bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes
Authors: Duong Thu Van-Quynh , Yaw Alexandra M. , Zhou Guoli , Sina Niharika , Cherukuri Aneesh Sai , Nguyen Duong , Cataldo Kylie , Ly Nicollette , Sen Aritro , Sempere Lorenzo , Detrie Cara , Seiler Robert , Nicholas Olomu I. , Cortese Rene , Long Robert , Hoffmann Hanne M. 
Published: November 2024

AbstractManagement of labor in women with diabetes is challenging due to the high risk of peri- and postpartum complications. To avoid cesarean section and assist with labor progression, Pitocin, a synthetic oxytocin, is frequently used to induce and augment labor. However, the efficacy of Pitocin is often compromised in diabetic pregnancies, leading to increased cesarian delivery. As diabetes deregulates the body’s circadian timekeeping system and the time-of-day of the first Pitocin administration contributes to labor duration, our objective was to determine how the time of day and the circadian clock gene,Bmal1, gates oxytocin efficacy. Our studies in mice show that, compared to the rest phase of the day (lights on), the uterotonic efficacy of oxytocin is significantly increased during the active phase (lights off). Usingin vitrostudies, a myometrium-specificBmal1conditional knockout mouse model, and a mouse model of food-induced gestational diabetes, we find thatBmal1is crucial for maintaining oxytocin receptor expression and response in the myometrium in mice. These findings also translate to humans, where oxytocin-induced human myometrial cell contraction is time-of-day dependent, and retrospective clinical data suggest that administration of Pitocin in the morning should be considered for pregnant women with gestational diabetes.
Distribution-preserved compression of single-cell atlases for privacy-protected data dissemination and novel cell type discovery
Authors: Cai Zhihan , Hu Zhibin , Sun Shuang-Rong , Wang Zexu , Yang Fan , Han Jiahuai , Zeng Feng 
Published: November 2024

AbstractWe introduce SUREv2, a tool for constructing lightweight, transmittable, and privacy-preserving references from single cell atlases. SUREv2 introduces a compressed data structure that maintain the distribution of cells within these atlases and develops an out-of-reference scoring method for identifying novel cell populations. This user-friendly tool shall enhance the analysis of single cell datasets by providing a consistent, privacy-focused reference framework.
Unraveling cfDNA Fragmentation Patterns: Linking Chromatin Architecture to Cancer Diagnostic Sensitivity
Authors: Johnston Andrew D , Antaw Fiach , Lu Jennifer , Stirzaker Clare , Trau Matt , Korbie Darren 
Published: November 2024

SummaryCirculating cell-free DNA (cfDNA) liquid biopsies offer a powerful, non-invasive approach for cancer diagnostics, leveraging DNA fragments primarily released during apoptosis. Using droplet digital PCR on cfDNA samples from 88 breast and colorectal cancer patients, we uncovered highly consistent nucleosome breakpoints across individuals. Proximity to these cfDNA breakpoints diminishes the sensitivity of somatic mutation assays, including those targetingIDH1andNRAShotspot mutations, underscoring the importance of precise nucleosome positioning data. We introduce a probabilistic nucleosome protection scoring method that enables high-resolution mapping of nucleosome positions and cfDNA breakpoints. These maps reveal distinct nucleosome spacing patterns between heterochromatin and euchromatin, corresponding to different chromatin fiber topologies. Analysis of X-chromosome inactivation further supports the topoisomer model: heterochromatin’s 187 bp nucleosome repeat length differs from euchromatin’s 182 bp, generating wave interference patterns in nucleosome signals. Our findings suggest that loop-mediated transitions from T2 to T1 topoisomers shape chromatin accessibility and cfDNA fragmentation, advancing the diagnostic potential of liquid biopsy assays.HighlightsNucleosome breakpoint conservation impacts somatic mutation assay sensitivityProbabilistic protection scoring enhances cfDNA nucleosome peak resolutionChromatin states exhibit unique nucleosome spacing linked to distinct topologies, influencing cfDNA fragmentationChromosome X-inactivation phasing analyses reveal waveform interference in nucleosome positioning signalsGraphical Abstract
Integrative cardiovascular dose-response to graded lower body negative pressure
Authors: Whittle Richard S. , Keller Nathan , Hall Eric A. , Patanam Safiyya , Dunbar Bonnie J. , Diaz-Artiles Ana 
Published: November 2024

