Salsolinol as an RNA m6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy.

JOURNAL/nrgr/04.03/01300535-202503000-00032/figure1/v/2024-06-17T092413Z/r/image-tiff Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an environmental toxin that causes Parkinson's disease. However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal significantly enhanced the global level of N6-methyladenosine (m6A) RNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5). RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway. The m6A reader YTH domain-containing family protein 2 (YTHDF2) promoted the degradation of m6A-containing Yes-associated protein 1 (YAP1) mRNA, which is a downstream key effector in the Hippo signaling pathway. Additionally, downregulation of YAP1 promoted autophagy, indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity. These findings reveal the role of Sal on m6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.

Role of NEL­like molecule­1 in osteogenesis/chondrogenesis (Review).

A dynamic balance exists between osteogenesis and osteoclastogenesis in bone tissue, which can lead to several bone diseases, such as osteoporosis, osteoarthritis, bone necrosis and bone defects, in cases of insufficient osteogenesis or excessive osteoclastogenesis. NEL­like molecule­1 (NELL­1) was first discovered in 1999 as an osteogenic factor that can prevent or treat bone diseases by increasing osteogenic levels. To date, research has identified multiple signaling pathways involved in improving osteogenic levels. Furthermore, to apply NELL­1 in clinical practice, researchers have optimized its osteogenic effect by combining it with other molecules, changing its molecular structure and performing bone tissue engineering. Currently, research on NELL­1 is gaining increasing attention. In the near future, it will definitely be applied in clinical practice to eliminate diseases. Thus, the present study provides a comprehensive review of NELL­1 in enhancing osteogenic levels from the perspectives of the molecular mechanism, interactions with other molecules/cells, molecular­level changes, applications in bone tissue engineering and its expression in tumors, providing a solid theoretical basis for its clinical application.

Agreement between Mycobacterium tuberculosis antigen-based skin test and interferon-gamma release assay in elderly individuals aged ≥ 65 years in China.

OBJECTIVES: To determine the agreement of Mycobacterium tuberculosis (MTB) antigen-based skin test (TBST) with interferon-gamma release assay (IGRA) in elderly individuals aged ≥ 65 years beyond instruction for use in China. METHODS: Based on the baseline survey of randomized controlled trial with objective to explore suitable regimen for tuberculosis (TB) preventive treatment, MTB infection was tested using TBST and IGRA in parallel in rural residents aged 50-70 years by means of a cross-sectional study design. RESULTS: A total of 21219 participants with both TBST and IGRA results were included in this analysis. The concordance between TBST and IGRA was 89.4% (95%CI: 89.0 - 89.8%) with a kappa coefficient of 0.61 (95%CI: 0.60 - 0.62). In those aged ≥ 65 years, the concordance was 86.5% (95%CI: 85.6 - 87.4%) with a kappa coefficient of 0.55 (95%CI: 0.52 - 0.58). 21.2% (35/165) of the participants with indeterminate IGRA results were TBST positive, and 9 of them aged ≥ 65 years. CONCLUSIONS: The consistent agreement between TBST and IGRA in individuals aged ≥ 65 years suggests that TBST has potential to be used in the elderly with age beyond instruction for use in China. The respective diagnostic performance of each test will be analyzed when the longitudinal data on incident TB be obtained in the future.

Behavioral effects of polylactic acid microplastics on the tadpoles of Pelophylax nigromaculatus.

