bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive identification of coronary artery disease-associated variants regulating vascular smooth muscle cell gene expression
Authors: Barbera Nicolas , Wallace Lexi , Perry Noah , Lei Lily , den Ruijter Hester M , Civelek Mete 
Published: October 2024

AbstractCoronary artery disease (CAD) is a complex disorder with genetic and environmental influences. Genome-wide association studies (GWAS) have identified over 300 genomic loci associated with disease risk. However, identifying the functional variants within these loci has been limited in large part due to linkage disequilibrium. This represents a critical step in understanding the molecular mechanisms underlying disease risk. To identify and prioritize candidate causal CAD-associated variants, we performed lentivirus-based massively parallel reporter assays (lentiMPRAs) in primary vascular smooth muscle cells (SMCs), which play significant roles in atherosclerosis, the underlying cause of CAD. We tested 25892 CAD-associated variants for their allele-specific enhancer activity in quiescent and proliferative SMCs, modeling healthy and disease conditions. We identified 122 candidate variants showing significant enhancer activity and differences in reporter gene expression between risk and non-risk alleles. We also identified 23 variants showing condition-biased allelic imbalance and 41 variants showing sex-biased allelic imbalance. We further functionally characterized 25892 variants by performing CUT&RUN assays to identify variants in enhancer and promoter regions of SMCs. By integrating the results of these experiments, we identified a credible set of 49 CAD-associated variants in functionally relevant regions. Furthermore, by comparing these identified variants with our previously obtained expression quantitative trait loci (eQTL) data, 27 of these 49 variants were associated with SMC gene expression levels. Finally, we performed CRISPRi experiments on 8 variants comprising 9 variant-gene pairs, rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF), rs4627080 (NRIP3), to confirm their regulatory potential of nearby gene expression. Taken together, our results comprehensively fine-map the causal variants that confer increased risk of CAD through their effects on vascular smooth muscle cells.
Effect of Ventilator Mode on Ventilator-Free Days in Critically Ill Adults: A Randomized Trial
Authors: Seitz Kevin P. , Lloyd Bradley D. , Wang Li , Shotwell Matthew S. , Qian Edward T. , Muhs Amelia L. , Richardson Roger K. , Rooks J. Craig , Hennings-Williams Vanessa , Sandoval Claire E. , Richardson Whitney D. , Morgan Tracy L. , Thompson Amber N. , Hastings Pamela G. , Ring Terry P. , Stollings Joanna L. , Talbot Erica M. , Krasinski David J. , DeCoursey Bailey R. , Marvi Tanya K. , DeMasi Stephanie C. , Gibbs Kevin W. , Self Wesley H. , Mixon Amanda S. , Rice Todd W. , Semler Matthew W. , Casey Jonathan D. ,   the Pragmatic Critical Care Research Group
Published: October 2024

ABSTRACTRationaleFor critically ill adults receiving invasive mechanical ventilation, the ventilator mode determines how breaths are delivered. Whether the choice of ventilator mode affects outcomes for critically ill patients is unknown. To compare the effects of three common ventilator modes (volume control, pressure control, and adaptive pressure control) on death and duration of mechanical ventilation.MethodsWe conducted a pragmatic, cluster-randomized, crossover trial among adults receiving invasive mechanical ventilation in a medical ICU between November 1, 2022 and July 31, 2023. Each month, patients in the participating unit were assigned to receive volume control, pressure control, or adaptive pressure control during continuous mandatory ventilation. The primary outcome was ventilator-free days through 28 days.ResultsAmong 566 patients included in the primary analysis, the median number of ventilator-free days was 23 [IQR, 0-26] in the volume control group, 22 [0-26] in the pressure control group, and 24 [0-26] in the adaptive pressure control group (P=0.60). The median tidal volume was similar in the three groups, but the percentage of breaths larger than 8mL/kg of predicted body weight differed between volume control (median, 4.0%; IQR, 0.0-14.1), pressure control (10.6%; 0.0-31.5), and adaptive pressure control (4.7%; 0.0-19.2). Incidences of hypoxemia, acidemia, and barotrauma were similar in the three groups.ConclusionsAmong critically ill adults receiving invasive mechanical ventilation, the use of volume control, pressure control, or adaptive pressure control did not affect the number of ventilator-free days, however, confidence intervals included differences that may be clinically meaningful.
Analysis of Eligibility Criteria Clusters Based on Large Language Models for Clinical Trial Design
Authors: Bornet Alban , Khlebnikov Philipp , Meer Florian , Haas Quentin , Yazdani Anthony , Zhang Boya , Amini Poorya , Teodoro Douglas 
Published: October 2024

