bluuebunny/crossref_metadata_2025_split huggingface dataset:
7-UP:generatingin silicoCODEX from a small set of immunofluorescence markers
Authors: Wu Eric , Trevino Alexandro E. , Wu Zhenqin , Swanson Kyle , Kim Honesty J. , D’Angio H. Blaize , Preska Ryan , Charville Gregory W. , Dalerba Piero D. , Duvvuri Umamaheswar , Levi Jelena , Colevas A. Dimitrios , Bedi Nikita , Chang Serena , Sunwoo John B. , Mayer Aaron T. , Zou James 
Published: June 2022

AbstractMultiplex immunofluorescence (mIF) assays multiple protein biomarkers on a single tissue section. Recently, high-plex CODEX (co-detection by indexing) systems enable simultaneous imaging of 40+ protein biomarkers, unlocking more detailed molecular phenotyping, leading to richer insights into cellular interactions and disease. However, high-plex imaging can be slower and more costly to collect, limiting its applications, especially in clinical settings. We propose a machine learning framework,7-UP,that can computationally generatein silico40-plex CODEX at single-cell resolution from a standard 7-plex mIF panel by leveraging cellular morphology. We demonstrate the usefulness of the imputed biomarkers in accurately classifying cell types and predicting patient survival outcomes. Furthermore,7-UP’simputations generalize well across samples from different clinical sites and cancer types.7-UPopens the possibility ofin silicoCODEX, making insights from high-plex mIF more widely available.
MarpolBase Expression: A Web-based, Comprehensive Platform for Visualization and Analysis of Transcriptomes in the Liverwort Marchantia polymorpha
Authors: Kawamura Shogo , Romani Facundo , Yagura Masaru , Mochizuki Takako , Sakamoto Mika , Yamaoka Shohei , Nishihama Ryuichi , Nakamura Yasukazu , Yamato Katsuyuki T. , Bowman John L. , Kohchi Takayuki , Tanizawa Yasuhiro 
Published: June 2022

AbstractThe liverwort Marchantia polymorpha is equipped with a wide range of molecular and genetic tools and resources that have led to its wide use to explore the evo-devo aspects of land plants. Although its diverse transcriptome data are rapidly accumulating, there is no extensive yet user-friendly tool to exploit such a compilation of data and to summarize results with the latest annotations. Here, we have developed a web-based suite of tools, MarpolBase Expression (MBEX, https://marchantia.info/mbex/), where users can visualize gene expression profiles, identify differentially expressed genes, perform co-expression and functional enrichment analyses, and summarize their comprehensive output in various portable formats. Using oil body biogenesis as an example, we demonstrated that the results generated by MBEX were consistent with the published experimental evidence and also revealed a novel transcriptional network in this process. MBEX should facilitate the exploration and discovery of the genetic and functional networks behind various biological processes in M. polymorpha, and promote our understanding of the evolution of land plants.
Intermediaries in phosphotransfer: structural features discriminating hybrid histidine kinase Rec domains from response regulator homologs
Authors: Brüderlin Mitchell , Böhm Raphael , Fadel Firas , Hiller Sebastian , Schirmer Tilman , Dubey Badri N. 
Published: June 2022

AbstractIn two-component systems, the information gathered by the histidine kinase (HK) is relayed to the cognate response regulator (RR). Thereby, the phosphoryl group of the autophosphorylated HK is transferred to the receiver domain of the RR to allosterically activate its effector domain. In contrast, multi-step phosphorelays comprise at least one additional Rec domain (Recinter) that is part of the HK and acts as an intermediary for phosphoryl-shuttling. While RR Rec domains have been studied extensively, little is known about Recinter domains and their potentially discriminating features. As a bona-fide Recinter domain, here we have studied the C-terminal Rec domain of the hybrid HK CckA (CckARec) from Caulobacter crescentus by X-ray crystallography and NMR spectroscopy. CckARec exhibits the canonical Rec-fold, though with a degenerated α4 helix, in which all active site residues are pre-arranged for phosphoryl-binding. BeF3- binding does not alter secondary structure nor the oligomeric state, indicating the absence of allosteric changes, the hall mark of RRs. Based on structural modeling and sequence co-variation analysis, we present a detailed picture for the intramolecular association of the CckA DHp/Rec domains and discuss the role of a FATGUY motif, a distinguishing feature of CckARec orthologs.
Characterization of the Pace-and-Drive Capacity of the Human Sinoatrial Node: a 3D in silico Study
Authors: Amsaleg Antoine , Sánchez Jorge , Mikut Ralf , Loewe Axel 
Published: June 2022

