these very same T cells.

"By using a stepwise approach to solve each issue as it arose, we developed protected Dual CAR T cells, which provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself," Allen said.

This Dual CAR T cell, a new type of CAR T cell, was made by engineering two CARs into a single T cell. Each CAR had a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. The first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

Since HIV frequently infects T cells, they also added in a protein called C34-CXCR4, developed in the lab of James Hoxie, MD, a professor of Hematology-Oncology at Penn. C34-CXCR4 prevents HIV from attaching to and then infecting the cell. The final CAR T cell was long-lived, replicated in response to HIV infection, killed infected cells effectively, and was partially resistant to HIV infection.

When the protected Dual CAR T cells were given to HIV-infected mice, the team saw slower HIV replication and fewer HIV infected cells than in untreated animals. They also saw reduced amounts of virus and preservation of CD4+ T cells, HIV's preferred target, in the blood of these animals. In addition, when they combined Dual CAR T cells with ART in HIV-infected mice, the virus was suppressed faster, which led to a smaller viral reservoir than in mice who were only treated with ART.

"The ability of these protected Dual CAR T cells to reduce the HIV burden in a variety of tissues and cell types, including long-lived memory CD4+ T cells, we believe supports the approach of using CAR T cell therapy as a new tool to target the HIV reservoir towards a functional cure for HIV," said Allen.

Particle accelerators generate high-energy beams of electrons, protons and ions for a wide range of applications, including particle colliders that shed light on nature's subatomic components, X-ray lasers that film atoms and molecules during chemical reactions and medical devices for treating cancer.

As a rule of thumb, the longer the accelerator, the more powerful it is. Now, a team led by scientists at the Department of Energy's SLAC National Accelerator Laboratory has invented a new type of accelerator structure that delivers a 10 times larger energy gain over a given distance than conventional ones. This could make accelerators used for a given application 10 times shorter.

The key idea behind the technology, described in a recent article in Applied Physics Letters, is to use terahertz radiation to boost particle energies.

In today's accelerators, particles draw energy from a radio-frequency (RF) field fed into specifically shaped accelerator structures, or cavities. Each cavity can deliver only a limited energy boost over a given distance, so very long strings of cavities are needed to produce high-energy beams.

Terahertz and radio waves are both electromagnetic radiation; they differ in their respective wavelengths. Because terahertz waves are 10 times shorter than radio waves, cavities in a terahertz accelerator can also be much smaller. In fact, the one invented in this study was only 0.2 inches long.

One major challenge to building these tiny cavity structures is to machine them very precisely. Over the past few years, SLAC teams developed a way to do just that. Instead of using the traditional process of stacking many layers of copper on top of each other, they built the minute structure by machining two halves and bonding them together.

The new structure also produces particle pulses a thousand times shorter than those coming out of conventional copper structures, which could be used to produce beams that pulse at a higher rate and unleash more power over a given time period.

Next, the researchers are planning to turn the invention into an electron gun - a device that could produce incredibly bright beams of electrons for discovery science, including next-generation X-ray lasers and electron microscopes that would allow us to see in real time how nature works on the atomic level. These beams could also be used for cancer treatment.

Delivering on this potential also requires further development of sources of terahertz radiation and their integration with advanced accelerators, such as the one described in this study. Because terahertz radiation has such a short wavelength, its sources are particularly challenging to develop, and there is little technology available at present. SLAC researchers are pursuing both electron beam and laser-based terahertz generation to provide the high peak powers needed to turn their accelerator research into future real-world applications.

Metformin is the first-line treatment for most cases of type 2 diabetes and one of the most commonly prescribed medications worldwide, with millions of individuals using it to optimise their blood glucose levels.

A new research study, conducted over six years in the Sydney Memory and Ageing Study in 1037 Australians (aged 70 to 90 years old at baseline), has revealed an additional effect: individuals with type 2 diabetes who used metformin experienced slower cognitive decline with lower dementia rates than those who did not use the medication.

The findings provide new hope for a means of reducing the risk of dementia in individuals with type 2 diabetes, and potentially those without diabetes who number nearly 47 million people worldwide.

The study was led by researchers at the Garvan Institute of Medical Research and the Centre for Healthy Brain Ageing (CHeBA), UNSW Sydney, and published in the Journal Diabetes Care.

"We've revealed the promising new potential for a safe and widely used medication, which could be life-changing for patients at risk of dementia and their families. For those with type 2 diabetes, metformin may add something extra to standard glucose lowering in diabetes care: a benefit for cognitive health," says first author Professor Katherine Samaras, Leader of the Healthy Ageing Research Theme at the Garvan Institute and endocrinologist at St Vincent's Hospital Sydney.

