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Melatonin produced in the lungs prevents infection by novel coronavirus

The hormone acts as a barrier against SARS-CoV-2, blocking the expression of genes that encode proteins in cells serving as

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The hormone acts as a barrier against SARS-CoV-2, blocking the expression of genes that encode proteins in cells serving as viral entry points, according to a study by researchers at the University of São Paulo

By Elton Alisson | Agência FAPESP – Melatonin synthesized in the lungs acts as a barrier against SARS-CoV-2, preventing expression of genes that encode proteins in cells such as resident macrophages in the nose and pulmonary alveoli, and epithelial cells lining the alveoli, all of which are entry points for the virus. The hormone, therefore, prevents infection of these cells by the virus and inhibits the immune response so that the virus remains in the respiratory tract for a few days, eventually leaving to find another host.

The discovery by researchers at the University of São Paulo (USP), in Brazil, helps understand why some people are not infected or do not manifest symptoms of COVID-19 even when reliably diagnosed as carriers of the virus by RT-PCR. In addition, it offers the prospect of nasal administration of melatonin, in drops or as a spray, to prevent disease from developing in pre-symptomatic patients.

Pre-clinical and clinical trials will be needed to prove the therapeutic efficacy of melatonin against the virus, the researchers stress in an article on the study published in the journal Melatonin Research.

The study was supported by FAPESP.

“We showed that melatonin produced in the lung acts as a barrier against SARS-CoV-2, preventing the virus from entering the epithelium, activating the immune system and triggering the production of antibodies,” Regina Pekelmann Markus, a professor at USP’s Institute of Biosciences (IB) and principal investigator for the project, told Agência FAPESP.

“This action mechanism by pulmonary melatonin must also involve other respiratory viruses such as influenza,” she added.

Markus began researching melatonin in the 1990s. In a study involving rodents, she showed that the hormone, produced at night by the pineal gland in the brain to tell the organism daylight has gone and it should prepare for sleep, can be produced in other organs, such as the lungs.

In a study also involving rodents, published in early 2020 in the Journal of Pineal Research, Markus and collaborators showed that resident macrophages in the pulmonary airspace absorb (phagocytize) particles of pollution. This aggressive stimulus induced the production of melatonin and other molecules by the macrophages, engulfing the particulate matter in the air breathed in by the animals and stimulating mucous formation, coughing, and expectoration to expel the particles from the respiratory tract.

When they blocked melatonin synthesis by resident macrophages, the researchers observed that the particles entered the bloodstream and spread throughout the organism, even invading the brain.

Based on the finding that melatonin produced in the lungs altered the entry points for particulate matter from air pollution, Markus and collaborators decided to investigate whether the hormone performed the same function with regard to SARS-CoV-2. “If so, the virus wouldn’t be able to bind to the ACE-2 receptor on cells, enter the epithelium and infect the organism,” Markus said.

Analysis of gene expression

To test this hypothesis, the researchers analyzed 455 genes associated in the literature with COVID-19 comorbidities, interaction between SARS-CoV-2 and human proteins, and viral entry points. The genes had been identified in studies conducted, among others, by Helder Nakaya, a professor at USP’s School of Pharmaceutical Sciences (FCF) and a co-author of the study on lung melatonin.

From this group of genes, they selected 212 genes involved in viral cell entry, intracellular traffic, mitochondrial activity, and transcription and post-translation processes, to create a physiological signature of COVID-19.

Using RNA sequencing data downloaded from a public database, they quantified the level of expression of the 212 COVID-19 signature genes in 288 samples from healthy human lungs.

They then correlated these gene expression levels with a gene index that estimated the capacity of the lungs to synthesize melatonin (MEL-Index), based on their analysis of the lungs in healthy rodents. They found that the lower the index the higher the level of expression of genes that encode proteins for resident macrophages and epithelial cells.

The index also correlated negatively with genes that modify proteins in cell receptor CD147, a viral entry point in macrophages and other immune cells, indicating that normal lung melatonin production may be a natural protector against the virus.

