Culture

If the eyes are the mirror of the soul, then thanks to the translucent corneas, we can look deep into that soul. And thanks to the work of scientists from the IPC PAS we can look into the depths of the cornea itself. And that without touching it! All thanks to the introduction of an innovative method of holographic optical tomography.

"Our idea was to spoil the coherent laser beam illuminating the cornea, so we could significantly extend the exposure time without endangering the delicate retina. At the same time, it allows us to maintain a high value of light power, which allows us to see even a very weak light backscattered from the cornea," explains professor Wojtkowski. Additionally, the volumetric nature of the collected data allowed for the optical "flattening" of the cornea curvature and obtaining exceptionally sharp images of all its layers across the entire section. This is not an easy task, because the transparency of the cornea, although it allows to look inside the eye, does not facilitate the examination of the cornea itself.

The old methods required contact of the measuring device with the eye, and thus anaesthesia of the eyeball was mandatory, and the measurement itself - long-lasting. However, even the newer ones, using the OCT (optical coherence tomography), have limitations due to not fast enough image collection, which, when examining an unanaesthetized eye, makes the obtained image blurry due to micro-movement of the eyeball.

The breakthrough came with super-fast cameras recording tens of thousands of frames per second, which made it possible to record images at lightning speed. The problem in standard OCT was the resolution and artifacts resulting from the fact that the cornea is curved and scanning it, the laser beam is arranged slightly differently in each part. This is where the scientists from the IPC PAS come in. Their method, known as holographic OCT tomography, allows them to capture the cornea in a fraction of a second and to record its entire depth in an extremely high, unprecedented resolution. The patient will not even have time to blink, and his cornea is already imaged, with the accuracy so high that even single cells can be viewed. And if she or he even blinks (well, let's say moves the eye), the computer will compensate for this movement, still giving a sharp image.

- Moreover our new device has no moving parts, and thanks to the phase modulation of the laser beam we can use more power without harming deeper tissues of the eye," explains professor Wojtkowski.

The method developed by scientists from the International Centre for Translational Eye Research at the IPC PAS has a chance to revolutionize the diagnosis of eye diseases, not only corneas, giving doctors a tool to examine patients quickly and painlessly. Thanks to the fact that it also makes visible what is invisible in an ordinary slit lamp and is equally non-invasive, patients will gain comfort and ophthalmologists will gain incomparably more information.

According to a study published in Nature Biotechnology, the sVNT is capable of detecting the functional neutralising antibodies (NAbs) that can block the binding of the coronavirus spike protein to the angiotensin-converting enzyme 2 (ACE2) host receptor, which mimics the virus-host interaction.

The sVNT was developed by scientists from Duke-NUS Medical School, in close collaboration with National Centre for Infectious Diseases (NCID), Agency for Science, Technology and Research (A*STAR)'s Institute of Molecular and Cell Biology (IMCB) Singapore, and GenScript Biotech. The scientists in Singapore and China validated the test across two patient cohorts, with a sample size of 250 from China and 375 from Singapore, achieving 99-100 per cent specificity and 95-100 per cent sensitivity.

"The sVNT kit can detect functional NAbs in an hour and differentiate them with binding antibodies (BAbs), without the need for live virus or a biocontainment facility. It also has the ability to detect total receptor binding domain (RBD)-targeting neutralising antibodies in patient samples, in contrast to most SARS-CoV-2 antibody tests published or marketed, which are isotype-specific. This makes the sVNT accessible to the broader community for both research and clinical applications," said Professor Wang Linfa, Director of Duke-NUS' Emerging Infectious Diseases programme. Prof Wang is considered among the most recognised international experts on emerging zoonotic viruses and is currently serving on multiple WHO committees on COVID-19.

Infection or immunity to the virus is diagnosed by the presence of NAbs in a patient's blood sample, which would block the RBD-ACE2 interaction. At this critical moment of the international response to the COVID-19 outbreak, there is an urgent need for a robust serological test that detects NAbs, for accurate assessment of infection prevalence and protective immunity at the individual and population level. Antibody tests, such as the conventional virus neutralization test (cVNT) and the pseudovirus-based virus neutralization test (pVNT), remain the only platforms for detecting NAbs. However, both require live viruses and cells, highly skilled operators, and days to obtain results. Other assays, such as the enzyme-linked immunosorbent assay (ELISA) detect Babs but are unable to differentiate between BAbs and NAbs.

The sVNT can also measure NAbs from different animals in a species-independent manner. It can therefore be a powerful tool to investigate the role of animals in the transmission of COVID-19 from natural reservoirs to intermediate hosts.

"It is an increasingly critical clinical question about what proportion of patients with COVID-19 develop antibodies to COVID-19, how long it lasts, and whether antibodies protect patients from reinfection. Neutralising antibody is the gold-standard serological platform to determine this. Unfortunately, the conventional virus neutralisation assay is laborious, time-consuming and requires Biosafety Level 3 for COVID-19. The sVNT developed by Prof Wang, in collaboration with the national COVID-19 PROTECT study, makes it accessible to all hospital laboratories, and is a great advance in COVID-19 serological assays," said Associate Professor David Lye, Director, Infectious Disease Research and Training Office (IDRTO), and Senior Consultant, NCID.

Dr Sidney Yee, CEO of A*STAR's Diagnostics Development Hub, said, "Due to the SARS outbreak in 2003, researchers in Singapore have gained important insights into that virus, which shares some similarities with SARS-Cov-2. A*STAR supported the clinical tests in this collaboration with Duke-NUS by sharing data drawn from our research experience in SARS. We are happy to have contributed to the validation of this innovative test, which will be instrumental in our fight against the global pandemic."

"We are very pleased that Prof Wang's work has come to fruition," said Mr David Martz, Vice President of New Product Management, Life Sciences Group, at GenScript. "This is great news for scientists researching herd immunity and vaccine efficacy as they will now have access to this innovative research tool to accurately determine the level of neutralising antibodies in a population. We believe the test will shed new light on the current plaguing mysteries of COVID-19."

