bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic analysis and evaluation of asymptomatic infection in the spread of COVID-19
Authors: Xu Chuanqing , Zhang Zonghao , Huang Xiaotong , Cui Jingan 
Published: December 2021

AbstractCOVID-19 has spread worldwide for nearly two years. Many countries have experienced repeated epidemics, that is, after the epidemic has been controlled for a period of time, the number of new cases per day is low, and the outbreak will occur again a few months later. In order to study the relationship between this low level of infection and the number of asymptomatic infections, and to evaluate the role of asymptomatic infections in the development of the epidemic, we have established an improved infectious disease dynamics model that can be used to evaluate the spread of the COVID-19 epidemic, and fitted the epidemic data in the three flat periods in England. According to the obtained parameters, according to the calculation of the model, the proportion of asymptomatic infections in these three flat periods are 41%, 53% and 58% respectively. After the first flat period, the number of daily newly confirmed cases predicted by the model began to increase around July 1, 2020. After more than four months of epidemic spread, it reached a peak on November 12, which is consistent with the actual case situation. Unanimous. After the second flat period, the model predicts that the number of new confirmed cases per day will increase from about May 7, 2021, and after about 73 days of epidemic development, it will reach a peak on July 20, showing the overall trend of the epidemic. In the above, the predicted results of the model are consistent with the actual cases. After the third flat period, the number of daily newly diagnosed cases predicted by the model began to increase around December 1, 2021, and reached a peak in December, and the number of cases will drop to a very low level after May 2022. According to our research results, due to the large number of asymptomatic infections, the spread of the epidemic is not easy to stop completely in a short time. However, when the epidemic enters a period of flat time, nucleic acid testing is performed, and asymptomatic infections are isolated at home for 14 days (the recovery period of symptomatic infection is about 10 days) may be an option that can be considered to interrupt the transmission of the case.
Compromised CDK12 activity causes dependency on the non-essential spliceosome components
Authors: Pallasaho Satu , Gondane Aishwarya , Duveau Damien , Thomas Craig , Loda Massimo , Itkonen Harri M 
Published: December 2021

AbstractProstate cancer (PC) is the most common cancer in men and after development of the castration-resistant PC (CRPC), there are no curative treatment options. Inactivating mutations in cyclin-dependent kinase 12 (CDK12) define an aggressive sub-type of CRPC. We hypothesized that compromised CDK12 activity leads to significant rewiring of the CRPC cells, and that this rewiring results in actionable synthetic lethal interactions.MethodsWe used combinatorial lethal screening, ChIP-seq data, RNA-seq data, global alternative splicing analysis, and comprehensive mass spectrometry (MS) profiling to understand how the compromised CDK12 activity rewires the CRPC cells. In addition, we used DepMap-, PC- and CRPC-datasets as a strategy to identify factors that are selectively required by the CDK12-mutant cells.ResultsWe show that inhibition of O-GlcNAc transferase (OGT) and CDK12 induces cancer cell-selective growth-defect. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation, and we use unbiased MS-profiling to show that the short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in PC and CRPC cells. Integration of DepMap- and a small scale-drug screen data reveled that depletion of CDK12 activity causes addiction to non-essential spliceosome components (CLK1/4 and SRPK1). CDK12-mutant tumors overexpress CLK1/4 and SRPK1. Finally, we show that the genomes of the CDK12-mutant tumors have lower DNA methylation, and that CDK12 inhibition induces the expression of the genes marked by DNA methylation.ConclusionsCompromised CDK12 activity rewires DNA methylation, transcription and splicing, and this rewiring renders the affected cells addicted on the non-essential spliceosome components. We propose that inactivation of CDK12 is a biomarker for sensitivity against inhibitors of the non-essential spliceosome components just entering the clinical trials.Abstract Figure
Semi-automated computational assessment of cancer organoid viability using rapid live-cell microscopy
Authors: Buehler Joseph D. , Bird Cylaina E. , Savani Milan R. , Gattie Lauren C. , Hicks William H. , Levitt Michael M. , Shami Mohamad El , Hatanpaa Kimmo J. , Richardson Timothy E. , McBrayer Samuel K. , Abdullah Kalil G. 
Published: December 2021

