bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated characterization of cell types, states and molecular programs in disseminated appendiceal neoplasms
Authors: Bui Linh T. , Cao Xu , Wang Jinhui , Meng Fan , Feng Mingye , Arvanitis Leonidas , Mannan Rifat , Woo Yanghee , Idrees Kamran , Banovich Nicholas E. , Raoof Mustafa 
Published: October 2023

AbstractAppendiceal neoplasms include a heterogeneous group of epithelial and non-epithelial tumors with varying malignant potential. Despite the rise in incidence of appendiceal neoplasms in recent years, limited progress has been made in the understanding, management and therapeutic treatment. To comprehensively characterize the cell types and molecular mechanisms driving cellular remodeling in epithelial appendiceal neoplasms, we performed an integrated scRNA-seq study. We analyzed 126,998 cells from 16 appendix samples (11 peritoneal metastases samples, 5 healthy controls) and identified 33 distinct cell types/cell states with seven being cancer-specific. Highlights of our study include the characterization of tumor cells across the histologic spectrum, the identification of a novel cancer-associated-fibroblast (CAF) subtypes (fiCAFs) and the identification of pathologic-specific cellular crosstalk between tumor cells and the tumor microenvironment (TME). Together, our study provides a high-resolution insight into the complexity and heterogeneity of epithelial appendiceal neoplasms and a valuable resource for therapeutic strategies.
Analysis of ductal carcinoma in situ by self-reported race reveals molecular differences related to outcome
Authors: Strand Siri H. , Houlahan Kathleen E. , Branch Vernal , Lynch Thomas , Harmon Bryan , Couch Fergus , Gallagher Kristalyn , Kilgore Mark , Wei Shi , DeMichele Angela , King Tari , McAuliffe Priscilla , Curtis Christina , Owzar Kouros , Marks Jeffrey R. , Colditz Graham A. , Hwang E. Shelley , West Robert B. 
Published: October 2023

AbstractDuctal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n=99) and White (n=191) women with DCIS in a large DCIS case-control cohort with longitudinal follow up. Gene expression and pathway analyses indicated that different genes and pathways are involved in ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. Our results suggest that different molecular mechanisms drive subsequent ipsilateral breast events in Black versus White women.
Characterization of Z chromosomal inversion and lineage-specific sweeps reveal widespread local adaptation inHelicoverpa armigera
Authors: Ke Fushi 
Published: October 2023

AbstractEfficient pest management requires comprehensive knowledge of its biology, ecology, and evolution, particularly adaptation that exacerbating pest damage.Helicoverpa armigera(Hübner) is a notorious pest that attacks more than 200 species, adapts to diverse environments, and has developed resistance to almost all applied insecticides. However, local adaptation of this species was less investigated. Here, we analyzed genomic variation ofHelicoverpa armigerain China and Oceania to identify adaptative loci in different lineages. Despite intensive gene flow, two differentiated Z chromosomal lineages in Central China (i.e., northern and southern lineages) were formed by chromosome inversion and local adaptation. Based on population genomic analysis, we identified genes related to circadian clock (period,cycle,cyr2anddaywake), insulin secretion (IGF2BP2) and energy metabolism (SLC25A25,CCG7766,D11DS,TSTPandCPQ) were under selection in northern lineage. These genes may have contributed to its adaptation to high latitudes. In the southern lineage however, the Z chromosome inversion harboring alien alleles of two clock genes (periodandcycle) and may have disrupted clock oscillator for adaptation. We further conducted selective sweep analysis in lineages from Northwestern China, Central China, and Oceania, and found several insecticide resistant genes that shared among different lineages were likely contributed by introgression. Nevertheless, many candidates, including a cadherin that involved in resistance toBacillus thuringiensisprotein in Oceanian populations, are lineage-specific. Our results highlight the importance of investigating local adaptation in effective pest control under globalization of agriculture.
COMPARISON OF HIGH-THROUGHPUT SINGLE-CELL RNA-SEQ METHODS FOR EX VIVO DRUG SCREENING
Authors: Gezelius Henrik , Enblad Anna Pia , Lundmark Anders , Åberg Martin , Blom Kristin , Rudfeldt Jakob , Raine Amanda , Harila Arja , Rendo Verónica , Heinäniemi Merja , Andersson Claes , Nordlund Jessica 
Published: October 2023

