bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embracing naturalistic paradigms: substituting GPT predictions for human judgments
Authors: Yang Xuan , O’Reilly Christian , Shinkareva Svetlana V. 
Published: June 2024

AbstractNaturalistic paradigms can assure ecological validity and yield novel insights in psychology and neuroscience. However, using behavioral experiments to obtain the human ratings necessary to analyze data collected with these paradigms is usually costly and time-consuming. Large language models like GPT have great potential for predicting human-like behavioral judgments. The current study evaluates the performance of GPT as a substitute for human judgments for affective dynamics in narratives. Our results revealed that GPT’s inference of hedonic valence dynamics is highly correlated with human affective perception. Moreover, the inferred neural activity based on GPT-derived valence ratings is similar to inferred neural activity based on human judgments, suggesting the potential of using GPT’s prediction as a reliable substitute for human judgments.
Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis
Authors: Chandran Rachana R. , Vijayaraj Preethi , Garcia-Milian Rolando , King Jade , Castillo Kristen , Chen Liang , Kwon Yumi , William Sarai , Rickabaugh Tammy M. , Langerman Justin , Choi Woosuk , Sen Chandani , Lever Jacelyn E.P , Li Qian , Pavelkova Nikoleta , Plosa Erin J. , Rowe Steven M. , Plath Kathrin , Clair Geremy , Gomperts Brigitte N. 
Published: June 2024

AbstractThe distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genesJUPandPLEC, that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease.One Sentence SummaryTwo-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.
Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease
Authors: Benjamin Kynon JM , Sauler Maor , Poonyagariyagorn Hataya , Neptune Enid R 
Published: June 2024

AbstractThe renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung,AGTR1andAGTR2, using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes forAGTR1and a subtype of alveolar epithelial type 2 cells forAGTR2. In the context of disease, we further pinpointAGTR2localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2B) andAGTR1localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, findingAGTR2associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway’s role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.
Distinct functions of three Wnt proteins control mirror-symmetric organogenesis in theC. elegansgonad
Authors: So Shuhei , Asakawa Masayo , Sawa Hitoshi 
Published: June 2024

AbstractOrganogenesis requires the proper production of diverse cell types and their positioning/migration. However, the coordination of these processes during development remains poorly understood. The gonad inC. elegansexhibits a mirror-symmetric structure guided by the migration of distal tip cells (DTCs), which result from asymmetric divisions of somatic gonadal precursors (SGPs; Z1 and Z4). We found that the polarity of Z1 and Z4, which possess mirror-symmetric orientation, is controlled by the redundant functions of the LIN-17/Frizzled receptor and three Wnt proteins (CWN-1, CWN-2, and EGL-20) with distinct functions. Inlin-17mutants, CWN-2 promotes normal polarity in both Z1 and Z4, while CWN-1 promotes reverse and normal polarity in Z1 and Z4, respectively. In contrast, EGL-20 inhibits the polarization of both Z1 and Z4. Inlin-17;egl-20 cwn-2triple mutants with a polarity reversal of Z1, DTCs from Z1 frequently miss-migrate to the posterior side. Our further analysis demonstrates that the mis-positioning of DTCs in the gonad due to the polarity reversal of Z1 leads to mis-migration. Similar mis-migration was also observed incki-1(RNAi)animals producing ectopic DTCs. These results highlight the role of Wnt signaling in coordinating the production and migration of DTCs to establish a mirror-symmetric organ.
Identification of BiP as a temperature sensor mediating temperature-induced germline sex reversal
Authors: Shi Jing , Sheng Danli , Guo Jie , Zhou Fangyuan , Wu Shaofeng , Tang Hongyun 
Published: June 2024