The sVNT kit is commercialised by GenScript and offered worldwide under the brand cPass™ for research use only. GenScript has also filed for Emergency Use Authorisation with the US Food and Drug Administration and this filing is currently under review.

Researchers at Lund University in Sweden have discovered a new method to treat human herpes viruses. The new broad-spectrum method targets physical properties in the genome of the virus rather than viral proteins, which have previously been targeted. The treatment consists of new molecules that penetrate the protein shell of the virus and prevent genes from leaving the virus to infect the cell. It does not lead to resistance and acts independently of mutations in the genome of the virus. The results are published in the journal PLOS Pathogenes.

Herpes virus infections are lifelong, with latency periods between recurring reactivations, making treatment difficult. The major challenge lies in the fact that all existing antiviral drugs to treat herpes viruses lead to rapid development of resistance in patients with compromised immune systems where the need for herpes treatment is the greatest (e.g. newborn children, patients with HIV, cancer or who have undergone organ transplantation).
Both the molecular and physical properties of a virus determine the course of infection. However, the physical properties have so far received little attention, according to researcher Alex Evilevitch.

"We have a new and unique approach to studying viruses based on their specific physical properties. Our discovery marks a breakthrough in the development of antiviral drugs as it does not target specific viral proteins that can rapidly mutate, causing the development of drug resistance - something that remains unresolved by current antiviral drugs against herpes and other viruses. We hope that our research will contribute to the fight against viral infections that have so far been incurable", says Alex Evilevitch, Associate Professor and senior lecturer at Lund University who, together with his research team, Virus Biophysics, has published the new findings.

The virus consists of a thin protein shell, a capsid, and inside it lies its genome, the genes. Alex Evilevitch has previously discovered that the herpes virus has high internal pressure because it is tightly packed with genetic material.

"The pressure is 20 atmospheres, which is four times higher than in a champagne bottle and this allows herpes viruses to infect a cell by ejecting its genes at high speed into the cell nucleus after the virus has entered the cell. The cell is then tricked into becoming a small virus factory that produces new viruses that can infect and kill other cells in the tissue, leading to different disease states", explains Alex Evilevitch.

He, with the help of preclinical studies at the National Institutes of Health in the United States, has identified small molecules that are able to penetrate the virus and "turn off" the pressure in the genome of the virus without damaging the cell. These molecules proved to have a strong antiviral effect that was several times higher than the standard treatment against certain herpes types with the drug Aciclovir, as well as against resistant herpesvirus strains where Aciclovir does not work. The approach prevented viral infection.

Since all types of herpes viruses have similar structure and physical properties, this antiviral treatment works on all types of viruses within the herpes family.

"The drugs available today for combatting viral infections are highly specialised against the viral proteins, and if the virus mutates, which regularly occurs, the drug is rendered ineffective. However, if you succeed in developing a treatment that attacks the physical properties of a virus, such as lowering the pressure inside the herpes virus shell, it should be possible to counter many different types of viral infections within the same virus family using the same drug. In addition, it would work even if the virus mutates because the mutations do not affect the internal pressure of the herpes virus.

"The result of the present study is a first step towards the goal of developing a drug and we already have positive preliminary data showing that a herpes infection can be stopped for all types of herpes virus including the resistant strains."

A UB study published in the journal Neurotherapeutics has validated a new pharmacological target for Alzheimer's disease. The results show the inhibition of the enzyme soluble epoxide hydrolase (sEH) in murine models with the disease reduces the neuroinflammatory process, improving the endogen response of the organism and reducing the neuronal damage and death that cause this type of dementia.

These results confirm the role of this enzyme in the evolution of Alzheimer's disease and pinpoint its inhibition as a potential strategic target for this disease and for others that feature neuroinflammation.

The new study is led by the lecturers of the Faculty of Pharmacy and Food Sciences Mercè Pallàs (Institute of Neurosciences), Santiago Vázquez (Institute of Biomedicine of the UB - IBUB) Carles Galdeano (IBUB), and Christian Griñán-Ferré (Institute of Neurosciences of the University of Barcelona - UBNeuro). Other participants are the experts of the Institute of Biomedical Research of Barcelona (IIBB) -- from CSIC and IDIBAPS--, the Autonomous University of Barcelona, the University of Santiago de Compostela and the California Davis University.

A strategy focused on inflammatory processes

The drugs that are currently used to treat Alzheimer's disease have a limited efficiency and only in light phases of the disease. The therapeutic strategies of the last years have been specifically targeted at counterbalancing molecular paths such as the accumulation of amyloid beta and the formation of plaques in the brain, typical in this pathology. In the study, researchers used a new approach related to the inflammatory processes that contribute to unchain this disease and shape its pathogenesis. "It is important to expand the research on the therapy to treat Alzheimer's towards new pharmacological targets, preferably related to pathophysiological pathways of the disease. In this case, our interest lied on sEH, since its inhibition showed powerful anti-inflammatory effects and some of its inhibitors were or had been in clinical phases in the treatment for hypertension, anti-inflammatory processes and neuropathic pain", notes Mercè Pallàs.

The enzyme sEH is present in the whole organism and which is relatively abundant in the murine and human brains. This enzyme makes the epoxyeicosatrienoic acids (EETs), molecules that reduce the inflammatory response under pathological conditions such as hypertension or diabetes, lose their anti-inflammatory activity and can even cause inflammation. Given these background, researchers analysed the effects of the inhibition of she in two animal models with Alzheimer's disease, one regarded as familiar Alzheimer's and the other linked to the progress of the disease with advanced ages. The first part of the study showed that the expression of this enzyme increased in two animal models -compared to the control group- as well as in brain samples from patients with Alzheimer's. "These findings make the sEH to be linked to the progression of Alzheimer's and we can consider it to be a new pharmacological target", notes the researcher.

