bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct genetic pathways define pre-leukemic and compensatory clonal hematopoiesis in Shwachman-Diamond syndrome
Authors: Kennedy Alyssa L. , Myers Kasiani C. , Bowman James , Gibson Christopher J. , Camarda Nicholas D. , Furutani Elissa , Muscato Gwen M. , Klein Robert H. , Ballotti Kaitlyn , Liu Shanshan , Harris Chad E. , Galvin Ashley , Malsch Maggie , Dale David , Gansner John M. , Nakano Taizo A. , Bertuch Alison , Vlachos Adrianna , Lipton Jeffrey M. , Castillo Paul , Connelly James , Churpek Jane , Edward John R. , Hijiya Nobuko , Ho Richard H. , Hofmann Inga , Huang James N. , Keel Siobán , Lamble Adam , Lau Bonnie W. , Norkin Maxim , Stieglitz Elliot , Stock Wendy , Walkovich Kelly , Boettcher Steffen , Brendel Christian , Fleming Mark D. , Davies Stella M. , Weller Edie A. , Bahl Christopher , Carter Scott L. , Shimamura Akiko , Lindsley R. Coleman 
Published: June 2020

AbstractShwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with predisposition to developing leukemia. We found that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations inEIF6orTP53.EIF6mutations cause functional compensation for the germline deficiency by alleviating the SDS ribosome joining defect, improving translation, and reducing p53 activation.TP53mutations decrease checkpoint activation without affecting ribosome assembly. We link development of leukemia with acquisition of biallelicTP53alterations. Our results define distinct pathways of clonal selection driven by germline fitness constraint and provide a mechanistic framework for clinical surveillance.
The conserved ASCL1/MASH-1 ortholog HLH-3 specifies sex-specific ventral cord motor neuron fate inC. elegans
Authors: Perez Lillian M. , Alfonso Aixa 
Published: June 2020

ABSTRACTNeural specification can be regulated by one or many transcription factors. Here we identify a novel role for one conserved proneural factor, the bHLH protein HLH-3, implicated in the specification of sex-specific ventral cord motor neurons inC. elegans. In the process of characterizing the role ofhlh-3in neural specification, we document that differentiation of the ventral cord type C neurons, VCs, within their motor neuron class, is dynamic in time and space. Expression of VC class-specific and subclass-specific identity genes is distinct through development and dependent on where they are along the A-P axis (and their position in proximity to the vulva). Our characterization of the expression of VC class and VC subclass-specific differentiation markers in the absence ofhlh-3function reveals that VC fate specification, differentiation, and morphology requireshlh-3function. Finally, we conclude thathlh-3cell-autonomously specifies VC cell fate.
Foot shock facilitates reward seeking in an experience-dependent manner
Authors: Strickland JA , Dileo AD , Moaddab M , Ray MH , Walker RA , Wright KW , McDannald MA 
Published: June 2020

AbstractAnimals organize reward seeking around aversive events. An abundance of research shows that foot shock, as well as a shock-associated cue, can elicit freezing and suppress reward seeking. Yet, there is evidence that experience can flip the effect of foot shock to facilitate reward seeking. Here we examine cue suppression, foot shock suppression and foot shock facilitation of reward seeking in a single behavioural setting. Male Long Evans rats received fear discrimination consisting of danger, uncertainty and safety cues. Discrimination took place over a baseline of rewarded nose poking. With limited experience, all cues and foot shock strongly suppressed reward seeking. With continued experience, suppression became specific to shock-associated cues and foot shock facilitated reward seeking. Our results provide a means of assessing positive properties of foot shock, and may provide insight into maladaptive behavior around aversive events.
GO-CRISPR: a highly controlled workflow to discover gene essentiality in loss-of-function screens
Authors: Perampalam Pirunthan , McDonald James I. , Dick Frederick A. 
Published: June 2020

