bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome analysis reveals genes associated with stem cell activation by physical exercise in the dentate gyrus of aged p16Ink4a knockout mice
Authors: Micheli Laura , D'Andrea Giorgio , Creanza Teresa Maria , Volpe Daniel , Ancona Nicola , Scardigli Raffaella , Tirone Felice 
Published: October 2023

Throughout adulthood neural stem cells divide in neurogenic niches–the dentate gyrus of the hippocampus and the subventricular zone–producing progenitor cells and new neurons. Stem cells self-renew, thus preserving their pool. Furthermore, the number of stem/progenitor cells in the neurogenic niches decreases with age. We have previously demonstrated that the cyclin-dependent kinase inhibitor p16Ink4a maintains, in aged mice, the pool of dentate gyrus stem cells by preventing their activation after a neurogenic stimulus such as exercise (running). We showed that, although p16Ink4a ablation by itself does not activate stem/progenitor cells, exercise strongly induced stem cell proliferation in p16Ink4a knockout dentate gyrus, but not in wild-type. As p16Ink4a regulates stem cell self-renewal during aging, we sought to profile the dentate gyrus transcriptome from p16Ink4a wild-type and knockout aged mice, either sedentary or running for 12 days. By pairwise comparisons of differentially expressed genes and by correlative analyses through the DESeq2 software, we identified genes regulated by p16Ink4a deletion, either without stimulus (running) added, or following running. The p16Ink4a knockout basic gene signature, i.e., in sedentary mice, involves upregulation of apoptotic, neuroinflammation- and synaptic activity-associated genes, suggesting a reactive cellular state. Conversely, another set of 106 genes we identified, whose differential expression specifically reflects the pattern of proliferative response of p16 knockout stem cells to running, are involved in processes that regulate stem cell activation, such as synaptic function, neurotransmitter metabolism, stem cell proliferation control, and reactive oxygen species level regulation. Moreover, we analyzed the regulation of these stem cell-specific genes after a second running stimulus. Surprisingly, the second running neither activated stem cell proliferation in the p16Ink4a knockout dentate gyrus nor changed the expression of these genes, confirming that they are correlated to the stem cell reactivity to stimulus, a process where they may play a role regulating stem cell activation.
Electrokinetic properties of healthy and β-thalassemia erythrocyte membranes under in vitro exposure to static magnetic field
Authors: Doltchinkova Virjinia , Lozanova Siya , Rukova Blaga , Nikolov Rumin , Ivanova Elitsa , Roumenin Chavdar 
Published: October 2023

Introduction: The current understanding of the biological impacts of a static magnetic field (SMF) is restricted to the direct interactions of the magnetic field with biological membranes. The electrokinetic (zeta) potential is an electrochemical property of erythrocyte surfaces which was negatively charged in physiological media after SMF exposure (0.1‒2.0 T).Methods: The novel data about electrokinetic parameters of the erythrocytes is determined by microelectrophoresis after SMF-exposure in norm and heterozygous β-thalassemia. The methods of light scattering, lipid peroxidation, fluorescence microscopy are used.Results: The electrokinetic potential of erythrocytes in norm is increased after SMF intensities due to enhanced negatively exposed charges on the outer surface of the membrane accompanied by an increase in light scattering where changes in cell morphology are observed. Conversely, a decrease in the zeta potential of β-thalassemia erythrocytes upon SMF-treatment was determined because of the reduction in the surface electrical charge of the membranes, where a significant decrease in light scattering at 1.5 T and 2.0 T was recorded. Exposure to SMF (0.5–2.0 T) was associated with an increase in the malondialdehyde content in erythrocytes. Biophysical studies regarding the influence of SMF on the electrostatic free energy of cells shows an increase in negative values in healthy erythrocytes, which corresponds to the implementation of a spontaneous process. This is also the process in β-thalassemia cells after SMF exposure with lower negative values of free electrostatic energy than erythrocytes in norm.Discussion: The effect of static magnetic field (SMF 0.1–2.0 T) on the electrokinetic and morphological characteristics of erythrocytes in norm and β-thalassemia is determined and correlated with the increase/reduction in surface charge and shrinkage/swelling of the cells, respectively. Lipid peroxidation of healthy and β-thalassemia erythrocytes caused an enhancement of lipid peroxidation because of the higher concentrations of TBARS products in cellular suspension. SMF (0.1‒2.0 T) altered the spontaneous chemical processes with negative values of electrostatic free energy of erythrocytes in norm and β-thalassemia accompanied by a lower FITC-Concanavalin A binding affinity to membrane receptors (SMF 2.0 T). The electrokinetic properties of human erythrocytes in norm and β-thalassemia upon SMF treatment and their interrelationship with the structural-functional state of the membrane were reported. The presented work would have future fundamental applications in biomedicine.
Persistent ciprofloxacin exposure induced the transformation of Klebsiella pneumoniae small colony variant into mucous phenotype
Authors: Zou Hua , Li Qian , Su Yan , Zhang Lei , Zhang Xinyuan , Li Chunli 
Published: October 2023