Drugs with neuroprotector effects

Once the sEH enzyme was considered a new therapeutic target, researchers validated it using three sEH inhibitors structurally different, one of them designed and synthetized by the group led by Santiago Vázquez. The results showed that all the used compounds, regardless of their chemical structure, were able to prevent cognitive deterioration in both animal models. "The oral treatment with different drugs allowed us to stop the cognitive damage and reduced all markers of the disease, such as the accumulation of amyloid plaques, tau phosphorylation, endoplasmic reticulum stress, and oxidative stress", notes Mercè Pallàs.

Moreover, the new therapeutic strategy can have implications in the treatment of other pathologies. "sEH leading to an increase of endogen antiinflamatory defenses in the organism means the inhibitors of the enzyme can be an appropriate, efficient and safe therapy in pathologies that feature inflammation", notes Santiago Vázquez. The researcher adds that they are assessing new inhibitors of sEH patented by the University of Barcelona not only in models for Alzheimer's disease but also in models of Niemann-Pick type C disease, neuropathic pain and acute pancreatitis, all of them with an important inflammatory element.

Dublin, Friday, 24 July 2020: The COVID-19 pandemic is a catalyst to accelerate the adoption of technology-enabled patient care for epilepsy, according to a new study published in Epilepsia.

Building on the HSE eHealth Ireland funded Epilepsy Lighthouse Project, the research was led by FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases, hosted by RCSI University of Medicine and Health Sciences. Funding for the project has continued through the Health Research Board (HRB) Applied Partnership Award.

The study describes an electronic patient portal for people with epilepsy that has been developed for patients in Ireland. Named PiSCES (providing individualised services and care for people with epilepsy), the portal is linked to the Irish National Epilepsy Electronic Patient Record.

PiSCES gives people access to their medical record documenting their epilepsy care anywhere there is an internet connection using a smartphone, tablet device or desktop computer. Users of PiSCES can access their clinic visit summaries and tools to report outcomes, such as frequency of seizures. The portal also allows people to track epilepsy care goals and send secure messages directly to their healthcare provider.

"Our work on the development of PiSCES patient portal for epilepsy began before the COVID-19 crisis with the aim of facilitating better patient and family-centred epilepsy care by improving the link between people with epilepsy and their clinicians," commented Mary Fitzsimons, eHealth Lead at FutureNeuro, RCSI.

"The COVID-19 pandemic has increased the urgency to accelerate much needed health service reform to implement innovations such as electronic patient portals. PiSCES has the capability to transform out-patient care for people with epilepsy, by maximizing health service resources that may be constrained in the aftermath of the pandemic.

"In the aftermath of COVID-19, it is highly unlikely that the healthcare sector will return to a 'business as usual' way of delivering services as we knew them previously. The pandemic is has been a catalyst for change in how patient care will be conducted in the future, delivering technology-enables care that is more responsive to individual patient needs and preferences," she said.

The research was carried out in collaboration with the Health Service Executive (HSE), Beaumont Hospital, St James's Hospital, DCU and Ergo. Dr Kevin Power, Research Engineer at RCSI and Futureneuro is first author on the paper.

Brendan Dunleavy, Head of Software Development Ergo Group said, "We are delighted to be part of this group that looks to utilise cloud and web technology to help support people with epilepsy. This is another step on the path to a true patient-centric approach to delivering acute clinical care services.

We have seen that COVID-19 has been an accelerator for technology adoption across industries and healthcare has been no exception. We look forward to seeing this work being used as an exemplar of empowering people with epilepsy."

TROY, N.Y. -- In a test of antiviral effectiveness against the virus that causes COVID-19, an extract from edible seaweeds substantially outperformed remdesivir, the current standard antiviral used to combat the disease. Heparin, a common blood thinner, and a heparin variant stripped of its anticoagulant properties, performed on par with remdesivir in inhibiting SARS-CoV-2 infection in mammalian cells.

Published online today in Cell Discovery, the research is the latest example of a decoy strategy researchers from the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselear Polytechnic Institute are developing against viruses like the novel coronavirus that spawned the current global health crisis.

The spike protein on the surface of SARS-CoV-2 latches onto the ACE-2 receptor, a molecule on the surface of human cells. Once secured, the virus inserts its own genetic material into the cell, hijacking the cellular machinery to produce replica viruses. But the virus could just as easily be persuaded to lock onto a decoy molecule that offers a similar fit. The neutralized virus would be trapped and eventually degrade naturally.

Previous research has shown this decoy technique works in trapping other viruses, including dengue, Zika, and influenza A. To hear the researchers discuss their findings, watch this video.

"We're learning how to block viral infection, and that is knowledge we are going to need if we want to rapidly confront pandemics," said Jonathan Dordick, the lead researcher and a professor of chemical and biological engineering at Rensselaer Polytechnic Institute. "The reality is that we don't have great antivirals. To protect ourselves against future pandemics, we are going to need an arsenal of approaches that we can quickly adapt to emerging viruses."

The Cell Discovery paper tests antiviral activity in three variants of heparin (heparin, trisulfated heparin, and a non-anticoagulant low molecular weight heparin) and two fucoidans (RPI-27 and RPI-28) extracted from seaweed. All five compounds are long chains of sugar molecules known as sulfated polysaccharides, a structural conformation that the results of a binding study published earlier this month in Antiviral Research suggested as an effective decoy.

The researchers performed a dose response study known as an EC50 -- shorthand for the effective concentration of the compound that inhibits 50% of viral infectivity -- with each of the five compounds on mammalian cells. For the results of an EC50, which are given in a molar concentration, a lower value signals a more potent compound.

RPI-27 yielded an EC50 value of approximately 83 nanomolar, while a similar previously published and independent in vitro test of remdesivir on the same mammalian cells yielded an EC50 of 770 nanomolar. Heparin yielded an EC50 of 2.1 micromolar, or about one-third as active as remdesivir, and a non-anticoagulant analog of heparin yielded an EC50 of 5.0 micromolar, about one-fifth as active as remdesivir.

A separate test found no cellular toxicity in any of the compounds, even at the highest concentrations tested.

