bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trogocytosis-mediated transfer of FOLR2 from Nurse-like cells to CLL cells is linked to their activation and proliferation
Authors: Domagala Marcin , Gerby Bastien , Bazile Chloe , Ysebaert Loïc , Pancaldi Vera , Laurent Camille , Poupot Mary 
Published: January 2025

ABSTRACTThis study, conducted on primary human samples, identifies a novel pro-tumoral interaction between nurse-like cells (NLCs) and chronic lymphocytic leukemia (CLL) cells, relying on the trogocytosis-mediated transfer of functional Folate Receptor β (FOLR2) from NLCs to cancer cells. Trogocytic CLL cells carrying NLC-derived FOLR2 exhibit an enhanced capacity for folic acid internalization. Furthermore, induction of the proliferative state of CLL cells with CD40L+IL-15 treatment in the presence of NLCs, to imitate lymph node (LN) environmentin vitro, revealed that trogocytic FOLR2+cancer cells are enriched in the fraction of active and proliferating cells, particularly under condition of folic acid depletion. FOLR2 remains detectable on CLL cells as long as they maintain their proliferative status. Moreover, its level remains stable in the actively cycling cells, implying that cancer cells engage in trogocytosis with NLCs between successive cell divisions. Analysis of the LNs from CLL patients reveals, for the first time, the presence of FOLR2+NLCs, whose frequency correlates with increased proliferation of cancer cells, and allowed detection of FOLR2+CLL cells, providing evidence of trogocytosis between NLCs and CLL cells in vivo. Finally, it proposes FOLR2 as a novel marker of M2-like NLCsin vitroand discovers a presence of heterogenous subpopulations of NLCs in the CLL lymph nodes, with varying expression of CD163 and FOLR2. These results shed light on the underappreciated role of trogocytosis in the increasing adaptability of malignant cells in the tumor microenvironment (TME) context and stress the importance of NLCs in the pathophysiology of CLL.Schematic representation of trogocytosis-mediated acquisition of NLC-derived FOLR2 by CLL cells as a novel mechanism of cancer cell’s interaction with TME and adaptation to the adverse conditions. 1) CLL cells enter the lymph node (LN) and engage in contact with FOLR2+NLCs. 2) Presence of T cells presenting CD40L and stromal cells producing IL-15 promotes the activation and trogocytosis-mediated acquisition of FOLR2 by CLL cells. FOLR2+ trogocytic CLL cells show increased acquisition of folates and are more likely to proliferate, as compared with the remaining population of cancer cells.KEY POINTSFOLR2 is a marker of M2-like protective NLCsCLL cells acquire functional FOLR2 from NLCs through trogocytosis, enabling them to enhance folate uptakeTrogocytic FOLR2+CLL cells are enriched in the fraction of activated and proliferative cells, especially during folic acid scarcityDetection of FOLR2+NLCs and FOLR2+trogocytic CLL cells in the LNs of CLL patients.
Single-shot label-free nanoscopy for quantitative organelle visualization on standard commercial microscopes
Authors: Inutsuka Yugo , Yamamoto Koki , Kuroda Masafumi , Okada Yasushi 
Published: January 2025

AbstractLabel-free microscopy techniques that overcome the limitations of fluorescence microscopy are increasingly needed in biological research. Quantitative phase imaging has emerged as a powerful label-free method for live cell imaging, particularly at multicellular scales. However, a critical gap exists in achieving easy-to-implement, high-speed, high-resolution microscopy at subcellular scales. Here, we report upgraded polarization-resolved differential phase contrast nanoscopy (UpDPC); this single-shot computational phase microscopy (CPM) enhances resolution and sensitivity to subcellular levels. UpDPC can be readily integrated into commercial fluorescence microscopes, enabling 100 nm gap separation, over 100 Hz imaging via single-shot phase retrieval, and 100 ms computation of phase image during observation. Our results demonstrate that high-performance CPM provides reproducible and comprehensive visualization of various organelles, offering a practical and scalable implementation for basic research and clinical applications.
The Artists’ Brain: A Data Fusion Approach to Characterize the Neural Bases of Professional Visual Artists
Authors: Taskiran Erdem , Bacci Francesca , Melcher David , Grecucci Alessandro , De Pisapia Nicola 
Published: January 2025

