bluuebunny/crossref_metadata_2025_split huggingface dataset:
Operating on the Oldest-Old: Vaginal Prolapse Surgery Outcomes in Women Over 90
Authors: Zuo Stephanie W. , Warner Kristina , Zyczynski Halina , Ackenbom Mary F. 
Published: January 2025

Importance
Women aged 90 years and older (“oldest-old”) represent a small but growing population who may experience bothersome pelvic organ prolapse and opt for surgical repair.

Objective
This study aimed to compare perioperative adverse events (AEs) within 8 weeks of prolapse surgery between women ≥90 years and younger patients.

Study Design
We performed a secondary analysis of a dual-center retrospective cohort study of women ≥61 years old undergoing major prolapse surgery from January 2016 to May 2023. We identified all women ≥90 years and matched them to women <90 years in a 1:4 fashion based on Charlson Comorbidity Index score and surgery type. Matching was performed without replacement. The primary outcome was a composite AE outcome, defined as all intraoperative and postoperative complications within 8 weeks of surgery.

Results
There were 24 oldest-old undergoing prolapse surgery who were matched to 96 women with mean ± standard deviation age of 77.2 ± 5.7 years. Women ≥90 years were more likely to have a lower body mass index (P < 0.01), greater preoperative prolapse stage (P = 0.049), and were less likely to have general anesthesia (P < 0.01). Patients did not differ in medical comorbidities, frailty status, concomitant hysterectomy or incontinence procedure, or length of postoperative stay. The oldest-old did not experience any intraoperative complications and had low rates of readmission (8.3%) and discharge to skilled nursing facilities (4.2%). Age ≥90 was not associated with composite AEs on multivariable analysis (adjusted odds ratio 1.60, 95% confidence interval [0.39–6.55]).

Conclusions
Age ≥90 years does not appear to increase the risk of perioperative AEs in women with similar comorbidities.
Integrated Multi-Omics Analyses of Synaptosomes Revealed Synapse-Centered Novel Targets in Alzheimer’s Disease
Authors: Kumar Subodh , Ramos Enrique , Hidalgo Axel , Rodarte Daniela , Sharma Bhupender , Torres Melissa M. , Devara Davin , Gadad Shrikanth S. 
Published: January 2025

AbstractSynapse dysfunction is an early event in Alzheimer’s disease (AD) caused by various factors such as Amyloid beta, p-tau, inflammation, and aging. However, the exact molecular mechanism of synapse dysfunction in AD is largely unknown. To understand this, we comprehensively analyzed the synaptosome fraction in postmortem brain samples from AD patients and cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes in microRNA (miRNA) and mRNA levels in synaptosomes extracted from the brains of both unaffected individuals and those with Alzheimer’s disease (AD). Additionally, we performed mass spectrometry analysis of synaptosomal proteins in the same sample group. These analyses revealed significant differences in the levels of miRNAs, mRNAs, and proteins between the groups. To further understand the pathways or molecules involved, we used an integrated omics approach and studied the molecular interactions of deregulated synapse miRNAs, mRNAs, and proteins in the samples from individuals with AD and the control group, which demonstrated the impact of deregulated miRNAs on their target mRNAs and proteins. Furthermore, the DIABLO analysis highlighted complex relationships between mRNAs, miRNAs, and proteins that could be key in understanding the pathophysiology of AD. Our study identified synapse-centered novel candidates that could be critical in restoring synapse dysfunction in AD.
Neuronal cell adhesion molecule (NRCAM) variant defined by microexon skipping is an essential, antigenically distinct, and targetable proteoform in high-grade glioma
Authors: Sehgal Priyanka , Naqvi Ammar S. , Higgins Makenna , Liu Jiageng , Harvey Kyra , Jarroux Julien , Kim Taewoo , Mankaliye Berk , Mishra Pamela , Watterson Grace , Fine Justyn , Davis Jacinta , Hayer Katharina E. , Castro Annette , Mogbo Adanna , Drummer Charles , Martinez Daniel , Koptyra Mateusz P. , Ang Zhiwei , Wang Kai , Farrel Alvin , Quesnel-Vallieres Mathieu , Barash Yoseph , Spangler Jamie B. , Rokita Jo Lynne , Resnick Adam C. , Tilgner Hagen U. , DeRaedt Thomas , Powell Daniel J , Thomas-Tikhonenko Andrei 
Published: January 2025

