bluuebunny/crossref_metadata_2025 huggingface dataset:
Practical Indicators for Risk of Airborne Transmission in Shared Indoor Environments and their Application to COVID-19 Outbreaks
Authors: Peng Z. , Pineda Rojas A.L. , Kropff E. , Bahnfleth W. , Buonanno G. , Dancer S.J. , Kurnitski J. , Li Y. , Loomans M.G.L.C. , Marr L.C. , Morawska L. , Nazaroff W. , Noakes C. , Querol X. , Sekhar C. , Tellier R. , Greenhalgh T. , Bourouiba L. , Boerstra A. , Tang J.W. , Miller S.L. , Jimenez J.L.
Published: April 2021

Some infectious diseases, including COVID-19, can be transmitted via aerosols that are emitted by an infectious person and inhaled by susceptible individuals. Most airborne transmission occurs at close proximity and is effectively reduced by physical distancing, but as time indoors increases, infections occur in those sharing room air despite maintaining distancing. There have been calls for quantified models to estimate the absolute and relative contribution of these different factors to infection risk. We propose two indicators of infection risk for this situation, i.e., relative risk parameter (Hr) and risk parameter (H). They combine the key factors that control airborne disease transmission indoors: virus-containing aerosol generation rate, breathing flow rate, masking and its quality, ventilation and particulate air cleaning rates, number of occupants, and duration of exposure. COVID-19 outbreaks show a clear trend in relation to these factors that is consistent with airborne infection The observed trends of outbreak size (attack rate) vs. H (Hr) allow us to recommend values of these parameters to minimize COVID-19 indoor infection risk. Transmission in typical pre-pandemic indoor spaces is highly sensitive to mitigation efforts. Previous outbreaks of measles, flu, and tuberculosis were assessed along with recently reported COVID-19 outbreaks. Measles outbreaks occur at much lower risk parameter values than COVID-19, while tuberculosis outbreaks are observed at much higher risk parameter values. Since both diseases are accepted as airborne, the fact that COVID-19 is less contagious than measles does not rule out airborne transmission. It is important that future outbreak reports include information on the nature and type of masking, ventilation and particulate-air cleaning rates, number of occupants, and duration of exposure, to allow us to understand the circumstances conducive to airborne transmission of different diseases.

Synopsis

We propose two infection risk indicators for indoor spaces and apply them to COVID-19 outbreaks analysis and mitigation.
The Impact of Face Masks on Performance and Physiological Outcomes during Exercise: A Systematic Review and Meta-analysis
Authors: Shaw Keely A. , Zello Gordon A. , Butcher Scotty J. , Ko Jong Bum , Bertrand Leandy , Chilibeck Philip D.
Published: April 2021

Face masks are promoted for preventing spread of viruses; however, wearing a mask during exercise might increase CO2 rebreathing, decrease arterial oxygenation, and decrease exercise performance. A systematic review and meta-analysis was conducted on the impact of wearing a mask during exercise. Data sources included SPORTDiscus, PubMed, and Medline. Eligibility criteria included all study designs comparing surgical, N95, or cloth masks to a no mask condition during any type of exercise where exercise performance and/or physiological parameters were evaluated. Healthy and clinical participants were included. Mean differences (MD) or standardized mean differences (SMD) with 95% confidence intervals were calculated and pooled effects assessed. Twenty-two studies involving 1,573 participants (620 females, 953 males) were included. Surgical, or N95 masks did not impact exercise performance (SMD −0.05 [-0.16,0.07] and −0.16 [-0.54,0.22], respectively) but increased ratings of perceived exertion (RPE) (SMD 0.33 [0.09,0.58] and 0.61 [0.23,0.99]) and dyspnea (SMD 0.6 [0.3,0.9] for all masks). End-tidal CO2 (MD 3.3 [1.0, 5.6] and 3.7 [3.0,4.4] mmHg), and heart rate (MD 2 [0,4] beats/min with N95 masks) slightly increased. Face masks can be worn during exercise with no influences on performance and minimal impacts on physiological variables.

PROSPERO Registration

CRD42020224988

Novelty Points

Face masks can be worn during exercise with no impacts on performance and minimal impacts on physiological variables.
The Barrier to Vaccination Is Not Vaccine Hesitancy: Patterns of COVID-19 Vaccine Acceptance over the Course of the Pandemic in 23 Countries
Authors: Kothari Ammina , Pfuhl Gerit , Schieferdecker David , Harris Casey Taggart , Tidwell Caitlin , Fitzpatrick Kevin M , Godleski Stephanie , Sanjay Saurabh
Published: April 2021

Background

At present, evidence is inconclusive regarding what factors influence vaccine intent, and whether there are widespread disparities across populations and time. The current study provides new insights regarding vaccine intent and potential differences across 23 countries and over time.

Methods

Our data come from a unique longitudinal survey that contains responses from Facebook users (N=1,425,172) from the 23 countries from four continents collected in 18 waves from July 2020 through March 2021.

