bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxytocinergic modulation of threat-specific amygdala sensitization in humans is critically mediated by serotonergic mechanisms
Authors: Liu Congcong , Lan Chunmei , Li Keshuang , Zhou Feng , Yao Shuxia , Xu Lei , Yang Ning , Zhou Xinqi , Yang Jiaxin , Yong Xue , Ma Yina , Scheele Dirk , Kendrick Keith M. , Becker Benjamin
Published: May 2020

Background

Overarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems. Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking.

Methods

To determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/ desensitization, we conducted a parallel-group randomized placebo-controlled double-blind experiment during which n = 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD, TRYP-) or the corresponding placebo-control protocols before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threat-specific amygdala reactivity towards threatening stimuli (angry faces) as assessed by fMRI served as the primary outcome.

Results

No treatment main or interaction effects on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with TRYP-.

Conclusions

The present findings provide the first evidence for a role of OXT in threat-specific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system. OXT may have a therapeutic potential to facilitate amygdala desensitization and adjunct up-regulation of 5-HT neurotransmission may facilitate OXT’s anxiolytic potential.

The trial was preregistered on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03426176, IDNCT03426176)
Prediction of regional wildfire activity with a probabilistic Bayesian framework
Authors: Pimont F , Fargeon H , Opitz T , Ruffault J , Barbero R , Martin StPaul N , Rigolot E , Rivière M , Dupuy JL
Published: May 2020

Modelling wildfire activity is crucial for informing science-based risk management and understanding fire-prone ecosystem functioning worldwide. Models also help to disentangle the relative roles of different factors, to understand wildfire predictability or to provide insights into specific events.

Here, we develop a two-component Bayesian hierarchically-structured probabilistic model of daily fire activity, which are modelled as the outcome of a marked point process in which individual fires are the points (occurrence component) and the fire sizes are the marks (size component). The space-time Poisson model for occurrence is adjusted to gridded fire counts using the integrated nested Laplace approximation (INLA) combined with the Stochastic Partial Differential Equation (SPDE) approach. The size model is based on piecewise-estimated Pareto and Generalized-Pareto distributions, also adjusted with INLA. The Fire Weather Index (FWI) and Forest Area are the main explanatory variables. Seasonal and spatial residuals as well as a post-2003 effect are included to improve the consistency of the relationship between climate and fire occurrence, in accordance with parsimonious criteria.

A set of 1000 simulations of the posterior model of fire activity is evaluated at various temporal and spatial scales in Mediterranean France. The number of escaped fires (≥1ha) across the region can be coarsely reproduced at the daily scale, and is more accurately predicted on a weekly basis or longer. The regional weekly total number of larger fires (10 to 100 ha) can be predicted as well, but the accuracy decays with size, as the model uncertainty increases with event rareness. Local predictions of fire numbers or burnt areas likewise require a longer aggregation period to maintain model accuracy.

Regarding the year 2003 -which was characterized by an extreme burnt area in France associated with a heat wave-, the estimation of the number of escaped fires was consistent with observations, but the model systematically underrepresents larger fires and burnt areas, which suggests that the FWI does not consistently rate the danger of large fire occurrence during heat waves.

Our study sheds new light on the stochastic processes underlying fire hazard, and is promising for predicting and projecting future fire hazard in the context of climate change.
Biosynthesis and heterologous expression of cacaoidin, the first member of the lanthidin family of RiPPs
Authors: Román-Hurtado Fernando , Sánchez-Hidalgo Marina , Martín Jesús , Ortíz-López Francisco Javier , Genilloud Olga
Published: May 2020

1.

Cacaoidin is the first member of the new lanthidin RiPP family, a lanthipeptide produced by the strainStreptomyces cacaoiCA-170360 with unprecedented features such as an unusually high number of D-amino acids, a double methylation in the N-terminal alanine and a tyrosine residue glycosylated with a disaccharide. In this work, we describe the complete identification, cloning and heterologous expression of the cacaoidin biosynthetic gene cluster, which shows unique RiPP genes.
Allelic expression analysis of Imprinted and X-linked genes from bulk and single-cell transcriptomes
Authors: Martini Paolo , Sales Gabriele , Diamante Linda , Perrera Valentina , Colantuono Chiara , Riccardo Sara , Cacchiarelli Davide , Romualdi Chiara , Martello Graziano
Published: May 2020

