bluuebunny/crossref_metadata_2025 huggingface dataset:
One Study of COVID-19 Spreading at The United States - Brazil - Colombia1
Authors: Cirilo E. R. , Natti P. L. , Romeiro N. M. L. , Candezano M.A.C. , Polo J. M. P.
Published: September 2020

The present work concerns the COVID-19’s spread over The United States, Brazil and Colombia. Although countries show differences in economic development, but similarities such as continental dimension or social interaction, the spread of COVID-19 in them has some similarities. At the moment, the countries are living the disease with temporal delay. Thus, we used a database on WHO Coronavirus, Mathematical Modeling and Numerical Simulations to describe the most recent COVID-19 development patterns in these countries, which we saw.
Relationship between In-person Instruction and COVID-19 incidence among University Students: A Prospective Cohort Study
Authors:   The Campus & Corona-study Team, Fretheim Atle , Flatø Martin , Helleve Arnfinn , Helseth Sølvi , Jamtvedt Gro , Løyland Borghild , Sandbekken Ida Hellum , Schjøll Alexander , Telle Kjetil , Watle Sara Sofie Viksmoen
Published: September 2020

Whether university teaching on campus with infection control measures in place is associated with higher risk of COVID-19 than online instruction, is unknown. We will assess this by conducting repeated surveys among students at universities and university colleges in Norway, where some instruction is given in-person, and some is provided online (hybrid model). We will ask about the students’ COVID-19 status, and how much in-person and online instruction they are getting. We will estimate the association between in-person instruction and COVID-19-risk using multivariate regression, controlling for likely confounders. We will also assess whether type of instruction is associated with how satisfied the students are with the instruction, their quality of life, and learning outcomes.
Suicide during the COVID-19 pandemic in Japan
Authors: Tanaka Takanao , Okamoto Shohei
Published: September 2020

The prolonged uncertainty of the COVID-19 pandemic, fear and anxiety regarding infections, precautionary social isolation, and the resulting economic disruption could deteriorate psychological health and exacerbate the suicidal risk. Utilizing month-level suicide records covering the entire Japanese population (126 million) in 1,861 administrative units, we assessed if suicide mortality changed during the pandemic. We employed difference-in-difference estimation and found that overall suicide rate declined by 14.8% (95% CI: −18.9% to −10.8%) after the outbreak and the subsequent measures (school closure and the state of emergency). The decline is larger among males than females and among adults than children and older adults. The government’s generous subsidies, reduced working hours, and fewer school sessions potentially account for its sizable decline.
Seroprevalence of anti-SARS-CoV-2 antibodies in COVID-19 patients and healthy volunteers
Authors: Figueiredo-Campos Patrícia , Blankenhaus Birte , Mota Catarina , Gomes Andreia , Serrano Marta , Ariotti Silvia , Costa Catarina , Nunes-Cabaço Helena , Mendes António M. , Gaspar Pedro , Pereira-Santos M. Conceição , Rodrigues Fabiana , Condeço Jorge , Escoval M. Antonia , Santos Matilde , Ramirez Mario , Melo-Cristino José , Simas J. Pedro , Vasconcelos Eugenia , Afonso Ângela , Veldhoen Marc
Published: September 2020

SARS-CoV-2 has emerged as a novel human pathogen, causing clinical signs, from fever to pneumonia – COVID-19 – but may remain mild or even asymptomatic. To understand the continuing spread of the virus, to detect those who are and were infected, and to follow the immune response longitudinally, reliable and robust assays for SARS-CoV-2 detection and immunological monitoring are needed and have been setup around the world. We quantified immunoglobulin M (IgM), IgG and IgA antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) or the Spike (S) protein over a period of five months following COVID-19 disease onset or in previously SARS-CoV-2 PCR-positive volunteers. We report the detailed setup to monitor the humoral immune response from over 300 COVID-19 hospital patients and healthcare workers, 2500 University staff and 187 post-COVID19 volunteers, and assessing titres for IgM, IgG and IgA. Anti-SARS-CoV-2 antibody responses followed a classic pattern with a rapid increase within the first three weeks after symptoms. Although titres reduce from approximately four weeks, the ability to detect SARS-CoV-2 antibodies remained robust for five months in a large proportion of previously virus-positive screened subjects. Our work provides detailed information for the assays used, facilitating further and longitudinal analysis of protective immunity to SARS-CoV-2. Moreover, it highlights a continued level of circulating neutralising antibodies in most people with confirmed SARS-CoV-2, at least up to five months after infection.
Test Sensitivity for Infection versus Infectiousness of SARS-CoV-2
Authors: Gans Joshua S.
Published: September 2020