AbstractArtistic creativity relies on complex perceptual, cognitive and motoric functions, yet the specific neural characterization of being an artist remain incompletely understood. To fill this gap in the literature, the present study aims to characterize the gray matter (GM) and white matter (WM) contributions to professional visual artists as compared to non-artists controls. The MRI brain scans of 12 professional artists and 12 matched non-artists were analyzed via an unsupervised machine learning method known as Transposed Independent Vector Analysis (tIVA) to detect joint GM-WM networks. Two independent networks were found. The first network (IC2), more expressed in artists, included increased GM-WM concentration in regions associated with the Default Mode Network (DMN), Executive Control Network (ECN), and sensorimotor networks possibly related with augmented cognitive and ideational control, and increased perceptual-motor integration skills critical for creative tasks. The second network (IC8), less expressed in artists, included decreased GM-WM density in regions related to the Salience Network, such as the Anterior Cingulate Cortex, suggesting attentional regulation processes that may not be as central to visual artists. In sum, these results suggest that artists may rely on specialized brain networks, reflecting unique neural adaptations in individuals with pronounced creativity and extensive creative training.
Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding
Authors: La Van Ngoc Thuy , Kang Lulu , Minh David D. L. 
Published: January 2025

AbstractThe coronavirus main protease (MPro) plays a pivotal role in viral replication and is the target of several antivirals against SARS-CoV-2. In some species, CRCs of MPro enzymatic activity can exhibit biphasic behavior in which low ligand concentrations activate the enzyme whereas higher ones inhibit it. While this behavior has been attributed to ligand-induced dimerization, quantitative enzyme kinetics models have not been fit to it. Here, we develop a kinetic model integrating dimerization and ligand binding. We perform a Bayesian regression to globally fit the model to multiple types of biochemical and biophysical data. The reversible covalent inhibitor GC376 strongly induces dimerization and binds to the dimer with no cooperativity. In contrast, the fluorescent peptide substrate has a minor effect on dimerization but binds to the dimer with positive cooperativity. The biphasic concentration response curve occurs because compared to substrate, the inhibitor accelerates turnover in the opposite catalytic site.
Promiscuous structural cross-compatibilities between major shell components ofKlebsiella pneumoniaebacterial microcompartments
Authors: Barthe Lucie , Balestrino Damien , Azizi Bessam , Dessaux Delphine , Soldan Vanessa , Esque Jeremy , Schiex Thomas , Barbe Sophie , Garcia-Alles Luis Fernando 
Published: January 2025

ABSTRACTBacterial microcompartments (BMC) are submicrometric reactors that encapsulate dedicated metabolic activities. BMC-H hexamers, the most abundant components of BMC shells, play major roles for shell plasticity and permeability. In part, chemical exchanges between the BMC lumen and the cellular cytosol will be defined by the disposition of amino acids lining the central BMC-H pores. Current models attribute to BMC-H a homo-oligomeric nature. The hexagonal symmetry of corresponding pores, however, would break down if hetero-hexamers formed, a possibility suggested by the frequent presence of multiple paralogs within BMC operons. Here, we gauged the degree of structural promiscuity between the 11 BMC-H paralogs fromKlebsiella pneumoniae, a potential human pathogen endowed with the capacity to express three different BMC types. Concomitant activation of transcription of several BMC operons was first shown to be possible. By leveraging an adapted tripartite GFP technology, all possible BMC-H pair combinations were screened inE. coli. Multiple structural cross-compatibilities were pinpointed between homologs arising not only from the same BMC operon, but also from different BMC types, results supported by Alphafold and ESMFold predictions. The structural stability and assembly propensity of selected hetero-associations was established by biochemical means. In light of these results, we reinterpreted published lysine cross-linking mass spectrometry data to demonstrate that one of these hetero-hexamers, involving PduA and PduJ, was already detected to form in the shell of a recombinantly-expressed 1,2-propanediol utilization compartment fromSalmonella enterica. Altogether, this study points to the need to embrace an augmented structural complexity in BMC shells.
Fibroblast–Neuron Interactions Driving Persistent Pain in Rheumatoid Arthritis (FiND-Pain RA) - a study protocol
Authors: Xenophontos Mikalena , Baldeweg Friederike C. , Ross Rosie , Rutter-Locher Zoe , Hill Sarah , Ryan Sarah , Awadelkareem Mosab Ali , Law Shing T. , Bennett David L. , Buckley Christopher D. , Humby Frances , Kirkham Bruce W. , Denk Franziska , Taams Leonie S. 
Published: January 2025