AbstractBackgroundLower body negative pressure (LBNP) has been posited as a potential spaceflight countermeasure to counteract the physiological deconditioning related to fluid shifts in micro-gravity. However, open questions remain as to the magnitude of LBNP that should be applied. We systematically characterized the cardiovascular effects of LBNP and quantified the effect size of varied LBNP doses across different parts of the cardiovascular system.MethodsTwenty-four subjects (12M, 12F) were exposed to graded LBNP from 0 mmHg to −50 mmHg in 10 mmHg increments, both in supine (0°) and 15° head-down tilt postures. We measured the steady-state response in a large range of variables, including those related to the systemic circulation, cardiovascular control, and hemodynamics of the eyes and neck.ResultsBuilding on the experimental data, dose-response curves were constructed using a Bayesian multivariate hierarchical modeling framework to quantify the effect size of every variable considered when subjected to LBNP. The methodology allows direct comparison of the variables and the underlying structural relationships between them. Further, we demonstrated the potential for LBNP to reduce jugular venous flow stagnation, which is considered one of the major health risks during human spaceflight.ConclusionsThe Dose-response curves and effect sizes generated from this research effort establish the most comprehensive framework available to date that characterizes physiological responses to LBNP. These results directly inform the development of countermeasures to mitigate the negative effects of spaceflight, including cardiovascular deconditioning, spaceflight-associated neuro-ocular syndrome, and venous thromboembolism events.Key Points SummaryLower body negative pressure (LBNP) has been posited as a potential countermeasure for multiple risks associated with spaceflight, including cardiovascular deconditioning, spaceflight-associated neuro-ocular syndrome, and venous thromboembolism events. However, the specific LBNP dose needed to mitigate these risks is still unknown.We constructed the LBNP dose-response curves in supine and 15° head-down-tilt positions to quantify the acute response of a large variety of hemodynamics, autonomic, ocular, and neck variables across a range of LBNP levels.We also used a Bayesian multivariate modeling framework to identify significant relationships between variables and to compare their effect sizes under different levels of LBNP.In addition, results indicate that LBNP is a promising countermeasure to reduce jugular venous flow stagnation occurring during microgravity exposure.This study constitutes the most comprehensive analysis of cardiovascular hemodynamics, autonomic, and cephalad response to LBNP to date. This framework informs the development of countermeasures to mitigate the detrimental effects of spaceflight.
Mitochondrial genome-encoded mitomiRs regulate cellular plasticity and susceptibility to ferroptosis in triple-negative breast cancer
Authors: Kandettu Amoolya , Ghosal Joydeep , Tharayil Jesline Shaji , Kuthethur Raviprasad , Mallya Sandeep , Narasimhamurthy Rekha Koravadi , Mumbrekar Kamalesh Dattaram , Subbannayya Yashwanth , Kumar Naveena AN , Radhakrishnan Raghu , Kabekkodu Shama Prasada , Chakrabarty Sanjiban 
Published: November 2024

