bluuebunny/crossref_metadata_2025_split huggingface dataset:
Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients
Authors: Loeb Anisha M. , Pattwell Siobhan S. , Meshinchi Soheil , Bedalov Antonio , Loeb Keith R. 
Published: April 2023

AbstractHematopoietic stem cell transplantation is a well known treatment of hematologic malignancies wherein nascent stem cells provide a regenerating marrow and immunotherapy against the tumor. The progeny of hematopoietic stem cells also populate a wide spectrum of tissues, including the brain, as bone marrow derived macrophages similar to microglial cells. We developed a sensitive and novel combined IHC and XY FISH assay to detect, quantify and characterize donor cells in the cerebral cortex of 19 female allogeneic stem cell transplant patients. We show that the number of male donor cells ranged from 0.14-3.0% of total cells or 1.2-25% of microglial cells. Using tyramide based fluorescent IHC we found at least 80% of the donor cells express the microglial marker Iba1 consistent with being bone marrow derived macrophages. The percentage of donor cells was related to pretransplant conditioning; donor cells from radiation based myeloablative cases averaged 8.1% of microglial cells, while those from non-myeloablative cases averaged only 1.3%. The number of donor cells in patients conditioned with Busulfan or Treosulfan based myeloablation were similar to TBI based conditioning; donor cells averaged 6.8% of microglial cells. Notably, patients who received multiple transplants and those with the longest post-transplant survival had the highest level of donor engraftment, with donor cells averaging 16.3% of microglial cells. Our work represents the largest study characterizing bone marrow-derived macrophages in post-transplant patients. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.Key PointsWe developed a sensitive Iba1 IHC and XY FISH co-stain assay to detect bone marrow derived donor cells in the brain of HSCT patients.Donor cells in the CNS express Iba1 and average 8% of microglia after myeloablative HSCT; double transplants increase engraftment up to 25%.
Exploring the Performance and Explainability of BERT for Medical Image Protocol Assignment
Authors: Talebi Salmonn , Tong Elizabeth , Mofrad Mohammad R. K. 
Published: April 2023

AbstractAlthough deep learning has become state of the art for numerous tasks, it remains untouched for many specialized domains. High stake environments such as medical settings pose more challenges due to trust and safety issues for deep learning algorithms. In this work, we propose to address these issues by evaluating the performance and explanability of a Bidirectional Encoder Representations from Transformers (BERT) model for the task of medical image protocol assignment. Specifically, we evaluate the performance and explainability on this medical image protocol classification task by fine tuning a pre-trained BERT model and measuring the word importance by attributing the classification output to every word through a gradient based method. We then have a trained radiologist review the resulting word importance scores and assess the validity of the model’s decision-making process in comparison to that of a human. Our results indicate that the BERT model is able to identify relevant words that are highly indicative of the target protocol. Furthermore, through the analysis of important words in misclassifications, we are able to reveal potential systematic errors in the model that may be addressed to improve its safety and suitability for use in a clinical setting.
Investigating the role of commoncis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders
Authors: Wigdor Emilie M. , Samocha Kaitlin E. , Eberhardt Ruth Y. , Chundru V. Kartik , Firth Helen V. , Wright Caroline F. , Hurles Matthew E. , Martin Hilary C. 
Published: April 2023

AbstractRecent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6,987 probands from the Deciphering Developmental Disorders (DDD) study and 9,720 controls, and found one gene,RAB2A, that passed multiple testing correction (p = 6.7×10−7). We then investigated whethercis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1,700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7×10−3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that commoncis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.
Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways
Authors: Jama Maymun , Zhang Min , Poile Charlotte , Nakas Apostolos , Sharkey Annabel , Dzialo Joanna , Dawson Alan , Kutywayo Kudazyi , Fennell Dean A. , Hollox Edward J 
Published: April 2023

AbstractMalignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene-fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal non-recurrent fusions, three of which were novel (FMO9P-OR2W5,GBA3andSP9). The number of early gene fusion events detected varied from zero to eight per tumour, and presence of gene fusions was associated with clonal SCNAs involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumour suppressorsBAP1,MTAP, andLRP1B,and a clonal oncogenic fusion involvingCACNA1D-ERC2, PARD3B-NT5DC2andSTAB2-NT5DC2fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.
SecretoMyc, a web-based database on mycobacteria secreted proteins and structure-based homology identification using bio-informatics tools
Authors: Gracy Jérôme , Vallejos-Sanchez Katherine , Cohen-Gonsaud Martin 
Published: April 2023