Results

We find that vaccine intent varies significantly across countries and over time. Across countries, there are notable disparities in intent to vaccinate. Regarding time, intent has recently reached an all-time high. Our data demonstrates that intent to vaccinate has increased as countries have deployed vaccines on larger scales with undecidedness declining. However, there are some countries where vaccine intent is stagnant and in one country – Egypt – where it seems to have declined.

Interpretations

Large numbers of citizens across the world are willing to get vaccinated. In the vast majority of countries in our sample, these were high enough to reach more conservative levels of herd immunity1 if combined with numbers of persons already infected. As such, the main barrier to vaccination is not vaccine hesitancy, but the shortage of vaccines. This sends a clear message to politicians who need to work on a quick and fair distribution of vaccine; and to scientists who need to focus their attention on understanding remaining pockets of vaccine skepticism or undecidedness and on factors that explain actual vaccine behavior, rather than intent.
Cognitive training in Parkinson’s disease induces local, not global, changes in white matter microstructure
Authors: Vriend Chris , van Balkom Tim D. , Berendse Henk W. , van der Werf Ysbrand D. , van den Heuvel Odile A.
Published: April 2021

Previous studies have shown that cognitive training can improve cognitive performance in various neurodegenerative diseases but relatively little is known about the effects of cognitive training on the brain. Here we investigated the effects of our cognitive training paradigm, COGTIPS, on regional white matter microstructure and topology of the structural network. We previously showed that COGTIPS has small, positive effects on processing speed. A subsample of 79 PD patients (N=40 cognitive training group, N=39 active control group) underwent multi-shell diffusion weighted imaging pre- and post-intervention. Our pre-registered analysis plan (osf.io/cht6g) entailed calculating white matter microstructural integrity in five tracts of interest, including the anterior thalamic radiation (ATR) and calculating the topology of the structural connectome. Training-induced changes were analyzed with linear mixed-models. Relative to the active control condition, cognitive training had no effect on network topology. Cognitive training did lead to a reduction in fractional anisotropy in the ATR (B[SE]: -0.32 [0.12], p=0.01). This reduction was associated with faster responses on the ToL task (r = 0.42, P = 0.007), but this just fell short of our statistical threshold (P<0.006). Post-hoc analyses showed that this was not due to changes in fiber density and cross-section, suggesting that that the observed effect in the ATR are due to training-induced alterations in neighboring fibers running through the same voxels, such as intra-striatal and thalamo-striatal fibers. These results indicate that eight weeks of cognitive training do not alter network topology, but can have subtle local effects on structural connectivity.
A new Far-UVC based method for germ free hospitals and travel: Initus-V
Authors: Olcay Ayhan , Albayrak Serdar Baki , Aktürk İbrahim Faruk , Akbülbül Mehmet Cengiz , Yolay Onur , İkitimur Hande , Çetin Bayer Mehmet
Published: April 2021

Direct contact and airborne spread are main mechanisms of transmission for SARS-CoV-2, and virus can stay viable for at least 3 hours in aerosols. Initus-V system uses a Far-ultraviolet C (UVC) system, UVC resistant textile and googles to provide virus, bacteria and spore free environments in hospitals, crowded public places and travel environments. Initus-V system may help in prevention of epidemic diseases such as Coronavirus disease-19 (Covid-19), influenza, treatment of airborne viral diseases and spread of hospital-borne resistant infections.
Paradox of Predictors in Critically ill COVID-19 Patients: Outcome of a COVID-dedicated Intensive Care Unit
Authors: Nasir Morshed , Perveen Rawshan Ara , Nazneen Rumana , Zahan Tahmina , Ahmad Sonia Nasreen , Chowdhury ASM Salauddin
Published: April 2021

Background

The study aimed to analyze the demographic, comorbidities, biomarkers, pharmacotherapy, and ICU-stay with the mortality outcome of COVID-19 patients admitted in the intensive care unit of a tertiary care hospital in a low-middle income country, Bangladesh.

Methods

The retrospective cohort study was done in Holy Family Red Crescent Medical College Hospital from May to September 2020. All 112 patients who were admitted to ICU as COVID-19 cases (confirmed by RT-PCR of the nasopharyngeal swab) were included in the study. Demographic data, laboratory reports of predictive biomarkers, treatment schedule, and duration of ICU-stay of 99 patients were available and obtained from hospital records (non-electronic) and treatment sheets, and compared between the survived and deceased patients.

Results

Out of 99 patients admitted in ICU with COVID-19, 72 were male and 27 were female. The mean age was 61.08 years. Most of the ICU patients were in the 60 - 69 years of age group and the highest mortality rates (35.89%) were observed in this age range. Diabetes mellitus and hypertension were the predominant comorbidities in the deceased group of patients. A significant difference was observed in neutrophil count, creatinine and, NLR, d-NLR levels that raised in deceased patients. There was no significant difference as a survival outcome of antiviral drugs remdesivir or favipiravir, while the use of cephalosporin was found much higher in the survived group than the deceased group (46.66% vs 20.51%) in ICU.