The most commonly used test for the presence of SARS-CoV-2 is a PCR test that is able to detect very low viral loads and inform on treatment decisions. Medical research has confirmed that many individuals might be infected with SARS-CoV-2 but not infectious. Knowing whether an individual is infectious is the critical piece of information for a decision to isolate an individual or not. This paper examines the value of different tests from an information-theoretic approach and shows that applying treatment-based approval standards for tests for infection will lower the value of those tests and likely causes decisions based on them to have too many false positives (i.e., individuals isolated who are not infectious). The conclusion is that test scoring be tailored to the decision being made.
COVID-19 Detection From Chest Radiographs Using Machine Learning and Convolutional Neural Networks
Authors: Li Andrew C. , Lee David T. , Misquitta Kristoff K. , Uno Kaiji , Wald Sasha
Published: September 2020

Accurate and efficient diagnosis of potential COVID-19 patients is vital in the fight against the current pandemic. However, even the gold-standard COVID-19 test—reverse transcription polymerase chain reaction—suffers from a high false negative rate and a turnaround time of up to one week, preventing the infected from accessing the timely care they require, and impeding efforts to isolate positive cases. To address these shortcomings, this study develops a machine learning model based on the DenseNet-201 deep convolutional neural network, that can classify COVID-19 from chest radiographs in less than one minute and far more accurately than conventional tests (F1-score: 0.96; precision: 0.95; recall: 0.98). It uses a significantly larger dataset and more control classes than previously published models, demonstrating the promise of a machine learning approach for accurate and efficient COVID-19 screening. A live web application of the trained model can be accessed at https://cov2d19-classifier.herokuapp.com/.
Seroprevalence of SARS-CoV-2 antibodies in children - A prospective multicentre cohort study
Authors: Waterfield Thomas , Watson Chris , Moore Rebecca , Ferris Kathryn , Tonry Claire , Watt Alison P , McGinn Claire , Foster Steven , Evans Jennifer , Lyttle Mark D , Ahmad Shazaad , Ladhani Shamez , Corr Michael , McFetridge Lisa , Mitchell Hannah , Brown Kevin , Amirthalingam Gayatri , Maney Julie-Ann , Christie Sharon
Published: September 2020

Background

Studies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity and timing of testing. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection, and to report the symptomatology of infection in children.

Design

This multicentre observational cohort study, conducted between 16th April – 3rd July 2020 at 5 UK sites, aimed to recruit 900 children aged 2 to 15 years of age. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms.

Results

1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10·1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariate analysis 4 independent variables were identified as significantly associated with SARS-CoV-2 infection. These were: known infected household contact; fatigue; gastrointestinal symptoms; and changes in sense of smell or taste.

Discussion

In this study children demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. The symptoms of SARS-CoV-2 infection in children were subtle but of those reported, fatigue, gastrointestinal symptoms and changes in sense of smell or taste were most strongly associated with antibody positivity.

Registration

This study was registered at https://www.clinicaltrials.gov (trial registration: NCT04347408) on the 15/04/2020.
Measurement of motivation states for physical activity and sedentary behavior: Development and validation of the CRAVE scale
Authors: Stults-Kolehmainen Matthew A. , Blacutt Miguel , Fogelman Nia , Gilson Todd A. , Stanforth Philip R. , Divin Amanda L. , Bartholomew John B. , Filgueiras Alberto , McKee Paul C. , Ash Garrett I. , Ciccolo Joseph T. , Decker Line Brotnow , Williamson Susannah L. , Sinha Rajita
Published: September 2020