AbstractThe creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to a variety of human solid tumor types. However, conventional methods used to assess cellular viability in tissue specimens are poorly suited for the evaluation of cancer organoids because they are time-intensive and involve tissue destruction. To address this issue, we established a suite of 3-dimensional patient-derived glioma organoids, treated them with chemoradiotherapy, stained organoids with non-toxic cell dyes, and imaged them using a rapid laser scanning confocal microscopy method termed “Apex Imaging”. We then developed and tested a fragmentation algorithm to quantify heterogeneity in the topography of the organoids as a potential surrogate marker of viability. This algorithm, SSDquant, provides a 3-dimensional visual representation of the organoid surface and a numerical measurement of the sum-squared distance (SSD) from the derived mass center of the organoid. We tested whether SSD scores correlate with traditional immunohistochemistry-derived cell viability markers (cellularity and cleaved caspase 3 expression) and observed statistically significant associations between them using linear regression analysis. Our work describes a quantitative, non-invasive approach for the serial measurement of patient-derived cancer organoid viability, thus opening new avenues for the application of these models to studies of cancer biology and therapy.
Using coexpression to explore cell-type diversity with the fcoex package
Authors: Lubiana Tiago , Nakaya Helder 
Published: December 2021

SummaryHere, we present the fcoex package, which infers coexpression from scRNA-seq data and yields multiple, overlapping classes of cells based on coexpression modules. The tool extends the current scRNA-seq toolbox, providing a multi-hierarchy view on cell functionality and enabling the development of more complete cell atlases. Single-cell RNA sequencing (scRNA-seq) captures details of the cellular landscape, basing a fine-grained view on biological processes. Current pipelines, however, are restricted to single-label perspectives, missing details of the classification landscape. In the pbmc3k blood cell dataset, fcoex detects known classes, like antigen-presenting cells and a new theoretical group of cells, marked by the expression of FCGR3A (CD16). Fcoex extends the current scRNA-seq toolbox, providing a multi-hierarchy view on cell functions as a tool to develop complete cell type atlases.Availability and ImplementationFcoex is written in R and openly available in Bioconductor (https://bioconductor.org/packages/fcoex/).Supplementary informationSupplementary data is available at the end of the manuscript. Source code for analysis is available at https://github.com/csbl-inovausp/fcoex_analysis;
The Spatial Reach of Neuronal Coherence and Spike-field Coupling across the Human Neocortex
Authors: Myers John C. , Smith Elliot H. , Leszczynski Marcin , O’Sullivan James , Yates Mark , McKhann Guy , Mesgarani Nima , Schroeder Charles , Schevon Catherine , Sheth Sameer A. 
Published: December 2021

SUMMARYNeuronal coherence is thought to be a fundamental mechanism of communication in the brain, where synchronized field potentials coordinate synaptic and spiking events to support plasticity and learning. Although the spread of field potentials has garnered great interest, little is known about the spatial reach of phase synchronization, or neuronal coherence. Functional connectivity between different brain regions is known to occur across long distances, but the locality of coherence within a brain region is understudied. Here we used simultaneous recordings from electrocorticography (ECoG) grids and high-density microelectrode arrays to estimate the spatial reach of neuronal coherence and spike-field coherence (SFC) across frontal, temporal, and occipital cortices during cognitive tasks in humans. We observed the strongest coherence within a 2-3 cm distance from the microelectrode arrays, potentially defining an effective range for local communication. This range was relatively consistent across brain regions, spectral frequencies, and cognitive tasks. The magnitude of coherence showed power law decay with increasing distance from the microelectrode arrays, where the highest coherence occurred between ECoG contacts, followed by coherence between ECoG and deep cortical LFP, and then SFC (i.e., ECoG > LFP > SFC). The spectral frequency of coherence also affected its magnitude. Alpha coherence (8-14 Hz) was generally higher than other frequencies for signals nearest the microelectrode arrays, whereas delta coherence (1-3 Hz) was higher for signals that were farther away. Action potentials in all brain regions were most coherent with the phase of alpha oscillations, which suggests that alpha waves could play a larger, more spatially local role in spike timing than other frequencies. These findings provide a deeper understanding of the spatial and spectral dynamics of neuronal coherence, further advancing knowledge about how activity propagates across the human brain.
Reconfigurations in brain networks upon awakening from slow wave sleep: Interventions and implications in neural communication
Authors: Hilditch Cassie J. , Bansal Kanika , Chachad Ravi , Wong Lily R. , Bathurst Nicholas G. , Feick Nathan H. , Santamaria Amanda , Shattuck Nita L. , Garcia Javier O. , Flynn-Evans Erin E. 
Published: December 2021