Protecting brain function

Type 2 diabetes occurs when the body can no longer produce enough insulin to meet its needs, leaving affected individuals unable to maintain blood glucose levels within a normal range. This can lead to long-term health complications, including cognitive decline.

"As they age, people living with type 2 diabetes have a staggering 60% risk of developing dementia, a devastating condition that impacts thinking, behaviour, the ability to perform everyday tasks and the ability to maintain independence. This has immense personal, family, economic and societal impacts," says Professor Samaras.

The researchers of this study investigated data from participants of CHeBA's Sydney Memory and Ageing Study. In this cohort, 123 study participants had type 2 diabetes, and 67 received metformin to lower blood sugar levels. The researchers tested cognitive function every two years, using detailed assessments that measured cognition over a number of capabilities, including memory, executive function, attention and speed, and language.

The findings revealed individuals with type 2 diabetes taking metformin had significantly slower cognitive decline and lower dementia risk compared to those not taking metformin. Remarkably, in those with type 2 diabetes taking metformin, there was no difference in the rate of decline in cognitive function over 6 years compared to those without diabetes.

New use for a common medication

Metformin has been used safely to treat type 2 diabetes for 60 years. It works by reducing the amount of glucose released from the liver into the blood stream and allows the body's cells to better respond to blood glucose levels.

Studies over the last decade have revealed evidence of metformin's benefit in cancer, heart disease, polycystic ovary syndrome and weight management. While the current study suggests metformin may have cognitive benefits for people living with type 2 diabetes, the researchers say it may also benefit those at risk of cognitive decline more broadly.

"This study has provided promising initial evidence that metformin may protect against cognitive decline. While type 2 diabetes is thought to increase dementia risk by promoting degenerative pathways in the brain and nerves, these pathways also occur in others at risk of dementia and it is possible insulin resistance may be the mediator," says Professor Samaras.

"To establish a definitive effect, we are now planning a large, randomised controlled trial of metformin in individuals at risk of dementia and assess their cognitive function over three years. This may translate to us being able to repurpose this cheap medication with a robust safety profile to assist in preventing against cognitive decline in older people."

CHeBA's Sydney Memory and Ageing Study is an observational study of older Australians that commenced in 2005 and researches the effects of ageing on cognition over time.

Professor Perminder Sachdev, senior author of the study and Co-Director of CHeBA, says: "While an observational study does not provide conclusive 'proof' that metformin is protective against dementia, it does encourage us to study this and other anti-diabetic treatments for dementia prevention. Metformin has even been suggested to be anti-ageing. The intriguing question is whether metformin is helpful in people in those with normal glucose metabolism. More work is clearly needed."

Computational biologists at the University of Toronto have developed an artificial intelligence algorithm that has the potential to create novel protein molecules as finely tuned therapeutics.

The team led by Philip M. Kim, a professor of molecular genetics and computer science at the Donnelly Centre for Cellular and Biomolecular Research at U of T's Faculty of Medicine, have developed ProteinSolver, a graph neural network that can design a fully new protein to fit a given geometric shape. The researchers took inspiration from the Japanese number puzzle Sudoku, whose constraints are conceptually similar to those of a protein molecule.

Their findings are published in the journal Cell Systems.

"The parallel with Sudoku becomes apparent when you depict a protein molecule as a network," says Kim, adding that the portrayal of proteins in graph form is standard practice in computational biology.

A newly synthesized protein is a string of amino-acids, stitched together according to the instructions in that protein's gene code. The amino-acid polymer then folds in and around itself into a three-dimensional molecular machine that can be harnessed for medicine.

A protein converted into a graph looks like a network of nodes, representing amino-acids, connected by edges, which are the distances between them within the molecule. By applying principles from graph theory, it then becomes possible to model the molecule's geometry for a specific purpose to, for example, neutralize an invading virus or shut down an overactive receptor in cancer.

Proteins make good drugs thanks to three-dimensional features on their surface with which they bind cellular targets with more precision than the synthetic small molecule drugs that tend to be broad spectrum and can lead to harmful off-target side effects.

Just over a third of all medications approved over the last couple of years were proteins, which also make up the vast majority of top ten drugs globally, Kim said. Insulin, antibodies and growth factors are only some examples of injectable cellular proteins, also known as biologics, already in use.

Designing proteins from scratch remains incredibly difficult however, owing to the vast number of possible structures to choose from.

"The main problem in protein design is that you have a very large search space," says Kim, referring to the many ways in which the 20 naturally occurring amino-acids can be combined into protein structures.

