bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptional mapping reveals genetic and non-genetic determinants of aberrant differentiation in AML
Authors: Zeng Andy G.X. , Iacobucci Ilaria , Shah Sayyam , Mitchell Amanda , Wong Gordon , Bansal Suraj , Chen David , Gao Qingsong , Kim Hyerin , Kennedy James A. , Arruda Andrea , Minden Mark D. , Haferlach Torsten , Mullighan Charles G. , Dick John E. 
Published: December 2023

AbstractIn acute myeloid leukemia (AML), genetic mutations distort hematopoietic differentiation, resulting in the accumulation of leukemic blasts. Yet, it remains unclear how these mutations intersect with cellular origins and whether they converge upon similar differentiation patterns. Single-cell RNA sequencing (scRNA-seq) has enabled high-resolution mapping of the relationship between leukemia and normal cell states, yet this application is hampered by imprecise reference maps of normal hematopoiesis and small sample sizes among patient cohorts. As a first step we constructed a reference atlas of human bone marrow hematopoiesis from 263,519 single-cell transcriptomes spanning 55 cellular states, that was benchmarked against independent datasets of immunophenotypically pure hematopoietic stem and progenitor cells. Using this reference atlas, we mapped over 1.2 million single-cell transcriptomes spanning 318 AML, mixed phenotype acute leukemia (MPAL), and acute erythroid leukemia (AEL) samples. This large-scale analysis, together with systematic mapping of genotype-to-phenotype associations between driver mutations and differentiation landscapes, revealed convergence of diverse genetic alterations on twelve recurrent patterns of aberrant differentiation in AML. This included unconventional lymphoid and erythroid priming linked toRUNX1andTP53mutations, respectively. We also identified non-genetic determinants of AML differentiation such as two subgroups ofKMT2A-rearranged AML that differ in the identity of their leukemic stem cells (LSCs), likely reflecting distinct cellular origins. Furthermore, distinct LSC-driven hierarchies can co-exist within individual patients, providing insights into AML evolution. Together, precise mapping of normal and malignant cell states provides a framework for advancing the study and disease classification of hematologic malignancies thereby informing therapy development.
Potential survival strategies of novel comammox and nitrite-oxidizingNitrospirapresent in a reactor treating high-ammonia brackish landfill leachate
Authors: Yasuda Shohei , Palomo Alejandro , Smets Barth F. , Terada Akihiko 
Published: December 2023

AbstractNitrification is mediated by numerous different microorganisms, but knowledge of their ecophysiologies is insufficient. Leachate in the late stages of landfill operation provides a brackish environment with a high ammonia concentration, and methanol is added as an electron donor for denitrification. Such a unique environment may contain novel nitrifiers. Here, we present metagenomic analysis of the microbiome from a closed landfill leachate treatment facility to investigate the identity and functions of nitrifiers. Using a genome-centric approach with metagenomic analysis, we retrieved draft genomes for a novel complete ammonia-oxidizing (comammox) bacteriumNitrospiraLAS72; and canonicalNitrospiraLAS18, clustered within a novel sub-lineage VII ofNitrospira;CandidatusNitrosocosmicus LAS21 andNitrosarchaeumLAS73, belonging to the ammonia-oxidizing archaea (AOA). This is the first evidence of comammoxNitrospirain a high-ammonia-containing brackish environment. Canonical ammonia-oxidizing bacteria were not detected. Given the brackish environment and supplementation of methanol used in the facility, we also investigated the methanol metabolism of these nitrifiers and their potential to produce compatible solutes as osmoprotectants. Uniquely amongNitrospira, comammoxNitrospiraLAS72 possesses genes associated with formaldehyde reductase and glycine betaine biosynthesis. Thus,NitrospiraLAS72 may proliferate because of the availability of formaldehyde upstream of carbon metabolism and adapt to fluctuating osmotic pressure by producing a variety of compatible solutes. The discovery of this novel comammoxNitrospira,and canonicalNitrospiraforming a new sub-lineage VII in an ammonia-concentrated brackish environment broadens our knowledge of the diversity and functions of nitrifying microorganisms.
Decoding mutational hotspots in human disease through the gene modules governing thymic regulatory T cells
Authors: Raposo Alexandre A. S. F. , Rosmaninho Pedro , Silva Susana L. , Paço Susana , Brazão Maria E. , Godinho-Santos Ana , Tokunaga Yumie , Nunes-Cabaço Helena , Serra-Caetano Ana , Almeida Afonso R. M. , Sousa Ana E. 
Published: December 2023

