bluuebunny/crossref_metadata_2025_split huggingface dataset:
hudson: A User-Friendly R Package to Extend Manhattan Plots
Authors: Lucas Anastasia , Verma Anurag , Ritchie Marylyn D. 
Published: January 2022

AbstractThe Manhattan plot is one of the most widely used visualization techniques when plotting summary statistics from genome-wide or phenome-wide association studies. While there are a number of existing tools to create these plots, there is room for extending their utility to satisfy increasingly complex and comprehensive analyses as well as the need for comparisons between different sets of results or between discovery and replication datasets. The R package presented here, hudson, provides user-friendly plotting functions intended for use with genome, phenome, and exposome-wide association studies, but its flexible framework can be utilized for a wide variety genome-wide analyses. Further, we have extended these figures to allow for interactive elements to facilitate results exploration for the ever-increasing large-scale dimensionality of these data. hudson can be obtained from https://github.com/RitchieLab/hudson.
Divergent binding mode for a protozoan BRC repeat to RAD51
Authors: Pantelejevs Teodors , Hyvönen Marko 
Published: January 2022

ABSTRACTInteraction of BRCA2 through ca. 30 amino acid residue motifs, BRC repeats, with RAD51 is a conserved feature of the double-strand DNA break repair process in eukaryotes. In humans the binding of the eight BRC repeats is relatively well understood, with structure of BRC4 repeat bound to human RAD51 showing how two sequence motifs, FxxA and LFDE, in the BRC repeat interact with distinct sites on RAD51. Little is known however of the interaction of BRC repeats in other species, especially in protozoans where variable number of BRC repeats are found in BRCA2 proteins. Here we have studied in detail the interactions of the two BRC repeats in Leishmania infantum BRCA2 with RAD51. We show that the LiBRC1 is a high affinity repeat with a KD of 0.29 μM while LiBRC2 binds to RAD51 with a KD of 13.5 μM. A crystal structure of LiBRC1 complexed with LiRAD51 revels an extended β-hairpin compared to human BRC4 and shows that the equivalent of human LFDE motif is not interacting with LiRAD51. A truncation analysis of LiBRC1 confirms that a shorter repeat is sufficient for high affinity interaction and this minimal repeat is functional in inhibiting the formation of LiRAD51-ssDNA nucleofilament.
Toll Like Receptor 9 Pathway Mediates Schlafen+-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias
Authors: Ding Lin , Chakrabarti Jayati , Sheriff Sulaiman , Li Qian , Thi Hong Hahn Nguyen , Sontz Ricky A , Mendoza Zoe E , Schreibeis Amanda , Helmrath Michael A. , Zavros Yana , Merchant Juanita L 
Published: January 2022

AbstractBackground and AimsA subset of MDSCs that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that individuals with a more robust response to damage-activated molecular patterns (DAMPs) and increased Toll-like receptor (TLR9) expression are predisposed to the neoplastic complications of Helicobacter infection.MethodsA mouse or human Transwell™ co-culture system comprised of dendritic cells (DCs), 2-dimensional gastric epithelial monolayers and Helicobacter were used to dissect the cellular source of interferon (IFNα) in the stomach by flow cytometry. Conditioned media from the cocultures polarized primary myeloid cells. Myeloid-derived suppressor cell (MDSC) activity was determined by T cell suppression assays. In human subjects with intestinal metaplasia or gastric cancer, the rs5743836 TLR9T>C variant was genotyped and linked to TLR9, IFNα and SLFN12L expression by immunohistochemistry. NFκB binding to the TLR9 C allele was determined by electrophoretic mobility shift assays.ResultsHelicobacter infection induced gastric epithelial and plasmacytoid DC expression of TLR9 and IFNα. Co-culturing primary mouse or human cells with DCs and Helicobacter induced TLR9, IFNα secretion and SLFN+-MDSC polarization. Neutralizing IFNα in vivo mitigated Helicobacter-induced SPEM. The TLR9 minor C allele creates an NFκb binding site associated with higher levels of TLR9, IFNα and SLFN12L in Helicobacter-infected stomachs that correlated with a greater incidence of metaplasias and cancer.ConclusionTLR9 plays an essential role in the production of IFNα and polarization of SLFN+-MDSCs upon Helicobacter infection. Subjects carrying the rs5743836 TLR9 minor C allele are predisposed to neoplastic complications if chronically infected.
Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer’s disease
Authors: Rosenberg Nadia , Reva Maria , Restivo Leonardo , Briquet Marc , Bernardinelli Yann , Rocher Anne-Bérengère , Markram Henry , Chatton Jean-Yves 
Published: January 2022