IntroductionSmall colony variant (SCV) is a bacterial phenotype closely related to persistent and recurrent infections. SCVs are mutations that occur within bacterial populations, resulting in a change in bacterial morphology and the formation of small colonies. This morphological change may enhance bacterial resistance to antibiotics and contribute to persistent and recurrent infections.MethodsWe isolated Klebsiella pneumoniae (KPN) and its SCV from a child with recurrent respiratory tract infections. KPN and SCV were treated with subinhibitory concentrations of antibiotics. growth curves, serum resistance experiments, macrophage phagocytosis experiments and whole genome sequencing were used to characterize KPN and SCV.ResultsAfter treating KPN and SCV with subinhibitory concentrations of antibiotics, we found that ciprofloxacin induced the SCV transition to the mucoid phenotype. We found that the growth of mucoid Klebsiella pneumoniae was significantly slower than maternal strain and SCV though growth curves. Serum resistance experiments showed that mucoid strains had significantly higher serum resistance compared to maternal strain and SCV. Macrophage phagocytosis experiments revealed that SCV had significantly higher intracellular survival rates compared to maternal strain and mucoid strains. Differential gene analysis of three strains revealed that the mucoid strain contained DNA polymerase V subunit UmuC gene on the plasmid, while the SCV strain had an additional IcmK family IV secretion protein on its plasmid.DiscussionOur study showed the SCV of KPN changed to a mucoid colony when exposed to subinhibitory concentrations of ciprofloxacin. The higher resistance of serum of mucoid colonies was possibly related to the UmuC gene, while the increased intracellular survival of SCV may be related to the IcmK family type IV secretion proteins.
Abnormal left ventricular systolic reserve function detected by treadmill exercise stress echocardiography in asymptomatic type 2 diabetes
Authors: Duan Yuyou , Ye Luwei , Shu Qinglan , Huang Yu , Zhang Hongmei , Zhang Qingfeng , Ding Geqi , Deng Yan , Li Chunmei , Yin Lixue , Wang Yi 
Published: October 2023

AimsSubclinical left ventricular (LV) dysfunction may occur in T2DM patients at the early asymptomatic stage, and LV reserve function is a sensitive index to detect subtle LV dysfunction. The purpose of our study is (1) to assess the LV reserve function using treadmill exercise stress echocardiography (ESE) in asymptomatic type 2 diabetes mellitus (T2DM) patients; (2) to explore the link of serum biological parameters and LV reserve function.MethodsThis study included 84 patients with asymptomatic T2DM from September 2021 to July 2022 and 41 sex- and age-matched healthy controls during the corresponding period. All subjects completed treadmill ESE, LV systolic function-related parameters such as global longitudinal strain (GLS) and systolic strain rate (SRs), as well as diastolic function-related parameters such as E wave (E), early diastolic velocity (e′), E/e′ ratio, early diastolic SR (SRe), and late diastolic SR (SRa) were compared at rest and immediately after exercise. The difference between LV functional parameters after treadmill exercise and its corresponding resting value was used to compute LV reserve function. In addition, the associations of LV reserve function and serum biological parameters were analyzed.ResultsPatients with T2DM did not significantly vary from the controls in terms of alterations in LV diastolic reserve measures, the changes of LVGLS and SRs (ΔGLS: 2.19 ± 2.72% vs. 4.13 ± 2.79%, P &lt; 0.001 and ΔSRs:0.78 ± 0.33 s−1 vs. 1.02 ± 0.28 s−1, P &lt; 0.001) in the T2DM group were both lower than those in the control group. Glycated hemoglobin (HbA1c), N-terminal pro-brain natriuretic peptide (NTproBNP), waist circumference, and high-sensitive C-reactive protein (hsCRP) were identified as independent predictors of LV systolic reserve by stepwise multiple linear regression analysis.ConclusionLV systolic reserve function, as measured by pre- and post-exercise differences in GLS and SRs were significantly impaired in patients with asymptomatic T2DM, whereas diastolic reserve remained normal during exercise and was comparable to that of the control group. This was different from previous findings. High levels of HbA1c, NTproBNP, hsCRP, and increasing waist circumference were independent predictors of LV systolic reserve.
Serial RV wall stress measurements: association with right ventricular function in repaired Tetralogy of Fallot patients
Authors: Minderhoud Savine C. S. , Hirsch Alexander , Marin Francesca , Kardys Isabella , Rodríguez-Matas José F. , Chiastra Claudio , Roos-Hesselink Jolien W. , Wentzel Jolanda J. , Helbing Willem A. , Akyildiz Ali C. 
Published: October 2023

BackgroundOptimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction.ObjectivesTo investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients.MethodsTen TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models.ResultsIncreased wall stress correlated with lower RV mass (rrm = −0.70, p = 0.017) and lower RV mass-to-volume (rrm = −0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p &lt; 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity.ConclusionsUsing a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.
Analysis of immortal-time effect in post-infarction ventricular septal defect
Authors: González-Pacheco Héctor , Ortega-Hernandez Jorge Arturo , Meza-López Jesús Ángel , Soliz-Uriona Luis Alejandro , Manzur-Sandoval Daniel , Gopar-Nieto Rodrigo , Araiza-Garaygordobil Diego , Sierra-Lara Daniel , Arias-Sánchez Eduardo , Sandoval Juan Pablo , Altamirano-Castillo Alfredo , Mendoza-García Salvador , Arzate-Ramírez Arturo , Baranda-Tovar Francisco Martin , Martinez Humberto , Montañez-Orozco Álvaro , Baeza-Herrera Luis Augusto , Sierra-González De Cossio Alejandro , Arias-Mendoza Alexandra 
Published: October 2023

IntroductionTime-fixed analyses have traditionally been utilized to examine outcomes in post-infarction ventricular septal defect (VSD). The aims of this study were to: (1) analyze the relationship between VSD closure/non-closure and mortality; (2) assess the presence of immortal-time bias.Material and methodsIn this retrospective cohort study, patients with ST-elevation myocardial infarction (STEMI) complicated by VSD. Time-fixed and time-dependent Cox regression methodologies were employed.ResultsThe study included 80 patients: surgical closure (n = 26), transcatheter closure (n = 20), or conservative management alone (n = 34). At presentation, patients without VSD closure exhibited high-risk clinical characteristics, had the shortest median time intervals from STEMI onset to VSD development (4.0, 4.0, and 2.0 days, respectively; P = 0.03) and from STEMI symptom onset to hospital arrival (6.0, 5.0, and 0.8 days, respectively; P &lt; 0.0001). The median time from STEMI onset to closure was 22.0 days (P = 0.14). In-hospital mortality rate was higher among patients who did not undergo defect closure (50%, 35%, and 88.2%, respectively; P &lt; 0.0001). Closure of the defect using a fixed-time method was associated with lower in-hospital mortality (HR = 0.13, 95% CI 0.05–0.31, P &lt; 0.0001, and HR 0.13, 95% CI 0.04–0.36, P &lt; 0.0001, for surgery and transcatheter closure, respectively). However, when employing a time-varying method, this association was not observed (HR = 0.95, 95% CI 0.45–1.98, P = 0.90, and HR 0.88, 95% CI 0.41–1.87, P = 0.74, for surgery and transcatheter closure, respectively). These findings suggest the presence of an immortal-time bias.ConclusionsThis study highlights that using a fixed-time analytic approach in post-infarction VSD can result in immortal-time bias. Researchers should consider employing time-dependent methodologies.
The molecular mechanism underlying dermatomyositis related interstitial lung disease: evidence from bioinformatic analysis and in vivo validation
Authors: Zeng Li , Tang Yiping , Zhang Yichen , Yue Li , Ma Gang , Ye Xumin , Yang Lijing , Chen Kai , Zhou Qiao 
Published: October 2023

