bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leisure-time physical activity trajectories from adolescence to adulthood in relation to several activity domains: a 27-year longitudinal study
Authors: Mathisen Frida Kathrine Sofie , Torsheim Torbjørn , Falco Coral , Wold Bente 
Published: March 2023

Abstract
Background
Insufficient physical activity (PA) levels among adolescents and adults make promoting PA a public health priority. Although most people exhibit low or decreasing levels of PA, other groups increase or maintain high levels of activity. These different groups may engage differently in activity domains during their leisure time. This study aimed to identify distinct trajectories of leisure-time vigorous physical activity (LVPA) and to explore whether these trajectories are characterised by differences in four activity domains (participation in organised sports clubs, diversity in leisure-time activities, outdoor recreation, and peer PA) over the life course.

Methods
Data were drawn from the Norwegian Longitudinal Health Behaviour Study. The sample of participants (n = 1103, 45.5% female) was surveyed 10 times from age 13 years in 1990 to age 40 years in 2017. LVPA trajectories were identified using latent class growth analysis, and mean differences in activity domains were studied using the one-step BCH approach.

Results
Four trajectories were identified: active (9%), increasingly active (12%), decreasingly active (25%), and low active (54%). Overall, this analysis showed a declining tendency in LVPA from age 13 to 40 years except for the increasingly active trajectory. Belonging to a trajectory with a higher LVPA level was related to higher mean levels of the included activity domains. Compared with those in the increasing trajectory, people belonging to the decreasing trajectory reported higher mean participation levels in and age at becoming a member of sports clubs, diversity in leisure-time activities, and best friend’s activity level during adolescence. However, in young adulthood, people in the increasingly active trajectory reported significantly higher mean levels for the same variables.

Conclusions
The development of LVPA from adolescence to adulthood is heterogeneous, suggesting the need for targeted health promotion initiatives. The largest trajectory group included more than 50 percent and was characterized by low levels of LVPA, less engagement in PA domains and fewer active friends. There seems to be little carry-over effect of engagement in organised sports in adolescence regarding level of LVPA later in life. Changes in social surroundings throughout the life span, such as having friends who are more or less engaged in PA, may assist or hinder health enhancing engagement in LVPA.
Identification of novel immune subtypes and potential hub genes of patients with psoriasis
Authors: Li Yingxi , Li Lin , Tian Yao , Luo Jing , Huang Junkai , Zhang Litao , Zhang Junling , Li Xiaoxia , Hu Lizhi 
Published: March 2023

Abstract
Background
Psoriasis is a common, chronic and relapsing immune-related inflammatory dermal disease. Patients with psoriasis suffering from the recurrences is mainly caused by immune response disorder. Thus, our study is aimed to identify novel immune subtypes and select targeted drugs for the precision therapy in different subtypes of psoriasis.

Methods
Differentially expressed genes of psoriasis were identified from the Gene Expression Omnibus database. Functional and disease enrichment were performed by Gene Set Enrichment Analysis and Disease Ontology Semantic and Enrichment analysis. Hub genes of psoriasis were selected from protein–protein interaction networks using Metascape database. The expression of hub genes was validated in human psoriasis samples by RT-qPCR and immunohistochemistry. Further, novel immune subtypes of psoriasis were identified by ConsensusClusterPlus package and its association with hub genes were calculated. Immune infiltration analysis was performed, and its candidate drugs were evaluated by Connectivity Map analysis.

Results
182 differentially expressed genes of psoriasis were identified from GSE14905 cohort, in which 99 genes were significantly up-regulated and 83 genes were down-regulated. We then conducted functional and disease enrichment in up-regulated genes of psoriasis. Five potential hub genes of psoriasis were obtained, including SOD2, PGD, PPIF, GYS1 and AHCY. The high expression of hub genes was validated in human psoriasis samples. Notably, two novel immune subtypes of psoriasis were determined and defined as C1 and C2. Bioinformatic analysis showed C1 and C2 had different enrichment in immune cells. Further, candidate drugs and mechanism of action that applicable to different subtypes were evaluated.

Conclusions
Our study identified two novel immune subtypes and five potential hub genes of psoriasis. These findings might give insight into the pathogenesis of psoriasis and provide effective immunotherapy regimens for the precise treatment of psoriasis.
Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy
Authors: Li Wenjie , Ding Lixia , Shi Wenhua , Wan Xinyu , Yang Xiaomin , Yang Jing , Wang Tianyi , Song Lili , Wang Xiang , Ma Yani , Luo Chengjuan , Tang Jingyan , Gu Longjun , Chen Jing , Lu Jun , Tang Yanjing , Li Benshang 
Published: March 2023

Abstract
Background
CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1).

