bluuebunny/crossref_metadata_2025_split huggingface dataset:
A conserved element in the first intron of Cd4 has a lineage specific, TCR signal-responsive, canonical enhancer function that matches the timing of cell surface CD4 upregulation required to prevent lineage choice error
Authors: Swan Gregory A. , Fujii Chika , Guzynski Mia E. , Page Sheridan M. , Meyers Isabelle V. , Penev Yordan P. , Littleton Sejiro , Azzahra Adinda , Richardson Christine , Sarafova Sophia D. 
Published: January 2025

IntroductionThe regulation of Cd4 expression during T-cell development and immune responses is essential for proper lineage commitment and function in the periphery. However, the mechanisms of genetic and epigenetic regulation are complex, and their interplay not entirely understood. Previously, we demonstrated the need for CD4 upregulation during positive selection to ensure faithful commitment of MHC-II-restricted T cells to the CD4 lineage. In this study, we investigate whether a conserved region, here called NCE, that is proximal to the Cd4 silencer and contains E4m has the required developmental-stage-specific canonical enhancer function and TCR responsiveness to mediate the CD4 upregulation required to prevent lineage errors.MethodsTo investigate the role of NCE, transient transfection of reporter plasmids was performed in thymoma cell lines arrested at the double-positive (DP, CD4+CD8+) and intermediate (INT, CD4+CD8lo) stages of development. CRISPR/Cas9-mediated deletion of the coreNCE/E4m region was carried out in these cell lines to assess its impact on CD4 surface expression, re-expression rates, and TCR signaling responsiveness. To avoid developmental alterations from direct manipulation of the endogenous Cd4 locus in vivo, BAC-transgenic reporter mice were generated with the locus modified to express EGFP in the presence or absence of NCE. EGFP mRNA levels were measured via RT-qPCR, and EGFP fluorescence was analyzed in post-selection thymocytes.ResultsOur in vitro experiments demonstrate that NCE by itself can function as an enhancer at the INT, but not the DP stage of development. Furthermore, CRISPR/Cas9-mediated deletion of coreNCE/E4m resulted in reduced CD4 surface levels, slower re-expression rates, and reduced TCR signaling responsiveness in INT cells, but not in DP cells. In vivo, NCE-sufficient transgenic mice exhibited upregulation of Cd4 reporter EGFP mRNA levels at the INT stage and a corresponding upregulation of EGFP fluorescence, whereas NCE-deficient mice showed a significant loss of Cd4 reporter EGFP mRNA and no detectable EGFP production in any post-selection thymocytes.DiscussionThis study demonstrates that the canonical enhancer function of coreNCE/E4m is essential for CD4 upregulation following positive selection. The NCE region, with its developmental-stage-specific activity and its known epigenetic regulatory capabilities, ensures faithful lineage commitment to the CD4 lineage.
Spinal cord injury enhances lung inflammation and exacerbates immune response following exposure to LPS
Authors: Berk Bradford C. , Pereira Amanda , Vizcarra Velia Sofia , Pröschel Christoph , Hsu Chia George 
Published: January 2025

IntroductionThe severity of spinal cord injury (SCI) is closely tied to pulmonary function, especially in cases of higher SCI levels. Despite this connection, the underlying pathological mechanisms in the lungs post-SCI are not well understood. Previous research has established a connection between disrupted sympathetic regulation and splenocyte apoptosis in high thoracic SCI, leading to pulmonary dysfunction. The aim of this study was to investigate whether mice with low-level SCI exhibit increased susceptibility to acute lung injury by eliciting systemic inflammatory responses that operate independently of the sympathetic nervous system. MethodsHere, we employed T9 contusion SCI and exposed mice to aerosolized lipopolysaccharide (LPS) to simulate lung inflammation associated with acute respiratory distress syndrome (ARDS). Twenty-four hours post-LPS exposure, lung tissues and bronchoalveolar lavage (BAL) fluid were analyzed. ResultsLPS markedly induced proinflammatory gene expression (SAA3, IRG1, NLRP3, IL-1beta, MCP-1) and cytokine release (IL-1beta, IL-6, MCP-1) in SCI mice compared to controls, indicating an exaggerated inflammatory response. Infiltration of Ly6G/C positive neutrophils and macrophages was significantly higher in SCI mice lungs post-LPS exposure. Interestingly, spleen size and weight did not differ between control and SCI mice, suggesting that T9 SCI alone does not cause spleen atrophy. Notably, bone-marrow-derived macrophages (BMDMs) from SCI mice exhibited hyper-responsiveness to LPS. DiscussionsThis study demonstrated an increase in lung inflammation and immune responses subsequent to low-level T9 SCI, underscoring the widespread influence of systemic inflammation post-SCI, especially pronounced in specific organs like the lungs.
Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients
Authors: Dumolard Lucile , Hilleret Marie-Noelle , Costentin Charlotte , Mercey-Ressejac Marion , Sturm Nathalie , Gerster Theophile , Decaens Thomas , Jouvin-Marche Evelyne , Marche Patrice N. , Macek Jilkova Zuzana 
Published: January 2025