"What interests us is a new way of getting at infection," said Robert Linhardt, a Rensselaer professor of chemistry and chemical biology who is collaborating with Dordick to develop the decoy strategy. "The current thinking is that the COVID-19 infection starts in the nose, and either of these substances could be the basis for a nasal spray. If you could simply treat the infection early, or even treat before you have the infection, you would have a way of blocking it before it enters the body."

Dordick added that compounds from seaweed "could serve as a basis for an oral delivery approach to address potential gastrointestinal infection."

In studying SARS-CoV-2 sequencing data, Dordick and Linhardt recognized several motifs on the structure of the spike protein that promised a fit compatible with heparin, a result borne out in the binding study. The spike protein is heavily encrusted in glycans, an adaptation that protects it from human enzymes which could degrade it, and prepares it to bind with a specific receptor on the cell surface.

"It's a very complicated mechanism that we quite frankly don't know all the details about, but we're getting more information," said Dordick. "One thing that's become clear with this study is that the larger the molecule, the better the fit. The more successful compounds are the larger sulfated polysaccharides that offer a greater number of sites on the molecules to trap the virus."

Molecular modeling based on the binding study revealed sites on the spike protein where the heparin was able to interact, raising the prospects for similar sulfated polysaccharides.

"This exciting research by Professors Dordick and Linhardt is among several ongoing research efforts at CBIS, as well as elsewhere at Rensselaer, to tackle the challenges of the COVID-19 pandemic through novel therapeutic approaches and the repurposing of existing drugs," said CBIS Director Deepak Vashishth.

Washington, DC - July 24, 2020 - A team of researchers showed that artificial intelligence (AI) could help predict the type of bacteria that caused the infection in patients with pneumonia. The research is presented at ASM Microbe Online, the annual meeting of the American Society for Microbiology.

"This research highlights the potential of AI as a supplementary tool for physicians in identifying causal pathogens of pneumonia, even before sputum culture results are available," said Joowhan Sung, M.D., hospitalist at MedStar Southern Maryland Hospital. "We demonstrated that physicians could be assisted by AI to decide appropriate antibiotics."

In the study, investigators showed that AI could use the information available in the emergency room and predict if the patient has MRSA or pseudomonas so that physicians can immediately prescribe specific antibiotics targeting specific bacteria.

Infection caused by antibiotic-resistant bacteria is difficult to treat and can be life-threatening. According to the CDC, "more than 2.8 million antibiotic-resistant infections occur, and more than 35,000 people die as a result".

Pneumonia caused by bacteria such as Methicillin-resistant Staphylococcus Aureus (MRSA) or pseudomonas can be fatal, as they are resistant to commonly prescribed antibiotics. Although there are effective antibiotics against these infections, the test, sputum culture, takes at least 48 hours to incubate and identify these bacteria from the sputum, while these patients might deteriorate within hours.

The investigators presented an analysis of more than 50,000 intensive care unit (ICU) admissions data from Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts. The researchers analyzed records of patients who were admitted with pneumonia and trained an AI, "neural network" agent using the dataset. The AI agent showed promising results in predicting bacteria that caused the infection.

"Similar techniques can be applied to future research on pneumonia amid the current pandemic, such as capturing bacterial co-infection in those with known COVID-19, which could be fatal if undetected," said Sung.

Jun Hyek Jang, M.S., senior researcher at AvoMD, Inc. and Joongheum Park, M.D., hospitalist at Beth Israel Deaconess Medical Center, also contributed to this work. This research received no external funding.

ASM Microbe Online brings you the dynamic, cutting-edge science of ASM Microbe 2020, the annual meeting of the American Society for Microbiology. Explore the latest research in the microbial sciences with ePosters, hear from experts in the field during live keynotes and access track-related content with a curated selection of on-demand sessions.

The United States should prepare for a triumphant or ascending People's Republic of China - scenarios that not only align with current PRC national development trends but also represent the most challenging future scenarios for the U.S. military, according to a new RAND Corporation report that examines China's grand strategy out to 2050.

The authors make the case that the kind of country China becomes, and the way that its military evolves, is neither foreordained nor completely beyond the influence of the United States or U.S. military. However, Beijing's intense preoccupation with internal security and deep suspicions regarding U.S. intentions toward China may frustrate attempts by Washington to improve bilateral relations and encourage more liberal domestic policies.

"The experience of COVID-19 is a prime example," said Andrew Scobell, the study's lead author and a senior political scientist at RAND, a nonprofit, nonpartisan research organization. "Beijing's secretive approach to the pandemic has exacerbated tensions with a wide array of other countries, including the United States, and contributed to economic dislocation (aka 'decoupling') between China and some of its key trading partners. While Beijing seems to have been effective in dealing with the pandemic at home, this has been accomplished through draconian and repressive measures."

To map out potential future scenarios - What will China, and its military, look like in 2050? What will U.S.-China relations look like in 2050? - researchers studied trends in the management of politics and society and analyzed the specific national-level strategies and plans that China's Communist Party rulers have put in place to further their vision of a China that is well governed, socially stable, economically prosperous, technologically advanced, and militarily powerful by 2049, the centenary of the founding of the PRC.

The report describes four possible scenarios for China at mid-century - triumphant, ascendant, stagnant and imploding - with the middle two most likely. If China proves ascendant, the U.S. military should anticipate increased risk to already threatened forward-based forces in Japan, South Korea, and the Philippines, as well as a loss of the ability to operate routinely in the air and sea space above and in the Western Pacific.

The report recommends that the U.S Army be prepared for a China whose role on the Asia-Pacific and global stages grows steadily. To prepare for military conflict in such circumstances, the U.S. Army should optimize its abilities to deter hostilities, get troops and equipment to hotspots quickly, operate from forward bases, and work with allied forces.

The U.S. could field more robust cyber and network attack capabilities and other means to counter China's unmanned aircraft systems, the authors assert. The capacity to respond quickly and effectively to China's burgeoning reconnaissance-strike system will play an important role in determining the extent to which China's leadership remains risk averse when considering military options to resolve regional disputes.