Polylactic acid microplastics (PLA-MPs), biobased plastics made from renewable resources, are considered to be a potential solution for alleviating the pollution pressure of plastics; however, the potential environmental risks of PLA-MPs must be further evaluated. In this study, the effects of PLA-MPs on the tadpoles of Pelophylax nigromaculatus were investigated by designing different PLA-MP exposure experiments. We found that PLA-MPs negatively affected the survival, growth and development of tadpoles. In addition, in open field tests, PLA-MPs also reduced tadpole locomotion while resulting in more repetitive searching behavior within a restricted area. This effect was more pronounced at higher concentrations of PLA-MPs (20 mg/mL) and in combination with the heavy metal Cd2+. In the tank tests, PLA-MPs increased tadpole aggregation, and their combined effect with Cd2+ resulted in a tendency for tadpole aggregation to increase and then decrease, with the distribution tending to favor aggregation in edge regions. PLA-MPs also strongly inhibited the spatiotemporal exploratory activities of tadpoles in the tanks. This study provides a more detailed investigation of the behavioral effects of PLA-MPs on tadpoles and provides a theoretical basis for subsequent ecotoxicological studies of PLA-MPs.

Plug-and-play segment anything model improves nnUNet performance.

BACKGROUND: The automatic segmentation of medical images has widespread applications in modern clinical workflows. The Segment Anything Model (SAM), a recent development of foundational models in computer vision, has become a universal tool for image segmentation without the need for specific domain training. However, SAM's reliance on prompts necessitates human-computer interaction during the inference process. Its performance on specific domains can also be limited without additional adaptation. In contrast, traditional models like nnUNet are designed to perform segmentation tasks automatically during inference and can work well for each specific domain, but they require extensive training on domain-specific datasets. PURPOSE: To leverage the advantages of both foundational and domain-specific models and achieve fully automated segmentation with limited training samples, we propose nnSAM, which combines the robust feature extraction capabilities of SAM with the automatic configuration abilities of nnUNet to enhance the accuracy and robustness of medical image segmentation on small datasets. METHODS: We propose the nnSAM model for small sample medical image segmentation. We made optimizations for this goal via two main approaches: first, we integrated the feature extraction capabilities of SAM with the automatic configuration advantages of nnUNet, which enables robust feature extraction and domain-specific adaptation on small datasets. Second, during the training process, we designed a boundary shape supervision loss based on level set functions and curvature calculations, enabling the model to learn anatomical shape priors from limited annotation data. RESULTS: We conducted quantitative and qualitative assessments on the performance of our proposed method on four segmentation tasks: brain white matter, liver, lung, and heart segmentation. Our method achieved the best performance across all tasks. Specifically, in brain white matter segmentation using 20 training samples, nnSAM achieved the highest DICE score of 82.77 ( ± $\pm$ 10.12) % and the lowest average surface distance (ASD) of 1.14 ( ± $\pm$ 1.03) mm, compared to nnUNet, which had a DICE score of 79.25 ( ± $\pm$ 17.24) % and an ASD of 1.36 ( ± $\pm$ 1.63) mm. A sample size study shows that the advantage of nnSAM becomes more prominent under fewer training samples. CONCLUSIONS: A comprehensive evaluation of multiple small-sample segmentation tasks demonstrates significant improvements in segmentation performance by nnSAM, highlighting the vast potential of small-sample learning.

Mining and expression analysis of color related genes in Bougainvillea glabra bracts based on transcriptome sequencing.

Bract coloration is one of the key ornamental traits in Bougainvillea, yet research has predominantly focused on phenotypic color traits and pigment composition, with limited understanding of the molecular mechanisms underlying color formation. This gap hinders the improvement and innovation in bract coloration. To elucidate the regulatory mechanisms of bract coloration in Bougainvillea and to enhance the utilization of its germplasm resources, this study employed the Illumina Novaseq 6000 sequencing platform to conduct transcriptomic sequencing on 21 samples of bracts exhibiting seven distinct phenotypes. Comparative analysis against Nr, Pfam, EggNOG, GO, and KEGG databases annotated 90,279 unigenes. The highest annotation rates were achieved with the Nr (40.13%), GO (30.44%), and EggNOG (25.64%) databases. Among the species annotated, Beta vulgaris (20.08%) and Chenopodium quinoa (14.58%) shared the highest homology with Bougainvillea bract transcriptomes. WGCNA analysis identified 12 positively correlated tissue-specific modules, of which 2 are related to bract color formation. By comparing transcriptome data and genes within these specific modules against the KEGG database, a total of 321 unigenes associated with bract color formation in Bougainvillea were discovered. Among these, 220 unigenes are involved in anthocyanin synthesis, 43 unigenes are involved in betalain synthesis, 23 unigenes are annotated as Chlorophyll a-b binding protein genes, and 35 unigenes participate in carotenoid synthesis. Quantitative real-time PCR (qRT-PCR) validation of 16 differentially expressed genes (DEGs) including PAL2, CHS1, ANS, BZ1, 6GT, CDOPA5GT, ANR, CHS2, and DOPA, revealed significant expression differences among magenta, yellow, white, and cherry-colored bracts, suggesting their potential as candidate genes for bract color development. This study not only enriches the transcriptomic data of Bougainvillea but also identifies genes associated with bract coloration, providing a valuable theoretical basis for future gene cloning, genetic engineering, and breeding efforts in Bougainvillea.