AbstractAlzheimer’s disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenge as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxydative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic-like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD-related stress at the early stages of the disease.
A comprehensive evaluation of consensus spectrum generation methods in proteomics
Authors: Luo Xiyang , Bittremieux Wout , Griss Johannes , Deutsch Eric W , Sachsenberg Timo , Levitsky Lev I. , Ivanov Mark V. , Bubis Julia A. , Gabriels Ralf , Webel Henry , Sanchez Aniel , Bai Mingze , Kall Lukas , Perez-Riverol Yasset 
Published: January 2022

AbstractSpectrum clustering is a powerful strategy to minimize redundant mass spectral data by grouping highly similar mass spectra corresponding to repeatedly measured analytes. Based on spectrum similarity, near-identical spectra are grouped in clusters, after which each cluster can be represented by its so-called consensus spectrum for downstream processing. Although several algorithms for spectrum clustering have been adequately benchmarked and tested, the influence of the consensus spectrum generation step is rarely evaluated. Here, we present an implementation and benchmark of common consensus spectrum algorithms, including spectrum averaging, spectrum binning, the most similar spectrum, and the best-identified spectrum. We have analyzed diverse public datasets using two different clustering algorithms (spectra-cluster and MaRaCluster) to evaluate how the consensus spectrum generation procedure influences downstream peptide identification. The BEST and BIN methods were found the most reliable methods for consensus spectrum generation, including for datasets with post-translational modifications (PTM) such as phosphorylation. All source code and data of the present study are freely available on GitHub at https://github.com/statisticalbiotechnology/representative-spectra-benchmark.
Slow-cycling cells in glioblastoma: a specific population in the cellular mosaic of cancer stem cells
Authors: Yang C , Tian G , Dajac M , Doty A , Wang S , Lee JH , Rahman M , Huang J , Reynolds BA , Sarkisian MR , Mitchell D , Deleyrolle LP 
Published: January 2022

AbstractGlioblastoma (GBM) exhibits populations of cells that drive tumorigenesis, treatment resistance, and disease progression. Cells with such properties have been described to express specific surface and intracellular markers or exhibit specific functional features including being slow-cycling or quiescent with the ability to generate proliferative progenies. In GBM, each of these cellular fractions was shown to harbor cardinal features of cancer stem cells 1-7. In this study we focus on the comparison of these cells and present evidence of great phenotypic and functional heterogeneity in brain cancer cell populations with stemness properties, especially between slow-cycling cells and cells phenotypically defined based on the expression of markers commonly used to enrich for cancer stem cells (CSCs). Our data support the cancer stem cell mosaicism model with slow-cycling cells representing critical tesserae.
Stimulus Whitening Improves the Efficiency of Reverse Correlation
Authors: Compton Alexis , Roop Benjamin W. , Parrell Benjamin , Lammert Adam C. 
Published: January 2022

AbstractHuman perception depends upon internal representations of the environment that help to organize the raw information available from the senses by acting as reference patterns. Internal representations are widely characterized using reverse correlation, a method capable of producing unconstrained estimates of the representation itself, all on the basis of simple responses to random stimuli. Despite its advantages, reverse correlation is often infeasible to apply because the number of stimulus-response trials needed to provide an accurate estimate is typically very large. Prior approaches have aimed to overcome this sampling inefficiency by incorporating prior knowledge of the representation, which biases the estimate and ultimately limits the essential power of reverse correlation. The present approach, however, improves efficiency via stimulus whitening, a statistical procedure that decorrelates stimuli, making them less redundant, and commensurately more favorable for efficient estimation of an arbitrary target. We provide a mathematical justification for whitening, and demonstrate in simulation that whitening provides greater than 85% improvement in efficiency for a given estimation accuracy, and also a two- to five-fold increase in accuracy for a given sample size. Improving the efficiency of reverse correlation may enable a broader scope of investigations into individual variability and potential universality of perceptual mechanisms.
Essential bromodomain TcBDF2 as a drug target against Chagas disease
Authors: Pezza Alejandro , Tavernelli Luis E , Alonso Victoria L , Perdomo Virginia , Gabarro Raquel , Prinjha Rab , Araya Elvio Rodríguez , Rioja Inmaculada , Docampo Roberto , Calderón Felix , Martin Julio , Serra Esteban 
Published: January 2022

