Identification of an unfolded protein response-related signature for predicting the prognosis of pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy. An effective prognosis prediction model is urgently needed for treatment optimization.MethodsThe differentially expressed unfolded protein response (UPR)‒related genes between pancreatic tumor and normal tissue were analyzed using the TCGA-PDAC dataset, and these genes that overlapped with UPR‒related prognostic genes from the E-MTAB-6134 dataset were further analyzed. Univariate, LASSO and multivariate Cox regression analyses were applied to establish a prognostic gene signature, which was evaluated by Kaplan‒Meier curve and receiver operating characteristic (ROC) analyses. E‒MTAB‒6134 was set as the training dataset, while TCGA-PDAC, GSE21501 and ICGC-PACA-AU were used for external validation. Subsequently, a nomogram integrating risk scores and clinical parameters was established, and gene set enrichment analysis (GSEA), tumor immunity analysis and drug sensitivity analysis were conducted.ResultsA UPR-related signature comprising twelve genes was constructed and divided PDAC patients into high- and low-risk groups based on the median risk score. The UPR-related signature accurately predicted the prognosis and acted as an independent prognostic factor of PDAC patients, and the AUCs of the UPR-related signature in predicting PDAC prognosis at 1, 2 and 3 years were all more than 0.7 in the training and validation datasets. The UPR-related signature showed excellent performance in outcome prediction even in different clinicopathological subgroups, including the female (p<0.0001), male (p<0.0001), grade 1/2 (p<0.0001), grade 3 (p=0.028), N0 (p=0.043), N1 (p<0.001), and R0 (p<0.0001) groups. Furthermore, multiple immune-related pathways were enriched in the low-risk group, and risk scores in the low-risk group were also associated with significantly higher levels of tumor-infiltrating lymphocytes (TILs). In addition, DepMap drug sensitivity analysis and our validation experiment showed that PDAC cell lines with high UPR-related risk scores or UPR activation are more sensitive to floxuridine, which is used as an antineoplastic agent.ConclusionHerein, we identified a novel UPR-related prognostic signature that showed high value in predicting survival in patients with PDAC. Targeting these UPR-related genes might be an alternative for PDAC therapy. Further experimental studies are required to reveal how these genes mediate ER stress and PDAC progression

Association between mobile phone addiction, sleep disorder and the gut microbiota: a short-term prospective observational study

Bidirectional communication between the gut microbiota and the brain has sparked interest in exploring the link between mobile phone addiction (MPA) and sleep disorders (SD) in microbiome research. However, investigating the role of gut microbiota in this relationship using animal models presents challenges due to the unique nature of MPA, and human research in this area is scarce. We recruited 99 healthy college students to evaluate the gut microbiome using 16S rRNA gene amplicon sequencing and assess MPA and SD at baseline and after a two-month follow-up. Multiple covariate-adjusted statistical models, including linear regression, permutational multivariate analysis of variance and so on, were employed to determine microbiome associations with MPA at baseline and changes in SD at follow-up. Our findings revealed negative associations between MPA and three alpha diversity metrics, along with alterations in bacterial composition. MPA showed negative associations with the relative abundance of Bacteroidetes, while displaying positive associations with Actinobacteria and Bifidobacteriales. Conversely, Actinobacteria exhibited a negative association with increased SD. This study has established a significant link between MPA and a decrease in the alpha diversity of the gut microbiota. Actinobacteria was associated with MPA and SD, respectively. Additional investigation is needed to fully comprehend the relationship between comorbid behavioral disorders and the gut microbiota

Identifying Key Factors Associated with Green Justice in Accessibility: A Gradient Boosting Decision Tree Analysis

Park green space (PGS) provides numerous environmental and health benefits for urban residents, and raises the issue of green justice for its uneven distribution in cities. Previous studies focus more on the measurements of spatial equity in accessibility, but are limited in exploring its impacts—especially the nonlinear influence. This study first measures accessibility and equity in two traffic modes, and then explores the nonlinear influence of multidimensional factors by using the gradient boosting decision tree (GBDT) model across the central urban area of Wuhan. The results show significant spatial disparities in spatial accessibility and equity by walking and driving within 15 min. Multidimensional factors—including characteristics of PGS, the built environment, and socioeconomic factors—present stronger nonlinear influences on spatial accessibility and equity, and the nonlinear influence indicates that the contributions of the built environment and socioeconomic factors are greater than those of park characteristics, accounting for at least 79.76%. The key variables affecting the accessibility and equity are not completely consistent, leading to synergistic and heterogeneous effects, which may provide policy implications for streets where accessibility and equity are mismatched. These findings could provide guidance for PGS planning by decision-makers to improve the living environment and urban health