Quantitative texture analysis using machine learning for predicting interpretable pulmonary perfusion from non-contrast computed tomography in pulmonary embolism patients.

BACKGROUND: Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis. METHODS: We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans. RESULTS: The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively. CONCLUSIONS: This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases. CLINICAL TRIAL NUMBER: Not applicable.

All-fiber GHz few-cycle pulse generation at 2†µm.

We demonstrate an all-fiber GHz mode-locked laser system with few-cycle duration operating at 2 µm. Based on a dispersion-managed mode-locked oscillator, a multi-stage fiber amplifier, and a nonlinear pulse compressor, the laser system can deliver watt-level few-cycle pulses at a fundamental repetition rate of 1.041 GHz. This 2-µm pulsed laser offers outstanding performance metrics, including a pulse duration of 33 fs (corresponding to ∼5 optical cycles) and an average power of 4.17 W. Moreover, the all-fiber laser system exhibits excellent power stability, and the integrated relative intensity noise (RIN) is only 0.052% (10 Hz-1 MHz). It is anticipated that this new, to the best of our knowledge, laser source is promising for frontier applications, including coherent supercontinuum generation, nonlinear frequency conversion, and laser-material interaction.

Hepatic adenosquamous carcinoma with sarcomatous transformation: a case report and review of the literature.

Adenosquamous carcinoma (ASC) with the presence of a sarcomatous component is exceptionally uncommon in intrahepatic cholangiocarcinoma (iCCA). We report a case of hepatic ASC with rhabdoid transformation, one variation of sarcomatous change. A 72-year-old man was admitted to our hospital after being diagnosed with a 45 mm-diameter neoplastic lesion in the right hepatic duct on abdominal computed tomography. Laboratory findings showed increases in AST, ALT, ALP, gamma-GT, CA19-9 and DUPAN-II. The patient then underwent an extended right hepatectomy. Histopathologically, the tumor was composed of an ASC component within an abundant fibrous stroma and a sarcomatoid carcinoma component. By immunohistochemistry, keratin 7 and keratin 19 were expressed by all tumor cells. Expression of keratin 5/6, p40 and p63 was restricted to the squamous component. The sarcomatoid component was immunoreactive for vimentin with no loss of INI1 expression. This component also showed a loss of membranous E-cadherin expression and a reduction of membranous ß-catenin expression. Staining for desmin, myoglobin and HepPar1 was negative in any tumor cells. The patient died of liver failure 3 months after surgery. This report aims to provide a better understanding of the clinicopathological characteristics and disease progression of the rare variants of iCCA to aid diagnosis and treatment.

Association of trimethylamine oxide and its precursors with cognitive impairment: a systematic review and meta-analysis.

