bluuebunny/crossref_metadata_2025_split huggingface dataset:
Target cell adhesion limits macrophage phagocytosis and promotes trogocytosis
Authors: Rollins Kirstin , Fiaz Sareen , Morrissey Meghan 
Published: February 2025

AbstractMacrophage phagocytosis is an essential immune response that eliminates pathogens, antibody-opsonized cancer cells and debris. Macrophages can also trogocytose, or nibble, targets. Trogocytosis and phagocytosis are often activated by the same signal, including IgG antibodies. What makes a macrophage trogocytose instead of phagocytose is not clear. Using both CD47 antibodies and a Her2 Chimeric Antigen Receptor (CAR) to induce phagocytosis, we found that macrophages preferentially trogocytose adherent target cells instead of phagocytose in both 2D cell monolayers and 3D cancer spheroid models. Disrupting target cell integrin using an RGD peptide or through CRISPR-Cas9 knockout of the αV integrin subunit in target cells increased macrophage phagocytosis. Conversely, increasing cell adhesion by ectopically expressing E-Cadherin in Raji B cell targets reduced phagocytosis. Finally, we examined phagocytosis of mitotic cells, a naturally occurring example of cells with reduced adhesion. Arresting target cells in mitosis significantly increased phagocytosis. Together, our data show that target cell adhesion limits phagocytosis and promotes trogocytosis.
Super-resolution compatible DNA labeling technique reveals chromatin mobility and organization changes during differentiation
Authors: Pabba Maruthi K. , Kuba Miroslav , Kraus Tomáš , Celikay Kerem , Meyer Janis , Pradhan Sunik Kumar , Maiser Andreas , Harz Hartmann , Leonhardt Heinrich , Rohr Karl , Hocek Michal , Cardoso M. Cristina 
Published: February 2025

ABSTRACTChromatin dynamics play a crucial role in cellular differentiation, yet tools for studying global chromatin mobility in living cells remain limited. Here, we developed a novel probe for the metabolic labeling of chromatin and tracking its mobility during neural differentiation. The labeling system utilizes a newly developed silicon rhodamine-conjugated deoxycytidine triphosphate (dCSiRTP). We show that this dCTP is efficiently delivered into living human induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) via a synthetic transporter (SNTT1). Using correlative confocal microscopy and stimulated emission depletion (STED) super-resolution microscopy, we quantified the sizes of labeled chromatin domains. Time lapse super-resolution microscopy combined with single particle tracking revealed that chromatin mobility decreases during the transition from iPSCs (pluripotent state) to NSCs and neurons (differentiated state). This reduction in mobility correlates with the differentiation state, suggesting a role for chromatin dynamics in cellular plasticity. Concomitant mechanistic insights obtained from MNase digestion assays, chromatin compaction and histone modification analyses revealed a decrease in chromatin accessibility during neuronal differentiation, indicating that chromatin adopts a more constrained and compacted structure. These findings provide new insights into chromatin regulation during neurogenesis.
AI-assisted protein design to rapidly convert antibody sequences to intrabodies targeting diverse peptides and histone modifications
Authors: Galindo Gabriel , Maejima Daiki , DeRoo Jacob , Burlingham Scott R. , Fixen Gretchen , Morisaki Tatsuya , Febvre Hallie P. , Hasbrook Ryan , Zhao Ning , Ghosh Soham , Mayton E. Handly , Snow Christopher D. , Geiss Brian J. , Ohkawa Yasuyuki , Sato Yuko , Kimura Hiroshi , Stasevich Timothy J. 
Published: February 2025