"For a standard-length protein of 100 amino-acids, there are 20100 possible molecular structures, that's more than the number of molecules in the universe," he says.

Kim decided to turn the problem on its head, by starting with a three-dimensional structure and working out its amino-acid composition.

"It's the protein design, or the inverse protein folding problem - you have a shape in mind and you want a sequence (of amino-acids) that will fold into that shape. Solving this is in some ways more useful than protein folding, as you can in theory generate new proteins for any purpose," says Kim.

That's when Alexey Strokach, a PhD student in Kim's lab, turned to Sudoku, after learning in a class about its relatedness to molecular geometry.

In Sudoku, the goal is to find missing values in a sparsely filled grid by observing a set of rules and the existing number values.

Individual amino-acids in a protein molecule are similarly constrained by their neighbours. Local electrostatic forces ensure that amino-acids carrying opposite electric charge pack closely together while those with the same charge are pulled apart.

Strokach first built the constraints found in Sudoku into a neural network algorithm. He then trained the algorithms on a vast database of available protein structures and their amino-acid sequences from across the tree of life. The goal was to teach the algorithm, ProteinSolver, the rules, honed by evolution over millions of years, of packing amino-acids together into smaller folds. Applying these rules to the engineering process should increase the chances of having a functional protein at the end.

The researchers then tested ProteinSolver by giving it existing protein folds and asking it to generate amino-acid sequences that can build them. They then took the novel computed sequences, which do not exist in nature, and manufactured the corresponding protein variants in the lab. The variants folded into the expected structures, showing that the approach works.

In its current form, ProteinSolver is able to compute novel amino-acid sequences for any protein fold known to be geometrically stable. But the ultimate goal is to engineer novel protein structures with entirely new biological functions, as new therapeutics, for example.

"The ultimate goal is for someone to be able to draw a completely new protein by hand and compute sequences for that, and that's what we are working on now," says Strokach.

The researchers made ProteinSolver and the code behind it open source and available to the wider research community through a user-friendly website.

Misconceptions about child marriage (marriage under 18) appear widespread among the American public, potentially hampering efforts to address the practice globally. David Lawson and colleagues at the University of California, Santa Barbara, present these findings in the open-access journal PLOS ONE on September 23, 2020.

Child marriage primarily affects girls and is most common in sub-Saharan Africa and South Asia. Initiatives enacted by the U.N. and other organizations seek to eradicate the practice. However, awareness campaigns often highlight extreme instances of child marriage that don't accurately represent most cases, potentially fostering harmful stereotypes and undermining the goals of such initiatives. The terminology 'child marriage' may also give the false impression that such marriages mainly take place at very young ages.

To help clarify popular understanding, Lawson and colleagues surveyed U.S. residents via Amazon Mechanical Turk. Of 609 participants, half incorrectly guessed that the U.N.'s cut-off age for child marriage is younger than the actual age of 18 years. Most guessed that child marriage primarily occurs at or below the age of 15. In fact, it usually occurs just below 18, leading the researchers to suggest that alternative terminology like 'adolescent marriage' is more appropriate in many contexts.

Most participants believed that child marriages are usually or always forced marriages. The researchers note that this is not always the case, such as when girls elope to marry against parental wishes. The authors argue that a failure to recognize female agency in the decision to marry, may limit the effectiveness of initiatives addressing the harms of early marriage.

Misconceptions also applied to America itself, where child marriage it is rare but only illegal in only four states. Most participants incorrectly guessed that it is banned in all 50, indicating they are unaware of the hypocrisy of efforts to change marriage laws in other nations. Most participants also overestimated the worldwide prevalence of the practice, and incorrectly guessed that it occurs primarily in regions with a Muslim majority.

The authors suggest that misconceptions about child marriage reinforce damaging stereotypes about low-income nations; exaggerating the extent to which girls and women at placed from risk from cultural traditions as opposed to other factors such as poverty. They call for a more nuanced approach to crafting narratives within the movement to end child marriage. Such efforts, they argue, could help minimize misinformation and improve cultural sensitivity.

The authors add: Tagged Manta rays (Mobula alfredi) from the never-studied-before population of New Caledonia showed unprecedented deep dive behaviour. More frequent and deeper dives than ever recorded before, Manta rays of New Caledonia set a new depth range to 672 meters.

Antibiotic resistance is one of the world's most urgent public health threats. In the United States alone, tens of thousands of deaths result each year from drug-resistant strains of common bacteria such as Staphylococcus aureus and Enterococcus faecium, which can cause virtually untreatable hospital-acquired infections. Perilously few new classes of antibiotics are being developed to fight infections that have become resistant to traditional treatments, and bringing any new drugs to market could take decades.