The report, conducted for the U.S. Army, is based on a review of Chinese and Western literature on the PRC's long-term strategic development and security plans and objectives, official statements by high-level Chinese officials and institutions, speeches by paramount leaders, white papers published by the Ministry of National Defense and other PRC government agencies, authoritative People's Liberation Army (PLA) texts, as well as Western and other non-Chinese analyses of these documents.

A Nature study authored by a global team of scientists and led by Sumit Chanda, Ph.D., professor at Sanford Burnham Prebys Medical Discovery Institute, has identified 21 existing drugs that stop the replication of SARS-CoV-2, the virus that causes COVID-19.

The scientists analyzed one of the world’s largest collections of known drugs for their ability to block the replication of SARS-CoV-2, and reported 100 molecules with confirmed antiviral activity in laboratory tests. Of these, 21 drugs were determined to be effective at concentrations that could be safely achieved in patients. Notably, four of these compounds were found to work synergistically with remdesivir, a current standard-of-care treatment for COVID-19.

“Remdesivir has proven successful at shortening the recovery time for patients in the hospital, but the drug doesn’t work for everyone who receives it. That’s not good enough,” says Chanda, director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. "As infection rates continue to rise in America and around the world, the urgency remains to find affordable, effective, and readily available drugs that can complement the use of remdesivir, as well as drugs that could be given prophylactically or at the first sign of infection on an outpatient basis."

Extensive testing conducted

In the study, the research team performed extensive testing and validation studies, including evaluating the drugs on human lung biopsies that were infected with the virus, evaluating the drugs for synergies with remdesivir, and establishing dose-response relationships between the drugs and antiviral activity.

Of the 21 drugs that were effective at blocking viral replication, the scientists found:

13 have previously entered clinical trials for other indications and are effective at concentrations, or doses, that could potentially be safely achieved in COVID-19 patients.

Two are already FDA approved: astemizole (allergies), clofazamine (leprosy), and remdesivir has received Emergency Use Authorization from the agency (COVID-19).

Four worked synergistically with remdesivir, including the chloroquine derivative hanfangchin A (tetrandrine), an antimalarial drug that has reached Phase 3 clinical trials.

"This study significantly expands the possible therapeutic options for COVID-19 patients, especially since many of the molecules already have clinical safety data in humans," says Chanda. "This report provides the scientific community with a larger arsenal of potential weapons that may help bring the ongoing global pandemic to heel."

The researchers are currently testing all 21 compounds in small animal models and "mini lungs," or lung organoids, that mimic human tissue. If these studies are favorable, the team will approach the U.S. Food and Drug Administration (FDA) to discuss a clinical trial(s) evaluating the drugs as treatments for COVID-19.

"Based on our current analysis, clofazimine, hanfangchin A, apilimod and ONO 5334 represent the best near-term options for an effective COVID-19 treatment," says Chanda. "While some of these drugs are currently in clinical trials for COVID-19, we believe it's important to pursue additional drug candidates so we have multiple therapeutic options if SARS-CoV-2 becomes drug resistant."

Screening one of the world's largest drug libraries

The drugs were first identified by high-throughput screening of more than 12,000 drugs from the ReFRAME drug repurposing collection—the most comprehensive drug repurposing collection of compounds that have been approved by the FDA for other diseases or that have been tested extensively for human safety.

Arnab Chatterjee, Ph.D., vice president of medicinal chemistry at Calibr and co-author on the paper, says ReFRAME was established to tackle areas of urgent unmet medical need, especially neglected tropical diseases. “We realized early in the COVID-19 pandemic that ReFRAME would be an invaluable resource for screening for drugs to repurpose against the novel coronavirus,” says Chatterjee.

The drug screen was completed as rapidly as possible due to Chanda’s partnership with the scientist who discovered the first SARS virus, Kwok-Yung Yuen, M.D., chair of Infectious Diseases at the University of Hong Kong; and Shuofeng Yuan, Ph.D., assistant research professor in the Department of Microbiology at the University of Hong Kong, who had access to the SARS-CoV-2 virus in February 2020.

NEW YORK, NY (July 24, 2020) -- The number of heart transplants in the United States declined sharply during the beginning of the pandemic, even in areas of the country with few COVID-19 cases at the time, according to an analysis by researchers at Columbia University Irving Medical Center.

The study found that the number of heart transplants performed nationwide dropped 26% during the 8-week period marking the height of the pandemic in the Northeast compared to the prior 8 weeks. The drop in transplants was similar across regions and occurred even in areas with lower infection rates.

The study was published in JAMA Cardiology.

"We had concerns that the availability of ICU beds and ventilators would impact our transplant patients, particularly in the Northeast," says Ersilia DeFilippis, MD, a postdoctoral clinical fellow in medicine and cardiology at Columbia University Vagelos College of Physicians and Surgeons and the first author of the paper.

"But we were surprised to see a decline in heart transplants in other parts of the country, where there were far fewer COVID-19 cases at that time. Our data show that this pandemic has had far-reaching impacts on the care our patients with advanced heart failure are receiving."

Heart Transplant Patients Require Many Hospital Resources

Heart transplant patients require a lot of hospital resources, DeFilippis says. "Many patients are sick enough to require hospitalization prior to transplant, often in an intensive care unit, sometimes for weeks or months. Some of these patients are supported on temporary machines to help their hearts pump blood to the body. In addition, the transplant surgery itself requires a ventilator, blood products, and significant personnel. Patients then require intensive care unit monitoring in the immediate post-transplant period."

At the beginning of the pandemic, clinicians had to weigh the risks of exposing medically fragile patients with heart failure, though well enough to remain at home, to SARS-CoV-2 infection with the risks of delaying a life-changing surgery.

DeFilippis and her colleagues found that many clinicians reacted by taking their patients off the waitlist -- a measure typically pursued when a patient encounters a health issue that temporarily or permanently disqualifies them for transplantation but was expanded during the pandemic to include patients at risk of SARS-CoV-2 infection and to accommodate transplant centers that deferred acceptance of donor organs due to the pandemic.

