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Aim Mitochondrial DNA dysfunction has been implicated in the pathogenesis of cardiovascular diseases. We aimed to investigate the associations between leukocyte mitochondrial DNA (mtDNA) abundance, as a proxy of mitochondrial function, and coronary artery disease (CAD) and heart failure (HF) in a cohort study and approximate the causal nature of these relationships using Mendelian randomization (MR) in genetic studies. Methods and results Multivariable-adjusted Cox regression analyses were conducted in 273 619 unrelated participants of European ancestry from the UK Biobank (UKB). For genetic studies, we first performed MR analyses with individual-level data from the UKB using a weighted genetic risk score (GRS); two-sample MR analyses were subsequently performed using summary-level data from the publicly available three consortia/biobank for CAD and two for HF. MR analyses were performed per database separately and results were subsequently meta-analysed using fixed-effects models. During a median follow-up of 11.8 years, restricted cubic spline Cox regression analyses showed associations between lower mtDNA abundance and higher risk of CAD and HF. Hazard ratios for participants in the lowest quintile of mtDNA abundance compared with those in the highest quintile were 1.08 (95% confidence interval: 1.03, 1.14) and 1.15 (1.05, 1.24) for CAD and HF. Genetically, no evidence was observed for a possible non-linear causal effect using individual-level weighted genetic risk scores calculated in the UKB on the study outcomes; the pooled odds ratios (95% confidence interval) from two-sample MR of genetically predicted per one-SD decrease in mtDNA abundance were 1.09 (1.03, 1.16) for CAD and 0.99 (0.92, 1.08) for HF, respectively. Conclusion Our findings support a possible causal role of lower leukocyte mtDNA abundance in higher CAD risk, but not in HF. [ABSTRACT FROM AUTHOR]

Background: Systemic Sclerosis (SSc) is an autoimmune disease that is characterized by vasculopathy, digital ulcers, Raynaud's phenomenon, renal failure, pulmonary arterial hypertension, and fibrosis. Regulatory T (Treg) cell subsets have recently been found to play crucial roles in SSc with interstitial lung disease (ILD) pathogenesis. This study investigates the molecular mechanism of Treg-related genes in SSc patients through bioinformatic analyses. Methods: The GSE181228 dataset of SSc was used in this study. CIBERSORT was used for assessing the category and proportions of immune cells in SSc. Random forest and least absolute shrinkage and selection operator (LASSO) regression analysis were used to select the hub Treg-related genes. Results: Through bioinformatic analyses, LIPN and CLEC4D were selected as hub Treg-regulated genes. The diagnostic power of the two genes separately for SSc was 0.824 and 0.826. LIPN was associated with the pathway of aminoacyl−tRNA biosynthesis, Primary immunodeficiency, DNA replication, etc. The expression of CLEC4D was associated with the pathway of Neutrophil extracellular trap formation, PPAR signaling pathway, Staphylococcus aureus infection, Systemic lupus erythematosus, TNF signaling pathway, and Toll−like receptor signaling pathway. Conclusion: Through bioinformatic analyses, we identified two Treg-related hub genes (LIPN, CLEC4D) that are mainly involved in the immune response and metabolism of Tregs in SSc with ILD. Moreover, our findings may provide the potential for studying the molecular mechanism of SSc with ILD. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association between mtDNA abundance, as a proxy measure of mitochondrial function, and incident stroke, using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. Cox-proportional hazard model analyses were conducted to assess the association between mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-year follow-up in European-ancestry participants from UK Biobank. MR was conducted using independent (R2 < 0.001) lead variants for mtDNA abundance (p < 5 × 10-8) as instrumental variables. Single-nucleotide polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/controls): MEGASTROKE (60,341/454,450), UK Biobank (2404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. In total, 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the Cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between low versus high mtDNA abundance and ischemic (HR: 1.06 [95% CI: 0.95, 1.18]) or hemorrhagic (HR: 0.97 [95% CI: 0.82, 1.15]) stroke. However, in the MR analyses after removal of platelet count-associated SNPs, we found evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.17; confidence interval, 1.03, 1.32). Although the results from both multivariable-adjusted prospective and basis MR analyses did not show an association between low mtDNA and increased risk of ischemic stroke, in-depth MR sensitivity analyses may suggest evidence for a causal relationship. [Display omitted] • Mitochondrial DNA (mtDNA) abundance might be causally associated with stroke. • The association between mtDNA abundance and stroke attenuated after correction. • Lower mtDNA abundance showed higher incidence of ischemic stroke. [ABSTRACT FROM AUTHOR]

Background Serum phospholipase A2 receptor (PLA2R) antibody (SAb) and glomerular deposits of PLA2R antigen (GAg) have been tested widely in idiopathic membranous nephropathy (MN). Recently, we noticed a special form of PLA2R-associated MN with positive circulating PLA2R antibody but negative PLA2R deposits in the glomeruli by immunofluorescence on frozen tissue (IF-F). The significance of this form of PLA2R-associated MN is yet to be elucidated. This study aimed to explore the clinicopathological features of these PLA2R-associated MN patients. Methods This study enrolled 229 biopsy-proven PLA2R-associated MN patients with SAb+. SAb was measured by enzyme-linked immunosorbent assay, and GAg was detected by IF-F. These patients were divided into SAb+/GAg+ and SAb+/GAg− groups. Clinicopathological characteristics of SAb+/GAg+ and SAb+/GAg− PLA2R-associated MN patients were compared. PLA2R antigens of 19 SAb+/GAg− PLA2R-associated MN patients were verified by immunohistochemistry on paraffin tissue (IHC-P). Results Among 229 SAb+ PLA2R-associated MN patients, 210 (91.70%) were GAg+ and 19 (8.3%) were GAg−. These 19 SAb+/GAg− PLA2R-associated MN patients presented positive PLA2R deposits by IHC-P. Compared with SAb+/GAg+ PLA2R-associated MN patients, SAb+/GAg- PLA2R-associated MN patients had higher levels of serum PLA2R antibody (P = 0.004), increased proteinuria (P = 0.008), lower serum albumin (P = 0.019), more prominent chronic pathological lesions in terms of glomerulosclerosis score (P = 0.025), interstitial fibrosis score (P = 0.016), tubular atrophy score (P = 0.010) and total renal chronicity score (P = 0.010), and were more likely to be accompanied by focal segmental glomerulosclerosis (P = 0.014). Higher SAb level was associated with the total renal chronicity score (odds ratio per 100 RU/mL, 1.16; 95% confidence interval 1.01–1.33; P = 0.033). Conclusions PLA2R-associated MN patients with seropositive PLA2R antibody but negative PLA2R deposits in the glomeruli by IF-F have higher levels of SAb and worse clinicopathological manifestations compared with their double-positive counterparts. IHC-P can be an alternative technique to reveal PLA2R glomerular deposits. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus (S.) aureus (MRSA) is a representative pathogen that produces numerous virulence factors involving manifold cytotoxins and exotoxins. The present study was designed to investigate the influence of Eleutheroside K (ETSK), a single compound isolated from the leaves of Acanthopanax (A.) henryi (Oliv.) Harms, on the exotoxins secreted by MRSA. The transcription and translation of the exotoxins (α-hemolysin and staphylococcal enterotoxins) related to virulence in S. aureus were determined via quantitative RT-PCR and western blot analysis. The effect of ETSK on the production of tumor necrosis factor (TNF)-α was evaluated using enzyme-linked immunosorbent assay. As a result, ETSK at sub-MIC concentrations could reduce the protein expression of α-hemolysin and enterotoxin, and the expression of genes that regulate virulence factors was also inhibited. In addition, the TNF-inducing activity of S. aureus was attenuated by ETSK in a dose-dependent manner. These results revealed that ETSK not only reduced the protein and gene expression levels of related exotoxins but also suppressed the ability of S. aureus to induce macrophages to release cytokines. This study indicated that the inhibition of MRSA infection by ETSK may be achieved by reducing the virulence of S. aureus and highlighted the potential of ETSK as an innovative strategy for the prevention and treatment of MRSA infections. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) plays an important role in regulating the hypothalamus-pituitary-gonadal (HPG) axis. However, the effects of NGF on spermatogenesis remain unclear. This study aimed to assess the potential application of NGF with nasal delivery on spermatogenesis in azoospermic mice. We established a model with azoospermia induced by a single intraperitoneal (i.p.) injection of busulfan. NGF pre-encapsulated with liposomes (25, 50, and 100 μg/kg) was delivered via internasal administration. Three weeks after busulfan injection, NGF treatments were performed twice a week for 8 weeks; the change of sperm quality, testis and epididymis histopathology, and androgenic hormone were analyzed to evaluate sperm regeneration. Furthermore, 30 mg/kg busulfan injection caused severe testicular atrophy of the seminiferous tubules, characterized by a loss of spermatogenic elements and sperms. NGF with nasal administration could significantly upregulate the markers expressing meiotic spermatogonia (Stra8) and spermatocytes (SYCP3), restore spermatogenesis, and improve sperm quality in busulfan-treated mice by increasing the secretion of sexual hormones. The convenient and noninvasive nasal delivery of NGF may be a new potential therapy for spermatogenesis via activating the HPG axis and elevating androgenic hormones. This study opened a new horizon for NGF application in reproductive endocrine. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CGA) exhibits substantial biological function in antioxidant, antibacterial, anti‐lipogenesis and anti‐inflammatory activities. Increased sebum production and inflammation are considered important for the development of acne. However, the therapeutic effects of CGA on acne vulgaris remain unexplored. In this study, to assess the effects and underlying mechanisms of CGA on acne, a model of skin inflammation in ears of ICR mouse induced by living Propionibacterium acnes was used. 24 hours after 1.0 × 107 CFU, P. acnes were intradermally injected into the ears of the ICR mouse. 1, 5 and 10 mg of CGA mixed with vaseline were applied to the surface of the skin every 12 hours for 3 days. Then, skin inflammation in the ears was assessed and the change of SREBP1 and TNF‐α expression was analysed after CGA treatment. The mechanisms of CGA in anti‐inflammatory activity and lipogenesis were also studied in primary sebocytes and HaCaT cells. We found that CGA treatment effectively rescued ear swelling, redness and erythema skin in ears of ICR mouse induced by P. acnes and significantly downregulated the expression of inflammatory cytokines by reducing the activity of the NF‐κB signalling pathway. Furthermore, CGA could inhibit lipogenesis at the protein secretion and transcription level by decreasing the AKT/mTOR/SREBP signalling pathway. Our findings suggest that CGA could become a potential alternative drug for the treatment of acne vulgaris. [ABSTRACT FROM AUTHOR]