Physical activity, and likely the motivation for it, varies throughout the day. The aim of this investigation was to create a short assessment (CRAVE) to measure motivation states (wants, desires, urges) for physical activity and sedentary behaviors. Five studies were conducted to develop and evaluate the construct validity and reliability of the scale, with 1,035 participants completing the scale a total of 1,697 times. In Study 1, 402 university students completed a questionnaire inquiring about the want or desire to perform behaviors “at the present moment (right now)”. Items related to physical activity (e.g., “move my body”) and sedentary behaviors (e.g., “do nothing active”). An exploratory structural equation model (ESEM) revealed that 10 items should be retained, loading onto two factors (5 each for Move and Rest). In Study 2, an independent sample (n= 444) confirmed these results and found that Move and Rest desires were associated with stage-of-change for exercise behavior. In Study 3, 127 community-residing participants completed the CRAVE at 6-month intervals over two years-two times each session. Across-session interclass correlations (ICC) for Move (ICC = .72-.95) and Rest (ICC = .69-.88) were higher than when when they were measured across 24-months (Move: ICC = .53; Rest: ICC = .49), indicating wants/desires have state-like qualities. In Study 4, a maximal treadmill test was completed by 21 university students. The CRAVE was completed immediately pre and post. Move desires decreased 26% and Rest increased 74%. Changes in Move and Rest desires were moderately associated with changes in perceived physical fatigue and energy. In Study 5, 41 university students sat quietly during a 50-minute lecture. They completed the CRAVE at 3 time points. Move increased 19.6% and Rest decreased 16.7%. Small correlations were detected between Move with perceived energy and tiredness, but not calmness or tension. In conclusion, the CRAVE scale has good psychometric properties. Data also support tenets of the WANT model of motivation states for movement and rest (Stults-Kolehmainen et al., 2020). Future studies need to explore how desires to move/rest relate to dynamic changes in physical activity and sedentarism.
Autoimmune Encephalitis Related to Cancer Treatment with Immune Checkpoint Inhibitors: Systematic Review
Authors: Nersesjan Vardan , McWilliam Oskar , Krarup Lars-Henrik , Kondziella Daniel
Published: September 2020

BACKGROUND

Immune checkpoint inhibitors (ICPI) are a game changer in the treatment of various metastasized cancers, but emerging reports of adverse events, including ICPI-associated autoimmune encephalitis (ICPI-AIE), are concerning. We aimed to collect all published cases of ICPI-AIE to identify the salient clinical and laboratory features of this disorder.

METHODS

We searched PubMed, The Cochrane Library and Embase for ICPI-AIE cases from the first description in 2015 until 01/2020 using standard bibliographic measures including PRISMA guidelines and pre-registration with PROSPERO (CRD42019139838).

RESULTS

Thirty-nine studies met inclusion criteria, resulting in 54 ICPI-AIE patients (mean age 58.6 years; 43% females). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred on average after 3.5 treatment cycles, but very early and late presentations were common. Non-limbic AIE was roughly twice as frequent as limbic AIE (p<0.05). The most common laboratory abnormalities included bitemporal FLAIR lesions on MRI, continuous slow waves and diffuse slowing on EEG, and monocytic pleocytosis on cerebrospinal fluid analysis. Of note, intraneuronal antibodies were more frequent than neuronal surface antibodies, and logistic regression identified the presence of intracellular antibodies as a significant predictor for lack of improvement after 1st line immunotherapy (p<0.05).

CONCLUSIONS

ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the exact pathophysiological mechanisms, the epidemiology and the best treatment approaches associated with ICPI-AIE.
Intrathecal Nicardipine for Cerebral Vasospasm Post Subarachnoid Hemorrhage – a Retrospective Analysis and Propensity-Based Comparison
Authors: Sadan Ofer , Waddel Hannah , Moore Reneé , Feng Chen , Mei Yajun , Pearce David , Kraft Jacqueline , Pimentel Cederic , Mathew Subin , Akbik Feras , Ameli Pouya , Taylor Alexis , Danyluk Lisa , Martin Kathleen S. , Garner Krista , Kolenda Jennifer , Pujari Amit , Asbury William , Jaja Blessing , Macdonald R. Loch , Cawley C. Michael , Barrow Daniel L. , Samuels Owen
Published: September 2020

Background and Purpose

Cerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, we describe our experience with intrathecal (IT) nicardipine for this indication.

Methods

Patients admitted to Emory University Hospital Neuroscience ICU between 2012-2017 with non-traumatic SAH, either aneurysmal or idiopathic, were included in the analysis. This patient cohort was compared using a propensity-score model to patients in the SAH international trialist (SAHIT) repository who did not receive intrathecal nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events.

Results

The analysis included 1,351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n=859) the treated group was younger (51.1±12.4 vs. 56.7±14.1, p<0.01), had a higher World Federation of Neurological Surgeons score (WFNS), modified Fisher grade, and more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs. 11.3%, p<0.01). Treatment with IT nicardipine decreased daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increase rate of bacterial ventriculitis (3.1% compared with 2.7%, p>0.1) yet higher rates of VP shunting were noted (19.9% vs. 8.8%, p<0.01). In a propensity score comparison to the SAHIT database, the odds ratio to develop DCI with IT nicardipine treatment was 0.61 with 95% CI[0.44-0.84], and to have a favorable functional outcome (mRS≤2) was 2.17[1.61-2.91].