ABSTRACTObjectivesClinical trials (CTs) are essential for improving patient care by evaluating new treatments’ safety and efficacy. A key component in CT protocols is the study population defined by the eligibility criteria. This study aims to evaluate the effectiveness of large language models (LLMs) in encoding eligibility criterion information to support CT protocol design.Materials and MethodsWe extracted eligibility criterion sections, phases, conditions, and interventions from CT protocols available in theClinicalTrials.govregistry. Eligibility sections were split into individual rules using a criterion tokenizer and embedded using LLMs. The obtained representations were clustered. The quality and relevance of the clusters for protocol design was evaluated through 3 experiments: intrinsic alignment with protocol information and human expert cluster coherence assessment, extrinsic evaluation through CT-level classification tasks, and eligibility section generation.ResultsSentence embeddings fine-tuned using biomedical corpora produce clusters with the highest alignment to CT-level information. Human expert evaluation confirms that clusters are well-structured and coherent. Despite the high information compression, clusters retain significant CT information, up to 97% of the classification performance obtained with raw embeddings. Finally, eligibility sections automatically generated using clusters achieve 95% of the ROUGE scores obtained with a generative LLM.ConclusionsWe show that clusters derived from sentence-level LLM embeddings are effective in summarizing complex eligibility criterion data while retaining relevant CT protocol details. Clustering-based approaches provide a scalable enhancement in CT design that balances information compression with accuracy.
Characterization of cell states in biliary tract cancers identifies mechanisms of therapeutic resistance in a phase II trial of DKN-01/nivolumab
Authors: Park Ryan J , Parikh Milan , Pappas Leon , Sade-Feldman Moshe , Kulkarni Anupriya S. , Bi Lynn , LaSalle Thomas J. , Galway Aralee , Kuhlman Caroline , Blaszkowsky Lawrence S , Meyerhardt Jeffrey A. , Enzinger Peter C , Biller Leah , Allen Jill N , Kagey Michael H. , Baum Jason , Sirard Cynthia , Duda Dan G. , Zhu Andrew X. , Abrams Thomas A. , Hacohen Nir , Ting David T. , Mehta Arnav , Goyal Lipika 
Published: October 2024

AbstractBiliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.
Insulin moderates the effects of early life adversity on executive functioning in a sex-specific manner
Authors: Batra Aashita , Pokhvisneva Irina , Elgbeili Guillaume , Ruge Olivia , Fitzgerald Eamon , Patel Sachin , Czamara Darina , Meaney Michael J , Binder Elisabeth B. , Silveira Patricia P 
Published: October 2024

