bluuebunny/crossref_metadata_2025 huggingface dataset:
How the COVID-19 pandemic is favoring the adoption of digital technologies in healthcare: a rapid literature review
Authors: Golinelli Davide , Boetto Erik , Carullo Gherardo , Landini Maria Paola , Fantini Maria Pia
Published: May 2020

Background

Healthcare is responding to the COVID-19 pandemic through the fast adoption of digital solutions and advanced technology tools. Many of the solutions implemented now could consolidate in the near future, contributing to the definition of new digital-based models of care. The aim of this study is to describe which digital solutions have been reported in the early scientific literature to respond and fight the COVID-19 pandemic.

Methods

We conducted a rapid literature review searching PubMed and MedrXiv with terms considered adequate to find relevant literature on the use of digital technologies in response to COVID-19.

Results

The search identified 52 articles, of which 38 full-text articles were assessed and 29 included in the review after screening. Of selected articles, most of them addressed the use of digital technologies for diagnosis, surveillance and prevention. We report that digital solutions and innovative technologies have mainly been proposed for the diagnosis of COVID-19. In particular, within the reviewed articles we identified numerous suggestions on the use of artificial intelligence-powered tools for the diagnosis and screening of COVID-19. Digital technologies are useful also for prevention and surveillance measures, for example through contact-tracing apps or monitoring of internet searches and social media usage.

Discussion

It is worth taking advantage of the push given by the crisis, and mandatory to keep track of the digital solutions proposed today to implement tomorrow’s best practices and models of care, and to be ready for any new moments of emergency.
Spread of virus during soccer matches
Authors: Knudsen Nikolas S. , Thomasen Manuel M. , Andersen Thomas B.
Published: May 2020

In the present study, the exposure to virus during soccer matches is calculated. Tracking data from 14 elite matches was used. One player in each match was carrying a virus. The exposure score (measured in seconds) was calculated as time spent closer than 1.5m from the infected player or time spent in an exponentially declining zone where the infected player was positioned earlier. The results reveal that, on average, each player was exposed for 87.8s per match.
Risk assessment via layered mobile contact tracing for epidemiological intervention
Authors: Guttal Vishwesha , Krishna Sandeep , Siddharthan Rahul
Published: May 2020

There is strong interest globally amidst the current COVID-19 pandemic in tracing contacts of infectious patients using mobile technologies, both as a warning system to individuals and as a targeted intervention strategy for governments. Several governments, including India, have introduced mobile apps for this purpose, which give a warning when the individual’s phone establishes bluetooth contact with the phone of an infected person. We present a methodology to probabilistically evaluate risk of infection given the network of contacts that individuals are likely to encounter in real life. Instead of binary “infected” or “uninfected” statuses, an infection risk probability is maintained which can be efficiently calculated based on probabilities of recent contacts, and updated when a recent contact is diagnosed with a disease. We demonstrate on realistic networks that this method sharply outperforms a naive immediate-contact method even in an ideal circumstance that all infected persons are known to the naive method. We demonstrate robustness to missing contact information (such as when phones fail to make bluetooth contact or the app is not installed). We show, within our model, a strong flattening of the infectious peak when even a small fraction of cases are identified, tested and isolated. In the real world, where most known-infected persons are isolated or quarantined and where many individuals may not carry their mobiles in public, we believe the improvement offered by our method warrants consideration. Importantly, in view of widespread concerns on privacy and contact-tracing, our method relies mainly on direct contact data that can be stored locally on users’ phones, and uses limited communication via intermediary servers only upon testing, mitigating privacy concerns.
Preparedness and Mitigation by projecting the risk against COVID-19 transmission using Machine Learning Techniques
Authors: Kumar Akshay , Khan Farhan Mohammad , Gupta Rajiv , Puppala Harish
Published: May 2020

The outbreak of COVID-19 is first identified in China, which later spread to various parts of the globe and was pronounced pandemic by the World Health Organization (WHO). The disease of transmissible person-to-person pneumonia caused by the extreme acute respiratory coronavirus 2 syndrome (SARS-COV-2, also known as COVID-19), has sparked a global warning. Thermal screening, quarantining, and later lockdown were methods employed by various nations to contain the spread of the virus. Though exercising various possible plans to contain the spread help in mitigating the effect of COVID-19, projecting the rise and preparing to face the crisis would help in minimizing the effect. In the scenario, this study attempts to use Machine Learning tools to forecast the possible rise in the number of cases by considering the data of daily new cases. To capture the uncertainty, three different techniques: (i) Decision Tree algorithm, (ii) Support Vector Machine algorithm, and (iii) Gaussian process regression are used to project the data and capture the possible deviation. Based on the projection of new cases, recovered cases, deceased cases, medical facilities, population density, number of tests conducted, and facilities of services, are considered to define the criticality index (CI). CI is used to classify all the districts of the country in the regions of high risk, low risk, and moderate risk. An online dashpot is created, which updates the data on daily bases for the next four weeks. The prospective suggestions of this study would aid in planning the strategies to apply the lockdown/ any other plan for any country, which can take other parameters to define the CI.
Super-spreading events initiated the exponential growth phase of COVID-19 with ℛ0 higher than initially estimated
Authors: Kochańczyk Marek , Grabowski Frederic , Lipniacki Tomasz
Published: May 2020