Objectives: The role of trimethylamine oxide (TMAO) in patients with cognitive impairment remains controversial. This study aimed to assess the association between TMAO and its precursors and the prevalence of cognitive impairment. Methods: PubMed, Embase, and Web of Science databases were searched for studies that met the inclusion criteria from their inception to 14 September 2024, and references were manually searched to identify any additions. Odds ratio (OR) was assessed by random-effects modeling, subgroup analyses to identify potential sources of heterogeneity, and the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) Inventory for qualitative evaluation. Results: Nine studies involving 82,246 participants were included in the analysis. Meta-analyses suggested that elevated TMAO levels were strongly associated with an increased risk of cognitive impairment (OR: 1.39, 95% confidence interval [95%CI]: 1.09-1.77, p < 0.05, I2:60%), and consistent results were obtained across all subgroups examined and sensitivity analyses. However, in the TMAO dose-response meta-analysis and TMAO precursor meta-analyses, the results were not significantly different (dietary choline: OR: 0.93, 95%CI: 0.78-1.10, p = 0.385, I2:68%, plasma choline: OR: 0.65, 95%CI: 0.41-1.02, p = 0.063, I2:76%, plasma betaine: OR: 0.74, 95%CI: 0.52-1.05, p = 0.094, I2:61%). Conclusion: We found that high TMAO concentrations were positively associated with the risk of cognitive impairment. TMAO is expected to be a potential risk predictor and therapeutic target for cognitive impairment. However, more high-quality studies are needed to further investigate the dose relationship between circulating TMAO concentrations and cognitive impairment. Systematic review registration: PROSPERO, identifier: CRD42023464543.

Prevalence, Features and Risk Factors of Macular Retinoschisis in High Myopic Population: the Beijing Eye Study 2011: Macular Retinoschisis in High Myopic Population.

PURPOSE: To investigate the prevalence, features and risk factors of macular retinoschisis (MRS) in highly myopic eyes and their morphological features in Chinese population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: From Beijing Eye Study 2011, a total of 213 highly myopic eyes from 129 participants were included. METHODS: All participants underwent Spectral-domain optical coherence tomography with a macula cube scan of 30°â€¯× 30°centered in the fovea. MAIN OUTCOME MEASURES: High myopia was defined as a refractive error ≤-6 diopters or an axial length ≥ 26.0 mm. MRS presence and its subtypes were assessed based on location and affected retinal layers were evaluated. Prevalence, features and associated factors of MRS and its subtypes in highly myopic population were assessed. RESULTS: Out of 213 highly myopic eyes (129 participants), MRS was observed in 48 eyes, with a prevalence of 22.5% (95%CI: 16.9, 28.6%) per eye, or 36 participants with 27.9% (95% CI: 20.5, 35.7%) per subject. In addition to well-documented factors like older age and higher myopia, the prevalence of MRS was found to be related with a higher intraocular pressure (P=0.013, OR: 1.25; 95%CI: 1.05, 1.48), a thinner subfoveal choroidal thickness (P=0.006 OR: 0.86; 95%CI: 0.77, 0.96), a wider Gamma zone (P=0.003, OR: 1.99; 95%CI: 1.05, 3.11), the presence of glaucoma (P=0.010, OR: 3.37; 95%CI: 1.34, 8.48) and the presence of epiretinal membrane (P=0.023, OR: 3.13; 95%CI: 1.17, 8.36), after multivariate analysis. Eyes with advanced high myopia (P=0.021) and wider gamma zone (P=0.005) were more likely to develop foveal MRS. Eyes with glaucoma tended to have a higher prevalence of outer retinal MRS compared to inner retinal MRS (60.9% versus 36.0%), though the difference was not statistically significant (P=0.06). MRS located in the foveal region or affecting the outer retina was related with a significant worse best corrected visual acuity (BCVA), as compared to MRS that was perifoveally located or affected other regions (P<0.05). CONCLUSIONS: The prevalence of MRS was 27.9% among the elderly highly myopic population. MRS occurring in the foveal region or involving the outer retina demands increased vigilance due to its significant impact on BCVA. The findings contribute to a deeper understanding of MRS, offering insights into its mechanisms and vision prognosis.