ABSTRACTIntrabodies are engineered antibodies that function inside living cells, enabling therapeutic, diagnostic, and imaging applications. While powerful, their development has been hindered by challenges associated with their folding, solubility, and stability in the reduced intracellular environment. Here, we present an AI-driven pipeline integrating AlphaFold2, ProteinMPNN, and live-cell screening to optimize antibody framework regions while preserving epitope-binding complementarity-determining regions. Using this approach, we successfully converted 19 out of 26 antibody sequences into functional single-chain variable fragment (scFv) intrabodies, including a panel targeting diverse histone modifications for real-time imaging of chromatin dynamics and gene regulation. Notably, 18 of these 19 sequences had failed to convert using the standard approach, demonstrating the unique effectiveness of our method. As antibody sequence databases expand, our method will accelerate intrabody design, making their development easier, more cost-effective, and broadly accessible for biological research.
Trymethylamine-N-oxide, a gut-derived metabolite, induces myofibroblastic activation of valvular interstitial cells through endoplasmic reticulum stress
Authors: Sudi Samanvitha , Suresh Sai Drishya , Kolli Tanmayee , Porras Ana Maria 
Published: February 2025

ABSTRACTCalcific aortic valve disease currently lacks effective treatments beyond surgical valve replacement, due to an incomplete understanding of its pathogenesis. Emerging evidence suggests that the gut microbiome influences cardiovascular health through the production of metabolites derived from dietary components. Among them, trimethylamine-N-oxide (TMAO) has been identified as a potential causal factor for several cardiovascular conditions. However, its role in the development of aortic valve disease remains poorly understood. This study sought to investigate the impact of TMAO on valvular interstitial cells (VICs), the most abundant cell type in the aortic valve. Here, we demonstrate that TMAO activates VICs towards a myofibroblastic profibrotic phenotype. Using anin vitroprotocol to generate quiescent VICs, we found that TMAO induces the upregulation of myofibroblastic markers in a sex-independent manner. These quiescent VICs were more sensitive to TMAO than conventionally cultured VICs. Treatment with TMAO also elevated extracellular matrix production and oxidative stress, phenotypic hallmarks of an activated profibrotic state. Finally, inhibition of the endoplasmic reticulum stress kinase prior to TMAO treatment blocked all effects of this metabolite. These findings suggest that TMAO contributes to the early stages of valve disease by promoting VIC activation through endoplasmic reticulum stress mechanisms. Understanding the role of TMAO and other gut-derived metabolites in the pathogenesis of valve disease could inform the development of novel preventive or therapeutic strategies to modify or delay disease progression. Furthermore, these insights underscore the importance of host-microbiome interactions and highlight the potential for targeted dietary interventions to mitigate cardiovascular disease risk.
A Retrospective Efficacy and Safety Study of Pembrolizumab/ Cetuximab Neoadjuvant Therapy in Locally Advanced Hypopharyngeal Cancer
Authors: Yao Guangnan , Wu Xiaobo , Lin Hanqing , Chen Zhihong , Lin Chang , Lin Gongbiao 
Published: February 2025

