bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review and meta-analysis to evaluate the clinical outcomes in COVID -19 patients on angiotensin converting enzyme inhibitors or angiotensin receptor blockers
Authors: Grover Abhinav , Oberoi Mansi
Published: May 2020

Introduction

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor upregulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence but there is need for an updated systematic review of latest clinical studies.

Methods

A search was conducted on PubMed, Google Scholar, EMBASE and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEI and/or ARB and a meta-analysis was performed.

Results

A total of sixteen studies were included for review and meta-analysis. There were conflicting findings reported in several studies as Meng J. et al, Liu Y. et al, Feng Y. et al, Zhang P. et al, Mancia G. et al and Reynolds H.R. et al reported that patients on ACE inhibitors/ARB had lower rates of severe outcomes whereas Richardson S. et al reported higher rates of invasive ventilation and intensive care unit (ICU) admissions in patients on ACE inhibitors/ARB as compared to non-users. Similarly, there were conflicting results in the rate of mortality reported in the various studies. Meng J. et al, Li J. et al, Zhang P. et al, Yang G. et al, Zeng Z. et al and Andrew Ip et al reported lower rates of mortality in ACE inhibitors/ARB users versus non-users whereas Richardson S. et al and Guo T. et al reported higher rates of mortality. In a pooled analysis of 9 studies, there was a statistically significant reduction (OR = 0.86, 95% CI = 0.75-0.99, I2 = 53.25, p value = 0.03) in the odds of death in those on ACEI/ARB as compared to patients not on ACEI/ARB. In a pooled analysis of five studies, there was a statistically non-significant reduction (OR = 0.90, 95% CI: 0.63-1.23, I2=70.36) in the odds of developing severe disease in patients on ACEI/ARB versus non-users.

Conclusion

It is concluded that ACEI and ARB should be continued in COVID-19 patients. Additionally, the individual patient factors like ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further.
Does weather affect the growth rate of COVID-19, a study to comprehend transmission dynamics on human health
Authors: Sil Arjun , Kumar Vanapalli Naveen
Published: May 2020

The undefendable outbreak of novel coronavirus (SARS-COV-2) lead to a global health emergency due to its higher transmission rate and longer symptomatic duration, created a health surge in a short time. Since Nov 2019 the outbreak in China, the virus is spreading exponentially everywhere. The current study focuses on the relationship between environmental parameters and the growth rate of COVID-19. The statistical analysis suggests that the temperature changes retarded the growth rate and found that −6.28°C and +14.51°C temperature is the favorable range for COVID-19 growth. Gutenberg-Richter’s relationship is used to estimate the mean daily rate of exceedance of confirmed cases concerning the change in temperature. Temperature is the most influential parameter that reduces the growth at the rate of 13–16 cases/day with a 1°C rise in temperature.
Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Authors: Dias David O. , Kalkitsas Jannis , Kelahmetoglu Yildiz , Estrada Cynthia P. , Tatarishvili Jemal , Ernst Aurélie , Huttner Hagen B. , Kokaia Zaal , Lindvall Olle , Brundin Lou , Frisén Jonas , Göritz Christian
Published: May 2020

Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employingin vivolineage tracing, we report that in all mouse models developing fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes.

We uncover pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation
Authors: Clawson Brittany C. , Pickup Emily J. , Enseng Amy , Geneseo Laura , Shaver James , Gonzalez-Amoretti John , Zhao Meiling , York A. Kane , Jiang Sha , Aton Sara J.
Published: May 2020

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.
Bacillus thuringiensisbioinsecticides induce developmental defects in non-targetDrosophila melanogasterlarvae
Authors: Nawrot-Esposito Marie-Paule , Babin Aurélie , Pasco Matthieu , Poirié Marylène , Gatti Jean-Luc , Gallet Armel
Published: May 2020