The basic reproduction number ℛ0 of the coronavirus disease 2019 has been estimated to range between 2 and 4. Here we used a SEIR model that properly accounts for the distribution of the latent period and, based on empirical estimates of the doubling time in the near-exponential phases of epidemic progression in several locations, we estimated that ℛ0 lies in the range 4.7–11.4. We explained this discrepancy by performing stochastic simulations of model dynamics in a population with a small proportion of super-spreaders. The simulations revealed two-phase dynamics, in which an initial phase of relatively slow epidemic progression diverts to a faster phase upon appearance of infectious super-spreaders. Early estimates obtained for this initial phase may suggest lower ℛ0.
Knowledge, Attitudes, and Practices (KAP) Towards COVID-19: An Online Cross-Sectional Survey of Tanzanian Residents
Authors: Rugarabamu Sima , Ibrahim Mariam , Byanaku Aisha
Published: May 2020

Background

The Corona Virus Disease -19 (COVID-19) pandemic is a global health emergency that requires the adoption of unprecedented measures to control its rapid spread. Tanzanians’ adherence to control measures is affected by their knowledge, attitudes, and practices (KAP) towards the disease. This study was carried out to investigate knowledge, attitudes and practices towards COVID-19 among residents in Tanzania during the April – May 2020 period of the epidemic.

Methods

This cross-sectional study analyzes responses of self-selected Tanzanians who responded to an invitation to complete an online questionnaire. Survey Monkey tool was used to develop the questionnaire used for data collection. The survey assessed demographic characteristics of participants as well as their knowledge, attitudes, and practices toward COVID-19. A Chi-square analysis was used to compare proportions. Analysis of variance (ANOVA) was used to determine differences among age groups, whereas results were considered significant if the p-value was <0.05

Results

Four hundred residents completed the survey. The mean age of study participants was 32 years, and the majority was female (n= 216,54.0%). There were no significant differences in demographic variables). Participants with a bachelor’s degree or above (n= 241, 60.3%) had higher scores. Overall, 84.4% (n=338) of participants had good knowledge, which was significantly associated with education level (p=0.001). Nearly all participants (n=384, 96.0%) had confidence that COVID-19 will be eliminated. The majority of respondents (n=308, 77.0%) did not go to a crowded place in recent days. Multiple linear regression analysis showed that males, age-group 16-29 years, and education of secondary or lower (OR = 1.2, CI = 1.3–1.5) were significantly associated with lower knowledge score.

Conclusions

Our findings revealed good knowledge, optimistic attitudes, and appropriate practices towards preventing COVID-19 infection. Suggesting that community-based health education programs about COVID-19 is helpful and necessary to control the disease.
Spatial-temporal variations of atmospheric factors contribute to SARS-CoV-2 outbreak
Authors: Fronza Raffaele , Lusic Marina , Schmidt Manfred , Lucic Bojana
Published: May 2020

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19) reached over two million confirmed cases worldwide, and numbers are still growing at a fast rate. The majority of new infections are now being reported outside of China, where the outbreak officially originated in December 2019 in Wuhan. Despite the wide outbreak of the infection, a remarkable asymmetry is observed in the number of cases and in the distribution of the severity of the COVID-19 symptoms in patients with respect to the countries/regions. In the early stages of a new pathogen outbreak, it is critical to understand the dynamics of the infection transmission, in order to follow contagion over time and project the epidemiological situation in the near future. While it is possible to reason that observed variation in the number and severity of cases stem from the initial number of infected individuals, the difference in the testing policies and social aspects of community transmissions, the factors that could explain high discrepancy in areas with a similar level of healthcare still remain unknown. Here we introduce a binary classifier based on an artificial neural network that can help in explaining those differences and that can be used to support the design of containment policies. We propose that air pollutants, and specifically particulate matter (PM) 2.5 and ozone, are oppositely related with the SARS-CoV-2 infection frequency and could serve as surrogate markers to complement the infection outbreak anticipation.
Elementary spatial structures and dispersion of COVID-19: health geography directing responses to public health emergency in São Paulo State, Brazil
Authors: Fortaleza Carlos Magno Castelo Branco , Guimarães Raul Borges , Catão Rafael de Castro , Ferreira Cláudia Pio , de Almeida Gabriel Berg , Pugliesi Edmur
Published: May 2020