AbstractBackgroundEarly life adversity (ELA) is associated with altered insulin signaling and altered EF behaviors, in a potentially sex-specific manner. Considering the high co-morbidity between altered metabolism and executive function (EF) problems, we hypothesized that the genetic background associated with altered fasting insulin (FI) and EF could be sharedMethodsOur study used conjunctional false discovery rate (ConjFDR) to identify the shared genetic architecture between FI and two EFs: impulsivity and attention deficit-hyperactivity disorder (ADHD). We identified the polygenic risk score (PRS) threshold from a FI genome-wide association study (GWAS) that best predicted insulin levels in male and female ALSPAC children [Nmales=1,901, Nfemales=1,834; pt-intial-males= 0.05 (11,121 SNPs), pt-intial-females= 0.15 (27,202 SNPs)], further refining it to only include SNPs significantly associated with insulin levels in children [NSNP-males= 635 SNPs, NSNP-females= 1,449 SNPs]. A phenome-wide association study (PheWAS) was also run to identify EFs associated with the interaction between the refined PRS (rPRS) and early adversity. To investigate the presence of a direct causal relationship between FI and impulsivity in the presence of adversity, we applied mendelian randomization (MR)ResultsConjFDR suggested that environmental factors could be involved in the association between insulin and EFs, as there was no shared genetic background. PheWAS highlighted impulsivity and attention-related outcomes in interaction models between FI rPRS and early adversity. Finally, two-sample MR suggested a causal association between higher fasting insulin levels and impulsive behavior, specifically in females exposed to adversity (p < 0.001). Overall, a sex-specific impulsivity GWAS demonstrated thatMYT1LandTSSC1, genes that are associated with motor impulsivity, were enriched only in females.ConclusionsOur study solidifies the evidence that the relationship between high FI and EF is not direct, but rather interacting with ELA exposure, especially in females.Key pointsEarly life adversity is associated with alterations in insulin signaling and executive functioning behaviors.We report a causal association between high fasting insulin and increased impulsivity in females exposed to adversity.Our findings also support the idea that fasting insulin moderates the long-term effects of early life adversity on executive functions in females.This research provides insights into the mechanisms by which insulin moderates the effects of early life adversity on executive function disorders and informs the development of potential interventions.
Mechanisms of cortical microtubule organization in epidermal keratinocytes
Authors: Guo Keying , Merdes Andreas 
Published: October 2024

AbstractMicrotubules in many differentiated cell types are reorganized from a radial, centrosome-bound array into a cell type-specific, non-centrosomal network. In epidermal keratinocytes, cortical microtubules are organized from desmosomes (Lechler, T., and Fuchs, E. 2007. J. Cell Biol. 176:147-154). Details of this organization are poorly understood. We used immunofluorescence expansion microscopy to visualize directly the contact between cortical microtubules and desmosomes in murine skin tissue. Microtubule bound laterally to desmosomes, or with their ends at mixed polarity. Experiments including time-lapse microscopy of EB3-GFP, microtubule regrowth after depolymerization, and expression of ectopic ninein that was sequestered to the plasma membrane with a CAAX sequence motif, indicated that limited nucleation of microtubules can occur at the cortex, but mostly, cortical microtubules may accumulate by translocation from non-cortical sites and anchorage to desmosomes.
Two temperature-responsive RNAs act in concert: The small RNA CyaR and the mRNAompX
Authors: Guanzon David A. , Pienkoß Stephan , Brandenburg Vivian B. , Röder Jennifer , Dietze Alisa , Wimbert Andrea , Twittenhoff Christian , Narberhaus Franz 
Published: October 2024

ABSTRACTBacterial pathogens, such as inYersinia pseudotuberculosis, encounter temperature fluctuations during host infection and upon return to the environment. These temperature shifts impact RNA structures globally. While previous transcriptome-wide studies have focused on RNA thermometers in the 5’-untranslated region of virulence-related mRNAs, our investigation revealed temperature-driven structural rearrangements in the small RNA (sRNA) CyaR. At 25°C, CyaR primarily adopts a conformation that occludes its seed region, but transitions to a liberated state at 37°C. By RNA-sequencing and in-line probing experiments, we identified the Shine-Dalgarno sequence ofompXas a direct target of CyaR. Interestingly, theompXtranscript itself exhibits RNA thermometer-like properties, facilitating CyaR base pairing at elevated temperatures. This interaction impedes ribosome binding toompXand accelerates degradation of theompXtranscript. Furthermore, we observed induced proteolytic turnover of the OmpX protein at higher temperatures. Collectively, our study uncovered multi-layered posttranscriptional mechanisms governingompXexpression, resulting in lower OmpX levels at 37°C compared to 25°C. We propose that CyaR remains mostly passive at 25°C but becomes primed to repressompXat 37°C, thereby expediting outer membrane remodelling in anticipation of pathogenesis.
Leveraging HILIC/ERLIC Separations for Online Nanoscale LC-MS/MS Analysis of Phosphopeptide Isoforms from RNA Polymerase II C-terminal Domain
Authors: Ficarro Scott B. , Kothiwal Deepash , Bae Hyun Jin , Tavares Isidoro , Giordano Gabriela , Buratowski Stephen , Marto Jarrod A. 
Published: October 2024

