bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractFounder 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WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific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 statementThe 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

AbstractTransposable 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 AvailabilityIn 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

SUMMARYCovid-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

AbstractPhosphorus (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.
The Estimations of the COVID-19 Incubation Period: A Scoping Reviews of the Literature
Authors: Zaki Nazar , Mohamed Elfadil A. 
Published: May 2020

AbstractBackgroundA 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.Objectivesto undertake a review and critical appraisal of all published/preprint reports that offer an estimation of incubation periods for COVID-19.Eligibility criteriaThis 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 evidenceCOVID-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 methodsA 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 conclusionsscreening 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.
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

AbstractCommon 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

SummarySingle 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

AbstractSprouting 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.SummaryRecent 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

ABSTRACTMultitask 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

SUMMARYThree-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

AbstractThe 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

ABSTRACTDe 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

AbstractNon-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

AbstractCOVID-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.