During tooth development, dental papilla cells differentiate into odontoblasts with polarized morphology and cell function. Our previous study indicated that the C-Jun N-terminal kinase (JNK) pathway regulates human dental papilla cell adhesion, migration, and formation of focal adhesion complexes. The aim of this study was to further examine the role of the JNK pathway in dental papilla cell polarity formation. Histological staining, qPCR, and Western Blot suggested the activation of JNK signaling in polarized mouse dental papilla tissue. After performing an in vitro tooth germ organ culture and cell culture, we found that JNK inhibitor SP600125 postponed tooth germ development and reduced the polarization, migration and differentiation of mouse dental papilla cells (mDPCs). Next, we screened up-regulated polarity-related genes during dental papilla development and mDPCs or A11 differentiation. We found that Prickle3, Golga2, Golga5, and RhoA were all up-regulated, which is consistent with JNK signaling activation. Further, constitutively active RhoA mutant (RhoA Q63L) partly rescued the inhibition of SP600125 on cell differentiation and polarity formation of mDPCs. To sum up, this study suggests that JNK signaling has a positive role in the formation of dental papilla cell polarization. [ABSTRACT FROM AUTHOR]

Background: Previously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation.Objectives: The purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR).Methods: Single-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed.Results: Among an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels.Conclusions: Evidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) is a highly validated target for the treatment of type 2 diabetes and obesity. Previous studies have shown that bromophenols from marine red alga Rhodomela confervoides can inhibit PTP1B activity. However, traditional in vitro enzymatic assays may result in false positive activity. Here, we reported a successful application of molecular docking and surface plasmon resonance (SPR) assay for the characterization of small-molecule PTP1B inhibitors with high affinity. First, molecular docking study indicated that six bromophenol compounds preferred to bind PTP1B with open conformation rather than one with closed conformation. Next, SPR study indicated that compound 3 was the most potent and stable PTP1B inhibitor at the nanomolar level. Then Lineweaver–Burk plot data showed that compound 3 was a competitive PTP1B inhibitor. Moreover, compound 3 could improve palmitate-induced insulin resistance in HepG2 cells. Taken together, molecular docking and SPR-based methodology could apply in the development of PTP1B inhibitors with high affinity. • Molecular docking study of marine bromophenols with protein tyrosine phosphatase 1B (PTP1B) of open and closed conformations. • Surface plasmon resonance (SPR) assay on the interaction of bromophenols and PTP1B protein. • Effect of compound 3 on insulin resistance was studied in palmiate-treated HepG2 cells. [ABSTRACT FROM AUTHOR]

To design a reasonable dimensional tolerance of a transmission shaft, the higher product quality while lower manufacturing cost must be considered. This paper provides a mathematical model and a flowchart which elucidates the relationship between process capability index (PCI), reliability, tolerance and manufacturing cost, considering the characteristics of the shaft diameter, the material and manufacturing process. A 10.904% cost reduction under certain PCI range of a real case shows the effectiveness of the model and flowchart, thus it can be applied to those technical area when optimizing product design. [ABSTRACT FROM AUTHOR]

To design a reasonable dimensional tolerance of a transmission shaft, the higher product quality while lower manufacturing cost must be considered. This paper provides a mathematical model and a flowchart which elucidates the relationship between process capability index (PCI), reliability, tolerance and manufacturing cost, considering the characteristics of the shaft diameter, the material and manufacturing process. A 10.904% cost reduction under certain PCI range of a real case shows the effectiveness of the model and flowchart, thus it can be applied to those technical area when optimizing product design. [ABSTRACT FROM AUTHOR]

Background and Purpose: Protein tyrosine phosphatase (PTP) 1B (PTP1B) plays a critical role in the regulation of obesity, Type 2 diabetes mellitus and other metabolic diseases. However, drug candidates exhibiting PTP1B selectivity and oral bioavailability are currently lacking. Here, the enzyme inhibitory characteristics and pharmacological benefits of 3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (BDB) were investigated in vitro and in vivo.Experimental Approach: Surface plasmon resonance (SPR) assay was performed to validate the direct binding of BDB to PTP1B, and Lineweaver-Burk analysis of the enzyme kinetics was used to characterise the inhibition by BDB. Both in vitro enzyme-inhibition assays and SPR experiments were also conducted to study the selectivity exhibited by BDB towards four other PTP-family proteins: TC-PTP, SHP-1, SHP-2, and LAR. C2C12 myotubes were used to evaluate cellular permeability to BDB. Effects of BDB on insulin signalling, hypoglycaemia and hypolipidaemia were investigated in diabetic BKS db mice, after oral gavage. The beneficial effects of BDB on pancreatic islets were examined based on insulin and/or glucagon staining.Key Results: BDB acted as a competitive inhibitor of PTP1B and demonstrated high selectivity for PTP1B among the tested PTP-family proteins. Moreover, BDB was cell-permeable and enhanced insulin signalling in C2C12 myotubes. Lastly, oral administration of BDB produced effective antidiabetic effects in spontaneously diabetic mice and markedly improved islet architecture, which was coupled with an increase in the ratio of β-cells to α-cells.Conclusion and Implications: BDB application offers a potentially practical pharmacological approach for treating Type 2 diabetes mellitus by selectively inhibiting PTP1B. [ABSTRACT FROM AUTHOR]