Bioinsecticides made from the bacteriumBacillus thuringiensis(Bt) are the best-selling bioinsecticide worldwide. AmongBtbioinsecticides, those based on the strainBt var. kurstaki(Btk) are widely used in farming to specifically control pest lepidopteran larvae. Although there is much evidence of the lack of acute lethality ofBtkproducts for non-target animals, only scarce data are available on their potential non-lethal developmental adverse effects. Using doses that could be reached in the field upon sprayings, we have shown thatBtkproducts impair growth and developmental time of the non-target dipteranDrosophila melanogaster. These effects are mediated by the synergy betweenBtkbacteria andBtkinsecticidal toxins, which induces a significant apoptosis of larval enterocytes, resulting in a decreased intestinal capacity to digest proteins. The harmful effects can be mitigated by a protein-rich diet or by adding the probiotic bacteriumLactobacillus plantaruminto the food. Finally, we showed that the larval midgut maintain its integrity uponBtkaggression thanks to both the flattening of surviving enterocytes and the generation of new immature cells arising from the adult midgut precursor cells.
Continued and Serious Lockdown Could Minimize Many Newly Transmitted Cases of COVID-19 in the U.S.: Wavelets, Deterministic Models, and Data
Authors: Srinivasa Rao Arni S.R. , Krantz Steven G.
Published: May 2020

All the newly reported COVID-19 cases of April in the U.S. have not acquired the virus in the same month. We estimate that there was an average of 29,000/day COVID-19 cases in the U.S. transmitted from infected to susceptible during April 1–24, 2020 after adjusting for under-reported and under-diagnosed. We have provided model-base d predictions of COVID-19 for the low and high range of transmission rates and with varying degrees of preventive measures including the lockdowns. We predict that even if 10% of the susceptible and 20 % of the infected who were not identified as of April 23, 2020, do not adhere to proper care or do not obey lockdown, then by the end of May and by end of June 50,000 and 55,000 new cases will emerge, respectively. These values for the months of May and June with worse adherence rates of 50% by susceptible and infected (but not identified) will be 251,000 and 511,000, respectively. Continued and serious lockdown measures could bring this average daily new cases to a further low at 4,300/day to 8,000/day in May.
The geography of COVID-19 spread in Italy and implications for the relaxation of confinement measures
Authors: Bertuzzo Enrico , Mari Lorenzo , Pasetto Damiano , Miccoli Stefano , Casagrandi Renato , Gatto Marino , Rinaldo Andrea
Published: May 2020

We examine the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Italy, to address the appropriate methodological choices for the design of selective relaxations of the current containment measures. Pressing relevance stems from the need to restart the economy dramatically affected by the lockdown. We employ a spatially explicit, data-intensive model of the patterns of disease spread in Italy, with the goal of providing tools to: estimate the baseline trajectory, i.e. the expected unfolding of the outbreak if the current containment measures were kept in place indefinitely; assess possible deviations from the baseline, should relaxations of the current lockdown result in increased disease transmission; and estimate the isolation effort required to prevent a resurgence of the outbreak. For instance, a 50% increase in effective transmission as a result of the loosening of confinement measures, to be instated on May 4, yields an epidemic curve that shows a major rebound larger than the previous peaks in most regions. A control effort, capable of isolating a daily percentage of approximately 7% of the individuals in the exposed and pre-symptomatic stages, proves necessary to counterbalance such an increase, and maintain the epidemic curve onto the decreasing baseline trajectory. We explore several scenarios, provide the basic data to design the related control strategies and discuss their feasibility. Should suitable control via tracing and testing prove unfeasible, stop-and-go enforcement or delay of the lockdown relaxations would be necessary to reduce the isolation effort required to maintain the epidemic trajectory under control.
COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area
Authors: Vuagnat Perrine , Frelaut Maxime , Ramtohul Toulsie , Basse Clémence , Diakite Sarah , Noret Aurélien , Bellesoeur Audrey , Servois Vincent , Hequet Delphine , Laas Enora , Kirova Youlia , Cabel Luc , Pierga Jean-Yves ,   Institut Curie Breast Cancer and COVID Group, Bozec Laurence , Paoletti Xavier , Cottu Paul , Bidard François-Clément
Published: May 2020

Background

Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France).

Methods

An IRB-approved prospective registry was set up at ICH for all breast cancer patients with COVID-19 symptoms or radiologic signs.

Results

Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (>70) were the two factors associated with a higher risk of intensive care unit admission and/or death.

Conclusions

This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe SARS-CoV-2 infection in breast cancer patients.
Prevalence of Chronic Hepatitis B and C in Malaysia- results from a community-based screening campaign
Authors: Lim ZZ , Teo JS , Tan AC , Siam Tan Soek , Mohamed Rosmawati , Goh KL , Jaya Fauziah , Senamjit K , Aun Azlida Che’ , Said Rosaida , Lim EK , Shahar Hamiza , Muhammad Radzi AH , Poh Tee Hoi , Seng Tan Soon , Menon Jayaram , Menon Rena , Lim TO
Published: May 2020

Introduction

The epidemiology of hepatitis, which is apparently endemic in Asia, is still poorly documented in Malaysia. Available statistics are modelled estimates based on expert input or estimated from small studies on special populations. We therefore determined the prevalence of chronic hepatitis B and C in Malaysia based on a large sample data from a screening campaign.