Conclusions

IT nicardipine was associated with improved outcome and reduced DCI compared with propensity matched controls. There was an increased need for permanent CSF diversion but no other safety issues. This data should be considered when selecting medications and treatments to study in future randomized controlled clinical trial for SAH.
Adjusting COVID-19 Reports for Countries’ Age Disparities: A Comparative Framework for Reporting Performances
Authors: Eryarsoy Enes , Delen Dursun , Davazdahemami Behrooz
Published: September 2020

Objectives

The COVID-19 outbreak has impacted distinct health care systems differently. While the rate of disease for COVID-19 is highly age-variant, there is no unified and age/gender-inclusive reporting taking place. This renders the comparison of individual countries based on their corresponding metrics, such as CFR difficult. In this paper, we examine cross-country differences, in terms of the age distribution of symptomatic cases, hospitalizations, intensive care unit (ICU) cases, and fatalities. In addition, we propose a new quality measure (called dissonance ratio) to facilitate comparison of countries’ performance in testing and reporting COVID-19 cases (i.e., their reporting quality).

Methods

By combining population pyramids with estimated COVID-19 age-dependent conditional probabilities, we bridge country-level incidence data gathered from different countries and attribute the variability in data to country demographics.

Results

We show that age-adjustment can account for as much as a 22-fold difference in the expected number of fatalities across different countries. We provide case, hospitalization, ICU, and fatality breakdown estimates for a comprehensive list of countries. Also, a comparison is conducted between countries in terms of their performance in reporting COVID-19 cases and fatalities.

Conclusions

Our research sheds light on the importance of and propose a methodology to use countries’ population pyramids for obtaining accurate estimates of the healthcare system requirements based on the experience of other, already affected, countries at the time of pandemics.
Take-Home Dosing Experiences among Persons Receiving Methadone Maintenance Treatment During COVID-19
Authors: Figgatt Mary C. , Salazar Zach , Day Elizabeth , Vincent Louise , Dasgupta Nabarun
Published: September 2020

Purpose

Methadone maintenance treatment is a life-saving treatment for people with opioid use disorders (OUD). The coronavirus pandemic (COVID-19) introduces many concerns surrounding access to opioid treatment. In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued guidance allowing the expansion of take-home methadone doses. We sought to describe changes to treatment experiences from the perspective of persons receiving methadone at outpatient treatment facilities for OUD.

Methods

We conducted an in-person survey among 104 persons receiving methadone from three clinics in central North Carolina. Surveys collected information on demographic characteristics, methadone treatment history, and experiences with take-home methadone doses in the context of COVID-19 (i.e., before and since March 2020).

Results

Before COVID-19, the clinic-level percent of participants receiving any amount of days’ supply of take-home doses at each clinic varied ranged from 56% to 82%, while it ranged from 78% to 100% since COVID-19. The clinic-level percent of participants receiving a take-homes days’ supply of a week or longer (i.e., ≥6 days) since COVID-19 ranged from 11% to 56%. Of the 87 participants who received take-homes since COVID-19 began, only four reported selling their take-home doses.

Conclusions

Our study found variation in experiences of take-home dosing by clinic and little diversion of take-home doses. While SAMSHA guidance should allow expanded access to take-home doses, adoption of these guidelines may vary at the clinic level. The adoption of these policies should be explored further, particularly in the context of benefits to patients seeking treatment for OUD.
Intraluminal thrombus effect on the progression of abdominal aortic aneurysms by using a multistate continuous-time Markov chain model
Authors: Zhang Liangliang , Zambrano Byron A. , Choi Jongeun , Lee Whal , Baek Seungik , Lim Chae Young
Published: September 2020

Objective

Recent studies reported the intraluminal thrombus (ILT) among others strongly affects abdominal aortic aneurysms (AAA) expansion rates. Thus, we investigate characteristics of ILT with AAA expansion.

Methods

We applied homogeneous multistate continuous-time Markov chain models to longitudinal data of 26 Korean AAA patients as a retrospective clinical study. We considered four states of AAA and maximal thickness of ILT (maxILT), fraction of wall area covered by ILT (areafrac) and fraction of ILT volume (volfrac) as possible covariates.

Results

Based on likelihood-ratio statistics, areafracis the most significant biomarker and maxILTis the second most significant. Besides, within AAAs that developed an ILT layer, we found that an AAA expands relatively fast at an early stage but the rate goes slower once AAA reaches in a large size.