The apolipoprotein E(APOE) ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism, vascular disease and dementia. The impact of the full range of structural genetic variation in APOE for lipids, lipoproteins and apolipoproteins and for vascular disease in the general population is not known. We systematically sequenced APOE in 10,296 individuals from the Copenhagen City Heart Study and genotyped nine rare variants (frequency≥2/10,296) in 95,227 individuals from the Copenhagen General Population Study. The UK Biobank was used for validation of common APOE variants. Rare mutations in APOE , predicted to be deleterious, are present in 1 in 257 individuals in the general population. In the meta-analysis, multifactorially adjusted hazard ratios (95% confidence intervals) for ϵ44 and ϵ22 versus ϵ33 were 1.15 (1.04–1.26) and 1.02 (0.83–1.24) for ischemic cerebrovascular disease (ICVD), 1.11 (1.04–1.19) and 0.94 (0.83–1.08) for ischemic heart disease (IHD) and 1.03 (0.89–1.17) and 1.49 (1.20–1.87) for peripheral arterial disease (PAD). A multifactorially and ϵ2/ϵ3/ϵ4 adjusted weighted allele score on the continuous scale including all common and rare structural variants showed that for individuals with genetically predicted high plasma apoE and remnant cholesterol the risk for PAD was increased. APOE variants with high apoE, triglycerides, and remnant cholesterol are associated with PAD, whereas common APOE variants with high LDL cholesterol, triglycerides and remnant cholesterol are associated with IHD. APOE variants with low apoE are associated with increased risk of ICVD. These findings highlight that both rare and common structural variations in APOE play a role in vascular disease. [Display omitted] • The APOE ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism. • We sequenced APOE in 10,296 and genotyped rare variants in 95,227 individuals. • ϵ2-like variants are associated with peripheral arterial disease. • Variants with low apoE are associated with ischemic cerebrovascular disease. • Structural variations in APOE beyond the ϵ2 and ϵ4 alleles play a role. [ABSTRACT FROM AUTHOR]

Gout is a common metabolic disease in humans, and it is due to persistently elevated levels of uric acid in the blood. At high levels, uric acid crystallizes and the crystals deposit in joints and surrounding tissues, resulting in an attack of gout. Interestingly, the gout attack can spontaneously resolve within a few days. However, the self-limited mechanism of gout remains elusive. It has been demonstrated that CD14 plays an important role in self-remission of gout. In this study, we found that the proportion of CD14-positive PBMCs was decreased in gout patients when compared with healthy controls and the serum sCD14 level was also considerably decreased in gout patients in comparison to healthy controls. In addition, sCD14 levels were positively correlated with CRP levels. Furthermore, the effect of MSU on the levels of CD14 in healthy volunteer's PBMC was explored in in vitro experiment. The results showed that CD14 expression on macrophage and sCD14 levels in the culture supernatants were significantly decreased after MSU treatment. However, there was no significance in the levels of membrane CD14 and sCD14 in healthy volunteer's PBMC stimulated by LPS. Taken together, these results suggest that CD14 might play an important role in self-remission of gout. [ABSTRACT FROM AUTHOR]

Abstract Some plant polysaccharides (PPSs) had been used as the adjuvants for systemic vaccination. In this study, we investigated whether PPSs could exhibit adjuvant effect at the mucosa. Groups of mice were intranasally immunized with Epimedium Polysaccharide (EPS), Trollius chinensis polysaccharide (TCPS), Siberian solomonseal rhizome polysaccharide (SSRPS) and Astragalus polysaccharides (APS) together with ovalbumin (OVA). Significantly higher levels of OVA-specific IgG in serum and secretory IgA in saliva, vaginal wash and intestinal lavage fluid were induced after immunization with OVA plus one of the four PPSs compared to OVA alone. Antigen absorption and TLR2 (Toll-like receptor 2) activation may be related to their mucosal adjuvant effect. Of note, when APS used as an adjuvant, intranasally vaccination with recombination UreB (rUreB, Urease subunit B) conferred more robust protection against Helicobacter pylori (H. pylori). Immunized with rUreB in combination APS resulted in mixed specific Th1 and Th17 immune response, which may contribute to the inhibition of H. pylori colonization. Though specific Th2-dominant responses were elicited when the other three PPS intranasally immunized with rUreB, no significant difference in the protective effect were found between those groups and rUreb alone group. Taken together, the four PPSs may be promising candidates for mucosal adjuvant, and APS could enhance rUreB-specific protective immunity against H. pylori infection. [ABSTRACT FROM AUTHOR]

High thermal cyclic stability is achieved in Ti-50.8at.%Ni alloy by fabricating hierarchical lath colonies along { 112 } B 2 planes using isothermal compression and aging. Transformation temperature shift between the 1st and 20th thermal cycle is 0.03∼0.27°C, which results from boundary strengthening of hierarchical lath colonies. Hierarchical lath colonies are controlled by dislocations. Compression induces b = 1 2 [ 1 ¯ 11 ] screw dislocations on [ 1 ¯ 11 ] (12 1 ¯) slip system with anti-phase boundaries (APBs) located on (12 1 ¯) B 2 plane, while aging promotes dislocation motion and rearrangement, and adjustment of atomic site occupation in local structure near APBs. When distance of APBs is large, one-direction lath-colony boundaries and one-direction lath colony form. When distance of APBs reduces, clover-shaped lath-colony boundaries form, and hierarchical lath colonies are recognized. If area of APB reduces, lath-colony boundaries and lath colony vanish. These findings show the potential for improving properties of NiTi alloy by dislocation engineering. [Display omitted] [ABSTRACT FROM AUTHOR]

The globularization behavior of the basketweave microstructure in TC17 alloy is quantitatively analyzed during deformation and subsequent heat treatment. Collaborative behavior in the α lamellae and β phase evolution are proposed to affect globularization based on the transmission electron microscopy (TEM) and high-resolution electron backscatter diffraction (EBSD) observations as follows: (i) the interleaved α lamellae restrain the rotation of neighboring α lamellae and promote the formation of low-angle boundaries (LABs) and grooves, and then (ii) the β phase has a positive effect on facilitating the complete separation of α lamellae during deformation. During heat treatment, (iii) the formation of the LABs in the β grain interiors accelerates the appearance of necklace-like α grains, and (iv) the α lamellae promotes the break-up of β phase while the β phase has a positive effect on facilitating the complete separation of α lamellae. In other words, Collaborative behavior in α lamellae and β phase evolution promotes the globularization of TC17 alloy containing a basketweave microstructure. Except for the boundary splitting and termination migration, the mechanism of substructure rotation also participates in the globularization of TC17 alloy containing a basketweave microstructure, which is different to that of the alloys containing a colony microstructure. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Compared with other therapies for diabetic patients, islet transplantation can effectively prevent and reverse diabetes-induced microvascular disease, such as diabetic retinopathy and nephropathy. PTX3 is the only long pentraxin that can be detected in renal tissue. In this study, we investigated the expression of PTX3 when early DN was reversed after islet transplantation. Methods. Diabetes was induced in rats by injecting streptozotocin (STZ). Twelve weeks later, the diabetic rats were divided into 2 groups: the islet transplantation group (IT) and the diabetic nephropathy group (DN). Renal injury, renal function, and the expression of PTX3 in the plasma and the kidneys were assessed with urinalysis, immunohistochemical staining, and Western blot, respectively. Results. The expression of PTX3 in the kidney was significantly decreased in the DN group but increased in the IT group because of the reversal of DN. Conclusions. Our data showed that the level of PTX3 in renal tissue is closely related to renal injury in DN. This may be used to quantify the extent of renal injury in DN, provide a potential early indicator of renal tubular injury in early DN patients, and assess DN clinical progression. [ABSTRACT FROM AUTHOR]