AbstractSleep inertia is the brief period of impaired alertness and performance experienced immediately after waking. While the neurobehavioral symptoms of sleep inertia are well-described, less is known about the neural mechanisms underlying this phenomenon. A better understanding of the neural processes during sleep inertia may offer insight into the cognitive impairments observed and the awakening process generally. We observed brain activity following abrupt awakening from slow wave sleep during the biological night. Using electroencephalography (EEG) and a network science approach, we evaluated power, clustering coefficient, and path length across frequency bands under both a control condition and a blue-enriched light intervention condition in a within-subject design. We found that under control conditions, the awakening brain is typified by an immediate reduction in global theta, alpha, and beta power. Simultaneously, we observed a decrease in the clustering coefficient and an increase in path length within the delta band. Exposure to blue-enriched light immediately after awakening ameliorated these changes, but only for clustering. Our results suggest that long-range network communication within the brain is crucial to the waking process and that the brain may prioritize these long-range connections during this transitional state. Our study highlights a novel neurophysiological signature of the awakening brain and provides a potential mechanistic explanation for the effect of light in improving performance after waking.One sentence summaryBlue-enriched light partially accelerates the rapid prioritization of long-range communication within the human brain that characterizes sleep inertia
What’s past is past, mostly: Brassicaceae host plants mask the feedback from the previous year’s soil history on bacterial communities, except when the Brassicaceae hosts experience drought
Authors: Blakney Andrew J.C. , Bainard Luke D. , St-Arnaud Marc , Hijri Mohamed 
Published: December 2021

AbstractPrevious soil history and the current plant hosts are two plant-soil feedbacks that operate at different time-scales to influence the structure soil bacterial communities. In this study, we used a MiSeq metabarcoding strategy to describe the impact of five Brassicaceae host plant species, and three different soil histories, on the structure of their bacterial root and rhizosphere communities at full flower. We found that the Brassicaceae host plants were consistently significant in structuring the bacterial communities. Four host plants (Sinapis alba, Brassica napus, B. juncea, B. carinata) formed nearly the same bacterial communities, regardless of soil history. Camelina sativa host plants structured phylogenetically distinct bacterial communities compared to the other hosts, particularly in their roots. Soil history established the previous year was only a significant factor for bacterial community structure when the feedback of the Brassicaceae host plants was weakened, potentially due to limited soil moisture during a dry year. Understanding how plant-soil feedbacks operate at different time-scales and are involved in how microbial communities are structured is a pre-requisite for employing microbiome technologies in improving agricultural systems.
Adaptive Ensemble Refinement of Protein Structures in High Resolution Electron Microscopy Density Maps with Radical Augmented Molecular Dynamics Flexible Fitting
Authors: Sarkar Daipayan , Lee Hyungro , Vant John W. , Turilli Matteo , Vermaas Josh V. , Jha Shantenu , Singharoy Abhishek 
Published: December 2021