Public health policies to contain the spread of COVID-19 rely mainly on non-pharmacological measures. Those measures, especially social distancing, are a challenge for developing countries, such as Brazil. In São Paulo, the most populous state in Brazil (45 million inhabitants), most COVID-19 cases up to April 18th were reported in the Capital and metropolitan area. However, the inner municipalities, where 20 million people live, are also at risk. As governmental authorities discuss the loosening of measures for restricting population mobility, it is urgent to analyze the routes of dispersion of COVID-19 in those municipalities. In this ecological study, we use geographical models of population mobility as patterns for spread of SARS-Cov-2 infection. Based on surveillance data, we identify two patterns: one by contiguous diffusion from the capital metropolitan area and other that is hierarchical, with long-distance spread through major highways to cities of regional relevance. We also modelled the impact of social distancing strategies in the most relevant cities, and estimated a beneficial effect in each and every setting studied. This acknowledgement can provide real-time responses to support public health strategies.
Decontamination of filtering facepiece respirators in primary care using medical autoclave
Authors: Harskamp Ralf E. , van Straten Bart , Bouman Jonathan , van Maltha - van Santvoort Bernadette , van den Dobbelsteen John J. , van der Sijp Joost R.M. , Horeman Tim
Published: May 2020

Objective

There are widespread shortages of personal protective equipment as a result of the coronavirus disease 2019 (COVID-19) pandemic. Reprocessing filtering facepiece respirators may provide an alternative solution in keeping health care professionals safe.

Design

prospective, bench-to-bedside

Setting

A primary care-based study using filtering facepiece particles (FFP) type 2 respirators without exhalation valve (3M Aura 1862+, Maco Pharma ZZM002), FFP2 respirators with valve (3M Aura 9322+ and San Huei 2920V), and valved FFP type 3 respirators (Safe Worker 1016).

Interventions

All masks were reprocessed using a medical autoclave (34-minute total cycle time of steam sterilization, with 17 minutes at 121°C) and subsequently tested up to 3 times whether these decontaminated respirators retained their integrity (seal check, pressure drop) and ability to filter small particles (0.3-5.0μm) in the laboratory using a particle penetration test.

Results

We tested 32 respirators, and 63 samples for filter capacity. All 27 FFP-2 respirators retained their shape, whereas half of the sterilized FFP-3 respirators (Safe Worker 1116) showed deformities and failed the seal check. The filtering capacity of the 3M Aura 1862 was best retained after 1, 2, and 3 sterilization cycles (0.3μm: 99.3±0.3% (new) versus 97.0±1.3, 94.2±1.3% or 94.4±1.6, p<0.001). Of the other FFP-2 respirators, the San Huei 2920V had 95.5±0.7% at baseline versus 92.3±1.7% versus 90.0±0.7 after one- and two-time sterilization, respectively (p<0.001). The tested FFP-3 respirator (Safe Worker 1016) had a filter capacity of 96.5±0.7% at baseline and 60.3±5.7% after one-time sterilization (p<0.001). Breathing and pressure resistance tests indicated no relevant pressure changes between respirators that were used once, twice or thrice.

Conclusion

This study shows that selected FFP2-type respirators may be reprocessed for use in primary care, as the tested masks retain their shape, ability to retain particles and breathing comfort after decontamination using a medical autoclave.

Strengths and limitations of this study

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Pragmatic use of autoclave to sterilize and reuse filter facepiece respirators

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Combining clinical and laboratory findings to evaluate the safety in terms of shape, ability to retain particles and breathing comfort

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The study is limited in sample size and restricted to selected FFP-2 and FFP-3 respirators

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The study is a first of its kind in primary care settings and thus unvalidated

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The study does not provide "hard" clinical evidence in terms of a randomized trial (i.e. reprocessed mask versus usual care)
Severe Acute Respiratory Syndrome Coronavirus 2 Serology in Asymptomatic Healthcare Professionals: Preliminary Experience of a Tertiary Italian Academic Center
Authors: Tosato F , Pelloso M , Gallo N , Giraudo C , Llanaj G , Cosma C , Pozzato C , Padoan A , Donato D , Plebani M
Published: May 2020

We investigated the SARS-CoV-2 specific antibody titers in 133 asymptomatic healthcare providers working at the Department of Laboratory Medicine of our tertiary center. A commercial chemiluminescence immunoassay, validated according to the ISO15189 standard requirements, was used. All the enrolled healthcare professionals underwent, simultaneously to the blood sampling, a nasopharyngeal swab for molecular testing with quantitative reverse-transcriptase-based polymerase chain reaction (RT-PCR). An overall positiveness of 5.25% was found. We strongly promote a wide use of validated serologic assays in asymptomatic, healthy individuals, as a crucial information for epidemiological surveillance.
Shedding of infectious SARS-CoV-2 in symptomatic neonates, children and adolescents
Authors: L’Huillier Arnaud G , Torriani G , Pigny F , Kaiser L , Eckerle I
Published: May 2020

Children are underrepresented in COVID-19 case numbers, with most pediatric cases exhibiting limited severity, and do not seem to be major drivers of transmission, unlike for other respiratory viruses. That said, SARS-CoV-2 infects children across all age groups, and despite the high proportion of mild or asymptomatic infections, it would be naïve not to consider them as transmitters. To address this point we used cell culture to systematically assess the presence of cultivable SARS-CoV-2 in the upper respiratory tract in a cohort of our institution’s first 23 symptomatic neonates, children and teenagers with COVID-19 diagnosed by RT-PCR.

