TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway.

OBJECTIVE: Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage. Notably, the knockout of transient receptor potential channel 6 (TRPC6) has shown promise in alleviating renal fibrosis. However, the regulatory impact of TRPC6 on renal fibrosis remains unclear. METHODS: In vivo, TRPC6 knockout (TRPC6-/-) mice and age-matched 129 SvEv (WT) mice underwent unilateral renal ischemia-reperfusion (uIR) injury surgery on the left renal pedicle or sham operation. Kidneys and serum were collected on days 7, 14, 21, and 28 after euthanasia. In vitro, primary tubular epithelial cells (PTECs) were isolated from TRPC6-/- and WT mice, followed by treatment with transforming growth factor ß1 (TGFß1) for 72 h. The anti-fibrotic effect of TRPC6-/- and the underlying mechanisms were assessed through hematoxylin-eosin staining, Masson staining, immunostaining, qRT-PCR, and Western blotting. RESULTS: Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFß1. TRPC6-/- alleviated renal fibrosis by reducing the expression of fibrotic markers (Col-1, α-SMA, and vimentin), as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro. Additionally, we found that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3ß) signaling pathway, a pivotal player in renal fibrosis, was down-regulated following TRPC6 deletion. CONCLUSION: These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3ß pathway. Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.

Increased SEMA6B expression as a potential prognostic and immune cell infiltration biomarker in thyroid cancer patients.

BACKGROUND: Even today, thyroid cancer (THCA) remains an important threat to global health. For THCA patients, differentiated thyroid cancer is the most commonly identified pathological subtype, and those diagnosed with papillary thyroid cancer generally have good overall prognosis. For poorly differentiated subtype THCA, patients have aggressive disease course, higher risk of distant organ metastasis and inferior overall prognosis. METHODS: RNA-seq data from TCGA and GTEx databases are collected and analyzed via R. The correlation between SEMA6B expression level and pathological as well as clinical parameters of THCA patients was respectively investigated. Gene expression profiling and subsequent functional clustering analysis was the performed utilizing GSEA. The receiver operating characteristic (ROC) curve was utilized to evaluate the diagnostic value of SEMA6B expression. RESULTS: Increased SEMA6B expression was characteristic in THCA tumor samples and was associated with specific pathologic and clinical features for TCHA patients. Univariate and multivariate analysis indicated that SEMA6B was independent predictive marker for THCA patients' prognosis. Gene expression profiling and functional clustering analysis suggested that SEMA6B high-expression was related with increased expression of multiple signal pathways and signatures of multiple immune cell infiltration. CONCLUSIONS: In this study, through bioinformatic analysis and clinical data investigation, we demonstrated the potential value of SEMA6B as diagnostic and prognostic marker in THCA patient treatment.

A Numerical Study of Elastic Wave Arrival Behavior in a Naturally Fractured Rock Based on a Combined Displacement Discontinuity-Discrete Fracture Network Model.

The arrival behavior of elastic waves in a naturally fractured rock is studied based on numerical simulations. We use the discrete fracture network method to represent the distribution of a natural fracture system and employ the displacement discontinuity method to compute the propagation of elastic waves across individual fractures. We analyze macroscopic wavefield arrival properties collectively arising from the interaction between elastic waves and numerous fractures in the system. We show that the dimensionless angular frequency ῶ = ωZ/κ exerts a fundamental control on the arrival behavior of a plane wave traveling through the fractured rock, where ω, Z, and κ are the angular frequency, seismic impedance, and fracture stiffness, respectively. An asynchronous arrival phenomenon of the wave energy occurs and becomes more significant with an increased ῶ. Two regimes are identified according to the two-branch dependency of the fractal dimension D of the FFAW on ῶ, where the wave arrival behavior is within a non-fractal regime for ῶ smaller than the critical frequency ῶ c ≈ 1.0, and enters the fractal regime for ῶ ≥ ῶ c. The self-affine properties of the FFAW, i.e., the roughness exponent α and the correlation length l c, both linearly decrease as a function of the exponent ξ (with ῶ = 10 ξ ) in the fractal regime. Early breakthrough of wave transport occurs in regions with relatively low fracture density, while late-time arrival happens in regions of high fracture density.

Establishment of a new arrhythmia model in SD rats induced by isoproterenol.