Conclusions

Susceptibility to developing critical illness due to COVID-19 was found more in comorbid males aged more than 60 years. There were wide variations of the biomarkers in critical COVID-19 patients in a different population, which put the healthcare workers into far more challenge to minimize the mortality in ICU in Bangladesh and around the globe during the peak of the pandemic.
Punishment insensitivity in humans is due to failures in instrumental contingency learning
Authors: Jean-Richard-dit-Bressel Philip , Lee Jessica C. , Liew Shi Xian , Weidemann Gabrielle , Lovibond Peter F. , McNally Gavan P.
Published: April 2021

Punishment maximises the probability of our individual survival by reducing behaviours that cause us harm, and also sustains trust and fairness in groups essential for social cohesion. However, some individuals are more sensitive to punishment than others and these differences in punishment sensitivity have been linked to a variety of decision-making deficits and psychopathologies. The mechanisms for why individuals differ in punishment sensitivity are poorly understood, although recent studies of conditioned punishment in rodents highlight a key role for punishment contingency detection (Jean-Richard-dit-Bressel et al., 2019). Here we applied a novel “Planets & Pirates” conditioned punishment task in humans, allowing us to identify the mechanisms for why individuals differ in their sensitivity to punishment. We show that punishment sensitivity is bimodally distributed in a large sample of normal participants. Sensitive and insensitive individuals equally liked reward and showed similar rates of reward-seeking. They also equally disliked punishment and did not differ in their valuation of cues that signalled punishment. However, sensitive and insensitive individuals differed profoundly in their capacity to detect and learn volitional control over aversive outcomes. Punishment insensitive individuals did not learn the instrumental contingencies, so they could not withhold behaviour that caused punishment and could not generate appropriately selective behaviours to prevent impending punishment. These differences in punishment sensitivity could not be explained by individual differences in behavioural inhibition, impulsivity, or anxiety. This bimodal punishment sensitivity and these deficits in instrumental contingency learning are identical to those dictating punishment sensitivity in non-human animals, suggesting that they are general properties of aversive learning and decision making.
Dental-Facial Midline: An Esthetic Based Classification
Authors: Niraula Nischal , Acharya Reecha , Humagain Manoj , Khurshid Zohaib , Adanir Necdet , Rokaya Dinesh
Published: April 2021

Background

The facial midline and dental midline play an important role in facial esthetics, cosmetic dentistry, facial plastic surgery, and anthropologic studies.

Objectives

This study studied the dental-facial midline in Nepalese subjects and to classify the midline.

Methods

The study was done in 150 Nepalese subjects, mostly consisting of University students (80 males and 70 females). After obtaining ethical approval, facial and dental midlines were analyzed using a scale.

Results

It showed 26 (18%) study subjects showed the coincidence of the facial midline with the maxillary and mandibular dental midlines. It showed that only 44 (30%) subjects showed the coincidence of facial midline with only maxillary dental midline, and 26 (17%) subjects showed the facial midline coincidence with only mandibular dental midline. The dental midline discrepancy was more prevalent in the maxillary arch and more prevalent on the right side. Midline discrepancy is seen more in males compared to females. The majority of the deviation showed 1 mm, followed by 2 mm, and 3 mm.

Conclusions

The coincidence of the facial midline with both the maxillary and mandibular dental midlines is uncommon. Midline discrepancy is seen more in males compared to females. The majority of the subjects show a mild discrepancy of 1 mm. The midline discrepancy was more seen on the right side and in the maxillary arch.
Contrasting epidemiology and population genetics of COVID-19 infections defined with 74 polymorphic loci in SARS-CoV-2 genomes sampled globally
Authors: Chan Felicia , Ataide Ricardo , Richards Jack S. , Narh Charles A.
Published: April 2021

SARS-CoV-2, the coronavirus causing COVID-19, has infected and killed several millions of people worldwide. Since the first COVID-19 outbreak in December 2019, SARS-CoV-2 has evolved with a few genetic variants associated with higher infectivity. We aimed to identify polymorphic loci in SARS-CoV-2 that can be used to define and monitor the viral epidemiology and population genetics in different geographical regions. Between December 2019 and September 2020, we sampled 5,959 SARS-CoV-2 genomes. More than 80% of the genomes sampled in Africa, Asia, Europe, North America, Oceania and South America were reportedly isolated from clinical infections in older patients, ≥ 20 years. We used the first indexed genome (NC_045512.2) as a reference and constructed multilocus genotypes (MLGs) for each sampled genome based on amino acids detected at 74 polymorphic loci located in ORF1ab, ORF3a, ORF8, matrix (M), nucleocapsid (N) and spike (S) genes. Eight of the 74 loci were informative in estimating the risk of carrying infections with mutant alleles among different age groups, gender and geographical regions. Four mutant alleles - ORF1ab L4715, S G614, and N K203 and R204 reached 90% prevalence globally, coinciding with peaks in transmission but not COVID-19 severity, from March to August 2020. During this period, the MLG genetic diversity was moderate in Asia, Oceania and North America; in contrast to Africa, Europe and South America, where lower genetic diversity and absence of linkage disequilibrium indicated clonal SARS-CoV-2 transmission. Despite close relatedness to Asian MLGs, MLGs in the global population were genetically differentiated by geographic region, suggesting structure in SARS-CoV-2 populations. Our findings demonstrate the utility of the 74 loci as a genetic tool to study and monitor SARS-CoV-2 transmission dynamics and evolution, which can inform future control interventions.
Reliability of COVID-19 data: An evaluation and reflection
Authors: Miller April R. , Charepoo Samin , Yan Erik , Frost Ryan W. , Sturgeon Zachary J. , Gibbon Grace , Balius Patrick , Thomas Cedonia S. , Schmitt Melanie A. , Sass Daniel A. , Walters James B. , Flood Tracy L. , Schmitt Thomas A.
Published: April 2021