Genomic imprinting and X chromosome inactivation (XCI) are two prototypical epigenetic mechanisms whereby a set of genes is expressed mono-allelically in order to fine-tune their expression levels. Defects in genomic imprinting have been observed in several neurodevelopmental disorders, in a wide range of tumours and in induced pluripotent stem cells (iPSCs). Single Nucleotide Variants (SNVs) are readily detectable by RNA-sequencing allowing determination of whether imprinted or X-linked genes are aberrantly expressed from both alleles, although standardised analysis methods are still missing. We have developed a tool, named BrewerIX, that provides comprehensive information about the allelic expression of a large, manually-curated set of imprinted and X-linked genes. BrewerIX does not require programming skills, runs on a standard personal computer, and can analyze both bulk and single-cell transcriptomes of human and mouse cells directly from raw sequencing data. BrewerIX confirmed previous observations regarding the bi-allelic expression of some imprinted genes in naive pluripotent cells and extended them to preimplantation embryos. BrewerIX identified also misregulated imprinted genes in breast cancer cells and in human organoids and identified new genes escaping XCI in human somatic cells. We believe BrewerIX will be useful for the study of genomic imprinting and XCI during development and reprogramming, and for detecting aberrations in cancer, iPSCs and organoids. Due to its ease of use to non-computational biologists, its implementation could become standard practice during sample assessment, thus raising robustness and reproducibility of future studies.
Body size and tree species composition determine variation in prey consumption in a forest-inhabiting generalist predator
Authors: van Schrojenstein Lantman Irene M. , Vesterinen Eero J. , Hertzog Lionel R. , Martel An , Verheyen Kris , Lens Luc , Bonte Dries
Published: May 2020

Trophic interactions may strongly depend on body size and environmental variation, but this prediction has been seldom tested in nature. Many spiders are generalist predators that use webs to intercept flying prey. The size and mesh of orb webs increases with spider size, allowing a more efficient predation on larger prey. We studied to this extent the orb-weaving spider Araneus diadematus inhabiting forest fragments differing in edge distance, tree diversity and tree species. These environmental variables are known to correlate to insect composition, richness and abundance. We anticipated these forest characteristics to be a principle driver of prey consumption. We additionally hypothesised them to impact spider size at maturity and expect shifts towards larger prey-size distributions in larger individuals independently from the environmental context.

We quantified spider diet by means of metabarcoding of nearly 1000 A. diadematus from a total of 53 forest plots. This approach allowed a massive screening of consumption dynamics in nature, though at the cost of identifying the exact prey identity, as well as their abundance and putative intraspecific variation. Our study confirmed A. diadematus as a generalist predator, with more than 300 prey ZOTUs detected in total. At the individual level, we found large spiders to consume fewer different species, but adding larger species to their diet. Tree species composition affected both prey species richness and size in the spider’s diet, although tree diversity per se had no influence on the consumed prey. Edges had an indirect effect on the spider diet as spiders closer to the forest edge were larger and therefore consumed larger prey. We conclude that both intraspecific size variation and tree species composition shape the consumed prey of this generalist predator.
Acetyl-Leucine slows disease progression in lysosomal storage disorders
Authors: Kaya Ecem , Smith David A , Smith Claire , Morris Lauren , Bremova-Ertl Tatiana , Cortina-Borja Mario , Fineran Paul , Morten Karl J , Poulton Joanna , Boland Barry , Spencer John , Strupp Michael , Platt Frances M
Published: May 2020

Acetyl-DL-leucine (ADLL) is a derivative of the branched chain amino acid leucine. In observational clinical studies ADLL improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder (LSD), Niemann-Pick disease type C 1 (NPC1). Here, we investigated ADLL and its enantiomers acetyl-L-leucine (ALL) and acetyl-D-leucine (ADL) in symptomaticNpc1-/-mice and observed an improvement in ataxia with both enantiomers and ADLL. When ADLL and ALL were administered pre-symptomatically toNpc1-/-mice, both treatments delayed disease progression and extended life span, whereas ADL did not. These data are consistent with ALL being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were found to be implicated as one of the potential mechanisms of action of the L enantiomer inNpc1-/-mice. When miglustat and ADLL were used in combination significant synergy resulted. In agreement with these pre-clinical data, when NPC1 patients were evaluated after 12 months of ADLL treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of ADLL on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its further evaluation in clinical trials in lysosomal disorders.
Identification a novel subset of alveolar type 2 cells expanding following pneumonectomy and enriched in PD-L1
Authors: Ahmadvand Negah , Khosravi Farhad , Lingampally Arun , Wasnick Roxana , Vazquez-Armendariz Ivonne , Heiner Monika , Rivetti Stefano , Lv Yuqing , Wilhelm Jochen , Gunther Andreas , Herold Susanne , Alam Denise Al , Chen Chengshui , Minoo Parviz , Zhang Jin-San , Bellusci Saverio
Published: May 2020

Alveolar type 2 (AT2) cells are heterogeneous cells; where specialized AT2 subpopulations within this lineage exhibit stem cell properties. However, the existence of quiescent, immature cells within the AT2 lineage, which get activated during lung regeneration, is unknown.