AbstractRecent advances in cryo-electron microscopy (cryo-EM) have enabled modeling macromolecular complexes that are essential components of the cellular machinery. The density maps derived from cryo-EM experiments are often integrated with manual, knowledge or artificial intelligence driven, and physics-guided computational methods to build, fit, and refine molecular structures. Going beyond a single stationary-structure determination scheme, it is becoming more common to interpret the experimental data with an ensemble of models, which contributes to an average observation. Hence, there is a need to decide on the quality of an ensemble of protein structures on-the-fly, while refining them against the density maps. We introduce such an adaptive decision making scheme during the molecular dynamics flexible fitting (MDFF) of biomolecules. Using RADICAL-Cybertools, and the new RADICAL augmented MDFF implementation (R-MDFF) is examined in high-performance computing environments for refinement of two protein systems, Adenylate Kinase and Carbon Monoxide Dehy-drogenase. For the test cases, use of multiple replicas in flexible fitting with adaptive decision making in R-MDFF improves the overall correlation to the density by 40% relative to the refinements of the brute-force MDFF. The improvements are particularly significant at high, 2 - 3 Å map resolutions. More importantly, the ensemble model captures key features of biologically relevant molecular dynamics that is inaccessible to a single-model interpretation. Finally, the pipeline is applicable to systems of growing sizes, which is demonstrated using ensemble refinement of capsid proteins from Chimpanzee adenovirus. The overhead for decision making remaining low and robust to computing environments. The software is publicly available on GitHub and includes a short user guide to install the R-MDFF on different computing environments, from local Linux based workstations to High Performance Computing (HPC) environments.
Standard Intein Gene Expression Ramps (SIGER) for protein-independent expression control
Authors: Fages-Lartaud Maxime , Mueller Yasmin , Elie Florence , Coutarde Gaston , Hohmann-Marriott Martin Frank 
Published: December 2021

AbstractCoordination of multi-gene expression is one of the key challenges of metabolic engineering for the development of cell factories. Constraints on translation initiation and early ribosome kinetics of mRNA are imposed by features of the 5’UTR in combination with the start of the gene, referred to as the “gene ramp”, such as rare codons and mRNA secondary structures. These features strongly influence translation yield and protein quality by regulating ribosome distribution on mRNA strands. The utilization of genetic expression sequences, such as promoters and 5’UTRs in combination with different target genes leads to a wide variety of gene ramp compositions with irregular translation rates leading to unpredictable levels of protein yield and quality. Here, we present the Standard Intein Gene Expression Ramps (SIGER) system for controlling protein expression. The SIGER system makes use of inteins to decouple the translation initiation features from the gene of a target protein. We generated sequence-specific gene expression sequences for two inteins (DnaB and DnaX) that display defined levels of protein expression. Additionally, we used inteins that possess the ability to release the C-terminal fusion proteinin vivoto avoid impairment of protein functionality by the fused intein. Overall, our results show that SIGER systems are unique tools to mitigate the undesirable effects of gene ramp variation and to control the relative ratios of enzymes involved in molecular pathways. As a proof of concept of the potential of the system, we also used a SIGER system to express two difficult-to-produce proteins, GumM and CBM73.Graphical abstract
Rapid bacterial and fungal successional dynamics in first year after Chaparral wildfire
Authors: Pulido-Chavez M. Fabiola , Randolph James W. J. , Zalman Cassandra , Larios Loralee , Homyak Peter M. , Glassman Sydney I. 
Published: December 2021

AbstractThe rise in wildfire frequency and severity across the globe has increased interest in secondary succession. However, despite the role of soil microbial communities in controlling biogeochemical cycling and their role in the regeneration of post-fire vegetation, the lack of measurements immediately post-fire and at high temporal resolution has limited understanding of microbial secondary succession. To fill this knowledge gap, we sampled soils at 17, 25, 34, 67, 95, 131, 187, 286, and 376 days after a southern California wildfire in fire-adapted chaparral shrublands. We assessed bacterial and fungal biomass with qPCR of 16S and 18S and richness and composition with Illumina MiSeq sequencing of 16S and ITS2 amplicons. Fire severely reduced bacterial biomass by 47%, bacterial richness by 46%, fungal biomass by 86%, and fungal richness by 68%. The burned bacterial and fungal communities experienced rapid succession, with 5-6 compositional turnover periods. Analogous to plants, turnover was driven by “fire-loving” pyrophilous microbes, many of which have been previously found in forests worldwide and changed markedly in abundance over time. Fungal secondary succession was initiated by the Basidiomycete yeastGeminibasidium, which traded off against the filamentous AscomycetesPyronema,Aspergillus, andPenicillium. For bacteria, the ProteobacteriaMassiliadominated all year, but the FirmicuteBacillusand ProteobacteriaNoviherbaspirillumincreased in abundance over time. Our high-resolution temporal sampling allowed us to capture post-fire microbial secondary successional dynamics and suggest that putative tradeoffs in thermotolerance, colonization, and competition among dominant pyrophilous microbes control microbial succession with possible implications for ecosystem function.
Structural basis for the peptidoglycan editing activity of YfiH
Authors: Lee Meng-Sheng , Hsieh Kan-Yen , Kuo Chiao-I , Lee Szu-Hui , Chang Chung-I 
Published: December 2021