Conclusion

Results recommends surgical intervention when any patient with areafracmore than 60% or maxILTmore than 30mm. Although this recommendation should be considered with caution given the limited sample size, one can use the proposed model as a tool to find such recommendations with their own data.
Towards Improved Social Distancing Guidelines: Space and Time Dependence of Virus Transmission from Speech-driven Aerosol Transport Between Two Individuals
Authors: Yang Fan , Pahlavan Amir A. , Mendez Simon , Abkarian Manouk , Stone Howard A.
Published: September 2020

It is now recognized that aerosol transport contributes to the transmission of the SARS-CoV-2. Existing social distancing guidelines are given in terms of distance, with vague statements about contact times. Also, estimates of inhalation of virus in a contaminated space typically assume a well-mixed environment, which is realistic for some, but not all, situations. We consider a local casual interaction of an infected individual and a susceptible individual, both maskless, account for the air flow and aerosol transport characteristics of speaking and breathing, and propose guidelines that involve both space and contact time, based on a conservative model of the interactions.
Age affects temporal response, but not durability, to serial ketamine infusions for treatment refractory depression
Authors: Pennybaker Steven , Roach Brian J , Fryer Susanna L , Badathala Anusha , Wallace Art W , Mathalon Daniel H , Marton Tobias F
Published: September 2020

Background

Ketamine is a rapid-acting treatment for patients with treatment refractory depression (TRD), however treatment responses are often transient and ketamine’s antidepressant action lacks robust clinical durability. Little is known about which patient characteristics are associated with faster or more durable ketamine responses. Ketamine’s antidepressant mechanism is proposed to involve modulation of glutamatergic signaling leading to long term potentiation (LTP) and synaptogenesis, and these neuroplasticity pathways have been shown to be attenuated with older age. We therefore investigated the impact of patient age on the speed and durability of ketamine’s antidepressant effects in veterans receiving serial intravenous ketamine infusions for TRD.

Methods

Beck Depression Inventory (BDI-II) scores from 49 veterans receiving six ketamine infusions (twice weekly) were examined from a retrospective case series. Percent change in BDI-II scores across the infusion series were assessed with respect to patient age using a mixed-linear model. Follow-up analyses examined the age x infusion number interaction effect at each assessment time point. To assess treatment durability, BDI-II change scores three weeks following the sixth infusion were correlated with age.

Results

There was a significant age x infusion number interaction (F=3.01, p=.0274) across the six infusions. Beta estimates at each infusion showed a significant effect of age at infusion #4 (B=.88% +/-.29%, t=3.02, p=. 004) and a trend towards significance at infusion #5 (B=.62% +/-.31%, t=1.95, p=.057). There was no significant correlation between percent change in BDI-II and age at three-week follow-up.

Conclusions

Older age is associated with an altered trajectory of antidepressant response across serial ketamine infusions, with a model-predicted difference of 8.8% less improvement in BDI-II score for each decade in age mid-way through the infusion course. In contrast, antidepressant durability at three-week follow-up was not related to age. These data suggest age is an important moderating factor of patient response to ketamine, and that differing mechanisms may underlie speed and durability of ketamine’s antidepressant activity.
Peri-adolescent THC exposure does not lead to anxiety-like behavior in adult mice
Authors: Sestan-Pesa Matija , Shanabrough Marya , Horvath Tamas L. , Miletta Maria Consolata
Published: September 2020

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illness, such as schizophrenia, depression, and anxiety. Ghrelin is a peptide produced primarily in the gut and is important for feeding behavior. Recent studies have shown that ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) play important roles in mediating stress, as well as anxiety and, depression-like behaviors in animal models. Here, we investigated the effects of chronic Tetrahydrocannabinol (THC) administration during adolescence (P42-55), in GHSR (GHSR-/-) knockout mice and their wild type littermates in relation to anxiety-like behaviors. We found that continuous THC exposure during peri-adolescence did not lead to any significant alterations in anxiety-like behavior of male adult mice, regardless of genotype. These data indicate that in the presence of intact GHSR signaling, THC exposure during peri-adolescence has limited if any long term impact on anxiety-like behaviors in mice.
Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2in vitro
Authors: Drayman Nir , Jones Krysten A. , Azizi Saara-Anne , Froggatt Heather M. , Tan Kemin , Maltseva Natalia Ivanovna , Chen Siquan , Nicolaescu Vlad , Dvorkin Steve , Furlong Kevin , Kathayat Rahul S. , Firpo Mason R. , Mastrodomenico Vincent , Bruce Emily A. , Schmidt Madaline M. , Jedrzejczak Robert , Muñoz-Alía Miguel Á. , Schuster Brooke , Nair Vishnu , Botten Jason W. , Brooke Christopher B. , Baker Susan C. , Mounce Bryan C. , Heaton Nicholas S. , Dickinson Bryan C. , Jaochimiak Andrzej , Randall Glenn , Tay Savaş
Published: September 2020

There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.
Heterogeneity of age-related neural hyperactivity along the CA3 transverse axis
Authors: Lee Heekyung , Wang Zitong , Zeger Scott , Gallagher Michela , Knierim James J.
Published: September 2020