SftpcCreERT2/+; tdTomatoflox/floxmice were used for the labelling of AT2 cells and labeled subpopulations were analyzed by flow cytometry, qPCR, ATAC-seq, gene arrays, pneumonectomy, and culture of precision-cut lung slides. Human lungs from donor and IPF were also analyzed.

In mice, we detected two distinct AT2 subpopulations with low tdTomato level (TomLow) and high tdTomato level (TomHigh). TomLowexpress lower level of AT2 differentiation markers,Fgfr2bandEtv5, while TomHigh, asbona fidemature AT2 cells, show higher level ofSftpc,Sftpb,Sftpa1,Fgfr2b, andEtv5. ATAC-seq analysis indicates that TomLowand TomHighconstitute two distinct cell populations with specific silencing ofSftpc,Rosa26and cell cycle gene loci in TomLow. Upon pneumonectomy, TomLowbut not TomHighcells proliferate and upregulate the expression ofFgfr2b,Etv5,Sftpc,Ccnd1andCcnd2compared to sham. TomLowcells overexpress PD-L1, an immune inhibitory membrane receptor ligand, which is used by flow cytometry to differentially isolate these two sub-populations. In the human lung, PD-L1 and HTII-280 antibodies are used by flow cytometry to differentially sort mature AT2 (HTII-280-high, PD-L1-low) as well as an additional subpopulation of epithelial cells characterized by HTII-280-Low and PD-L1-high.

We have identified a novel population of AT2 quiescent immature progenitor cells in mouse that proliferate upon pneumonectomy and provided evidence for the existence of such cells in human.

Significance of the work

The characterization and mechanism of the proliferation of a novel and relevant pool of AT2 progenitor cells for the repair/regeneration process after injury are critical to improving respiratory function in patients with lung disease.
Type I PRMT inhibition protects against C9ORF72 arginine-rich dipeptide repeat toxicity
Authors: Premasiri Alan S. , Gill Anna L. , Vieira Fernando G.
Published: May 2020

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a repeat expansion mutation in the C9orf72 gene. Repeat-associated non-AUG (RAN) translation of this expansion produces five species of dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR and polyPR, are consistently reported to be the most toxic. Here, we uncover Type I protein arginine methyltransferase (PRMT) inhibitors as possible therapeutics for polyGR- and polyPR- related toxicity. Furthermore, we reveal data that suggest that asymmetric dimethylation (ADMe) of polyGR is a determining factor in its pathogenesis.
Fold recognition by scoring protein map similarities using the congruence coefficient
Authors: Di Lena Pietro , Baldi Pierre
Published: May 2020

Motivation

Protein fold recognition is a key step for template-based modeling approaches to protein structure prediction. Although closely related folds can be easily identified by sequence homology search in sequence databases, fold recognition is notoriously more difficult when it involves the identification of distantly related homologues. Recent progress in residue-residue contact and distance prediction opens up the possibility of improving fold recognition by using structural information contained in predicted distance and contact maps.

Results

Here we propose to use thecongruence coefficientas a metric of similarity between maps. We prove that this metric has several interesting mathematical properties which allow one to compute in polynomial time its exact mean and variance over all possible (exponentially many) alignments between two symmetric matrices, and assess the statistical significance of similarity between aligned maps. We perform fold recognition tests by recovering predicted target contact/distance maps from the two most recent CASP editions and over 27,000 non-homologous structural templates from the ECOD database. On this large benchmark, we compare fold recognition performances of different alignment tools with their own similarity scores against those obtained using the congruence coefficient. We show that the congruence coefficient overall improves fold recognition over other methods, proving its effectiveness as a general similarity metric for protein map comparison.