Co- and post-seismic Deformation Mechanisms of the M_W 7.3 Iran Earthquake (2017) Revealed by Sentinel-1 InSAR Observations

The extraction of high-accuracy co- and post-seismic deformation fields and inversions of seismic slip distributions is significant in the comprehension of seismogenic mechanisms. On 12 November 2017, a MW 7.3 earthquake occurred on the border between Iran and Iraq. To construct the co-seismic deformation field, Sentinel-1A synthetic aperture radar (SAR) images from three tracks were used. Based on a prior knowledge, least-squares iterative approximation was employed to construct the three-dimensional (3D) co-seismic deformation field. to derive a time series of 2D post-seismic deformation, the multidimensional small baseline subset (MSBAS) technique was use. Co-seismic deformation fields were asymmetric; the maximum relative displacement was nearly 90cm in the radar line-of-sight between two centers of co-seismic deformation. The 3D co-seismic deformation field showed southwestward horizontal motion and continuous subsidence-to-uplift variation from northeast to southwest. The two-dimensional (2D) post-seismic deformation time series showed a gradual decaying trend and good correspondence with the aftershock distribution. The main mechanism of post-seismic deformation was an afterslip of the post-seismic faults. We used the elastic half-space model to invert co-seismic deformation fields and obtain source parameters of the slip model. The maximum and average slips were 2.5 and 0.72 m, respectively. The average slip angle was 126.38° and the moment magnitude was MW 7.34. The results of this study will contribute to research on regional tectonic activities

Novel heterozygous variants in the EP300 gene cause Rubinstein–Taybi syndrome 2: Reports from two Chinese children

Abstract Background Rubinstein–Taybi syndrome (RSTS) is a rare autosomal‐dominant genetic disease caused by variants of CREBBP (RSTS1) or EP300 (RSTS2) gene. RSTS2 is much less common, with less than 200 reported cases worldwide to date. More reports are still needed to increase the understanding of its clinical manifestations and genetic characteristics. Methods The clinical data of two children with RSTS2 were analyzed retrospectively, and their clinical manifestations, auxiliary examinations, and mutational spectrum were summarized. Liquid chromatography–tandem mass spectrometer (LC–MS/MS) technology was used to detect the levels of steroid hormones if possible. Results After analyzing the clinical and genetic characteristics of two boys with RSTS2 (0.7 and 10.4 years old, respectively) admitted in our hospital, we identified two novel heterozygous variants in the EP300 exon 22 (c.3750C > A, p. Cys1250*, pathogenic; c.1889A > G, p. Tyr630Cys, likely pathogenic), which could account for their phenotype. In addition to common clinical manifestations such as special facial features, microcephaly, growth retardation, intellectual disability, speech delay, congenital heart defect, recurrent respiratory infections, and immunodeficiency, we found one of them had a rare feature of adrenal insufficiency, and LC–MS/MS detection showed an overall decrease in steroid hormones. Conclusion In our study, we identified two novel variants in the EP300 exon 22, and for the first time, we reported a case of RSTS2 associated with adrenal insufficiency, which will enrich the clinical and mutational spectrum of this syndrome

Selenium Forms and Dosages Determined Their Biological Actions in Mouse Models of Parkinson’s Disease

Selenium (Se), an essential antioxidant trace element, is reported to play a role in Parkinson’s disease (PD). However, there is a lack of systematic studies on different Se forms against PD. Our study is designed to compare the neuroprotective effects of inorganic and organic Se in two classical PD mice models and investigate the underlying mechanisms for their potentially differential actions against PD. In this study, different dosages of inorganic sodium selenite (Se-Na) or organic seleno-L-methionine (Se-Met) were fed to either acute or chronic PD mice models, and their neuroprotective effects and mechanisms were explored and compared. Se-Na provided better neuroprotective effects in PD mice than Se-Met administered at the same but at a relatively low Se dosage. Se-Na treatment could influence GPX activities but not their mRNA expressions in the midbrains of PD mice. The enhanced GPX activities caused by Se-Na, but not Se-Met, in PD mice could be the major reason for the positive actions of inorganic Se to prevent dopaminergic neuronal loss in this study. In vivo bio-distribution experiments found MPTP injection greatly changed Se bio-distribution in mice, which led to reversed alterations in the bioavailability of Se-Met and Se-Na. Se-Na had higher bioavailability than Se-Met in PD mice, which could explain its better neuroprotective effects compared to Se-Met. Our results proved that Se forms and dosages determined their biological actions in mouse models of PD. Our study will provide valuable scientific evidence to researchers and/or medical professionals in using Se for PD prevention or therapy