Culture

Researchers from the University of Helsinki, Finland, examined 48 Staffordshire Bull Terriers, of which eight dogs - four healthy and four atopic - were selected for RNA sequencing where their skin gene expression was compared between both atopic and healthy dogs as well as between dogs that ate dry food or raw food.

The diet appears to make a great difference in skin gene expression.

"Before the dietary intervention comparing atopic and healthy dogs, only a total of eight genes functioning in a range of ways in the skin were found, but the intervention increased this figure manifold. In other words, dietary intervention is extremely important for actual differences in gene expression to emerge," says researcher Johanna Anturaniemi from the Faculty of Veterinary Medicine, University of Helsinki.

The effect of the diet on skin gene expression was mostly associated with the immune system, antioxidants and inflammatory processes. Raw food appeared to activate the skin's immune defence system as well as the expression of genes that increase antioxidant production or that have anti-inflammatory effects.

"A previously conducted study also demonstrated that diets based on raw meat engender an anti-inflammatory effect on blood gene expression," Anturaniemi says.

In terms of puppyhood, the researchers consider a particularly important finding the fact that the immune defence of dogs whose diet is based on raw food is activated. What is known is that in people suffering from atopic dermatitis the development of immunity has been disturbed and that diverse exposure to microbes in childhood reduces the risk of becoming atopic.

The differences in skin gene expression between atopic and healthy dogs highlighted the possibility of deficiencies in the lipid metabolism and keratinocyte proliferation of atopic individuals. Both hold a key role in the normal functioning of the skin barrier.

Additionally, the expression of genes that boost the formation of new blood vessels, a phenomenon known to be associated with the inflammatory response of the skin, was seen to have increased in atopic dogs. The findings support those made in prior studies.

"We identified several genes whose link with canine atopic dermatitis had not been reported earlier. Some of them are associated with previously known disturbed metabolic pathways, while the role of others in atopic dermatitis requires further investigation. Since the number of dogs involved in the study was small, the results can be considered preliminary. Indeed, the aim is to confirm them at a later date by utilising the rest of the skin samples collected," Anturaniemi says.

The dietary intervention trial on Staffordshire Bull Terriers was carried out at the Faculty of Veterinary Medicine, University of Helsinki. In the trial, the dogs were divided into groups whose diet was based on either dry food or raw food for approximately four months. A total of 48 dogs were involved in the trial, of which eight were selected for RNA sequencing. Four of the eight dogs were healthy, and they represented both dietary groups equally, as did the other four dogs selected for sequencing that suffered from atopic dermatitis.

Algorithms have shown that the compositional structure of Western landscape paintings changed "suspiciously" smoothly between 1500 and 2000 AD, potentially indicating a selection bias by art curators or in art historical literature, physicists from the Korea Advanced Institute of Science and Technology (KAIST) and colleagues report in the Proceedings of the National Academy of Sciences (PNAS).

KAIST statistical physicist Hawoong Jeong worked with statisticians, digital analysts and art historians in Korea, Estonia and the US to clarify whether computer algorithms could help resolve long-standing questions about design principles used in landscape paintings, such as the placement of the horizon and other primary features.

"A foundational question among art historians is whether artwork contains organizing principles that transcend culture and time and, if yes, how these principles evolved over time," explains Jeong. "We developed an information-theoretic approach that can capture compositional proportion in landscape paintings and found that the preferred compositional proportion systematically evolved over time."

Digital versions of almost 15,000 canonical landscape paintings from the Western renaissance in the 1500s to the more recent contemporary art period were run through a computer algorithm. The algorithm progressively divides artwork into horizontal and vertical lines depending on the amount of information in each subsequent partition. It allows scientists to evaluate how artists and various art styles compose landscape artwork, in terms of placement of a piece's most important components, in addition to how high or low the landscape's horizon is placed.

The scientists started by analysing the first two partitioning lines identified by the algorithm in the paintings and found they could be categorized into four groups: an initial horizontal line followed by a second horizontal line (H-H); an initial horizontal line followed by a second vertical line (H-V); a vertical followed by horizontal line (V-H); or a vertical followed by a vertical line (V-V) (see image 1 and 2). They then looked at the categorizations over time.

They found that before the mid-nineteenth century, H-V was the dominant composition type, followed by H-H, V-H, and V-V. The mid-nineteenth century then brought change, with the H-V composition style decreasing in popularity with a rise in the H-H composition style. The other two styles remained relatively stable.

The scientists also looked at how the horizon line, which separates sky from land, changed over time. In the 16th century, the dominant horizon line of the painting was above the middle of the canvas, but it gradually descended to the lower middle of the canvas by the 17th century, where it remained until the mid-nineteenth century. After that, the horizon line began gradually rising again.

Interestingly, the algorithm showed that these findings were similar across cultures and artistic periods, even through periods dominated by a diversity in art styles. This similarity may well be a function, then, of a bias in the dataset.

"In recent decades, art historians have prioritized the argument that there is great diversity in the evolution of artistic expression rather than offering a relatively smoother consensus story in Western art," Jeong says. "This study serves as a reminder that the available large-scale datasets might be perpetuating severe biases."