Methods
In this study, we recruited five patients who relapsed after CD19-targeted CAR-T. CD19- and CD22-CAR lentivirus-transfected T cells were cultured separately and mixed before infusion in an approximate ratio of 1:1. The total dose range of CD19 and CD22 CAR-T was 4.3 × 106–1.5 × 107/kg. Throughout the trial, we evaluated the patients’ clinical responses, side effects, and the expansion and persistence of CAR-T cells.

Results
After CART2, all five patients had minimal residual disease (MRD)-negative complete remission (CR). The 6- and 12-month overall survival (OS) rates were 100%. The median follow-up time was 26.3 months. Three of the five patients bridged to consolidated allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CART2 and remained in MRD-negative CR at the cut-off time. In patient No. 3 (pt03), CAR-T cells were still detected in the peripheral blood (PB) at 347 days post-CART2. Cytokine release syndrome (CRS) only occurred with a grade of ≤ 2, and no patients experienced symptoms of neurologic toxicity during CART2.

Conclusions
Mixed infusion of CD19- and CD22-targeted CAR-T cells is a safe and effective regimen for children with B-ALL who relapse after prior CD19-targeted CAR-T therapy. Salvage CART2 provides an opportunity for bridging to transplantation and long-term survival.
Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032211. Retrospectively registered: April 23, 2020.
PHF6 recruits BPTF to promote HIF-dependent pathway and progression in YAP-high breast cancer
Authors: Gao Sheng , Zhang Wensheng , Ma Jingjing , Ni Xiaojian 
Published: March 2023

Abstract
Background
Aberrant epigenetic remodeling events contribute to progression and metastasis of breast cancer (Bca). The specific mechanims that epigenetic factors rely on to mediate tumor aggressiveness remain unclear. We aimed to elucidate the roles of epigenetic protein PHF6 in breast tumorigenesis.

Methods
Published datasets and tissue samples with PHF6 staining were used to investigate the clinical relevance of PHF6 in Bca. CCK-8, clony formation assays were used to assess cell growth capacity. Cell migration and invasion abilities were measured by Transwell assay. The gene mRNA and protein levels were measured by quantitative real-time PCR and western blot. Chromatin immunoprecipitation (ChIP)-qPCR assays were used to investigate transcriptional relationships among genes. The Co-immunoprecipitation (Co-IP) assay was used to validate interactions between proteins. The CRISPR/Cas9 editing technology was used to construct double HIF knockout (HIF-DKO) cells. The subcutaneous xenograft model and orthotopic implantation tumor model were used to asess in vivo tumor growth.

Results
In this study, we utilized MTT assay to screen that PHF6 is required for Bca growth. PHF6 promotes Bca proliferation and migration. By analyzing The Cancer Genome Atlas breast cancer (TCGA-Bca) cohort, we found that PHF6 was significantly higher in tumor versus normal tissues. Mechanistically, PHF6 physically interacts with HIF-1α and HIF-2α to potentiate HIF-driven transcriptional events to initiate breast tumorigenesis. HIF-DKO abolished PHF6-mediated breast tumor growth, and PHF6 deficiency in turn impaired HIF transcriptional effects. Besides, hypoxia could also rely on YAP activation, but not HIF, to sustain PHF6 expressions in Bca cells. In addition, PHF6 recuits BPTF to mediate epigenetic remodeling to augment HIF transcriptional activity. Targeting PHF6 or BPTF inhibitor (AU1) is effective in mice models. Lastly, PHF6 correlated with HIF target gene expression in human breast tumors, which is an independent prognostic regulator.

Conclusions
Collectively, this study identified PHF6 as a prognostic epigenetic regulator for Bca, functioning as a HIF coactivator. The fundamental mechanisms underlying YAP/PHF6/HIF axis in breast tumors endowed novel epigenegtic targets for Bca treatment.
Multi-omics and experimental analysis unveil theragnostic value and immunological roles of inner membrane mitochondrial protein (IMMT) in breast cancer
Authors: Lin Hung-Yu , Wu Hsing-Ju , Chu Pei-Yi 
Published: March 2023

Abstract
Background
The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear.

Methods
Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings.

Results
High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression.

Conclusion
This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.
Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma
Authors: Hou Xiaoying , Du Hongzhi , Deng Yufei , Wang Haiping , Liu Jinmi , Qiao Jialu , Liu Wei , Shu Xiji , Sun Binlian , Liu Yuchen 
Published: March 2023

Abstract
Background
Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ’s application, there still lack of strategies to increase the chemotherapy sensitivity.

Methods
Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman’s correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response.

Results
Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α+ T cell) recruitment.