SUMMARYGenome-wide CRISPR screens are an effective discovery tool for genes that underlie diverse cellular mechanisms that can be scored through cell fitness. Loss-of-function screens are particularly challenging compared to gain-of-function because of the limited dynamic range of decreased sgRNA sequence detection. Here we describeGuide-Only controlCRISPR(GO-CRISPR), an improved loss-of-function screening workflow, and its companion software package,Toolset for theRankedAnalysis of GO-CRISPRScreens (TRACS). We demonstrate a typical GO-CRISPR workflow in a non-proliferative 3D spheroid model of dormant high grade serous ovarian cancer and demonstrate superior performance to standard screening methods. The unique integration of the pooled sgRNA library quality and guide-only controls allows TRACS to identify novel molecular pathways that were previously unidentified in tumor dormancy. Together, GO-CRISPR and TRACS can robustly improve the discovery of essential genes in challenging biological scenarios.
A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb targets
Authors: Zheng Yueyuan , Huang Guowei , Silva Tiago C. , Yang Qian , Koeffler H Phillip , Berman Benjamin P. , Lin De-Chen 
Published: June 2020

AbstractCpG Island promoter genes make up more than half of human genes, and a subset regulated by Polycomb-Repressive Complex 2 (PRC2+-CGI) become DNA methylated and silenced in cancer. Here, we perform a systematic regulatory analysis of CGI genes across TCGA cancer types, finding that PRC2+-CGI genes are frequently prone to transcriptional upregulation as well. These upregulated PRC2+-CGI genes control important pathways such as Epithelial-Mesenchymal Transition and TNFα-associated inflammatory response, and have the greatest cancer-type specificity among any class of CGI genes. Using publicly available chromatin datasets and genetic perturbations, we show that transcription factor binding sites (TFBSs) within distal enhancers underlie transcriptional activation of PRC2+-CGI genes, in contrast to PRC2-free CGI genes which are predominantly regulated by promoter TFBSs. Surprisingly, a large subset of PRC2+-CGI genes that are upregulated in one cancer type are also hypermethylated/silenced in at least one other cancer type, highlighting the high degree of regulatory plasticity likely derived from their complex regulatory patterns during normal development.
Donor-derived mitochondrial DNA variant peptides elicit allo-specific immune response in transplant patients
Authors: Marishta Argit , Yang Yanqin , Hu Xiaomeng , Jang Moon Kyoo , Cuttin Karen , Jackson Annette M. , Luikart Helen , Deuse Tobias , Khush Kiran K. , Schrepfer Sonja , Agbor-Enoh Sean , Valantine Hannah 
Published: June 2020

AbstractIn stem cell transplant, mitochondrial DNA (mtDNA) nonsynonymous single nucleotide variants (SNVs) between donor and recipient (D-R) trigger alloimmune responses and transplant rejection. Whether similar alloimmune responses occurs in solid-organ transplantation remains unknown, particularly with the presence of human leukocyte antigen mismatches. This study characterized mtDNA SNVs between D-R of 163 human lung transplant pairs, and then, post-transplantation, assessed alloimmune responses against donor-derived mitochondrial peptides using ELISpot to measure interferon gamma (IFNγ) release from recipient’s monocytes. We identified a median of 6 nonsynonymous mtDNA SNVs (Interquartile Range = 4 – 9) per D-R pair. SNVs were predominantly located atMT-CYB, MT-ATP6, andMT-ND3genes. The number of SNVs was higher in D-R race non-concordant pairs than in race-concordant pairs. Donor-derived mitochondrial peptides triggered a 19.8-fold higher IFNγ release compared to recipient-derived peptide. These findings were validated in heart transplantation and show that donor-derived mitochondrial peptides trigger allo-specific immune responses after transplantation.
Multivariate analysis reveals a generalizable human electrophysiological signature of working memory load
Authors: Adam Kirsten C.S. , Vogel Edward K. , Awh Edward 
Published: June 2020