AbstractFerroptosis is a distinct form of regulated cell death promoted by iron-dependent lipid peroxidation. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. Although mitochondrial dysfunction contributes to metabolic reprogramming in cancer cells, its role in ferroptosis remains to be identified. We identified that the mitochondrial genome encodes 13 miRNAs (mitomiRs) that are highly expressed in breast cancer cell lines and patient-derived tumor samples. Expression analysis revealed that mitomiRs are upregulated in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Interestingly, 11 out of the 13 mitomiRs bind to the 3′UTR of zinc finger E-box-binding homeobox 1 (ZEB1), a transcription factor, involved in epithelial to mesenchymal transition (EMT) in breast cancer. Using mitomiR-3 mimic, inhibitor and sponges, we confirmed that mitomiR-3 indeed regulate ZEB1 expression in TNBC cells. Increased mesenchymal features in TNBC contributed to vulnerability to pro-ferroptotic metabolic reprogramming sensitizing to cell death inin vitroandin vivomodels. Some of the challenges associated with pro-ferroptotic drugs includes lack of cancer cell specificity, low targeting ability, normal tissue toxicity contributing to their limited clinical application as cancer therapeutics. Here, we identified mitomiRs which are highly expressed in TNBC subtypes with low expression in normal breast cells making them an ideal candidate for selective inhibition for targeted therapy. Further, we demonstrated that the inhibition of mitomiRs in triple-negative breast cancer cells promote pro-ferroptotic metabolic reprogramming which can be exploited as novel vulnerability for targeted ferroptotic induction in cancer cells avoiding the normal tissue toxicity. Collectively, our results indicate a novel mechanism of mitochondrial miRNA mediated ferroptosis sensitivity in TNBC subtypes which could be exploited to develop potential miRNA-based therapeutics.
Squidiff: Predicting cellular development and responses to perturbations using a diffusion model
Authors: He Siyu , Zhu Yuefei , Tavakol Daniel Naveed , Ye Haotian , Lao Yeh-Hsing , Zhu Zixian , Xu Cong , Chauhan Sharadha , Garty Guy , Tomer Raju , Vunjak-Novakovic Gordana , Zou James , Azizi Elham , Leong Kam W. 
Published: November 2024

AbstractSingle-cell sequencing has revolutionized our understanding of cellular heterogeneity and responses to environmental stimuli. However, mapping transcriptomic changes across diverse cell types in response to various stimuli and elucidating underlying disease mechanisms remains challenging. Studies involving physical stimuli, such as radiotherapy, or chemical stimuli, like drug testing, demand labor-intensive experimentation, often hindering the rapid advancement of mechanistic insight and drug discovery. To address this, we present Squidiff, a diffusion model-based generative framework designed to predict transcriptomic changes across diverse cell types in response to a wide range of environmental changes. We demonstrate Squidiff’s robustness across various scenarios, including cell differentiation, gene perturbation, and drug response prediction. Through continuous denoising and semantic feature integration, Squidiff effectively learns transient cell states and predicts high-resolution transcriptomic landscapes over time and conditions. Furthermore, we applied Squidiff to model the development of blood vessel organoids and cellular responses to neutron irradiation and growth factors. Our results demonstrate that Squidiff enablesin silicoscreening of cell molecular landscapes, facilitating rapid hypothesis generation and providing valuable insights for precision medicine.
Nonlinear brain connectivity from neurons to networks: quantification, sources and localization
Authors: Raffaelli Giulio Tani , Jiříček Stanislav , Hlinka Jaroslav 
Published: November 2024

Since the first studies in functional connectivity, Pearson’s correlation has been the primary tool to determine relatedness between the activity of different brain locations. Over the years, concern over the information neglected by correlation pushed toward using different measures accounting for non-linearity. However, some studies suggest that, at the typical observation scale, a linear description of the brain captures a vast majority of the information. Therefore, we measured the fraction of information that would be lost using a linear description and which regions would be affected the most. We considered fMRI, EEG, iEEG, and single unit spikes to assess how the observation scale impacts the amount of non-linearity. We observe that the information loss is reduced for modalities with large temporal or spatial averaging (fMRI and EEG) and gains relevance on more fine descriptions of the activity (iEEG and single unit spikes). We conclude that for most human applications, Pearson’s correlation coefficient adequately describes pairwise interactions in time series from current recording techniques.Significance StatementIn neuroimaging, as in other complex systems fields, the increasing interest in network inference by statistical dependencies (i.e. functional connectivity) invites advanced ways to quantify it. Various nonlinear measures, ultimately the Mutual Information, are used as alternatives to conventional linear Pearson’s correlation coefficient. We systematically assess the amount and reliability of detectable non-linearity of brain functional connectivity across imaging modalities and spatial scales. We demonstrate more pronounced nonlinearity in micro-scale recordings, while rather limited and unreliable in more accessible, noninvasive, large-scale modalities: functional magnetic resonance imaging and scalp electro-physiology. This fundamentally supports the use of robust and easily interpretable linear tools in large-scale neuroimaging, and important insights concerning the microscale connectivity nonlinearity, including the link to brain state dynamics.
Single Particle Tracking of Genetically Encoded Nanoparticles: Optimizing Expression for Cytoplasmic Diffusion Studies
Authors: Korunova Elizaveta , Sikirzhystki Vitali , Twiss Jeffery L , Vasquez Paula , Shtutman Michael 
Published: November 2024

