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Introduction: Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive. Objectives: This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach. Methods: Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro. Results: LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. Conclusion: We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy.

Abstract Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8+ T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8+ T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rβ and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8+ T cells.

Abstract Background Surgical therapy is the most optimal treatment for hepatocellular carcinoma (HCC) combined with bile duct tumor thrombus (BDTT) patients. However, whether to perform bile duct resection (BDR) is still controversial. The purpose of this multicenter research is to compare the effect of BDR on the prognosis of extrahepatic BDTT patients. Methods We collected the data of 111 HCC patients combined with extrahepatic BDTT who underwent radical hepatectomy from June 1, 2004 to December 31, 2021. Those patients had either received hepatectomy with extrahepatic bile duct resection (BDR group) or hepatectomy without bile duct resection (NBDR group). Inverse probability of treatment weighting (IPTW) was used to reduce the potential bias between two groups and balance the influence of confounding factors in baseline data. Then compare the prognosis between the two groups of patients. Cox regression model was used for univariate and multivariate analysis to further determine the independent risk factors that influence the prognosis of HCC-BDTT patients. Results There were 38 patients in the BDR group and 73 patients in the NBDR group. Before and after IPTW, there were no statistical significance in OS, RFS and intraoperative median blood loss between the two groups (all P > 0.05). Before IPTW, the median postoperative hospital stay in the NBDR group was shorter (P = 0.046) and the grade of postoperative complications was lower than BDR group (P = 0.014). After IPTW, there was no difference in postoperative hospital stay between the two groups (P > 0.05). The complication grade in the NBDR group was still lower than that in the BDR group (P = 0.046). The univariate analysis showed that TNM stage and portal vein tumor thrombus (PVTT) were significantly correlated with OS (both P

Abstract Background Although it is generally believed that the femoral neck fracture is related to the femoral neck geometric parameters (FNGPs), the association between the risk of osteoporotic fracture of the femoral neck and FNGPs in native Chinese women is still unclear. Methods A total of 374 female patients (mean age 70.2 ± 9.32 years) with osteoporotic fracture of the femoral neck, and 374 non-fracture control groups were completely matched with the case group according to the age ratio of 1:1. Using DXA bone densitometer to measured eight FNGPs: the outer diameter (OD), cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), buckling ratio (BR), section modulus (SM), cross-sectional moment of inertia (CSMI), and compressive strength index (CSI) at the narrowest point of the femoral neck. Results Compared with the control group, the average values of OD (2.9%), ED (4.5%), and BR (26.1%) in the patient group significantly increased (p = 0.015 to

Abstract Objectives In comparison to the subjects without diabetes, a greater concentration of serum carbohydrate antigen 19 − 9 (CA 19 − 9) was observed in the subjects with diabetes. Nevertheless, since the occurrence of abnormal CA 19 − 9 is not widespread among the whole diabetic population, this phenomenon has not attracted enough attention. The prevalence of abnormal CA 19 − 9 in hospitalized patients with diabetes was the focus of our research. Method A total of 385 subjects with diabetes and 200 controls were enrolled and all had been tested the CA19-9 levels. Cases of cancers were excluded through examination and followup for 1 year. Results We found that the rate of patients with abnormal CA19-9 level was 8.3%. The rate of patients with abnormal CA19-9 level was 14.0% in the HbA1c ≥ 9% group, and 3.0% in the HbA1c

Osteoarthritis (OA) is the most prevalent joint disease in the elderly population and its substantial morbidity and disability impose a heavy economic burden on patients and society. Knee osteoarthritis (KOA) is the most common subtype of OA, which is characterized by damage to progressive articular cartilage, synovitis, and subchondral bone sclerosis. Most current treatments for OA are palliative, primarily aim at symptom management, and do not prevent the progression of the disease or restore degraded cartilage. The activation of α-granules in platelets releases various growth factors that are involved in multiple stages of tissue repair, suggesting potential for disease modification. In recent years, platelet-based therapies, such as platelet-rich plasma, platelet-rich fibrin, and platelet lysates, have emerged as promising regenerative treatments for KOA, but their related effects and mechanisms are still unclear. Therefore, this review aims to summarize the biological characteristics and functions of platelets, classify the products of platelet-based therapy and related preparation methods. Moreover, we summarize the basic research of platelet-based regeneration strategies for KOA and discuss the cellular effects and molecular mechanisms. Further, we describe the general clinical application of platelet-based therapy in the treatment of KOA and the results of the meta-analysis of randomized controlled trials.