AbstractBesides regulation by karyotype, sex determination is also modulated by environmental cues like temperature, but the involving temperature-transduction mechanism remains elusive. Moreover, while sex determination was traditionally seen as dictated exclusively by either karyotype or temperature, recent observations suggest these factors can co-regulate sex, posing a mechanistic mystery. Here, we discovered that certain wild-isolated and mutantC. elegansstrains displayed genotypic-germline-sex-determination (GGSD) but with a temperature override. We found that ER chaperone BiP transduces temperature into germline-sex-governing signal and enables the co-existence of GGSD and temperature-dependent-germline-sex-determination (TGSD). Mechanistically, BiP availability is reduced at warmer temperatures through detecting increased ER-protein-folding burden, which promotes male-germline-fate through ERAD-mediated downregulation of the oocyte-fate driving factor, TRA-2. Remarkably, we can induce a switch between GGSD and TGSD by manipulating this newly-discovered process. Functionally, TGSD facilitatesC. eleganshermaphrodites in maintaining brood size at warmer temperatures. Moreover, BiP also acts in germline-sex-determination in a dioecious nematode. Collectively, our findings identify thermosensitive BiP as a conserved temperature sensor in TGSD and provide mechanistic insights into the fascinating transition of GGSD and TGSD.
SpatialQPFs: An R package for deciphering cell-cell spatial relationship
Authors: Li Xiao 
Published: June 2024

ABSTRACTUnderstanding spatial dynamics within tissue microenvironments is crucial for deciphering cellular interactions and molecular signaling in living systems. These spatial characteristics govern cell distribution, extracellular matrix components, and signaling molecules, influencing local biochemical and biophysical conditions. Despite significant progress in analyzing digital pathology images, current methods for capturing spatial relationships are limited. They often rely on specific spatial features that only partially describe the complex spatial distributions of cells and are frequently tied to particular outcomes within predefined model frameworks. To address these limitations, we presentSpatialQPFs, an R package designed to extract interpretable spatial features from cell imaging data using spatial statistical methodologies. Leveraging segmented cell information, our package offers a comprehensive toolkit for applying a range of spatial statistical methods within a stochastic process framework, including analyses of point process data, areal data, and geostatistical data. By decoupling feature extraction from specific outcome models,SpatialQPFsenables thorough large-scale spatial analyses applicable across diverse clinical and biological contexts. This approach enhances the depth and accuracy of spatial insights derived from tissue data, empowering researchers to conduct comprehensive spatial analyses efficiently and reproducibly. By providing a flexible and robust framework for spatial feature extraction,SpatialQPFsfacilitates advanced spatial analyses, paving the way for new discoveries in tissue biology and pathology.
PINK1 deficiency rewires early immune responses in a mouse model of Parkinson’s disease triggered by intestinal infection
Authors: Recinto Sherilyn Junelle , Kazanova Alexandra , Bessaiah Hicham , Cordeiro Brendan , Mukherjee Sriparna , Premachandran Shobina , MacDonald Adam , Pei Jessica , Allot Alexis , Afanasiev Elia , Yaqubi Moein , McBride Heidi M , Trudeau Louis-Eric , Gruenheid Samantha , Stratton Jo Anne 
Published: June 2024

AbstractParkinson’s disease (PD) is characterized by a protracted period of non-motor symptoms, including gastrointestinal (GI) dysfunction, which can precede the development of the cardinal motor deficits by decades. This long prodrome of disease is highly suggestive of immune cell involvement in the initiation of disease, but currently the field lacks robust model systems to study such mechanisms. It has been hypothesized that pathology may be first initiated in the periphery due to environmental triggers, such as pathogens that enter the GI tract. We further speculate that the impact of such pathogens on the immune system could be exacerbated in genetically predisposed individuals. Our group has developed a GI-targeted pathogen-induced PD mouse model system in PINK1 KO mice with Gram-negative bacterial infections and found that T cells are a major player in driving PD-like motor symptoms at late stages following infection. Herein, we now map the initiating immune events at the site of infection at the earliest stages with the goal of shedding light on the earliest mechanisms triggering immune-mediated pathological processes relevant to PD. Using unbiased single cell sequencing, we demonstrate that myeloid cells are the earliest dysregulated immune cell type in PINK1 KO infected mice at 1-week post-infection, followed by a dysregulated T cell response shortly after, at 2 weeks post-infection. We find that these myeloid cells have an enhanced proinflammatory profile, are more mature, and develop enhanced capacity for antigen presentation. Using unbiased prediction analysis, our data suggest that cytotoxic T cells and myeloid cells are particularly poised for interacting with each other, and we identify possible direct cell-cell interaction pathways that might be implicated. Taken together, deciphering the earliest immune mechanisms in the periphery underpinning PD autoimmunity will be instrumental in the development of effective therapeutic targeting strategies before irrevocable neuronal damage ensues.
Advanced Cardiovascular Toxicity Screening: Integrating Human iPSC-Derived Cardiomyocytes with In Silico Models
Authors: Berezhnoy Andrey , Sinitsyna Anastasiya , Semidetnov Ivan , Naumov Vadim , Sergeeva Tatyana , Bakumenko Sergey , Slotvitsky Mikhail , Tsvelaya Valeriya , Agladze Konstantin 
Published: June 2024

