bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative atlas of genome-wide chromatin-associated protein co-occupancy
Authors: White Shannon M. , Moyers Belle A. , Wang Tao , Mackiewicz Mark , Weimer Annika K. , Grubert Fabian , Ramalingam Vivekanandan , Luo Jay X. J. , Jiang Lixia , Shi Minyi , Yang Xinqiong , Chou Tristan , Zhai Jie , Von Kraut Konor , Adrian Jessika , Partridge E. Christopher , Paul Kristina , Kundaje Anshul , Mendenhall Eric M. , Myers Richard M. , Snyder Michael P. 
Published: December 2024

ABSTRACTAccurate transcriptional regulation and chromatin dynamics requires the coordination and activity of chromatin-associated proteins (CAPs) at distinct loci. While the combinatorial activity of a select set of CAPs has been previously examined, these studies are limited by the underrepresentation of proteins and cell types explored, making it difficult to identify the global associations as well as the conservation of these associations across different cell types. Here, we performed 270 CAP chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) experiments in both K562 and HepG2 cancer cell lines and explored the relationship between cell identity and CAP co-association using three distinct approaches. We employed a machine learning algorithm to organize the genome-wide binding profiles into 56 and 70 interpretable co-association modules for HepG2 and K562 cell lines, respectively. We found CAP co-association modules are mostly cell type-specific, however those present in both cell lines are largely comprised of TFs from a single TF family and anchor to unique loci via lineage-specific factors. While enhancer-associated co-binding modules were largely composed of cell type-specific CAPs, we found regulatory activity at promoter-enhancer module contacts to be enriched for chromatin remodeling proteins. Additionally, we used colocalization information derived from co-association models in conjunction with neural network models of transcription factor (TF) activity to identify high-confidence candidate TF cooperative pairs. Finally, through comparing CAP enrichment in high occupancy target (HOT) regions in K562 and HepG2 cell lines, we found cell type-specific HOT sites, but not common HOT sites, are selectively enriched at high copy number loci. Overall, this study uncovers principles of sequence-level and large-scale CAP genomic organization and demonstrates how this contributes to cell type-specific regulatory mechanisms and cellular functions.
Lost to science for 126 years: Indigenous Knowledge and Camera Trapping Document the Critically Endangered Black-Naped Pheasant-PigeonOtidiphaps insularis
Authors: Gregg Jason J. , Boersma Jordan , Nason Doka , Malesa Elimo , Le Breton Cosmo , Ketaloya Serena , Iova Bulisa , Mittermeier John C. 
Published: December 2024

AbstractWe combined questionnaires collecting local ecological knowledge with passive and directed camera trapping and bird surveys to scientifically document the Black-Naped Pheasant-PigeonOtidiphaps insularisfor the first time since 1896. This species is endemic to Fergusson Island, in eastern Papua New Guinea, and is New Guinea’s most endangered terrestrial bird species. Indigenous subsistence-based hunters who participated in this research as informants had high levels of local bird knowledge and helped direct camera trapping for one of two successful camera trap captures. Local participants also shared traditional ecological knowledge about the Black-Naped Pheasant-Pigeon, including legends, chants, and a local name for this taxon, Auwo. The scarcity of observations over the course of a month-long expedition, its obscurity to the majority of local respondents interviewed, and prevalent threats from habitat destruction and introduced alien species further support its current Red List status (CR). Our results provide a case study for leveraging local ecological knowledge in combination with standardized survey techniques and may be an especially effective strategy for determining the status of other undocumented or data-deficient species in the southwest Pacific.
CD38 biallelic loss is a recurrent mechanism of resistance to anti-CD38 antibodies in multiple myeloma
Authors: Diamond Benjamin , Baughn Linda , Poorebrahim Mansour , Poos Alexandra M. , Lee Holly , Kaddoura Marcella , Wiedmeier-Nutor J. Erin , Durante Michael , Otteson Gregory , Jevremovic Dragan , Tang Hongwei , Fröhling Stefan , Baertsch Marc A. , Papadimitriou Marios , Ziccheddu Bachisio , Jelinek Tomas , Lemoine Cendrine , Rak Alexey , Green Damian J. , Landgren Ola , Neri Paola , Bergsagel Leif , Braggio Esteban , Kumar Shaji , Raab Marc S. , Fonseca Rafael , Bahlis Nizar , Weinhold Niels , Maura Francesco 
Published: December 2024

ABSTRACTMonoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of theCD38gene locus. Here, by using whole genome and whole exome sequencing data from 701 newly diagnosed patients, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse following anti-CD38 antibodies. We report a loss of CD38 in 20% (10/50) of patients post-CD38 therapy, three of which exhibited a loss of both copies. Two of these cases showed convergent evolution where distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that two variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies Daratumumab and Isatuximab. However, a third mutation, R140G, conferred selective resistance to Daratumumab, while retaining sensitivity to Isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies following disease progression and these data support a role for next generation sequencing to guide treatment selection.
All-at-once RNA folding with 3D motif prediction framed by evolutionary information
Authors: Karan Aayush , Rivas Elena 
Published: December 2024

AbstractStructural RNAs exhibit a vast array of recurrent short 3D elements involving non-Watson-Crick interactions that help arrange canonical double helices into tertiary structures. We present CaCoFold-R3D, a probabilistic grammar that predicts these RNA 3D motifs (also termed modules) jointly with RNA secondary structure over a sequence or alignment. CaCoFold-R3D uses evolutionary information present in an RNA alignment to reliably identify canonical helices (including pseudoknots) by covariation. We further introduce the R3D grammars, which also exploit helix covariation that constrains the positioning of the mostly non-covarying RNA 3D motifs. Our method runs predictions over an almost-exhaustive list of over fifty known RNA motifs (everything). Motifs can appear in any non-helical loop region (including 3-way, 4-way and higher junctions) (everywhere). All structural motifs as well as the canonical helices are arranged into one single structure predicted by one single joint probabilistic grammar (all-at-once). Our results demonstrate that CaCoFold-R3D is a valid alternative for predicting the all-residue interactions present in a RNA 3D structure. Furthermore, CaCoFold-R3D is fast and easily customizable for novel motif discovery.AvailabilityThe source code can be downloaded from the websiterivaslab.org, the githttps://github.com/EddyRivasLab/R-scape, as well as from the supplementary materials associated to this manuscript.Supplementary informationSupplementary materials (data and code) are provided with this manuscript, and atrivaslab.org.
Assessment of cortical excitability in awake rhesus macaques with transcranial magnetic stimulation: translational insights from recruitment curves
Authors: Padányi Anna , Knakker Balázs , Lendvai Balázs , Hernádi István 
Published: December 2024

AbstractBackground and objectivesCortical excitability (CE) is commonly assessed by recording motor evoked potentials (MEPs) in response to single-pulse transcranial magnetic stimulation (sp-TMS). While the motor threshold (MT) remains the most widely used measure of CE, it provides a one-dimensional, criterion-based assessment. In contrast, the recruitment curve (RC) offers a more comprehensive characterization of the full dynamics of cortical recruitment. Yet, only a few preclinical studies involving translationally relevant non-human primates were conducted, and most were under anaesthesia. Hence, we aimed to characterise CE in awake rhesus macaques by recording traditionally defined MT and RCs.MethodsTraditional MT with a 100 µV MEP criterion (‘tradMT’) was measured in 8 awake adult male rhesus macaques using C-B65 coil and MagVenture stimulator. RCs were recorded at nine relative intensity levels (0.5 – 1.5 × tradMT) in 4 macaques. A sigmoid function was fitted to obtain key CE parameters: the inflection point, lower ankle point, and plateau.ResultsTradMT values were stable and replicable, and aligned most closely with the inflection point of the RC. The lower ankle points were found around at 0.9 × tradMT, marking the transition from a constant to a logarithmic phase, representing a physiologically relevant threshold. Plateau MEP amplitudes were substantially smaller compared to those reported in humans.ConclusionFitted RC parameters revealed a distinction between tradMT and the physiologically relevant threshold. The overall RC shape was consistent with human data, suggesting similar recruitment processes, leading to high translational validity. However, the marked difference in maximal MEP magnitude emphasises the importance of species-specific adaptations.
Temporally overlapping mechanisms diversify clonal B cell responsesin vivo
Authors: Skinner Oliver P. , Asad Saba , Moreira Marcela L. , Lee Hyun Jae , Williams Cameron G. , Li Shihan , Jin Wang , Steiner Thiago M. , Asatsuma Takahiro , Lim Jorene , Ruan Zheng , Soon Megan S.F. , Engel Jessica A. , Khoury David S. , Tuong Zewen Kelvin , King Hamish W. , Haque Ashraful 
Published: December 2024