ABSTRACTThe sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically (“pacing”) and excites the surrounding non-automatic cardiac cells (“drive”) to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEP). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA). Additionally, we investigated the influence of the SEPs by varying their number, length and width. SEPs created a transition zone of transmembrane voltage (TMV) and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized TMV (−66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted towards the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46±1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared to a larger distance from the LPS to the areas where SEPs were located (7.17±0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace-and-drive in silico.SIGNIFICANCEThe human sinoatrial node (SAN) is the intrinsic natural pacemaker of the heart. Despite its remarkable robustness to failure, the electrophysiological properties, and mechanisms by which the SAN overcomes the source-sink mismatch towards the hyperpolarized surrounding cardiac tissue remains a mystery. The SAN is electrically isolated from the hyperpolarized cardiac tissue, except at a discrete number of sinoatrial exit pathways (SEP). Using in silico experiments, we explore the influence of the fiber orientation, the SEPs’ number, geometry and location on the activation of the SAN and the surrounding atrial tissue. We provide the mechanisms in a first 3D model of the human SAN-SEP structure that can successfully drive the working myocardium.
Causal effects of prefrontal transcranial magnetic stimulation on dopamine-mediated reinforcement learning in healthy adults
Authors: Biernacki Kathryn , Myers Catherine E. , Cole Sally , Cavanagh James F. , Baker Travis E. 
Published: June 2022

AbstractBackground10-Hz repetitive transcranial magnetic stimulation (rTMS) to the left dorsal lateral prefrontal cortex (DLPFC) has been shown to increase dopaminergic activity in the dorsal striatum, a region strongly implicated in reinforcement learning. However, the behavioural influence of this effect remains largely unknown.ObjectiveHere, we tested the causal effects of rTMS on behavioral and computational characteristics of reinforcement learning.Methods40 healthy individuals were randomized into Active and Sham rTMS groups. Each participant underwent one 10-Hz rTMS session (1500 pulses) in which stimulation was applied over the left DLPFC using a robotic arm. Participants then completed a reinforcement learning task sensitive to striatal dopamine functioning. Participants’ trial-to-trial training choices were modelled using a reinforcement learning model (Q-learning) that calculates separate learning rates associated with positive and negative reward prediction errors.ResultsSubjects receiving Active TMS exhibited an increased reward rate (number of correct responses per second of task activity) compared to the Sham rTMS group. Computationally, the Active rTMS group displayed a higher learning rate for correct trials (αG) compared to incorrect trials (αL). Finally, when tested with novel pairs of stimuli, the Active group displayed extremely fast reaction times, and a trend towards a higher reward rate.ConclusionsThe present study provided specific behavioral and computational accounts of altered striatal-mediated reinforcement learning induced by a proposed increase of dopamine activity by 10-Hz rTMS to the left DLPFC. Together, these findings bolster the use of TMS to target neurocognitive disturbances attributed to the dysregulation of dopaminergic-striatal circuits.
Mature rotavirus particles contain equivalent amounts of7meGpppGcap and noncapped viral positive-sense RNAs
Authors: Moreno-Contreras Joaquin , Sánchez-Tacuba Liliana , Arias Carlos F. , López Susana 
Published: June 2022