Importance

The rapid proliferation of COVID-19 has left governments scrambling, and several data aggregators are now assisting in the reporting of county cases and deaths. The different variables affecting reporting (e.g., time delays in reporting) necessitates a well-documented reliability study examining the data methods and discussion of possible causes of differences between aggregators.

Objective

To statistically evaluate the reliability of COVID-19 across aggregators.

Design, Setting, and Participants

Cases and deaths were collected daily by volunteers via state and local health departments, as primary sources and newspaper reports, as secondary sources. In an effort to begin comparison for reliability statistical analysis, BroadStreet collected data from other COVID-19 aggregator sources, including USAFacts, Johns Hopkins University, New York Times, The COVID Tracking Project.

Main Outcomes and Measures

COVID-19 cases and death counts at the county and state levels.

Results

Lower levels of inter-rater agreement were observed across aggregators associated with the number of deaths, which manifested itself in state level Bayesian estimates of COVID-19 fatality rates.

Conclusions and Relevance

A national, publically available data set is needed for current and future disease outbreaks and improved reliability in reporting.
Interneuronal dynamics facilitate the initiation of cortical spreading depression
Authors: Stein Wolfgang , Harris Allison L.
Published: April 2021

Cortical spreading depression (CSD) is thought to precede migraine attacks with aura and is characterized by a slowly traveling wave of inactivity through cortical pyramidal cells. During CSD, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that propagates slowly across the cortex. While the identifying characteristic of CSD is the pyramidal cell hyperexcitation and subsequent spike block, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of CSD.

We tested the contribution of cortical inhibitory interneurons to the initiation of spike block using a cortical microcircuit model that takes into account changes in ion concentrations that result from neuronal firing. Our results show that interneuronal inhibition provides a wider dynamic range to the circuit and generally improves stability against spike block.

Despite these beneficial effects, strong interneuronal firing contributed to rapidly changing extracellular ion concentrations, which facilitated hyperexcitation and led to spike block first in the interneuron and then in the pyramidal cell. In all cases, a loss of interneuronal firing triggered pyramidal cell spike block. However, preventing interneuronal spike block was insufficient to rescue the pyramidal cell from spike block. Our data thus demonstrate that while the role of interneurons in cortical microcircuits is complex, they are critical to the initiation of pyramidal cell spike block and CSD. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit.
Curating and translating the evidence about SARS-CoV-2 and COVID-19 for frontline public health and clinical care: The Novel Coronavirus Research Compendium (NCRC)
Authors: Redd Andrew D. , Peetluk Lauren , Jarrett Brooke , Hanrahan Colleen , Schwartz Sheree , Rao Amrita , Jaffe Andrew , Jones Carli , Lutz Chelsea , McKee Clif , Patel Eshan , Rosen Greg , Desany Henri Garrison , McKay Heather , Muschelli John , Andersen Kayte , Link Malen A. , Wada Nikolas , Baral Prativa , Young Ruth , Boon Denali , Grabowski M. Kate , Gurley Emily S. ,   the NCRC Team
Published: April 2021

The public health crisis created by the SARS-CoV-2 pandemic has spurred a deluge of scientific research aimed at informing public health and medical response to the COVID-19 pandemic. However, those working in frontline public health and clinical care had insufficient time to parse the rapidly evolving evidence and use it for decision making. Academics in public health and medicine were well-placed to translate the evidence for use by frontline clinicians and public health practitioners. The Novel Coronavirus Research Compendium (NCRC), a group of >50 faculty and trainees, began in March 2020 with the goal to quickly triage and review the large volume of preprints and peer-reviewed publications on SARS-CoV-2 and COVID-19, and to summarize the most important, novel evidence to inform pandemic response. From April 6, 2020 through January 1, 2021, 54,192 papers and preprints were screened by NCRC teams and 527 were selected for review and uploaded to the NCRC website for public consumption. The majority of papers reviewed were peer-reviewed publications (n=395, 75%), published in 102 journals; 25% (n=132) of papers reviewed were of preprints. The NCRC is a successful model of how academics can support practitioners by translating scientific knowledge into action and help to build capacity among students for this work. This approach could be used for health problems beyond COVID-19, but the effort is resource intensive and may not be sustainable over the long term.
Is large-scale rapid CoV-2 testing a substitute for lockdowns?
Authors: Diederichs Marc , Glawion René , Kremsner Peter G. , Mitze Timo , Müller Gernot J. , Papies Dominik , Schulz Felix , Wälde Klaus
Published: April 2021

BACKGROUND

Various forms of contact restrictions have been adopted in response to the Covid-19 pandemic. Around February 2021, rapid testing appeared as a new policy instrument. Some claim it may serve as a substitute for contact restrictions.