Second phase particles (SPPs) that are formed during melting process have a significant effect on the hot extrusion and re-extrusion processes of NiTi. In the present work, the evolution of Ti 4 Ni 2 O x (with x ≤ 1) particles during hot extrusion and re-extrusion of near equiatomic Ti-50.6 at.% Ni billets, and their effects on the surrounding matrix microstructure were studied using OM, SEM, TEM and EBSD. The analyses indicate that Ti 4 Ni 2 O x (with x ≤ 1) are the particles that precipitate in the austenite matrix. After hot extrusion and re-extrusion, some particles are elongated and preferentially oriented along the ED. Eventually, these elongated particles are located at the grain boundaries. The size distribution of the SPPs is non-uniform after the first hot extrusion, and this non-uniformity increases after re-extrusion. The presence of non-deforming SPPs produces inhomogeneous deformation with a sharp increase in dislocation density in the surrounding matrix. This is shown to exert a profound effect on the processes of recovery and recrystallization for the surrounding matrix. [ABSTRACT FROM AUTHOR]

Background and Purpose: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling by tyrosine dephosphorylation of the insulin receptor. It is a highly validated target for type 2 diabetes therapeutics. Here, the anti-diabetic effects of HPN were evaluated in the diabetic BKS db mice.Experimental Approach: The mode of inhibition of PTP1B by HPN was determined according to the Lineweaver-Burk plot. A surface plasmon resonance assay and molecular docking were used to study the interaction between HPN and PTP1B. C2C12 skeletal muscle cells were used to investigate the cell permeability of HPN and the effect of HPN on insulin signalling pathways. Long-term effects of HPN on glycaemic control were investigated in diabetic BKS db mice. Glycogen contents in liver and muscle were determined. Furthermore, changes in the number of beta cells were evaluated by Gomori staining.Key Results: HPN was identified as a specific PTP1B inhibitor. HPN directly interacted with PTP1B by binding to the catalytic domain through hydrogen bonds in a competitive mode. Approximately 56.98% of HPN entered into the cultured C2C12 myotubes. HPN ameliorated the impaired insulin signalling in palmitate-treated C2C12 myocytes. Notably, oral administration of HPN significantly protected mice from hyperglycaemia, dyslipidemia and hyperinsulinaemia. HPN also enhanced the storage of glycogen in liver and muscle. Moreover, HPN obviously improved the beta cell numbers of the pancreatic islets.Conclusion and Implications: Our results indicate that HPN is a specific PTP1B inhibitor, with anti-diabetic properties and good cell permeability and oral availability. [ABSTRACT FROM AUTHOR]

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. [ABSTRACT FROM AUTHOR]

As-received and vacuum arc-cast near equiatomic Ti-50.6 at.% Ni billets were extruded and re-extruded at 815 °C at Case Western Reserve University (CWRU) with an extrusion ratio of 4 to 1. The effects of arc-casting, extrusion and re-extrusion on the grain size, volume fraction of recrystallized grains, grain boundary misorientation and texture were analyzed via the high-resolution electron backscatter diffraction (EBSD). The results show that extruding and re-extruding the as-received NiTi shape memory alloy produces a 〈111〉texture//ED and {110}〈uvw〉texture//TD. The size of austenite grains and the volume fraction of recrystallized grains significantly decrease but the fraction of LABs slightly increases and the grain size distribution becomes more homogeneous for the re-extruded NiTi in comparison to the first extrusion. For the vacuum arc-cast extruded NiTi shape memory alloy, the microstructure predominantly consists of elongated austenite grains. There is a strong {001}〈001〉texture//TD at the Butt (i.e. as-cast NiTi). Re-extrusion of the vacuum arc-cast NiTi shape memory alloy produces a material that exhibits two strong textures: ( 110 ) [ 1 1 ¯ 0 ] //CD(ED) and {001}〈100〉//TD in the Extrudate ①. The re-extruded material exhibits few elongated grains at this location. Instead, the second extrusion of the as-cast material produces fine and equiaxed recrystallized grains. [ABSTRACT FROM AUTHOR]

Fas and its ligand FasL, members of tumor necrosis factor receptor superfamily, have been implicated in the process of cell apoptosis. FasL consists of two forms, membrane FasL (mFasL) and soluble FasL (sFasL). sFasL can be produced by mFasL cleaved by matrix metalloproteinases (MMP) and also reveals a role for binding to Fas which is expressed on cell surface. Although Fas/FasL axis has been implicated in a variety of diseases, its role in Sjogren’s syndrome still remains ill defined. In this study, we investigated the potential of sFasL in the pathogenesis of Sjogren’s syndrome (SS). We found that the serum levels of sFasL in SS patients were significantly lower than healthy subjects. Moreover, serum levels of sFasL in patients with mild disease activity were higher than patients with severe disease activity. There is a positive correlation of the serum level of sFasL with uptake index of parotid gland in our expectation. In addition, liver injury involvement in SS patients showed decreased level of sFasL. Furthermore, we here also observed that the protective cytokine IL-10 expression was positively correlated with sFasL expression. Thus, our results here suggest a potential of sFasL in maintaining gland organ homeostasis. [ABSTRACT FROM AUTHOR]

[Display omitted] Alcohol dehydrogenases (ADHs) play vital roles in alcohol metabolism and alcohol toxicity, yet little is known about microRNA-mediated regulation of the ADH gene cluster. Here, we showed that miR-29c activated ADH gene cluster transcription by targeting an enhancer element within the ADH6 gene. miR-29c is differentially expressed in alcoholic liver disease. Following biochemical and molecular evidence demonstrated that miR-29c increased ADH6 mRNA and protein levels without affecting the stability of the ADH6 transcript. Further evidence showed that exogenous miR-29c translocated into the nucleus and then unconventionally bound an enhancer element within the ADH6 gene. Luciferase reporter assay and chromatin immunoprecipitation data indicated that miR-29c activated the enhancer and increased the enrichment of RNA polymerase II at the promoter regions of ADH1A , ADH1B , ADH1C , ADH4 , and ADH6. Finally, exogenous miR-29c transfection promoted the expression of ADH1A , ADH1B , ADH1C , and ADH4 pre-mRNA and mRNA transcripts from the ADH gene cluster. In conclusion, our data suggest that miR-29c might be a novel epigenetic regulator involved in ADH gene cluster activation. [ABSTRACT FROM AUTHOR]