AbstractTo overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30 nucleotide-long microexons. Several of these skipped microexons mapped to L1-IgCAM family members, such asNRCAM. Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping ofNRCAMmicroexons 5 and 19 in virtually every pHGG sample. Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that “painting” of pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.Statement of significanceExisting targets for chimeric antigen receptors (CAR)-armed T cells are often shared by CNS tumors and normal tissues, creating the potential for on-target/off-tumor toxicities. Here we demonstrate that in CNS tumors of glial origin, cell adhesion molecules have alternatively spliced proteoforms, which could be targeted by highly selective therapeutic antibodies.
Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging
Authors: Runyan Constance E. , Luo Lucy , Welch Lynn C. , Lu Ziyan , Chen Fei , Schleck Maxwell J. , Nafikova Radmila A. , Grant Rogan A. , Aillon Raul Piseaux , Senkow Karolina J. , Bunyan Elsie G. , Plodzeen William T. , Abdala-Valencia Hiam , Weiss Craig , Dada Laura A. , Thorp Edward B. , Sznajder Jacob I. , Chandel Navdeep S. , Misharin Alexander V. , Budinger G.R. Scott 
Published: January 2025

AbstractSarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.
Spatiotemporal temperature control by holographic heating microscopy unveils cellular thermosensitive calcium signaling
Authors: Oyama Kotaro , Ishii Ayumi , Matsumura Shuhei , Oyama Tomoko Gowa , Taguchi Mitsumasa , Suzuki Madoka 
Published: January 2025

AbstractOptical microheating technologies have revealed how biological systems sense heating and cooling at the microscopic scale. Sensing is based on thermosensitive biochemical reactions that frequently engage membrane proteins, Ca2+channels, and pumps to convert sensing information as the Ca2+signaling in cells. These findings highlight the feasibility of thermally manipulating intracellular Ca2+signaling. However, how the thermosensitive Ca2+signaling would behave, particularly in multicellular systems, remains elusive. In this study, to extend the ability of the spatiotemporal temperature control by optical microheating technologies, we propose holographic heating microscopy. Water-absorbable infrared (IR) laser light is modulated by a reflective liquid crystal on a silicon spatial light modulator (LCOS-SLM). A computer-generated hologram displayed on the LCOS-SLM modulates the spatial phase pattern of the IR laser light to generate predesigned temperature gradients at the microscope focal plane. The holographic heating microscopy visualizes how thermosensitive Ca2+signaling is generated and propagated in MDCK cells, rat hippocampal neurons, and rat neonatal cardiomyocytes. Moreover, the optical control of the temporal temperature gradient reveals the cooling-rate dependency of Ca2+signaling in HeLa cells. These findings demonstrate the extended ability of holographic heating microscopy in investigating cellular thermosensitivities and thermally manipulating cellular functions.
Signed motif analysis of theCaenorhabditis elegansneuronal network reveals positive feedforward and negative feedback loops
Authors: Szilagyi Gabor S. , Gulyas Attila , Vassy Zsolt , Csermely Peter , Fenyves Bank G. 
Published: January 2025

AbstractNervous systems are complex biological networks with largely unknown structural and functional characteristics. Motif analysis is a robust tool that can reveal unique aspects of connectivity of a complex network. An ideal candidate for motif analysis is the connectome of the nematodeCaenorhabditis eleganswhich is the only fully reconstructed nervous system. Utilizing recent data on the connection signs of this network and a novel structure-preserving randomization method, we performed signed motif analysis on theC. elegansconnectome for the first time, to our knowledge. We identified 56 significantly over- and 1 underrepresented three-node signed motifs and revealed that certain motifs (e.g. positive feedforward, negative feedback, disinhibitory feedback, and incoherent feedforward loops) are overabundant in theC. elegansconnectome. We further distinguished (coloured) nodes by corresponding neuron modalities (e.g. sensory vs. motor neurons) and found that there is characteristic neuronal layout for each significant feedforward and feedback loop. Our findings demonstrate the importance and potential of signed motif analysis in understanding biological networks. Our motif enumerating tool and definition system can be utilized in signed motif analysis of other complex networks.
A proteo-transcriptomic investigation of toxin evolution in planarians and their role in flatworm terrestrialization
Authors: García-Vernet Raquel , Benítez-Álvarez Lisandra , Palma-Guerrero Javier , Chiva Cristina , Eleftheriadi Klara , Rojo Iñaki , Sabidó Eduard , Fernández Rosa 
Published: January 2025