The scientists next aim to broaden their analyses to include more diverse artwork, as this particular dataset was ultimately Western and male biased. Future analyses should also consider diagonal compositions in paintings, they say.

An international team led by the University of Geneva (UNIGE) has studied which types of forest, in terms of biodiversity, are the most effective in storing carbon. Inventory data from natural forests on five continents show that species diversity is optimal for equatorial and tropical rainforests, and that, conversely, in forests located in cold or dry regions, it is the abundance of trees and not their diversity that favours the recapture of CO2. The results of the study, published in Nature Communications, are valuable in defining natural strategies to combat climate change.
Global warming is stressing forests through higher mean annual temperatures, longer-lasting droughts and more frequent and extreme weather events. At the same time, forests – and the wood they produce – can trap and store carbon dioxide (CO2), they therefore play a crucial role in mitigating climate change. Trees and forests remove carbon dioxide from the atmosphere and convert it to carbon during photosynthesis, which they then store in the form of wood and vegetation, a process referred to as «carbon sequestration». However, not all forests have the same capacity to capture and store carbon.

Opposite Assumptions

In recent decades, researchers have suggested that species diversity allows for denser stacking and niche compartmentalisation that promotes the abundance of trees within a forest and that this abundance increases the forest’s carbon storage capacity. But another hypothesis suggests that it is not diversity that allows tree abundance but the availability of energy substrate. Areas with higher energy content allows more trees to thrive per unit area and thus increase carbon recapture. While these two hypotheses question the scientific community on the relationship between diversity and abundance, knowing the answer could pragmatically guide the fight against CO2 emissions.
An international team around Jaime Madrigal-Gonzalez, scientific collaborator at the Institute for Environmental Sciences of the Sciences Faculty of UNIGE, investigated which of these hypotheses is more likely and under which climatic conditions one is more likely than the other. The question was addressed using inventory data from natural forests from five continents.

Forests of the Five Continents

“Having more species may not always be what is needed to achieve greater carbon storage in forests”, states Dr. Madrigal-Gonzalez. Instead, this relation only seems to prevail in the most productive forest regions of the planet that are basically restricted to equatorial and tropical rain forests, and some temperate forests – in regions where deforestation and human-induced forest fires have ravaged pristine environments lately. On the contrary, in the forests located in the coldest or driest regions on Earth, it is seemingly the abundance, promoted by productivity, that determines the diversity. Here, any increase in the number of species will not necessarily result in more trees and will not therefore have a big contribution to carbon storage.
The findings of these studies are of substantial practical relevance as they will aid decision makers identifying nature-based climate change mitigation strategies and to successfully use forests and their sequestration of carbon to reach the climate goals defined in the Paris Agreement. “Increasing climatic stress in the most productive forests of the planet could diminish or even collapse the role of diversity against climate change” says Prof. Markus Stoffel, Professor at the Institute for Environmental Sciences of the UNIGE.

Kyoto, Japan -- Scanning lasers -- from barcode scanners at the supermarket to cameras on newer smartphones -- are an indispensable part of our daily lives, relying on lasers and detectors for pinpoint precision.

Distance and object recognition using LiDAR -- a portmanteau of light and radar -- is becoming increasingly common: reflected laser beams record the surrounding environment, providing crucial data for autonomous cars, agricultural machines, and factory robots.

Current technology bounces the laser beams off of moving mirrors, a mechanical method that results in slower scanning speeds and inaccuracies, not to mention the large physical size and complexity of devices housing a laser and mirrors.

Publishing in Nature Communications, a research team from Kyoto University's Graduate School of Engineering describe a new beam scanning device utilizing 'photonic crystals', eliminating the need for moving parts.

Instead of arranging the lattice points of the crystals in an orderly array, the researchers found that varying the lattice points' shapes and positions caused the laser beam to be emitted in unique directions.

"What results is a lattice of photonic crystals that looks like a slab of Swiss cheese, where each crystal is calculated to emit the beam in a specific direction," explains Susumu Noda, who led the team.

"By eliminating mechanical mirrors, we've made a faster and more reliable beam-scanning device."

Photonic crystal lasers are a type of 'semiconductor laser' whose lattice points can be regarded as nanoscale antennae, which can be arranged to cause a laser beam to be emitted perpendicularly from the surface. But initially the beam would only go in a single direction on a two-dimensional plane; the team needed more area to be covered.

Arranging the antennae positions cyclically resulted in a successful direction change, but a decrease in power output and deformed shape made this solution unviable.

"Modulating the antennae positions caused light emitted from adjacent antennae to cancel each other out," continues Noda, "leading us to try changing antenna sizes."

"Eventually, we discovered that adjusting both position and size resulted in a seemingly random photonic crystal, producing an accurate beam without power loss. We called this a 'dually modulated photonic crystal'."

By organizing these crystals -- each designed to emit a beam in a unique direction -- in a matrix, the team was able to build a compact, switchable, two-dimensional beam scanner without the need for any mechanical parts.