OBJECTIVES/METHODS

We evaluate the effects of a unique policy experiment: In March and April 2021, the city of Tübingen set up a testing scheme while relaxing contact restrictions. We compare case rates in Tübingen county to an appropriately identified control unit.

CONCLUSIONS

The experiment led to an increase in the reported case rate. This increase is robust across alternative statistical specifications. An epidemiological model that corrects for ‘more cases due to more testing’ and ‘reduced testing and reporting during the Easter holiday’ also confirms the finding.
Measuring the tolerance of the genetic code to altered codon size
Authors: DeBenedictis E. , Söll D. , Esvelt K.
Published: April 2021

Protein translation using four-base codons occurs in both natural and synthetic systems. What constraints contributed to the universal adoption of a triplet-codon, rather than quadruplet-codon, genetic code? Here, we investigate the tolerance of theE. coligenetic code to tRNA mutations that increase codon size. We found that tRNAs from all twenty canonical isoacceptor classes can be converted to functional quadruplet tRNAs (qtRNAs), many of which selectively incorporate a single amino acid in response to a specified four-base codon. However, efficient quadruplet codon translation often requires multiple tRNA mutations, potentially constraining evolution. Moreover, while tRNAs were largely amenable to quadruplet conversion, only nine of the twenty aminoacyl tRNA synthetases tolerate quadruplet anticodons. These constitute a functional and mutually orthogonal set, but one that sharply limits the chemical alphabet available to a nascent all-quadruplet code. Our results illuminate factors that led to selection and maintenance of triplet codons in primordial Earth and provide a blueprint for synthetic biologists to deliberately engineer an all-quadruplet expanded genetic code.
Direct Nanopore Sequencing of Individual Full Length tRNA Strands
Authors: Thomas Niki , Poodari Vinay , Jain Miten , Olsen Hugh , Akeson Mark , Abu-Shumays Robin
Published: April 2021

We describe a method for direct tRNA sequencing using the Oxford Nanopore MinION. The principal technical advance is custom adapters that facilitate end-to-end sequencing of individual tRNA molecules. A second advance is a Nanopore sequencing pipeline optimized for tRNA. We tested this method using purifiedE. colitRNAfMet, tRNALys, and tRNAPhesamples. 76-to-92% of individual aligned tRNA sequence reads were full length. As proof of concept, we showed that Nanopore sequencing detected all 42 expected tRNA isoacceptors in totalE. colitRNA. Alignment-based comparison between the three purified tRNAs and their synthetic controls revealed systematic miscalls at or adjacent to the positions of known nucleotide modifications. Systematic miscalls were also observed proximal to known modifications in totalE. colitRNA alignments.
Rcompadre and Rage - two R packages to facilitate the use of the COMPADRE and COMADRE databases and calculation of life history traits from matrix population models
Authors: Jones Owen R. , Barks Patrick , Stott Iain , James Tamora D. , Levin Sam , Petry William K. , Capdevila Pol , Che-Castaldo Judy , Jackson John , Römer Gesa , Schuette Caroline , Thomas Chelsea C. , Salguero-Gómez Roberto
Published: April 2021

Matrix population models (MPMs) are an important tool for biologists seeking to understand the causes and consequences of variation in vital rates (e.g., survival, reproduction) across life cycles. Empirical MPMs describe the age- or stage-structured demography of organisms and usually represent the life history of a population during a particular time frame at a specific geographic location.

The COMPADRE Plant Matrix Database and COMADRE Animal Matrix Database are the most extensive resources for MPM data, collectively containing >12,000 individual projection matrices for >1,100 species globally. Although these databases represent an unparalleled resource for researchers, land managers, and educators, the current computational tools available to answer questions with MPMs impose significant barriers to potential COM(P)ADRE database users by requiring advanced knowledge to handle diverse data structures and program custom analysis functions.

To close this knowledge gap, we present two interrelated R packages designed to (i) facilitate the use of these databases by providing functions to acquire, quality control, and manage both the MPM data contained in COMPADRE and COMADRE, and a user’s own MPM data (Rcompadre), and (ii) present a range of functions to calculate life history traits from MPMs in support of ecological and evolutionary analyses (Rage). We provide examples to illustrate the use of both.

RcompadreandRagewill facilitate demographic analyses using MPM data and contribute to the improved replicability of studies using these data. We hope that this new functionality will allow researchers, land managers, and educators to unlock the potential behind the thousands of MPMs and ancillary metadata stored in the COMPADRE and COMADRE matrix databases, and in their own MPM data.
Evolution of a cytoplasmic determinant: evidence for the biochemical basis of functional evolution of a novel germ line regulator
Authors: Blondel Leo , Besse Savandara , Extavour Cassandra G.
Published: April 2021