AbstractThe transition from aquatic to terrestrial environments represents a major evolutionary transition in animals, requiring significant adaptations in physiology and defense mechanisms to the challenges presented by the harsh terrestrial environment. Platyhelminthes, which include both aquatic and terrestrial species with a single terrestrialization event in the family Geoplaniidae, serve as excellent model organisms for studying the evolutionary adaptations required for terrestrialization. This study investigates the evolutionary dynamics of toxin orthologous groups (as a proxy to gene families) in aquatic and terrestrial flatworms, together with mucus composition, focusing on their role in terrestrialization from a molecular ecology perspective. Using a proteo-transcriptomic approach, we predicted and identified a broader toxin gene repertoire in terrestrial flatworms compared to freshwater ones. Although most toxins in flatworms arose before terrestrial planarian diversification—gaining a novel evolutionary origin at the Tricladida and Continenticola nodes—the mucus protein repertoire appears to have a far older evolutionary origin in both species. Moreover, distinct orthologous groups underpin the toxin gene repertoire and mucus composition in each lineage, highlighting the contrasting evolutionary trajectories of these two functional components. While toxin families in both aquatic and terrestrial flatworms revealed overall common functions, including cytokine modulation and ion channel regulation, terrestrial flatworms exhibited specific expansions of lectin-like proteins and pro-inflammatory responses, highlighting their potential key role to respond to land-based threats. This study provides new insights into the differential evolutionary trajectories of toxin and mucus proteins in planarians, offering a deeper understanding of the genetic innovations that facilitated flatworm terrestrialization.
The Role of Genetic Variation in Shaping Phenotypic Responses to Diet in AgingDrosophila melanogaster
Authors: Bak Nikolaj Klausholt , Mackay Trudy F. C. , Morgante Fabio , Nielsen Kåre Lehmann , Nielsen Jeppe Lund , Kristensen Torsten Nygaard , Rohde Palle Duun 
Published: January 2025

AbstractNutrition plays a central role in healthy living, however, extensive variability in individual responses to dietary interventions complicates our understanding of its effects. Here we present a comprehensive study utilizing theDrosophilaGenetic Reference Panel (DGRP), investigating how genetic variation influences responses to diet and aging. Quantitative genetic analyses of the impact of dietary restriction on lifespan, locomotor activity, dry weight, and heat knockdown time were performed. Locomotor activity, dry weight and heat knockdown time were measured on the same individual flies. We found significant genotype-by-diet interaction (GDI) and genotype-by-age interaction (GAI) for all traits. Therefore, environmental factors play a crucial role in shaping trait variation at different ages and diets, and/or distinct genetic variation influences these traits at different ages and diets. Our genome wide association study also identified a quantitative trait locus for age-dependent dietary response. The observed GDI and GAI indicates that susceptibility to environmental influences changes as organisms age, which could have significant implications for dietary recommendations and interventions aimed at promoting healthy aging in humans. The identification of associations between DNA sequence variation and age-dependent dietary responses opens new avenues for research into the genetic mechanisms underlying these interactions.
Microscopy Nodes: versatile 3D microscopy visualization with Blender
Authors: Gros Oane , Bhickta Chandni , Lokaj Granita , Schwab Yannick , Köhler Simone , Banterle Niccolò 
Published: January 2025

AbstractEffective visualization of 3D microscopy data is essential for communicating biological results. While scientific 3D rendering software is specifically designed for this purpose, it often lacks the flexibility found in non-scientific software like Blender, which is a free and open-source 3D graphics platform. However, loading microscopy data in Blender is not trivial. To bridge this gap, we introduce Microscopy Nodes, an extension for Blender that enables the seamless integration of large microscopy data. Microscopy Nodes provides efficient loading and visualization of up to 5D microscopy data from Tif and OME-Zarr files. Microscopy Nodes supports various visualization modes including volumetric, isosurface, and label-mask representations, and offers additional tools for slicing, annotation, and dynamic adjustments. By leveraging Blender’s advanced rendering capabilities, users can create high-quality visualizations that accommodate both light and electron microscopy. Microscopy Nodes makes powerful, clear data visualization available to all researchers, regardless of their computational experience, and is available through the Blender extensions platform with comprehensive tutorials.
Precision mRNA Nanomedicine for Targeted Vascular Therapies in ARDS and Atherosclerosis
Authors: Zhou Zhengjie , Zhu Jiayu , Yeh Chih-Fan , Meliton Angelo , Wu David , Huang Ru-Ting , Shentu Tzu-Pin , Ray Aleepta Guha , Wiseman Destini , Budina Erica , Alpar Aaron , Yang Kai-Chien , Hubbell Jeffrey A , Weinstock Ada , Mutlu Gokhan M , Tirrell Matthew V , Fang Yun 
Published: January 2025