Fine-Regulating the Carbon Flux of l-Isoleucine Producing Corynebacterium glutamicum WM001 for Efficient l-Threonine Production.

l-Threonine, an essential amino acid, is widely used in various industries, with an annually growing demand. However, the present Corynebacterium glutamicum strains are difficult to achieve industrialization of l-threonine due to low yield and purity. In this study, we engineered an l-isoleucine-producing C. glutamicum WM001 to efficiently produce l-threonine by finely regulating the carbon flux. First, the threonine dehydratase in WM001 was mutated to lower the level of l-isoleucine production, then the homoserine dehydrogenase and aspartate kinase were mutated to release the feedback inhibition of l-threonine, and the resulting strain TWZ006 produced 14.2 g/L l-threonine. Subsequently, aspartate ammonia-lyase and aspartate transaminase were overexpressed to accumulate the precursor l-aspartate. Next, phosphoenolpyruvate carboxylase, pyruvate carboxylase and pyruvate kinase were overexpressed, and phosphoenolpyruvate carboxykinase, oxaloacetate decarboxylase were inactivated to fine-regulate the carbon flux among oxaloacetate, pyruvate and phosphoenolpyruvate. The resulting strain TWZ017 produced 21.5 g/L l-threonine. Finally, dihydrodipicolinate synthase was mutated with strong allosteric inhibition from l-lysine to significantly decrease byproducts accumulation, l-threonine export was optimized, and the final engineered strain TWZ024/pXTuf-thrE produced 78.3 g/L of l-threonine with the yield of 0.33 g/g glucose and the productivity of 0.82 g/L/h in a 7 L bioreactor. To the best of our knowledge, this represents the highest l-threonine production in C. glutamicum, providing possibilities for industrial-scale production.

ECM-mimetic glucomannan hydrogel promotes pressure ulcer healing by scavenging ROS, promoting angiogenesis and regulating macrophages.

Pressure ulcers (PUs) have emerged as a significant burden on both individuals and society. Effective treatment of PUs is a significant clinical challenge due to the compromised tissue microenvironment characterized by extracellular matrix (ECM) depletion, increased levels of reactive oxygen species (ROS), excessive inflammation and impaired angiogenesis. To this end, we have developed a glucomannan hydrogel (GM-Pgel) that mimics the skin's extracellular matrix to accelerate wound healing by regulating chronic inflammation in the PUs. This hydrogel not only faithfully replicates the components and nanofibrous architecture of ECM-like glycoproteins but also exhibits remarkable capabilities in enhancing neovascularization, scavenging ROS, and promoting macrophage polarization toward the M2 phenotype. In summary, this ECM-mimetic multifunctional hydrogel emerges as a promising dressing with diverse functionalities, capable of reshaping the compromised tissue environment without the need for additional drugs, exogenous cytokines, or cells. This presents a compelling and effective strategy for the repair and regeneration of chronic cutaneous wounds.

Stepwise de novo establishment of inactive X chromosome architecture in early development.

X chromosome inactivation triggers a dramatic reprogramming of transcription and chromosome architecture. However, how the chromatin organization of inactive X chromosome is established de novo in vivo remains elusive. Here, we identified an Xist-separated megadomain structure (X-megadomains) on the inactive X chromosome in mouse extraembryonic lineages and extraembryonic endoderm (XEN) cell lines, and transiently in the embryonic lineages, before Dxz4-delineated megadomain formation at later stages in a strain-specific manner. X-megadomain boundary coincides with strong enhancer activities and cohesin binding in an Xist regulatory region required for proper Xist activation in early embryos. Xist regulatory region disruption or cohesin degradation impaired X-megadomains in extraembryonic endoderm cells and caused ectopic activation of regulatory elements and genes near Xist, indicating that cohesin loading at regulatory elements promotes X-megadomains and confines local gene activities. These data reveal stepwise X chromosome folding and transcriptional regulation to achieve both essential gene activation and global silencing during the early stages of X chromosome inactivation.

The critical role of Gαi3 in oral squamous cell carcinoma cell growth.