AbstractIntroductionPain in patients with rheumatoid arthritis (RA) is an unmet clinical need. Targeting joint inflammation with disease modifying antirheumatic drugs (DMARDs) has not resulted in the anticipated reduction in pain for many patients. This can partly be explained by the concept of central sensitisation whereby spinal and supraspinal pathways have a lower threshold of activation leading to increased perception of pain. Synovial stromal cells such as fibroblasts are also thought to play a role through peripheral sensitisation of nerves in the joint. Synovial fibroblasts are known to produce pro-algesic mediators such as interleukin 6 (IL-6) and nerve growth factor (NGF) at the mRNA level. These pro-algesic mediators could activate sensory nerve fibres that send signals from the joint to the spinal cord, thereby driving persistent pain in RA. The purpose of this study is to evaluate which pro-algesic mediators are produced by lining versus sublining fibroblasts and whether the level of these mediators correlates with clinical measures of pain in patients with RA.Methods and analysisFiND-Pain RA is a multi-centre observational study which will recruit 50 patients with seropositive RA who attend the rheumatology department of Guy’s and St Thomas’ Hospital, London and the Nuffield Orthopaedic Centre, Oxford. Clinical examination, pain-focused patient reported outcome measures (PROMs), ultrasound examination and ultrasound guided synovial biopsy of the knee will be performed. The levels of known and putative pro-algesic mediators will be measured in fibroblasts from the lining and sublining layer of the synovium. The location and spatial morphology of sensory nerve fibres and their proximity to lining and sub-lining fibroblasts will be characterized. The primary outcome will be to determine whether the knee pain scores of participants correlate with the level of LIF, a novel putative pain-mediator expressed in sub-lining fibroblasts. The secondary outcomes will be to determine whether other pro-algesic mediators produced by lining or sub-lining fibroblasts correlate with clinical measures of pain and to assess the location and proximity of sensory nerve fibres to lining versus sub-lining fibroblasts.Ethics and disseminationThe study has been approved by the Bromley Research Ethics Committee (REC: 21/LO/0712). The findings of this study will be disseminated through open-access publications, as well as scientific and clinical conferences.
In vivo itaconate tracing reveals degradation pathway and turnover kinetics
Authors: Willenbockel Hanna F. , Williams Alexander T. , Lucas Alfredo , Dowerg Birte , Cabrales Pedro , Metallo Christian M. , Cordes Thekla 
Published: January 2025

AbstractItaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo13C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
The Potential of Dietary Strategies: The Impact of Low-Carbohydrate Diet on Cardiovascular-Kidney-Metabolic Syndrome
Authors: Li Zhuoxing , Liu Xiunan , Ma Xin , Xiao Mao , Zhang Xue , Deng Yanyi , Liu Hao , Sun Yun , Xiao Xiang 
Published: January 2025