The scientists have successfully constructed a scanner that can generate beams in one hundred different directions: a resolution of 10×10. This has also been combined with a diverging laser beam, resulting in a new type of LiDAR with enhanced scope to detect objects.

The team estimates that with further refinements, the resolution could be increased by a factor of 900: up to a 300×300 resolution range.

"At first there was a great deal of interest in whether a structure that is seemingly so random could actually work," concludes Noda. "We now believe that eventually we will be able to develop a LiDAR system small enough to hold on a fingertip."

New Rochelle, NY, November 12, 2020--Future human missions to Mars depend on field research in an environment similar to that of Mars. It will enable the evaluation of operational concepts and optimization of strategies. The goals and results of the AMADEE-18 Mars analog mission are detailed in a special collection of articles in the peer-reviewed journal Astrobiology. Click here to read the articles now.

The AMADEE-18 expedition was designed in preparation for future human missions to the Mars surface. The mission took place in the Dhofar Desert in the Sultanate of Oman and was directed by a Mission Support Center in Austria. Brief descriptions of some of the papers in the collection follow.

A comprehensive overview of the mission, describing its technical and organizational infrastructure, is provided by Gernot Groemer, Austrian Space Forum, and coauthors. They describe the proposed workflow for coordinating the timing and location of the instruments and experiments. "In validation of this workflow, the decision-making interaction between the field and the Mission Support Center was studied," state the authors.

A performance metrics analysis is presented by Sophie Gruber, Austrian Space Forum, and coauthors. Their aim is to develop a benchmarking tool for mission planning and evaluation. "We propose a method to compare analog missions across agencies, disciplines, and complexities/fidelities to improve scientific output and mission safety and maximize effectiveness and efficiency," say the authors.

Methods to localize an unmanned aerial vehicle on Mars, such as an autonomous helicopter, were tested by Eren Allak, University of Klagenfurt, and coauthors. "In the absence of a global positioning system, a computationally efficient localization technology that can be applied on Mars is visual-inertial odometry (VIO). The AMADEE-18 mission provided an opportunity to test the feasibility of a state-of-the-art VIO algorithm and the camera in a Mars-like analog environment," state the authors.

Alzheimer's disease is the most common cause of dementia. Still incurable, it directly affects nearly one million people in Europe, and indirectly millions of family members as well as society as a whole. In recent years, the scientific community has suspected that the gut microbiota plays a role in the development of the disease. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) in Switzerland, together with Italian colleagues from the National Research and Care Center for Alzheimer's and Psychiatric Diseases Fatebenefratelli in Brescia, University of Naples and the IRCCS SDN Research Center in Naples, confirm the correlation, in humans, between an imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of the neurodegenerative disorders characteristic of Alzheimer's disease. Proteins produced by certain intestinal bacteria, identified in the blood of patients, could indeed modify the interaction between the immune and the nervous systems and trigger the disease. These results, to be discovered in the Journal of Alzheimer's Disease, make it possible to envisage new preventive strategies based on the modulation of the microbiota of people at risk.

The research laboratory of neurologist Giovanni Frisoni, director of the HUG Memory Centre and professor at the Department of Rehabilitation and Geriatrics of the UNIGE Faculty of Medicine, has been working for several years now on the potential influence of the gut microbiota on the brain, and more particularly on neurodegenerative diseases. &laquoWe have already shown that the gut microbiota composition in patients with Alzheimer's disease was altered, compared to people who do not suffer from such disorders,» he explains. &laquoTheir microbiota has indeed a reduced microbial diversity, with an over-representation of certain bacteria and a strong decrease in other microbes. Furthermore, we have also discovered an association between an inflammatory phenomenon detected in the blood, certain intestinal bacteria and Alzheimer's disease; hence the hypothesis that we wanted to test here: could inflammation in the blood be a mediator between the microbiota and the brain? »

The brain under influence

Intestinal bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways: they can indeed influence the regulation of the immune system and, consequently, can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of people with Alzheimer's disease. In addition, the intestinal microbiota produces metabolites - in particular some short-chain fatty acids - which, having neuroprotective and anti-inflammatory properties, directly or indirectly affect brain function.

&laquoTo determine whether inflammation mediators and bacterial metabolites constitute a link between the gut microbiota and amyloid pathology in Alzheimer's disease, we studied a cohort of 89 people between 65 and 85 years of age. Some suffered from Alzheimer's disease or other neurodegenerative diseases causing similar memory problems, while others did not have any memory problems,» reports Moira Marizzoni, a researcher at the Fatebenefratelli Center in Brescia and first author of this work. &laquoUsing PET imaging, we measured their amyloid deposition and then quantified the presence in their blood of various inflammation markers and proteins produced by intestinal bacteria, such as lipopolysaccharides and short-chain fatty acids.»

A very clear correlation

&laquoOur results are indisputable: certain bacterial products of the intestinal microbiota are correlated with the quantity of amyloid plaques in the brain,» explains Moira Marizzoni. &laquoIndeed, high blood levels of lipopolysaccharides and certain short-chain fatty acids (acetate and valerate) were associated with both large amyloid deposits in the brain. Conversely, high levels of another short-chain fatty acid, butyrate, were associated with less amyloid pathology.»

