The Dominant Role of Recrystallization and Grain Growth Behaviors in the Simulated Welding Heat-Affected Zone of High-Mn Steel.

Single-pass-welding thermal cycles with different peak temperatures (Tp) were reproduced by a Gleeble 3800 to simulate the heat-affected zone (HAZ) of a Fe-24Mn-4Cr-0.4C-0.3Cu (wt.%) high manganese austenitic steel. Then, the effect of Tp on the microstructure and mechanical properties of the HAZ were investigated. The results indicate that recrystallization and grain growth play dominant roles. Based on this, the HAZ is proposed to categorize into three zones: the recrystallization heat-affected zone (RHAZ) with a Tp of 700~900 °C, the transition heat-affected zone (THAZ) with a Tp of 900~1000 °C, and the coarse grain heat-affected zone (CGHAZ) with a Tp of 1000~1300 °C. The recrystallization fraction was 29~44% in the RHAZ, rapidly increased to 87% in the THAZ, and exceeded 95% in the CGHAZ. The average grain size was 17~19 µm in the RHAZ, slightly increased to 22 µm in the THAZ, and ultimately increased to 37 µm in the CGHAZ. The yield strength in the RHAZ and THAZ was consistent with the change in recrystallization fraction, while in the CGHAZ, it satisfied the Hall-Petch relationship with grain size. In addition, compared with the base material, the Charpy impact absorbed energy at -196 °C decreased by 22% in the RHAZ, but slightly increased in the CGHAZ. This indicates that the theory of fine grain strengthening and toughening is not entirely applicable to the HAZ of the investigated high-Mn steel.

[Research progress on structures, activities, and biosynthesis of blazeispirol compounds from Agaricus blazei].

Agaricus blazei is a rare medicinal and edible fungus with a crispy taste and delicious flavor. Both fruiting body and mycelium are rich in polysaccharides, sterols, terpenoids, peptides, lipids, polyphenols, and other active ingredients, which have strong pharmacological activities such as anti-tumor, lipid-lowering, glucose-lowering, immunomodulation, optimization of intestinal flora, and anti-oxidation. Therefore, it is a kind of fungal resource with a great prospect of edible and medicinal development. Among the reported chemical components of A. blazei, blazeispirol is a series of sterol compounds unique to A. blazei, which has a spiral structure and is different from classical steroids. It is an important active ingredient found in the mycelium of A. blazei and has significant hepatoprotective activity. It can be used as a phylogenetic and chemotaxonomic marker of A. blazei strains and is considered an excellent lead compound for drug development. According to the skeleton structure characteristics, the 17 discovered blazeispirol compounds can be divided into two types: blazeispirane and problazeispirane. In order to further explore the resource of blazeispirol compounds of A. blazei, the discovery, isolation, structure, biological activity, and biosynthetic pathways of blazeispirol compounds of A. blazei were systematically reviewed. Besides, the metabolic regulation strategies related to the fermentation synthesis of blazeispirol A by A. blazei were discussed. This review could provide a reference for the efficient synthesis and development of blazeispirol compounds, the research and development of related drugs and functional foods, and the quality improvement of A. blazei and other medicinal and edible fungi resources and derivatives.

Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives.

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field.

Endoplasmic reticulum stress is upregulated in inflammatory bowel disease and contributed TLR2 pathway-mediated inflammatory response.

OBJECTIVE: Endoplasmic reticulum stress (ERS) and Toll-like receptor 2 (TLR2) signaling play an important role in inflammatory bowel disease (IBD); however, the link between TLR2 and ERS in IBD is unclear. This study investigated whether Thapsigargin (TG) -induced ER protein expression levels contributed to TLR2-mediated inflammatory response. METHODS: The THP-1 cells were treated with TLR2 agonist (Pam3CSK4), ERS inducer Thapsigargin (TG) or inhibitor (TUDCA). The mRNA expressions of TLR1-TLR10 were detected by qPCR. The production and secretion of inflammatory factors were detected by PCR and ELISA. Immunohistochemistry was used to detect the expressions of GRP78 and TLR2 in the intestinal mucosa of patients with Crohn's disease (CD). The IBD mouse model was established by TNBS in the modeling group. ERS inhibitor (TUDCA) was used in the treatment group. RESULTS: The expression of TLRs was detected via polymerase chain reaction (PCR) in THP-1 cells treated by ERS agonist Thapsigargin (TG). According to the findings, TG could promote TLR2 and TLR5 expression. Subsequently, in TLR2 agonist Pam3CSK4 induced THP-1 cells, TG could lead to increased expression of the inflammatory factors such as TNF-α, IL-1ß and IL-8, and ERS inhibitor (TUDCA) could block this effect. However, Pam3CSK4 did not significantly impact the GRP78 and CHOP expression. Based upon the immunohistochemical results, TLR2 and GRP78 expression were significantly increased in the intestinal mucosa of patients with Crohn's disease (CD). For in vivo experiments, TUDCA displayed the ability to inhibit intestinal mucosal inflammation and reduce GRP78 and TLR2 proteins. CONCLUSIONS: ERS and TLR2 is upregulated in inflammatory bowel disease, ERS may promote TLR2 pathway-mediated inflammatory response. Moreover, ERS and TLR2 signaling could be novel therapeutic targets for IBD.