AbstractTo better understand the interaction between the host and theMycobacterium tuberculosispathogen, it is critical to identify its potential secreted proteins. While various experimental methods have been successful in identifying proteins under specific culture conditions, they have not provided a comprehensive characterisation of the secreted proteome. We utilized a combination of bioinformatics servers and in-house software to identify all potentially secreted proteins from six mycobacterial genomes through the three secretion systems: SEC, TAT, and T7SS. The results are presented in a database that can be crossed with selected proteomics and transcriptomics studies (https://secretomyc.cbs.cnrs.fr/myc). In addition, thanks to the recent availability of Alphafold models, we developed a tool in order to identify the structural homologues among the mycobacterial genomes.
DLL4-Notch3-WNT5B axis is a novel mediator of bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells
Authors: Alve Sanni , Gramolelli Silvia , Jukonen Joonas , Juteau Susanna , Pink Anne , Manninen Atte , Monto Elisa , Lackman Madeleine H. , Carpén Olli , Karaman Sinem , Saharinen Pipsa , Vaahtomeri Kari , Ojala Päivi M. 
Published: April 2023

ABSTRACTDespite strong indications that melanoma interaction with lymphatic vessels actively promotes melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk we established human primary lymphatic endothelial cell (LEC) co-cultures with human melanoma cell lines. Here, we show that co-culture with melanoma cells induced transcriptomic changes in LECs and led to multiple alterations in their function. WNT5B, a paracrine signaling molecule upregulated in melanoma cells upon LEC interaction, was found contributing to the functional changes in LECs. Moreover,WNT5Btranscription was regulated by Notch3 in melanoma cells following the co-culture with LECs, and Notch3 and WNT5B were co-expressed in melanoma patient primary tumor and metastasis samples. Moreover, melanoma cells derived from LEC co-culture escaped efficiently from the primary site to the proximal tumor draining lymph nodes, which was impaired upon WNT5B depletion. This supports the role of WNT5B in promoting the metastatic potential of melanoma cells through its effects on LECs. Finally, DLL4, a Notch ligand expressed in LECs, was identified as an upstream inducer of the Notch3-WNT5B axis in melanoma. This study elucidates WNT5B as a novel molecular factor mediating bi-directional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.
Contribution of the IGCR1 regulatory element and the 3’IghCBEs to Regulation ofIghV(D)J Recombination
Authors: Liang Zhuoyi , Zhao Lijuan , Yongxin Ye Adam , Lin Sherry G. , Zhang Yiwen , Guo Chunguang , Dai Hai-Qiang , Ba Zhaoqing , Alt Frederick W. 
Published: April 2023

ABSTRACTImmunoglobulin heavy chain variable region exons are assembled in progenitor-B cells, from VH, D, and JHgene segments located in separate clusters across theIghlocus. RAG endonuclease initiates V(D)J recombination from a JH-based recombination center (RC). Cohesin-mediated extrusion of upstream chromatin past RC-bound RAG presents Ds for joining to JHs to form a DJH-RC.Ighhas a provocative number and organization of CTCF-binding-elements (CBEs) that can impede loop extrusion. Thus,Ighhas two divergently oriented CBEs (CBE1 and CBE2) in the IGCR1 element between the VHand D/JHdomains, over 100 CBEs across the VHdomain convergent to CBE1, and 10 clustered 3’Igh-CBEs convergent to CBE2 and VHCBEs. IGCR1 CBEs segregate D/JHand VHdomains by impeding loop extrusion-mediated RAG-scanning. Down-regulation of WAPL, a cohesin unloader, in progenitor-B cells neutralizes CBEs, allowing DJH-RC-bound RAG to scan the VH domain and perform VH-to-DJH rearrangements. To elucidate potential roles of IGCR1-based CBEs and 3’Igh-CBEs in regulating RAG-scanning and elucidate the mechanism of the “ordered” transition from D-to-JHto VH-to-DJHrecombination, we tested effects of deleting or inverting IGCR1 or 3’Igh-CBEs in mice and/or progenitor-B cell lines. These studies revealed that normal IGCR1 CBE orientation augments RAG-scanning impediment activity and suggest that 3’Igh-CBEs reinforce ability of the RC to function as a dynamic loop extrusion impediment to promote optimal RAG scanning activity. Finally, our findings indicate that ordered V(D)J recombination can be explained by a gradual WAPL down-regulation mechanism in progenitor B cells as opposed to a strict developmental switch.SIGNIFICANCE STATEMENTTo counteract diverse pathogens, vertebrates evolved adaptive immunity to generate diverse antibody repertoires through a B lymphocyte-specific somatic gene rearrangement process termed V(D)J recombination. Tight regulation of the V(D)J recombination process is vital to generating antibody diversity and preventing off-target activities that can predispose the oncogenic translocations. Recent studies have demonstrated V(D)J rearrangement is driven by cohesin-mediated chromatin loop extrusion, a process that establishes genomic loop domains by extruding chromatin, predominantly, between convergently-oriented CTCF looping factor-binding elements (CBEs). By deleting and inverting CBEs within a critical antibody heavy chain gene locus developmental control region and a loop extrusion chromatin-anchor at the downstream end of this locus, we reveal how these elements developmentally contribute to generation of diverse antibody repertoires.
PEELing: an integrated and user-centric platform for spatially-resolved proteomics data analysis
Authors: Peng Xi , Clements Jody , Jiang Zuzhi , Han Shuo , Preibisch Stephan , Li Jiefu 
Published: April 2023