This work thus provides proof of an association between certain proteins of the gut microbiota and cerebral amyloidosis through a blood inflammatory phenomenon. Scientists will now work to identify specific bacteria, or a group of bacteria, involved in this phenomenon.

A strategy based on prevention

This discovery paves the way for potentially highly innovative protective strategies - through the administration of a bacterial cocktail, for example, or of pre-biotics to feed the &laquogood» bacteria in our intestine. &laquoHowever, we shouldn't be too quick to rejoice,» says Frisoni. &laquoIndeed, we must first identify the strains of the cocktail. Then, a neuroprotective effect could only be effective at a very early stage of the disease, with a view to prevention rather than therapy. However, early diagnosis is still one of the main challenges in the management of neurodegenerative diseases, as protocols must be developed to identify high-risk individuals and treat them well before the appearance of detectable symptoms.» This study is also part of a broader prevention effort led by the UNIGE Faculty of Medicine and the HUG Memory Centre.

A team of immunology experts from research organisations in Belgium and the UK have come together to apply their pioneering research methods to put individuals' COVID-19 response under the microscope. Published today in the journal Clinical and Translational Immunology, their research adds to the developing picture of the immune system response and our understanding of the immunological features associated with the development of severe and life-threatening disease following COVID-19. This understanding is crucial to guide the development of effective healthcare and 'early-warning' systems to identify and treat those at risk of a severe response.

One of the most puzzling questions about the global COVID-19 pandemic is why individuals show such a diverse response. Some people don't show any symptoms, termed 'silent spreaders', whereas some COVID-19 patients require intensive care support as their immune response becomes extreme. Age and underlying health conditions are known to increase the risk of a severe response but the underlying reasons for the hyperactive immune response seen in some individuals is unexplained, although likely to be due to many factors contributing together.

To investigate the immune system variations that might explain the spectrum of responses, teams of researchers from the VIB Centre for Brain and Disease Research and KU Leuven in Belgium and the Babraham Institute in the UK worked with members of the CONTAGIOUS consortium to compare the immune system response to COVID-19 in patients showing mild-moderate or severe effects, using healthy individuals as a control group.

Professor Adrian Liston, senior group leader at the Babraham Institute in the UK, explains: "One of our main motivations for undertaking this research was to understand the complexities of the immune system response occurring in COVID-19 and identify what the hallmarks of severe illness are. We believe that the open sharing of data is key to beating this challenge and so established this data set to allow others to probe and analyse the data independently."

The researchers specifically looked at the presence of T cells - immune cells with a diverse set of functions depending on their sub-type, with 'cytotoxic' T cells able to kill virus-infected cells directly, while other 'helper' T cell types modulate the action of other immune cells. The researchers used flow cytometry to separate out the cells of interest from the participants' blood, based on T cell identification markers, cell activation markers and cytokine cell signalling molecules.

Surprisingly, the T cell response in the blood of COVID-19 patients classified as severe showed few differences when compared to healthy volunteers. This is in contrast to what would usually be seen after a viral infection, such as the 'flu. However, the researchers identified an increase in T cells producing a suppressor of cell inflammation called interleukin 10 (IL-10). IL-10 production is a hallmark of activated regulatory T cells present in tissues such as the lungs. While rare in healthy individuals, the researchers were able to detect a large increase in the number of these cells in severe COVID-19 patients.

Potentially, monitoring the level of IL-10 could provide a warning light of disease progression, but the researchers state that larger-scale studies are required to confirm these findings.

"We've made progress in identifying the differences between a helpful and a harmful immune response in COVID-19 patients. The way forward requires an expanded study, looking at much larger numbers of patients, and also a longitudinal study, following up patients after illness. This work is already underway, and the data will be available within months," says Professor Stephanie Humblet-Baron, at the KU Leuven in Belgium.

"This is part of an unprecedented push to understand the immunology of COVID-19", concludes Professor Liston. "Our understanding of the immunology of this infection has progressed faster than for any other virus in human history - and it is making a real difference in treatment. Clinical strategies, such as switching to dexamethasone, have arisen from a better understanding of the immune pathology of the virus, and survival rates are increasing because of it".

New Rochelle, NY, November 11, 2020--New data highlight safety concerns for the replication of recombinant adeno-associated viral (rAAV) vectors commonly used in gene therapy. These findings, which emphasize the need for mobilization resistant AAV vectors, are reported in the peer-reviewed journal Human Gene Therapy. Click here to read the full-text article free through December 11, 2020.

The risk of rAAV mobilization has been underappreciated in the AAV research community.

"The data generated herein highlight the potential of rAAV vector production in treated patients upon subsequent wtAAV and helper virus infection," state Matthew Hirsch, PhD, University of North Carolina at Chapel Hill, and coauthors. "They raise safety concerns for the treated individual and for the unintended animal and human populations in general."

"Viral gene therapy vectors are, by their nature, viruses capable of replicating as viruses under certain conditions. These studies help to define the conditions under which that might occur in patients receiving rAAV vectors," according to Editor-in-Chief of Human Gene Therapy Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School.