Achieving Excellent Strength-Ductility Balance in Single-Phase CoCrNiV Multi-Principal Element Alloy.

CoCrNi alloys exhibit excellent strength and ductility. In this work, the CoCrNiV multi-principal alloy with single-phase fine grained (FG) structure was prepared by rolling and heat treatment. The characteristics of deformation microstructures and mechanical properties were systematically investigated by scanning electron microscope (SEM) and transmission electron microscope (TEM). The results indicate that the CoCrNiV alloy successfully attains a yield strength of 1060 MPa while maintaining a uniform elongation of 24.1%. The enhanced strength originates from FG structure and severe lattice distortion induced by V addition. Meanwhile, the exceptional ductility arises from the stable strain-hardening ability facilitated by dislocations and stacking faults. The deformation mechanisms and the optimization strategies for attaining both strength and ductility are thoroughly discussed.

A Transformer-Based Prediction Method for Depth of Anesthesia During Target-Controlled Infusion of Propofol and Remifentanil.

Accurately predicting anesthetic effects is essential for target-controlled infusion systems. The traditional (PK-PD) models for Bispectral index (BIS) prediction require manual selection of model parameters, which can be challenging in clinical settings. Recently proposed deep learning methods can only capture general trends and may not predict abrupt changes in BIS. To address these issues, we propose a transformer-based method for predicting the depth of anesthesia (DOA) using drug infusions of propofol and remifentanil. Our method employs long short-term memory (LSTM) and gate residual network (GRN) networks to improve the efficiency of feature fusion and applies an attention mechanism to discover the interactions between the drugs. We also use label distribution smoothing and reweighting losses to address data imbalance. Experimental results show that our proposed method outperforms traditional PK-PD models and previous deep learning methods, effectively predicting anesthetic depth under sudden and deep anesthesia conditions.

Effects of V Addition on the Deformation Mechanism and Mechanical Properties of Non-Equiatomic CoCrNi Medium-Entropy Alloys.

Equiatomic CoCrNi medium-entropy alloys exhibit superior strength and ductility. In this work, a non-equiatomic CoCrNi alloy with low stacking fault energy was designed, and different fractions of V were added to control the stacking fault energy and lattice distortion. Mechanical properties were evaluated by tensile tests, and deformation microstructures were characterized by transmission electron microscope (TEM). The main deformation mechanisms of CoCrNiV alloy with low V content are dislocation slip, stacking faults, and deformation-induced HCP phase transformation, while the dominant deformation patterns of CoCrNiV alloy with high V contents are dislocation slip and stacking faults. The yield strength increases dramatically when the V content is high, and the strain-hardening behavior changes non-monotonically with increasing the V content. V addition increases the stacking fault energy (SFE) and lattice distortion. The lower strain-hardening rate of 6V alloy than that of 2V alloy is dominated by the SFE. The higher strain-hardening rate of 10V alloy than that of 6V alloy is dominated by the lattice distortion. The effects of V addition on the SFE, lattice distortion, and strain-hardening behavior are discussed.

Ubiquitin ligase enzymes and de-ubiquitinating enzymes regulate innate immunity in the TLR, NLR, RLR, and cGAS-STING pathways.

Ubiquitination (or ubiquitylation) and de-ubiquitination, which are both post-translational modifications (PTMs) of proteins, have become a research hotspot in recent years. Some ubiquitinated or de-ubiquitinated signaling proteins have been found to promote or suppress innate immunity through Toll-like receptor (TLR), RIG-like receptor (RIG-I-like receptor, RLR), NOD-like receptor (NLR), and the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-STING pathway. This article aimed to provide a review on the role of ubiquitination and de-ubiquitination, especially ubiquitin ligase enzymes and de-ubiquitinating enzymes, in the above four pathways. We hope that our work can contribute to the research and development of treatment strategies for innate immunity-related diseases such as inflammatory bowel disease.