Germ line specification is essential in sexually reproducing organisms. Despite their critical role, the evolutionary history of the genes that specify animal germ cells is heterogeneous and dynamic. In many insects, the geneoskaris required for the specification of the germ line. However, the germ line role ofoskaris thought to be a derived role resulting from co-option from an ancestral somatic role. To address how evolutionary changes in protein sequence could have led to changes in the function of Oskar protein that enabled it to regulate germ line specification, we searched foroskarorthologs in 1565 publicly available insect genomic and transcriptomic datasets. The earliest-diverging lineage in which we identified anoskarortholog was the order Zygentoma (silverfish and firebrats), suggesting thatoskaroriginated before the origin of winged insects. We noted some order-specific trends inoskarsequence evolution, including whole gene duplications, clade-specific losses, and rapid divergence. An alignment of all known 379 Oskar sequences revealed new highly conserved residues as candidates that promote dimerization of the LOTUS domain. Moreover, we identified regions of the OSK domain with conserved predicted RNA binding potential. Furthermore, we show that despite a low overall amino acid conservation, the LOTUS domain shows higher conservation of predicted secondary structure than the OSK domain. Finally, we suggest new key amino acids in the LOTUS domain that may be involved in the previously reported Oskar-Vasa physical interaction that is required for its germ line role.
Integrative biology defines novel biomarkers of resistance to strongylid infection in horses
Authors: Sallé Guillaume , Canlet Cécile , Cortet Jacques , Koch Christine , Malsa Joshua , Reigner Fabrice , Riou Mickaël , Perrot Noémie , Blanchard Alexandra , Mach Nuria
Published: April 2021

The widespread failure of anthelmintic drugs against nematodes of veterinary interest requires novel control strategies. Selective treatment of the most susceptible individuals could reduce drug selection pressure but requires appropriate biomarkers of the intrinsic susceptibility potential. To date, this has been missing in livestock species. Here, we selected Welsh ponies with divergent intrinsic susceptibility to cyathostomin infection and found that their potential was sustained across a 10-year time window. Using this unique set of individuals, we monitored variations in their blood cell populations, plasma metabolites and faecal microbiota over a grazing season to isolate core differences between their respective responses under worm-free or natural infection conditions. Our analyses identified the concomitant rise in plasmatic phenylalanine level and faecal Prevotella abundance and the reduction in circulating monocyte counts as biomarkers of the need for drug treatment. This biological signal was replicated in other independent populations. We also unravelled an immunometabolic network encompassing plasmatic beta-hydroxybutyrate level, short-chain fatty acid producing bacteria and circulating neutrophils that forms the discriminant baseline between susceptible and resistant individuals. Altogether our observations open new perspectives on the susceptibility of equids to cyathostomin infection and leave scope for both new biomarkers of infection and nutritional intervention.
Antiviral defense via nucleotide depletion in bacteria
Authors: Tal Nitzan , Millman Adi , Stokar-Avihail Avigail , Fedorenko Taya , Leavitt Azita , Melamed Sarah , Yirmiya Erez , Avraham Carmel , Amitai Gil , Sorek Rotem
Published: April 2021

DNA viruses and retroviruses need to consume large quantities of deoxynucleotides (dNTPs) when replicating within infected cells. The human antiviral factor SAMHD1 takes advantage of this vulnerability in the viral life cycle, and inhibits viral replication by degrading dNTPs into their constituent deoxynucleosides and inorganic phosphate. In this study we report that bacteria employ a similar strategy to defend against phage infection. We found a family of defensive dCTP deaminase proteins that, in response to phage infection, convert dCTP into deoxy-uracil nucleotides. A second family of phage resistance genes encode dGTPase enzymes, which degrade dGTP into phosphate-free deoxy-guanosine (dG) and are distant homologs of the human SAMHD1. Our results show that the defensive proteins completely eliminate the specific deoxynucleotide (either dCTP or dGTP) from the nucleotide pool during phage infection, thus starving the phage of an essential DNA building block and halting its replication. Both defensive genes are found in a diverse set of bacterial species and are specifically enriched inVibriogenomes. Our study demonstrates that manipulation of the deoxynucleotide pool is a potent antiviral strategy shared by both prokaryotes and eukaryotes.
Mitochondrial ribosomal proteins developed unconventional mitochondrial targeting signals due to structural constraints
Authors: Bykov Yury S. , Flohr Tamara , Boos Felix , Herrmann Johannes M. , Schuldiner Maya
Published: April 2021

Mitochondrial ribosomes are complex molecular machines indispensable for respiration. Their assembly involves the import of several dozens of mitochondrial ribosomal proteins (MRPs), encoded in the nuclear genome, into the mitochondrial matrix. Available proteomic and structural data as well as computational predictions indicate that up to 25% of MRPs do not have a conventional N-terminal mitochondrial targeting signal (MTS). We characterized a set of 15 yeast MRPsin vivoand showed that 30% of them use internal mitochondrial targeting signals. We isolated a novel internal targeting signal from the conserved MRP Mrp17 (bS6). The Mrp17 targeting signal shares some properties as well as import components with conventional MTS-containing proteins but is not reliably predicted indicating that mitochondrial protein targeting is more versatile than expected. We hypothesize that internal targeting signals arose in MRPs when the N-terminus extension was constrained by ribosome assembly interfaces.
Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops
Authors: Sabino João C. , de Almeida Madalena R. , Abreu Patricia L. , Ferreira Ana M. , Domingues Marco M. , Santos Nuno C. , Azzalin Claus M. , Grosso Ana R. , de Almeida Sérgio F.
Published: April 2021

DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed DNA promotes the annealing of the nascent RNA to its template DNA strand, leading to the formation of an R-loop. The genome-wide distribution of 5hmC and R-loops show a positive correlation in mouse and human embryonic stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, and disclose novel links between R-loops and the regulation of gene expression programs in stem cells.
Mechanical vibration patterns elicit behavioral transitions and habituation in crawlingDrosophilalarvae
Authors: Berne Alexander , Zhang Tom , Shomar Joseph , Ferrer Anggie J. , Valdes Aaron , Ohyama Tomoko , Klein Mason
Published: April 2021

How animals respond to repeatedly applied stimuli, and how animals respond to mechanical stimuli in particular, are important questions in behavioral neuroscience. We study adaptation to repeated mechanical agitation using theDrosophilalarva. Vertical vibration stimuli elicit a discrete set of responses in crawling larvae: continuation, pause, turn, and reversal. Through high-throughput larva tracking, we characterize how the likelihood of each response depends on vibration intensity and on the timing of repeated vibration pulses. By examining transitions between behavioral states at the population and individual levels, we investigate how the animals habituate to the stimulus patterns. We identify time constants associated with desensitization to prolonged vibration, with re-sensitization during removal of a stimulus, and additional layers of habituation that operate in the overall response. Known memory-deficient mutants exhibit distinct behavior profiles and habituation time constants. An analogous simple electrical circuit suggests possible neural and molecular processes behind adaptive behavior.
Fasting reduces inhibitory and attentional control of food-related cues
Authors: Ballestero-Arnau M , Rodríguez-Herreros B , Nuño-Bermúdez N , Cunillera T.
Published: April 2021

The metabolic and cognitive systems interact to create the motivational drive that occasionally leads to disrupted consummatory eating behaviors. In this study, we investigated whether stimulus-specific alterations of the inhibitory function are present following a period of food deprivation. Twenty-six participants with normal weight performed the Stop Signal Task (SST) and the Go/No-go (GNG) task to measure response inhibition to food images containing high or low caloric content after following –or not- a 12-hour fasting period. Response inhibition performance in the SST did not exhibit significant differences when considering neither fasting, stimulus type nor food caloric content. We instead found a higher percentage of commission errors in the No-go trials of the GNG task in the fasting session, and specially with high-caloric food items. In contrast, the accuracy in the Go trials was similar between conditions. A mixed logistic regression model confirmed the remarkable impact of fasting on the performance of response inhibition. Overall, our findings support an interpretation of the motivational drive to eat strongly associated with aspects of the inhibitory function underlying high attentional control, rather than to a proper response inhibition per se.
Evaluating the Anti-aging Effects of Chinese Herbal MedicineRhodiola roseaL. in Cultured Keratinocytes
Authors: Toh Wu Han , Chen Chun-Bing , Clapper Jude , Hsu Cheng-Chang , Lee Hua-en , Chung Wen-Hung
Published: April 2021

Among the many health benefits Chinese herbal medicine (CHM) presents, anti-aging is of special interest (Shen, Jiang, Yang, Wang, & Zhu, 2017; Zhao & Luo, 2017). Reported to possess anti-aging effects, the CHMRhodiola roseaL., known colloquially as the “golden root”, has been widely incorporated in various drinks, daily supplements, and even cosmetics. This study investigates the effects of commercialR. roseaextracts and naturalR. rosearoots on preventing UV-induced photoaging of the skin and correlates such effects with the composition of active ingredients in the extracts. To simulate the photoaging process, drug treated HaCaT cells were exposed to UVA and UVB radiation. The pharmacological anti-aging effects ofR. roseaextracts were evaluated qualitatively and quantitatively through confocal immunofluorescence images with γ-H2A.X marker and telomerase activity assay (Telo TAGGG Telomerase PCR-ELISA). Preparatory thin layer chromatography and high-performance liquid chromatography were performed to isolate and quantify active ingredients. Cultured HaCaT cells showed morphological change after exposure to both UVA (>15.0 J) and UVB (>2000 mJ). The photoaging of keratinocytes was rescued by pretreating cells withR. roseaextracts as well as salidroside and rosavin active ingredients (P < 0.05).R. rosea-treated cells were characterized by increased telomerase activity and fewer γ-H2A.X foci compared to that of the control. Extracts with better preventative effects contained higher salidroside and rosavin content. The findings in this study reaffirmR. rosea’sefficacy as an anti-aging remedy and provide a basis for CHM’s integration into the mainstream of global healthcare.
The role of insulators and transcription in 3D chromatin organisation of flies
Authors: Chathoth Keerthi T , Mikheeva Liudmila A , Crevel Gilles , Wolfe Jareth C. , Hunter Ioni , Beckett-Doyle Saskia , Cotterill Sue , Dai Hongsheng , Harrison Andrew , Zabet Nicolae Radu
Published: April 2021