Median age was 12.0 years (interquartile range [IQR 3.8–14.5], range 7 days-15.9 yrs). Most patients had an upper respiratory tract infection (n=13), followed by fever without source and pneumonia (each, n=2). Samples were collected at a median of 2 days (IQR 1–3) after symptom onset. Median viral load (VL) at time of diagnosis was 3.0×106 copies/ml (mean 4,4×108, IQR 6.9×103–4.4×108) from a nasopharyngeal swab (NPS).

SARS-CoV-2 virus isolation was successful in 12/23 (52%) children after inoculating VeroE6 cells with a NPS specimen. SARS-CoV-2 isolation was determined by the presence of a typical cytopathic effect (CPE) and increased viral RNA in the supernatant. SARS-CoV-2 replication in all positive isolates (12/12) was confirmed by a second passage using new VeroE6 cells.

Virus isolation was successful from NPS from all age groups, with a median initial VL of 1.7×108 copies/ml (mean 7.9×108, IQR 4.7×106–1.0×109) (Figure 1). The youngest patient that SARS-CoV-2 was isolated from was a 7-day old neonate. No correlation between disease presentation and success of virus isolation was observed.

Our data show that initial VLs at diagnosis in symptomatic children is comparable to those in adults, and that symptomatic children of all ages shed infectious virus in early acute illness. Infectious virus isolation success was largely comparable to that of adults, although two specimens yielded an isolate at a lower VL (1.2×104 and 1.4×105 copies/ml) than what was observed in adults.

SARS-CoV-2 shedding patterns of culture competent virus in symptomatic children resemble those observed in adults. Therefore, transmission of SARS-CoV-2 from children is plausible. Considering the relatively low frequency of infected children at this time, biological or other unknown factors could reduce transmission in this population. Both large serological investigations and systematic surveillance of acute respiratory diseases are needed to understand the role of children in this new pandemic.
COVID-19-induced acute respiratory failure – an exacerbation of organ-specific autoimmunity?
Authors: Gagiannis D , Steinestel J , Hackenbroch C , Hannemann M , Umathum V , Gebauer N , Stahl M , Witte H , Steinestel K
Published: May 2020

Background

Understanding the pathophysiology of respiratory failure (ARDS) in coronavirus disease 2019 (COVID-19) patients is of utmost importance for the development of therapeutic strategies and identification of risk factors. Since we observed clinical and histopathological similarities between COVID-19 and lung manifestations of connective tissue disease (CTD-ILD) in our clinical practice, aim of the present study is to analyze a possible role of autoimmunity in SARS-CoV-2-associated respiratory failure.

Methods

In this prospective, single-center trial, we enrolled 22 consecutive patients with RT-PCR-confirmed SARS-CoV-2 infection hospitalized in March and April, 2020. We performed high-resolution computed tomography (HR-CT) and full laboratory testing including autoantibody (AAB) screening (anti-ANA, SS-B/La, Scl-70, Jo-1, CENP-B, PM-Scl). Transbronchial biopsies as well as post mortem tissue samples were obtained from 3 and 2 cases, respectively, and subsequent histopathologic analysis with special emphasis on characterization of interstitial lung disease was performed.

Results

Twelve of 22 patients (54.5%) were male and median age was 69.0 (range: 28-88). 11 (50.0%) patients had to be undergo intensive care unit (ICU) treatment. Intubation with ventilation was required in 10/22 cases (46%). Median follow-up was 26 days. Clinical and serological parameters were comparable to previous reports. Radiological and histopathological findings were highly heterogeneous including patterns reminiscent of CTD-ILD. AAB titers ≥1:100 were detected in 10/11 (91.9%) COVID-19 patients who required ICU treatment, but in 4/11 (36.4%) patients with mild clinical course (p=0.024). Patients with AABs tended to require invasive ventilation and showed significantly more severe complications (64.3% vs. 12.5%, p=0.031). Overall COVID-19-related mortality was 18.2% among hospitalized patients at our institution.