[Display omitted] • The distribution probability of lamellar intersection is modelled to describe the relationship of various α lamellae. • The distributed relationship between lamellar and globular grains is described by the equivalent circle method. • The effect of grain orientation and size is considered compared to the classical grain distribution probability model. • The novelty nearest-surface function is established and used to reveal the uniformity of different morphology grains. A novel probability model of grain morphology distribution considering the orientation and size of non-spherical grains, including P 01 (r) , P 11 (r) , P 02 (r) , P 33 (r) , P 12 (r) , is established based on the nearest-surface function, and it is used to reveal the dispersion and uniformity degree of different morphology grains in titanium alloys. Especially, the distribution probability of lamellar α intersection is introduced instead of the distributed relationship of different α lamellae, and the distributed relationship between lamellar and globular grains is transformed into the distribution of globular grains by the equivalent circle method. Then, several corresponding distribution probabilities are selected in terms of describing different microstructure states (equiaxed, basketweave, duplex microstructures). The model is applied to the quantitative analysis of TC4 alloy with different morphology grains. The results show that the distribution of α grains with different morphology in the β matrix becomes more inhomogeneous with increasing height reduction and cooling rate. Moreover, the larger the globular α size is, the greater the aggregation degree and the smaller the uniformity of other α grains around it is. The reliability of probability model is verified by the comparison between the predicted and the measured frequency distributions for the nearest neighbor surface distance r. [ABSTRACT FROM AUTHOR]

R and B2 nano-domains are introduced in NiTi shape memory alloy (SMA) through isothermal compression followed by post aging, and high superelastic stability is achieved. Results show that recovery ratios for as-deformed and as-aged NiTi in 10 loading-unloading cycles are 50.31%±6.28% and 92.19%±0.94%, respectively. A three-step shear stress-induced martensitic transformation (SIMT) in and between (0 1 ¯ 1) B 2 plane is proposed, resulting in transformation of B2→B19′+metastable B2 for as-deformed NiTi, and B2+ R →R→B19′+metastable B2 for as-aged NiTi. During unloading, inverse martensitic transformation-induced stacking faults (SFs) along { 211 } B 2 planes, dislocation multiplication and residual B19′ formation are reasons for plasticity and superelastic instability, indicating B19′+metastable B2→B2+SFs occurs in as-deformed NiTi. Furthermore, B19′+metastable B2→R→B2+ R occurs without SFs because of complex stacking sequence of R phase, rationalizing the superelastic stability of as-aged NiTi. This research opens an avenue to improve superelastic stability of NiTi SMAs by inhibiting the formation of transformation-induced SFs. [Display omitted] [ABSTRACT FROM AUTHOR]

The evolution behavior of α lamellae and evolution relationship between α lamellae and β phase in TC17 alloy during isothermal heating and subsequent compression were investigated. The results show that the α/β interface of TC17 alloy is made up of stable terrace plane and movable ledge plane. The ledge plane migrates along the length direction of α lamellae during isothermal heating, which results in rapid decrease of length and slow decrease of thickness of α lamellae. During compression, the continuous dynamic recrystallization (CDRX) are the main evolution mechanism of α and β phases. The slip systems of β phase are easily activated and the slip in β phase (i.e. (110)[ 1 ̅ 11 ]) will promote the slip in α phase (i.e. (0001)[ 11 2 ̅ 0 ]) at the initial stage of compression. Thus the CDRX of β phase is preferentially initiated by more activated slip and it will promotes the CDRX of α phase, then the HABs are formed in α lamellae. Meanwhile, the β stabilized elements Cr and Mo diffuse into the α/α boundaries in a short-time deformation. The α→β phase transformation is promoted by the enrichment of Cr and Mo elements and finally the α lamellae are separated with further compression. [Display omitted] • The dissolution mechanism of α lamellae during heating and the motion of atoms at α/β interface were investigated. • The CDRX was the main evolution mechanism of α and β phases during high temperature compression. • The easier activated slip system in β phase was beneficial to the slip in α phase at the beginning of compression. • The CDRX of β phase was preferentially initiated and it promoted the CDRX of α phase during compression. • The α→β phase transformation was promoted by the enrichment of β stabilized elements at the HABs of α lamellae. [ABSTRACT FROM AUTHOR]

In this paper, we study one-dimensional reflected backward doubly stochastic differential equations (RBDSDEs) with one continuous barrier and discontinuous (left or right continuous) generator. We obtain an existence theorem and a comparison theorem for solutions of the class of RBDSDEs. [ABSTRACT FROM AUTHOR]

Background: Animal horns (AHs) have been applied to traditional medicine for more than thousands of years, of which clinical effects have been confirmed by the history. But now parts of AHs have been listed in the items of wildlife conservation, which limits the use for traditional medicine. The contradiction between the development of traditional medicine and the protection of wild resources has already become the common concern of zoophilists, traditional medical professionals, economists, sociologists. We believe that to strengthen the identification for threatened animals, to prevent the circulation of them, and to seek fertile animals of corresponding bioactivities as substitutes are effective strategies to solve this problem. Methodology/Principal Findings: A powerful technique of DNA barcoding based on the mitochondrial gene cytochrome c oxidase I (COI) was used to identify threatened animals of Bovidae and Cervidae, as well as their illegal adulterants (including 10 species and 47 specimens). Meanwhile, the microcalorimetric technique was used to characterize the differences of bio-responses when those animal specimens acted on model organism (Escherichia coli). We found that the COI gene could be used as a universal primer to identify threatened animals and illegal adulterants mentioned above. By analyzing 223 mitochondrial COI sequences, a 100% identification success rate was achieved. We further found that the horns of Mongolian Gazelle and Red Deer could be exploited as a substitute for some functions of endangered Saiga Antelope and Sika Deer in traditional medicine, respectively. Conclusion/Significance: Although it needs a more comprehensive evaluation of bioequivalence in order to completely solve the problem of substitutes for threatened animals, we believe that the identification (DNA barcoding) of threatened animals combined with seeking substitutions (bio-response) can yet be regarded as a valid strategy for establishing a balance between the protection of threatened animals and the development of traditional medicine. [ABSTRACT FROM AUTHOR]

Abstract: Chronic arsenic exposure has an adverse effect on neurobehavioral function. Our previous study demonstrated an elevated arsenic level, ultra-structure changes and reduced NR2A gene expression in hippocampus, and impaired spatial learning in arsenite-exposed rats. The NMDA receptor and the postsynaptic signaling proteins CaMKII, postsynaptic density protein 95 (PSD-95), synaptic Ras GTPase-activating protein (SynGAP) and nuclear activated extracellular-signal regulated kinase (ERK1/2) play important roles in synaptic plasticity, learning and memory. We hypothesized that the above molecular expression changes may contribute to arsenic neurotoxicity. In present study, the expression of NMDA receptor and postsynaptic signaling proteins in hippocampus were evaluated in rats exposed to 0, 2.72, 13.6 and 68mg/L sodium arsenite for 3 months. Decreased protein expression of NR2A, PSD-95 and p-CaMKII α in the hippocampus of arsenite-exposed rats was observed, while the expression of SynGAP, a negative regulator of Ras-MAPK activity, was increased when compared with the controls. Additionally, decreased p-ERK1/2 activity was found in the hippocampus of arsenite-exposed rats. These data suggest that altered expression of NMDA receptor complex and postsynaptic signaling proteins may explain arsenic-induced neurotoxicity. [Copyright &y& Elsevier]

Abstract: A novel symmetric conjugated oligo(phenylene-ethynylene) (OPE) linear molecule (1,4-bis(4-aminophenylethynyl)benzene); BAB) was synthesized by Sonogashira cross-coupling reactions. The structure and purity of the compound were confirmed by 1H NMR, 13C NMR and infrared (IR) and mass spectrometry (MS). The electrochemical oxidation process and mechanism of BAB were investigated via in situ Fourier transform infrared (FTIR) spectroelectrochemistry and electrochemical quartz crystal microbalance (EQCM). The electrochemical oxidation mechanism of BAB was proposed. The studies revealed that the BAB concentration and oxidation potential had a significant influence on the growth of the polymer film. A densely packed polymer film, which exhibited nonelectroactivity, was formed when a high monomer concentration and a high oxidation potential were used. When the electropolymerization of BAB was conducted at a lower concentration, a new pair of redox peaks appeared, and the resultant thin film had better electroactivity. The in situ FTIR studies confirmed that BAB could be electro-oxidized into radical cations and then electropolymerized via para (N-N) and/or ortho (N-C) coupling reactions to form polymers with a larger conjugated π-electron system. The surface morphology of the poly-BAB was also investigated with atomic force microscopy (AFM) and scanning electron microscopy (SEM). [Copyright &y& Elsevier]