Conclusions
The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.
Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism
Authors: Lou Bowen , Wu Haoyu , Ott Hannes , Bennewitz Katrin , Wang Chen , Poschet Gernot , Liu Hui , Yuan Zuyi , Kroll Jens , She Jianqing 
Published: March 2023

Abstract
Background
Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction.

Methods and results
Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation.

Conclusions
Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.
Microglia/macrophages require vitamin D signaling to restrain neuroinflammation and brain injury in a murine ischemic stroke model
Authors: Cui Pan , Lu Wanting , Wang Junjie , Wang Fei , Zhang Xiyue , Hou Xiaodan , Xu Fang , Liang Yan , Chai Guoliang , Hao Junwei 
Published: March 2023

AbstractVitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia–reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood–brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.
Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease
Authors: Grotemeyer Alexander , Fischer Judith F. , Koprich James B. , Brotchie Jonathan M. , Blum Robert , Volkmann Jens , Ip Chi Wang 
Published: March 2023

AbstractNeuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4+ and CD8+ T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.

Graphical Abstract
Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis
Authors: Wyatt-Johnson Season K. , Kersey Holly N. , Codocedo Juan F. , Newell Kathy L. , Landreth Gary E. , Lamb Bruce T. , Oblak Adrian L. , Brutkiewicz Randy R. 
Published: March 2023

Abstract
Background
Neuroinflammation is an important feature of Alzheimer’s disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells.

Methods
Having found that MR1 gene expression is elevated in the brain tissue of AD patients by mining the Agora database, we sought to examine the role of the MR1/MAIT cell axis in AD pathology. Brain tissue from AD patients and the 5XFAD mouse model of AD were used to analyze MR1 expression through qPCR, immunofluorescence, and flow cytometry. Furthermore, mice deficient in MR1 and MAIT cells were crossed with the 5XFAD mice to produce a model to study how the loss of this innate immune axis alters AD progression. Moreover, 5XFAD mice were also used to study brain-resident MAIT cells over time.

Results
In tissue samples from AD patients and 5XFAD mice, MR1 expression was substantially elevated in the microglia surrounding plaques vs. those that are further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD mice lacking the MR1/MAIT cell axis, the development of amyloid-beta plaque pathology occurred at a significantly slower rate than in those mice with MR1 and MAIT cells. Furthermore, in brain tissue from 5XFAD mice, there was a temporal increase in MAIT cell numbers (P < 0.01) and their activation state, the latter determined by detecting an upregulation of both CD69 (P < 0.05) and the interleukin-2 receptor alpha chain (P < 0.05) via flow cytometry.

Conclusions
Together, these data reveal a previously unknown role for the MR1/MAIT cell innate immune axis in AD pathology and its potential utility as a novel therapeutic target.
Associated factors for multidimensional attitudes and behaviors of reproductive health toward pregnancy among early and late adolescents in Tanzania: a cross-sectional study
Authors: Hirose Naoki , Sanmei Chen , Okamoto Mariko , Madeni Frida E. , Madeni Nicolaus , Teshima Ayaka , Ando Yasunobu , Takahama Koji , Yoshikawa Mayu , Kunimoto Yu , Shimpuku Yoko 
Published: March 2023

Abstract
Background
Adolescent pregnancy is a serious reproductive health problem in Tanzania. However, the risk factors for multidimensional attitudes and behaviors of reproductive health toward pregnancy in Tanzanian adolescents remain unexplored.

Methods
We collected baseline characteristics and information on attitudes and behaviors of reproductive health from 4161 Tanzanian adolescents in all 54 primary and secondary schools in the Korogwe district. We applied mixed effect multiple regression analyses stratified by sex to find the factors related to reproductive health attitudes and behaviors toward pregnancy.

Results
In female students, regarding the attitudes of reproductive health, higher age, hope for marriage in the future, a talk with a parent about sex or pregnancy, and a higher hope score were significantly associated with a lower score. For the behaviors of reproductive health, higher age, a talk with a parent about sex or pregnancy, time to talk with a parent about daily life, and a higher hope score were significantly associated with a lower score. In male students, regarding the attitudes of reproductive health, a higher hope score was significantly associated with a lower score. For the behaviors of reproductive health, higher age, time to talk with a parent about daily life, and a higher hope score was significantly associated with a lower score.

Conclusions
The heterogeneous factor-outcomes association between female and male students suggested that sex-specialized interventions may be required to change their risky attitudes or behaviors of reproductive health. Although we cannot conclude as points of intervention, our study suggested that it may be practical to improve parent-adolescents communication about sex or reproductive health and change adolescents’ views of pregnancy or marriage for gaining financial or social status.