High-Efficiency Fermentation of Nattokinase by Recombinant PSP2 Using Oyster Protein Hydrolysate as a Substrate.

In recent years, cardiovascular and cerebrovascular diseases have been the focus of several studies. In this study, oyster protein hydrolysate was produced via enzyme hydrolysis and used as a fermentation substrate to ferment recombinant strain PSP2 to produce nattokinase. Using the synergism strategy, fermentation products with fibrinolytic and angiotensin I-converting enzyme (ACE) inhibitory activities were obtained and evaluated. The fermentation medium contained 1.0% trypsin, 1.0% oyster protein hydrolysate, 2.0% maltose, and 0.5% sodium chloride, with an initial pH of 7.0. The maximum nattokinase activity was 390.23 ± 10.24 FU/mL after 72 h of fermentation. The flavor of the product was improved, and heavy metals and volatile salt nitrogen were partially removed via fermentation. The ACE inhibitory activity (IC50) of the fermentation products was 1.433 mg/mL. This study provides a novel approach for the development of marine functional foods with hypotensive and antithrombotic properties.

Polymeric nano-system for macrophage reprogramming and intracellular MRSA eradication.

Intracellular Methicillin-Resistant Staphylococcus aureus (MRSA) remains a major factor of refractory and recurrent infections, which cannot be well addressed by antibiotic therapy. Here, we design a cellular infectious microenvironment-activatable polymeric nano-system to mediate targeted intracellular drug delivery for macrophage reprogramming and intracellular MRSA eradication. The polymeric nano-system is composed of a ferrocene-decorated polymeric nanovesicle formulated from poly(ferrocenemethyl methacrylate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PFMMA-b-PMPC) copolymer with co-encapsulation of clofazimine (CFZ) and interferon-γ (IFN-γ). The cellular-targeting PMPC motifs render specific internalization by macrophages and allow efficient intracellular accumulation. Following the internalization, the ferrocene-derived polymer backbone sequentially undergoes hydrophobic-to-hydrophilic transition, charge reversal and Fe release in response to intracellular hydrogen peroxide over-produced upon infection, eventually triggering endosomal escape and on-site cytosolic drug delivery. The released IFN-γ reverses the immunosuppressive status of infected macrophages by reprogramming anti-inflammatory M2 to pro-inflammatory M1 phenotype. Meanwhile, intracellular Fe2+-mediated Fenton reaction together with antibiotic CFZ contributes to increased intracellular hydroxyl radical (•OH) generation. Ultimately, the nano-system achieves robust potency in ablating intracellular MRSA and antibiotic-tolerant persisters by synchronous immune modulation and efficient •OH killing, providing an innovative train of thought for intracellular MRSA control.

Humoral and cellular immunity of two-dose inactivated COVID-19 vaccination in Chinese children: A prospective cohort study.

Children are the high-risk group for COVID-19, and in need of vaccination. However, humoral and cellular immune responses of COVID-19 vaccine remain unclear in vaccinated children. To establish the rational immunization strategy of inactivated COVID-19 vaccine for children, the immunogenicity of either one dose or two doses of the vaccine in children was evaluated. A prospective cohort study of 322 children receiving inactivated COVID-19 vaccine was established in China. The baseline was conducted after 28 days of the first dose, and the follow-up was conducted after 28 days of the second dose. The median titers of receptor binding domain (RBD)-IgG, and neutralizing antibody (NAb) against prototype strain and Omicron variant after the second dose increased significantly compared to those after the first dose (first dose: 70.0, [interquartile range, 30.0-151.0] vs. second dose: 1261.0 [636.0-2060.0] for RBD-IgG; 2.5 [2.5-18.6] vs. 252.0 [138.6-462.1] for NAb against prototype strain; 2.5 [2.5-2.5] vs. 15.0 [7.8-26.5] for NAb against Omicron variant, all p < 0.05). The flow cytometry results showed that the first dose elicited SARS-CoV-2 specific cellular immunity, while the second dose strengthened SARS-CoV-2 specific IL-2+ or TNF-α+  monofunctional, IFN-γ+ TNF-α+  bifunctional, and IFN-γ- IL-2+ TNF-α+ multifunctional CD4+ T cell responses (p < 0.05). Moreover, SARS-CoV-2 specific memory T cells were generated after the first vaccination, including the central memory T cells and effector memory T cells. The present findings provide scientific evidence for the vaccination strategy of the inactive vaccines among children against COVID-19 pandemic.