ABSTRACTFunctional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughputex vivodrug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporatesex vivotreatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27,327 cells are freely available to extend to future scRNA-seq methodological comparisons.
Knowledge-Driven Online Multimodal Automated Phenotyping System
Authors: Xiong Xin , Sweet Sara Morini , Liu Molei , Hong Chuan , Bonzel Clara-Lea , Panickan Vidul Ayakulangara , Zhou Doudou , Wang Linshanshan , Costa Lauren , Ho Yuk-Lam , Geva Alon , Mandl Kenneth D. , Cheng Suchun , Xia Zongqi , Cho Kelly , Gaziano J. Michael , Liao Katherine P. , Cai Tianxi , Cai Tianrun 
Published: October 2023

AbstractThough electronic health record (EHR) systems are a rich repository of clinical information with large potential, the use of EHR-based phenotyping algorithms is often hindered by inaccurate diagnostic records, the presence of many irrelevant features, and the requirement for a human-labeled training set. In this paper, we describe a knowledge-driven online multimodal automated phenotyping (KOMAP) system that i) generates a list of informative features by an online narrative and codified feature search engine (ONCE) and ii) enables the training of a multimodal phenotyping algorithm based on summary data. Powered by composite knowledge from multiple EHR sources, online article corpora, and a large language model, features selected by ONCE show high concordance with the state-of-the-art AI models (GPT4 and ChatGPT) and encourage large-scale phenotyping by providing a smaller but highly relevant feature set. Validation of the KOMAP system across four healthcare centers suggests that it can generate efficient phenotyping algorithms with robust performance. Compared to other methods requiring patient-level inputs and gold-standard labels, the fully online KOMAP provides a significant opportunity to enable multi-center collaboration.
Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5
Authors: Callegari I. , Oechtering J. , Schneider M. , Perriot S. , Mathias A. , Voortman M.M. , Cagol A. , Lanner U. , Diebold M. , Holdermann S. , Kreiner V. , Becher B. , Granziera C. , Junker A. , Du Pasquier R. , Khalil M. , Kuhle J. , Kappos L. , Sanderson NSR , Derfuss T. 
Published: October 2023

AbstractIntrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS-related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification. We produced 5 cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR+ plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an EAE model. CSF IgM might contribute to CNS inflammation in MS by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain.
Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media
Authors: Axemaker Hailey , Plesselova Simona , Calar Kristin , Jorgensen Megan , Wollman Jared , de la Puente Pilar 
Published: October 2023

SUMMARYCancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present a translatable-based approach for the reprogramming of normal uterine fibroblasts into ovarian CAFs using ovarian tumor-derived conditioned media to establish two well-characterized ovarian conditioned CAF lines. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression and resembled a CAF-like subtype associated with worse prognosis. The present study provides a reproducible, cost-effective, and clinically relevant protocol to reprogram normal fibroblasts into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF-mediated chemoresistance in OC are further warranted.
Clay larvae do not accurately measure biogeographic patterns in predation
Authors: Rodriguez-Campbell Antonio , Rahn Olivia , Chiuffo Mariana , Hargreaves Anna 
Published: October 2023

AbstractAimSpatial variation in predation can shape geographic patterns in ecology and evolution, but testing how predation varies across ecosystems is challenging as differing species compositions and defensive adaptations can mask underlying patterns. Recently, biogeography has borrowed a tool from ecology –clay prey models. But clay models have not been adequately tested for geographic comparisons, and a well-known problem –that clay prey only appeal to a subset of potential predators– could lead to inaccurate detection of geographic patterns whenever the relative importance of predator guilds varies among sites. Here, we test whether clay larvae accurately capture geographic differences in predation on real larvae.Location90° of latitude and >2000 m elevation across the AmericasTaxonvertebrate and invertebrate predation on ‘superworms’ (Zophobaslarve)MethodsAcross six sites that vary dramatically in latitude, elevation, and biome, we quantified predation on live, dead, and clay larvae. We physically excluded vertebrate predators from some larvae to distinguish total predation and invertebrate-only predation.ResultsPredation on live superworms almost doubled from our high-elevation high-latitude site to out low-elevation tropical site. Geographic patterns were highly consistent among live and dead larvae, but clay larvae missed extremely high predation at some sites and therefore mismeasured true geographic patterns. Clay larvae did a particularly bad job at capturing geographic patterns in predation by invertebrates.Main conclusionsClay larvae are inappropriate for large-scale tests of predation, and should be abandoned for biogeographic studies. Biogeographic experiments should instead employ realistic baits, and clay prey should be reserved for comparisons within, rather than across, predator communities.
Inferring B cell phylogenies from paired heavy and light chain BCR sequences with Dowser
Authors: Jensen Cole G. , Sumner Jacob A. , Kleinstein Steven H. , Hoehn Kenneth B. 
Published: October 2023