AbstractTrypanosoma cruzi is a unicellular parasite that causes Chagas disease, which is endemic in the American continent but also worldwide distributed by migratory movements. A striking feature of trypanosomatids is the polycistronic transcription associated with post-transcriptional mechanisms that regulate the levels of translatable mRNA. In this context, epigenetic regulatory mechanisms have been revealed of great importance, since they are the only ones that would control the access of RNA polymerases to chromatin. Bromodomains are epigenetic protein readers that recognize and specifically bind to acetylated lysine residues, mostly at histone proteins. There are seven coding sequences for BD-containing proteins in trypanosomatids, named TcBDF1 to TcBDF7, and a putative new protein-containing a bromodomain that was recently described. Using the Tet regulated overexpression plasmid pTcINDEX-GW and CRISPR/Cas9 genome editing we were able to demonstrate the essentiality of TcBDF2 in T cruzi. This bromodomain is located in the nucleus, through a bipartite nuclear localization signal. TcBDF2 was shown to be important for host cell invasion, amastigote replication, and differentiation from amastigotes to trypomastigotes. Overexpression of TcBDF2 diminished epimastigote replication. Also, some processes involved in pathogenesis were altered in these parasites, such as infection of mammalian cells, replication of amastigotes, and the number of trypomastigotes released from host cells. In in vitro studies, TcBDF2 was also able to bind inhibitors showing a specificity profile different from that of the previously characterized TcBDF3. These results, point to TcBDF2 as a druggable target against T. cruzi.
Gut bacterial nutrient preferences quantified in vivo
Authors: Zeng Xianfeng , Xing Xi , Gupta Meera , Keber Felix C , Lopez Jaime G , Roichman Asael , Wang Lin , Neinast Michael D , Donia Mohamed S , Wühr Martin , Jang Cholsoon , Rabinowitz Joshua D 
Published: January 2022

AbstractGreat progress has been made in understanding gut microbiome’s products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber, and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate and urea (but not glucose or amino acids) feed the gut microbiome. To determine nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We find systematic differences in nutrient use: Most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.
Physiological Responses to Caprine Coccidiosis During a 100-year Rain Event in Oklahoma: An Opportunistic Case Study with a implications for climate change and clinical diagnosis
Authors: McCallum Malcolm L. , Tilahun Yonathan , Pinango Jessica Quijada , Wang Zaisen 
Published: January 2022

AbstractThe interaction between inclement weather and disease acquisition is a long-recognized relationship. In the case of coccidiosis, a parasitic infestation of the intestines, wet weather is known to promote incidences in livestock. Our opportunistic investigation tracks blood chemistries of goats that were exposed to coccidian in a 100 year rain event in Oklahoma. Our results suggest a potentially patterned response of blood chemistries that may be developed into a clinical tool in the future and provide warnings for producers of the risks associated with growing incidences of excessively wet weather related to climate change.
Target-dependent siRNA suppression distinguishes self from non-self endogenous siRNAs in C. elegans germline
Authors: Gajic Zoran , Kaur Diljeet , Ni Julie , Zhu Zhaorong , Zhebrun Anna , Gajic Maria , Kim Matthew , Hong Julia , Priyadarshini Monika , Frøkjær-Jensen Christian , Gu Sam 
Published: January 2022

AbstractDespite their prominent role in transposon silencing, expression of endo-siRNAs is not limited to the “non-self” DNA elements. Transcripts of protein-coding genes (“self” DNA) in some cases also produce endo-siRNAs in yeast, plants, and animals [1]. How cells distinguish these two populations of siRNAs to prevent unwanted silencing of self-genes in animals is not well understood. To address this question, we examined the expression of ectopic siRNAs from an LTR retrotransposon in C. elegans germline. We found that the abundance of ectopic siRNAs was dependent on their homologous target genes: ectopic siRNAs against genes expressed only in somatic cells can be abundantly expressed. In contrast, ectopic siRNAs against germline-expressed genes are often suppressed. This phenomenon, which we termed “target-directed siRNA suppression”, is dependent on the target mRNA and requires germline P-granule components. We found that siRNA suppression can also occur to naturally produced endo-siRNAs. We suggest that siRNA suppression plays an important role in regulating siRNA expression and preventing self-genes from aberrant epigenetic silencing.
A phenotype-based forward genetic screen identifiesDnajb6as a sick sinus syndrome gene
Authors: Ding Yonghe , Lang Di , Yan Jianhua , Bu Haisong , Li Hongsong , Jiao Kunli , Yang Jingchun , Le Tai , Clark Karl J. , Ekker Stephen C. , Cao Hung , Zhang Yuji , Li Yigang , Glukhov Alexey V. , Xu Xiaolei 
Published: January 2022