Abstract: Isothermal compression of Ti–6Al–4V alloy at the deformation temperatures ranging from 1093K to 1303K with an interval 20K, the strain rates ranging from 0.001s−1 to 10.0s−1 and the height reductions ranging from 20% to 60% with an interval 10% were carried out on a Thermecmaster-Z simulator. Based on the experimental results, a model for the flow stress in isothermal compression of Ti–6Al–4V alloy was established in terms of the fuzzy neural network (FNN) with a back-propagation learning algorithm using strain, strain rate and deformation temperature as inputs. The maximum difference and the average difference between the predicted and the experimental flow stress are 18.7% and 4.76%, respectively. The comparison between the predicted results based on the FNN model for flow stress and those using the regression method has illustrated that the FNN model is more efficient in predicting the flow stress of Ti–6Al–4V alloy. [Copyright &y& Elsevier]

Abstract: The deformation behavior in isothermal compression of Ti–6Al–4V alloy is investigated in the deformation temperatures ranging from 1093K to 1303K, the strain rates ranging from 0.001s−1 to 10.0s−1 at an interval of an order magnitude and the height reductions ranging from 20% to 60% at an interval of 10%. Based on the experimental results in isothermal compression of Ti–6Al–4V alloy, the effect of processing parameters and grain size of primary α phase on the strain rate sensitivity exponent m and the strain hardening exponent n is in depth analyzed. The strain rate sensitivity exponent m at a strain of 0.7 and strain rate of 0.001s−1 firstly tends to increase with the increasing of deformation temperature, and maximum m value is obtained at deformation temperature close to the beta-transus temperature, while at higher deformation temperature it drops to the smaller values. Moreover, the strain rate sensitivity exponent m decreases with the increasing of strain rate at the deformation temperatures below 1253K, but the m values become maximal at a strain rate of 0.01s−1 and the deformation temperature above 1253K. The strain rate affects the variation of strain rate sensitivity exponent with strain. Those phenomena can be explained reasonably based on the microstructural evolution. On the other hand, the strain hardening exponent n depends strongly on the strain rate at the strains of 0.5 and 0.7. The strain affects significantly the strain hardening exponent n due to the variation of grain size of primary α phase with strain, and the competition between thermal softening and work hardening. [Copyright &y& Elsevier]

Abstract: The internal state variable approach nowadays is more and more used to describe the deformation behavior in all of the metallic materials. In this paper, firstly the dislocation density rate and the grain growth rate varying with the processing parameters (deformation temperature, strain rate and strain) are established using the dislocation density rate as an internal state variable. Secondly the flow stress model in high temperature deformation process is analyzed for each phase of titanium alloys, in which the flow stress contains a thermal stress and an athermal stress. A Kock–Mecking model is adopted to describe the thermally activated stress, and an athermal stress model is established using two-parameter internal state variables. Finally, a constitutive model coupling the grain size, volume fraction and dislocation density is developed based on the microstructure and crystal plasticity models. And, the material constants in present model may be identified by a genetic algorithm (GA)-based objective optimization technique. Applying the constitutive model to the isothermal compression of Ti–6Al–4V titanium alloy in the deformation temperature ranging from 1093 to1303K and the strain rate ranging from 0.001 to 10.0s−1, the 20 material constants in those models are identified with the help of experimental flow stress and grain size of prior α phase in the isothermal compression of Ti–6Al–4V titanium alloy. The relative difference between the predicted and experimental flow stress is 6.13%, and those of the sampled and the non-sampled grain size are 6.19% and 7.94%, respectively. It can be concluded that the constitutive model with high prediction precision can be used to describe the high temperature deformation behavior of titanium alloys. [Copyright &y& Elsevier]

Abstract: The deformation behavior of isothermally compressed Ti–6Al–4V alloy in the deformation temperature range from 1093K to 1303K, the strain rate range from 0.001s−1 to 10.0s−1 and the height reduction range from 20% to 60% has been investigated in depth. Effect of the strain on the flow stress, the grain size and the apparent activation energy for deformation of isothermally compressed Ti–6Al–4V alloy is analyzed. The results show that the apparent activation energy for deformation and the grain size of isothermally compressed Ti–6Al–4V alloy in the α+β two-phase region vary slightly with strain: the activation energy increases with strain after an early drop as the primary α grain size varies with strain. On the other hand, the apparent activation energy for deformation of isothermally compressed Ti–6Al–4V alloy in the β single-phase region increases firstly with the increasing of strain and then does that slightly in the strain range from 0.3 to 0.7. A processing map of the isothermally compressed Ti–6Al–4V alloy is constructed at a strain of 0.6. The processing map of isothermally compressed Ti–6Al–4V alloy exhibits that the optimal processing parameters are the deformation temperature of 1143K and the strain rate of 0.001s−1. Meanwhile, two instability domains in the processing map of isothermally compressed Ti–6Al–4V alloy are as follows: one is in the deformation temperature range from 1093K to 1183K and the strain rate range from 0.011s−1 to 2.02s−1, and another is in the deformation temperature range from 1243K to 1303K and the strain rate range from 1.0s−1 to 10.0s−1. [Copyright &y& Elsevier]

Abstract: Effect of the strain on the grain size, the efficiency of power dissipation and the instability parameter are investigated in the isothermal compression of Ti–6Al–4V alloy. And, the processing maps in the isothermal compression of Ti–6Al–4V alloy, Ti–5.6Al–4.8Sn–2.0Zr alloy and Ti–10V–4.5Fe–1.5Al alloy are constructed at a series of strains. Those results show that the grain size of primary α phase of Ti–6Al–4V alloy varies significantly with strain. The effect of strain on the efficiency of power dissipation is significant at strain rates of 0.001s−1 and 10.0s−1. However, the efficiency of power dissipation varies significantly with strain at a strain rate of 0.1s−1 in the α+β two-phase region, but that does slightly in the β single-phase region. And, the instability parameter of Ti–6Al–4V alloy varies significantly with strain at each strain rate and deformation temperature. Effect of the strain on the unstable regions in the processing maps of isothermally compressed Ti–6Al–4V alloy, Ti–5.6Al–4.8Sn–2.0Zr alloy and Ti–10V–4.5Fe–1.5Al alloy are obtained. Compared with the processing maps of different types titanium alloys, it can be found that the effect of strain on the processing map of Ti–10V–4.5Fe–1.5Al alloy (a kind of β type titanium alloy) is most significant, that of Ti–6Al–4V alloy (a kind of α+β type titanium alloy) is secondary and that of Ti–5.6Al–4.8Sn–2.0Zr alloy (a kind of near α type titanium alloy) is less. [Copyright &y& Elsevier]