They found that waitlist inactivations increased 75% during the pandemic, driven largely by the Northeast. At the same time, 37% fewer people were placed on heart transplant waitlists during the pandemic, with the most significant decreases occurring in the Northeast, the Great Lakes region, and the Southwest.

In addition, the researchers found that the availability of donor hearts decreased by 26% during the COVID-19 period compared with the pre-COVID-19 period.

"It is possible that limited access to testing for donors as well as restrictions on organ procurement organizations may have contributed to the decrease we observed in donor recovery," says DeFilippis.

Next, the researchers plan to study the impact of these changes on patient survival while on the transplant waitlist and post-transplant survival.

"It will be similarly important to determine how the pandemic has affected the timing of transplant evaluations and changes in left ventricular assist device implantation. As the pandemic continues, we must be mindful of the effects of these delays on our patients," says DeFilippis.

University of Rochester researchers are setting a new standard when it comes to producing ultrafast laser pulses over a broader range of wavelengths than traditional laser sources.

In work published in Physical Review Letters, William Renninger, an assistant professor of optics, along with members of his lab, describe a new device, called the "stretched-pulse soliton Kerr resonator," that enhances the performance of ultrafast laser pulses. The work has important implications for a range of engineering and biomedical applications, including spectroscopy, frequency synthesis, distance ranging, pulse generation, and others.

The device creates an ultrafast laser pulse--on the order of femtoseconds, or one quadrillionth of a second--that's freed from the physical limits endemic to sources of laser light--what laser scientists call laser gain--and the limits of the sources' wavelengths.

"Simply put, this is the shortest pulse ever from a gain-free fiber source," Renninger says.

Renninger and his team of graduate research and postdoctoral associates improved upon Kerr resonators, an exciting new alternative for generating femtosecond laser pulses that have been the subject of considerable research.

The lab overcame a challenge to pulse duration in other versions of Kerr resonators by discovering a new soliton--a short burst or localized envelope of a wave--that maintains its shape while propagating at a constant velocity. The solitons generated in Renninger's device differ from the solitons in other Kerr resonators, specifically in the shape and behavior of the stretching pulses they create.

"It is stable in the sense it keeps repeating the same thing over and over, getting longer, then shorter, longer then shorter," Renninger says.

The pulses "feature a broad spectral bandwidth and a compressed pulse duration of 210 femtoseconds, which is the shortest pulse duration observed to date from fiber Kerr resonators," the researchers state in the paper.

Lead author Xue Dong is a graduate research associate in the Renninger lab. In addition to Renninger, other coauthors are Qian Yang and Christopher Spiess, also graduate research associates in the lab, and Victor Bucklew, a former postdoctoral associate in the lab.

The study was funded by in part by the University's Technology Development Fund, a University Research Award, and by the National Institutes of Health. A patent is pending. Interested parties can contact Curtis Broadbent, licensing manager at URVentures, about licensing the technology.

Making ultrafast lasers more accessible

Renninger, an expert in creating sources for femtosecond lasers, received his BS and PhD degrees in applied physics from Cornell University. Before joining the Institute of Optics, he was a postdoctoral associate and an associate research scientist in the Department of Applied Physics at Yale University.

He recently received a National Science Foundation CAREER award, which includes funding to create open source access to information for designing and creating advanced lasers sources generating femtosecond pulses.

"There are now commercial products, but they're very expensive. They are prohibitive for many research groups with limited budgets for equipment," Renninger says.

Much of the cost is for expertise, not components, so his group will use part of the CAREER funding to provide consulting for research groups at smaller universities in how to design and build femtosecond lasers for basic research.

"The ultimate goal is to have a design guide published on our website for everybody," Renninger says.

URBANA, Ill. - With more ethanol in production and a greater ability to upcycle co-products into animal feed ingredients, companies are creating custom products and partnering with University of Illinois researchers to test for quality and digestibility.

In a recent study published in the Journal of Animal Science, Illinois researchers show a new high-protein distillers dried grains with solubles (DDGS) product from Marquis Energy has greater energy and protein digestibility than conventional DDGS.

"We've never seen a corn co-product with such a high energy concentration or amino acid digestibility," says Hans H. Stein, professor in the Department of Animal Sciences at Illinois and co-author on the study. "It's clearly a high-value product."

The product, branded ProCap DDGS, contains 48% crude protein, far higher than conventional de-oiled DDGS, which the research team evaluated at 31% in a nutrient analysis of each ingredient. ProCap DDGS also provided approximately 1,200 kcal per kilogram of metabolizable energy more than conventional DDGS, according to the analysis.

The study consisted of three experiments. In the first, the researchers evaluated the apparent and standardized ileal digestibility of crude protein and amino acids in three diets: ProCap DDGS, conventional de-oiled DDGS (also from Marquis Energy), and a nitrogen-free diet used to determine endogenous losses of amino acids and crude protein. Vitamins and minerals were added to each diet to meet or exceed dietary requirements. The researchers fed each diet to nine growing pigs for six days at three times the maintenance energy requirement.

On the fifth and sixth days, researchers collected ileal digesta and analyzed dry matter, crude protein, and amino acids. As suggested by their nutrient analysis of the raw products, the researchers found the ProCap DDGS contained more crude protein and amino acids than de-oiled DDGS, and the standardized ileal digestibility of nearly all amino acids was greater in ProCap DDGS.

The second experiment focused on energy digestibility. In this case, the researchers evaluated three diets: corn, corn + ProCap DDGS, and corn + de-oiled DDGS. Again, all diets were supplemented with vitamins and minerals as needed. The team fed each diet to 24 growing barrows for 13 days at 3.2 times the maintenance energy requirement. Researchers calculated digestible energy and metabolizable energy values for all diets by collecting feces and urine over a four-day period during the experiment.