Background Septic shock is associated with increases in end‐diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. Methods and Results Purpose‐bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular‐arterial coupling, and circumferential strain. Early during sepsis, (0–24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. Conclusions The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

The efficacy of berberine in managing diabetes through modulation of gut microbiome has been established through fecal sample analyses. However, relying solely on fecal materials constrains our comprehension of berberine's effects on diverse gastrointestinal locations. This study specifically explores the ileocecal region, a segment characterized by higher microbial diversity than fecal samples. Berberine exhibits a robust hypoglycemic impact by significantly reducing glucose levels in blood and urine. Beyond glycemic control, berberine ameliorates various diabetes-related symptoms in serum, including increased insulin and leptin, but decreased NEFA and MDA. Notably, berberine demonstrates liver-protective functions by alleviating oxidative stress and enhancing hepatic glycogen abundance. These outcomes prompted a high-throughput sequencing analysis of the ileocecal microbiome, revealing an augmentation of beneficial bacterial genera (four genera in the Lachnospiraceae family, Erysipelatoclostridium, and Escherichia-Shigella), along with a reduction in harmful bacterial genera (Romboutsia). Additionally, we predicted the impact of the ileocecal microbiome on clinically relevant factors associated with diabetes. These findings elucidate the multi-pathway mechanisms of berberine in treating T2D, underscoring its potential as a natural anti-diabetic agent or functional food, particularly through the modulation of the gut microbiota.

Abstract Backgroud We aimed to develop a novel preoperative nomogram to predict lymph node metastasis (LNM) in perihilar cholangiocarcinoma (pCCA) patients. Methods 160 pCCA patients were enrolled at Lihuili Hospital from July 2006 to May 2022. A novel nomogram model was established to predict LNM in pCCA patients based on the independent predictive factors selected by the multivariate logistic regression model. The precision of the nomogram model was evaluated through internal and external validation with calibration curve statistics and the concordance index (C-index). Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate and determine the clinical utility of the nomogram. Results Multivariate logistic regression demonstrated that age (OR = 0.963, 95% CI: 0.930–0.996, P = 0.030), CA19-9 level (> 559.8 U/mL vs. ≤559.8 U/mL: OR = 3.162, 95% CI: 1.519–6.582, P = 0.002) and tumour diameter (OR = 1.388, 95% CI: 1.083–1.778, P = 0.010) were independent predictive factors of LNM in pCCA patients. The C-index was 0.763 (95% CI: 0.667–0.860) and 0.677 (95% CI: 0.580–0.773) in training cohort and validation cohort, respectively. ROC curve analysis indicated the comparative stability and adequate discriminative ability of nomogram. The sensitivity and specificity were 0.820 and 0.652 in training cohort and 0.704 and 0.649 in validation cohort, respectively. DCA revealed that the nomogram model could augment net benefits in the prediction of LNM in pCCA patients. Conclusions The novel prediction model is useful for predicting LNM in pCCA patients and showed adequate discriminative ability and high predictive accuracy.