BackgroundDermatomyositis (DM) is an autoimmune and inflammatory disease that can affect the lungs, causing interstitial lung diseases (ILD). However, the exact pathophysiological mechanisms underlying DM-ILD are unknown. Idiopathic pulmonary fibrosis (IPF) belongs to the broader spectrum of ILD and evidence shows that common pathologic pathways might lie between IPF and DM-ILD.MethodsWe retrieved gene expression profiles of DM and IPF from the Gene Expression Omnibus (GEO) and utilized weighted gene co-expression network analysis (WGCNA) to reveal their co-expression modules. We then performed a differentially expressed gene (DEG) analysis to identify common DEGs. Enrichment analyses were employed to uncover the hidden biological pathways. Additionally, we conducted protein-protein interaction (PPI) networks analysis, cluster analysis, and successfully found the hub genes, whose levels were further validated in DM-ILD patients. We also examined the relationship between hub genes and immune cell abundance in DM and IPF. Finally, we conducted a common transcription factors (TFs)-genes network by NetworkAnalyst.ResultsWGCNA revealed 258 intersecting genes, while DEG analysis identified 66 shared genes in DM and IPF. All of these genes were closely related to extracellular matrix and structure, cell-substrate adhesion, and collagen metabolism. Four hub genes (POSTN, THBS2, COL6A1, and LOXL1) were derived through intersecting the top 30 genes of the WGCNA and DEG sets. They were validated as active transcripts and showed diagnostic values for DM and IPF. However, ssGSEA revealed distinct infiltration patterns in DM and IPF. These four genes all showed a positive correlation with immune cells abundance in DM, but not in IPF. Finally, we identified one possible key transcription factor, MYC, that interact with all four hub genes.ConclusionThrough bioinformatics analysis, we identified common hub genes and shared molecular pathways underlying DM and IPF, which provides valuable insights into the intricate mechanisms of these diseases and offers potential targets for diagnostic and therapeutic interventions.
Molecular and clinical characterization of ANG expression in gliomas and its association with tumor-related immune response
Authors: Wang Jin , Shan Aijun , Shi Fei , Zheng Qijun 
Published: October 2023

BackgroundAngiogenin (ANG) has been widely reported as a crucial molecular regulator in multiple malignancies. However, its role in gliomagenesis remains unclear. This study aimed to investigate the molecular and clinical characterization of ANG expression at transcriptome level and the association with glioma-related immune response.MethodsA total of 301 glioma samples with mRNA microarray data (CGGA301) was obtained from the official website of CGGA project for yielding preliminary results, followed by validation in two independent RNAseq datasets, including TCGA with 697 samples and CGGA325 with 325 patients. Moreover, CGGA single-cell RNAseq (scRNAseq) data were analyzed to identify differential and dynamic ANG expression in different cells. Immunohistochemistry was performed to evaluate ANG protein expression across different WHO grades in a tissue microarray (TMA). Figure generation and statistical analysis were conducted using R software.ResultsANG expression was associated with clinical features, malignant phenotypes, and genomic alterations. Based on significantly correlated genes of ANG, subsequent gene ontology (GO) and gene set enrichment analysis (GSEA) concordantly pointed to the significant association of ANG in immune-related biological processes. Moreover, ANG showed robust correlations with canonical immune checkpoint molecules, including PD1 signaling, CTLA4, TIM3, and B7H3. Gene sets variation analysis (GSVA) found that ANG was particularly associated with activities of macrophages and antigen presentation cells (APCs) in both LGG and GBM across different datasets. Furthermore, the higher-ANG milieu seemed to recruit monocyte–macrophage lineage and dendritic cells into the glioma microenvironment. According to scRNAseq analysis, ANG was mainly expressed by neoplastic cells and tumor-associated macrophages (TAMs) and was correlated with the initiation and progression of tumor cells and the polarization of TAMs. Finally, Kaplan–Meier plots demonstrated that higher expression of ANG was significantly correlated with shorter survival in gliomas. Cox regression analysis further confirmed ANG as an independent predictor of prognosis for gliomas of all three datasets.ConclusionANG is significantly correlated with a range of malignant and aggressive characteristics in gliomas and reveals considerable prognostic value for glioma patients. ANG seems to be primarily associated with immune activities of macrophages and APCs in gliomas. Furthermore, ANG is mainly expressed in neoplastic cells and TAMs and is involved in the initiation and progression of neoplastic cells as well as macrophage polarization.
Cardiovascular disease and thinning of retinal nerve fiber layer in a multi-ethnic Asian population: the Singapore epidemiology of eye diseases study
Authors: Majithia Shivani , Quek Debra Q. Y. , Chee Miao Li , Lim Zhi Wei , Nusinovici Simon , Soh Zhi-Da , Thakur Sahil , Rim Tyler Hyungtaek , Sabanayagam Charumathi , Cheng Ching-Yu , Tham Yih-Chung 
Published: October 2023

IntroductionOur study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study.Methods6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure.ResultsWe observed a significant association between CVD history and thinner average RNFL (β = −1.63; 95% CI, −2.70 to −0.56; p = 0.003). This association was consistent for superior (β = −1.79, 95% CI, −3.48 to −0.10; p = 0.038) and inferior RNFL quadrant (β = −2.14, 95% CI, −3.96 to −0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (β = −1.75, 95% CI, −3.08 to −0.42; p = 0.010), superior (β = −2.22, 95% CI, −4.36 to −0.09; p = 0.041) and inferior (β = −2.42, 95% CI, −4.64 to −0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (β = −1.92, 95% CI, −3.52 to −0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (β = −0.22, 95% CI, −1.15 to 0.71; p = 0.641).DiscussionIn this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.