AbstractSingle naive B cells amplify and diversify their responses when activated by cognate antigen, via Myc-dependent clonal expansion, immunoglobulin class switch recombination (CSR), phenotypic variation, and somatic hypermutation (SHM). Whether these mechanisms act combinatorially in vivo to diversify clonal responses to a single complex pathogen remains unclear. Since diversity in the antigenic targets, functional classes, and production kinetics of parasite-specific antibodies influences immunity to malaria, we test here whether individual B cell clones diversify over time during Plasmodium infection and treatment. During the first week of infection, amid widespread Type I Interferon (IFN)-mediated, bystander activation, CSR initiates soon after Myc up-regulation. CSR then overlaps with clonal expansion, resulting in isotype variegation amongst certain clones. In the second week of infection, expanded clones seeding germinal centres (GC) both bifurcate into extra-follicular plasmablasts and exhibit isotype variegation, revealing substantial intra-clonal diversification. Over the following month, GC clones undergo SHM at approximately four mutations per week, with IgG mutational diversity and IgM+cells preserved in GCs over time. Anti-malarial intervention does not impede SHM, but instead exerts quantitative limits on GC size, plasma cell emergence and circulating antibody titres. Finally, we reveal a contemporaneous B cell developmental pathway that relocates from bone marrow to the spleen during infection and treatment. Thus, multiple temporally overlapping mechanisms combine in vivo to amplify, diversify, and safeguard humoral immune responses.Graphical abstractHighlightsEarly temporal overlap of CSR with clonal expansion leads to isotype variegation in clones.Clones seeding GCs bifurcate into plasmablasts and exhibit isotype variegation.GC B cells accrue mutations at rates unaffected by anti-malarials.Plasmodiuminfection triggers antigen-independent Type I IFN-mediated bystander activation.B cell development is preserved in malaria by shifting from bone marrow to spleen.
Lotus japonicusVIH2 is an inositol pyrophosphate synthase that regulates arbuscular mycorrhiza
Authors: Raj Kiran , Gaugler Verena , Lu Mengsi , Schädel Maren , Gaugler Philipp , Grothaus Charlotte M. M. , Jochimsen Ulrike A. , Liu Guizhen , Harings Michael , Jessen Henning J. , Schaaf Gabriel , Ried-Lasi Martina K. 
Published: December 2024

AbstractPlant yield is often maximized by the extensive use of mineral fertilizers, which, however, has severe environmental consequences. Phosphate is particularly problematic, as it represents a globally limited resource, and its runoff and soil erosion threaten open water bodies. Many crops engage in arbuscular mycorrhizal (AM) symbiosis with nutrient-acquiring fungi, aiding in the uptake of phosphate and other mineral nutrients. However, AM colonization is strongly reduced under high soil phosphate levels. A mechanistic understanding of phosphate sensing, phosphate starvation responses, and their connection to AM remains enigmatic. Here, we show that inLotus japonicus, low-abundant, energy-rich inositol pyrophosphates act as master regulators of AM, orchestrating the crosstalk between phosphate starvation responses and plant root endosymbiosis. These findings hold promise for breeding nutrient-efficient crops.
The invasions ofAedes aegyptiandAedes albopictusin Cyprus: current situation, risk modelling and public health implications for the wider Eastern Mediterranean region
Authors: Caminade Cyril , Vasquez Marlen I. , Herodotou Herodotos , Notarides Gregoris , Pavlou Costas , Fayad Filip , Papakonstantinou Apostolos , Violaris Marios , Petric Dusan , Mamai Wadaka , Tompkins Adrian M. , Bouyer Jeremy 
Published: December 2024