Researchers at UC San Francisco are tackling antibiotic resistance using a different approach: redesigning existing antibiotic molecules to evade a bacterium's resistance mechanisms. By devising a set of molecular LEGO pieces that can be altered and joined together to form larger molecules, the researchers have created what they hope is the first of many "rebuilds" of drugs that had been shelved due to antibiotic resistance. The research was published September 23, 2020, in Nature.

"The aim is to revive classes of drugs that haven't been able to achieve their full potential, especially those already shown to be safe in humans," said Ian Seiple, PhD, an assistant professor in the UCSF School of Pharmacy's Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute (CVRI), and lead author on the paper. "If we can do that, it eliminates the need to continually come up with new classes of drugs that can outdo resistant bacteria. Redesigning existing drugs could be a vital tool in this effort."

In work descibed in the new Nature paper, Seiple and his collaborator James Fraser, Ph.D. a professor in the School of Pharmacy's Department of Bioengineering and Therapeutic Sciences in the UCSF School of Pharmacy, have demonstrated this approach with a class of antibiotics called streptogramins. Until recently, streptogramins were very effective against S. aureus infections, until the bacteria evolved a clever resistance mechanism.

Streptogramins disable bacteria by gumming up the works in the bacterial ribosome, making it impossible for the bacteria to make proteins. But bacteria resistant to streptogramins produce proteins called virginiamycin acetyltransferases (Vats), which recognize these antibiotics when they enter the bacterial cell. The Vats grab the drug and chemically deactivate it before it can bind to the ribosome, rendering it useless.

Streptogramins, like most other antibiotics, are derived from naturally occurring antibiotic compounds produced by other organisms (usually bacteria) that are then tweaked to optimize their performance in the human body. Seiple figured that there must also be a way to make further changes to the drug molecule that would allow it to evade capture by the Vat proteins.

Seiple set out to build new streptogramins from the ground up, rather than modifying existing structures. To make the building process easier, Qi Li, PhD, a postdoctoral fellow in the Seiple lab and co-first author on the paper, created seven molecular modules that can be tweaked as needed to build a set of variations on the streptogramin molecule.

"This system allows us to manipulate the building blocks in ways that wouldn't be possible in nature," said Seiple. "It gives us an efficient route to re-engineering these molecules from scratch, and we have a lot more latitude to be creative with how we modify the structures."

Once Seiple and Li had their building blocks, the next step was to get a molecular-level view of the chemistry involved in order to better understand how to modify and piece together those molecular LEGOs.

For that, Seiple teamed up with Fraser, who specializes in creating visual models of biological molecules.

"My lab's contribution was to say, 'Now that you've got the seven pieces, which one of them should we modify and in what way?'" said Fraser, whose work on the project was supported by the inaugural Sanghvi-Agarwal Innovation Award.

To get answers to that question, Jenna Pellegrino, a graduate student in the Fraser Group and co-first author on the paper, used two complementary techniques, cryo-electron microscopy and x-ray crystallography, to create three-dimensional pictures of the drug at near-atomic resolution, as well as its target the bacterial ribosome, and its nemesis, the Vat protein.

Using the models, Li, Pellegrino, Seiple, and Fraser could see which parts of the streptogramin molecule are essential to the antibiotic's function. Then Li was free to fiddle with the drug's non-essential regions to find modifications that prevented Vats from interacting with the drug while still allowing it to bind to its ribosomal targets and disable the bacterium.

The team found that two of the seven building blocks seemed to offer potentially interesting sites for modification. They made variations of the drug that contained tweaks in those regions and found that these variations had activity in dozens of strains of pathogenic bacteria. The researchers also tested their most promising candidate against streptogramin-resistant S. aureus in infected mice, and found it was over 10 times more effective than other streptogramin antibiotics.

Seiple points out that the knowledge gained through these collaborative experiments can be applied to modifying many other antibiotics.

"We learned about mechanisms that other classes of antibiotics use to bind to the same target," he said. "In addition, we established a workflow for using chemistry to overcome resistance to antibiotics that haven't reached their potential."

Seiple will continue to refine these synthetic streptogramins and then hopes to move the work to the private sector where the reengineered antibiotics could be further developed and tested in human trials. He and Fraser plan to continue working together on reviving other antibiotics that have been shelved because of microbial resistance, refining a set of tools that can help researchers stay one step ahead of bacterial evolution.