The results were corroborated by three statistical techniques: the Pearson test, which measures the degree of linear correlation between two variables; a gene set enrichment analysis; and a network analysis tool that maps the connections among the most expressed genes so as to compare the same set of genes in different states. The latter was developed by Marcos Buckeridge, a professor at IB-USP and also a co-author of the study.

“We found that when MEL-Index was high the entry points for the virus in the lungs were closed, and when it was low these ‘doors’ were open. When the doors are shut, the virus wanders around for a time in the pulmonary airspace and then tries to escape in search of another host,” Markus said.

Because lung melatonin inhibits transcription of these genes that encode proteins for viral entry point cells, application of melatonin directly into the lungs in the form of drops or spray could block the virus. More research is required to prove that this is indeed the case, however, the researchers note.

Another idea could be to use MEL-Index, the pulmonary melatonin metric, as a prognostic biomarker to detect asymptomatic carriers of SARS-CoV-2.

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About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

Source: https://bioengineer.org/melatonin-produced-in-the-lungs-prevents-infection-by-novel-coronavirus/

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Reduced microbial stability linked to soil carbon loss in active layer under alpine permafrost degra

Credit: NIEER Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active

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Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active layer of degraded alpine permafrost on the Qinghai-Tibet Plateau (QTP).

The researchers, headed by Prof. CHEN Shengyun from the Northwest Institute of Eco-Environment and Resources (NIEER) of the Chinese Academy of Sciences (CAS), and XUE Kai from University of Chinese Academy of Sciences, conducted a combined in-depth analysis of soil microbial communities and their co-occurrence networks in the active permafrost layer along an extensive gradient of permafrost degradation.

The QTP encompasses the largest extent of high-altitude mountain permafrost in the world. This permafrost is different than high-latitude permafrost and stores massive soil carbon. An often ignored characteristic of permafrost is that the carbon pool in the active layer soil is more active and directly affected by climate change, compared to deeper layers.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

In this study, the researchers found that alpine permafrost degradation reduced the stability of active layer microbial communities as evidenced by increased sensitivity of microbial composition to environmental change, promoted destabilizing network properties and reduced resistance to node or edge attacking of the microbial network.

They discovered that soil organic carbon loss in severely degraded permafrost is associated with increased microbial dissimilarity, thereby potentially contributing to a positive carbon feedback in alpine permafrost on the QTP.

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The results were published in PNAS in an article entitled “Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation”.

This research was financially supported by the National Natural Science Foundation of China, the Strategic Priority Research Program (A) of CAS and the Second Tibetan Plateau Scientific Expedition and Research Program.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

Source: https://bioengineer.org/reduced-microbial-stability-linked-to-soil-carbon-loss-in-active-layer-under-alpine-permafrost-degra/

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SNMMI Image of the Year: PET imaging measures cognitive impairment in COVID-19 patients

Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of

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Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg.

Reston, VA–The effects of COVID-19 on the brain can be accurately measured with positron emission tomography (PET), according to research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2021 Annual Meeting. In the study, newly diagnosed COVID-19 patients, who required inpatient treatment and underwent PET brain scans, were found to have deficits in neuronal function and accompanying cognitive impairment, and in some, this impairment continued six months after their diagnosis. The detailed depiction of areas of cognitive impairment, neurological symptoms and comparison of impairment over a six-month time frame has been selected as SNMMI’s 2021 Image of the Year.

Each year, SNMMI chooses an image that best exemplifies the most promising advances in the field of nuclear medicine and molecular imaging. The state-of-the-art technologies captured in these images demonstrate the capacity to improve patient care by detecting disease, aiding diagnosis, improving clinical confidence, and providing a means of selecting appropriate treatments. This year, the SNMMI Henry N. Wagner, Jr., Image of the Year was chosen from more than 1,280 abstracts submitted to the meeting and voted on by reviewers and the society leadership.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

To study cognitive impairment associated with COVID-19, researchers carried out a prospective study on recently diagnosed COVID-19 patients who required inpatient treatment for non-neurological complaints. A cognitive assessment was performed, followed by imaging with 18F-FDG PET if at least two new neurological symptoms were present. By comparing COVID-19 patients to controls, the Freiburg group established a COVID-19-related covariance pattern of brain metabolism with most prominent decreases in cortical regions. Across patients, the expression of this pattern showed a very high correlation with the patients’ cognitive performance.