Conclusion

Our findings point out serological, radiological and histomorphological similarities between COVID-19-associated ARDS and acute exacerbation of CTD-ILD. While the exact mechanism is still unknown, we postulate that SARS-CoV-2 infection might trigger or simulate a form of organ-specific autoimmunity in predisposed patients. The detection of autoantibodies might identify patients who profit from immunosuppressive therapy to prevent the development of respiratory failure.
Assessment of Adverse Events Reported to The Poison Control and Forensic Chemistry Center in Jeddah, Saudi Arabia
Authors: Almuntashiri Nawaf , Alsahafi Osama , Gamaruddin Mohammad , Hammad Sherif Attia , Tobaiqy Mansour
Published: May 2020

Background

Poisoning is a major public health threat in many countries across the globe, including Saudi Arabia. Poison control facilities help to provide immediate treatment to the patients affected by poisoning. Poisoning cases from various regions of the Kingdom are reported to the Poison Control and Forensic Chemistry Centers.

Aims

This study aimed at assessment of the demographics, risk factors and management of various poisoning cases reported at the Poison Control and Forensic Chemistry Center in Jeddah, Saudi Arabia.

Methods

Data was collected from the poisoning archived forms, between 01-01-2019 to 30-12-2019. A data collection sheet was designed to collect information about the region of call, age and gender of the patient, type, place, route and pattern of poisoning. All the data was analyzed through SPSS software.

Results

Most cases of intoxications were occurred and reported from the Western Region of Saudi Arabia (n=97, 38%), and were for males (n=137, 54%). The majority of poisoning cases occurred in children under 5-years of age (n=198, 78%). Poisoning cases were accidental (n=233, 92%) and intentional (n=11, 4%), and most (n=246, 96%) occurred at home. Drug poisoning was more common (n=155, 61%) than chemical poisoning (n=92, 36%). The rout of poisoning was oral in the vast majority of incidents (n=242, 94%). Intentional poisoning was more common in females (n=8, 3%). All poisoning reports initiated by physicians and other healthcare professionals (n=253, 100%), within one hour of the poisoning (n=144, 57%) and after one home (n=109, 43%). Decontamination with active charcoal (n=62, 24%) was the most common method recommended to manage intoxicated patients, followed by gastric lavage (n=9, 3.5%).

Conclusion

The current study assessed the reports of adverse events in a poisoning center in Saudi Arabia, most cases were related to medicines, followed by chemicals and most occurred at home. Most of poisoning cases are unintentional and occurred at home due to ingestion of medicinal products. Therefore, awareness of parents about the potent poisons at home may help to minimize the occurrence of such adverse events.
A Novel Gene ZNF862 Causes Hereditary Gingival Fibromatosis
Authors: Wu Juan , Chen Dongna , Huang Hui , Luo Ning , Chen Huishuang , Zhao Junjie , Wang Yanyan , Ren Yang , Zhai Teng , Sun Weibin , Li Houxuan , Li Wei
Published: May 2020

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis which is featured as a localized or generalized overgrowth of gingivae. HGF is genetically heterogeneous and usually be transmitted as an autosomal-dominant inheritance pattern, also can be as autosomal-recessive or occur sporadically. Currently only two genes (SOS1 and REST), as well as four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15), have been identified as associated with HGF in a dominant inheritance pattern. Here we report thirteen individuals with autosomal-dominant non-syndromic HGF from a large four-generation Chinese family. Whole-exome sequencing followed by further genetic co-segregation analysis was performed for the family members across three generations. A novel heterozygous missense mutation (NM_001099220.3: c.2812G>A) in zinc finger protein 862 gene (ZNF862) was identified, and it is absent among the population as reported from the Genome Aggregation Database, Exome Aggregation Consortium (ExAC) and 1000 Genomes. ZNF862 is a predicted intracellular protein which function is not yet identified, as a zinc finger protein it may be involved in transcriptional regulation. ZNF862 is expressed ubiquitously across tissues, it may play various roles under different physiological condition. Here for the first time we identify the physiological role of ZNF862 for the association with the HGF trait.
Protective elements of mental health status during the COVID-19 outbreak in the Portuguese population
Authors: Moreira PS , Ferreira S , Couto B , Machado-Sousa M , Fernández M , Raposo-Lima C , Sousa N , Picó-Pérez M , Morgado P
Published: May 2020

The outbreak of COVID-19 might produce dramatic psychological effects on the individuals’ life. In this study, we aimed to explore the elements that may reduce the negative effects on mental health of the quarantine period imposed by most governments during this worldwide crisis. We conducted an online survey to evaluate demographic, lifestyle and mental health variables in the Portuguese population. We observed that factors related with living conditions, maintaining the work either online or in the workplace, frequency of exercise and absence of a previous psychological or physic disorders are protective features of psychological well-being (anxiety, depression, stress and obsessive-compulsive symptoms). Finally, the individuals previously receiving psychotherapeutic support exhibited better psychological indicators if they did not interrupt the process as a consequence of the outbreak. Our results indicate that the practice of physical exercise, reduced consumption of COVID-19 information and the implementation of remote mental healthcare measures might prevent larger impacts on mental health during the COVID-19 outbreak.
Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice
Authors: Osman Aya , Mervosh Nicholas L. , Strat Ana N. , Euston Tanner J. , Zipursky Gillian , Pollak Rebecca M. , Meckel Katherine R. , Tyler Scott R. , Chan Kenny L. , Grice Ariela Buxbaum , Drapeau Elodie , Litichevskiy Lev , Gill Jasleen , Thaiss Christoph A. , Buxbaum Joseph. D. , Breen Michael S. , Kiraly Drew D.
Published: May 2020