ABTRACTComputational strategies to extract meaningful biological information from multiomics data are in great demand for effective clinical use. This is most relevant in immune-mediated disorders, where the combined impact of multiple variants is difficult to determine. Regulatory T cells (Tregs), particularly those lineage-committed in the thymus, are essential for immune homeostasis and self-tolerance, controlling inflammatory and autoimmune processes in many diseases with a multigenic basis. Here, we quantify the Transcription Factor (TF) differential occupancy landscape to uncover the Gene Regulatory Modules governing human thymic Tregs, providing a tool to prioritise variants in complex diseases. Combined RNA-seq and ATAC-seq generated a matrix of differential TF binding to genes differentially expressed in Tregs, in contrast to their counterpart conventional CD4 single-positive thymocytes. The gene loci of both established and novel genetic interactions uncovered by the Gene Regulatory Modules were significantly enriched in rare variants carried by patients with common variable immunodeficiency, here used as a model of polygenic-based disease with severe inflammatory and autoimmune manifestations. The Gene Regulatory Modules controlling the Treg signature can, therefore, be a valuable resource for variant classification, and to uncover new therapeutic targets. Overall, we provide a tool to decipher mutational hotspots in individual genomes.
Species-specific design of artificial promoters by transfer-learning based generative deep-learning model
Authors: Xia Yan , Du Xiaowen , Liu Bin , Guo Shuyuan , Huo Yi-Xin 
Published: December 2023

AbstractNative prokaryotic promoters share common sequence patterns, but are species dependent. For understudied species with limited data, it is challenging to predict the strength of existing promoters and generate novel promoters. Here, we developed PromoGen, a collection of nucleotide language models to generate species-specific functional promoters, across dozens of species in a data and parameter efficient way. Twenty-seven species-specific models in this collection were finetuned from the pretrained model which was trained on multi-species promoters. When systematically compared with native promoters, theEscherichia coli-andBacillus subtilis-specific artificial PromoGen-generated promoters (PGPs) were demonstrated to hold all distribution patterns of native promoters. A regression model was developed to score generated either by PromoGen or by another competitive neural network, and the overall score of PGPs is higher. Encouraged byin silicoanalysis, we further experimentally characterized twenty-twoB. subtilisPGPs, results showed that four of tested PGPs reached the strong promoter level while all were active. Furthermore, we developed a user-friendly website to generate species-specific promoters for 27 different species by PromoGen. This work presented an efficient deep-learning strategy forde novospecies-specific promoter generation even with limited datasets, providing valuable promoter toolboxes especially for the metabolic engineering of understudied microorganisms.
PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation
Authors: Campaña Maria B. , Perkins Madison R. , McCabe Maxwell C. , Neumann Andrew , Larson Eric D. , Fantauzzo Katherine A. 
Published: December 2023