AbstractAntibodies are vital to human immune responses and are composed of genetically variable heavy and light chains. These structures are initially expressed as B cell receptors (BCRs). BCR diversity is shaped through somatic hypermutation and selection during immune responses. This evolutionary process produces B cell clones, cells that descend from a common ancestor but differ by mutations. Phylogenetic trees inferred from BCR sequences can reconstruct the history of mutations within a clone. Until recently, BCR sequencing technologies separated heavy and light chains, but advancements in single cell sequencing now pair heavy and light chains from individual cells. However, it is unclear how these separate genes should be combined to infer B cell phylogenies. In this study, we investigated strategies for using paired heavy and light chain sequences to build phylogenetic trees. We found incorporating light chains significantly improved tree accuracy and reproducibility across all methods tested. This improvement was greater than the difference between tree building methods and persisted even when mixing bulk and single cell sequencing data. However, we also found that many phylogenetic methods estimated significantly biased branch lengths when some light chains were missing, such as when mixing single cell and bulk BCR data. This bias was eliminated using maximum likelihood methods with separate branch lengths for heavy and light chain gene partitions. Thus, we recommend using maximum likelihood methods with separate heavy and light chain partitions, especially when mixing data types. We implemented these methods in the R package Dowser:https://dowser.readthedocs.io.
Psychological well-being modulates neural synchrony during naturalistic fMRI
Authors: Klamer K. , Craig J. , Sullivan K. , Haines C. , Ekstrand C. 
Published: October 2023

AbstractPsychological well-being (PWB) is a combination of self-acceptance, life purpose, personal growth, positive relationships, and autonomy, and has a significant relationship with physical and mental health. Previous studies using resting-state functional magnetic resonance imaging (fMRI) and static picture stimuli have implicated the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), orbitofrontal cortex (OFC), insula and thalamus in PWB, however, the replication of associations across studies is scarce, both in strength and direction, resulting in the absence of a model of how PWB impacts neurological processing. Naturalistic stimuli better encapsulate everyday experiences and can elicit more “true-to-life” neurological responses, and therefore may be a more appropriate tool to study PWB. The current study seeks to identify how differing levels of PWB modulate neural synchrony in response to an audiovisual film. With consideration of the inherent variability of the literature, we aim to ascertain the validity of the regions previously mentioned and their association with PWB. We identified that higher levels of PWB were associated with heightened neural synchrony in the bilateral OFC and left PCC, and that lower levels of PWB were associated with heightened neural synchrony in the right temporal parietal junction (TPJ) and left superior parietal lobule (SPL), regions related to narrative processing. Taken together, this research confirms the validity of several regions in association with PWB and suggests that varying levels of PWB produce differences in the processing of a narrative during complex audiovisual processing.
Reviving collapsed networks from a single species: the importance of trait variation and network architecture
Authors: Baruah Gaurav , Wittmann Meike 
Published: October 2023