Availability

The software CCpro is available as part of the Scratch suitehttp://scratch.proteomics.ics.uci.edu/
A large accessory protein interactome is rewired across environments
Authors: Liu Zhimin , Miller Darach , Li Fangfei , Liu Xianan , Levy Sasha
Published: May 2020

To characterize how protein-protein interaction (PPI) networks change, we quantified the relative PPI abundance of 1.6 million protein pairs in yeast across 9 growth conditions, with replication, for a total of 44 million measurements. Our multi-condition screen identified 13,764 pairwise PPIs, a 3-fold increase over PPIs identified in one condition. A few “immutable” PPIs are present across all conditions, while most “mutable” PPIs are rarely observed. Immutable PPIs aggregate into highly connected “core” network modules, with most network remodeling occurring within a loosely connected “accessory” module. Mutable PPIs are less likely to co-express, co-localize, and be explained by simple mass action kinetics, and more likely to contain proteins with intrinsically disordered regions, implying that environment-dependent association and binding is critical to cellular adaptation. Our results show that protein interactomes are larger than previously thought and contain highly dynamic regions that reorganize to drive or respond to cellular changes.
Maturation of Purkinje cell firing properties relies on granule cell neurogenesis
Authors: van der Heijden Meike E. , Lackey Elizabeth P. , Işleyen Fatma S. , Brown Amanda M. , Perez Ross , Lin Tao , Zoghbi Huda Y. , Sillitoe Roy V.
Published: May 2020

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Granule cells are especially vulnerable, and they likely instigate disease by impairing the function of Purkinje cells. Here, we use regional genetic manipulations andin vivoelectrophysiology to test whether granule cells help establish the firing properties of Purkinje cells during postnatal mouse development. We generated mice that lack granule cell neurogenesis and tracked the structural and functional consequences on Purkinje cells in these agranular pups. We reveal that Purkinje cells fail to acquire their typical connectivity and morphology, and the formation of characteristic Purkinje cell firing patterns is delayed by one week. We also show that the agranular pups have impaired motor behaviors and vocal skills. These data argue that granule cell neurogenesis sets the maturation time window for Purkinje cell function and refines cerebellar-dependent behaviors.
High-resolution population-specific recombination rates and their effect on phasing and genotype imputation
Authors: Hassan Shabbeer , Surakka Ida , Taskinen Marja-Riitta , Salomaa Veikko , Palotie Aarno , Wessman Maija , Tukiainen Taru , Pirinen Matti , Palta Priit , Ripatti Samuli
Published: May 2020

Founder population size, demographic changes (eg. population bottlenecks or rapid expansion) can lead to variation in recombination rates across different populations. Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analysis like haplotype phasing, genotype imputation and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10kb and 50kb scale using high-coverage (20-30x) whole-genome sequenced 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman’s ρ =0.67-0.79) with non-Finnish Europeans, although on average (across all autosomal chromosomes), Finnish rates (2.268±0.4209 cM/Mb) are 12-14% lower than NFE (2.641±0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates ~ 2%) and average imputation concordance rates (97-98% for common, 92-96% for low frequency and 78-90% for rare variants). Our results suggest that downstream population genomic analyses like haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps or effective population sizes. Currently, available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.
WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific
Authors: Salter Eric W. , Lei Gang , Choi Sun-Lim , Ralph Liam T. , Zhang Lijia , Jin Fuzi , Kadia Ashish , Wang Junhui , Georgiou John , Collingridge Graham L.
Published: May 2020

Withdrawal statement

The authors have withdrawn their manuscript owing to the results of this pre-print being based on experiments performed prior to COVID-19 shutdowns, which required a near complete culling of the mouse colony. Upon re-initiating the colony, the phenotype outlined in the pre-print could no longer be observed and as such we have decided to withdraw the pre-print. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Cis-regulatory elements within TEs can influence expression of nearby maize genes
Authors: Noshay Jaclyn M , Marand Alexandre P , Anderson Sarah N , Zhou Peng , Guerra Maria Katherine Mejia , Lu Zefu , O’Connor Christine , Crisp Peter A , Hirsch Candice N. , Schmitz Robert J , Springer Nathan M
Published: May 2020

Transposable elements (TEs) have the potential to create regulatory variation both through disruption of existing DNA regulatory elements and through creation of novel DNA regulatory elements. In a species with a large genome, such as maize, the many TEs interspersed with genes creates opportunities for significant allelic variation due to TE presence/absence polymorphisms among individuals. We used information on putative regulatory elements in combination with knowledge about TE polymorphisms in maize to identify TE insertions that interrupt existing accessible chromatin regions (ACRs) in B73 as well as examples of polymorphic TEs that contain ACRs among four inbred lines of maize including B73, Mo17, W22, and PH207. The TE insertions in three other assembled maize genomes (Mo17, W22 or PH207) that interrupt ACRs that are present in the B73 genome can trigger changes to the chromatin suggesting the potential for both genetic and epigenetic influences of these insertions. Nearly 20% of the ACRs located over 2kb from the nearest gene are located within an annotated TE. These are regions of unmethylated DNA that show evidence for functional importance similar to ACRs that are not present within TEs. Using a large panel of maize genotypes we tested if there is an association between the presence of TE insertions that interrupt, or carry, an ACR and the expression of nearby genes. TEs that carry ACRs exhibit an enrichment for being associated with higher expression of nearby genes, suggesting that these TEs may create novel regulatory elements. These analyses highlight the potential for TEs to rewire transcriptional responses in eukaryotic genomes.