AbstractBacterial cells are encased in peptidoglycan (PG), a polymer of disaccharide N-acetyl-glucosamine (GlcNAc) and N-acetyl-muramic acid (MurNAc) cross-linked by peptide stems. PG is synthesized in the cytoplasm as UDP-MurNAc-peptide precursors, of which the amino-acid composition of the peptide is unique, with L-Ala added at the first position in most bacteria but L-Ser or Gly in some bacteria. YfiH is a PG-editing factor whose absence causes misincorporation of L-Ser instead of L-Ala into peptide stems; but its mechanistic function is unknown. Here we report the crystal structures of substrate-bound and product-bound YfiH, showing that YfiH is a cytoplasmic amidase that controls the incorporation of the correct amino acid to the nucleotide precursors by preferentially cleaving the nucleotide precursor byproduct UDP-MurNAc-L-Ser. This work reveals an editing mechanism in the cytoplasmic steps of peptidoglycan biosynthesis.
Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation
Authors: Wang Jinfan , Alvarado Carlos , Shin Byung-Sik , Bohlen Jonathan , Dever Thomas E. , Puglisi Joseph D. 
Published: December 2021

AbstractHow the eukaryotic 43S preinitiation complex scans along the 5′ untranslated region (5′UTR) of a capped mRNA to locate the correct start codon remains elusive. Here, we directly track yeast 43S-mRNA binding, scanning, and 60S subunit joining by real-time single-molecule fluorescence spectroscopy. Once engaged with the mRNA, 43S scanning occurs at >100 nucleotides per second, independent of multiple cycles of ATP-hydrolysis by RNA helicases. The scanning ribosomes can proceed through RNA secondary structures, but 5′UTR hairpin sequences near start codons drive scanning ribosomes at start codons back in the 5′ direction, requiring rescanning to arrive once more at a start codon. Direct observation of scanning ribosomes provides a mechanistic framework for translational regulation by 5′UTR structures and upstream near-cognate start codons.One Sentence SummaryDirect observation of scanning eukaryotic ribosomes establishes a quantitative framework of scanning and its regulation.
The p97-UBXD8 complex modulates ER-Mitochondria contact sites by modulating membrane lipid saturation and composition
Authors: Ganji Rakesh , Paulo Joao A. , Xi Yuecheng , Kline Ian , Zhu Jiang , Clemen Christoph S. , Weihl Conrad C. , Purdy John G. , Gygi Steve P. , Raman Malavika 
Published: December 2021

AbstractThe intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-mitochondria contact sites serves as a platform for several critical cellular processes, in particular lipid synthesis. Enzymes involved in lipid biosynthesis are enriched at contacts and membrane lipid composition at contacts is distinct relative to surrounding membranes. How contacts are remodeled and the subsequent biological consequences of altered contacts such as perturbed lipid metabolism remains poorly understood. Here we show that the p97 AAA-ATPase and its ER-tethered ubiquitin-X domain adaptor 8 (UBXD8) regulate the prevalence of ER-mitochondria contacts. The p97-UBXD8 complex localizes to contacts and loss of this complex increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics of purified contacts demonstrates alterations in proteins regulating lipid metabolism upon loss of UBXD8. Furthermore, lipidomics studies indicate significant changes in distinct lipid species in UBXD8 knockout cells. We show that loss of p97-UBXD8 results in perturbed contacts due to an increase in membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts in p97-UBXD8 loss of function cells can be rescued by supplementation with unsaturated fatty acids or overexpression of SCD1. Perturbation of contacts and inherent lipid synthesis is emerging as a hallmark to a variety of human disorders such as neurodegeneration. Notably, we find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. Our results suggest that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation in a manner that is dependent on p97-UBXD8.