BackgroundPatients with chronic hepatitis B virus (HBV) infection are characterized by impaired immune response that fails to eliminate HBV. Immune checkpoint molecules (ICMs) control the amplitude of the activation and function of immune cells, which makes them the key regulators of immune response.MethodsWe performed a multiparametric flow cytometry analysis of ICMs and determined their expression on intrahepatic lymphocyte subsets in untreated and treated patients with HBV in comparison with non-pathological liver tissue.ResultsThe liver of untreated HBV patients exhibited a high accumulation of PD-1+CD8+ T cells, while the frequencies of 4-1BB+ T cells, 4-1BB+ natural killer (NK) cells, and TIM-3+CD8+ T cells were the highest in the chronic hepatitis phase. Our findings showed that the HBeAg status is linked to a distinct immune phenotype of intrahepatic CD8+ T cells and NK cells characterized by high expression of ICMs, particularly 4-1BB. Importantly, antiviral treatment partially restored the normal expression of ICMs. Finally, we described important differences in ICM expression between intrahepatic and circulating NK cells in HBV patients.ConclusionsOur study shows clear differences in the intrahepatic expression of ICMs on NK cells and T cells in chronic HBV patients depending on their clinical stage.
The impact of signaling pathways on the desmosome ultrastructure in pemphigus
Authors: Schmitt Thomas , Huber Julia , Pircher Julia , Schmidt Enno , Waschke Jens 
Published: January 2025

IntroductionThe autoantibody-driven disease pemphigus vulgaris (PV) impairs desmosome adhesion in the epidermis. In desmosomes, the pemphigus autoantigens desmoglein 1 (Dsg1) and Dsg3 link adjacent cells. Dsgs are clustered by plaque proteins and linked to the keratin cytoskeleton by desmoplakin (Dp). The aim of this study was to identify the impact of several PV-related signaling pathways on desmosome ultrastructure.MethodsSTED microscopy, Dispase-based dissociation assay.ResultsAs observed using STED microscopy, pemphigus autoantibodies (PV-IgG) reduced desmosome number, decreased desmosome size, increased plaque distance and thickness and caused loss of adhesion. Decreased desmosome number, increased plaque distance and thickness and loss of adhesion correlate with features found for newly assembled immature desmosomes, observed after Ca2+ depletion and repletion. This was paralleled by plaque asymmetry, keratin filament retraction and fragmentation of Dsg1 and Dsg3 immunostaining. Inhibition of each individual signaling pathway investigated here prevented the loss of adhesion and ameliorated keratin retraction. In addition, inhibition of p38MAPK or PLC completely rescued all parameters of desmosomes ultrastructure and increased desmosome number under basal conditions. In contrast, inhibition of MEK1/2 was only partially protective for desmosome size and plaque thickness, whereas inhibition of Src or increase of cAMP decreased desmosome size but increased the desmosome number even in the presence of PV-IgG. DiscussionAlterations of the desmosomal plaque ultrastructure are closely related to loss of adhesion and regulated differently by signaling pathways involved in pemphigus pathogenesis. This insight may allow identification of novel treatment options targeting specific steps of desmosome turn-over in the future.
Spatiotemporal dynamics and influencing factors of native and invasive saltmarshes in a rapidly silting bay during 1985–2023
Authors: Xu Mingshan , Gu Jiali , Yun Peng , Gan Jianjun , Fan Wenzhou , Chen Zhentao , Shao Jie , Zhang Guangzhi , Zeng Jian 
Published: January 2025