Unexpected Cascade Dehydrogenation Triggered by Pd/Cu-Catalyzed C(sp3)-H Arylation/Intramolecular C-N Coupling of Amides: Facile Access to 1,2-Dihydroquinolines.

In this work, we successfully explored an unexpected dehydrogenation triggered by Pd/Cu-catalyzed C(sp3)-H arylation and intramolecular C-N coupling of amides to synthesize the bioactive 1,2-dihydroquinoline scaffold with good regioselectivity and good compatibility of functional groups. This strategy provides an alternative route to realize molecular complexity and diversity from simple and readily available molecules via multiple C-H bond activation. Preliminary mechanistic studies demonstrated that ß,γ-dehydrogenation is triggered by the arylation of the C(sp3)-H bond and the intramolecular C-N coupling.

Strong yet ductile nanolamellar high-entropy alloys by additive manufacturing.

Additive manufacturing produces net-shaped components layer by layer for engineering applications1-7. The additive manufacture of metal alloys by laser powder bed fusion (L-PBF) involves large temperature gradients and rapid cooling2,6, which enables microstructural refinement at the nanoscale to achieve high strength. However, high-strength nanostructured alloys produced by laser additive manufacturing often have limited ductility3. Here we use L-PBF to print dual-phase nanolamellar high-entropy alloys (HEAs) of AlCoCrFeNi2.1 that exhibit a combination of a high yield strength of about 1.3 gigapascals and a large uniform elongation of about 14 per cent, which surpasses those of other state-of-the-art additively manufactured metal alloys. The high yield strength stems from the strong strengthening effects of the dual-phase structures that consist of alternating face-centred cubic and body-centred cubic nanolamellae; the body-centred cubic nanolamellae exhibit higher strengths and higher hardening rates than the face-centred cubic nanolamellae. The large tensile ductility arises owing to the high work-hardening capability of the as-printed hierarchical microstructures in the form of dual-phase nanolamellae embedded in microscale eutectic colonies, which have nearly random orientations to promote isotropic mechanical properties. The mechanistic insights into the deformation behaviour of additively manufactured HEAs have broad implications for the development of hierarchical, dual- and multi-phase, nanostructured alloys with exceptional mechanical properties.

LMWP (S3-3) from the Larvae of Musca domestica Alleviate D-IBS by Adjusting the Gut Microbiota.

Diarrhea-based Irritable Bowel Syndrome (D-IBS) and diarrhea are both associated with ecological imbalance of the gut microbiota. Low Molecular Weight Peptides (LMWP) from the larvae of Musca domestica have been shown to be effective in the treatment of diarrhea and regulation of gut microbiota. Meanwhile, the single polypeptide S3-3 was successfully isolated and identified from LMWP in our previous studies. It remains unclear exactly whether and how LMWP (S3-3) alleviate D-IBS through regulating gut microbiota. We evaluated the gut microbiota and pharmacology to determine the regulation of gut microbiota structure and the alleviating effect on D-IBS through LMWP (S3-3). The rates of loose stools, abdominal withdrawal reflex (AWR) and intestinal tract motility results revealed that LMWP (S3-3) from the larvae of Musca domestica had a regulating effect against diarrhea, visceral hypersensitivity and gastrointestinal (GI) dysfunction in D-IBS model mice. Additionally, 16S rRNA gene sequencing was utilized to examine the gut microbiota, which suggests that LMWP induce structural changes in the gut microbiota and alter the levels of the following gut microbiota: Bacteroidetes, Proteobacteria and Verrucomicrobia. LMWP putatively functioned through regulating 5-HT, SERT, 5-HT2AR, 5-HT3AR and 5-HT4R according to the results of ELISA, qRT-PCR and IHC. The findings of this study will contribute to further understanding how LMWP (S3-3) attenuate the effects of D-IBS on diarrhea, visceral hypersensitivity and GI dysfunction.

Correntropy based semi-supervised concept factorization with adaptive neighbors for clustering.