Methods

A total of 10,914 subjects participated in the hepatitis screening campaign in 2018 and 2019. A low-cost Point-of-care test, which has previously been validated, was used to screen for HBsAg and anti-HCV. All screen positive subjects were recalled to undergo confirmatory serology tests and nucleic acid tests.

Results

We estimated 1.17% or 238,971 Malaysian adults aged 20 or older had chronic HBV, while only 0.74% or 151,144 adults had chronic HCV. Young adults below age 30 years had very low prevalence of HBV (0.09%). Women had lower prevalence of HBV and HCV, Chinese had the highest prevalence of HBV while Malay had the highest prevalence of HCV.

Conclusion

Young adults seems to be protected from HBV perhaps owing to the introduction of universal HBV vaccination since 1989. Chronic HBV however remains prevalent in older adults especially among the Chinese. Chronic HCV is uncommon in Malaysia.
A clinical and biological framework on the role of visceral fat tissue and leptin in SARS-CoV-2 infection related respiratory failure
Authors: van der Voort Peter HJ , Moser Jill , Zandstra Durk F , Kobold Anneke C Muller , Knoester Marjolein , Calkhoven Cornelis F. , Hamming Inge , van Meurs Matijs
Published: May 2020

Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross sectional study was performed. The mean BMI was 31 kg/m2 (range 24.8 – 48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m2 (range 22.4-33.5) for the 8 controls. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0-85.2) vs 5.6 (2.4-8.2) ug/L for SARS-CoV-2 and controls respectively (p=0.0007). With these findings we designed a clinical and biological framework that explains clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This is enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment.
Machine Learning for Pattern Detection in Cochlear Implant FDA Adverse Event Reports
Authors: Crowson Matthew G. , Hamour Amr , Lin Vincent , Chen Joseph M. , Chan Timothy C. Y.
Published: May 2020

Importance

The United States Food & Drug Administration (FDA) passively monitors medical device performance and safety through submitted medical device reports (MDRs) in the Manufacturer and User Facility Device Experience (MAUDE) database. These databases can be analyzed for patterns and novel opportunities for improving patient safety and/or device design.

Objectives

The objective of this analysis was to use supervised machine learning to explore patterns in reported adverse events involving cochlear implants.

Design

The MDRs for the top three CI manufacturers by volume from January 1st 2009 to August 30th 2019 were retained for the analysis. Natural language processing was used to measure the importance of specific words. Four supervised machine learning algorithms were used to predict which adverse event narrative description pattern corresponded with a specific cochlear implant manufacturer and adverse event type - injury, malfunction, or death.

Setting

U.S. government public database.

Participants

Adult and pediatric cochlear patients.

Exposure

Surgical placement of a cochlear implant.

Main Outcome Measure

Machine learning model classification prediction accuracy (% correct predictions).

Results

27,511 adverse events related to cochlear implant devices were submitted to the MAUDE database during the study period. Most adverse events involved patient injury (n = 16,736), followed by device malfunction (n = 10,760), and death (n = 16). Submissions to the database were dominated by Cochlear Corporation (n = 13,897), followed by MedEL (n = 7,125), and Advanced Bionics (n = 6,489). The random forest, linear SVC, naïve Bayes and logistic algorithms were able to predict the specific CI manufacturer based on the adverse event narrative with an average accuracy of 74.8%, 86.0%, 88.5% and 88.6%, respectively.

Conclusions & Relevance

Using supervised machine learning algorithms, our classification models were able to predict the CI manufacturer and event type with high accuracy based on patterns in adverse event text descriptions.

Level of evidence

3
Efficacy and safety of antidepressants for the treatment of low back pain and osteoarthritis: protocol for a systematic review and meta-analysis
Authors: Ferreira Giovanni , Lin Chung-Wei Christine , Zadro Joshua R , O'Keeffe Mary , Abdel Shaheed Christina , McLachlan Andrew , Maher Chris G
Published: May 2020

Objectives: To systematically review the efficacy and safety of antidepressants for patients with spinal pain (including sciatica) and osteoarthritis of the hip and knee.