AbstractSummaryMolecular compartmentalization is vital for cellular physiology. Spatially-resolved proteomics allows biologists to survey protein composition and dynamics with subcellular resolution. Here we present PEELing, an integrated package and user-friendly web service for analyzing spatially- resolved proteomics data. PEELing assesses data quality using curated or user-defined references, performs cutoff analysis to remove contaminants, connects to databases for functional annotation, and generates data visualizations—providing a streamlined and reproducible workflow to explore spatially-resolved proteomics data.Availability and ImplementationPEELing and its tutorial are publicly available athttps://peeling.janelia.org/. A Python package of PEELing is available athttps://github.com/JaneliaSciComp/peeling/.ContactTechnical support for PEELing:peeling@janelia.hhmi.org.
CoSIA: an R Bioconductor package for CrOss Species Investigation and Analysis
Authors: Haldar Anisha , Oza Vishal H. , DeVoss Nathaniel S. , Clark Amanda D. , Lasseigne Brittany N. 
Published: April 2023

AbstractSummaryHigh throughput sequencing technologies have enabled cross-species comparative transcriptomic studies; however, there are numerous challenges for these studies due to biological and technical factors. We developed CoSIA (Cross-Species Investigation and Analysis), an Bioconductor R package and Shiny app that provides an alternative framework for cross-species transcriptomic comparison of non-diseased wild-type RNA sequencing gene expression data from Bgee across tissues and species (human, mouse, rat, zebrafish, fly, and nematode) through visualization of variability, diversity, and specificity metrics.Availability and Implementationhttps://github.com/lasseignelab/CoSIAContactBrittany Lasseigne (bnp0001@uab.edu)Supplementary informationSee Supplementary Files
Genomic mechanisms and consequences of diverse postzygotic barriers between monkeyflower species
Authors: Sotola V. Alex , Berg Colette S. , Samuli Matt , Chen Hongfei , Mantel Samuel J. , Beardsley Paul A. , Yuan Yao-Wu , Sweigart Andrea L. , Fishman Lila 
Published: April 2023

AbstractThe evolution of genomic incompatibilities causing postzygotic barriers to hybridization is a key step in species divergence. Incompatibilities take two general forms – structural divergence between chromosomes leading to severe hybrid sterility in F1hybrids and epistatic interactions between genes causing reduced fitness of hybrid gametes or zygotes (Dobzhansky-Muller incompatibilities). Despite substantial recent progress in understanding the molecular mechanisms and evolutionary origins of both types of incompatibility, how each behaves across multiple generations of hybridization remains relatively unexplored. Here, we use genetic mapping in F2and RIL hybrid populations between the phenotypically divergent but naturally hybridizing monkeyflowersMimulus cardinalisandM. parishiito characterize the genetic basis of hybrid incompatibility and examine its changing effects over multiple generations of experimental hybridization. In F2s, we found severe hybrid pollen inviability (< 50% reduction vs. parental genotypes) and pseudolinkage caused by a reciprocal translocation between Chromosomes 6 and 7 in the parental species. RILs retained excess heterozygosity around the translocation breakpoints, which caused substantial pollen inviability when interstitial crossovers had not created compatible heterokaryotypic configurations. Strong transmission ratio distortion and inter-chromosomal linkage disequilibrium in both F2s and RILs identified a novel two-locus genic incompatibility causing sex-independent gametophytic (haploid) lethality. The latter interaction eliminated three of the expected nine F2genotypic classes via F1gamete loss without detectable effects on the pollen number or viability of F2double heterozygotes. Along with the mapping of numerous milder incompatibilities, these key findings illuminate the complex genetics of plant hybrid breakdown and are an important step toward understanding the genomic consequences of natural hybridization in this model system.
Non-canonical D1-D2 recombination produces two types of rearrangements and represents a conservative hidden stage of T-cell receptor beta chain generation
Authors: Smirnova Anastasia O. , Miroshnichenkova Anna M. , Belyaeva Laima D. , Kelmanson Ilya V. , Lebedev Yuri B. , Mamedov Ilgar Z. , Chudakov Dmitriy M. , Komkov Alexander Y. 
Published: April 2023