Data Availability

In this study we utilize previously published datasets that are available through the following accessions: SRX4727413, SRR8738272, and SRR8740852.
A modular framework for the development of targeted Covid-19 blood transcript profiling panels
Authors: Rinchai Darawan , Kabeer Basirudeen , Toufiq Mohammed , Calderone Zohreh , Deola Sara , Brummaier Tobias , Garand Mathieu , Branco Ricardo , Baldwin Nicole , Alfaki Mohamed , Altman Matthew , Ballestrero Alberto , Bassetti Matteo , Zoppoli Gabriele , De Maria Andrea , Tang Benjamin , Bedognetti Davide , Chaussabel Damien
Published: May 2020

Covid-19 morbidity and mortality are associated with a dysregulated immune response. Tools are needed to enhance existing immune profiling capabilities in affected patients. Here we aimed to develop an approach to support the design of focused blood transcriptome panels for profiling the immune response to SARS-CoV-2 infection. We designed a pool of candidates based on a pre-existing and well-characterized repertoire of blood transcriptional modules. Available Covid-19 blood transcriptome data was also used to guide this process. Further selection steps relied on expert curation. Additionally, we developed several custom web applications to support the evaluation of candidates. As a proof of principle, we designed three targeted blood transcript panels, each with a different translational connotation: therapeutic development relevance, SARS biology relevance and immunological relevance. Altogether the work presented here may contribute to the future expansion of immune profiling capabilities via targeted profiling of blood transcript abundance in Covid-19 patients.
One enzyme many faces: alkaline phosphatase-based phosphorus-nutrient strategies and the regulatory cascade revealed by CRISPR/Cas9 gene knockout
Authors: Zhang Kaidian , Zhou Zhi , Wang Jierui , Li Jiashun , Lin Xin , Li Ling , Wu Xiaomei , You Yanchun , Lin Senjie
Published: May 2020

Phosphorus (P) is an essential macronutrient for marine phytoplankton responsible for ∼50% of global carbon fixation. As P availability is variable and likely will decrease in future warming oceans, phytoplankton growth will be constrained by their strategies to scavenge dissolved organophosphate. To enhance our mechanistic understanding of these strategies, here we employ CRISPR/Cas9 to create mutants of alkaline phosphatase (AP) PhoA and PhoD and a putative regulator in the diatom model Phaeodactylum tricornutum, coupled with transcriptomic profiling to interrogate their modes of function and P- regulatory network. Results indicate that these two AP isoforms are differentiated in subcellular localization and substrate specialization, and are mutually compensatory and replaceable. Further analyses reveal a regulatory cascade of P scavenging and potential roles of AP in iron and ammonium uptake as well as diverse metabolic pathways. These findings have important implications in how phytoplankton community will respond to future changing microenvironments of global oceans.
Estimating the size of the COVID-19 outbreak in Italy: Application of an exponential decay model to the weighted and cumulative average daily growth rate
Authors: Bartolomeo Nicola , Trerotoli Paolo , Serio Gabriella
Published: May 2020

To estimate the size of the novel coronavirus (COVID-19) outbreak in Italy, this paper introduces the cumulated and weighted average daily growth rate (WR) to evaluate an epidemic curve, On the basis of an exponential decay model (EDM), we provide estimations of the WR in four-time intervals from February 27 to April 07, 2020. By calibrating the parameters of the EDM to the reported data in Hubei Province of China, we also attempt to forecast the evolution of the outbreak. We compare the EDM applied to WR and the Gompertz model, which is based on exponential decay and is often used to estimate cumulative events. Specifically, we assess the performance of each model to short-term forecast of the epidemic, and to predict the final epidemic size.
Based on the official counts for confirmed cases, the model applied to data from February 27 until the 17st of March estimate that the cumulative number of infected could reach 131,280 (with a credibility interval 71,415-263,501) by April 25 (credibility interval April 12 to May 3). With the data available until the 24st of March the peak date should be reached on May 3 (April 23 to May 23) with 197,179 cumulative infections expected (130033-315,269); with data available until the 31st of March the peak should be reached on May 4 (April 25 to May 18) with 202,210 cumulative infections expected (155.235-270,737); with data available until the 07st of April the peak should be reached on May 3 (April 26 to May 11) with 191,586 (160,861-232,023) cumulative infections expected. Based on the average mean absolute percentage error (MAPE), cumulated infections forecasts provided by the EDM applied to WR performed better across all scenarios than the Gompertz model.
An exponential decay model applied to the cumulated and weighted average daily growth rate appears to be useful in estimating the number of cases and peak of the COVID-19 outbreak in Italy and the model was more reliable in the exponential growth phase.
The Estimations of the COVID-19 Incubation Period: A Scoping Reviews of the Literature
Authors: Zaki Nazar , Mohamed Elfadil A.
Published: May 2020