Age-related memory deficits are correlated with neural hyperactivity in the CA1 and CA3 regions of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between the normal tradeoff between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from male young and aged Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite trend, with a decreasing gradient from proximal to distal CA3. Thus, CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared to young rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus, the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote bistable representations under certain conditions.
Climate change alters plant-herbivore interactions
Authors: Hamann Elena , Blevins Cameron , Franks Steven J. , Jameel M. Inam , Anderson Jill T.
Published: September 2020

Plant-herbivore interactions have evolved in response to co-evolutionary dynamics, along with selection driven by abiotic conditions. We examine how abiotic factors influence trait expression in both plants and herbivores to evaluate how climate change will alter this long-standing interaction. The paleontological record documents increased herbivory during periods of global warming in the deep past. In phylogenetically-corrected meta-analyses, we find that elevated temperatures, CO2concentration, drought stress and nutrient conditions directly and indirectly induce greater herbivore consumption, primarily in agricultural systems. Additionally, elevated CO2delays herbivore development, but increased temperatures accelerate development. For annual plants, higher temperatures, CO2, and drought stress increase foliar herbivory, and our meta-analysis suggests that greater temperatures and drought may heighten florivory in perennials. Human actions are causing concurrent shifts in CO2, temperature, precipitation regimes and nitrogen deposition, yet few studies evaluate interactions among these changing conditions. We call for additional multifactorial studies that simultaneously manipulate multiple climatic factors, which will enable us to generate more robust predictions of how climate change could disrupt plant-herbivore interactions. Finally, we consider how shifts in insect and plant phenology and distribution patterns could lead to ecological mismatches, and how these changes may drive future adaptation and coevolution between interacting species.
Decoding of attentional state using high-frequency local field potential is as accurate as using spikes
Authors: Prakash Surya S , Das Aritra , Kanth Sidrat Tasawoor , Mayo J. Patrick , Ray Supratim
Published: September 2020

Local field potentials (LFPs) in visual cortex are reliably modulated when the subject’s focus of attention is cued into versus out of the receptive field of the recorded sites, similar to modulation of spiking activity. However, human psychophysics studies have used an additional attention condition, neutral cueing, for decades. The effect of neutral cueing on spiking responses was examined recently and found to be intermediate between cued and uncued conditions. However, whether LFPs are also precise enough to represent graded states of attention is unknown. We found that LFPs during neutral cueing were intermediate between cued and uncued conditions, and, for a single electrode, attention was more discriminable using high frequency (>30 Hz) LFP power than spikes. Surprisingly, spikes did not outperform LFPs even when discriminability was computed using multiple electrodes. These results constrain the spatial scale attention operates over and highlight the usefulness of LFPs in studying attention.
Pre-existing intratumoral CD8 T cells substantially contribute to control tumors following therapeutic anti-CD40 and polyI:C based vaccination
Authors: Stevens Aaron D. , Bullock Timothy N.J.
Published: September 2020

Background

Dendritic cells are potently activated by the synergistic action of CD40 stimulation in conjunction with signaling through toll like receptors, subsequently activating antigen specific T cells. Cancer vaccines targeting the activation of dendritic cells in this manner show promise in murine models and are being developed for human cancer patients. While vaccine efficacy has been established, further investigation is needed to understand the mechanism of tumor control and how vaccination alters tumor infiltrating immune cells.

Methods

Mice bearing established murine melanoma tumors were vaccinated with agonist anti-CD40, polyI:C, and tumor antigen. Intratumoral T cell numbers, differentiation state, proliferation, and survival were assessed by flow cytometry. T cell effector function was measured both within the tumor and ex vivo by flow cytometry. T cell trafficking was blocked to examine changes to intratumoral T cells present at the time of vaccination.

Results

Vaccination led to increased intratumoral T cell numbers and delayed tumor growth. Expansion of T cells and tumor control did not require trafficking of T cells from the periphery. The increase in intratumoral T cells was associated with an acute burst in proliferation but not changes in viability. Intratumoral T cells had lower PD-1 and Eomes expression but were less functional after vaccination on a per cell basis. However, the increased intratumoral T cell numbers yielded increased effector T cells per tumor.