AbstractWorking memory (WM) is an online memory system that is critical for holding information in a rapidly accessible state during ongoing cognitive processing. Thus, there is strong value in methods that provide a temporally-resolved index of WM load. While univariate EEG signals have been identified that vary with WM load, recent advances in multivariate analytic approaches suggest that there may be rich sources of information that do not generate reliable univariate signatures. Here, using data from 4 published studies (n= 286 and >250,000 trials), we demonstrate that multivariate analysis of EEG voltage topography provides a sensitive index of the number of items stored in WM that generalizes to novel human observers. Moreover, multivariate load detection (“mvLoad”) can provide robust information at the single-trial level, exceeding the sensitivity of extant univariate approaches. We show that this method tracks WM load in a manner that is (1) independent of the spatial position of the memoranda, (2) precise enough to differentiate item-by-item increments in the number of stored items, (3) generalizable across distinct tasks and stimulus displays and (4) correlated with individual differences in WM behavior. Thus, this approach provides a powerful complement to univariate analytic approaches, enabling temporally-resolved tracking of online memory storage in humans.
Molecular characterization of mosquitoes (Diptera: Culicidae) from the tropical rainforest of Sierra Nevada de Santa Marta, Colombia
Authors: Muñoz-Gamba Andrew , Laiton-Donato Katherine , Perdomo-Balaguera Erick , Usme-Ciro José , Parra-Henao Gabriel 
Published: June 2020

ABSTRACTBACKGROUNDThe Sierra Nevada de Santa Marta rainforest has diverse fauna due to its position in northern Colombia, a Caribbean region with predominantly tropical, dry, and rainforest ecosystems in which there is a high diversity of mosquito species that may act as arbovirus vectors.OBJECTIVESThe present study reports the molecular characterization of select mosquito species in this rainforest.METHODSManual capture methods were used to collect mosquitoes, and the specimens were identified via classical taxonomy. TheCOImarker was used for species confirmation, and phylogenetic analysis was performed, using the neighbor-joining method, with the Kimura-2-Parameters model.FINDINGSAedes serratus,Psorophora ferox,Johnbelkinia ulopus,Sabethes cyaneus,Wyeomyia aporonoma,Wyeomyia pseudopecten,Wyeomyia ulocomaandWyeomyia luteoventraliswere identified and intra-species variation >2% for most species.MAIN CONCLUSIONSWe report the first records on the genetic variability of mosquitoes in this area and phylogenetic reconstructions allowed for identification at the species level, and the corroboration by means of classical taxonomy suggested complementarity of both methods, which may be employed when morphological or molecular data are poor or not available. The genetic and morphological characterization of jungle mosquito populations will help to understand their biology.
Ventral pallidum neurons signal relative threat
Authors: Moaddab Mahsa , Ray Madelyn H. , McDannald Michael A. 
Published: June 2020

AbstractVentral pallidum (VP) neurons scale firing increases to reward value and decrease firing to aversive cues. Anatomical connectivity suggests a critical role for the VP in threat-related behavior. Here we tested whether firing decreases in VP neurons conform to relative threat by recording single units while male rats discriminated cues predicting unique foot shock probabilities. Rats behavior and VP single unit firing discriminated danger, uncertainty and safety cues. We found that two VP populations (Low firing and Intermediate firing) signaled relative threat, proportionally decreased firing according shock probability: danger < uncertainty < safety. Low firing neurons showed reward firing increases, consistent with a general signal for relative value. Intermediate firing neurons were unresponsive to reward, revealing a specific signal for relative threat. The results suggest an integral role for the VP in threat-related behavior.
The specificity of sperm-mediated paternal effects in threespined sticklebacks
Authors: Chen Eunice , Zielinski Christian , Deno Jack , Singh Raiza , Bell Alison M , Hellmann Jennifer K 
Published: June 2020