AbstractSingle particle tracking (SPT) is a powerful technique for probing the diverse physical properties of the cytoplasm. Genetically encoded nanoparticles provide an especially convenient tool for such investigations, as they can be expressed and tracked in cells via fluorescence. Among these, 40-nm GEMs provide a unique opportunity to explore the cytoplasm. Their size corresponds to that of ribosomes and big protein complexes, allowing us to investigate the effects of the cytoplasm on the diffusivity of these objects while excluding the influence of chemical interactions during stressful events and pathological conditions. However, it has been shown that cytoplasmic viscosity is tightly regulated and plays a crucial role in maintaining homeostasis during protein synthesis and degradation. Despite this, the effects of GEM expression levels on diffusivity remain largely uncharacterized in mammalian cells. To optimize the GEMs tracking and estimate GEMs-expression effects we constructed dox-inducible GEM expression system and compare with a previously reported constitutive expression system. The optimized level of GEMs expression increases the measured diffusivity from 0.29 ± 0.02 μm2/sec in GEMs-overexpressed cells to 0.35 ± 0.02 μm2/sec; improve homogeneity throughout the cell population; and facilitates particle tracking. We also improved the analyses of GEM diffusivity by applying effective diffusion coefficient while considering the type of motion and assessing the heterogeneity in the type of motion by calculating the standard deviations of particle displacements.Statement of significanceDescribing cytoplasmic properties, such as environmental viscosity and protein complex motion, is essential for understanding molecular-level changes in cell function and pathology. A recently developed approach uses self-assembling fluorescent protein probes, expressed in cells, to investigate cytoplasmic properties through single-particle tracking (SPT). One such system employs genetically encoded multimeric (GEM) nanoparticles— scaffold protein structures similar in size to ribosomes. This study addresses a key limitation in SPT of GEMs by examining how varying GEM expression levels affect measured diffusivity and tracking quality in mammalian cells. Our findings demonstrate that controlled GEM expression reduces particle overcrowding, increases measured diffusivity, and enhances track detection. This work contributes valuable insights into optimizing GEM nanoparticle applications for studying cytoplasmic viscosity and motion dynamics.
Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation
Authors: Kulkarni Hrishikesh S. , Tague Laneshia K. , Calabrese Daniel R. , Liao Fuyi , Liu Zhiyi , Garnica Lorena , Shankar Nishanth , Wu Xiaobo , Kulkarni Devesha H. , Bernardt Cory , Byers Derek , Chen Catherine , Huang Howard J. , Witt Chad A. , Hachem Ramsey R. , Kreisel Daniel , Atkinson John P. , Greenland John R. , Gelman Andrew E. 
Published: November 2024

ABSTRACTA greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation, is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSA). In a mouse orthotopic lung transplantation model, impaired recipient complement regulation resulted in more severe obstructive airway lesions when compared to wildtype controls, despite only moderate differences in graft-infiltrating effector T cells. Impaired complement regulation promoted the intragraft accumulation of memory B cells and antibody-secreting cells, resulting in increased DSA levels. In summary, genetic predisposition to complement activation is associated with B cell activation and worse CLAD-free survival.BRIEF SUMMARYLung transplant recipients genetically predisposed to impaired complement regulation demonstrate worse chronic rejection-free survival. This phenotype is associated with intragraft B cell-activation and donor-specific antibodies.
Mechanism of cooperative strigolactone perception by the MAX2 ubiquitin ligase–receptor–substrate complex
Authors: Vancea Alexandra I. , Huntington Brandon , Steinchen Wieland , Savva Christos , Shahul Hameed Umar F. , Arold Stefan T. 
Published: November 2024