Background

A novel coronavirus (COVID-19) has taken the world by storm. The disease has spread very swiftly worldwide. A timely clue which includes the estimation of the incubation period among COVID-19 patients can allow governments and healthcare authorities to act accordingly.

Objectives

to undertake a review and critical appraisal of all published/preprint reports that offer an estimation of incubation periods for COVID-19.

Eligibility criteria

This research looked for all relevant published articles between the dates of December 1, 2019, and April 25, 2020, i.e. those that were related to the COVID-19 incubation period. Papers were included if they were written in English, and involved human participants. Papers were excluded if they were not original (e.g. reviews, editorials, letters, commentaries, or duplications).

Sources of evidence

COVID-19 Open Research Dataset supplied by Georgetown’s Centre for Security and Emerging Technology as well as PubMed and Embase via Arxiv, medRxiv, and bioRxiv.

Charting methods

A data-charting form was jointly developed by the two reviewers (NZ and EA), to determine which variables to extract. The two reviewers independently charted the data, discussed the results, and updated the data-charting form.

Results and conclusions

screening was undertaken 44,000 articles with a final selection of 25 studies referring to 18 different experimental projects related to the estimation of the incubation period of COVID-19. The majority of extant published estimates offer empirical evidence showing that the incubation period for the virus is a mean of 7.8 days, with a median of 5.01 days, which falls into the ranges proposed by the WHO (0 to 14 days) and the ECDC (2 to 12 days). Nevertheless, a number of authors proposed that quarantine time should be a minimum of 14 days and that for estimates of mortality risks a median time delay of 13 days between illness and mortality should be under consideration. It is unclear as to whether any correlation exists between the age of patients and the length of time they incubate the virus.
Effects of a DPP-4 inhibitor and RAS blockade on clinical outcomes of patients with diabetes and COVID-19
Authors: Rhee Sang Youl , Lee Jeongwoo , Nam Hyewon , Kyoung Dae-Sung , Kim Dae Jung
Published: May 2020

Background: Dipeptidyl peptidase-4 inhibitor (DPP-4i) and renin-angiotensin system (RAS) blockade are reported to affect the clinical course of coronavirus disease 2019 (COVID-19) in patients with diabetes mellitus (DM). However, the effectiveness of these drugs in large populations is unclear.
Subjects and Methods: As of May 2020, data analysis was conducted on all subjects who could confirm their history of claims related to COVID-19 in the National Health Review and Assessment Service database in Korea. Using the COVID-19 and claims data of the past 5 years, we compared the short-term prognosis of COVID-19 infection according to the use of DPP-4i and RAS blockade.
Results: Totally, data of 67850 subjects were accessible. Of these, 5080 were confirmed COVID-19. Among these, 832 subjects with DM were selected for analysis in this study. Among the subjects, 263 (31.6%) and 327 (39.3%) were DPP-4i and RAS blockade users, respectively. Thirty-four subjects (4.09%) received intensive care or died. The adjusted odds ratio for severe treatment among DPP-4i users was 0.362 [95% confidence interval (CI), 0.135-0.971], and that for RAS blockade users was 0.599 (95% CI, 0.251-1.431). No synergy was observed for subjects using both drugs.
Conclusion: This population-based study suggests that DPP-4i is significantly associated with a better clinical outcome of patients with COVID-19. However, the effect of RAS blockade is not significant.
Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation
Authors: Jerber J , Seaton DD , Cuomo ASE , Kumasaka N , Haldane J , Steer J , Patel M , Pearce D , Andersson M , Bonder MJ , Mountjoy E , Ghoussaini M , Lancaster MA ,   HipSci Consortium, Marioni JC , Merkle FT , Stegle O , Gaffney DJ
Published: May 2020