AbstractParental effects can help offspring cope with challenging environments, but whether these effects are unique to specific environmental conditions is largely unknown. Parental effects may evolve via a core pathway that generally prepares offspring for risky environments or could be stimuli-specific, with offspring developing phenotypes that are tailored to specific environmental challenges. We exposed threespined sticklebacks (Gasterosteus aculeatus) fathers to a potentially threatening stimulus (net) versus native predator (sculpin). Offspring of sculpin-exposed fathers were more responsive (greater change in activity) to a simulated predator attack, while offspring of net-exposed fathers were less responsive (lower plasma cortisol and fewer antipredator behaviors). To evaluate offspring response to native and non-native stimuli, we sequentially exposed offspring of net-exposed, sculpin-exposed or control fathers to a net, native sculpin model, or non-native trout model. Paternal treatment did not influence offspring response to stimuli; instead, offspring were more responsive to the native sculpin predator compared to nets or non-native trout predator. Collectively, we demonstrate that sperm-mediated paternal effects in response to different, potentially stressful stimuli result in distinct offspring phenotypes. This specificity may be key to understanding the evolution of adaptive parental effects and how parents prime offspring for encountering both evolved and novel environmental stimuli.
GermlineAPOBEC3Bdeletion in Asian women increases somatic hypermutation in breast cancer that is associated with Her2 subtype,PIK3CAmutations, immune activation, and increased survival
Authors: Pan Jia-Wern , Ahmad Zabidi Muhammad Mamduh , Chong Boon-Keat , Meng Mei-Yee , Ng Pei-Sze , Hasan Siti Norhidayu , Sandey Bethan , Bahnu Saira , Rajadurai Pathmanathan , Yip Cheng-Har , Rueda Oscar M. , Caldas Carlos , Chin Suet-Feung , Teo Soo-Hwang 
Published: June 2020

AbstractA 30-kb deletion that eliminates the coding region ofAPOBEC3B(A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with theAPOBEC3A(A3A) coding region andA3B3’UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between theA3Bdeletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germlineA3Bdeletion polymorphism leads to expression of theA3A-Bhybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless ofA3Bgermline status, were associated with the Her2 molecular subtype andPIK3CAmutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germlineA3Bdeletion polymorphism, via theA3A-Bhybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless ofA3Bbackground, may be an important clinical biomarker for Asian breast cancers.Graphical Abstract
Cryopreservation of human cancers conserves tumour heterogeneity for single-cell multi-omics analysis
Authors: Wu Sunny Z. , Roden Daniel L. , Al-Eryani Ghamdan , Bartonicek Nenad , Harvey Kate , Cazet Aurélie S. , Chan Chia-Ling , Junankar Simon , Hui Mun N. , Millar Ewan A. , Beretov Julia , Horvath Lisa , Joshua Anthony M. , Stricker Phillip , Wilmott James S. , Quek Camelia , Long Georgina V. , Scolyer Richard A. , Yeung Bertrand Z. , Segara Davendra , Mak Cindy , Warrier Sanjay , Powell Joseph E. , O’Toole Sandra , Lim Elgene , Swarbrick Alexander 
Published: June 2020

AbstractBackgroundHigh throughput single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for exploring cellular heterogeneity amongst complex human cancers. scRNA-Seq studies using fresh human surgical tissue is logistically difficult, precludes histopathological triage of samples and limits the ability to perform batch processing. This hinderance can often introduce technical biases when integrating patient datasets and increase experimental costs. Although tissue preservation methods have been previously explored to address such issues, it is yet to be examined on complex human tissues, such as solid cancers, and on high throughput scRNA-Seq platforms.ResultsWe show that the viable cryopreservation of human cancers provides high quality single-cell transcriptomes using the Chromium 10X platform. We sequenced a total of ∼120,000 cells from fresh and cryopreserved replicates across three breast cancers, two prostate cancers and a cutaneous melanoma. Importantly, tumour heterogeneity identified from fresh tissues was largely conserved in cryopreserved replicates. We show that sequencing of single cells prepared from cryopreserved tissue fragments or from cryopreserved cell suspensions is comparable to sequenced cells prepared from fresh tissue, with cryopreserved cell suspensions displaying higher correlations with fresh tissue in gene expression. We then show that cryopreservation had minimal impacts on results of downstream analyses such as biological pathway enrichment. Further, we demonstrate the advantage of cryopreserving whole-cells for immunophenotyping methods such as CITE-Seq, which is impossible using other preservation methods such as single nuclei-sequencing.ConclusionsOur study guides new experimental designs for tissue biobanking for future clinical single-cell RNA sequencing studies.
Characterization of the substitution hotspots in SARS-CoV-2 genome using BioAider and detection of a SR-rich region in N protein providing further evidence of its animal origin
Authors: Zhou Zhi-Jian , Qiu Ye , Ge Xing-Yi 
Published: June 2020