The DNA in many organisms, including humans, is shown to be organised in topologically associating domains (TADs). InDrosophila, several architectural proteins are enriched at TAD borders, but it is still unclear whether these proteins play a functional role in the formation and maintenance of TADs. Here, we show that depletion of BEAF-32, Cp190, Chro and Dref leads to changes in TAD organisation and chromatin loops. Their depletion predominantly affects TAD borders located in heterochromatin, while TAD borders located in euchromatin are resilient to these mutants. Furthermore, transcriptomic data has revealed hundreds of genes displaying differential expression in these mutants and showed that the majority of differentially expressed genes are located within reorganised TADs. Our work identifies a novel and functional role for architectural proteins at TAD borders inDrosophilaand a link between TAD reorganisation and subsequent changes in gene expression.
Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders
Authors: Alsaqati Mouhamed , Davis Brittany A , Wood Jamie , Jones Megan , Jones Lora , Westwood Aishah , Petter Olena , Isles Anthony R , Linden David , Van den Bree Marianne , Owen Michael , Hall Jeremy , Harwood Adrian J
Published: April 2021

Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.
Perivascular cells support folliculogenesis in the developing ovary
Authors: Li Shuyun , Bhandary Bidur , DeFalco Tony
Published: April 2021

Granulosa cells, supporting cells of the ovary, are essential for ovarian differentiation by providing a nurturing environment for oogenesis. Sufficient numbers of granulosa cells are vital for establishment of follicles and the oocyte reserve; therefore, identifying the cellular source from which granulosa cells are derived is critical for understanding basic ovarian biology. One cell type that has received little attention in this field is the perivascular cell. Here we use lineage tracing and organ culture techniques in mice to identify ovarian Nestin+ perivascular cells as multipotent progenitors that contribute to granulosa, thecal, and pericyte lineages. Maintenance of these progenitors was dependent on vascular-mesenchymal Notch signaling. Ablation of postnatal Nestin+ cells resulted in a disruption of granulosa cell specification and an increased incidence of polyovular ovarian follicles, thus uncovering key roles for vasculature in ovarian differentiation. These findings may provide new insights into the origins of female gonad dysgenesis and infertility.
Beta bursting in the retrosplenial cortex is a neurophysiological correlate of environmental novelty which is disrupted in a mouse model of Alzheimer’s disease
Authors: Walsh Callum , Ridler Thomas , Garrido Maria Garcia , Witton Jonathan , Randall Andrew D. , Brown Jonathan T.
Published: April 2021

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory, and is functionally disrupted in the early stages of Alzheimer’s disease. In order to investigate neurophysiological correlates of spatial learning and memory in this region we employedin vivoelectrophysiology in awake, behaving mice, comparing neural activity between wild-type and J20 mice, a mouse model of Alzheimer’s disease-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of beta (20-30 Hz) oscillations (beta bursts) which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of beta bursts. Additionally, theta-beta cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during beta bursts. Finally, aberrant beta bursting was seen in J20 mice, including increased beta bursting during novelty and familiarity, yet a loss of coupling between beta bursts and spiking activity. These findings, support the concept that beta bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.
Vascular and perivascular cell profiling reveals the molecular and cellular bases of blood-brain barrier heterogeneity
Authors: Pfau Sarah J. , Langen Urs H. , Fisher Theodore M. , Prakash Indumathi , Nagpurwala Faheem , Lozoya Ricardo A. , Lee Wei-Chung Allen , Wu Zhuhao , Gu Chenghua
Published: April 2021

SUMMARY

The blood-brain barrier (BBB) is critical for protecting the brain and maintaining neuronal homeostasis. Although the BBB is a unique feature of the central nervous system (CNS) vasculature, not all brain regions have the same degree of impermeability. Differences in BBB permeability are important for controlling the local extracellular environment of specific brain regions to regulate the function and plasticity of particular neural circuits. However, how BBB heterogeneity occurs is poorly understood. Here, we demonstrate how regional specialization of the BBB is achieved. With unbiased cell profiling in small, defined brain regions, we compare the median eminence, which has a naturally leaky BBB, with the cortex, which has an impermeable BBB. We identify hundreds of molecular differences in endothelial cells (ECs) and demonstrate the existence of differences in perivascular astrocytes and pericytes in these regions, finding 3 previously unknown subtypes of astrocytes and several key differences in pericytes. By serial electron microscopy reconstruction and a novel, aqueous-based tissue clearing imaging method, we further reveal previously unknown anatomical specializations of these perivascular cells and their unique physical interactions with neighboring ECs. Finally, we identify ligand-receptor pairs between ECs and perivascular cells that may regulate regional BBB integrity in ECs. Using a bioinformatic approach we identified 26 and 26 ligand-receptor pairs underlying EC-pericyte and EC-astrocyte interactions, respectively. Our results demonstrate that differences in ECs, together with region-specific physical and molecular interactions with local perivascular cells, contribute to BBB functional heterogeneity. These regional cell inventories serve as a platform for further investigation of the dynamic and heterogeneous nature of the BBB in other brain regions. Identification of local BBB specializations provides insight into the function of different brain regions and will permit the development of region-specific drug delivery in the CNS.