Abstract: Epidemiological investigations indicate that chronic arsenic exposure can damage neurobehavioral function in children. The present study was aimed to study the effects of arsenic exposure from drinking water on the spatial memory, and hippocampal ultra-structures and N-methyl-d-aspartate receptor (NMDAR) gene expression in rats. Sprague–Dawley rats were assigned to four groups: rats in control group drank regular water, rats in other groups drank water with final arsenic concentration of 2.72mg/L (group A), 13.6mg/L (group B) and 68mg/L (group C), respectively, for 3 months. The levels of arsenic in blood serum and hippocampus were monitored. Rats were tested in Morris water maze (MWM) for memory status. Samples of hippocampus were collected from two rats in each group for transmission electron microscopic study and the detection of NMDAR expression by RT-PCR. The rats in group C showed a significant delay in hidden platform acquisition. Neurons and endothelial cells presented pathological changes and the expression of NR2A was down-regulated in hippocampus in arsenic exposed rats. Our data indicated that arsenic exposure of 68mg/L caused spatial memory damage, of which the morphological and biochemical bases could be the ultra-structure changes and reduced NR2A expression in hippocampus. [Copyright &y& Elsevier]

Abstract: The modeling of constitutive relationships and microstructural variables of the Ti–6.62Al–5.14Sn–1.82Zr alloy during high temperature deformation by using a fuzzy set and artificial neural network (FNN) technique with a back-propagation learning algorithm is the basis of this research. To obtain experimental results for the modeling, the isothermal compression of the titanium alloy in different deformation scenarios was conducted and quantitative metallography was thus obtained. The predicted results of flow stress and microstructural variables, including grain size and volume fraction of the α phase, are compared with the experimental data and the difference is less than 15%. The predicted results are consistent with the experimental data. Furthermore, the comparison between the predicted results of flow stress based on the FNN approach and those by using the regression method has illustrated that the FNN approach is efficient in predicting the flow stress of the alloy. [Copyright &y& Elsevier]

ALK‐positive histiocytosis is a rare histiocytic disease characterized by ALK positivity. It was first described in 2008 as a systemic disease in infants. The disease often shows positivity for CD68 and CD163 on immunohistochemistry, and genomic analysis frequently reveals KIF5B::ALK fusions. ALK‐positive histiocytosis typically follows an indolent course and has a promising prognosis, with conventional treatments usually being effective. Here, we report a rare case of ALK‐positive histiocytosis with exclusive involvement of the central nervous system in a 33‐year‐old Asian adult woman. Although cranial MRI suggested a meningioma, immunohistochemical workup showed that the ALK‐positive tumor cells expressed macrophage/histiocyte markers such as CD163 and CD68. Additionally, second‐generation sequencing revealed a KIF5B::ALK fusion. Our case highlights the importance of the differential diagnosis in adult central nervous system tumors, emphasizing the combination of morphology, immunophenotype, and molecular approach with ALK status evaluation to confirm a diagnosis of ALK‐positive histiocytosis. This case also expands the clinicopathologic spectrum of ALK‐positive histiocytosis. [ABSTRACT FROM AUTHOR]

The available evidence on the connection between excessive alcohol consumption and diabetes is controversial. Therefore, the primary objective of this investigation was to examine the connection between excessive alcohol consumption and incident diabetes in a Japanese population through the utilization of propensity score matching (PSM) analysis. Our retrospective cohort study encompassed a sample of 15,464 Japanese individuals who were initially free of diabetes between the years 2004 and 2015. The study utilized comprehensive medical records of individuals who underwent a physical examination. Employing a one:one PSM analysis, the current research included 2298 individuals with and without excessive alcohol consumption. Furthermore, a doubly robust estimation method was employed to ascertain the connection between excessive alcohol consumption and diabetes. The findings revealed that individuals with excessive alcohol consumption exhibited a 73% higher likelihood of developing diabetes (HR = 1.73, 95% CI 1.08–2.77). Furthermore, upon adjusting for variables, the PSM cohort demonstrated that individuals with excessive alcohol consumption had a 78% increased risk of developing diabetes in comparison to those with non-excessive alcohol consumption (HR = 1.78, 95% CI 1.08–2.93). Individuals with excessive alcohol consumption were found to have a 73% higher risk of developing diabetes compared to those with non-excessive alcohol consumption, even after controlling for propensity score (HR = 1.73, 95% CI 1.08–2.78). Participants in the PSM cohort with excessive alcohol consumption had a 73% higher risk of developing diabetes than those with non-excessive alcohol consumption after controlling for confounding factors. These findings underscore the importance of alcohol consumption guidelines aimed at reducing excessive drinking. Clinicians should be vigilant in screening for alcohol use in patients, particularly those at risk for diabetes, and provide appropriate counseling and resources to support alcohol reduction. [ABSTRACT FROM AUTHOR]

Frequency–time conversion is a crucial step in grounded electrical-source transient electromagnetic response calculation, and the performance of the algorithm is directly related to the overall accuracy and speed of forward modeling. In mainstream algorithms, algorithms with high accuracy often have slow computation speed while algorithms with high efficiency have unsatisfactory accuracy, especially when facing inversion problems that are difficult to meet requirements. This paper introduces three inverse Laplace transform algorithms for this problem: the Gaver–Stehfest algorithm, the Euler algorithm, and the Talbot algorithm. The performance of each algorithm in forward modeling was analyzed using half-space and layered models, and the optimal selection schemes for algorithm weight coefficients were provided. The numerical calculation results show that the Gaver–Stehfest algorithm has a unique advantage in computational efficiency, while the Talbot algorithm and Euler algorithm meet the accuracy requirements. After considering both accuracy and efficiency, the Talbot algorithm is selected to replace conventional algorithms for calculation of grounded electrical-source transient electromagnetic forward modeling. In addition, this paper combines the characteristics of the Gaver–Stehfest algorithm and the Talbot algorithm to implement an adaptive hybrid algorithm. This algorithm uses the Gaver–Stehfest algorithm for forward modeling in the early times and the Talbot algorithm to compensate for the decrease in accuracy in the later times. Through the comparison of forward modeling calculations, it can be seen that the hybrid algorithm proposed in this paper fully utilizes the advantages of both algorithms. The hybrid algorithm greatly improves computational speed while meeting accuracy requirements, and has significant advantages over conventional algorithms. • Compared and analyzed the characteristics of three inverse Laplace transform algorithms. • The optimal selection for the number of nodes with inverse Laplace transform algorithms coefficients is provided. • The Talbot algorithm has been selected as the most suitable algorithm for forward modeling of grounded electrical-source TEM. • Proposed an adaptive hybrid algorithm and verified its advantages. [ABSTRACT FROM AUTHOR]

• Islet transplantation was superior to mere insulin therapy in diabetic nephropathy protection. • C-peptide suppressed high glucose-induced epithelial-mesenchymal transition and renal fibrosis in podocytes. • C-peptide ameliorated high-glucose induced podocyte injury via down-regulating the Notch and TGF-β signaling pathways. The podocyte is one of the main components of the glomerular filtration barrier in the kidney, and its injury may contribute to proteinuria, glomerulosclerosis and eventually kidney failure. C-peptide, a cleavage product of proinsulin, shows therapeutic potential for treating diabetic nephropathy (DN). The aim of this study was to investigate the effect of C-peptide on high glucose-induced podocyte dysfunction. In the present study, we found that the protective effects of islet transplantation were superior to simple insulin therapy for the treatment of DN in streptozotocin (STZ)-treated rats. And such superiority may due to the function of C-peptide secreted at the implanted site. Based on this background, we determined that the application of C-peptide significantly prevented high glucose-induced podocyte injury by increasing the expression of nephrin and synaptopodin. Meanwhile, C-peptide suppressed high glucose-induced epithelial-mesenchymal transition (EMT) and renal fibrosis via decreasing the expression of snail, vimentin, α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Moreover, the Notch and transforming growth factor-β (TGF-β) signaling pathways were activated by high glucose, and treatment with C-peptide down-regulated the expression of the Notch signaling molecules Notch 1 and Jagged 1 and the TGF-β signaling molecule TGF-β1. These findings suggested that C-peptide might serve as a novel treatment method for DN and podocyte dysfunction. [ABSTRACT FROM AUTHOR]