Concept factorization (CF) has shown the effectiveness in the field of data clustering. In this paper, a novel and robust semi-supervised CF method, called correntropy based semi-supervised concept factorization with adaptive neighbors (CSCF), is proposed with improved performance in clustering applications. Specifically, on the one hand, the CSCF method adopts correntropy as the cost function to increase the robustness for non-Gaussian noise and outliers, and combines two different types of supervised information simultaneously for obtaining a compact low-dimensional representation of the original data. On the other hand, CSCF assigns the adaptive neighbors for each data point to construct a good data similarity matrix for reducing the sensitiveness of data. Moreover, a generalized version of CSCF is derived for enlarging the clustering application ranges. Analysis is also presented for the relationship of CSCF with several typical CF methods. Experimental results have shown that CSCF has better clustering performance than several state-of-the-art CF methods.

Effects of Chang-Kang-Fang Formula on the Microbiota-Gut-Brain Axis in Rats With Irritable Bowel Syndrome.

Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicine, has been used in clinical settings to treat irritable bowel syndrome (IBS). Recent studies show that 5.0 g/kg/d CKF can alleviate the symptoms of IBS rats by modulating the brain-gut axis through the production of brain-gut peptides (BGPs), thus relieving pain, and reversing the effects of intestinal propulsion disorders. However, the exact mechanisms underlying the therapeutic effects of CKF in IBS remain unclear. The microbiota-gut-brain axis (MGBA) is central to the pathogenesis of IBS, regulating BGPs, depression-like behaviors, and gut microbiota. Given that CKF ameliorates IBS via the MGBA, we performed metabolomic analyses, evaluated the gut microbiota, and system pharmacology to elucidate the mechanisms of action of CKF. The results of intestinal tract motility, abdominal withdrawal reflex (AWR), sucrose preference test (SPT), and the forced swimming test (FST) showed that the male Sprague-Dawley rats subjected to chronic acute combining stress (CACS) for 22 days exhibited altered intestinal motility, visceral hypersensitivity, and depression-like behaviors. Treatment of IBS rats with CKF normalized dysfunctions of CACS-induced central and peripheral nervous system. CKF regulated BDNF and 5-HT levels in the colon and hippocampus as well as the expressions of the related BGP pathway genes. Moreover, the system pharmacology assays were used to assess the physiological targets involved in the action of CKF, with results suggesting that CKF putatively functioned through the 5-HT-PKA-CREB-BDNF pathway. LC-MS-based metabolomics identified the significantly altered 5-HT pathway-related metabolites in the CKF treatment group, and thus, the CKF-related signaling pathways were further examined. After pyrosequencing-based analysis of bacterial 16S rRNA (V3 + V4 region) using rat feces, the Lefse analysis of gut microbiota suggested that CKF treatment could induce structural changes in the gut microbiota, thereby regulating it by decreasing Clostridiales, and the F-B ratio while increasing the levels of Lactobacillus. Furthermore, the integrated analysis showed a correlation of CKF-associated microbes with metabolites. These findings showed that CKF effectively alleviated IBS, which was associated with the altered features of the metabolite profiles and the gut microbiota through a bidirectional communication along the microbiota-gut-brain axis.

Maximum Correntropy with Variable Center Unscented Kalman Filter for Robust Power System State Estimation.

The robust Kalman filter with correntropy loss has received much attention in recent years for forecasting-aided state estimation in power systems, since it efficiently reduces the negative influence of various abnormal situations, such as non-Gaussian communication, changing environment, and instrument failures, and obviously improves the stability of power systems. However, the existing correntropy-based robust Kalman filters usually use the Gaussian function with a fixed center as the kernel function in correntropy, which may not be a suitable choice in practical applications of power system forecasting-aided state estimation (PSSE). To address this issue, a new and robust unscented Kalman filter, called the maximum correntropy with variable center unscented Kalman filter (MCVUKF), is proposed in this paper for PSSE. Specifically, MCVUKF adopts an extended version of correntropy, whose center can be located at any position, to replace the original correntropy in an unscented Kalman filter to improve the performance in PSSE. Moreover, by using an exponential function of the innovation vector to adjust a covariance matrix, an enhanced MCVUKF (En-MCVUKF) method is also developed for suppressing the influence of bad data to the innovation vector and further improving the accuracy of PSSE. Finally, extensive simulations have been conducted on IEEE 14-bus, 30-bus, and 57-bus test power systems, and the simulation results have shown the superiority of the proposed MCVUKF and En-MCVUKF methods compared with several related state-of-the-art Kalman filter methods.