AbstractThis study aims to explore the prevalence of Low-carbohydrate diet (LCD) among individuals with cardiovascular-kidney-metabolic (CKM) syndrome and its relationship with prognosis.MethodsThe individuals diagnosed with CKM were included from the National Health and Nutrition Examination Survey (NHANES) database between 2009 and 2018. Participants were divided into two groups: those on a LCD and those not on a LCD. Multivariate logistic regression analysis was conducted to assess the factors influencing the choice of LCD among CKM individuals. Kaplan-Meier survival curve analysis and multivariate Cox regression analysis were performed to evaluate the association between LCD and the risk of all-cause mortality. Stratified analysis was performed to assess the consistency of results.ResultsA total of 1000 non-CKM (stage 0) individuals and 11,141 CKM individuals (stages 1, 2, 3, and 4) were included. The proportions of individuals on LCD for CKM stages 0, 1, 2, 3, and 4 were 1.16%, 2.49%, 1.94%, 1.24%, and 1.68%, respectively. Multivariate logistic regression analysis indicated that age, and race might influence the choice of LCD among CKM individuals. Multivariate Cox regression analysis revealed that compared to non-LCD individuals, those on LCD had a 62% reduced risk of all-cause mortality (HR = 0.38; 95% CI, 0.15-0.92, P = 0.03). Stratified analysis showed no interaction between LCD and CKM stages (Pfor interaction < 0.05).ConclusionThe proportion of individuals on LCD in CKM is relatively low. Furthermore, LCD can decrease the risk of all-cause mortality among CKM individuals, regardless of CKM stage.
Risk of Hypertensive Disorders of Pregnancy in Patients With Cardiac Disease
Authors: Jones Maura , Quist-Nelson Johanna , Fuller Matthew , Volz Elizabeth , Snow Sarah , Habib Ashraf S , Federspiel Jerome , Boggess Kim , Meng Marie-Louise 
Published: January 2025

ABSTRACTBackgroundPregnant patients with cardiovascular disease (CVD) face increased risk of preeclampsia and preterm delivery, yet data is limited data regarding degree of risk and impact of hypertensive disorders of pregnancy (HDP) on gestational age at delivery.ObjectivesTo examine HDP risk and impact on delivery timing in patients with CVD.MethodsThis retrospective cohort study included patients >18 years old who delivered between 10/1/2015 and 12/31/2020 using the Premier Healthcare Database. Patients with CVD were divided into six categories: congenital, ischemic, aortic pathology, pulmonary hypertension, cardiomyopathy, and valvular disease. The primary outcome was risk of HDP (gestational hypertension/ preeclampsia). The secondary outcome was gestational age at delivery. Multivariable mixed effects regression models were used to estimate adjusted outcomes, adjusting for CVD subtype, >1 CVD subtype present, demographics, hospital characteristics, and comorbidities.ResultsAmong 4,606,247 obstetric patients, 20,021 had CVD. The risk of HDP among people with CVD varied by CVD subtype, lowest in those with congenital heart disease (aOR,0.9; 95% CI [0.8, 1.0]) and highest in those with pulmonary hypertension (aOR, 1.5; 95% CI [1.3, 1.8]) and cardiomyopathy (aOR,1.5; 95% CI [1.4,1.6]). Patients with CVD delivered earlier than those without CVD, even in the absence of HDP(36.4–38.0 weeks versus 38.4 weeks). Among those with HDP, patients with severe pre-eclampsia with CVD, delivered earlier than those without CVD (33.1–34.6 weeks versus 35.5 weeks).ConclusionRisk of HDP and preterm delivery is higher those with CVD, particularly in pulmonary hypertension and cardiomyopathy. Patients with CVD should be advised of their increased risk.
Effects of Immediate Postpartum Diuretic Treatment on Postpartum Blood Pressure among Individuals with Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-Analysis
Authors: Keen Susan K. , Sall Koura , Koczo Agnes , Wang Yisi , Miller Rebekah S. , Muldoon Matthew F. , Hauspurg Alisse K. , Countouris Malamo E. 
Published: January 2025