Common genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards a midbrain neural fate, including dopaminergic neurons, and profile over 1 million cells sampled across three differentiation timepoints using single cell RNA sequencing. We find that the proportion of neuronal cells produced by each cell line is highly reproducible over different experimental batches, and identify robust molecular markers in pluripotent cells that predict line-to-line differences in cell fate. We identify expression quantitative trait loci (eQTL) that manifest at different stages of neuronal development, and in response to oxidative stress, by exposing cells to rotenone. We find over one thousand eQTL that colocalise with a known risk locus for a neurological trait, nearly half of which are not found in GTEx. Our study illustrates how coupling single cell transcriptomics with long-term iPSC differentiation can profile mechanistic effects of human trait-associated genetic variants in otherwise inaccessible cell states.
Breaking the next Cryo-EM resolution barrier – Atomic resolution determination of proteins!
Authors: Yip Ka Man , Fischer Niels , Paknia Elham , Chari Ashwin , Stark Holger
Published: May 2020

Single particle cryo-EM is a powerful method to solve the three-dimensional structures of biological macromolecules. The technological development of electron microscopes, detectors, automated procedures in combination with user friendly image processing software and ever-increasing computational power have made cryo-EM a successful and largely expanding technology over the last decade. At resolutions better than 4 Å, atomic model building starts becoming possible but the direct visualization of true atomic positions in protein structure determination requires significantly higher (< 1.5 Å) resolution, which so far could not be attained by cryo-EM. The direct visualization of atom positions is essential for understanding protein-catalyzed chemical reaction mechanisms and to study drug-binding and -interference with protein function. Here we report a 1.25 Å resolution structure of apoferritin obtained by cryo-EM with a newly developed electron microscope providing unprecedented structural details. Our apoferritin structure has almost twice the 3D information content of the current world record reconstruction (at 1.54 Å resolution1). For the first time in cryo-EM we can visualize individual atoms in a protein, see density for hydrogen atoms and single atom chemical modifications. Beyond the nominal improvement in resolution we can also show a significant improvement in quality of the cryo-EM density map which is highly relevant for using cryo-EM in structure-based drug design.
Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks
Authors: Zhou Qi , Perovic Tijana , Fechner Ines , Edgar Lowell T. , Hoskins Peter R. , Gerhardt Holger , Krüger Timm , Bernabeu Miguel O.
Published: May 2020

Sprouting angiogenesis is an essential vascularisation mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarise and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (well-known as RBCs) and their haemodynamics impact affects vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC depletion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.

Recent studies demonstrate that during sprouting angiogenesis, blood flow provides crucial hydrodynamic cues (e.g.wall shear stress) for the remodelling of primitive plexuses towards a functional network. Notwithstanding, the role of RBCs in this process remains poorly understood. We report on the inherent heterogeneity of RBC perfusion within primitive vasculatures, and uncover a strong association between RBC depletion and vessel regression. Our work indicates the essential role of RBC dynamics in the establishment of regional WSS differences driving vascular remodelling. The RBC-driven process of pruning cell-depleted vessels not only importantly contributes to the optimal patterning of vascular networks during development, but also provides a remodelling mechanism to support clinical findings of microangiopathic complications associated with impaired RBC deformability in diseases such as diabetes mellitus and hypertension.
Adding stochastic negative examples into machine learning improves molecular bioactivity prediction
Authors: Cáceres Elena L. , Mew Nicholas C. , Keiser Michael J.
Published: May 2020

Multitask deep neural networks learn to predict ligand-target binding by example, yet public pharmacological datasets are sparse, imbalanced, and approximate. We constructed two hold-out benchmarks to approximate temporal and drug-screening test scenarios whose characteristics differ from a random split of conventional training datasets. We developed a pharmacological dataset augmentation procedure, Stochastic Negative Addition (SNA), that randomly assigns untested molecule-target pairs as transient negative examples during training. Under the SNA procedure, ligand drug-screening benchmark performance increases from R2= 0.1926 ± 0.0186 to 0.4269±0.0272 (121.7%). This gain was accompanied by a modest decrease in the temporal benchmark (13.42%). SNA increases in drug-screening performance were consistent for classification and regression tasks and outperformed scrambled controls. Our results highlight where data and feature uncertainty may be problematic, but also show how leveraging uncertainty into training improves predictions of drug-target relationships.
Multi-Scale 3D Cryo-Correlative Microscopy for Vitrified Cells
Authors: Wu Gong-Her , Mitchell Patrick G. , Galaz-Montoya Jesus G. , Hecksel Corey W. , Sontag Emily M. , Gangadharan Vimal , Marshman Jeffrey , Mankus David , Bisher Margaret E. , Lytton-Jean Abigail K. R. , Frydman Judith , Czymmek Kirk , Chiu Wah
Published: May 2020