Eligibility criteria: We will include randomised placebo-controlled trials published as full-text in peer-reviewed journals enrolling Participants with a diagnosis of non-specific spinal pain (low back and/or neck pain), spinal pain with radicular symptoms and/or radiculopathy; and hip and/or knee OA. Studies with mixed populations will be included. Studies that include participants with serious spinal pathologies (e.g. cauda equina syndrome, cervical myelopathy, spinal tumours, spinal infection) will be excluded. We will exclude
studies including participants with inflammatory arthritis eg axial spondyloarthritis, rheumatoid arthritis unless data for knee and/or hip OA is reported separately. Studies where participants received previous spinal or OA surgery are eligible, but studies evaluating immediate post-operative pain management (ie within past month) will not be included. We will include trials testing any type of antidepressant drug prescribed at any dose, as treatment for spinal pain and/or hip and/or knee OA. Studies testing drug combinations (e.g. antidepressants in addition to other analgesics) will only be included if the treatment contrast is other analgesic in addition to placebo Types of antidepressants drugs to be included. Comparators will include both inert (e.g. an inert substance that does not contain an active drug treatment) and active placebos (i.e. drugs that have no known effect on pain but may mimic the adverse effects of
antidepressants).

Outcomes: Primary outcomes will be Pain intensity and disability. Secondary outcomes will include adverse events (serious and any adverse event), as well as the number and proportion of participants who stopped the study medicicine due to adverse events and who dropped out because of adverse events.

Data synthesis: All outcomes will be converted to a 0-100 scale. We will group studies by condition and antidepressant class. If studies are considered to be sufficiently homogenous, results will be pooled. The I2 statistics will be used to analyse the between-trial heterogeneity, and a random effects model will be used among trials when I2 > 0%.
Robust Inference of Kinase Activity Using Functional Networks
Authors: Yılmaz Serhan , Ayati Marzieh , Schlatzer Daniela , Çiçek A. Ercüment , Chance Mark R. , Koyutürk Mehmet
Published: May 2020

Mass spectrometry enables high-throughput screening of phospho-proteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer’s disease and Parkinson’s disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool athttp://rokai.io.
A novel DNA binding mode, conformational change and intramolecular signaling in MutS upon mismatch recognition in replication DNA structures
Authors: Busseti Milagros Inés Ibáñez , Margara Lucía Malvina , Castell Sofía Daiana , Fernández Marisa Mariel , Malchiodi Emilio Luis , Montich Guillermo Gabriel , Miguel Virginia , Argaraña Carlos Enrique , Monti Mariela Roxana
Published: May 2020

MutS initiates mismatch repair by recognizing mismatches in newly replicated DNA. Specific interactions between MutS and mismatches within double-stranded DNA promote ADP-ATP exchange and a conformational change into a sliding clamp. Here, we demonstrated that MutS fromPseudomonas aeruginosaassociates with primed DNA replication substrates. The predicted structure of this MutS-DNA complex revealed a new DNA binding site, in which Asn 279 and Arg 272 appeared to directly interact with the 3’-OH terminus of primed DNA. Mutation of these residues resulted in a noticeable defect in the interaction of MutS with replication DNA substrates. Remarkably, MutS interaction with a mismatch within primed DNA induced a compaction of the protein structure and impaired the formation of an ATP-bound sliding clamp. Our findings reveal a novel DNA binding mode, conformational change and intramolecular signaling for MutS recognition of mismatches within DNA replication structures.
The complete genome sequence of theStaphylococcusbacteriophage Metroid
Authors: Crane Adele , Abaidoo Joy , Beltran Gabriella , Fry Danielle , Furey Colleen , Green Noe , Johal Ravneet , La Rosa Bruno , Jimenez Catalina Lopez , Luong Linh , Maag Garett , Porche Jade , Reyes Lauren , Robinson Aspen , Sabbara Samantha , Herrera Lucia Soto , Negrete Angelica Urquidez , Wilson Pauline , Geiler-Samerotte Kerry , Pfeifer Susanne P.
Published: May 2020