According to the Centers for Disease Research, 1 in 54 children is diagnosed with autism spectrum disorder (ASD) each year, and the number has been rising. The disease causes perplexing, lifelong developmental disabilities, which usually arise during early childhood and affect social skills, communication, personal relationships, and self-control.

In new research appearing in the journal mSphere, Rosa Krajmalnik-Brown, James Adams and their colleagues highlight the crucial importance of bacterial microbes in the human gut for the diagnosis and treatment of ASD.

Autism is considered a "spectrum disorder," characterized by a range of stereotypic behaviors that can affect people to varying degrees. While genetic correlates have been implicated, the full panoply of underlying causes of ASD remain murky. Despite the prevalence of the disease and its profound societal impact, no effective FDA-approved treatment for the disorder currently exists.

In earlier studies, the researchers observed the effects on ASD symptoms following the use of a revolutionary approach, known as microbial transfer therapy (MTT). The procedure, in which gut microbiota from healthy donors are transplanted into ASD patients over a period of 7-8 weeks, produced marked alterations in the ASD gut, improving both gastrointestinal and behavioral symptoms of the disease. Remarkably, symptom improvement continued for two years after completion of the study.

The new research takes a closer look at plasma and fecal metabolites altered through MTT. According to Krajmalnik Brown, Professor at ASU's School of Sustainable Engineering and the Built Environment, researcher in the Biodesign Swette Center for Environmental Biotechnology and Director of the newly formed Biodesign Center for Health Through Microbiomes, "looking at metabolites is important because it can help us understand how microorganisms affect gastrointestinal symptoms and behavior. They can also be used as biomarkers."

Indeed, analysis of 619 plasma metabolites in the new study showed a distinctive metabolic profile in ASD children prior to the MTT procedure. Careful investigation of metabolites in blood and feces, as opposed to simply tabulating microbial species in the gut, is crucial when trying to tease out the complex bacterial interactions, which can form both collaborative and competing networks, depending on the particulars of their environment.

Following the procedure, levels of key metabolites in plasma became more similar to levels in typically-developing children, suggesting that this was a result of adjusting the constellation of bacteria to more closely resemble conditions in the normal healthy gut, including a marked increase in microbial diversity.

The new research highlights significant metabolic changes in plasma samples and more modest alterations in fecal samples. "It was exciting to identify many differences in metabolite levels between children with autism and typically developing children, and to observe that many of the metabolite levels improved after microbiome transplant," says Adams, a Professor at ASU's School for Engineering of Matter, Transport and Energy and Director the Autism/Asperger's Research Program at ASU.

Further research will help advance the understanding of the complex and vital interactions between the gut microbiome and neurological features associated with ASD and help fine-tune MTT therapy or other microbial based therapies, for greater effectiveness in mitigating symptoms of ASD.

WASHINGTON (Nov. 13, 2020) -- Researchers at Georgetown University Medical Center have successfully used molecules comprised of small strands of RNA to shut down the production of destructive proteins generated by the COVID-19 virus. Additionally, the researchers are working to aerosolize the RNA molecules so that they could be incorporated in an inhalable drug that would mitigate viral chaos. The finding appears online today in Gene Therapy.

A key to the Georgetown research efforts was the use of either microRNA (miRNA) or silencing RNA (siRNA, also known as small interfering RNA), both of which are RNA molecules. These molecules can guide the ultimate expression of how protein production occurs in a virus. And it is the proteins produced by SARS-CoV-2 (the virus that causes COVID-19) that wreak havoc in people.

SARS-CoV-2 bears biological similarities to other respiratory viruses, such as the seasonal flu. The use of Tamiflu® (oseltamivir) to treat and prevent infection from the flu has proved to be helpful in lessening flu symptoms and its lethality in some people.

"We believe that our approach suppresses viral protein production and could be used against virtually any respiratory virus," says G. Ian Gallicano, PhD, associate professor in the Department Biochemistry and Molecular and Cellular Biology at Georgetown University Medical Center. "Because of our results, Georgetown University has filed a patent application on on the siRNA sequences that were shown to have the best effect on viral protein suppression."

Another key to the researcher's effort was the fact that miRNAs and siRNAs can be made fat-soluble, making them more easily absorbed using sprays into nasal passages lined with mucous membranes. Non-soluble fat compounds have been found to irritate nasal passages if inhaled.

While Tamiflu is a pill that can help control the flu, the Georgetown researchers' proposed drug has a tougher disease to try to control and thus its mechanism of action would be different. An aerosolized RNA-targeting agent against SARS-CoV-2 would interfere with the production of the protein spikes associated with the infectivity of the virus and thereby reduce subsequent viral spreading.

The scientist's viral strategy is based on research Gallicano and his collaborators have been conducting to treat heart failure, which uses miRNA to target genes that can affect the heart's ability to function well. Modifying this cardiac approach, the researchers showed that miRNAs and siRNAs can target messenger RNA inside a virus. As SARS-CoV-2 uses messenger RNA to generate the proteins necessary for multiplication and infection, the ability to target viral machinery within cells via siRNA, in particular, could help shut the virus down, noted Gallicano.