Isothermal compression tests, electron backscatter diffraction (EBSD) observations and quantitative analysis are performed to investigate the effect of process parameters on the microstructure variables (i.e. recrystallized fraction, size of austenite grain and grain boundary misorientation) during isothermal compression of NiTi shape memory alloy. And the evolution of dynamic recrystallization and recrystallization texture for this alloy is thoroughly discussed in the present study. The results show that the dynamic recovery is a dominated softening mechanism at less than 0.5 strain. As the strain increases, the discontinuous dynamic recrystallization (original grain boundary bulging and strain-induced grain boundary migration) and the subsequent continuous dynamic recrystallization (subgrain rotation) also participate in the softening of NiTi shape memory alloy, leading to a steady state of flow behavior. In the deformation end stage, the grain refinement of the austenite phase due to the effect of dynamic recrystallization improves the flow stress of NiTi shape memory alloy. The texture intensity increases significantly with increasing strain during isothermal compression of NiTi shape memory alloy, and the occurrence of dynamic recrystallization during deformation promotes the formation of a strong γ-fiber texture {111}//CA. [Display omitted] • The critical strain for DRX is located in the range of 0.5~0.7 at 800 °C and 0.1 s-1. • CDRX mechanism is easily developed under the higher strains at 800 °C and 0.1 s-1. • The texture intensity in ODF maps increases with increasing strain. • A strong γ-fiber recrystallization texture {111} is formed during deformation. [ABSTRACT FROM AUTHOR]

[Display omitted] The alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) play critical roles in alcoholism development and alcohol toxicology; however, few studies have focused on the miRNA-mediated mechanisms underlying the expressions of alcohol-metabolizing enzymes. In the present study, we showed the expression changes of each alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver samples of alcoholic hepatitis (AH) patients, and predicted the miRNAs targeting the dysregulated alcohol-metabolizing genes by a systematic in silico analysis. 13 miRNAs were predicted to regulate the expressions of ADH1A , ADH4 , and ALDH2 , respectively, with hsa-miR-148a-3p (miR-148a) showing the most significant down-regulation in AH patients. Following experimental evidence using HepG2 cells proved that miR-148a promoted ADH4 expression by directly binding to the coding sequence of ADH4 and increasing the mRNA stability via an AGO1-dependent manner. Additional assays showed that secondary structure of ADH4 transcript affected the target accessibility and binding of miR-148a-3p. In sum, our results suggest that the expressions of key alcohol-metabolizing enzymes are repressed in AH patients, and the non-canonical positive regulation of miR-148a on ADH4 reveals a new regulationary mechanism for ADH genes. [ABSTRACT FROM AUTHOR]

[Display omitted] Cytochrome P450 (CYP) enzymes play critical roles in drug transformation, and the total CYPs are markedly decreased in alcoholic hepatitis (AH), a fatal alcoholic liver disease. miRNAs are endogenous small noncoding RNAs that regulate many essential biological processes. Knowledge concerning miRNA regulation of CYPs in AH disease is limited. Here we presented the changes of key CYPs in liver samples of AH patients retrieved from GEO database, performed in silico prediction of miRNAs potentially targeting the dysregulated CYP transcripts, and deciphered a novel mechanism underlying miRNA mediated CYPs expression in liver cells. Nine miRNAs were predicted to regulate CYP1A2 , CYP2A6 , CYP2B6 , CYP2C8 , CYP2C19 , CYP2J2 , and CYP3A4 , among which hsa-miR-148a-3p was selected as a case study. Biochemical and molecular evidences demonstrated that miR-148a promoted CYP2B6 expression by increasing mRNA stability via directly binding to the 3′UTR sequence, and that this positive posttranscriptional regulation was AGO1/2-dependent. Further, luciferase reporter gene assay and RNA secondary structure analysis illustrated that the seedless target site, not the seed target site, controlled miR-148a-mediated CYP2B6 upregulation. Moreover, we identified HNF4A as a liver-specific transcription factor of MIR-148A through EMSA and chromatin immunoprecipitation experiments. In conclusion, ethanol downregulated miR-148a in hepatocytes through HNF4A regulation, which eventually decreased CYP2B6 expression. Our finding will benefit the understanding of dysregulated drug metabolism in AH patients and highlight an unconventional mechanism for epigenetic regulation of CYP gene expression. [ABSTRACT FROM AUTHOR]

Compound 5a was identified as a potent and selective PTP1B inhibitor with promising antidiabetic effects both in vitro and in vivo. • Novel 2,4-thiazolidinediones as uncharged PTP1B inhibitors were synthesized. • Compound 5a displayed selectivity against TC-PTP. • Compound 5a exhibited excellent antidiabetic activities in BKS db mice. Protein tyrosine phosphatase 1B (PTP1B) is a well-validated target in therapeutic interventions for type 2 diabetes mellitus (T2DM), however, PTP1B inhibitors containing negatively charged nonhydrolyzable pTyr mimetics are difficult to convert to the corresponding in vivo efficacy owing to poor cell permeability and oral bioavailability. In this work, molecules bearing less acidic heterocycle 2,4-thiazolidinedione and hydantoin were designed, synthesized and evaluated for PTP1B inhibitory potency, selectivity and in vivo antidiabetic efficacy. Among them, compound 5a was identified as a potent PTP1B inhibitor (IC 50 = 0.86 μM) with 5-fold selectivity over the highly homologous TCPTP. Long-term oral administration of 5a at a dose of 50 mg/kg not only significantly reduced blood glucose levels, triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels but also ameliorated insulin sensitivity in diabetic BKS db mice. Moreover, 5a enhanced the insulin-stimulated phosphorylation of IRβ, IRS-1 and Akt in C2C12 myotubes. A histopathological evaluation of liver and pancreas demonstrated that 5a increased liver glycogen storage and improved islet architecture with more β-cells and fewer α-cells in diabetic mice. Thus, our work demonstrated that compound 5a could serve as a lead compound for the discovery of new antidiabetic drugs. [ABSTRACT FROM AUTHOR]

In present study, isothermal compression, solution treatment, electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) observations were carried out to correlate the microstructure and deformation-solution parameters for GH4586 superalloy. And, the recrystallized mechanisms, twin evolution, γ′ precipitation and their interaction were clearly illustrated based on the analysis of the recrystallized fraction, size of γ grains, grain boundary misorientation and length fraction of twin boundaries. The results show that the process of dynamic recrystallization is controlled by the mechanisms of sub-grain rotation and strain-induced boundary migration while the process of static recrystallization is controlled by the mechanism of subgrain boundary migration. The evolution of twin boundaries during deformation is affected by two aspects: (i) the losing of twin's identity due to higher strain; and (ii) the nucleation and growth of new twins within the DRX grains. During deformation of GH4586 superalloy, fine γ′ precipitates have a hindered effect on the recrystallization nucleated from pre-existing subgrains and twin growth. Moreover, the recrystallization process has a noticeable influence on the formation of new twins. Conversely, the existing of these twins is also beneficial for the recrystallization. Image 1 • DRX is controlled by subgrain rotation and strain-induced boundary migration. • Static recrystallization is controlled by subgrain boundary migration. • New twins nucleate and grow within the DRX grains. • The existing of twins is also beneficial for the recrystallization. • Fine γ′ precipitates have a hindered effect on the recrystallization and twin growth. [ABSTRACT FROM AUTHOR]