ABSTRACTViruses have evolved different strategies to overcome their recognition by the host innate immune system. Addition of cap at their 5’RNA ends is an efficient mechanism to ensure escape from detection by the innate immune system, but also to ensure the efficient synthesis of viral proteins. Rotavirus mRNAs contain a type 1 cap structure at their 5’end that is added by the viral capping enzyme VP3. This is a multifunctional protein with all the enzymatic activities necessary to add the cap, and also functions as an antagonist of the OAS-RNase L pathway. Here, the relative abundance of capped and noncapped viral RNAs during the replication cycle of rotavirus was determined. We found that both classes of rotaviral +RNAs are encapsidated, and they were present in a 1:1 ratio in the mature infectious particles. The capping of viral +RNAs is dynamic since different ratios of capped and noncapped RNAs were detected at different times post infection. Similarly, when the relative amount of capped and uncapped viral +RNAs produced in anin vitrotranscription system was determined, we found that the proportion was very similar to that in the mature viral particles and in infected cells, suggesting that the capping efficiency of VP3 both,in vivoandin vitro,might be close to 50%. Unexpectedly, when the effect of simultaneously knocking down the expression of VP3 and RNase L on the cap status of viral +RNAs was evaluated, we found that even though at late times post infection there was an increased proportion of capped viral RNAs in infected cells, the viral particles isolated from this condition contained an equal ratio of capped and noncapped viral RNA, suggesting that there might be a selective packaging of capped-noncapped RNAs.SIGNIFICANCERotaviruses have a genome composed of eleven segments of double stranded RNA. Whether all 5’ ends of the positive sense genomic RNA contained in the mature viral particles are modified by a cap structure is unknown. In this work, using a direct quantitative assay we characterized the relative proportion of capped and noncapped viral RNA in rotavirus infected cells and in viral particles. We found that independently of the relative proportions of cap/noncapped RNA present in rotavirus infected cells, there is a similar proportion of these two kinds of 5’-modified positive sense RNAs in the viral particles.
Designing a flow-controlled STA-MCA anastomosis based on the Hagen-Poiseuille law for preventing postoperative hyperperfusion in adult moyamoya disease
Authors: Zhang Jianjian , Fujimura Miki , Lau Tsz Yeung , Chen Jincao 
Published: June 2022

AbstractOBJECTIVETechnical improvements for preventing postoperative symptomatic cerebral hyperperfusion (CHP) during superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD) were seldom reported. The aim of this study was to investigate the significance of application of a novel flow-controlled concept which voluntarily reduces the hemodynamic difference between the donor and recipient arteries based on the Hagen-Poiseuille law when performing direct anastomoses of recipient parasylvian cortical arteries (PSCAs) with anterograde hemodynamic sources from the MCA (M-PSCAs) in adult MMD.METHODSRecently direct anastomoses of recipient M-PSCAs were performed on 89 symptomatic hemispheres in 82 adult MMD patients in our hospital. They were divided into the flow-controlled group and non-flow-controlled group. The patients’ basic characteristics and incidence of postoperative CHP were compared between the two groups. Risk factors for occurrence of postoperative CHP were analyzed.RESULTSThe earlier 36 and later 53 anastomoses were respectively included in the non-flow-controlled group and flow-controlled group. The incidences of postoperative focal (22.6%) and symptomatic CHP (5.7%) in the flow-controlled group were significantly lower than those (focal, 52.8%; symptomatic, 25.0%) in the non flow-controlled group (P = 0.003 and 0.009, respectively). Multivariate analysis revealed that the flow-controlled concept used or not was significantly associated with the development of focal (P = 0.005) and symptomatic (P = 0.012) CHP.CONCLUSIONSThe flow-controlled STA-MCA anastomosis can significantly decrease the incidence of postoperative CHP during direct anastomoses of recipient M-PSCAs in adult MMD.
Multiomic prioritisation of risk genes for anorexia nervosa
Authors: Adams Danielle M. , Reay William R. , Cairns Murray J. 
Published: June 2022

ABSTRACTAnorexia nervosa is the leading cause of mortality among psychiatric disorders worldwide. Currently no medications are approved for anorexia nervosa treatment, and thus, identification of risk factors for this disorder is pivotal to improve patient outcomes. We used models of genetically imputed expression and splicing from 17 tissues (two blood and fifteen brain regions), leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with anorexia nervosa risk. We uncovered 134 genes for which genetically predicted mRNA expression was associated with anorexia nervosa after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with anorexia nervosa. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6, for which increased genetically predicted mRNA expression was correlated with anorexia, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1) as statistically overrepresented. In summary, we leveraged multiomic datasets to genetically prioritise novel risk genes for anorexia nervosa that warrant further exploration.
Senescence rewires microenvironment sensing to facilitate anti-tumor immunity
Authors: Chen Hsuan-An , Ho Yu-Jui , Mezzadra Riccardo , Adrover Jose M. , Smolkin Ryan , Zhu Changyu , Luan Wei , Wuest Alexandra , Tian Sha , Li Xiang , Hendrickson Ronald C. , Egeblad Mikala , Alonso-Curbelo Direna , Lowe Scott W. 
Published: June 2022

ABSTRACTCellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.SIGNIFICANCEOur work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity.
Protective human anti-poxvirus monoclonal antibodies are generated from rare memory B cells isolated by multicolor antigen tetramers
Authors: Gu Xiuling , Zhang Yufan , Jiang Wei , Wang Dongfang , Lu Jiao , Gu Guanglei , Qin Cheng-Feng , Fang Min 
Published: June 2022