Conclusions

Pre-infiltrated CD8 T cells are responsive to CD40/TLR-mediated vaccination and sufficient for vaccination to delay tumor growth when additional T cell trafficking is blocked. This indicates that the existing T cell response and intratumoral DC could be critical for vaccination efficacy. This also suggests that circulating T cells may not be an appropriate biomarker for vaccination efficacy.
Population and comparative genetics of thermotolerance divergence between yeast species
Authors: Abrams Melanie B. , Dubin Claire A. , AlZaben Faisal , Bravo Juan , Joubert Pierre M. , Weiss Carly V. , Brem Rachel B.
Published: September 2020

Many familiar traits in the natural world—from lions’ manes to the longevity of bristlecone pine trees—arose in the distant past, and have long since fixed in their respective species. A key challenge in evolutionary genetics is to figure out how and why species-defining traits have come to be. We used the thermotolerance growth advantage of the yeastSaccharomyces cerevisiaeover its sister speciesSaccharomyces paradoxusas a model for addressing these questions. Analyzing loci at which theS. cerevisiaeallele promotes thermotolerance, we detected robust evidence for positive selection, including amino acid divergence between the species and conservation withinS. cerevisiaepopulations. Since such signatures were particularly strong at the chromosome segregation geneESP1, we used this locus as a case study for focused mechanistic follow-up. Experiments revealed that, in culture at high temperature, theS. paradoxus ESP1allele conferred a qualitative defect in biomass accumulation and cell division relative to theS. cerevisiaeallele. Only genetic divergence in theESP1coding region mattered phenotypically, with no functional impact detectable from the promoter. Together, these data support a model in which an ancient ancestor ofS. cerevisiae, under selection to boost viability at high temperature, acquired amino acid variants atESP1and many other loci, which have been constrained since then. Complex adaptations of this type hold promise as a paradigm for interspecies genetics, especially in deeply diverged traits that may have taken millions of years to evolve.
Confirmatory evidence that healthy individuals can adaptively adjust prior expectations and interoceptive precision estimates
Authors: Smith Ryan , Kuplicki Rayus , Teed Adam , Upshaw Valerie , Khalsa Sahib S.
Published: September 2020

Theoretical proposals have previously been put forward regarding the computational basis of interoception. Following on this, we recently reported using an active inference approach to 1) quantitatively simulate interoceptive computation, and 2) fit the model to behavior on a cardiac awareness task. In the present work, we attempted to replicate our previous results in an independent group of healthy participants. We provide evidence confirming our previous finding that healthy individuals adaptively adjust prior expectations and interoceptive sensory precision estimates based on task context. This offers further support for the utility of computational approaches to characterizing the dynamics of interoceptive processing.
Designing and studying a mutant form of the ice-binding protein fromChoristoneura fumiferana
Authors: Glukhova Ksenia A. , Okulova Julia D. , Melnik Bogdan S.
Published: September 2020

Ice-binding proteins are expressed in the cells of some organisms, helping them to survive extremely low temperatures. One of the problems in study of such proteins is the difficulty of isolation and purification. For example, eight cysteine residues in cfAFP fromChoristoneura fumiferana(the eastern spruce budworm) form intermolecular bridges during the overexpression of this protein. This impedes the process of the protein purification dramatically.

In this work we designed a mutant form of ice-binding protein cfAFP, which is much more easy to isolate that the wild-type protein. The mutant form named mIBP83 did not lose the ability to bind to ice surface. Besides, observation of the processes of freezing and melting of ice in presence of mIBP83 showed that this protein affects the process of ice melting, increasing its melting temperature, and at least does not decrease the freezing temperature.
Date palm virus A: first plant virus found in date palm trees
Authors: Maachi Ayoub , Nagata Tatsuya , Silva João Marcos Fagundes
Published: September 2020

In this work, a novel ssRNA (+) viral genomic sequence with gene organization typical of members of the subfamilyQuinvirinae(familyBetaflexiviridae) was identified using high throughput sequencing data of date palm obtained from the Sequence Read Archive database. The viral genome sequence consists of 7860 nucleotides and contains five ORFs encoding for the replication protein (Rep), triple gene block proteins 1, 2, 3 (TGB 1, 2 and 3) and coat protein (CP). Phylogenetic analysis based on the Rep and the CP amino acid sequences showed the closest relationship to garlic yellow mosaic-associated virus (GYMaV). Based on the demarcation criteria of the familyBetaflexiviridae, this new virus, provisionally named date palm virus A (DPVA), could constitute a member of a novel genus. However, considering that DPVA and GYMaV share the same genomic organization and that they cluster together on the Rep phylogenetic analysis, they could also constitute a novel genus together, highlighting the necessity of a revision of the taxonomic criteria of the familyBetaflexiviridae.
IL-4-induced hysteresis in naïve T cell activation
Authors: Meli Alexandre P. , Wang Yaqiu , de Kouchkovsky Dimitri A. , Kong Yong , Basu Malay K. , Ghosh Sourav , Rothlin Carla V.
Published: September 2020