Three-dimensional (3D) visualization of vitrified cells can uncover structures of subcellular complexes without chemical fixation or staining. Here, we present a pipeline integrating three imaging modalities to visualize the same specimen at cryogenic temperature at different scales: cryo-fluorescence confocal microscopy, volume cryo-focused ion beam scanning electron microscopy, and transmission cryo-electron tomography. Our proof-of-concept benchmark revealed the 3D distribution of organelles and subcellular structures in whole heat-shocked yeast cells, including the ultrastructure of protein inclusions that recruit fluorescently-labelled chaperone Hsp104. Since our workflow efficiently integrates imaging at three different scales and can be applied to other types of cells, it could be used for large-scale phenotypic studies of frozen-hydrated specimens in a variety of healthy and diseased conditions with and without treatments.
A new perspective on the evolution of the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors
Authors: Mesrouze Yannick , Aguilar Gustavo , Bokhovchuk Fedir , Martin Typhaine , Delaunay Clara , Villard Frédéric , Meyerhofer Marco , Zimmermann Catherine , Fontana Patrizia , Wille Roman , Vorherr Thomas , Erdmann Dirk , Furet Pascal , Scheufler Clemens , Schmelzle Tobias , Affolter Markus , Chène Patrick
Published: May 2020

The most downstream elements of the Hippo pathway, the TEAD transcription factors, are regulated by several cofactors, such as Vg/VGLL1-3. Earlier findings on human VGLL1 and here on human VGLL3 show that these proteins interact with TEAD via a conserved amino acid motif called the TONDU domain. Surprisingly, our studies reveal that the TEAD-binding domain ofDrosophilaVg and of human VGLL2 is more complex and contains an additional structural element, an Ω-loop, that contributes to TEAD binding andin vivofunction. To explain this unexpected structural difference between proteins from the same family, we propose that, after the genome-wide duplications at the origin of vertebrates, the Ω-loop present in an ancestralVGLLgene has been lost in some VGLL variants. These findings illustrate how structural and functional constraints can guide the evolution of transcriptional cofactors to preserve their ability to compete with other cofactors for binding to transcription factors.
Postzygotic and germinalde novomutations in ASD: exploring their biological role
Authors: Alonso-González A , Calaza M , Amigo J , González-Peñas J , Martínez-Regueiro  , Fernández-Prieto M , Parellada M , Rodriguez-Fontenla C , Carracedo A
Published: May 2020

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined cohort (N=2171 trios) with ASC (Autism Sequencing Consortium) previously published data was created. New plausible candidate genes for ASD such asFMR1andNFIAwere found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.
A release-and-capture mechanism generates an essential non-centrosomal microtubule array during tube budding
Authors: Gillard Ghislain , Girdler Gemma , Röper Katja
Published: May 2020

Non-centrosomal microtubule arrays serve crucial functions in cells, yet the mechanisms of their generation are poorly understood. During budding of the epithelial tubes of the salivary glands in theDrosophilaembryo, we previously demonstrated that the activity of pulsatile apical-medial actomyosin depends on a longitudinal non-centrosomal microtubule array. Here we uncover that the exit from the last embryonic division cycle of the epidermal cells of the salivary gland placode leads to the mother centrosome in the cells losing all microtubule-nucleation capacity. This restriction of nucleation activity to the daughter centrosome is key for proper morphogenesis. Furthermore, the microtubule-severing protein Katanin and the minus-end-binding protein Patronin accumulate in an apical-medial position only in placodal cells. Loss of either in the placode prevents formation of the longitudinal microtubule array and leads to loss of apical-medial actomyosin and apical constriction. We thus propose a mechanism whereby Katanin-severing at the single active centrosome releases microtubule minus-ends that are then anchored by apical-medial Patronin to promote formation of the longitudinal microtubule array crucial for apical constriction and tube formation.
Open source 3D printed Ventilation Device
Authors: Faryami Ahmad , Harris Carolyn A
Published: May 2020

COVID-19 is an acute respiratory tract infection caused by a coronavirus known as SARS-CoV-2. The common signs of infection include respiratory symptoms such as shortness of breath, breathing difficulties, dry cough, fever, and in some patients, severe acute respiratory syndrome, kidney failure, and death. 312,009 deaths from COVID-19 has been reported as of today. While respiratory symptoms are commonly caused by the infection, the use of mechanical ventilation is required for some patients. The following is intended to review the development and testing of a 3D printed and open-source mechanical ventilation device that is capable of adjusting breathing rate, volume, and pressure simultaneously and was designed according to the latest clinical observations of the current pandemic. The intuitive design of this device along with the use of primarily 3D printed or readily available components allow the rapid manufacturing and transportation of this ventilation device to the impacted regions.