Follow-up PET imaging was performed six months after the initial COVID-19 diagnosis. Imaging results showed a significant improvement in the neurocognitive deficits in most patients, accompanied by an almost complete normalization of the brain metabolism.

“We can clearly state that a significant recovery of regional neuronal function and cognition occurs for most COVID-19 patients based on the results of this study. However, it is important to recognize the evidence of longer-lasting deficits in neuronal function and accompanying cognitive deficits is still measurable in some patients six months after manifestation of disease,” noted Blazhenets. “As a result, post-COVID-19 patients with persistent cognitive complaints should be presented to a neurologist and possibly allocated to cognitive rehabilitation programs.”

“18F-FDG PET is an established biomarker of neuronal function and neuronal injury,” stated SNMMI’s Scientific Program Committee chair, Umar Mahmood, MD, PhD. “As shown the Image of the Year, it can be applied to unravel neuronal correlates of the cognitive decline in patients after COVID-19. Since 18F-FDG PET is widely available, it may therefore aid in the diagnostic work-up and follow-up in patients with persistent cognitive impairment after COVID-19.”

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Abstract 41. “Altered regional cerebral function and its association with cognitive impairment in COVID 19: A prospective FDG PET study.” Ganna Blazhenets, Johannes Thurow, Lars Frings and Philipp Meyer, Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Nils Schroeter, Tobias Bormann, Cornelius Weiller, Andrea Dressing and Jonas Hosp; Department of Neurology and Clinical Neuroscience, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; and Dirk Wagner, Department of Internal Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

All 2021 SNMMI Annual Meeting abstracts can be found online at https://jnm.snmjournals.org/content/62/supplement_1.

About the Society of Nuclear Medicine and Molecular Imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging, vital elements of precision medicine that allow diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes.

SNMMI’s members set the standard for molecular imaging and nuclear medicine practice by creating guidelines, sharing information through journals and meetings and leading advocacy on key issues that affect molecular imaging and therapy research and practice. For more information, visit http://www.snmmi.org.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

Source: https://bioengineer.org/snmmi-image-of-the-year-pet-imaging-measures-cognitive-impairment-in-covid-19-patients/

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Scientists demonstrate promising new approach for treating cystic fibrosis

Scientists led by UNC School of Medicine researchers Silvia Kreda, Ph.D., and Rudolph Juliano, Ph.D., created an improved oligonucleotide therapy

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Scientists led by UNC School of Medicine researchers Silvia Kreda, Ph.D., and Rudolph Juliano, Ph.D., created an improved oligonucleotide therapy strategy with the potential for treating other pulmonary diseases, such as COPD and asthma

CHAPEL HILL, NC – UNC School of Medicine scientists led a collaboration of researchers to demonstrate a potentially powerful new strategy for treating cystic fibrosis (CF) and potentially a wide range of other diseases. It involves small, nucleic acid molecules called oligonucleotides that can correct some of the gene defects that underlie CF but are not addressed by existing modulator therapies. The researchers used a new delivery method that overcomes traditional obstacles of getting oligonucleotides into lung cells.

As the scientists reported in the journal Nucleic Acids Research, they demonstrated the striking effectiveness of their approach in cells derived from a CF patient and in mice.

“With our oligonucleotide delivery platform, we were able to restore the activity of the protein that does not work normally in CF, and we saw a prolonged effect with just one modest dose, so we’re really excited about the potential of this strategy,” said study senior author Silvia Kreda, PhD, an associate professor in the UNC Department of Medicine and the UNC Department Biochemistry & Biophysics, and a member of the Marsico Lung Institute at the UNC School of Medicine.