BACKGROUND: The main purpose of this study was to establish an ideal arrhythmia model using isoproterenol and explore its mechanism. METHODS: Fifty healthy male SD rats were randomly divided into the following groups: control (CON), subcutaneous injection (SC; 5 mg/kg ISO for 2 consecutive days), intraperitoneal injection (IP; ISO 5 mg/kg for 2 consecutive days), 2 + 1 (5 mg/kg ISO by SC for 2 consecutive days and then 3 mg/kg ISO by IP for 1 day), and 6 + 1 (5 mg/kg ISO by SC for 6 consecutive days and then 3 mg/kg ISO by IP for 1 day). Electrocardiograms (ECGs) were recorded using a BL-420F system, and the pathological changes in myocardial tissue were observed by HE and Masson staining. The serum cTnI, TNF-α, IL-6, and IL-1ß levels were detected by ELISA, and serum CK, LDH and oxidative stress-related indicators were detected with an automatic biochemical analyser. RESULTS: The cardiomyocytes of the rats belonging to the CON group were normal, whereas those of the rats in the other groups, particularly the 6 + 1 group, showed signs of disorder, unclear borders, and lysis and necrosis. The incidence of arrhythmia, arrhythmia score, and levels of serum myocardial enzymes, troponin, and some inflammatory factors were higher in the 2 + 1 and 6 + 1 groups than in the single injection group (p < 0.01 or p < 0.05). The indicator levels found for the 6 + 1 group were generally higher than those found for the 2 + 1 group (p < 0.01), and the 6 + 1 group exhibited a lower SOD level and higher MDA and NO levels compared with the CON group (p < 0.01 or p < 0.05). CONCLUSION: The combined mode of ISO injection (SC with IP) was more likely to induce arrhythmia than a single ISO injection. The "6 + 1" method of ISO injection can establish a more stable arrhythmia model and cardiomyocyte damage induced by oxidative stress and inflammation was an important mechanism.

A three-dimensional particle finite element model for simulating soil flow with elastoplasticity.

Soil flow is involved in many earth surface processes such as debris flows and landslides. It is a very challenging task to model this large deformational phenomenon because of the extreme change in material configurations and properties when soil flows. Most of the existing models require a two-dimensional (2D) simplification of actual systems, which are however three-dimensional (3D). To overcome this issue, we develop a novel 3D particle finite element method (PFEM) for direct simulation of complex soil flows in 3D space. Our PFEM model implemented in a fully implicit solution framework based on a generalised Hellinger-Reissner variational principle permits the use of a large time step without compromising the numerical stability. A mixed quadratic-linear element is used to avoid volumetric locking issues and ensure computational accuracy. The correctness and robustness of our 3D PFEM formulation for modelling large deformational soil flow problems are demonstrated by a series of benchmarks against analytical or independent numerical solutions. Our model can serve as an effective tool to support the assessment of catastrophic soil slope failures and subsequent runout behaviours.

[Oocyte maturation arrest due to compound heterozygous variants of the PATL2 gene in a case].

OBJECTIVE: To explore the genetic etiology of a patient with primary infertility and repeated failure of assisted reproductive technology. METHODS: Peripheral blood samples of the patient and her husband were collected for the extraction of genomic DNA and clinical exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The patient was found to harbor compound heterozygous variants of the PATL2 gene, namely c.223-14_223-2del and c.1369G>T (p.G457*). Sanger sequencing has verified that they were respectively inherited from her father and mother. The patient was diagnosed with oocyte maturation defect type 4. CONCLUSION: Oocyte maturation arrest due to mutations of the PATL2 gene can result in primary female infertility. Discovery of the novel c.1369G>T (p.G457*) variant has expanded the spectrum of pathogenic variants of the PATL2 gene.

The Predictive Effect of Health Examination in the Incidence of Diabetes Mellitus in Chinese Adults: A Population-Based Cohort Study.

BACKGROUND: The incidence of diabetes mellitus (DM) was increasing in recent years, and it is important to screen those nondiabetic populations through health examination to detect the potential risk factors for DM. We aimed to find the predictive effect of health examination on DM. METHODS: We used the public database from Rich Healthcare Group of China to evaluate the potential predictive effect of health examination in the onset of DM. The colinear regression was used for estimating the relationship between the dynamics of the health examination index and the incident year of DM. The time-dependent ROC was used to calculate the best cutoff in predicting DM in the follow-up year. The Kaplan-Meier method and Cox regression were used to evaluate the HR of related health examination. RESULTS: A total of 211,833 participant medical records were included in our study, with 4,172 participants diagnosing as DM in the following years (among 2-7 years). All the initial health examination was significantly different in participants' final diagnosing as DM to those without DM. We found a negative correlation between the incidence of years of DM and the average initial FPG (r = -0.1862, P < 0.001). Moreover, the initial FPG had a strong predictive effect in predicting the future incidence of DM (AUC = 0.961), and the cutoff was 5.21 mmol/L. Participants with a higher initial FPG (>5.21 mmol/L) had a 2.73-fold chance to develop as DM in follow-up (95%CI = 2.65-2.81, P < 0.001). CONCLUSION: Initial FPG had a good predictive effect for detecting DM. The FPG should be controlled less than 5.21 mmol/L.