Naïve T cells are generally considered to be a homogeneous population, but for their unique T cell receptors (TCRs). Naïve T cells are activated within a specific cytokine milieu upon interaction with antigen-presenting cells through cognate TCR::MHC-peptide interaction and co-stimulation. Here we demonstrate that naïve T cells are transcriptionally heterogeneous, and that the relative proportions of transcriptionally distinct naïve T cell subpopulations are modified by immune responses, such as during helminth infection. Not only are cognate naïve T cells activated during an immune response, but the cytokine produced - such as IL-4 during helminth infection - changes the transcriptome of bystander naïve T cells. Such changes in gene expression and population level heterogeneity in bystander naïve T cells result in altered responses to a concurrent immune challenge, for instance, hypo-responsiveness to vaccination. Thus, naïve T cell activation is not the result of a singular temporal event, but is characterized by hysteresis. Our studies suggest that antigen-agnostic, cytokine-dependent naïve T cell conditioning and resulting hysteresis is a mechanism that integrates input signals from concurrent infections for the regulation of the overall magnitude of the immune response.
SLEAP: Multi-animal pose tracking
Authors: Pereira Talmo D. , Tabris Nathaniel , Li Junyu , Ravindranath Shruthi , Papadoyannis Eleni S. , Wang Z. Yan , Turner David M. , McKenzie-Smith Grace , Kocher Sarah D. , Falkner Annegret L. , Shaevitz Joshua W. , Murthy Mala
Published: September 2020

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation to quantify and model natural animal behavior. This has led to important advances in deep learning-based markerless pose estimation that have been enabled in part by the success of deep learning for computer vision applications. Here we present SLEAP (Social LEAP Estimates Animal Poses), a framework for multi-animal pose tracking via deep learning. This system is capable of simultaneously tracking any number of animals during social interactions and across a variety of experimental conditions. SLEAP implements several complementary approaches for dealing with the problems inherent in moving from single-to multi-animal pose tracking, including configurable neural network architectures, inference techniques, and tracking algorithms, enabling easy specialization and tuning for particular experimental conditions or performance requirements. We report results on multiple datasets of socially interacting animals (flies, bees, and mice) and describe how dataset-specific properties can be leveraged to determine the best configuration of SLEAP models. Using a high accuracy model (<2.8 px error on 95% of points), we were able to track two animals from full size 1024 × 1024 pixel frames at up to 320 FPS. The SLEAP framework comes with a sophisticated graphical user interface, multi-platform support, Colab-based GPU-free training and inference, and complete tutorials available, in addition to the datasets, atsleap.ai.
Ciliary signaling-patterned smooth muscle drives tubular elongation
Authors: Yang Ying , Paivinen Pekka , Xie Chang , Krup Alexis Leigh , Makela Tomi P. , Mostov Keith E. , Reiter Jeremy F.
Published: September 2020

During development, many tubular organs undergo extensive longitudinal growth to reach their defined length, essential for their function, but how they lengthen is poorly understood. Here, we found that primary cilia are critical for the elongation of the small intestine and esophagus during murine embryonic development. More specifically, HH ligands produced by the epithelium signaled via cilia in the surrounding mesenchyme to pattern the smooth muscle. Like attenuated ciliary HH signaling, partial ablation of the smooth muscle reduced elongation, revealing an essential role for smooth muscle in longitudinal growth. Disruption of cilia, HH signaling or the smooth muscle reduced residual stress within the gut wall, indicating that smooth muscle contributes to the mechanical properties of the developing gut. Reducing residual stress decreased nuclear YAP, an effector of the mechanotransductive Hippo pathway. Removing YAP in the mesenchyme did not affect smooth muscle formation, but attenuated proliferation and elongation, demonstrating that YAP interprets smooth muscle-generated force to promote proliferation. Together, our results reveal that ciliary signaling directs the formation of the smooth muscle layer which, in turn, generates mechanical forces that activate YAP-mediated proliferation. As this interplay of biochemical and mechanical signals drives elongation of both the esophagus and small intestine, we propose that this mechanism may underlie tubular organ elongation generally.

Highlights

Primary cilia are essential for the elongation of the small intestine and esophagus during embryonic development

Ciliary signaling patterns the smooth muscle in the developing intestine and esophagus

The smooth muscle contributes to tissue mechanics

Smooth muscle-generated strain activates YAP to drive longitudinal growth of the tubular organs
SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response
Authors: Soni Bhavnita , Singh Shailza
Published: September 2020

Macrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified bothin silicoas well asin vitro, indicating an immune axis which governs the macrophage phenotype duringL. majorinfection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.