The scientists tested their approach using two types of cells in the lab, including one type of cell from a human windpipe (trachea). Against tracheal and non-tracheal cells, the researchers used siRNAs and found that they could suppress protein function in a dose-dependent manner, which they subsequently found was due to messenger RNA degradation.

The researchers investigated if miRNAs and siRNAs would shut down production of proteins vital to a healthy cell. Through a series of experiments, they found that there were fewer 'off-target' effects using siRNA compared to miRNA; off-target effects can cause normal cells to go haywire.

"If our approach proves successful in future experiments, we are confident this technology can be quickly moved from bench to bedside," concludes Gallicano.

While COVID-19 infected patients should be treated with standard anticoagulation therapies, such as blood thinning medication, a new study by researchers at the George Washington University (GW) shows that anticoagulating patients at higher doses, without traditional medical indications to do so, may be ineffective and even harmful. The study was published in the journal Thrombosis Research.

"COVID-19 patients appear to have an increased incidence of blood clots. Many hospitals and health care providers began to use high doses of blood thinners to prevent these clots or treat them preemptively," said Juan Reyes, MD, MPH, co-author of the study and director of hospital medicine at the GW School of Medicine and Health Sciences (SMHS). "We wanted to review the data of our subset of COVID-19 patients treated with blood thinners to determine if the higher-dose medication was helpful."

The research team evaluated 402 patients diagnosed with COVID-19 admitted to GW Hospital between March 15 and May 31, 2020. Clinical outcomes were compared between 152 patients treated with high-dose blood thinners, and 250 patients treated with the standard low-dose blood thinners, typically prescribed to hospitalized medical patients. "Our findings did not demonstrate any additional benefit for those treated with higher doses of blood thinners above and beyond the standard of care," said Shant Ayanian, MD, MS, co-author and assistant professor of medicine at GW SMHS.

"While it's true that COVID-19 patients could be dying of blood clots, the data we've evaluated does not support giving every patient a high dose of blood thinners. That's a challenge, as the benefits still remain unclear," said Lei Lynn, MD, first author of the study and assistant professor of medicine at GW SMHS. "We caution against an aggressive blood thinner regimen for everyone, unless there is clear evidence to do so."

At the beginning of the pandemic, all patients admitted with COVID-19 to the GW Hospital were treated with standard dose anticoagulation, unless contraindicated. As awareness of the elevated risk of blood clots developed, many providers began treating patients with high-dose blood thinners. At GW Hospital, for non-critically ill patients, medical teams were advised to especially consider initiating a high dose of anticoagulation if a patient's D-dimer level exceeded 3 micrograms per milliliter. The research team previously published a study finding higher levels of the biomarker D-dimer, a medical indicator found in the blood, is associated with higher odds of clinical deterioration and death from COVID-19. This study is the first of its kind to utilize D-dimer levels to analyze clinical outcomes of anticoagulation in patients who are not critically ill.

"Though we would have loved to have seen a clinical benefit to our patients from anticoagulation, our research found that higher doses of blood thinners were potentially harmful, with no clear benefits," said Karolyn Teufel, MD, co-author of the study and assistant professor of medicine at GW SMHS. "Our research highlights the challenges with treating COVID-19. So much remains unknown."

A new saliva-based test developed by a team at Johns Hopkins Bloomberg School of Public Health has been found to accurately detect the presence of antibodies to SARS-CoV-2, the virus that causes COVID-19, from small samples of saliva, according to a study led by Bloomberg School researchers. Such tests, the results of which can be obtained in a matter of hours, are seen as potential alternatives to blood-sample antibody tests for research and clinical use.

The test is based on multiple fragments, or "antigens," from the SARS-CoV-2 coronavirus, mostly from its outer spike and nucleocapsid proteins. In the study, the researchers found that their test detected antibodies to several of these antigens in saliva samples from all 24 participants who had confirmed SARS-CoV-2 exposure and whose symptoms had begun more than two weeks prior to the test. The test also reliably yielded negative results for saliva samples that had been collected from people prior to the COVID-19 pandemic.

The study appears online in the Journal of Clinical Microbiology.

"If our saliva-based assay's accuracy is borne out in larger studies, this noninvasive approach could make it easier to identify, at a population level, who has already had a SARS-CoV-2 infection and where gaps in seropositivity remain heading into the winter and beyond," says study senior author Christopher D. Heaney, PhD, MS, an associate professor with appointments in the departments of Environmental Health and Engineering, Epidemiology, and International Health at the Bloomberg School. "This could inform targeted vaccination efforts and, after vaccines start to roll out, help figure out how long vaccine-induced antibodies last--all without repeated, invasive blood draws," Heaney says.

The pandemic spread of SARS-CoV-2 has officially caused over 40 million infections and more than 1 million deaths worldwide. Many epidemiologists suspect that the actual spread of the virus has been much more extensive, but that and many other questions about the pandemic's extent and dynamics have so far been difficult or impossible to answer specifically. A relatively quick, inexpensive, noninvasive, and highly accurate antibody test could make such research much easier, however.