"If you look at the energy, which is of very high value for producers, and you compare with corn, we had much greater energy concentration in the ProCap DDGS, whereas conventional DDGS was lower than corn," Stein says.

The third experiment evaluated phosphorous digestibility. Researchers fed 32 barrows ProCap DDGS and de-oiled DDGS with or without microbial phytase. The pigs consumed these diets, along with supplemental vitamins and minerals (except phosphorus and calcium), for 13 days. Researchers collected feces from day six to day 12, and found that phytase + ProCap DDGS increased the digestibility of phosphorus. However, without phytase, phosphorus digestibility of ProCap DDGS was lower than de-oiled DDGS.

The three experiments confirm ProCap DDGS has greater amino acid digestibility and contains more metabolizable energy than de-oiled DDGS, but has reduced phosphorus digestibility.

"The ethanol industry is clearly moving toward trying to separate the different streams that come out after fermentation so they can identify high-value, high-quality products. I think we'll see even more innovation and new feed ingredients in the future thanks to more advanced technologies in ethanol plants," Stein says.

Have you ever wondered why our hands have five fingers? And what about amphibians? They usually only have four. Until now it was assumed that this was already the case with the early ancestors of today's frogs and salamanders, the Temnospondyli. However, a new find of the crocodile-like Temnospondyl Metoposaurus krasiejowensis from the late Triassic (about 225 million years old) in Poland shows five metacarpal bones and thus five fingers. As the researchers from the Universities of Bonn and Opole (Poland) note, this finding is very important, because until now, fossil animal tracks may have been wrongly assigned. The results have now been published in the Journal of Anatomy.

Modern amphibians usually have four fingers on the forelimb (and never more), which is called a "four-rayed hand", as opposed to our five-rayed hand. Of all groups of terrestrial vertebrates, amphibians show the greatest variation in the number of frontfingers Reptiles are the most conservative and usually have five. In birds, the finger bones in the wing have been lost completely. In mammals, the number of toes in the forelimb also varies greatly: Primates and raccoons have five, in horses only the third has survived, while in cattle and other even-toed ungulates fingers three and four remain. What they all have in common, however, is that this loss of toes or fingers originates from a five-ray pattern, which is why amphibians cannot be the ancestors of all these terrestrial vertebrate groups.

Exact number of toes is controversial

It has been known for some time that the earliest quadrupeds had significantly more fingers than five, such as Acanthostega, which had eight in the forelimb, or Ichthyostega with seven in the hind foot. As early as 300 million years ago, all but the five-fingered forms became extinct. The five-ray pattern was then retained in the real land animals, but was reduced again and again (see horses). The ancestors of today's amphibians, the Temnospondyli, presented contradictory evidence of skeletons with four fingers, but also tracks that had five.

Temnospondyli is an important group of the early, very diverse quadrupeds. Some temnospondyls became as big as crocodiles, others were rather small. However, like all amphibians, they were dependent on water during their larval stage. Their most famous representatives include Eryops or Mastodonsaurus. "It's also important to understand the evolution of modern amphibians, as this group probably evolved from the Temnospondyli," says Dr. Dorota Konietzko-Meier from the Institute for Geosciences at the University of Bonn, who discovered and prepared the left forelimb of a Metoposaurus krasiejowensis in Krasiejów (southwest Poland).

However, despite the long history of research, the exact number of fingers in Metoposaurus and other temnospondyls is still controversial. "It's remarkable that even in the case of the very well-researched Eryops, the skeletal reconstruction exhibited at the Muséum National d'Histoire Naturelle in Paris has five fingers, while only four fingers can be seen at the National Museum of Natural History in Washington," says Ella Teschner, a doctoral student from Bonn and Opole. Lately, science has assumed that, similar to most modern amphibians, all Temnospondyli have only four toes in their forelimbs. This resulted in the five-toed footprints common in the Permian and Triassic periods being almost automatically assumed to not belong to Temnospondyli.

"The find from the famous Upper Triassic site Krasiejów in Poland therefore offers a new opportunity to study the architecture and development of the hand of the early quadrupeds," says paleontologist Prof. Dr. Martin Sander from the University of Bonn. A considerably broader view of the entire group of Temnospondyli did not show a clear trend with regard to the five-ray pattern and suggested that the number of digits was not as limited in the phylogenetic context as was assumed. "Evidently, the temnospondyls were already experimenting with the four-ray pattern, and the five-ray pattern died out before the emergence of modern amphibians," adds Sander.

Five fingers on each hand?

"Even if the ossification of five metacarpal bones described here was only a pathology, it still shows that a five-ray pattern was possible in Temnospondyli," says Konietzko-Meier. However, it could not be assumed with certainty that the reduction in the number of fingers/digits from five to four always affected the fifth place on the hand in these fossil taxa. The possibility that some of the four-fingered taxa were caused by the loss of the first ray cannot be excluded. Sander: "The new finding of a five-fingered hand is particularly important for the interpretation of tracks, as it shows that a five-fingered forefoot print could also belong to the Temnospondyli and thus indicate a considerably wider distribution area of these animals."

These results are also of general importance, since limb development plays an important role in evolutionary biology and medicine, and fossils may therefore provide important information for the evaluation of theories of hand development.

Proteins are essential to the life of cells, carrying out complex tasks and catalyzing chemical reactions. Scientists and engineers have long sought to harness this power by designing artificial proteins that can perform new tasks, like treat disease, capture carbon, or harvest energy, but many of the processes designed to create such proteins are slow and complex, with a high failure rate.

In a breakthrough that could have implications across the healthcare, agriculture, and energy sectors, a team lead by researchers in the Pritzker School of Molecular Engineering (PME) at the University of Chicago has developed an artificial intelligence-led process that uses big data to design new proteins.

By developing machine-learning models that can review protein information culled from genome databases, the researchers found relatively simple design rules for building artificial proteins. When the team constructed these artificial proteins in the lab, they found that they performed chemistries so well that they rivaled those found in nature.