ABSTRACTBackgroundHypertensive disorders of pregnancy (HDP) are associated with ongoing postpartum hypertension (HTN) and increased morbidity. Extravascular water and sodium mobilization is implicated in postpartum blood pressure (BP) elevation, however trials of postpartum diuretics in HDP have had mixed results. Our meta-analysis aimed to analyze the impact of postpartum diuretics on postpartum hypertension following HDP.MethodsSystematic review identified randomized controlled trials (RCTs) studying the efficacy of diuretics in the treatment of postpartum BP. Meta-analysis outcomes included persistent HTN up to 10 days postpartum, mean postpartum systolic and diastolic BPs, and use of additional antihypertensive medications.ResultsFrom 9 RCTs, 1273 subjects were included in the meta-analysis. Postpartum diuretic use was associated with lower systolic BP (SMD standard mean difference]: -0.36; 95% confidence interval [CI]: -0.72; -0.01) without a difference in diastolic BP (SMD: 0.01; 95% CI: -0.22; 0.23) compared with controls. There was no difference in rates of persistent HTN between the postpartum diuretics group versus controls (OR: 0.70; 95% CI: 0.4; 1.05) or in antihypertensive medication use (OR: 0.66; 95% CI: 0.42; 1.05).ConclusionPostpartum diuretic use was associated with lower systolic BP compared with controls and non-significant trends of lower rates of persistent HTN and postpartum antihypertensive medication use. Due to the low certainty of evidence, uniform postpartum diuretic use with HDP cannot be recommended. Future studies are needed to evaluate specific HDP subgroups who may benefit from diuretic use.
Causal mediation analysis of the neuroprotection ofAPOE2through lipid pathways
Authors: Xiang Qingyan , Lok Judith J. , Roth Nicole , Andersen Stacy L. , Perls Thomas T. , Song Zeyuan , Yashin Anatoli I. , Mengel-From Jonas , Patti Gary J. , Sebastiani Paola 
Published: January 2025

AbstractBackgroundRecent studies have revealed a strong association between the e2 allele of the Apolipoprotein E (APOE2)gene and lipid metabolites. In addition,APOE2carriers appear to be protected from cognitive decline and Alzheimer’s disease. This correlation supports the hypothesis that lipids may mediate the protective effect ofAPOE2on cognitive function, thereby providing potential targets for therapeutic intervention.MethodsWe conducted a causal mediation analysis to estimate both the direct effect ofAPOE2and its indirect effect through 19 lipid species on cognitive function, using metrics from the digital Clock Drawing Test (CDT) in 1291 Long Life Family Study (LLFS) participants. The CDT metrics included think-time, ink-time, and their sum as total-time to complete the test.ResultsCompared to carriers of the commonAPOE3,APOE2carriers completed the CDT significantly faster. Two lipids showed protective mediation when elevated in the blood, resulting in shorter CDT think-time (CE 18:3), ink-time (TG 56:5), and total completion time (CE 18:3 and TG 56:5). Elevated TG 56:4, in contrast, showed deleterious mediation resulting in increased ink-time. The combined indirect effect through all lipids significantly mediated 23.1% of the total effect ofAPOE2 on total-time, reducing it by 0.92s (95% CI: 0.17, 2.00). Additionally, the sum of total indirect effect from all lipids also mediated 27.3% of the total effect on think-time, reducing it by 0.75s, and 13.6% of the total effect on ink-time, reducing it by 0.17s, though these reductions were statistically insignificant. Sensitivity analysis yielded consistent results of the combined indirect effects and total effects and identified additional significant lipid pathways (CE 22:6, TG 51:3, and TG 54:2).ConclusionsWe found that the combined indirect effect through all lipids could mediate 10%-27% of the total direct effect ofAPOE2on CDT times. We identified both protective and deleterious lipids, providing insights for new therapeutics targeting those lipids to modulate the protective effects ofAPOE2on cognition.
Divergent endothelial mechanisms drive arteriovenous malformations in Alk1 and SMAD4 loss-of-function
Authors: Oppenheim Olya , Giese Wolfgang , Park Hyojin , Baumann Elisabeth , Ivanov Andranik , Beule Dieter , Eichmann Anne , Gerhardt Holger 
Published: January 2025

AbstractHereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell population tracking of mutant cells validates unique endothelial cell migration defects. Mosaic cell culture models further illustrate that mutant cells co-opt wild-type cells driving distinct Alk1 or SMAD4 mutant-like behavioral defects. These findings demonstrate that arteriovenous malformations develop through fundamentally different cellular mechanisms based on the specific genetic mutation emphasizing the need for tailored diagnostic and therapeutic strategies.