AbstractThe novel human coronavirus (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19) pandemic worldwide. The increasing sequencing data have shown abundant single nucleotide variations in SARS-CoV-2 genome. However, it is difficult to quickly analyze genomic variation and screen key mutations of SARS-CoV-2. In this study, we developed a visual program, named BioAider, for quick and convenient sequence annotation and mutation analysis on multiple genome-sequencing data. Using BioAider, we conducted a comprehensive genome variation analysis on 3,240 sequences of SARS-CoV-2 genome. Herein, we detected 14 substitution hotspots within SARS-CoV-2 genome, including 10 non-synonymous and 4 synonymous ones. Among these hotspots, NSP13-Y541C was predicted to be a crucial substitution which might affect the unwinding activity of NSP13, a key protein for viral replication. Besides, we also found 3 groups of potentially linked substitution hotspots which were worth further study. In particular, we discovered a SR-rich region (aa 184-204) on the N protein of SARS-CoV-2 distinct from SARS-CoV, indicating more complex replication mechanism and unique N-M interaction of SARS-CoV-2. Interestingly, the quantity of SRXX repeat fragments in the SR-rich region well reflected the evolutionary relationship among SARS-CoV-2 and SARS-CoV-2 related animal coronaviruses, providing further evidence of its animal origin. Overall, we developed an efficient tool for rapid identification of mutations, identified substitution hotspots in SARS-CoV-2 genomes, and detected a distinctive polymorphism SR-rich region in N protein. This tool and the detected hotspots could facilitate the viral genomic study and may contribute for screening antiviral target sites.
Chaperone-mediated stress-sensing inMycobacterium tuberculosisenables fast activation and sustained response
Authors: Rao Satyajit D. , Datta Pratik , Gennaro Maria Laura , Igoshin Oleg A. 
Published: June 2020

ABSTRACTDynamical properties of gene-regulatory networks are tuned to ensure bacterial survival. In mycobacteria, MprAB-σEnetwork responds to the presence of stressors, such as surfactants causing surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e. different responses to identical stressor levels for pre-stressed and unstressed cells. Here we show that hysteresis does not occur in non-pathogenicMycobacterium smegmatisbut occurs inMycobacterium tuberculosis. However, the observed rapid temporal response inM. tuberculosisis inconsistent with the model predictions. To reconcile these observations, we implement a recently proposed mechanism for stress-sensing: the release of MprB from the inhibitory complex with chaperone DnaK upon the stress exposure. Using modeling and parameter fitting, we demonstrate that this mechanism can accurately describe the experimental observations. Furthermore, we predict perturbations in DnaK expression that can strongly affect dynamical properties. Experiments with these perturbations agree with model predictions, confirming the role of DnaK in fast and sustained response.IMPORTANCEGene-regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches enabling the bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood. In this paper, combining quantitative experiments and mathematical modeling, we uncover how interactions between two master regulators of stress response -- MprAB two-component system and alternative sigma factorσE– shape the dynamical properties of surface-stress network. The result show hysteresis (history dependence) in the response of pathogenic bacteriaM. tuberculosisto surface stress and lack of the hysteresis in non-pathogenicM. smegmatis. Furthermore, to resolve the apparent contradiction between the existence of hysteresis and fast activation of the response, we utilize a recently proposed role of chaperone DnaK in stress-sensing. The results leads to a novel system-level understanding of bacterial stress-response dynamics.
LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation
Authors: Yeboah Muchaala , Papagregoriou Charys , Jones Des C. , Chan H.T. Claude , Hu Guangan , McPartlan Justine S. , Schiött Torbjörn , Mattson Ulrika , Mockridge C. Ian , Tornberg Ulla-Carin , Hambe Björn , Ljungars Anne , Mattsson Mikael , Tews Ivo , Glennie Martin J. , Thirdborough Stephen M. , Trowsdale John , Frendeus Björn , Chen Jianzhu , Cragg Mark S. , Roghanian Ali 
Published: June 2020

AbstractDespite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress for this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responsesin vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppresive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.