Globally, native saltmarshes are declining, while invasive saltmarshes are expanding rapidly. However, the underlying processes and driving mechanisms behind these trends remain poorly understood, particularly in rapidly silting coastal bays. Here, we investigated the spatiotemporal dynamics and influencing factors of native saltmarshes (Scirpus mariqueter and Phragmites australis) and invasive Spartina alterniflora in Yueqing Bay, eastern China, by interpreting Landsat series images during 1985-2023. Results showed that native saltmarshes significantly decreased from 632.24 ha to complete disappearance, while S. alterniflora expanded from zero to 2872.90 ha in Yueqing Bay during 1985-2023. Specifically, S. mariqueter experienced a notable decline from 1985 to 1995, subsequent growth between 2000 and 2005, and another reduction from 2005 to 2010. P. australis expanded from 2005 to 2010 but shrank from 2010 to 2015 as S. alterniflora encroached upon its habitats. By contrast, S. alterniflora consistently expanded annually, except when it was eradicated by human interference. Both natural factors and human activities influenced native and invasive saltmarshes; for instance, mudflat reclamation facilitated saltmarsh expansion by creating suitable habitats during a certain period, particularly for S. alterniflora. From 1984 to 2018, the coastline extended seaward, causing sedimentation and landward transformation, which contributed to the expansion of S. alterniflora. However, the 118.05 ha mangrove forests negatively impacted S. alterniflora, as planting mangroves often involves the removal of existing S. alterniflora. Additionally, maximum tidal range and mean annual temperature positively affected saltmarshes. Our study highlighted the influence of natural factors and human activities on the spatiotemporal dynamics of both native and invasive saltmarshes in rapidly silting bays, underscoring the urgent need for conservation, restoration, and management of native saltmarshes.
Re-evaluating large for gestational age: differential effects on perinatal outcomes in term and premature births
Authors: Kuo Chun-Heng , Wu Yi-Ling , Chen Chi-Nien , Lo Yu-Ru , Yen I-Weng , Fan Kang-Chih , Tai Yi-Yun , Lin Ming-Wei , Hsu Chih-Cheng , Li Hung-Yuan 
Published: January 2025

ObjectivePregnancies with large-for-gestational-age (LGA) fetuses are associated with increased risks of various adverse perinatal outcomes. While existing research primarily focuses on term neonates, less is known about preterm neonates. This study aims to explore the risks of adverse maternal and neonatal perinatal outcomes associated with LGA in term neonates and neonates with different degrees of prematurity, compared to appropriate-for-gestational-age (AGA) neonates.MethodsUsing the Birth Reporting Databases (2007–2018) linked to Taiwan's National Health Insurance Research Database, we conducted a retrospective nationwide cohort study of singleton neonates delivered between 24 and 42 weeks of gestation. Based on gestational age at delivery, the enrolled neonates were classified into term (37–42 weeks of gestation), late preterm (34–36 weeks of gestation), moderate preterm (32–33 weeks of gestation), very preterm (28–31 weeks of gestation), and extremely preterm (24–27 weeks of gestation). LGA was defined by the 2013 World Health Organization (WHO) growth standard and the Taiwan growth standard. Perinatal outcomes were compared between LGA and AGA neonates across different gestational age groups.ResultsAmong the 1,602,638 neonates, 44,359 were classified as LGA by the 2013 WHO growth standard. Compared to AGA neonates, LGA neonates in term and late preterm groups exhibited higher risks of primary cesarean section, prolonged labor, neonatal hypoglycemia, birth trauma, hypoxic ischemic encephalopathy, jaundice needing phototherapy, respiratory distress, neonatal intensive care unit (NICU) admission, newborn sepsis, and fetal death. However, most of these risks were not increased in moderate, very, and extremely preterm groups. Conversely, being LGA was associated with lower risks of primary cesarean section (very preterm group), jaundice needing phototherapy (moderate and very preterm groups), respiratory distress (moderate and very preterm groups), NICU admission (moderate and very preterm groups), newborn sepsis (very preterm group), retinopathy of prematurity (late, moderate, and very preterm groups), and bronchopulmonary dysplasia (very preterm group). These findings remained consistent when the Taiwan growth standard was applied.ConclusionBeing LGA is associated with increased risks of perinatal complications in term and late preterm neonates, but not in earlier preterm groups. These findings underscore the importance of tailoring management strategies for LGA neonates to consider different degrees of prematurity.
Trends in the prevalence of Chronic Kidney Disease in the United States, 1999–2018
Authors: Zhuang Mansi , Lv Xiaogang , Zhu Yanan , Zheng Nan , Zhan Yiqiang 
Published: January 2025