AbstractBackgroundThe primary objective of this study was to retrospectively assess the efficacy and safety profiles of two neoadjuvant regimens combining either pembrolizumab or cetuximab with paclitaxel and cisplatin in patients with locally advanced hypopharyngeal cancer (LAHPC).MethodsLAHPC patients who received surgical resection at our hospital between August 2022 and February 2024 were enrolled in the study. All patients received neoadjuvant treatment before surgery and postoperative adjuvant therapy. They were categorized into two groups based on the neoadjuvant regimen: the paclitaxel + cisplatin + pembrolizumab (TP + PEMBRO) group and the paclitaxel + cisplatin + cetuximab (TP + CETUX) group. We evaluated various parameters including treatment response rate, adverse effects, surgical modalities, and survival outcomes for both groups.ResultsA total of 32 LAHPC patients were enrolled into the study, with 16 patients in each group. The TP + PEMBRO group demonstrated a significantly superior objective response rate (ORR) of neoadjuvant treatment compared to the TP + CETUX group (87.5% vs 68.75%, P < 0.05). In terms of surgical procedures, the TP + PEMBRO group exhibited a higher proportion of minimally invasive surgeries (87.5% vs 56.25%, P < 0.05), and both the tracheotomy rate and indwelling gastric tube rate were relatively lower in this group. Regarding patient prognosis, the 1-year overall survival (OS) rate in the TP + PEMBRO group was 100%, and the 1-year relapse-free survival (RFS) rate was 92.31%. In contrast, the TP + CETUX group had a 1-year OS rate of 93.75% and a 1-year RFS rate of 81.25%. There was no significant disparity in adverse events between the two groups, and no grade 3 - 4 severe adverse events occurred.ConclusionThe neoadjuvant TP regimen integrating pembrolizumab or cetuximab was associated with higher transoral surgery (TOS) rates and laryngeal preservation rates. Notably, the TP + PEMBRO regimen outperformed the TP + CETUX regimen in terms of treatment response rate and the proportion of minimally invasive surgeries, suggesting a novel and efficacious neoadjuvant treatment for LAHPC.
Novel Genetic Variants Associated with Gout Identified Through a Genome-Wide Study in the UK Biobank (N = 150,542)
Authors: Tao Yiwen , Cai Tengda , Pan Qi , Yang Luning , Lin Sen , Haque Mainul , Dottorini Tania , Abhishek Abhishek , Meng Weihua 
Published: February 2025

AbstractGout is a prevalent and painful form of inflammatory arthritis associated with hyperuricemia, which leads to monosodium urate crystal deposition in joints and surrounding tissues, triggering acute inflammatory responses. This disease is also closely linked to serious comorbidities, including cardiovascular diseases, chronic kidney diseases, diabetes, and increased mortality risk, significantly impacting global health. In this study, we conducted a comprehensive genome-wide association study (GWAS) based on the UK Biobank pain questionnaire 2019, comprising 10,474 gout cases and 140,068 controls, identifying 13 loci associated with gout, including four novel loci. These findings were further explored in the FinnGen cohort, with 12 loci being replicated significantly. Sex-stratified analyses revealed notable differences, with 16 loci identified in males and two loci identified in females, reflecting both shared and sex-specific genetic influences on gout susceptibility. In addition, genetic correlation analyses demonstrated strong associations between gout and traits related to urate levels, specific medication use, and metabolic functions. Transcriptome-wide association studies highlighted several genes, such asSLC16A9andASAH2B, which showed significant expression patterns across various tissues, implicating metabolic and immune pathways in gout. Phenome-wide association studies of significant SNPs revealed links to metabolic, immunological, and skeletal traits, underscoring the multi-faceted nature of gout. These results contribute valuable insights into the genetic architecture and biological mechanisms underlying gout, suggesting potential avenues for tailored interventions.
Neighborhood Socioeconomic Status and Cardiometabolic Outcomes in Urban Jamaica: Exploring Novel Measures
Authors: Dyer Harika P. , Ferguson Trevor S. , Mckenzie Joette , Coleman Novie Younger- , Tulloch-Reid Marshall , Blake Alphanso L , Bennett Nadia R. , McFarlane Shelly , Wilks Rainford J. , Gary-Webb Tiffany L. 
Published: February 2025