AbstractMutualistic ecological networks can suddenly transition to undesirable states, due to small changes in environmental conditions. Recovering from such a collapse can be difficult as reversing the original environmental conditions may be infeasible. Additionally, such networks can also exhibit hysteresis, implying that ecological networks may not recover. Here, using a dynamical eco-evolutionary framework, we try to resurrect mutualistic networks from an undesirable low-functional collapse state to a high-functioning state. We found that restoring the original environmental conditions rarely aided in recovering the original network due to the presence of hysteresis. By combining concepts from signal propagation theory and eco-evolutionary dynamical modeling, we show that network resurrection could be readily achieved by perturbing a single species that controls the response of the dynamical networks. We show that during the resurrection of collapsed networks, the historical network architecture, levels of trait variation, and eco-evolutionary dynamics could aid in the revival of the network even in undesirable environmental conditions. Our study argues that focus should be applied to a few species whose dynamics one could steer to resurrect the entire network from a collapsed state.
Synthesis, Insertion, and Characterization of SARS-CoV-2 Membrane Protein Within Lipid Bilayers
Authors: Zhang Yuanzhong , Anbir Sara , McTiernan Joseph , Li Siyu , Worcester Michael , Mishra Pratyasha , Colvin Michael E. , Gopinathan Ajay , Mohideen Umar , Zandi Roya , Kuhlman Thomas E. 
Published: October 2023

SUMMARY/ABSTRACTThe membrane protein (M) is the most abundant structural protein in the SARS-CoV-2 virus and functions exclusively as a membrane-embedded homodimer. M protein is required for the formation of the SARS-CoV-2 virus particle and has been shown to interact with the Spike and Envelope proteins, as well as the RNA-packaging Nucleocapsid protein. Our knowledge of M protein is very limited due to its small size and challenges in expressing enough protein for use in structural and biophysical experiments. We report the successful development of a SUMO tag-based expression system to produce and purify significant quantities of M protein, and a method to insert the synthesized dimers into a suspended lipid membrane in a homogeneous orientation. We used AFM and Cryo-EM to image individual membrane-bound M protein dimers and characterize the configurations that they can assume. Our experimental results are in agreement with our molecular dynamics simulations which predict thinning of the membrane around the M protein and a propensity to induce local membrane curvature. Taken together, our results shed new light on M protein properties within the lipid bilayer and suggest mechanisms that could contribute to viral assembly and budding.
The near-normal viability of heterozygote for a lethal enhancer allele suggests a route forcis-regulatory evolution
Authors: Ludwig Michael Z. 
Published: October 2023

AbstractA variety of evolutionary processes shape the structure ofcis-regulatory elements such as enhancers. Functionally important regulatory sequences tend to be conserved as result of negative selection against deleterious mutations and positive selection for better-canalized performance. However, some forms of stabilizing selection can maintain functional conservation ofcis-regulatory elements for long periods of evolutionary time despite structural transcription binding sites turnover (Ludwig et al, 1998). In addition, compensatory evolution can even accelerate the substitution process in large populations to level greater than the neutral rate of substitution (Carter and Wagner, 2002). The effects of lethal mutations incis-regulatory regions on viability in heterozygotes and the impact of such mutations on evolutionary processes have not been substantially addressed.We ask a fundamental biological question: How does a lethal mutant in an enhancer region affect viability when carried over a dominant “normal” allele?Herecis-regulatory mutationeveΔMSEofeven-skippedgene (eve)inD. melanogaster, that is lethal in homozygote, has been tested for relative viability in heterozygous state. IneveΔMSEthe 480-bp fragment corresponding to MSE (Minimal Stipe Element) of theevestripe 2 enhancer was deleted and replaced with an unrelated DNA fragment (containingwhite+gene marker) by ends-out homologous recombination (Ludwig et al, 2011). We discovered that relative viability of flies carryingcis-regulatory mutationeveΔMSEin heterozygote was not reduced compared to the viability of wild-type flies. In contrast, the viability of heterozygotes carrying a homozygote-lethal nonsenseeveR13mutation (Fujioka et al, 1999) was significantly impacted. Our explanation to this surprising phenomenon relays on action ofevetranscriptional autoregulation. The transcription factor (TF) EVE regulates its own expression level through the autoregulatorycis-regulatory module. It could elevate the expression level from one dose to the level sufficient to restore up to 100% fitness in the heterozygote witheveΔMSElethal allele.This example suggests that somecis-regulatory mutants (including the deleterious ones) may exist in populations as heterozygotes with high fitness for many generations, before possibly encountering an epistatic interaction with a compensatory mutation at a different site in the genome. Our study is consistent with the compensatory mechanisms of evolution for functionally importantcis-regulatory elements.