Association Between Triglyceride-Glucose Index and the Risk of Type 2 Diabetes Mellitus in an Older Chinese Population Aged Over 75 Years.

Background: The association between the triglyceride-glucose (TyG) index and type 2 diabetes mellitus (T2DM) in older adults has not been fully understood. This research aims to explore the association between the TyG index and the incidence of T2DM in an older Chinese population aged over 75 years. Methods: This longitudinal analysis study was performed based on a database from a health check screening program in China. The participants were stratified based on the quintile ranges of the TyG index (Q1 to Q5 groups). T2DM was defined as fasting plasma glucose (FPG) ≥ 7.00 mmol/L and/or self-reported T2DM. The cumulative incidences of T2DM in various quintile groups were estimated by the Kaplan-Meier method. The Cox proportional hazard model was used to examine the independent impact of the TyG index on the risk of T2DM during the follow-up period. Subgroup analysis was performed by gender and BMI to further validate the credibility of the results. Results: During the follow-up period, a total of 231 new-onset T2DM cases were recorded among the 2,571 individuals aged over 75 years. After adjusting confounding factors, elevated TyG index independently indicated a higher risk of T2DM (HR = 1.89; 95% CI, 1.47-2.44; p < 0.01). Higher TyG index quintile groups (Q3 to Q5) also presented with a higher risk of T2DM (hazard ratio (HR) = 1.36, 1.44, and 2.12, respectively) as compared with the lowest quintile group (Q1). Subgroup analysis showed that increased TyG index led to a higher risk of T2DM with HR = 2.35 (95% CI, 1.73-3.19), 1.90 (95% CI, 1.27-2.83), 2.95 (95% CI, 1.94-4.50), and 1.72 (95% CI, 1.25-2.35) in male subgroup, female subgroup, BMI < 24 kg/m2 subgroup, and BMI ≥ 24 kg/m2 subgroup, respectively. Conclusions: Triglyceride-glucose index independently correlated with the risk of incident T2DM in Chinese adults aged over 75 years. The TyG index might be useful in monitoring T2DM in the older populations.

Polyaxial stress-dependent permeability of a three-dimensional fractured rock layer.

A study about the influence of polyaxial (true-triaxial) stresses on the permeability of a three-dimensional (3D) fractured rock layer is presented. The 3D fracture system is constructed by extruding a two-dimensional (2D) outcrop pattern of a limestone bed that exhibits a ladder structure consisting of a "through-going" joint set abutted by later-stage short fractures. Geomechanical behaviour of the 3D fractured rock in response to in-situ stresses is modelled by the finite-discrete element method, which can capture the deformation of matrix blocks, variation of stress fields, reactivation of pre-existing rough fractures and propagation of new cracks. A series of numerical simulations is designed to load the fractured rock using various polyaxial in-situ stresses and the stress-dependent flow properties are further calculated. The fractured layer tends to exhibit stronger flow localisation and higher equivalent permeability as the far-field stress ratio is increased and the stress field is rotated such that fractures are preferentially oriented for shearing. The shear dilation of pre-existing fractures has dominant effects on flow localisation in the system, while the propagation of new fractures has minor impacts. The role of the overburden stress suggests that the conventional 2D analysis that neglects the effect of the out-of-plane stress (perpendicular to the bedding interface) may provide indicative approximations but not fully capture the polyaxial stress-dependent fracture network behaviour. The results of this study have important implications for understanding the heterogeneous flow of geological fluids (e.g. groundwater, petroleum) in subsurface and upscaling permeability for large-scale assessments.

Une étude sur l'influence des tensions polyaxiales (triaxiales véritables) sur la perméabilité d'une couche de roche fracturée en 3D est. présentée. Le système de fractures 3D est. construit en extrayant le motif d'affleurement 2D d'un niveau calcaire qui présente une structure en échelle consistant en un ensemble de joints parallèles contigu à des fractures courtes d'un stade ultérieur. Le comportement géomécanique de la roche fracturée en 3D en réponse aux contraintes in-situ est. modélisé par la méthode des éléments finis discrets, qui peut saisir la déformation des blocs de matrice, les variations du champ de contraintes, la réactivation de fractures préexistantes rugueuses et la propagation de nouvelles fissures. Une série de simulations numériques est. conçue pour imposer des contraintes à une roche fracturée en utilisant différentes tensions in situ polyaxiales et les propriétés d'écoulement dépendantes des tensions sont ensuite calculées. La couche fracturée a tendance à présenter une localisation plus forte des flux et une perméabilité équivalente supérieure lorsque le rapport des contraintes du champ éloigné augmente et que le champ de contraintes pivote de telle manière que les fractures sont orientées préférentiellement en faveur du cisaillement. La dilatation par cisaillement de fractures préexistantes a des effets dominants sur la localisation du flux dans le système, tandis que la propagation de nouvelles fractures a des impacts mineurs. Le rôle de la contrainte liée à la surcharge suggère que l'analyse conventionnelle 2D qui néglige l'effet de la contrainte hors plan (perpendiculaire à l'interface de stratification) peut fournir des approximations indicatives mais ne traduit pas entièrement le comportement du réseau de fractures soumis à des tensions polyaxiales. Les résultats de cette étude ont d'importantes implications pour comprendre l'écoulement hétérogène de fluides géologiques (par ex. eau souterraine, pétrole) en milieu souterrain et pour améliorer la perméabilité pour des évaluations à grande échelle.