AbstractThe Asian tiger mosquito,Aedes albopictusand the yellow fever mosquito,Aedes aegyptihave been spreading worldwide and are reshaping the distribution of arboviruses. BothAedesspecies have recently been observed in densely populated cities of Cyprus, a touristic island that is a historic bridge between Europe and Asia. Given the high public health stakes for Cyprus and the wider East Mediterranean region, the objectives of this study are three-fold. First, we present a novel delimitation strategy using spatially dense networks of ovitraps deployed in 500×500m cells in Limassol and Larnaca following the detection ofAedesspecies. Second, we use a dynamical vector model to estimate the potential of both species to spread further over Cyprus. Finally, we employ a basic reproduction number (R0) model to assess the potential transmission risk of arboviruses for the wider East Mediterranean region. Our results underline our delimitation strategy’s usefulness in delineatingAe. albopictuspopulations in Limassol and indicate the need for increased surveillance efforts forAe. aegyptiin Larnaca. Our vector model reveals that cities such as Nicosia, Paphos and Ayia Napa are climatically suitable for the establishment of bothAe. aegyptiandAe. albopictus. Finally, the R0model captures historical hotspots of dengue transmission over the East Mediterranean region, with large R0values simulated over Cyprus, Greece, Turkey, southern Italy and southern Spain. We recommend stringent vector surveillance at entry points in Greece and a rapid elimination in Cyprus to prevent the return ofAe. aegyptito the European continent.
Pro-Inflammatory Molecules Implicated in Multiple Sclerosis Divert the Development of Human Oligodendrocyte Lineage Cells
Authors: Blaszczyk Gabriela J. , Mohammadnia Abdulshakour , Piscopo Valerio E. C. , Sirois Julien , Cui Qiao-Ling , Yaqubi Moein , Durcan Thomas M. , Schneider Raphael , Antel Jack P. 
Published: December 2024

AbstractBackground and ObjectivesOligodendrocytes (OL) and their myelin-forming processes are targeted and lost during the disease course of Multiple Sclerosis (MS), targeted by infiltrating leukocytes and their effector cytokines. Myelin repair is considered to be dependent on recruitment and differentiation of oligodendrocyte precursor cells (OPCs). The basis of failure of re-myelination during the disease course of MS remains to be defined. The aim of this study is to determine the impact of pro-inflammatory molecules tumor necrosis factor ⍰ (TNF⍰) and interferon gamma (IFNγ) on the differentiation of human OPCs.MethodsWe generated human OPCs from induced pluripotent stem cells with a reporter gene under the OL-specific transcription factor SOX10. We treated the cellsin vitrowith TNF⍰ or IFNγand evaluated effects in terms of cell viability, expression of OL-lineage markers, and co- expression of astrocyte markers. To relate our findings to the molecular properties of OPCs as found in the MS brain we re-analyzed publicly available single nuclear RNAseq datasets.ResultsOur analysis indicated that both TNF⍰ and IFNγdecreased the proportion of cells differentiating into the OL-lineage; consistent with previous reports. We now observe the TNF⍰ effect is linked to aberrant OPC differentiation. A subset of O4+, reporter-positive cells co- expressed the astrocytic marker Aquaporin-4 (AQP4). On the transcriptomic level, the cells acquire an astrocyte-like signature alongside a conserved reactive phenotype. Analysis of single- nuclear RNAseq datasets from human MS brain revealed a subset of OPCs expressing an astrocytic signature.DiscussionIn the context of MS, these results imply that OPCs are present but inhibited from differentiating along the OL-lineage, with a subset acquiring a reactive and stem-cell like phenotype, reducing their capacity to contribute towards repair. These findings help define a potential basis for the impaired myelin repair in MS and provide a prospective route for regenerative treatment.
In vitrobiofilm formation only partially predicts beneficialPseudomonas fluorescensprotection against rhizosphere pathogens
Authors: Liu Yang , Gates Alexandra D. , Liu Zhexian , Duque Quinn , Chen Melissa Y. , Hamilton Corri D. , O’Toole George A. , Haney Cara H. 
Published: December 2024