AbstractIntroductionCardiometabolic outcomes burden Afro-Caribbean populations disproportionately and their relationship with neighborhood socioeconomic status (SES) is unclear. This study explores neighborhood SES and cardiometabolic outcomes in urban Jamaica.MethodsWe analyzed data from 833 participants (women=557, men=276) to examine associations between neighborhood SES, determined by median property sales price, and measured diabetes, hypertension, high cholesterol, and obesity outcomes. We adjusted for covariates using survey-weighted Poisson regression models.ResultsHigh neighborhood SES was associated with increased prevalence of hypertension (PR=1.33, p=0.044) and high cholesterol (PR=2.46, p<0.001) in fully adjusted models compared with low neighborhood SES. We observed increased obesity for the middle (PR=1.46, p<0.001) and high (PR=1.60, p<0.001) SES tiers and several sex-specific relationships. High neighborhood SES was associated with more obesity among women (P=1.32, p=0.015) and high total cholesterol among men (PR=4.70, p=0.005). Mid SES was associated with increased hypertension among men (PR=2.02, p=0.024).ConclusionAssociations between neighborhood SES and cardiometabolic outcomes in urban Jamaica appear to be nonlinear and influenced by a combination of sex, individual risk factors, and neighborhood characteristics. These findings challenge some conventional assumptions about the protective effects of higher SES on health and underscore the need for a robust understanding of the complex interplay individual and neighborhood determinants in similar contexts worldwide.
Human amyotrophic lateral sclerosis/motor neuron disease: The disease-associated microglial pathway is upregulated and APOE ε2 is protective
Authors: Ashford Bridget A , Simpson Julie E , Dawson Charlotte , Boche Delphine , Cooper-Knock Johnathan , Heath Paul R , Fillingham Daniel , Appleby-Mallinder Charlie , Wei Wenbin , Dunning Mark , Highley J Robin 
Published: February 2025

AbstractA key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post mortem frozen and formalin-fixed paraffin embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were re-analysed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord, motor cortex, and regions across the brain and validate changes found at during transcriptomic analyses. In the spinal cord, marked inflammation was observed while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlightedTREM2,TYROBP,APOE, andCD163as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity, and involvement of TREM2, ApoE (encoded byAPOE) and TYROBP was confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between theAPOEhaplotype and ALS/MND risk, age of onset and survival. We confirm associations betweenAPOEε4 and a more aggressive disease; and between ε2 and a less severe disease phenotype. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.
Dynamic dysregulation of Tenascin-X/Tenascin-C balance controlled by Transforming Growth Factor-β leads to tumor cell proliferation during pancreatic carcinogenesis
Authors: Liot Sophie , Schmitter Céline , Mercier-Gouy Perrine , Kholti Naïma El , Balas Jonathan , Prigent Laura , Aubert Alexandre , Lethias Claire , Chitty Jessica L. , Koch Manuel , Fenouil Tanguy , Cox Thomas R. , Hennino Ana , Hervieu Valérie , Ricard-Blum Sylvie , Valcourt Ulrich , Lambert Elise 
Published: February 2025

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to late diagnosis and poor therapeutic efficiency. Throughout PDAC progression, a dense extracellular matrix (ECM) is deposited around neoplastic cells and accompanies tumor development and aggressiveness. This significant stroma, both in terms of quantity and through its impact on tumor cells, is now considered as a target for innovative therapies to improve patient survival. Among ECM proteins, Tenascins (TNs) are a family of four glycoproteins (TNC, TNW, TNR and TNX) sharing a common modular structure, but exhibiting different expression patterns and functions depending on the physiological and physio-pathological contexts. In PDAC, TNC is up-regulated and is considered as a pro-tumorigenic actor, whereas TNX’s role remains to be elucidated. Herein, we demonstrated that unlike TNC, TNX is drastically decreased in PDAC, and that this loss is correlated with reduced patient survival. Dysregulation of the TNX/TNC balance is attributable to Transforming Growth Factor-beta (TGF-β) upregulation during pancreatic carcinogenesis. Interestingly, we found that TNX is first highly deposited in low grade lesions before being clearly decreased in later stages suggesting an elaborate stromal remodelling during PDAC development. Finally, low TNX and high TNC deposition around precursor lesions are correlated with increased preneoplastic cell proliferation. Altogether, our results (i) demonstrate the importance of Tenascin ratios during pancreatic carcinogenesis, (ii) suggest an anti-proliferative role for TNX unlike its pro-tumoral counterpart, TNC and (iii) underscore TNX and TNC as valuable targets for the development of new drugs for pancreatic cancer and/or solid tumor treatment.Statement of significanceThe tumor microenvironment plays a prominent but contradictory role in pancreatic cancer. Our study highlights the role of a TGF-β-controlled TNX/TNC balance and designates TNX as an inhibitor of tumor cell proliferation.
Robustness of high-throughput prediction of leaf ecophysiological traits using near infra-red spectroscopy and poro-fluorometry
Authors: Coindre Eva , Boulord Romain , Chir Laurine , Freitas Virgilio , Ryckewaert Maxime , Laisné Thomas , Bouckenooghe Virginie , Lis Maëlle , Cabrera-Bosquet Llorenç , Doligez Agnès , Simonneau Thierry , Pallas Benoît , Coupel-Ledru Aude , Segura Vincent 
Published: February 2025