Heaney and colleagues previously have invented accurate saliva-based antibody tests for other disease-causing viruses including the enteric pathogen norovirus and liver-infecting hepatitis E virus.

Early in the pandemic, the research team developed a saliva-based test for SARS-CoV-2 antibodies, using a panel of 12 known viral antigens that are already used for blood-based antibody tests. Saliva samples for the test are collected by rubbing a sponge between people's teeth and gums, where saliva is known to be particularly enriched with antibodies.

That the test detected antibodies to several SARS-CoV-2 antigens in saliva samples from all 24 people who had confirmed SARS-CoV-2 exposure and whose symptoms had arisen more than two weeks before the test showed that the test could be very sensitive--that is, capable of identifying positive results.

The experiments also showed that the test could be highly specific--that is, capable of identifying those without the antibodies with a low rate of "false positives." In a set of 134 saliva samples that had been collected from people long before the COVID-19 pandemic--and thus presumed to be free of SARS-CoV-2 antibodies--several antigens in the test gave negative results in all but a few cases. Antibodies to one viral antigen seemed particularly specific: The scientists found negative results for it in all 134 of the pre-COVID-19 samples.

Saliva-based testing for immunoglobulin G antibodies to SARS-CoV-2 appeared to be just as sensitive and specific as blood-based serological testing. After SARS-CoV-2 infection, IgG antibodies typically elevate around day 10 after symptom onset, and these antibodies spill over from the blood into saliva.

The experiments on the whole have suggested that people who become infected with SARS-CoV-2 develop detectable antibodies in saliva at roughly the same time as they do in blood, about 10 days after COVID-19 symptom onset. The researchers expect that with an optimal algorithm that integrates results for just a few especially sensitive and specific antigens, their saliva-based test may be able to reliably detect SARS-CoV-2 antibodies starting around that same 10-day mark, but not earlier.

Since submitting their paper several months ago, Heaney and colleagues have been refining the test with experiments on thousands more saliva samples. They expect that their saliva-based test will be useful for future research applications, especially large-scale or longitudinal studies for which invasive and potentially painful blood-based tests could be problematic. For example:

Measuring levels of SARS-CoV-2 exposure and immunity in a given neighborhood, city, county, or state, or in a particular category of workers.

Identifying populations that might particularly benefit from focused vaccination campaigns.

Monitoring changes in antibody-positivity rates over time to help assess government or corporate risk-reduction campaigns.

Determining how long antibody levels persist in large populations following infection or vaccination.

The researchers also believe that their test is sensitive and specific enough to have potential use in clinical settings, such as screening individuals for prior SARS-CoV-2 exposures before they receive a vaccine or undergo some other medical procedure.

For clinical applications, the test would need Food and Drug Administration approval--at least emergency-use authorization--and Heaney says that with this goal in mind he and his colleagues are initiating discussions with the agency.

Two independent clinical studies – one by researchers at the Center for Cell-Based Therapy (CTC) in Ribeirão Preto, state of São Paulo (Brazil), on the monoclonal antibody eculizumab, and the other by scientists at the University of Pennsylvania in Philadelphia (USA) on an experimental drug called AMY-101 – observed a significant anti-inflammatory effect that contributed to a faster recovery by severe COVID-19 patients. The results of the two studies, which set out to compare the compounds’ therapeutic potential, are reported in an article published in Clinical Immunology.

The two medications were administered separately. The monoclonal antibody, routinely used to treat blood diseases, was tested on patients at the teaching hospital (“Hospital das Clínicas”) run by the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP). AMY-101, a candidate drug developed by US-based pharmaceutical company Amynda, was given to patients at a hospital in Milan, Italy. Both produced promising results, but because AMY-101 is cheaper and performed better in the clinical trial, the two research groups envisage testing it on a larger number of patients in Brazil.

“Both compounds caused a robust anti-inflammatory response that culminated in a fairly rapid recovery of respiratory function in the patients,” Rodrigo Calado, who led the study at FMRP-USP, told Agência FAPESP. Calado is affiliated with CTC, a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and based at FMRP-USP’s blood center.

The researchers concluded that the therapeutic benefits of eculizumab and AMY-101 were due to inhibition of a bloodstream cascade of proteins involved in immune response and known as the complement system.

Persistent dysregulated complement activation triggers the exacerbated inflammatory response to SARS-CoV-2 infection characterized by a systemic increase in pro-inflammatory cytokines and often referred to as a “cytokine storm”.

Unable to prevent infection of cells by the virus, the complement system enters a spiral of runaway continuous activation that leads to massive infiltration of monocytes and neutrophils into the infected tissues. This process can result in inflammatory damage to the walls of blood vessels surrounding vital organs, as well as disseminated microvascular injury and thrombosis, potentially culminating in multiple organ failure.

“Previous studies had shown the use of complement inhibitors to be a promising therapeutic strategy to ameliorate thromboinflammation in COVID-19 patients, and there were reports of cases with positive results,” Calado said. “However, as yet no one had elucidated the action or evaluated the efficacy of drugs already in use to treat diseases caused by complement alterations, such as eculizumab, or candidate drugs with this function such as AMY-101.”