Kreda and her lab collaborated on the study with a team headed by Rudolph Juliano, PhD, Boshamer Distinguished Professor Emeritus in the UNC Department of Pharmacology, and co-founder and Chief Scientific Officer of the biotech startup Initos Pharmaceuticals.

About 30,000 people in the United States have CF, an inherited disorder in which gene mutations cause the functional absence of an important protein called CFTR. Absent CFTR, the mucus lining the lungs and upper airways becomes dehydrated and highly susceptible to bacterial infections, which occur frequently and lead to progressive lung damage.

Treatments for CF now include CFTR modulator drugs, which effectively restore partial CFTR function in many cases. However, CFTR modulators cannot help roughly ten percent of CF patients, often because the underlying gene defect is of the type known as a splicing defect.

CF and splicing defects

Splicing is a process that occurs when genes are copied out – or transcribed – into temporary strands of RNA. A complex of enzymes and other molecules then chops up the RNA strand and re-assembles them, typically after deleting certain unwanted segments. Splicing occurs for most human genes, and cells can re-assemble the RNA segments in different ways so different versions of a protein can be made from a single gene. However, defects in splicing can lead to many diseases – including CF when CFTR’s gene transcript is mis-spliced.

In principle, properly designed oligonucleotides can correct some kinds of splicing defects. In recent years the U.S. Food and Drug Administration has approved two “splice switching oligonucleotide” therapies for inherited muscular diseases.

In practice, though, getting oligonucleotides into cells, and to the locations within cells where they can correct RNA splicing defects, has been extremely challenging for some organs.

“It has been especially difficult to get significant concentrations of oligonucleotides into the lungs to target pulmonary diseases,” Kreda said.

Therapeutic oligonucleotides, when injected into the blood, have to run a long gauntlet of biological systems that are designed to keep the body safe from viruses and other unwanted molecules. Even when oligonucleotides get into cells, the most usually are trapped within vesicles called endosomes, and are sent back outside the cell or degraded by enzymes before they can ever do their work.

A new delivery strategy

The strategy developed by Kreda, Juliano, and their colleagues overcomes these obstacles by adding two new features to splice switching oligonucleotides: Firstly, the oligonucleotides are connected to short, protein-like molecules called peptides that are designed to help them to distribute in the body and get into cells. Secondly, there is a separate treatment with small molecules called OECs, developed by Juliano and Initos, which help the therapeutic oligonucleotides escape their entrapment within endosomes.

The researchers demonstrated this combined approach in cultured airway cells from a human CF patient with a common splicing-defect mutation.

“Adding it just once to these cells, at a relatively low concentration, essentially corrected CFTR to a normal level of functioning, with no evidence of toxicity to the cells,” Kreda said.

The results were much better with than without OECs, and improved with OEC dose.

There is no mouse model for splicing-defect CF, but the researchers successfully tested their general approach using a different oligonucleotide in a mouse model of a splicing defect affecting a reporter gene. In these experiments, the researchers observed that the correction of the splicing defect in the mouse lungs lasted for at least three weeks after a single treatment – hinting that patients taking such therapies might need only sporadic dosing.

The researchers now plan further preclinical studies of their potential CF treatment in preparation for possible clinical trials.

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Yan Dang, Catharina van Heusden, Veronica Nickerson, Felicity Chung, Yang Wang, Nancy Quinney, Martina Gentzsch, and Scott Randell were other contributors to this study from the Marsico Lung Institute; Ryszard Kole a co-author from the UNC Department of Pharmacology.

The Cystic Fibrosis Foundation and the National Institutes of Health supported this work.

Scientists Demonstrate Promising New Approach for Treating Cystic Fibrosis

Source: https://bioengineer.org/scientists-demonstrate-promising-new-approach-for-treating-cystic-fibrosis/

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