BackgroundChronic Kidney Disease (CKD) is an escalating public health concern in the United States, linked with significant morbidity, mortality, and healthcare costs. Despite known risk factors like age, hypertension, and diabetes, comprehensive studies examining temporal trends in CKD prevalence are scarce. This study aims to analyze these trends using data from the National Health and Nutrition Examination Survey (NHANES).MethodsThis cross-sectional study analyzed NHANES data spanning 20 years (1999–2018), including 55,081 adults aged 20 years and above. Key renal function indicators like estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) were assessed, and CKD stages were categorized accordingly.ResultsA fluctuating trend in CKD prevalence was observed, with early CKD stages (G1–G3) increasing from 9.28% in 1999–2000 to 12.93% in 2017–2018. Advanced CKD stages (G4–G5) showed a slight increase in prevalence from 0.3% in 1999–2000 to 0.51% in 2017–2018. Notable disparities were observed across age groups, diabetes status, and racial categories. Relatively, the elderly, women, and non-Hispanic whites have a higher prevalence of CKD, while individuals with diabetes have a consistently higher prevalence of early CKD from 1999 to 2018. The increasing prevalence of diabetes during the study period highlights its significant role as a CKD risk factor.ConclusionThe prevalence of CKD in the U.S. has been rising over the period 1999–2018, and varying across demographic groups, underscoring significant disparities and risk factors. These insights are crucial for healthcare planning, policy formulation, and targeted interventions for CKD management.
Influence of kinesiophobia on activity, function, and anxiety levels in patients with rheumatoid arthritis
Authors: Xueying Shang , Yanli You , Wei Xu , Lingling Zhang , Lili Li 
Published: January 2025

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and affects quality of life. Appropriate physical activity can enhance joint function and lower cardiovascular disease risk. However, individuals with RA often have reduced physical activity levels, likely due to kinesiophobia, or fear of movement.AimThis study aimed to assess the prevalence of kinesiophobia among RA patients and its influence on functional impairment, physical activity, and pain-related anxiety.MethodsUsing a convenience sampling method, we surveyed 350 RA patients attending outpatient clinics in the rheumatology and immunology departments of three tertiary hospitals in Henan Province, China, from August 18 to September 1, 2023. Participants completed the Tampa Scale of Kinesiophobia (TSK), the Signals of Functional Impairment Scale (SOFI), the International Physical Activity Scale—Short Form (IPAQ-SF), and the Pain Anxiety Symptoms Scale-20 (PASS-20). The Disease Activity Score 28 (DAS28) was retrieved for each participant to assess disease activity in RA patients. Descriptive analysis, Chi-square tests, Spearman correlation, and multiple linear regression assessed factors influencing kinesiophobia, with significance set at p &lt; 0.05.ResultsResults indicated that 70.86% of participants experienced kinesiophobia, which was positively correlated with functional impairment and pain-related anxiety, while inversely related to physical activity levels (p &lt; 0.001). Regression analysis revealed that kinesiophobia was explained by 65.5% of the variance, with gender, education level, functional impairment, pain-related anxiety, and pain severity identified as significant predictors (p &lt; 0.05).ConclusionThe findings suggest that RA patients exhibit a high prevalence of kinesiophobia, predominantly influenced by factors such as gender, lower educational attainment, increased pain levels, greater functional impairment, and pain-related anxiety. Notably, physical activity levels did not serve as a predictor of kinesiophobia in this cohort.
Effect of acupuncture on the gait disturbance and hemodynamic changes in the prefrontal cortex: a study protocol for a randomized controlled trial
Authors: Hong Zhenmei , Zhang Shuijing , Zhang Shuqing , Zhao Yuqi , Ye Xiancong , Shu Xinxin , Chen Yufan , Yan Shuding , Ma Ruijie 
Published: January 2025