Phages infecting bacteria of the genusStaphylococcusplay an important role in their host’s ecology and evolution. On one hand, horizontal gene transfer from phage can encourage the rapid adaptation of pathogenicStaphylococcusenabling them to escape host immunity or access novel environments. On the other hand, lytic phages are promising agents for the treatment of bacterial infections, especially those resistant to antibiotics. As part of an ongoing effort to gain novel insights into bacteriophage diversity, we characterized the complete genome of theStaphylococcusbacteriophage Metroid, a cluster C phage with a genome size of 151kb, encompassing 254 predicted protein-coding genes as well as 4 tRNAs. A comparative genomic analysis highlights strong similarities – including a conservation of the lysis cassette – with otherStaphylococcuscluster C1 bacteriophages, several of which were previously characterized for therapeutic applications.
Close encounters of the three morphs: does color affect aggression in a polymorphic lizard?
Authors: Scali Stefano , Mangiacotti Marco , Sacchi Roberto , Coladonato Alan Jioele , Falaschi Mattia , Saviano Luca , Rampoldi Marina Giulia , Crozi Matteo , Perotti Cesare , Zucca Francesco , Gozzo Elisabetta , Luca Zuffi Marco Alberto
Published: May 2020

Color polymorphism is genetically controlled and the process generating and maintaining morphs can affect speciation and/or extinction rates. Competition and aggression among morphs can contribute to polymorphism maintenance and color badges are useful signals in intraspecific communication, because they convey information about alternative strategies and avoid unnecessary conflicts. This could lead to an uneven spatial distribution of morphs in a population, because the local frequency of each morph establishes the intensity of the competition in that neighborhood, and then the fitness of each male. We used a polymorphic lizard,Podarcis muralis, to assess if aggression varies among morphs under two contrasting hypotheses: a heteromorphic vs. a homomorphic aggression. We used laboratory mirror tests after lizard color manipulation and we verified the results consistency with the analysis of the spatial distribution of morphs in a wild population. Both the experiments confirmed that aggression is morph-specific and notably homomorphic. The adoption of behavioral alternative strategies that minimize risks and costs of unwanted conflicts could facilitate the stable coexistence of the phenotypes and reduce the resource competition. A bias in aggression to like-coloured males would advantage rarer morph, which would suffer less harassment by common morphs and obtain a fitness advantage. This process would be negatively-frequency-dependent and would stabilize polymorphism in the populations, possibly leading to sympatric speciation.
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Authors: Vuong Wayne , Khan Muhammad Bashir , Fischer Conrad , Arutyunova Elena , Lamer Tess , Shields Justin , Saffran Holly A. , McKay Ryan T. , van Belkum Marco J. , Joyce Michael , Young Howard S. , Tyrrell D. Lorne , Vederas John C. , Lemieux M. Joanne
Published: May 2020

The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mprofrom both SARS-CoV and SARS-CoV-2 with IC50values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mprowith these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.
Pathogen Reduction of SARS-CoV-2 Virus in Plasma and Whole Blood using Riboflavin and UV Light
Authors: Ragan Izabela , Hartson Lindsay , Pidcoke Heather , Bowen Richard , Goodrich Raymond P.
Published: May 2020

BACKGROUND

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has recently been identified as the causative agent for Coronavirus Disease 2019 (COVID-19). The ability of this agent to be transmitted by blood transfusion has not been documented, although viral RNA has been detected in serum. Exposure to treatment with riboflavin and ultraviolet light (R + UV) reduces blood-borne pathogens while maintaining blood product quality. Here, we report on the efficacy of R + UV in reducing SARS-CoV-2 infectivity when tested in human plasma and whole blood products.

STUDY DESIGN AND METHODS

SARS-CoV-2 (isolate USA-WA1/2020) was used to inoculate plasma and whole blood units that then underwent treatment with riboflavin and UV light (Mirasol Pathogen Reduction Technology System, Terumo BCT, Lakewood, CO). The infectious titers of SARS-CoV-2 in the samples before and after R + UV treatment were determined by plaque assay on Vero cells. Each plasma pool (n=9) underwent R + UV treatment performed in triplicate using individual units of plasma and then repeated using individual whole blood donations (n=3).

RESULTS

Riboflavin and UV light reduced the infectious titer of SARS-CoV-2 below the limit of detection for plasma products at 60-100% of the recommended energy dose. At the UV light dose recommended by the manufacturer, the mean log reductions in the viral titers were ≥ 4.79 ± 0.15 Logs in plasma and 3.30 ± 0.26 in whole blood units.