ABSTRACTStrigolactones (SLs) are a group of plant hormones that regulate various aspects of plant growth and development. Additionally, SLs exuded into the soil promote symbiotic relationships with arbuscular mycorrhizal fungi and stimulate the germination of parasitic plants such asStriga hermonthica. The binding and hydrolysis of SLs by their receptors (D14 in Arabidopsis and HTL inStriga) promote the ubiquitination of transcriptional repressors by Skp1–cullin–F-box (SCF)–type E3 ubiquitin ligases. The mechanistic link between SL perception by D14/HTL and substrate recognition by the E3 remains unclear. We identified an E3–HTL–substrate complex that is sufficiently stable for cryogenic electron microscopy. This complex, composed of SKP1 (ASK1) and substrate (SMAX1) from Arabidopsis, and Striga F-box (MAX2) and SL receptor (HTL7), reveals that the substrate engages in a bidentate association through its N and D2 domains. This interaction, which is both conformationally and compositionally dynamic, directly and allosterically stabilises the MAX2–(SL)HTL7 complex and affects the positioning of ASK1 relative to MAX2. This dynamic positioning influences the proximity between the substrate D2 domain and the ubiquitin-conjugated E2 enzyme. This work advances our understanding of how E3 ligases in plants translate hormone perception into genetic adaptations.
Simultaneous loss of CAMK2A and CAMK2B reveals endogenous in vivo substrates
Authors: Rigter Pomme M.F. , Bezstarosti Karel , Koc Oguz Can , Perfitt Tyler L. , Demmers Jeroen A.A. , Colbran Roger J. , Stratton Margaret , Elgersma Ype , van Woerden Geeske M. 
Published: November 2024

AbstractCa2+/calmodulin-dependent protein kinase 2 (CAMK2) plays a critical role in calcium signaling. Recent gene knockout studies show that CAMK2A and CAMK2B can have distinct roles yet also partially compensate for each other in yet unknown brain functions. In order to provide insight into potential novel CAMK2 functions, we performed parallel phosphoproteomic analyses on non-stimulated cortex tissue from inducibleCamk2aandCamk2bdouble knockout (Camk2af/f;Camk2bf/f;CAG-CreESR) mice and from wild type mice. A total of 5622 phosphorylated peptides derived from 2080 proteins were identified. Phosphorylation at serine/threonine residues in 130 proteins were downregulated in the double knockout mice, including residues in 113 proteins that have not previously been identified as potential CAMK2 substrates. Comparison of amino acid sequences surrounding the downregulated phosphorylation residues provided new insights into the CAMK2-substrate consensus sequencesin vivo. This dataset provides an important resource for future studies examining novel roles for CAMK2 in the brain.
Time-Dependent Material Properties and Composition of the Nonhuman Primate Uterine Layers Through Gestation
Authors: Fodera Daniella M. , Xu Echo Z. , Duarte-Cordon Camilo A. , Wyss Michelle , Fang Shuyang , Chen Xiaowei , Oyen Michelle L. , Rosado-Mendez Ivan , Hall Timothy , Vink Joy Y. , Feltovich Helen , Myers Kristin M. 
Published: November 2024

ABSTRACTThe uterus is central to the establishment, maintenance, and delivery of a healthy pregnancy. Biomechanics is an important contributor to pregnancy success, and alterations to normal uterine biomechanical functions can contribute to an array of obstetric pathologies. Few studies have characterized the passive mechanical properties of the gravid human uterus, and ethical limitations have largely prevented the investigation of mid-gestation periods. To address this key knowledge gap, this study seeks to characterize the structural, compositional, and time-dependent micro-mechanical properties of the nonhuman primate (NHP) uterine layers in nonpregnancy and at three time-points in pregnancy: early 2nd, early 3rd, and late 3rdtrimesters. Distinct material and compositional properties were noted across the different tissue layers, with the endometrium-decidua being the least stiff, most viscous, least diffusible, and most hydrated layer of the NHP uterus. Pregnancy induced notable compositional and structural changes to the endometrium-decidua and myometrium, but no micro-mechanical property changes. Further comparison to published human data revealed notable similarities across species, with minor differences noted for the perimetrium and nonpregnant endometrium. This work provides insights into the material properties of the NHP uterus and demonstrates the validity of NHPs as a model for studying certain aspects of human uterine biomechanics.