AbstractBackgroundWater resource is a major limiting factor impacted by climate change that threatens crop production and quality. Understanding the ecophysiological mechanisms involved in the response to water deficit is crucial to select new varieties more drought tolerant. A major bottleneck hampering such advances is the lack of methods for measuring ecophysiological traits on large populations of individuals. We investigated the relevance of spectroscopy and poro-fluorometry with related high-throughput measurement devices to predict leaf morphological and ecophysiological traits using partial least square regression (PLSR) models. This work relies on a grapevine diversity panel grown in pots under contrasted conditions, outdoors under well watered conditions and in a greenhouse with three different soil water treatments. We took advantage of these experimental designs to specifically assess the robustness of predictive models.ResultsSome complementarity between measuring devices were found, with spectrometers being able to predict leaf mass per area, water content and water quantity (R²>0.58), while the poro-fluorometer could predict net CO2assimilation (R²>0.72), regardless of the water treatment. The prediction of leaf mass per area appeared to be quite robust between outdoors and greenhouse experiments. The prediction of water use efficiency was highly dependent on the water treatment, with much better predictions under moderate (R²>0.73) than severe water deficit. We then used the high-throughput devices alone to measure the whole grapevine panel, by applying calibration models to predict ecophysiological traits and estimated their broad sense heritability. Leaf mass per area was also directly determined on the entire diversity panel and its heritability was similar whether calculated on observed or predicted values. The highest computed heritabilities for these traits reached values close to 0.5.ConclusionsThis study showed that spectrometers and poro-fluorometer could be reliable nondestructive tools for the high-throughput phenotyping of ecophysiological traits on thousands of plants, paving the way for studying the genetic determinism of such traits.
Polarity reversal of stable microtubules during neuronal development
Authors: Iwanski Malina K. , Serweta Albert K. , Verwei H. Noor , Donders Bronte C. , Kapitein Lukas C. 
Published: February 2025

ABSTRACTNeurons critically depend on long-distance transport orchestrated by motor proteins walking over their highly asymmetric microtubule cytoskeleton. These microtubules are organized uniformly in axons with their plus-end pointing away from the soma. In contrast, in the dendrites of vertebrate neurons, microtubules are of mixed polarity, but organized into bundles of uniform polarity with stable, long-lived microtubules preferentially oriented minus-end-out and dynamic microtubules oriented plus-end-out. This organization is thought to be essential for guiding selective transport into dendrites, yet how this organization is established is unclear. Here we use a combination of single molecule localization microscopy, expansion microscopy, and live-cell imaging to examine how the microtubule cytoskeleton is reorganized during neuronal development of cultured rat hippocampal neurons. We find that, while the youngest neurites contain microtubules of mixed polarity, stable microtubules are initially preferentially oriented plus-end-out. At this stage of development many stable microtubules are connected to the centrioles, providing an explanation for their plus-end out orientation in emerging neurites. In later stages, these microtubules are released from the centrioles and reorient by sliding between or within neurites to become progressively more minus-end-out. Moreover, prior to axon specification, we commonly observed already one or two minor neurites with an almost uniformly plus-end-out microtubule network, indicative of transient polarization. Together, our findings reveal how stable microtubules are reorganized to help establish the stereotypical microtubule networks seen in the axon and dendrites of mature vertebrate neurons.