AbstractThe pharmaceutical industry is evolving with the use of hiPSC-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT interval prolongation as a main cardiotoxicity marker is being challenged. In addition, Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as more comprehensive approach for cardiotoxicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents such an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess cardiotoxicity. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modelling. We show, using the example of lidocaine and other antiarrhythmics, that using a integrative experimental and computer platform, the possibility to correctly display the clinical manifestations of side effects in advance.
Decoupling shear stress and pressure effects in the biomechanics of autosomal dominant polycystic kidney disease using a perfused kidney-on-chip
Authors: Lapin Brice , Gropplero Giacomo , Vandensteen Jessica , Mazloum Manal , Bienaimé Frank , Descroix Stéphanie , Coscoy Sylvie 
Published: June 2024

AbstractKidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical properties of the surrounding extracellular matrix modulate tubule deformation under constraints. These mechanical factors likely play a role in the pathophysiology of kidney diseases as exemplified by autosomal dominant polycystic kidney disease, in which pressure, flow and matrix stiffness have been proposed to modulate the cystic dilation of tubules withPKD1mutations. The lack ofin vitrosystems recapitulating the mechanical environment of kidney tubules impedes our ability to dissect the role of these mechanical factors. Here we describe a perfused kidney-on-chip with tunable extracellular matrix mechanical properties and hydrodynamic constraints, that allows a decoupling of shear stress and flow. We used this system to dissect how these mechanical cues affectPkd1-/-tubule dilation. Our results show two distinct mechanisms leading to tubular dilation. For PCT cells (proximal tubule), overproliferation mechanically leads to tubular dilation, regardless of the mechanical context. For mIMCD-3 cells (collecting duct), tube dilation is associated with a squamous cell morphology but not with overproliferation and is highly sensitive to extracellular matrix properties and hydrodynamic constraints. Surprisingly, flow alone suppressedPkd1-/-mIMCD-3 tubule dilation observed in static conditions, while the addition of luminal pressure restored it. Ourin vitromodel emulating nephron geometrical and mechanical organization sheds light on the roles of mechanical constraints in ADPKD and demonstrates the importance of controlling intraluminal pressure in kidney tubule models.
Harmonic imaging for nonlinear detection of acoustic biomolecules
Authors: Nayak Rohit , Duan Mengtong , Ling Bill , Jin Zhiyang , Malounda Dina , Shapiro Mikhail G. 
Published: June 2024