"It's a never-ending arms race with bacteria," said Fraser. "But by studying the structures involved--before resistance arises--we can get an idea of what the potential resistance mechanisms will be. That insight will be a guide to making antibiotics that bacteria can't resist."

What The Study Did: The potential use of red blood cell distribution width for risk stratification of patients with COVID-19 was looked at in this observational study.

Authors: John M. Higgins, M.D., and Jonathan C. T. Carlson, M.D., Ph.D., of Massachusetts General Hospital and Harvard Medical School in Boston, are the corresponding authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.22058)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

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The warmer it gets, the faster Antarctica loses ice - and much of it will then be gone forever. Consequences for the world's coastal cities and cultural heritage sites would be detrimental, from London to Mumbai, and from New York to Shanghai. That's what a team of researchers from the Potsdam Institute for Climate Impact Research, Potsdam University and New York's Columbia University has found out in their new study, published in Nature (cover story), on how much warming the Antarctic Ice Sheet can survive. In around one million hours of computation time, their unprecedentedly detailed simulations delineate where exactly and at which warming levels the ice would become unstable and eventually melt and drain into the ocean. They find a delicate concert of accelerating and moderating effects, but the main conclusion is that unmitigated climate change would have dire long-term consequences: If the global mean temperature level is sustained long enough at 4 degrees above pre-industrial levels, Antarctic melting alone could eventually raise global sea levels by more than six meters.

"Antarctica holds more than half of Earth's fresh water, frozen in a vast ice-sheet which is nearly 5 kilometers thick," explains Ricarda Winkelmann, researcher at the Potsdam Institute for Climate Impact Research (PIK) and University of Potsdam, and corresponding author of the study. "As the surrounding ocean water and atmosphere warm due to human greenhouse-gas emissions, the white cap on the South Pole loses mass and eventually becomes unstable. Because of its sheer magnitude, Antarctica's potential for sea-level contribution is enormous: We find that already at 2 degrees of warming, melting and the accelerated ice flow into the ocean will, eventually, entail 2.5 meters of global sea level rise just from Antarctica alone. At 4 degrees, it will be 6.5 meters and at 6 degrees almost 12 meters if these temperature levels would be sustained long enough."

Long-term change: it's not rapid, but it's forever

The paper's title refers to the complex physical phenomenon of hysteresis. In this case, that translates into irreversibility. Anders Levermann, co-author and researcher at PIK and Columbia University describes: "Antarctica is basically our ultimate heritage from an earlier time in Earth's history. It's been around for roughly 34 million years. Now our simulations show that once it's melted, it does not regrow to its initial state even if temperatures eventually sank again. Indeed, temperatures would have to go back to pre-industrial levels to allow its full recovery - a highly unlikely scenario. In other words: What we lose of Antarctica now, is lost forever."

The reasons behind this irreversibility are self-enforcing mechanisms in the ice sheets' behavior under warming conditions. Co-author Torsten Albrecht lays out: "In West Antarctica for instance, the main driver of ice loss is warm ocean water leading to higher melting underneath the ice shelves, which in turn can destabilize the grounded ice sheet. That makes glaciers the size of Florida slide into the ocean. Once temperatures cross the threshold of six degrees above pre-industrial levels, effects from the ice surface become more dominant: As the gigantic mountains of ice slowly sink to lower heights where the air is warmer, this leads to more melt at the ice surface - just as we observe in Greenland."

The fate of New York, Tokyo, Hamburg is in our hands

Ice loss and melting have accelerated significantly over the last decades in Antarctica. The authors however have explicitly not addressed the question of time scale in their work, but rather assess the critical warming levels at which parts of the Antarctic Ice Sheet become unstable. Winkelmann explains this approach: "In the end, it is our burning of coal and oil that determines ongoing and future greenhouse-gas emissions and therefore, if and when critical temperature thresholds in Antarctica are crossed. And even if the ice loss happens on long time scales, the respective carbon dioxide levels can already be reached in the near future. We decide now whether we manage to halt the warming. So Antarctica's fate really lies in our hands - and with it that of our cities and cultural sites across the globe, from Rio de Janeiro's Copacabana to Sydney's Opera House. Thus, this study really is another exclamation mark behind the importance of the Paris Climate Accord: Keep global warming below two degrees."

Levermann adds: "If we give up the Paris Agreement, we give up Hamburg, Tokyo and New York."

What The Study Did: Researchers investigated whether cannabis use during pregnancy was associated with various childhood outcomes, including cognition, social problems and brain structure.

Authors: Sarah E. Paul, B.A., and Ryan Bogdan, Ph.D., of Washington University in St. Louis, are the corresponding authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapsychiatry.2020.2902)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.