AbstractSmallpox, an epidemic disease caused by Orthopoxvirus variola, was eradicated worldwide through immunization. The immunization against smallpox was discontinued in 1980. However, incidences of monkeypox virus infection in humans have occurred sporadically, and there is also great fear that engineered forms of poxvirus could be used as biological weapons. Therefore, monoclonal antibodies against poxvirus are in urgent need for the detection and treatment of poxvirus infection. The vaccinia virus extracellular envelope protein A33 is a potential candidate for subunit vaccine. We used multi-fluorescence-labeled tetrameric A33 antigen to identify rare poxvirus specific memory B cells from PBMC of volunteers with vaccinia virus immunization more than 40 years ago. Despite extremely low frequencies of the poxvirus specific memory B cells, we successfully sorted A33 tetramer-labeled single memory B cells and reconstructed antibodies with single-cell RT-PCR of the B-cell receptor. Among the monoclonal antibodies, one clone H2 exhibited high specificity and affinity with A33. H2 efficiently inhibited viral infection and spread in cells. Passive immunotherapy of H2 in mice protected mice from lethal infection when administered either prophylactically or therapeutically. These results suggest the potential of the anti-A33 human antibody-based detection and therapeutics for poxvirus infection.
Pseudoalignment facilitates assignment of error-prone Ultima Genomics reads
Authors: Booeshaghi A. Sina , Pachter Lior 
Published: June 2022

AbstractWe analyze single-cell RNA-seq data sequenced with Ultima Genomics technology and find high error rates in and near homopolymers. To compensate for these errors, we explore the use of pseudoalignment for read assignment, and find that it can perform better than standard read alignment. Our pseudoalignment read assignment for Ultima Genomics data is available as part of the kallisto-bustools kb-python package available at https://github.com/pachterlab/kb_python.
Meta-analysis reveals obesity associated gut microbial alteration patterns and reproducible contributors of functional shift
Authors: Chanda Deep , De Debojyoti 
Published: June 2022

SummaryCohort-specific 16S rRNA sequence-based studies associating gut microbiota with obesity are often marred with contradictory findings regarding community structure and composition leading to “reproducibility crisis” of the signals. Moreover, taxonomic drivers of the obesity-linked gut microbial functional imbalances and their replicability also remains unexplored which should be useful for in-depth understanding of obese host-gut microbiota interaction and, strategizing therapeutics. We addressed these questions through unbiased meta-analysis and further machine-learning validation of 692 curated fecal whole metagenomic sequence datasets from diverse geographical locations. Further, obesity-linked pathway shifts were traced back to their specific drivers by integrating the species and pathway profiles through genomic content of the species. We found reproducible depletion of diversity in obese gut microbiome without any pattern in Firmicutes/Bacteroidetes ratio. Additionally, we also identified obesity-linked robust and reproducible gut microbial species and pathway features. Contributors of these pathway features identified as both dataset-specific and shared across the datasets.
Capturing the liquid-crystalline phase transformation: Implications for protein targeting to sterol ester-rich lipid droplets
Authors: Braun R. Jay , Swanson Jessica M.J. 
Published: June 2022

AbstractLipid droplets are essential organelles that store and traffic neutral lipids. The phospholipid monolayer surrounding their neutral lipid core engages with a highly dynamic proteome that changes according to cellular and metabolic conditions. Recent work has demonstrated that when the abundance of sterol esters increases above a critical concentration, such as under conditions of starvation or high LDL exposure, the lipid droplet core can undergo an amorphous to liquid-crystalline phase transformation. Herein we study the consequences of this transformation on the physical properties of lipid droplets that are thought to regulate protein association. Using simulations of different sterol-ester concentrations we have captured the liquid-crystalline phase transformation at the molecular level, highlighting the alignment of sterol esters in alternating orientations to form concentric layers. We demonstrate how ordering in the core permeates into the neutral lipid/phospholipid interface, changing the magnitude and nature of neutral lipid intercalation and inducing ordering in the phospholipid monolayer. Increased phospholipid packing is concomitate with altered surface properties, including smaller area per phospholipid and substantially reduced packing defects. Additionally, the ordering of sterol esters in the core causes less hydration in more ordered regions. We discuss these findings in the context of their expected consequences for preferential protein recruitment to lipid droplets under different metabolic conditions.