AbstractT-cell receptor (TCR) diversity is generated by VDJ recombination. The classical course of TCR beta (TRB) chain production starts with D and J segment recombination and finishes with subsequent recombination between the resulting DJ junction and V segment. In this study, we performed deep sequencing of poorly explored incomplete TRBD1 to TRBD2 rearrangements in T-cell genomic DNA. We reconstructed full repertoires of human incomplete TRB DD rearrangements and validated its authenticity by detecting excision circles with RSS (recombination signal sequence) junctions for the first time. The identified rearrangements generated in compliance with the classical 12/23 rule are common for humans, rats, and mice and contain typical VDJ recombination footprints. Detected bimodal distribution of DD junctions indicates two active recombination sites producing long and short DD rearrangements. Unlike long DD rearrangements, the short ones have unusual origin resulting from non-canonical intrachromosomal RSSs’ junctions formation. Identified DD rearrangements lead to deleting J1 and C1 segments and creating diverse hybrid D segments, which recombine further with J2 and V segments. Resulting functional TRB VDDJ rearrangements are present in the memory T-cells subset proving its participation in antigen recognition.
Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones
Authors: Cao Wei , Wang Xuefei , Luo Kaiwen , Li Yang , Sun Jiahong , Fu Ruqing , Zhang Qi , Hong Ni , Cheung Edwin , Jin Wenfei 
Published: April 2023

AbstractTo explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNVand DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNVtends to involve in cell-cell contact while DEGregtends to involve in secreted signaling, which further support that DEGCNVand DEGregare two regulatorily and functionally distinct categories.
Chromatin condensation delays human mesenchymal stem cells senescence by safeguarding nuclear damages during long termin vitroexpansion
Authors: Joshi Rohit , Suryawanshi Tejas , Mukherjee Sourav , Shukla Shobha , Majumder Abhijit 
Published: April 2023

AbstractHuman mesenchymal stem cells (hMSCs) are multipotent cells that can differentiate into adipocytes, chondrocytes and osteoblasts. Due to their differentiation potential, hMSCs are among the most frequently used cells for therapeutic applications in tissue engineering and regenerative medicine. However, the number of cells obtained through isolation alone is insufficient for hMSC-based therapies and basic research, necessitating theirin-vitroexpansion. Conventionally, this is often carried out on rigid surfaces such as tissue culture petriplates (TCPs). However, duringin-vitroexpansion, hMSCs lose their proliferative ability and multilineage differentiation potential, making them unsuitable for clinical use. Although multiple approaches have been tried to maintain hMSC stemness over prolonged expansion, finding a suitable culture system to achieve this remains an unmet need. Recently, few research groups including ours have shown that hMSCs maintain their stemness over long passages when cultured on soft substrate. In addition, it has been shown that hMSCs cultured on soft substrates have more condensed chromatin and lower levels of histone acetylation compared to those cultured on stiff substrates. It has also been shown that condensing/decondensing chromatin by deacetylation/acetylation can delay/hasten replicative senescence in hMSCs during long-term expansion on TCPs. However, how chromatin condensation/decondensation influences nuclear morphology and DNA damage - which are strongly related to the onset of senescence and cancer - is still not known.To answer this question, here we cultured hMSCs for long duration (P4-P11) in presence of epigenetic modifiers histone acetyltransferase inhibitor (HATi) which promotes chromatin condensation by preventing histone acetylation and histone deacetylase inhibitor (HDACi) which promotes chromatin decondensation and investigated their effect on various nuclear markers related to senescence and cancer. We have found that consistent acetylation causes severe nuclear abnormalities whereas chromatin condensation by deacetylation helps in safeguarding nucleus from damages caused byin-vitroexpansion.