ABSTRACTThe eukaryotic RNA polymerase II (Pol II) multi-protein complex transcribes mRNA and coordinates several steps of co-transcriptional mRNA processing and chromatin modification. The largest Pol II subunit, Rpb1, has a C-terminal domain (CTD) comprising dozens of repeated heptad sequences (Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7), each containing five phospho-accepting amino acids. The CTD heptads are dynamically phosphorylated, creating specific patterns correlated with steps of transcription initiation, elongation, and termination. This CTD phosphorylation ‘code’ choreographs dynamic recruitment of important co-regulatory proteins during gene transcription. Genetic tools were used to engineer protease cleavage sites across the CTD (msCTD), creating tryptic peptides with unique sequences amenable to mass spectrometry analysis. However, phosphorylation isoforms within each msCTD sequence are difficult to resolve by standard reversed phase chromatography typically used for LC-MS/MS applications. Here, we use a panel of synthetic CTD phosphopeptides to explore the potential of hydrophilic interaction and electrostatic repulsion hydrophilic interaction (HILIC and ERLIC) chromatography as alternatives to reversed phase separation for CTD phosphopeptide analysis. Our results demonstrate that ERLIC provides improved performance for separation of singly- and doubly-phosphorylated CTD peptides for sequence analysis by LC-MS/MS. Analysis of native yeast msCTD confirms that phosphorylation on Ser5 and Ser2 represents the major endogenous phosphoisoforms. We expect this methodology will be especially useful in the investigation of pathways where multiple protein phosphorylation events converge in close proximity.
Motifs of human hippocampal and cortical high frequency oscillations structure processing and memory of naturalistic stimuli
Authors: Mishra Akash , Tostaeva Gelana , Nentwich Maximilian , Espinal Elizabeth , Markowitz Noah , Winfield Jalen , Freund Elizabeth , Gherman Sabina , Mehta Ashesh D. , Bickel Stephan 
Published: October 2024

AbstractThe discrete events of our narrative experience are organized by the neural substrate that underlies episodic memory. This narrative process is segmented into discrete units by event boundaries. This permits a replay process that acts to consolidate each event into a narrative memory. High frequency oscillations (HFOs) are a potential mechanism for synchronizing neural activity during these processes. Here, we use intracranial recordings from participants viewing and freely recalling a naturalistic stimulus. We show that hippocampal HFOs increase following event boundaries and that coincident hippocampal-cortical HFOs (co-HFOs) occur in cortical regions previously shown to underlie event segmentation (inferior parietal, precuneus, lateral occipital, inferior frontal cortices). We also show that event-specific patterns of co-HFOs that occur during event viewing re-occur following the subsequent three event boundaries (in decaying fashion) and also during recall. This is consistent with models that support replay as a mechanism for memory consolidation. Hence, HFOs may coordinate activity across brain regions serving widespread event segmentation, encode naturalistic memory, and bind representations to assemble memory of a coherent, continuous experience.
Spectroscopic study of
Mo97, Mo99
, and
Mo101
Authors: Kumar V. , Chapman R. , Ollier J. , Orlandi R. , Smith J. F. , Spohr K.-M. , Torres D. A. , Wady P. , Tandel S. K. , Shukla A. , Freeman S. J. , de Angelis G. , Valiente-Dobón J. J. , Aydin S. , Farnea E. , Mărginean R. , Mengoni D. , Kröll T. 
Published: October 2024