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associatedShank3gene (Shank3KO).Shank3KOhave altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits inShank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer
Authors: Chirravuri-Venkata Ramakanth , Ghersi Dario , Ganti Apar K. , Lakshmanan Imayavaramban , Chaudary Sanjib , Batra Surinder K. , Nasser Mohd Wasim
Published: May 2020

The contrast in therapy sensitivity and response across triple negative breast cancer (TNBC) patients suggest underlying genotypic heterogeneity. Using publicly available data, we found significant associations between DNA-level copy number alterations of 1q21.3 locus and therapy sensitivity. We show that in spite of their aggressive nature, 1q21.3 amplified tumors are more responsive to commonly used cytotoxic therapies, highlighting the relevance of 1q21.3 copy number status as a genetic marker for risk stratification, therapy selection and response.
Optimal time frequency analysis for biological data - pyBOAT
Authors: Mönke Gregor , Sorgenfrei Frieda A. , Schmal Christoph , Granada Adrián E.
Published: May 2020

Methods for the quantification of rhythmic biological signals have been essential for the discovery of function and design of biological oscillators. Advances in live measurements have allowed recordings of unprecedented resolution revealing a new world of complex heterogeneous oscillations with multiple noisy non-stationary features. However, our understanding of the underlying mechanisms regulating these oscillations has been lagging behind, partially due to the lack of simple tools to reliably quantify these complex non-stationary features. With this challenge in mind, we have developed pyBOAT, a Python-based fully automatic stand-alone software that integrates multiple steps of non-stationary oscillatory time series analysis into an easy-to-use graphical user interface. pyBOAT implements continuous wavelet analysis which is specifically designed to reveal time-dependent features. In this work we illustrate the advantages of our tool by analyzing complex non-stationary time-series profiles. Our approach integrates data-visualization, optimized sinc-filter detrending, amplitude envelope removal and a subsequent continuous-wavelet based time-frequency analysis. Finally, using analytical considerations and numerical simulations we discuss unexpected pitfalls in commonly used smoothing and detrending operations.
A Behavioral Association Between Prediction Errors and Risk-Seeking: Theory and Evidence
Authors: Moeller Moritz , Grohn Jan , Manohar Sanjay , Bogacz Rafal
Published: May 2020

Reward prediction errors (RPEs) and risk preferences have two things in common: both can shape decision making behavior, and both are commonly associated with dopamine. RPEs drive value learning and are thought to be represented in the phasic release of striatal dopamine. Risk preferences bias choices towards or away from uncertainty; they can be manipulated with drugs that target the dopaminergic system. The common neural substrate suggests that RPEs and risk preferences might be linked on the level of behavior as well, but this has never been tested. Here, we aim to close this gap. First, we apply a recent theory of learning in the basal ganglia to predict how exactly RPEs might influence risk preferences. We then test our behavioral predictions using a novel bandit task in which value and risk vary independently across options. Critically, conditions are included where options vary in risk but are matched for value. We find that subjects become more risk seeking if choices are preceded by positive RPEs, and more risk averse if choices are preceded by negative RPEs. These findings cannot be explained by other known effects, such as nonlinear utility curves or dynamic learning rates. Finally, we show that RPE-induced risk-seeking is indexed by pupil dilation: participants with stronger pupillary correlates of RPE also show more pronounced behavioral effects.

Author’s summary

Many of our decisions are based on expectations. Sometimes, however, surprises happen: outcomes are not as expected. Such discrepancies between expectations and actual outcomes are called prediction errors. Our brain recognises and uses such prediction errors to modify our expectations and make them more realistic--a process known as reinforcement learning. In particular, neurons that release the neurotransmitter dopamine show activity patterns that strongly resemble prediction errors. Interestingly, the same neurotransmitter is also known to regulate risk preferences: dopamine levels control our willingness to take risks. We theorised that, since learning signals cause dopamine release, they might change risk preferences as well. In this study, we test this hypothesis. We find that participants are more likely to make a risky choice just after they experienced an outcome that was better than expected, which is precisely what out theory predicts. This suggests that dopamine signalling can be ambiguous--a learning signal can be mistaken for an impulse to take a risk.
Histone deacetylase inhibitors butyrate and bufexamac inhibitde novoHIV-1 infection in CD4 T-cells
Authors: Chen Lin , Zutz Ariane , Phillippou-Massier Julia , Liebner Tim , Keppler Oliver T. , Choudhary Chunaram , Blum Helmut , Schölz Christian
Published: May 2020