Molecular characterization of matrix metalloproteinase gene family across primates.

Deregulation of matrix metalloproteinases (MMPs) contributes considerably to cancers, psychiatric disorders, macular degeneration and bone diseases. The use of humans in the development of MMPs as prognostic biomarkers and therapeutic targets is complicated by many factors, while primate models can be useful alternatives for this purpose. Here, we performed genome-enabled identification of putative MMPs across primate species, and comprehensively investigated the genes. Phylogenetic topology of the MMP family showed each type formulates a distinct clade, and was further clustered to classes, largely agreeing with classification based on biochemical properties and domain organization. Across primates, the excess of candidate sites of positive selection was detected for MMP-19, in addition to 1-3 sites in MMP-8, MMP-10 and MMP-26. MMP-26 showed Ka/Ks value above 1 between human and chimpanzee copies. We observed two copies of MMP-19 in the old-world monkey genomes, suggesting gene duplication at the early stage of or prior to the emergence of the lineage. Furin-activatable MMPs demonstrate the most variable properties regarding Domain organization and gene structure. During human aging, MMP-11 showed gradually decreased expression in testis, so as MMP-2, MMP-14, MMP15 and MMP-28 in ovary, while MMP-7 and MMP-21 showed elevated expression, implying their distinct roles in different reproductive organs. Co-expression clusters were formed among human MMPs both within and across classes, and expression correlation was observed in MMP genes across primates. Our results illuminate the utilization of MMPs for the discovery of prognostic biomarkers and therapeutic targets for aging-related diseases and carry new messages on MMP classification.

The Impact of BCL11A Polymorphisms on Endometrial Cancer Risk Among Chinese Han Females.

Background: Endometrial carcinoma (EC) is one of the most common malignant gynecological malignancies. BCL11A gene may have a tumor-suppressor role in EC. Until now, no studies have reported the effect of BCL11A variants on EC predisposition in Chinese population. Methods: Six BCL11A polymorphisms were genotyped using Agena MassARRAY system among 509 EC patients and 506 matched healthy women. Risk assessment of the BCL11A polymorphisms for EC risk was performed by calculating odds ratios (OR) with 95% confidence intervals (CI) through logistic regression models. Results: We found that rs7581162 (OR = 1.29, p = 0.012), rs10189857 (OR = 1.26, p = 0.028), rs1427407 (OR = 1.30, p = 0.015), rs766432 (OR = 1.27, p = 0.025), and rs6729815 (OR = 1.32, p = 0.008) in BCL11A were associated with higher susceptibility to EC in Chinese Han women. Age and BMI stratified analysis displayed that the risk association between BCL11A variants and EC predisposition might be age- and BMI-dependent. Haplotype analysis revealed that Ars10189857Trs1427407 and Grs10189857Grs1427407 haplotypes were related to an increased risk of EC. MDR analysis indicated that rs1427407 was the most influential attributor on EC risk in the single-locus model, and the best combination was the two-locus model containing rs7581162 and rs766432. Conclusion: Our study provided the first evidence that rs7581162, rs10189857, rs1427407, rs766432, and rs6729815 in BCL11A were risk factors for EC in Chinese Han women. These findings add our understanding of the role of BCL11A gene in EC pathogenesis.

Beneficial effect of simvastatin on human umbilical vein endothelial cells gap junctions induced by TNF-α.

Although simvastatin has been shown to inhibit vascular permeability, which might be amplified via gap junction intercellular communication (GJIC), the underlying mechanism of action remains unclear. In the present study, we investigated the effects and mechanisms of simvastatin on endothelial cells GJIC. Specifically, human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α (10 ng/mL) alone or in combination with simvastatin (5 µM), and their effects on vascular endothelial cell GJIC tested via the scrape loading/dye transfer (SL/DT) assay. Next, we performed immunofluorescence, real-time PCR and western blot assays to analyze expression of Cx37, Cx40 and Cx43 in HUVECs. Results showed that GJIC activity in HUVECs was markedly elevated in HUVECs treated with TNF-α in combination with simvastatin. In addition, simvastatin treatment significantly upregulated expression of Cx37 and Cx40 but downregulated Cx43 mRNAs and proteins. Taken together, these marked changes indicated that simvastatin exerts its regulatory effects on gap junction function by upregulating Cx37 and Cx40 and downregulating Cx43 expression.