The identification of novel and effective therapeutic targets for oral squamous cell carcinoma (OSCC) is of paramount importance. This study investigates the expression, potential functions, and mechanistic insights of G protein inhibitory subunit 3 (Gαi3) in OSCC. Gαi3 is found to be upregulated in human OSCC tissues as well as in various primary and established OSCC cells. In different OSCC cells, silencing of Gαi3 through shRNA resulted in inhibited cell proliferation and migration, while also inducing apoptosis. Knockout (KO) of Gαi3 via the CRISPR/Cas9 method produced significant anti-cancer effects in OSCC cells. Conversely, ectopic overexpression of Gαi3 enhanced OSCC cell growth, promoting cell proliferation and migration. Gαi3 plays a crucial role in activating the Akt-mTOR signaling pathway in OSCC cells. Silencing or KO of Gαi3 led to decreased phosphorylation levels of Akt and S6K, whereas overexpression of Gαi3 increased their phosphorylation. Restoration of Akt-mTOR activation through a constitutively active mutant Akt1 mitigated the anti-OSCC effects induced by Gαi3 shRNA. In vivo, Gαi3 silencing significantly suppressed the growth of subcutaneous OSCC xenografts in nude mice, concomitant with inactivation of the Akt-mTOR pathway and induction of apoptosis. Collectively, these findings underscore the critical role of Gαi3 in OSCC cell growth both in vitro and in vivo.

High-performance hydrogen evolution reaction in quadratic nodal line semimetal Na2CdSn.

Topological nodal line semimetals (TNLSMs), which exhibit one-dimensional (1D) band crossing in their electronic band structure, have been predicted to be potential catalysts in electrocatalytic processes. However, the current studies are limited to the TNLSMs where the dispersion around the nodal line is linear in all directions. Here, the potential application of the quadratic nodal line (QNL) semimetal Na2CdSn in hydrogen evolution reaction is explored. Based on the bulk-boundary correspondence, we find that the topological surface states (TSSs) of the QNL are extended in the entire Brillouin zone. A linear relationship between the density of states of the TSSs and the Gibbs free energy is established in Na2CdSn. Remarkably, the best performance of Na2CdSn can be comparable to that of the noble metal Pt. Therefore, our work not only identifies an innovative type of topological catalyst with a QNL state but also confirms the relationship between TSSs and catalytic performance.

Genetics of Female Pelvic Organ Prolapse: Up to Date.

Pelvic organ prolapse (POP) is a benign disease characterized by the descent of pelvic organs due to weakened pelvic floor muscles and fascial tissues. Primarily affecting elderly women, POP can lead to various urinary and gastrointestinal tract symptoms, significantly impacting their quality of life. The pathogenesis of POP predominantly involves nerve-muscle damage and disorders in the extracellular matrix metabolism within the pelvic floor. Recent studies have indicated that genetic factors may play a crucial role in this condition. Focusing on linkage analyses, single-nucleotide polymorphisms, genome-wide association studies, and whole exome sequencing studies, this review consolidates current research on the genetic predisposition to POP. Advances in epigenetics are also summarized and highlighted, aiming to provide theoretical recommendations for risk assessments, diagnoses, and the personalized treatment for patients with POP.

Outdoor light at night, air pollution and risk of incident type 2 diabetes.