Excited states of the molybdenum isotopes Mo4297,99,101 have been populated in two experiments which used fusion-fission and binary grazing reactions to populate yrast states of the nuclei of interest. In the first experiment, the GASP array of escape-suppressed Ge detectors was used to detect γ rays from fusion-fission products initiated by the interaction of a 230-MeV beam of S36 ions with a thick target of Yb176. In the multinucleon transfer experiment, a 530-MeV beam of Zr96 ions was incident on a thin Sn124 target; projectile-like ejectiles were detected and identified using the PRISMA magnetic spectrometer and their associated γ rays were detected using the CLARA array of escape-suppressed Ge detectors. In Mo99, the previously known positive-parity νd5/2 decay sequence was extended to spin (25/2+) while, in Mo101, a similar, but hitherto unobserved νg7/2 positive-parity decay sequence was established to spin (27/2+). In Mo99 and in Mo101, previously observed νh11/2 negative-parity decay sequences were also observed to spin 27/2−. Although the observed decay sequences in Mo97 have not been extended beyond the results of earlier work, a disagreement in the published level structure of the h11/2 band has been resolved. The observed positive-parity decay sequences have been compared with the results of state-of-the-art shell-model calculations; the general features of the energy spectrum of excited states of Mo97, Mo99, and Mo101 are reproduced, but not in detail. The experimental energies of the negative-parity states of Mo99 and Mo101 are reasonably well reproduced in particle-rotor (PRM) calculations. For Mo97, better agreement with the high-spin states was obtained when the core in the PRM calculations was treated in a variable moment of inertia approach. For the νh11/2 negative-parity decay sequences of the three isotopes studied here, model-dependent evidence is presented for nuclear shape changes with increasing neutron number.

Published by the American Physical Society
2024
Impact of gauge fixing precision on the continuum limit of nonlocal quark-bilinear lattice operators
Authors: Zhang Kuan , Huo Yi-Kai , Ji Xiangdong , Schäfer Andreas , Shi Chun-Jiang , Sun Peng , Wang Wei , Yang Yi-Bo , Zhang Jian-Hui ,   Lattice Parton Collaboration
Published: October 2024

We analyze the gauge fixing precision dependence of some nonlocal quark-bilinear lattice operators interesting in computing parton physics for several measurements, using five lattice spacings ranging from 0.032 to 0.121 fm. Our results show that gauge-dependent nonlocal measurements are significantly more sensitive to the precision of gauge fixing than anticipated. The impact of imprecise gauge fixing is significant for fine lattices and long distances. For instance, even with the typically defined precision of Landau gauge fixing of 10−8, the deviation caused by imprecise gauge fixing can reach 12%, when calculating the trace of Wilson lines at 1.2 fm with a lattice spacing of approximately 0.03 fm. Similar behavior has been observed in ξ gauge and Coulomb gauge as well. For both quasi-parton-distribution functions (quasi-PDFs) and quasi-transverse-momentum-dependent PDFs operators renormalized using the regularization independent momentum subtraction (RI/MOM) scheme, convergence for different lattice spacings at long distance is only observed when the precision of Landau gauge fixing is sufficiently high. To describe these findings quantitatively, we propose an empirical formula to estimate the required precision.

Published by the American Physical Society
2024
X-ray crystal structure of proliferating cell nuclear antigen 1 from Aeropyrum pernix
Authors: Yamauchi Takahiro , Kikuchi Makiko , Iizuka Yasuhito , Tsunoda Masaru 
Published: October 2024

Proliferating cell nuclear antigen (PCNA) plays a critical role in DNA replication by enhancing the activity of various proteins involved in replication. In this study, the crystal structure of ApePCNA1, one of three PCNAs from the thermophilic archaeon Aeropyrum pernix, was elucidated. ApePCNA1 was cloned and expressed in Escherichia coli and the protein was purified and crystallized. The resulting crystal structure determined at 2.00 Å resolution revealed that ApePCNA1 does not form a trimeric ring, unlike PCNAs from other domains of life. It has unique structural features, including a long interdomain-connecting loop and a PIP-box-like sequence at the N-terminus, indicating potential interactions with other proteins. These findings provide insights into the functional mechanisms of PCNAs in archaea and their evolutionary conservation across different domains of life. A modified medium and protocol were used to express recombinant protein containing the lac operon. The expression of the target protein increased and the total incubation time decreased when using this system compared with those of previous expression protocols.