ABSTRACTGas vesicles (GVs) based on acoustic reporter genes have emerged as potent contrast agents for cellular and molecular ultrasound imaging. These air-filled, genetically encoded protein nanostructures can be expressed in a variety of cell typesin vivoto visualize cell location and activity or injected systemically to label and monitor tissue function. Distinguishing GVs from tissue signal deep inside intact organisms requires imaging approaches such as amplitude modulation (AM) or collapse-based pulse sequences, however they have limitations in sensitivity or require irreversible collapse of the GVs that restricts its scope for imaging dynamic cellular processes. To address these limitations, this study explores the utility of harmonic imaging to enhance the sensitivity of non-destructive imaging of GVs and cellular processes. Traditional fundamental-frequency imaging utilizing cross-wave AM (xAM) sequences has been deemed optimal for GV imaging. Contrary to this, we hypothesize that harmonic imaging, integrated with xAM could significantly elevate GV detection sensitivity. To verify our hypothesis, we conducted imaging on tissue-mimicking phantoms embedded with purified GVs, mammalian cells genetically modified to express GVs, and live mice after systemic GV infusion. Our findings reveal that harmonic xAM (HxAM) imaging markedly surpasses traditional xAM in isolating GVs’ nonlinear acoustic signature, showcasing significant enhancements in signal-to-background and contrast-to-background ratios across all tested samples. Further investigation into the backscattered spectra elucidates the efficacy of harmonic imaging in conjunction with xAM. HxAM imaging enables the detection of lower concentrations of GVs and cells with ultrasound and extends the imaging depthin vivoby up to 20% and imaging performance metrics by up to 10dB. These advancements bolster the capabilities of ultrasound for molecular and cellular imaging, underscoring the potential of using harmonic signals to amplify GV detection.
AEon: A global genetic ancestry estimation tool
Authors: Warren Naomi M , Pinese Mark 
Published: June 2024

AbstractGenetic ancestry is a significant confounding factor in genetic association studies. It is therefore essential to estimate and account for ancestry if we hope to translate genomic research into equitable clinical utility for ethnically diverse populations. Despite this importance, accurate ancestry information is difficult to obtain, and existing methods to estimate ancestry are not designed for modern sequencing data. This methodological gap hinders the integration of genetic ancestry information in modern research, and limits progress in finding the genetic determinants of disease in diverse populations. To address this gap we present AEon, a probabilistic model-based global ancestry estimation tool, ready for use on modern genomic data. AEon predicts fractional population membership, accounting for possible admixture. Unlike previous global ancestry estimation tools such as EIGENSTRAT and ADMIXTURE, AEon takes input directly from a VCF/BCF, includes default training data based on the 26 reference populations of the 1000 Genomes Project, and produces visualisation aids and diagnostics to complement data output. AEon’s turnkey design significantly reduces the time taken to estimate ancestry from VCFs, without compromising on accuracy compared to ADMIXTURE analysis. AEon is available atgithub.com/GenomicRisk/aeon.
The expanded immunoregulatory protease network in mosquitoes is governed by gene co-expression
Authors: Morejon Bianca , Michel Kristin 
Published: June 2024

AbstractSerine protease cascades regulate key innate immune responses. In mosquitoes, these cascades involve clip-domain serine proteases and their non-catalytic homologs (CLIPs), forming a complex network whose make-up and structural organization is not fully understood. This study assessed the impact of 85 CLIPs on humoral immunity inAnopheles gambiae. By coupling RNAi with assays measuring antimicrobial activity and melanization, we identified 27 CLIPs as immunoregulators that together form two distinct subnetworks. CLIPs regulating antimicrobial activity were found to control infection resistance, as knockdowns reduced bacterial load and improved survival. Furthermore, our analysis of CLIP gene expression unveiled a novel immunoregulatory mechanism reliant on protease baseline co-expression rather than infection-induced upregulation. These findings underscore that despite its complexity mosquito immune regulation may be targeted for malaria interventions.
SMARCA4mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy
Authors: Wang Yawen , Meraz Ismail M , Qudratullah Md , Kotagiri Sasikumar , Han Yanyan , Xi Yuanxin , Wang Jing , Lissanu Yonathan 
Published: June 2024

AbstractCancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex includingSMARCA4andARID1A. Importantly, clinical reports indicate thatSMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboringSMARCA4deficiency. Specifically, we show thatSMARCA4loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show thatSMARCA4loss in tumor cells led to profound downregulation ofSTING, IL1βand other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such asSTING, IL1β,type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility uponSMARCA4deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated withSTINGandIL1β,indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response ofSMARCA4-mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.
Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline
Authors: Jang Yeongjun , Tomasini Livia , Bae Taejeong , Szekely Anna , Vaccarino Flora M. , Abyzov Alexej 
Published: June 2024

AbstractLittle is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We found that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyses of public data from several multi-children families and from 1,934 familial quads confirmed this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyses of all the data consistently suggest that germline has a balanced 50:50 lineage allocation from the first two blastomeres.