Se presenta un estudio sobre la influencia de los esfuerzos poliaxiales (triaxiales verdaderas) sobre la permeabilidad de una capa tridimensional (3D) de rocas fracturadas. El sistema de fractura en 3D se construye mediante la extrusión de un patrón de afloramiento 2D de un lecho de caliza que exhibe una estructura de escalera que consiste en un conjunto articulado limitado por fracturas cortas de una etapa posterior. El comportamiento geomecánico de la roca fracturada en 3D en respuesta a los esfuerzos in situ es modelado por el método de elementos finitos y discretos, que puede capturar la deformación de bloques de matriz, la variación de campos de esfuerzos, la reactivación de fracturas irregulares preexistentes y la propagación de nuevas grietas. Una serie de simulaciones numéricas está diseñada para cargar la roca fracturada utilizando diferentes esfuerzos poliaxiales in situ y se calculan además las propiedades de flujo dependientes del esfuerzo. La capa fracturada tiende a exhibir una localización de flujo más fuerte y una permeabilidad equivalente más alta a medida que se incrementa la relación del esfuerzo en el campo lejano y se hace girar el campo de esfuerzo de tal manera que las fracturas se orientan preferentemente para el cizallamiento. La dilatación por cizalladura de fracturas preexistentes tiene efectos dominantes sobre la localización del flujo en el sistema, mientras que la propagación de nuevas fracturas tiene impactos menores. El papel del esfuerzo de la sobrecarga sugiere que el análisis 2D convencional que descuida el efecto del esfuerzo fuera del plano (perpendicular a la interfase del lecho) puede proporcionar aproximaciones indicativas pero no capturar completamente el comportamiento de la red de fractura dependiente del esfuerzo poliaxial. Los resultados de este estudio tienen importantes implicancias para la comprensión del flujo heterogéneo de fluidos geológicos (por ejemplo, aguas subterráneas, petróleo) en el subsuelo y en el escalado de la permeabilidad para evaluaciones a gran escala.

Um estudo é apresentado sobre a influência de esforço poliaxial (verdadeiramente triaxial) sobre a permeabilidade de uma camada de rocha fraturada tridimensional. O sistema fraturado 3D é construído extraindo-se um padrão de afloramento 2D de uma camada de calcário que exibe uma estrutura de escada consistindo de um conjunto de juntas interceptadas posteriormente por fraturas pequenas. O comportamento geomecânico 3D da rocha fraturada em resposta aos esforços locais é modelado pelo método de elementos discretos finitos, que pode capturar a deformação da matriz dos blocos, variação do campo de esforços, reativação de fraturas pré-existentes e propagação de novas rachaduras. Uma serie de simulações numéricas é desenvolvida para sobrecarregar a rocha fraturada usando diversos esforços poliaxiais locais e as propriedades de fluxo dependente dos esforços são posteriormente calculadas. A camada fraturada tende a mostrar forte fluxo localizado e maior permeabilidade equivalente assim que a taxa de esforço do campo externo é aumentada e o campo de esforço é rotacionado de forma que as fraturas são preferencialmente orientadas para cisalhamento. A dilatação por cisalhamento de fraturas pré-existentes tem efeitos dominantes no sistema de fluxo localizado, enquanto que a propagação de novas fraturas tem um impacto menor. O efeito do esforço do sobrecarregamento sugere que a análise 2D convencional que negligencia os efeitos dos esforços de fora do plano (perpendicular à interface do acamamento) pode fornecer indicações aproximadas, porém não captar integralmente o comportamento a rede de fraturas dependente do esforço poliaxial. Os resultados deste estudo possuem importantes implicações para entender o fluxo heterogêneo de fluidos geológicos (ex. águas subterrâneas e petróleo) em subsuperfície e aumentar a escala da avaliação da permeabilidade em grande escala.