AbstractThe platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases allows cells to communicate with one another by binding to growth factors at the plasma membrane and activating intracellular signaling pathways to elicit responses such as migration, proliferation, survival and differentiation. The PDGFR family consists of two receptors, PDGFRα and PDGFRβ, that dimerize to form PDGFRα homodimers, PDGFRα/β heterodimers and PDGFRβ homodimers. Here, we overcame prior technical limitations in visualizing and purifying PDGFRα/β heterodimers by generating a cell line stably expressing C-terminal fusions of PDGFRα and PDGFRβ with bimolecular fluorescence complementation fragments corresponding to the N-terminal and C-terminal regions of the Venus fluorescent protein, respectively. We found that these receptors heterodimerize relatively quickly in response to PDGF-BB ligand treatment, with a peak of receptor autophosphorylation following 5 minutes of ligand stimulation. Moreover, we demonstrated that PDGFRα/β heterodimers are rapidly internalized into early endosomes, particularly signaling endosomes, where they dwell for extended lengths of time. We showed that PDGFRα/β heterodimer activation does not induce downstream phosphorylation of ERK1/2 and significantly inhibits cell proliferation. Further, we characterized the PDGFR dimer-specific interactome and identified MYO1D as a novel protein that preferentially binds PDGFRα/β heterodimers. We demonstrated that knockdown of MYO1D leads to retention of PDGFRα/β heterodimers at the plasma membrane, resulting in increased phosphorylation of ERK1/2 and increased cell proliferation. Collectively, our findings impart valuable insight into the molecular mechanisms by which specificity is introduced downstream of PDGFR activation to differentially propagate signaling and generate distinct cellular responses.One-sentence summaryPDGFRα/β heterodimer binding to MYO1D contributes to rapid internalization of the dimerized receptors, thereby negatively affecting downstream ERK1/2 signaling and cellular proliferation.
The genetic consequences of population marginality: a case study in maritime pine
Authors: Theraroz Adélaïde , Guadaño-Peyrot Carlos , Archambeau Juliette , Pinosio Sara , Bagnoli Francesca , Piotti Andrea , Avanzi Camilla , Vendramin Giovanni G. , Alía Ricardo , Grivet Delphine , Westergren Marjana , González-Martínez Santiago C. 
Published: December 2023

AbstractAimMarginal tree populations, either those located at the edges of the species’ range or in suboptimal environments, are often a valuable genetic resource for biological conservation. However, there is a lack of knowledge about the genetic consequences of population’s marginality, estimated across entire species’ ranges. Our study addresses this gap by providing information about several genetic indicators and their variability in marginal and core populations identified using quantitative marginality indices.LocationSouthwestern Europe and North Africa.MethodsUsing 10,185 SNPs across 82 populations of maritime pine (Pinus pinasterAit.), a widespread and economically important conifer characterised by a fragmented range, we modelled the relationship of seven genetic indicators potentially related to population evolutionary resilience, namely genetic diversity (based on all SNPs and two kind of outlier loci), inbreeding, genetic differentiation, recessive genetic load and genomic offset, with population geographical, demo-historical and ecological marginality (as estimated by nine quantitative indices). Models were constructed for both regional (introducing gene pool as random factor) and range-wide spatial scales.ResultsWe showed a trend towards decreasing overall genetic diversity (albeit not necessarily for genetic diversity estimates based on outlier loci) and increasing differentiation with geographic marginality, supporting the centre-periphery hypothesis (CPH). Moreover, we found no correlation between population inbreeding and marginality, while geographically marginal populations had a lower recessive genetic load (only models without the gene pool effect) and ecologically marginal populations had a higher genomic offset, suggesting higher maladaptation to future climate.Main conclusionsOverall, our results indicate that marginal populations could be at higher risk of maladaptation to climate change than core populations, despite reduced levels of genetic load, a risk that is exacerbated by typically small effective population sizes and increasing human impact.
Structural basis for constitutive activation and CXCL1 recognition of human herpesvirus 8-encoded G protein-coupled receptor KSHV-GPCR
Authors: Liu Aijun , Liu Yezhou , Llinàs del Torrent Masachs Clàudia , Zhang Weijia , Pardo Leonardo , Ye Richard D. 
Published: December 2023

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi’s Sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. KSHV-GPCR is also unique for its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent as well as constitutive activity of KSHV-GPCR through cryo-EM structural determination of KSHV-GPCR-Gi signaling complexes with and without bound CXCL1 chemokine ligand. Analysis of the apo-KSHV-GPCR-Gi structure, with an overall resolution of 2.81 Å, unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. This and other structural motifs serve to stabilize the constitutively-active KSHV-GPCR. The CXCL1-bound KSHV-GPCR-Gi structure was solved to an overall resolution of 3.01 Å, and showed a two-site binding of the chemokine by the receptor. Together with functional validations, this work shed light on the structural basis for constitutive as well as CXCL1-induced activation of KSHV-GPCR. The work also demonstrates evolutionary advantage in immune evasion by KSHV through its virally encoded chemokine receptor, with potential implications in developing therapeutic strategies for KSHV infection.
Chitinase 3-like-1 (CHI3L1) Inhibits Innate Anti-Tumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα and CD24-Siglec10-Mediated Phagocytosis
Authors: Ma Bing , Kamle Suchitra , Lee Chang-Min , Lee Joyce H , Yee Daniel C , Zhu Zhou , Silverman Edwin K. , DeMeo Dawn L. , Choi Augustine M.K. , Lee Chun Geun , Elias Jack A. 
Published: December 2023