While current combined antiretroviral therapy (cART) allows control of HIV replication in patients and effectively suppresses plasma viral loads, it is unable to target latent reservoirs, which are responsible for virus rebound after discontinuation of therapy. Several histone deacetylase inhibitors (HDACIs) have been shown to target reservoirs and to reactivate latent HIV. While this effect is highly desired, it carries the risk that HIV-1 may be reactivated in tissue compartments were cART concentrations are insufficient and thus leading tode novoinfections in this sites. To address this concern, we evaluated the effect of different HDACIs for their ability to reverse HIV latency and to modulatede novoinfections. Two of the inhibitors, sodium butyrate and bufexamac, significantly inhibitedde novoHIV-1 infection in activated CD4+T-cells. Transcriptome and proteome analysis indicated global changes of protein abundancies, exhibited reduced proliferation of CD4+T-cells, and revealed butyrate-based proteasomal degradation of EP300, an important factor for HIV-1 replication. Our results disclose new potential treatment strategies and minimizes the concern of potential reservoir reseeding by HDACIs.
Fluorescence Lifetimes and Spectra of RPE and sub-RPE Deposits in Histology of Normal and AMD Eyes
Authors: Schultz Rowena , Gamage Kushmali C. L. K. , Messinger Jeffrey D. , Curcio Christine A. , Hammer Martin
Published: May 2020

Purpose

To investigate autofluorescence lifetimes as well as spectral characteristics of drusen and retinal pigment epithelium (RPE) in age-related macular degeneration (AMD).

Method

Fluorescence lifetimes and spectra of five eyes with AMD and nine control eyes were analyzed in cryosections by means of two-photon excited fluorescence at 960 nm. Spectra were detected at 490 – 647nm. Lifetime was measured using time-correlated single photon counting in two spectral channels: 500-550nm and 550-700nm. The fluorescence decays over time were approximated by a series of three exponential functions and the amplitude-weighted mean fluorescence lifetime τmwas determined.

Results

196 sub-RPE deposits were identified (AMD n=76, healthy n=120) and 230 RPE sites recorded. The peak emission wavelength of drusen was significantly green-shifted compared to RPE (peak at 570nm vs. 610nm), but not different between patients and controls. Drusen showed considerably longer τmthan RPE: (ch1: 581 ± 163 ps vs. 177 ± 25 ps, ch2: 541 ± 125 ps vs. 285 ± 31 ps, p < 0.001). Drusen found in AMD eyes had longer lifetimes than drusen of controls (ch1: 650 ± 167 ps vs. 537 ± 145 ps, ch2: 600 ± 125 ps vs. 504 ± 111 ps, p < 0.001). In addition, drusen in AMD eyes showed a more homogenous fluorescence distribution and more drusen were larger than 63µm than in control eyes.

Conclusions

Ex vivo fluorescence imaging of drusen in cross-sections enables the separation of their autofluorescence from that of over- or underlying structures. Our analysis showed considerable variability of drusen lifetimes but not spectra. This indicates that drusen consist of a variety of different fluorophores or expose the same fluorophores to different microenvironments. Changes in drusen lifetimes could be related to AMD progression.
Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma
Authors: Mills Lauren J. , Scott Milcah C. , Shah Pankti , Cunanan Anne R. , Deshpande Archana , Auch Benjamin , Curtin Bridget , Beckman Kenneth B. , Spector Logan G. , Sarver Aaron L. , Subramanian Subbaya , Richmond Todd A. , Modiano Jaime F.
Published: May 2020

Osteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor suppressor p53TP53is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples.

Significance

This is the first large scale study of DNA methylation in osteosarcoma and lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of different genomic landscapes.
An Axon-Pathfinding Mechanism Preserves Epithelial Tissue Integrity
Authors: Cammarota Christian M. , Finegan Tara M. , Wilson Tyler J. , Yang Sifan , Bergstralh Dan T.
Published: May 2020

Dividing cells often move apically within epithelial tissue layers, likely to escape the spatial confinement of their neighbors. Because of this movement, daughter cells may be born displaced from the tissue layer. Reintegration of these displaced cells helps support tissue growth and maintain tissue architecture. In theDrosophilafollicular epithelium, reintegration relies on the immunoglobulin-superfamily cell-adhesion molecules (IgCAMs) Neuroglian and Fasciclin 2, which line cell-cell borders1. These molecules have been described in epithelia, but are well-studied for their roles in neural development2–8. We show here that reintegration works in the same way as IgCAM-mediated axon growth and pathfinding; it relies not only on extracellular adhesion but also mechanical coupling between IgCAMs and the lateral Spectrin-Based Membrane Skeleton. Our work indicates that reintegration is mediated by a distinct epithelial cell-cell junction that is compositionally and functionally equivalent to junctions made between axons.
Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma
Authors: Grover Priyanka , Nath Sritama , Bose Mukulika , Sanders Alexa J. , Brouwer Cory , Nitika  , Zhou Ru , Yazdanifar Mahboubeh , Ahmad Mohammad , Wu Shu-ta , Truman Andrew W. , Mukherjee Pinku
Published: May 2020