"We have all wondered how a simple process like evolution can lead to such a high-performance material as a protein," said Rama Ranganathan, Joseph Regenstein Professor in the Department of Biochemistry and Molecular Biology, Pritzker Molecular Engineering, and the College. "We found that genome data contains enormous amounts of information about the basic rules of protein structure and function, and now we've been able to bottle nature's rules to create proteins ourselves."

The results were published July 24 in the journal Science.

Using artificial intelligence to learn design rules

Proteins are made up of hundreds or thousands of amino acids, and these amino acid sequences specify the protein's structure and function. But understanding just how to build these sequences to create novel proteins has been challenging. Past work has resulted in methods that can specify structure, but function has been more elusive.

What Ranganathan and his collaborators realized over the past 15 years is that genome databases--which are growing exponentially--contain enormous amounts of information about the basic rules of protein structure and function. His group developed mathematical models based on this data and then began using machine-learning methods to reveal new information about proteins' basic design rules.

For this research, they studied the chorismate mutase family of metabolic enzymes, a type of protein that is important for life in many bacteria, fungi, and plants. Using machine-learning models, the researchers were able to reveal the simple design rules behind these proteins.

The model shows that just conservation at amino acid positions and correlations in the evolution of pairs of amino acids are sufficient to predict new artificial sequences that would have the properties of the protein family.

"We generally assume that to build something, you have to first deeply understand how it works," Ranganathan said. "But if you have enough data examples, you can use deep learning methods to learn the rules of design, even as you are understanding how it works or why it's built that way."

He and his collaborators then created synthetic genes to encode for the proteins, cloned them into bacteria, and watched as the bacteria then made the synthetic proteins using their normal cellular machinery. They found that the artificial proteins had the same catalytic function as the natural chorismate mutase proteins.

A platform to understand other complex systems

Because the design rules are so relatively simple, the number of artificial proteins that researchers could potentially create with them is extremely large.

"The constraints are much smaller than we ever imagined they would be," Ranganathan said. "There is a simplicity in nature's design rules, and we believe similar approaches could help us search for models for design in other complex systems in biology, like ecosystems or the brain."

Though artificial intelligence revealed the design rules, Ranganathan and his collaborators still don't fully understand why the models work. Next they will work to understand just how the models came to this conclusion. "There is much more work to be done," he said.

In the meantime, they also hope to use this platform to develop proteins that can address pressing societal problems, like climate change. Ranganathan and Assoc. Prof. Andrew Ferguson have founded a company called Evozyne that will commercialize this technology with applications in energy, environment, catalysis, and agriculture. Ranganathan has worked with UChicago's Polsky Center for Entrepreneurship and Innovation to file patents and license the IP to the company.

"This system gives us a platform for rationally engineering protein molecules in a way that we always dreamed we could," he said. "Not only can it teach us the physics of how proteins work and how they evolve, it can help us find solutions for issues like carbon capture and energy harvesting. Even more generally, the studies in proteins might even help teach us how the deep neural networks behind modern machine learning actually work."

HANOVER, N.H. - July 24, 2020 - Researchers at Dartmouth, in collaboration with industry partners, have developed software techniques that make lighting in computer-generated images look more realistic. The research will be presented at the upcoming ACM SIGGRAPH conference, the premier venue for research in computer graphics.

The new techniques focus on "real time" graphics which need to maintain the illusion of interactivity as scenes change in response to user moves. These graphics can be used in applications such as video games, extended reality, and scientific visualization tools.

Both papers demonstrate how developers can create sophisticated lighting effects by adapting a popular rendering technique known as ray tracing.

"Over the last decade, ray tracing has dramatically increased the realism and visual richness of computer-generated images in movies where producing just a single frame can take hours," said Wojciech Jarosz, an associate professor of computer science at Dartmouth who served as the senior researcher for both projects. "Our papers describe two very different approaches for bringing realistic ray-traced lighting to the constraints of real time graphics."

The first project, developed with NVIDIA, envisions the possibilities for future games once developers incorporate NVIDIA's hardware-accelerated RTX ray tracing platform. Recent games have started to use RTX for physically correct shadows and reflections, but quality and complexity of lighting is currently limited by the small number of rays that can be traced per frame.

The new technique, called reservoir-based spatiotemporal importance resampling (ReSTIR), creates realistic lighting and shadows from millions of artificial light sources. The ReSTIR approach dramatically increases the quality of rendering on a computer's graphics card by reusing rays that were traced in neighboring pixels and in prior frames.

The new technique can be integrated into the design of future games and works up to 65 times faster than previous rendering techniques.

"This technology is not just exciting for what it can bring to real-time applications like games, but also its impact in the movie industry and beyond," said Benedikt Bitterli, a PhD student at Dartmouth who served as the first author of a research paper on the technique.

The second project, conducted in collaboration with Activision, describes how the video game publisher has incorporated increasingly realistic lighting effects into its games.

Traditionally, video games create lighting sequences in real time using what are called "baked" solutions: the complex ray-traced illumination is computed only once through a time-consuming process. The lighting created using this technique can be displayed easily during gameplay, but it is constrained to assuming a fixed configuration for a scene. As a result, the lighting cannot easily react to the movement of characters and cameras.

The research paper describes how Activision gradually evolved its "UberBake" system from the static approach to one which can depict subtle lighting changes in response to player interactions, such as turning lights on and off, or opening and closing doors.

Since UberBake was developed over many years to work on current games, it needed to work on a variety of existing hardware, ranging from high-end PCs to previous-generation gaming consoles.

"Video games are used by millions of people around the world," said Dario Seyb, a PhD student at Dartmouth who served as the research paper's co-first author. "With so many people interacting with video games, this technology can have a huge impact."

Dartmouth researchers on both projects are affiliated with the Dartmouth Visual Computing Lab.

"These industry collaborations have been fantastic. They allow our students to work on foundational academic research informed by practical problems in industry, allowing the work to have a more immediate, real-world impact," said Jarosz.

The research papers will be published in ACM Transactions on Graphics and presented at SIGGRAPH 2020 taking place online during the summer.