AbstractInnate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in Chronic Obstructive Pulmonary Disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. Here we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage “eat me” signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are mediated by CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and the inhibition of the accumulation and phosphorylation of cytoskeleton-regulating non-muscle myosin IIa. This inhibition of innate immune responses like phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases like COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell co-stimulation, and regulate a number of other oncogenic and inflammation pathways suggest that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD and other disorders.
Identification of genes supporting cold resistance of mammalian cells: lessons from a hibernator
Authors: Sone Masamitsu , Mitsuhashi Nonoka , Sugiura Yuki , Matsuoka Yuta , Maeda Rae , Yamauchi Akari , Okahashi Ryoto , Yamashita Junpei , Sone Kanako , Enju Sachiyo , Anegawa Daisuke , Yamaguchi Yoshifumi 
Published: December 2023

AbstractSusceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic or pharmacological inhibition of Gpx4 in a hamster cell line under prolonged cold culture led to cell death, which resembles ferroptosis characterized by accumulation of lipid peroxide and ferrous iron dependency. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans.
Neuroprotective Effects of VEGF-B in a Murine Model of Aggressive Neuronal Loss With Childhood Onset
Authors: Pérez-Revuelta L. , Pérez-Boyero D. , Pérez-Martín E. , Cabedo VL , Téllez de Meneses PG , Weruaga E , Díaz D , Alonso JR 
Published: December 2023

ABSTRACTIn recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed at identifying an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.
Cell-Specific Gene Networks and Drivers in Rheumatoid Arthritis Synovial Tissues
Authors: Pelissier Aurelien , Laragione Teresina , Gulko Percio S. , Martínez María Rodríguez 
Published: December 2023

AbstractRheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18,16,19,11 key regulators of fibroblast-like synoviocyte (FLS), T cells, B cells, and monocyte signatures and networks, respectively, in RA synovial tissues. Interestingly, FLS and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (synovial B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of NKT cell and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected KDG, TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.
Gene Network Analyses Identify Co-regulated Transcription Factors and BACH1 as a Key Driver in Rheumatoid Arthritis Fibroblast-like Synoviocytes
Authors: Pelissier Aurelien , Laragione Teresina , Harris Carolyn , Martínez María Rodríguez , Gulko Percio S. 
Published: December 2023

AbstractRNA-sequencing and differential gene expression studies have significantly advanced our understanding of pathogenic pathways underlying Rheumatoid Arthritis (RA). Yet, little is known about cell-specific regulatory networks and their contributions to disease. In this study, we focused on fibroblast-like synoviocytes (FLS), a cell type central to disease pathogenesis and joint damage in RA. We used a strategy that computed sample-specific gene regulatory networks (GRNs) to compare network properties between RA and osteoarthritis FLS. We identified 28 transcription factors (TFs) as key regulators central to the signatures of RA FLS. Six of these TFs are new and have not been previously implicated in RA, and included BACH1, HLX, and TGIF1. Several of these TFs were found to be co-regulated, and BACH1 emerged as the most significant TF and regulator. The main BACH1 targets included those implicated in fatty acid metabolism and ferroptosis. The discovery of BACH1 was validated in experiments with RA FLS. Knockdown of BACH1 in RA FLS significantly affected the gene expression signatures, reduced cell adhesion and mobility, interfered with the formation of thick actin fibers, and prevented the polarized formation of lamellipodia, all required for the RA destructive behavior of FLS. This is the first time that BACH1 is shown to have a central role in the regulation of FLS phenotypes, and gene expression signatures, as well as in ferroptosis and fatty acid metabolism. These new discoveries have the potential to become new targets for treatments aimed at selectively targeting the RA FLS.