AbstractPlant roots form associations with both beneficial and pathogenic soil microorganisms. While members of the rhizosphere microbiome can protect against pathogens, the mechanisms are poorly understood. We hypothesized that the ability to form a robust biofilm on the root surface is necessary for the exclusion of pathogens; however, it is not known if the same biofilm formation components requiredin vitroare necessaryin vivo. Pseudomonas fluorescensWCS365 is a beneficial strain that is phylogenetically closely related to an opportunistic pathogenP. fluorescensN2C3 and confers robust protection againstP. fluorescensN2C3 in the rhizosphere. We used this plant-mutualist-pathogen model to screen collections ofP. fluorescensWCS365 increasedattachmentmutants (iam) andsurfaceattachmentdefective (sad) transposon insertion mutants that form increased or decreased levels of biofilm on an abiotic surface, respectively. We found that while theP. fluorescensWCS365 mutants had altered biofilm formationin vitro, only a subset of these mutants, including those involved in large adhesion protein (Lap) biosynthesis, flagellin biosynthesis and O-antigen biosynthesis, lost protection againstP. fluorescensN2C3. We found that the inability ofP. fluorescensWCS365 mutants to growin planta, and the inability to suppress pathogen growth, both partially contributed to loss of plant protection. We did not find a correlation between the extent of biofilm formedin vitroand pathogen protectionin plantaindicating that biofilm formation on abiotic surfaces may not fully predict pathogen exclusionin planta. Collectively, our work provides insights into mechanisms of biofilm formation and host colonization that shape the outcomes of host-microbe-pathogen interactions.
De novoevolution of antibiotic resistance to Oct-TriA1
Authors: Chowdhury Farhan R. , Mercado Laura Domínguez , Kharitonov Katya , Findlay Brandon L. 
Published: December 2024

AbstractThe rise of antimicrobial resistance as a global health concern has led to a strong interest in compounds able to inhibit the growth of bacteria without detectable levels of resistance evolution. A number of these compounds have been reported in recent years, including the tridecaptins, a small family of lipopeptides typified by the synthetic analogue octyl-tridecaptin A1. Hypothesizing that prior reports of negligible resistance evolution have been due in part to limitations in the laboratory evolution systems used, we have attempted to select for resistant mutants using a soft agar gradient evolution (SAGE) system developed by our lab. Following optimization of the media conditions by incorporation of the anti-synaeresis agent xanthan gum into the agar matrix, we successfully evolved high-level resistance to both octyl-tridecaptin A1as well as the challenging lipopeptide antibiotic polymyxin B. Decreased tridecaptin susceptibility was linked to mutations in outer membrane proteinsompC,lptDandmlaA, with the effect of these genes confirmed through a mix of allelic replacement and knockout studies. Overall, this work demonstrates the robust evolutionary potential of bacteria, even in the face of challenging antimicrobial agents.
Predictive Modeling of Gene Expression and Localization of DNA Binding Site Using Deep Convolutional Neural Networks
Authors: Karshenas Arman , Röschinger Tom , Garcia Hernan G. 
Published: December 2024

AbstractDespite the sequencing revolution, large swaths of the genomes sequenced to date lack any information about the arrangement of transcription factor binding sites on regulatory DNA. Massively Parallel Reporter Assays (MPRAs) have the potential to dramatically accelerate our genomic annotations by making it possible to measure the gene expression levels driven by thousands of mutational variants of a regulatory region. However, the interpretation of such data often assumes that each base pair in a regulatory sequence contributes independently to gene expression. To enable the analysis of this data in a manner that accounts for possible correlations between distant bases along a regulatory sequence, we developed the Deep learning Adaptable Regulatory Sequence Identifier (DARSI). This convolutional neural network leverages MPRA data to predict gene expression levels directly from raw regulatory DNA sequences. By harnessing this predictive capacity, DARSI systematically identifies transcription factor binding sites within regulatory regions at single-base pair resolution. To validate its predictions, we benchmarked DARSI against curated databases, confirming its accuracy in predicting transcription factor binding sites. Additionally, DARSI predicted novel unmapped binding sites, paving the way for future experimental efforts to confirm the existence of these binding sites and to identify the transcription factors that target those sites. Thus, by automating and improving the annotation of regulatory regions, DARSI generates experimentally actionable predictions that can feed iterations of the theory-experiment cycle aimed at reaching a predictive understanding of transcriptional control.