CONCLUSION

Riboflavin and UV light effectively reduced the titer of SARS-CoV-2 to the limit of detection in human plasma and by 3.30 ± 0.26 on average in whole blood. Two clades of SARS-CoV-2 have been described and questions remain about whether exposure to one strain confers strong immunity to the other. Pathogen-reduced blood products may be a safer option for critically ill patients with COVID-19, particularly those in high-risk categories.
Community succession of the grapevine fungal microbiome in the annual growth cycle
Authors: Liu Di , Howell Kate
Published: May 2020

Microbial ecology is an integral component of wine production. From the vineyard to the winery, microbial activity influences grapevine health and productivity, conversion of sugar to ethanol during fermentation, wine aroma production, wine quality and distinctiveness. Fungi in the vineyard ecosystem are not well described. Here, we characterised the spatial and temporal dynamics of fungal communities associated with the grapevine (grapes, flowers, leaves, and roots) and soils over an annual growth cycle in two vineyards to investigate the influences of grape habitat, plant developmental stage (flowering, fruit set, veraison, and harvest), vineyards, and climatic conditions. Fungi were influenced by both the grapevine habitat and plant development stage. The core microbiome was prioritised over space and time, and the identified core members drove seasonal community succession. The development stage of veraison, where the grapes undergo a dramatic change in metabolism and start accumulating sugar, displayed a distinct shift in fungal communities. Co-occurrence networks showed strong correlations between the plant microbiome, the soil microbiome, and weather indices. Our study describes the complex ecological dynamics that occur in microbial assemblages over a growing season and highlight the importance of core community succession in vineyards. In addition to enriching our understanding of how plants and microbes interact, these findings may provide insights to craft wine regional distinctiveness and cope with global climate change.
Host adaptations in thefixLJpathway of theBurkholderia cepaciacomplex increase virulence
Authors: Schaefers Matthew M. , Wang Benjamin X. , Boisvert Nicole M. , Martini Sarah J. , Bonney Sarah L. , Marshall Christopher W. , Laub Michael T. , Cooper Vaughn S. , Priebe Gregory P.
Published: May 2020

TheBurkholderia cepaciacomplex (BCC) is composed of multiple species, includingB. multivoransandB. dolosa,that are significant pathogens for people with cystic fibrosis (CF) and are extensively resistant to many antibiotics. ThefixLgene of thefixLJ2-component system (TCS) in these BCC species shows evidence of positive selection for nonsynonymous mutations during chronic lung infection in CF. Previous work showed that theB. dolosa fixLJsystem regulates 11% of the genome and modulates biofilm formation, motility, persistence within macrophages, and virulence in a murine pneumonia model. Here, we assess the impacts of clinically observed FixL evolved variants infixLJpathway-mediated phenotypes inB. dolosaandB. multivorans.BCC carrying the ancestralfixLsequence are less pathogenic than constructs carrying evolved variants in both a macrophage infection model and a murine pneumonia model.In vitrophospho-transfer experiments demonstrate that the evolvedB. dolosaFixL variants are able to reducefixLJpathway activity by either having lower levels of kinase activity or increased phosphatase activity. Notably, the ancestralfixLgenotype has increased ability to survive within the soil compared to isogenic constructs with evolvedfixLgenotypes, demonstrating that increased virulence comes at an expense. Modulation of the FixLJ system has profound effects on many BCC phenotypes including full pathogenicity, and this modulation is critical for BCC adaptation to the host.
Design of 18 nm Doxorubicin-loaded 3-helix Micelles: Cellular Uptake and Cytotoxicity in Patient-derived GBM6 Cells
Authors: Jung Benson T. , Jung Katherine , Lim Marc , Li Michael , Santos Raquel , Ozawa Tomoko , Xu Ting
Published: May 2020