BACKGROUND: Air pollution and outdoor light at night (LAN) have been reported to be related to type 2 diabetes (T2D). However, their interaction with risk of T2D remains uncertain. Therefore, our study aimed to explore the relationship between outdoor LAN, air pollution and incident T2D. METHODS: Our study included a cohort of 24,147 subjects recruited from 2015 to 2018 in Ningbo, China. Land use regression models were used to evaluate particulate matter with a diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10) and nitrogen dioxide (NO2). Satellite images data with a spatial resolution of 500m was used to estimate outdoor LAN levels. T2D new cases were identified by medical records based on health information system. Cox proportional hazards models were used to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs). Moreover, we investigated the multiplicative and additive interactions between air pollution and outdoor LAN. RESULTS: During 108,908 person-years of follow-up period, 1016 T2D incident cases were identified. The HRs (95% CIs) were 1.22 (1.15, 1.30) for outdoor LAN, 1.20 (1.00, 1.45) for PM2.5, 1.23 (1.11, 1.35) for PM10 and 1.19 (1.04, 1.37) for NO2 in every interquartile range increase, respectively. Furthermore, significant interactions were observed between outdoor LAN and NO2. CONCLUSIONS: Our findings indicated that air pollution and outdoor LAN were positively associated with T2D. Moreover, we observed an interaction between outdoor LAN and NO2 suggesting that stronger associations for outdoor LAN and T2D in areas with higher levels of NO2, and for NO2 and T2D in areas with higher levels of outdoor LAN.

Remote limb ischemic preconditioning alleviated spinal cord injury through inhibiting proinflammatory immune response and promoting the survival of spinal neurons.

STUDY DESIGN: Experimental animal study. OBJECTIVES: To investigate the protective effect of remote limb ischemia preconditioning (RLPreC) on traumatic spinal cord injury (SCI) and explore the underlying biological mechanisms using RNA sequencing. SETTING: China Rehabilitation Science Institute; Beijing; China. METHODS: spinal cord injury was induced in mice using a force of 0.7 N. RLPreC treatment was administered. Motor function, pain behavior, and gene expression were assessed. RESULTS: RLPreC treatment significantly improved motor function and reduced pain-like behavior in SCI mice. RNA-Seq analysis identified 5247 differentially expressed genes (DEGs). GO analysis revealed enrichment of immune response, inflammatory signaling, and synaptic transmission pathways among these DEGs. KEGG analysis indicated suppression of inflammation and promotion of synapse-related pathways. CONCLUSIONS: RLPreC is a promising therapeutic strategy for improving motor function and alleviating pain after traumatic SCI. RNA-Seq analysis provides insights into potential therapeutic targets and warrants further investigation.

The role of ß2-AR/PI3K/AKT pathway in the proliferation, migration and invasion of THLE-2 cells induced by nicotine.

Nicotine, the primary constituent of tobacco, is one of the important factors that induce the occurrence of hepatocellular carcinoma (HCC). The ß2-adrenergic receptor (ß2-AR) is implicated in the growth and advancement of tumors. However, the role of ß2-AR and its mediated cascades in nicotine-induced HCC remains unclear. This present study aims to observe the effects of nicotine on the proliferation, migration, and invasion of immortalized human liver epithelial (THLE-2) cells, as well as to explore the underlying mechanisms of action. The results of cell counting kit-8 (CCK-8) assay showed that 0.3125 µM nicotine had the ability to promote the proliferation of THLE-2 cells with a significant time-dependent manner. Therefore, THLE-2 cells were mainly selected for chronic treatment with 0.3125 µM nicotine in the later stage to cause transformation. After 30 passages of THLE-2 cells with 0.3125 µM nicotine treatment, chronic exposure to nicotine significantly enhanced the proliferation, metastasis, and invasion of cells. Besides, it also upregulated the intracellular levels of ß2-AR, phosphoinositide 3-kinase (PI3K), AKT, matrix metalloproteinase-2 (MMP-2) and Cyclin D1, as well as downregulated the expression of p53. More importantly, the ß2-AR/PI3K/AKT pathway was found to mediate the expression of MMP-2, Cyclin D1, and p53 in THLE-2 cells, playing a crucial role in their proliferation, migration, and invasion after continuous exposure to nicotine. Simply put, it demonstrated the role of ß2-AR/PI3K/AKT pathway in the transformation of THLE-2 cells induced by nicotine. This study could provide valuable insights into the relationship between nicotine and HCC. Additionally, it lays the groundwork for investigating potential anticancer treatments for liver cancer linked to tobacco consumption.