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDAin vitroandin vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibodyin vivoshowing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β’s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.
UV damage induces G3BP1-dependent stress granule formation that is not driven by translation arrest via mTOR inhibition
Authors: Ying Shan , Khaperskyy Denys A.
Published: May 2020

Translation arrest is a part of the cellular stress response that decreases energy consumption and enables rapid reprioritisation of gene expression. Often translation arrest leads to condensation of untranslated messenger ribonucleoproteins (mRNPs) into stress granules (SGs). Studies into mechanisms of SG formation and functions are complicated because various types of stress cause formation of SGs with different properties and composition. In this work we focused on the mechanism of SG formation triggered by UV damage. We demonstrate that UV-induced inhibition of translation does not cause dissociation of the 48S preinitiation complexes. The catalytic activity of the general control non-derepressible 2 (GCN2) kinase contributes to UV-induced SG formation, which is independent of the GCN2-mediated phosphorylation of the eukaryotic translation initiation factor 2α. Like many other types of SGs, condensation of UV-induced granules specifically requires the Ras-GTPase-Activating Protein SH3-Domain-Binding Protein 1 (G3BP1). Our work reveals that in UV-treated cells the mechanisms of translation arrest and SG formation may be unlinked, resulting in condensation of ribonucleoproteins that do not represent the major type of polysome-free preinitiation complexes that accumulate in the cytoplasm.
Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction
Authors: Safi Fatemeh , Dhapola Parashar , Warsi Sarah , Erlandsson Eva , Sitnicka Ewa , Bryder David , Böiers Charlotta , Thakur Ram Krishna , Karlsson Göran
Published: May 2020

The emerging notion of hematopoietic stem- and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular fate options emerge, and at which stem-like stage lineage priming is initiated. Here we investigated single-cell chromatin accessibility of Lineage−, cKit+, Sca1+(LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor-motifs revealed a population of LSK FMS-like tyrosine kinase 3(Flt3)intCD9highcells that concurrently display stem-like and lineage-affiliated chromatin signatures pointing to a simultaneous gain of both Lympho-Myeloid and Megakaryocyte-Erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors, display multi-lineage capacity in vitro and in vivo, but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.
TwoCaenorhabditis eleganscalponin-related proteins have overlapping functions to maintain cytoskeletal integrity and are essential for reproduction
Authors: Ono Shoichiro , Ono Kanako
Published: May 2020

Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, and some of these are known to regulate actin cytoskeletal dynamics and contractility. However, functional similarities and differences among these proteins are largely unknown. In the nematodeCaenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, has an overlapping function with UNC-87 to maintain actin cytoskeletal integrityin vivoand has both common and different actin-regulatory activitiesin vitro. CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad, where UNC-87 is also expressed.unc-87mutation causes cytoskeletal defects in the body wall muscle and somatic gonad, whereasclik-1depletion alone causes no detectable phenotypes. However, simultaneous depletion ofclik-1andunc-87caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad.In vitro, UNC-87 bundles actin filaments. However, CLIK-1 binds to actin filaments without bundling them and is antagonistic to UNC-87 in filament bundling. UNC-87 and CLIK-1 share common functions to inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. Thus, partially redundant functions of UNC-87 and CLIK-1 in ovulation is likely mediated by their common actin-regulatory activities, but their distinct activities in actin bundling suggest that they also have different biological functions.
Making ends meet: new functions of mRNA secondary structure
Authors: Ermolenko Dmitri N. , Mathews David
Published: May 2020

The 5’ cap and 3’ poly(A) tail of mRNA are known to synergistically regulate mRNA translation and stability. Recent computational and experimental studies revealed that both protein-coding and non-coding RNAs will fold with extensive intramolecular secondary structure, which will result in close distances between the sequence ends. This proximity of the ends is a sequence-independent, universal property of most RNAs. Only low-complexity sequences without guanosines are without secondary structure and exhibit end-to-end distances expected for RNA random coils. The innate proximity of RNA ends might have important biological implications that remain unexplored. In particular, the inherent compactness of mRNA might regulate translation initiation by facilitating the formation of protein complexes that bridge mRNA 5’ and 3’ ends. Additionally, the proximity of mRNA ends might mediate coupling of 3′ deadenylation to 5′ end mRNA decay.