The fate of nanocarrier materials at the cellular level constitutes a critical checkpoint in the development of effective nanomedicines, determining whether tissue level accumulation results in therapeutic benefit. The cytotoxicity and cell internalization of ~18 nm 3-helix micelle (3HM) loaded with doxorubicin (DOX) was analyzed in patient-derived glioblastoma (GBM) cellsin vitro. The inhibitory concentration (IC50) of 3HM-DOX increased to 6.2 µg/mL from < 0.5 µg/mL for free DOX in patient derived GBM6 cells, 15.0 µg/mL from 6.5 µg/mL in U87MG cells, and 21.5 µg/mL from ~0.5 µg/mL in LN229 cells. Modeling analysis of previous 3HM biodistribution results predict these cytotoxic concentrations are achievable with intravenous injection in rodent GBM models. 3HM-DOX formulations were internalized intact and underwent intracellular trafficking distinct from free DOX. 3HM was quantified to have an internalization half-life of 12.6 h in GBM6 cells, significantly longer than comparable reported liposome and polymer systems. 3HM was found to traffic through active endocytic processes, with clathrin-mediated endocytosis being the most involved of the pathways studied. Inhibition studies suggest substantial involvement of low density lipoprotein receptor (LDLR) in initiating 3HM uptake. Since 3HM surface is polyethylene glycol (PEG)-ylated with no targeting functionalities, protein corona involvement in 3HM recognition is expected. The present work develops insights of the cytotoxicity, pharmacodynamics and cellular interactions of 3HM and 3HM-DOX relevant for ongoing pre-clinical studies. This work also contributes to efforts to develop predictive mathematical models tracking accumulation and biodistribution kinetics at a systemic level.

Graphical Abstract
Pre-TCR signaling intensity shapes the TCRβ repertoire
Authors: Bovolenta Elena R. , García-Cuesta Eva M. , Ponomarenko Julia , Mellado Mario , Castro Mario , Abia David , van Santen Hisse M.
Published: May 2020

Signaling via pre-TCR is essential for initial T cell differentiation. How the signal is triggered and whether its alteration impacts on lymphocyte repertoires is nevertheless debated. We show that a mutation in the transmembrane domain of the CD3ζ chain impairs murine thymocyte development at the double negative (DN) stage coinciding with reduced levels of steady-state pre-TCR signaling. Single particle tracking and TIRF microscopy on mouse primary DN3/DN4 thymocytes shows that wild-type pre-TCR form particles with a broad range of fluorescent intensities whereas mutant complexes are less intensely labeled and move faster, suggesting reduced pre-TCR nanoclustering. Notably, the mutant early-pre-TCR-selected-DP population shows less TCRβ repertoire diversity. We thus propose that the pre-TCR forms stable nanoclusters, the size of which determines signaling efficacy. This signaling does not merely promote maturation of any thymocyte expressing a rearranged TCRβ chain, but shapes the repertoire of DP thymocytes that can audition for positive and negative selection.
Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach
Authors: Wang Yafei , Brodin Erik , Nishii Kenichiro , Frieboes Hermann B. , Mumenthaler Shannon , Sparks Jessica L. , Macklin Paul
Published: May 2020

Colorectal cancer (CRC) and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic (PVE) model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could “reawaken” after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.
Crystal Structure of the Werner’s Syndrome Helicase
Authors: Newman Joseph A. , Gavard Angeline E. , Lieb Simone , Ravichandran Madhwesh C. , Hauer Katja , Werni Patrick , Geist Leonhard , Böttcher Jark , Engen John. R. , Rumpel Klaus , Samwer Matthias , Petronczki Mark , Gileadi Opher
Published: May 2020

Werner syndrome helicase (WRN) plays important roles in multiple pathways of DNA repair and the maintenance of genome integrity. Recently, loss of WRN was identified as a strong synthetic lethal interaction for microsatellite instable (MSI) cancers making WRN a promising drug target. Yet, structural information for the helicase domain is lacking, which prevents structure-based design of drug molecules. In this study, we show that ATP binding and hydrolysis in the helicase domain are required for genome integrity and viability of MSI cancer cells. We then determined the crystal structure of an ADP bound form of the WRN helicase core at 2.2 Å resolution. The structure features an atypical mode of nucleotide binding with extensive contacts formed by motif VI, which in turn defines the relative positioning of the two RecA like domains. The structure features a novel additional β-hairpin in the second RecA and an unusual helical hairpin in the Zn2+ binding domain, and modelling DNA substrates based on existing RecQ DNA complexes suggests roles for these features in the binding of alternative DNA structures. We have further analysed possible interfaces formed from the interactions between the HRDC domain and the helicase core by NMR. Together, this study will facilitate the structure-based design of inhibitors against WRN helicase.
Pain and breathlessness: Salient, somatosensory and similar, but not the same
Authors: Harrison Olivia K. , Hayen Anja , Wager Tor D. , Pattinson Kyle T. S.
Published: May 2020