To fill the gap the researchers conducted two clinical studies in which they compared the biological efficacy of eculizumab with that of the synthetic peptide AMY-101 in independent small groups of severe COVID-19 patients.

Ten patients aged between 18 and 80 were undergoing treatment at FMRP-USP’s Hospital das Clínicas. Once a week while hospitalized, they were given 900 mg of eculizumab, which inhibits the complement protein C5. Three patients hospitalized in Milan, Italy, were given 5 mg of AMY-101, developed to inhibit complement protein C3, also once a week. These two proteins perform the most important activities in the complement system.

The patients’ clinical responses showed that eculizumab and AMY-101 elicited a robust anti-inflammatory process, a sharp fall in levels of C reactive protein (CRP) and interleukin-6 (IL-6), and a marked improvement in lung function.

Inhibition of C3 by AMY-101 afforded broader therapeutic control, stronger lymphocyte recovery, a pronounced decline in neutrophil count, and more robust attenuation of the thromboinflammation induced by the exacerbated response to viral infection.

“The results of the clinical trials showed that inhibiting components of the complement system sharply reduces inflammation,” Calado said.

New clinical study

In light of the promising results of the two clinical trials, the CTC and UPenn researchers now plan to conduct a Phase 3 trial with more than 100 severe COVID-19 patients, who will be given only AMY-101 in an effort to assess the drug’s efficacy on a wider scale.

The study will be conducted at FMRP-USP’s Hospital das Clínicas, and will probably involve other research institutions in Brazil. “One of the advantages of AMY-101 is its low cost. It’s much less expensive than eculizumab,” Calado said.

New Rochelle, NY, November 13, 2020--Patients are seeking plastic surgery in record numbers, citing their appearance on Zoom as a cause. Of particular concern are noses and wrinkles, according to Facial Plastic Surgery & Aesthetic Medicine. Click here to read the article now.

"A life disproportionately spent on Zoom may trigger a self-critical comparative response that leads people to rush to their physicians for treatments they may not have considered before months confronting a video screen, a new phenomenon of 'Zoom Dysmorphia,'" state Arianne Shadi Kourosh, MD, Massachusetts General Hospital, and coauthors.

"The COVID-19 pandemic has radically changed the frequency with which we are confronted with our own image. The shift to online work, learning, and even socializing has dramatically increased the time we have to observe ourselves," says Benjamin Marcus, MD, University of Wisconsin Hospitals and Clinics, in an accompanying commentary.

Facial Plastic Surgery & Aesthetic Medicine Editor-in-Chief Travis T. Tollefson, MD, MPH, University of California, Davis, states: "It has always been incumbent on surgeons to understand the motivations that are driving individuals to seek plastic surgery in order to assure realistic goals that allow for successful surgeries. Now, more than ever, unique circumstances can be driving patient expectations that we should be taking into consideration."

For COVID-19, the difference between surviving and not surviving severe disease may be due to the quality, not the quantity, of the patients' antibody development and response, suggests a new Cell paper published by Galit Alter, PhD, a member of the Ragon Institute of MGH, MIT and Harvard.

The study, published in the journal Cell, used Alter's systems serology approach to profile the antibody immune responses of 193 hospitalized COVID-19 patients, comparing responses from patients with moderate and severe disease and patients who passed away from COVID-19.

While all patients developed antibodies against SARS-CoV-2, the way the antibodies developed, or evolved, differed between the three groups. For patients that didn't survive the disease, the antibody response never fully evolved.

"There was a significant defect in the development of IgG antibodies, which may be essential in the early control and elimination of the virus, " Alter says. "Here, we were able to see the global impact of this defective IgG evolution, resulting in a compromised ability to promote essential viral clearing immune functions."

In a mature immune response, antibodies both block infection and direct the immune system to kill infected cells. To guide the killer immune response, antibodies attach to the Fc-receptor, a "docking site" specific to antibodies that is found on all immune cells. Without strong Fc-receptor binding, antibodies may fail to grab and destroy virus following infection.

Compared to survivors, patients who passed from COVID-19 had antibodies that never fully developed the ability to strongly bind to Fc-receptors and therefore may not have been able to fully trigger immune killing activity.

Alter's group, led by Tomer Zohar, Carolin Loos, Stephanie Fischinger, and Caroline Atyeo, PhD, also found that survivors' immune systems could recognize and target an area of the SARS-CoV-2 spike protein known as the S2-domain. The S2 domain is found in other coronaviruses that infect humans, so patients whose antibodies can target it may have pre-existing immunity to the S2 domain because of exposure to other, common coronaviruses.

Patients with antibodies that can recognize S2 domains on different coronaviruses may be able to use this pre-existing immunity to generate killer antibodies faster and sooner following SARS-CoV-2 infection.

"If we can further understand the importance of cross-coronavirus immunity," says Zohar, "researchers may be able to design vaccines able to counteract a much broader range of coronaviruses."

With studies like these, Alter and her team are working to understand the nature of protective immunity against SARS-CoV-2, including partnering with COVID-19 vaccine developers, to help bring an end to this pandemic.