AbstractVascular diseases, including acute respiratory distress syndrome (ARDS) and atherosclerosis, are leading causes of global morbidity and mortality, underscoring the critical need for innovative therapies. While human genetics has uncovered specific molecular mechanisms in endothelial cells that drive acute and chronic vascular inflammation central to these conditions, effectivein vivostrategies to spatiotemporally target these disease-causing pathways using therapeutic mRNAs remain limited. Here, we present a modular and tunable nanoparticle platform (PROGRAMMED nanoparticles) engineered to selectively deliver therapeutic mRNAs to target cells with distinct molecular signatures, such as inflamed endothelial cells expressing vascular cell adhesion molecule 1 (VCAM1). This approach restores key genetics-informed endothelial pathways implicated in disease, including the loss of Krüppel-like factor 2 (KLF2) in acute inflammation underlying ARDS and the suppression of phospholipid phosphatase 3 (PLPP3) in chronic inflammation driving atherosclerosis. In multiple preclinical models, these precision mRNA nanomedicine strategies demonstrated compelling therapeutic efficacy. VCAM1-targeting PROGRAMMED nanoparticles delivering KLF2 mRNA to inflamed lung microvascular endothelial cells significantly improved microvascular health and alleviated virus-induced ARDS. Similarly, PLPP3 mRNA delivery by VCAM1-targeting PROGRAMMED nanoparticles attenuated arterial inflammation, slowed atherosclerosis progression, and promoted regression of advanced plaques. This innovative platform offers a transformative approach for spatiotemporal mRNA therapies targeting inflamed endothelial cells, providing a minimally invasive and highly specific strategy to address acute and chronic vascular diseases. Moreover, the modularity of PROGRAMMED nanoparticles, particularly their ability to display diverse targeting motifs, holds substantial potential for addressing a broad spectrum of vascular complications and other diseases that require precise spatiotemporal correction of dysregulated genes.
Effector-triggered processing body formation attenuates host translation via ER stress responses and autophagy upon bacterial infection
Authors: González-Fuente Manuel , Schulz Nico , Abdrakhmanov Alibek , Izzati Gaiea , Zhu Shanshuo , Langin Gautier , Gouguet Paul , Franz-Wachtel Mirita , Macek Boris , Hafrén Anders , Dagdas Yasin , Üstün Suayib 
Published: January 2025

AbstractCompartmentalization of transcripts in biomolecular condensates allows rapid and cost-efficient responses to environmental stimuli. Processing bodies (P-bodies) are dynamic ribonucleoprotein condensates formed by phase separation in the cytosol. P-bodies are involved in translational arrest and mRNA decay and regulate several developmental processes and stress responses. Pathogens have evolved strategies to exploit host degradation pathways for their own benefit, however little is known about how they impact translation. Here we show that upon infection with pathogenic bacteriaPseudomonas syringaepathovartomato(Pst), P-body assembly is enhanced in an effector-dependent manner. Moreover, a P-body-defective mutant is more tolerant to bacterial infection due to altered endoplasmic reticulum (ER) stress responses, suggesting a role of P-bodies as novel susceptibility hubs.Pstinfection is accompanied by a general host translation attenuation, which is both effector-dependent, and deregulated in the P-body-defective mutant. This indicates that P-bodies are required for the bacterial modulation of the plant translation, probably to hinder the defense responses. Additionally, host autophagy is also exploited by the bacteria to modulate P-body dynamics and its subsequent translation attenuation, revealing a complex interplay between P-body formation and disassembly during infection. Altogether, our discoveries provide novel insights on how host translation is targeted by bacteria via effector-triggered P-body formation to promote disease and uncover unknown connections between ER stress responses and autophagy with P-body dynamics.
Improved Functional Classification of Hydrolases through Pairwise Structural Similarity of Reaction Cores
Authors: Ferdous Sakib , Gupta Priyanshu , Teoh Yee Chuen , Sajeevan Karuna Anna , Vaishnavey SR , Hainlin Kaelie , Reuel Nigel , Qamhiyah Abir , Aluru Narayana R. , Kumar Manish , Chowdhury Ratul 
Published: January 2025

AbstractWe report a systematic pipeline is for extracting the catalytically relevant reactive site in addition to the surrounding allosterically linked residue shells around the reaction site of the most diverse enzyme class - hydrolases, with known experimental structures. We first successfully extract 40196 such hydrolase reaction cores (RC) and collates them into a publicly accessible reaction core collection (RC-Hydrolase). We perform 128M pairwise shape comparison across RC-Hydrolase using a three-dimensional search engine and present 155,329 pair instances clustering them by 60% or higher similarities in a publicly available, visually interactive dataset. Robustness of defined RCs is shown to successfully capture experimentally known function-enhancing mutations distal to the active site in PETases. Allowing comparisons of enzyme reaction centers across functional spaces (ligands bound, EC classification numbers, and expression hosts) enables identification of enzyme backbones which can be minimally mutated to accommodate more than one type of catalytic activity thereby aiding rational design of multifunctional enzymes. We also demonstrate how such versatile enzyme backbones could be leveraged by the latest diffusion-based protein design models to design bespoke libraries of small molecule inhibitors, and structurally stable multifunctional enzyme pockets. With only sporadic successes in multifunctional enzyme design thus far, we provide strong structural priors for machine-learning-guided advanced enzyme engineering in the future.