Abstract Background Osteoporotic fractures are a growing problem in an aging society. The association between body mass index (BMI) and osteoporotic fractures varies by fracture site and ethnicity. Limited knowledge exists regarding this association in native Chinese, particularly utilizing local databases as reference sources. Objective To investigate the association between BMI and osteoporotic fractures at different sites in Chinese women. Methods Three thousand ninety-eight female patients with radiographic fractures and 3098 age- and sex-matched healthy controls without fractures were included in the study. Both of them underwent assessment using dual-energy X-ray absorptiometry (DXA), with BMD measurements calculated using our own BMD reference database. Participants were classified into underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 24.0 kg/m2), overweight (24 ≤ BMI < 28 kg/m2) and obese (BMI ≥ 28 kg/m2) according to the Chinese BMI classification standard. Results There were 2296 (74.1%) vertebral fractures, 374 (12.1%) femoral neck fractures, and 428 (13.8%) other types of fractures in the case group. Bone mineral density (BMD) was almost lower in the fracture groups compared to the control groups (p = 0.048 to < 0.001). Compared with normal weight, underweight had a protective effect on total [odds ratio (OR) = 0.61; 95% confidence interval (CI), 0.49 –0.75; P< 0.001], and lumbar fractures (OR = 0.52; 95% CI, 0.41 – 0.67; P < 0.001), while obesity was associated with an increased risk for total (OR = 2.26; 95% CI, 1.85 – 2.76; P < 0.001), lumbar (OR = 2.17; 95% CI, 1.72 – 2.73; P < 0.001), and femoral neck fractures (OR = 4.08; 95% CI, 2.18 – 7.63; P < 0.001). Non-linear associations were observed between BMI and fractures: A J-curve for total, lumbar, and femoral neck fractures, and no statistical change for other types of fractures. Underweight was found to be a risk factor for other types of fracturess after adjusting for BMD (OR = 2.29; 95% CI, 1.09 – 4.80; P < 0.001). Osteoporosis and osteopenia were identified as risk factors for almost all sites of fracture when compared to normal bone mass. Conclusions Underweight has a protective effect on total and lumbar spine fractures in Chinese women, while obesity poses a risk factor for total, lumbar, and femoral neck fractures. The effect of BMI on fractures may be mainly mediated by BMD.

Abstract Domain wall structures form spontaneously due to epitaxial misfit during thin film growth. Imaging the dynamics of domains and domain walls at ultrafast timescales can provide fundamental clues to features that impact electrical transport in electronic devices. Recently, deep learning based methods showed promising phase retrieval (PR) performance, allowing intensity-only measurements to be transformed into snapshot real space images. While the Fourier imaging model involves complex-valued quantities, most existing deep learning based methods solve the PR problem with real-valued based models, where the connection between amplitude and phase is ignored. To this end, we involve complex numbers operation in the neural network to preserve the amplitude and phase connection. Therefore, we employ the complex-valued neural network for solving the PR problem and evaluate it on Bragg coherent diffraction data streams collected from an epitaxial La2-xSrxCuO4 (LSCO) thin film using an X-ray Free Electron Laser (XFEL). Our proposed complex-valued neural network based approach outperforms the traditional real-valued neural network methods in both supervised and unsupervised learning manner. Phase domains are also observed from the LSCO thin film at an ultrafast timescale using the complex-valued neural network.

Resveratrol (RES) is a naturally occurring polyphenolic compound. Recent studies have identified multiple potential health benefits of RES, including antioxidant, anti-inflammatory, anti-obesity, anticancer, anti-diabetic, cardiovascular, and neuroprotective properties. The objective of this review is to summarize and analyze the studies on the biological activities of RES in disease prevention and treatment, as well as its metabolism and bioavailability. It also discusses the challenges in its clinical application and future research directions. RES exhibits significant potential in the prevention and treatment of many diseases. The future direction of RES research should focus on improving its bioavailability, conducting more clinical trials to determine its effectiveness in humans, and investigating its mechanism of action. Once these challenges have been overcome, RES is expected to become an effective health intervention.

BackgroundThis study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS.MethodsA total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied.ResultsThe male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8–13.1 years), the disease duration was 1.0 month (IQR, 0.5–2.0 months), and follow-up was 36.5 months (IQR, 25.7–50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)—these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P < 0.001).ConclusionEndothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.