BackgroundAlzheimer’s disease (AD) is characterized by cognitive impairment and behavioral impairment. The gait of AD patients is attracting the increasing attention. The aim of this randomized controlled trial (RCT) is to explore the effect of acupuncture on the cognitive function, gait performance, and hemodynamic changes in the prefrontal cortices.MethodsIn this RCT, a total of 108 AD patients will be randomly assigned into acupuncture group or control group for 8 weeks. The primary outcome will be three-dimensional gait analysis and cerebral hemodynamics using functional near-infrared spectroscopy (fNIRS). Secondary outcomes will include Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Barthel Index (BI).DiscussionThis trial is expected to explore the effect of acupuncture on cognitive function, gait performance, and hemodynamic changes in the prefrontal cortices for AD patients.
Exploring the clinical significance of anti-acetylcholine receptor antibody titers, changes, and change rates in Myasthenia Gravis
Authors: Luo Lijun , Zhu Xinyi , Wen Chunbei , Guo Yifan , Yang Jie , Wei Dongsheng , Yu Ping , Wan Mei 
Published: January 2025

Introduction/AimsMyasthenia Gravis (MG) is a common neuromuscular junction disorder that is primarily mediated by anti-acetylcholine receptor antibodies (AChR-Ab). However, using AChR-Ab titers to predict MG severity and improvement remains controversial. This study aims to explore the relationship between AChR-Ab titers and AChR-Ab rate of change (RR-AChR-Ab, %) and MG scores.MethodsWe used a prospective study approach, and included 62 patients with generalized MG (GMG) who were positive for AChR-Ab. We measured AChR-Ab titers, MGFA-QMGS, and MG-ADL scores at baseline (before treatment) and at 3 and 6 months into treatment. Pearson and Spearman correlation analyses were used to study the relationships between changes in AChR-Ab titers, rates of change, and MG scores.Results(1) At baseline, there was no correlation between AChR-Ab titers and age, duration of illness, gender, MGFA classification, or presence of thymic abnormalities. (2) The trend of decreasing AChR-Ab titers matched the trend of reduced QMGS and ADL scores. (3) Six months into treatment,there was a correlation between AChR-Ab titer changes and changes in ADL scores. (4) Three months into treatment, RR-AChRAb showed a correlation with the rate of change in ADL at the same time point.ConclusionWe found the trend of decreased AChR-Ab titers after standardized treatment that was consistent with reductions in QMGS and ADL scores. Additionally, the rate of change in AChR-Ab titers at 3 months and the change in AChR-Ab titers at 6 months into treatment did reflect improvements in activities of daily living for MG patients.
Long COVID-19–related and non-COVID-19 postviral olfactory dysfunction a comparative MRI study focusing on the olfactory cleft and bulbs
Authors: Li Yifan , Liu Mengfan , Zhang Ruoqi , Wang Yibei , Liu Jianfeng 
Published: January 2025

ObjectiveTo compare the magnetic resonance imaging (MRI) features of the olfactory cleft (OC) and olfactory bulbs (OBs) in patients with long COVID-19-related (LCOD) and non-COVID-19 postviral olfactory dysfunction (NCPVOD) to explore mechanisms underlying persistent olfactory dysfunction.MethodsThis retrospective analysis included patients diagnosed with LCOD or NCPVOD at the China–Japan Friendship Hospital between February 2023 and July 2024. All patients underwent olfactory psychophysical testing (Sniffin’ Sticks), a visual analogue scale (VAS) for olfactory function, and high-resolution MRI scans of the olfactory pathway. MRI features, including OC opacity, OB morphology, OB volume, and olfactory sulcus depth, were compared between groups. Correlations between MRI findings and olfactory test scores were assessed.ResultsSeventy patients were included (35 LCOD, 35 NCPVOD). LCOD patients had significantly higher OC opacity scores than NCPVOD patients (p &lt; 0.001). No significant differences were found in OB morphology, abnormal OB signals, OB volume reduction, or distances between OBs and surrounding structures (p &gt; 0.05). LCOD patients had significantly greater right olfactory sulcus depth than NCPVOD patients (p = 0.026), with negative correlation to age (r = −0.25, p = 0.04). OB volumes positively correlated with TDI and VAS scores.ConclusionLCOD patients exhibited greater OC opacity than NCPVOD patients, suggesting OC inflammation may contribute to persistent olfactory dysfunction. Treating inflammation in the OC could improve long-term olfactory outcomes. OB volume reduction was common in both groups.