Quantifying pain currently relies upon subjective self-report. Alongside the inherent variability embedded within these metrics, added complications include the influence of ambiguous or prolonged noxious inputs, or in situations when communication may be compromised. As such, there is continued interest in the development of brain biomarkers of pain, such as in the form of neural ‘signatures’ of brain activity. However, issues pertaining to pain-related specificity remain, and by understanding the current limits of these signatures we can both progress their development and investigate the potentially generalizable properties of pain to other salient and/or somatomotor tasks. Here, we utilized two independent datasets to test one of the established Neural Pain Signatures (the NPS (Wager et al. 2013)). In Study 1, brain activity was measured using functional magnetic resonance imaging (fMRI) in 40 healthy subjects during experimentally induced breathlessness, conditioned anticipation of breathlessness and a simple finger opposition task. In Study 2, brain activity was again measured during anticipation and breathlessness in 19 healthy subjects, as well as a modulation with the opioid remifentanil. We were able to identify significant NPS-related brain activity during anticipation and perception of breathlessness, as well as during finger opposition using the global NPS. Furthermore, localised NPS responses were found in early somatomotor regions, bilateral insula and dorsal anterior cingulate for breathlessness and finger opposition. In contrast, no conditions were able to activate the local signature in the dorsal posterior insula - thought to be critical for pain perception. These results provide properties of the present boundaries of the NPS, and offer insight into the overlap between breathlessness and somatomotor conditions with pain.
Multimodal principal component analysis to identify major features of white matter structure and links to reading
Authors: Geeraert Bryce L. , Chamberland Maxime , Lebel R. Marc , Lebel Catherine
Published: May 2020

The role of white matter fibers in reading has been established by diffusion tensor imaging (DTI), but DTI cannot identify specific microstructural features driving these relationships. Neurite orientation dispersion and density imaging (NODDI), inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT) can be used to link more specific aspects of white matter microstructure and reading due to their sensitivity to axonal packing and fiber coherence (NODDI) and myelin (ihMT and mcDESPOT). We applied principal component analysis (PCA) to combine DTI, NODDI, ihMT and mcDESPOT measures (10 in total), identify major features of white matter structure, and link these features to both reading and age. Analysis was performed for nine reading-related tracts in 46 neurotypical 6-16 year olds. We identified three principal components (PCs) which explained 79.5% of variance in our dataset. PC1 probed tissue complexity, PC2 described myelin and axonal packing, while PC3 was related to axonal diameter. Mixed effects models regressions did not identify any relationships between principal components and reading skill. Further Bayes factor analysis revealed that absence of relationships was not due to low power. PC1 suggested increases in tissue complexity with age in the left arcuate fasciculus, while PC2 suggested increases in myelin and axonal packing with age in the bilateral arcuate, inferior longitudinal, inferior fronto-occipital fasciculi, and splenium. Multimodal white matter imaging and PCA produce microstructurally informative, powerful principal components which can be used by future studies of development and cognition.
Inclusion bodies formed by polyglutamine and poly(glycine-alanine) are enriched with distinct proteomes but converge in proteins that are risk factors for disease and involved in protein degradation
Authors: Radwan Mona , Lilley Jordan D. , Ang Ching-Seng , Reid Gavin E. , Hatters Danny M.
Published: May 2020

Poly(glycine-alanine) (polyGA) is one of the dipolypeptides expressed in Motor Neuron Disease caused by C9ORF72 mutations and accumulates as inclusion bodies in the brain of patients. Superficially these inclusions are similar to those formed by polyglutamine (polyQ) in Huntington’s disease and both have been reported to form an amyloid-like structure suggesting they might aggregate via similar mechanisms to confer cellular dysfunction similarly. Here we investigated which endogenous proteins were enriched in these inclusions and whether aggregation-prone lengths of polyQ (Q97), in context of Huntingtin exon 1, shared similar patterns to aggregation-prone lengths of polyGA (101GA). When co-expressed in the same cell, polyGA101and HttQ97inclusions adopted distinct phases with no overlap suggesting different endogenous proteins would be enriched. Proteomic analyses indeed yielded distinct sets of endogenous proteins recruited into the inclusion types. The proteosome, microtubules, TriC chaperones, and translational machinery were enriched in polyGA aggregates, whereas Dnaj chaperones, nuclear envelope and RNA splicing proteins were enriched in polyQ aggregates. Both structures revealed a synergy of degradation machinery including proteins in the polyQ aggregates that are risk factors for other neurodegenerative diseases involving protein aggregation when mutated, which suggests a convergence point in the pathomechanisms of these diseases.