AbstractSick sinus syndrome (SSS) is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. Here, we aim to develop a phenotype-based forward genetic approach in the zebrafish (Danio rerio) animal model for discovering essential genes which dysfunction could result in SSS-like phenotypes. Previously we showed the generation of protein trap library by using a revertible gene-breaking transposon (GBT)-based insertional mutagenesis system. Here, we reported the generation of a collection of 35 zebrafish insertional cardiac lines derived from this protein trap library, which was screened using electrocardiographic measurements. As a result, three mutants with SSS-like phenotypes were identified. We then focused on one of these 3 GBT mutants calledGBT411in whichdnajb6bgene was disrupted, and conducted expressional, genetic, transcriptome, and electrophysiological studies using both zebrafish and mouse models. These studies confirmed the identity ofDnajb6as a novel SSS causative gene with a unique expression pattern within the specialized population of sinus node pacemaker cardiomyocytes that lack the expression of HCN4 channels. Together, this study demonstrates the feasibility of a genetic screening approach in an adult vertebrate animal model for discovering new genetic factors for a heart rhythm disorder such as SSS.
Defining the Substrate Envelope of SARS-CoV-2 Main Protease to Predict and Avoid Drug Resistance
Authors: Shaqra Ala M. , Zvornicanin Sarah , Huang Qiu Yu , Lockbaum Gordon J. , Knapp Mark , Tandeske Laura , Barkan David T. , Flynn Julia , Bolon Daniel N.A. , Moquin Stephanie , Dovala Dustin , Kurt Yilmaz Nese , Schiffer Celia A. 
Published: January 2022

AbstractCoronaviruses, as exemplified by SARS-CoV-2, can evolve and spread rapidly to cause severe disease morbidity and mortality. Direct acting antivirals (DAAs) are highly effective in decreasing disease burden especially when they target essential viral enzymes, such as proteases and polymerases, as demonstrated in HIV-1 and HCV and most recently SARS-CoV-2. Optimization of these DAAs through iterative structure-based drug design has been shown to be critical. Particularly, the evolutionarily conserved molecular mechanisms underlying viral replication can be leveraged to develop robust antivirals against rapidly evolving viral targets. The main protease (Mpro) of SARS-CoV-2, which is evolutionarily constrained to recognize and cleave 11 specific sites to promote viral maturation, exemplifies one such target. In this study we define the substrate envelope of Mpro by determining the molecular basis of substrate recognition, through nine high-resolution cocrystal structures of SARS-CoV-2 Mpro with the viral cleavage sites. These structures enable identification of evolutionarily vulnerable sites beyond the substrate envelope that may be susceptible to drug resistance and compromise binding of the newly developed Mpro inhibitors.
Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability
Authors: Shi Wei , Wang Lingshu , Zhou Tongqing , Sastry Mallika , Yang Eun Sung , Zhang Yi , Chen Man , Chen Xuejun , Choe Misook , Creanga Adrian , Leung Kwan , Olia Adam S. , Pegu Amarendra , Rawi Reda , Shen Chen-Hsiang , Stancofski Erik-Stephane D. , Talana Chloe Adrienna , Teng I-Ting , Wang Shuishu , Corbett Kizzmekia S. , Tsybovsky Yaroslav , Mascola John R. , Kwong Peter D. 
Published: January 2022

SummaryImmunization with SARS-CoV-2 spike elicits diverse antibodies, but can any of these neutralize broadly? Here, we report the isolation and characterization of antibody WS6, from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, MERS-CoV, and hCoV-OC43. The crystal structure at 2-Å resolution of WS6 with its S2 epitope revealed recognition to center on a conserved helix, which was occluded in both prefusion and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion, post-viral attachment. Comparison of WS6 to other antibodies recently identified from convalescent donors or mice immunized with diverse spikes indicated a stem-helical supersite – centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156 – to be a promising target for vaccine design.HighlightsSARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronavirusesWS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related virusesCrystal structure at 2-Å resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitopeWS6 neutralizes by inhibition of fusion, post-viral attachmentWS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodiesHelical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turnGenetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogenies