Previously we showed that bisphenol A (BPA), an environmental estrogenic endocrine disruptor, rapidly altered Ca(2+) handling and promoted arrhythmias in female rat hearts. The underlying molecular mechanism was not known. Here we examined the cardiac-specific signaling mechanism mediating the rapid impact of low-dose BPA in female rat ventricular myocytes. We showed that protein kinase A (PKA) and Ca(2+)/CaM-dependent protein kinase II (CAMKII) signaling pathways are the two major pathways activated by BPA. Exposure to 1 nM BPA rapidly increased production of cAMP and rapidly but transiently increased the phosphorylation of the ryanodine receptors by PKA but not by CAMKII. BPA also rapidly increased the phosphorylation of phospholamban (PLN), a key regulator protein of sarcoplasmic reticulum Ca(2+) reuptake, by CAMKII but not PKA. The increase in CAMKII phosphorylation of PLN was mediated by phospholipase C and inositol trisphosphate receptor-mediated Ca(2+) release, likely from the endoplasmic reticulum Ca(2+) storage. These two pathways are likely localized, impacting only their respective target proteins. The rapid impacts of BPA on ryanodine receptors and PLN phosphorylation were mediated by estrogen receptor-β but not estrogen receptor-α. BPA's rapid signaling in cardiac myocytes did not involve activation of ERK1/2. Functional analysis showed that PKA but not CAMKII activation contributed to BPA-induced sarcoplasmic reticulum Ca(2+) leak, and both PKA and CAMKII were necessary contributors to the stimulatory effect of BPA on arrhythmogenesis. These results provide mechanistic insight into BPA's rapid proarrhythmic actions in female cardiac myocytes and contribute to the assessment of the consequence and potential cardiac toxicity of BPA exposure.

The gene delivery vector for DNA-based therapy should ensure its transfection efficiency and safety for clinical application. The Micro-Linear vector (MiLV) was developed to improve the limitations of traditional vectors such as viral vectors and plasmids.

The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.

Genome-wide association studies (GWAS) have identified multiple genetic variants associated with leprosy. To investigate the single and combined associations between single-nucleotide polymorphisms (SNPs) and the development of leprosy, we therefore performed generalized multi-analytical (GMDR) analysis in Chinese leprosy household contacts and constructed a risk prediction model.

Nucleotide metabolism is the driving force of cell proliferation, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in the initial synthesis of nucleotides. Previous studies reported that TYMS activity significantly affected the proliferation of tumour cells. However, the diagnostic and prognostic significance of TYMS expression in breast cancer remains unclear. Here, we used the Breast Cancer Integrative Platform (BCIP) to investigate the relationship between progression and prognosis of breast cancer with TYMS expression, and then verified the database analysis using immunohistochemical staining. Our results indicated TYMS expression was greater in breast cancer than adjacent normal tissues and greater in triple-negative breast cancer (TNBC) than non-TNBC tissues. TYMS expression also had significant positive correlations with histological grade, tumour size, and ER negativity, and PR negativity. The increased copy number of the TYMS gene appears to be the reason for its upregulation in breast cancer. Breast cancer patients with higher TYMS expression had poorer prognosis. Our data suggest that TYMS has potential use as a diagnostic and prognostic marker for breast cancer patients.

Invertebrates are recognized as important species in endocrine disrupting chemical (EDC) testing. However, it is poorly understood whether the effects of EDCs in invertebrates are mediated by hormonal mechanisms. Previously, we showed that bisphenol A (BPA) affected the physiology of the freshwater oligochaete Lumbriculus variegatus. In the present study, we examined the mechanism of the impact of BPA on L. variegatus, using pulse rate of the dorsal blood vessel (DBV) as an endpoint. Both long term and acute exposures to BPA increased the pulsing rate of DBV. The former had a distinct inverted-U dose response relationship with a most efficacious dose of 10-9 M, which increased the pulse rate from 8.97 to 10.9 beats/min. The effects of BPA were mimicked by the synthetic estrogen ethinylestradiol with a most efficacious dose of 10-12 M. Interestingly E2 had no effect on pulsing rate, either acute or long term. The sensitivity of L. variegatus to estrogens were exquisite, with detectable effects at 10-14 to 10-10 M range. Both the long term and acute effects of BPA were partially or fully blocked by various vertebrate estrogen receptor (ER) antagonists, including ICI 182,780, MPP and G15. Our results suggest that the impact of BPA on pulsing rate of L. variegatus is likely mediated by an estrogenic mechanism instead of general toxicity. The exceptionally high sensitivity of L. variegatus to some estrogens makes it a possible tool for estrogenic EDC screening.

We investigated a case of cutaneous infection in an immunocompromised patient in China that was caused by a novel species within the Mycobacterium gordonae complex. Results of whole-genome sequencing indicated that some strains considered to be M. gordonae complex are actually polyphyletic and should be designated as closely related species.

The EIF3 gene family is essential in controlling translation initiation during the cell cycle. The significance of the EIF3 subunits as prognostic markers and therapeutic targets in breast cancer is not yet clear. We analyzed the expression of EIF3 subunits in breast cancer on the GEPIA and Oncomine databases and compared their expression in breast cancer and normal tissues using BRCA data downloaded from TCGA. Then we performed clinical survival analysis on the Kaplan-Meier Plotter database and clinicopathologic analysis on the bc-genexMiner v4.1 database. And EIF3B was chosen for mutation analysis via the Cancer SEA online tool. Meanwhile, we performed the immunohistochemical assay, real-time RT-PCR, and Western blotting to analyze EIF3B expression levels in breast cancer. An EIF3B knockdown and a negative control cell line were conducted for MTT assay and cell cycle analysis to assess cell growth. Specifically, the results of TCGA and online databases demonstrated that upregulated EIF3B was associated with poorer overall and advanced tumor progression. We also confirmed that EIF3B was more highly expressed in breast cancer cells and tissues than normal and correlated with a worse outcome. And knockdown of EIF3B expression inhibited the cell cycle and proliferation. Furthermore, EIF3B was highly mutated in breast cancer. Collectively, our results suggested EIF3B as a potential prognostic marker and therapeutic target for breast cancer.

Necroptosis is considered to be a new form of programmed necrotic cell death, which is associated with metastasis, progression and prognosis of various types of tumors. However, the potential role of necroptosis-related genes (NRGs) in the triple negative breast cancer (TNBC) is unclear.

Abnormal lipoprotein metabolism is associated with a variety of diseases, cardiovascular disease in particular. Free fatty acids (FAs) and triglycerides (TGs) are the principal lipid species in adipocytes and are the major components of lipoproteins. However, in routine clinical laboratory testing, only the total plasma concentrations of FAs and TGs are typically measured.

A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. However, the precise mechanisms affecting SR function and leading to arrhythmias remain elusive.

Triple-negative breast cancer (TNBC) patients have poor prognosis due to the aggressive metastatic behaviors. Our study reveals that expression of estrogen related receptor α (ERRα) is significantly (p < 0.01) positively associated with high grade tumors and lymph node metastasis, while negatively correlated with overall survival (OS), in 138 TNBC patients. Targeted inhibition of ERRα by its inverse agonist XCT-790 or si-RNA obviously inhibits in vitro motility of TNBC cells. While over expression of ERRα triggers the invasion and migration of TNBC cells. Further, si-ERRα and XCT-790 inhibit the epithelial mesenchymal transition (EMT) of TNBC cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. While XCT-790 has no effect on the expression of EMT related transcription factors such as Snail or Slug. Further, inhibitors of MAPK, PI3K/Akt, NF-κB signal molecules, which are activated by XCT-790, can not attenuate the suppression effects of XCT-790 on EMT. Alternatively, luciferase reporter gene assays and ChIP analysis indicate that ERRα can directly bind with FN promoter at ERR response element-3 (ERRE-1), ERRE-3, and ERRE-4, while XCT-790 reduces this bond. In vivo data show that ERRα expression is significantly (p < 0.05) correlated with FN in clinical TNBC patients. In MDA-MB-231 tumor xenograft models, XCT-790 decreases the expression of FN, inhibits the growth and lung metastasis, and suppresses the EMT. Our results demonstrate that ERRα functions as a metastasis stimulator and its targeted inhibition may be a new therapeutic strategy for TNBC treatment.

Transmural electrical dispersion determines the repolarization sequence across the ventricular wall, and plays an important role in the development of arrhythmias under pathological conditions. While it is clear that the transmural gradient of the transient outward current (I(to)) underlies the dramatic difference in phase 1 repolarization across the ventricle, its contribution to the transmural action potential duration (APD) dispersion is not clear. We investigated this problem using the dynamic clamp technique in canine ventricular myocytes. The dynamic clamp allows quantitative 'insertion' of simulated conductances in real, biological cells, bridging pure computer modelling and experimental electrophysiology. 'Insertion' of an epicardial level of I(to) in endocardial cells produced a prominent phase 1 repolarization and a 'spike-and-dome' action potential morphology, but did not significantly affect the APD. Increasingly larger I(to) densities prolonged, and then dramatically shortened the endocardial APD. We also used the dynamic clamp to subtract, or 'block' the native I(to) in epicardial cells. Such 'blockade' eliminated the epicardial action potential notch, but had no significant effect on the APD. We conclude that I(to), while being a key regulator of phase 1 repolarization, does not significantly affect the APD of canine ventricular myocytes, and that the I(to) gradient is not a significant contributor to the transmural APD dispersion in the canine ventricle. By allowing computer simulation on a biological background, the dynamic clamp is a new and effective tool to study the ionic basis of the electrical properties of cardiac cells.

Fibroblast activation protein α (FAPα) is a potential target for cancer therapy. However, elimination of FAPα+ fibroblasts activates secretion of IFN-γ and TNF-α. IFN-γ can in turn induce expression indolamine-2,3-dioxygenase (IDO), thereby contributing to immunosuppression, while TNF-α can induce EMT. These two reactive effects would limit the efficacy of a tumor vaccine. We found that curcumin can inhibit IDO expression and TNF-α-induced EMT. Moreover, FAPαc vaccine and CpG combined with curcumin lavage inhibited tumor growth and prolonged the survival of mice implanted with melanoma cells. The combination of FAPαc vaccine, CpG and curcumin stimulated FAPα antibody production and CD8+ T cell-mediated killing of FAPα-expressing stromal cells without adverse reactive effects. We suggest a combination of curcumin and FAPαc vaccine for melanoma therapy.

Natural killer (NK) cells play an important role in preventing cancer development. NK group 2 member D (NKG2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG2DL become susceptible to an immune-dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta (TGF-β) in regulation of NKG2DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF-β up-regulated the expression of NKG2DLs in both PC3 and HepG2 cells. The up-regulation of NKG2DLs was characterized by increasing the expression of UL16-binding proteins (ULBPs) 1 and 2. TGF-β treatment also increased the expression of transcription factor SP1. Knockdown of SP1 significantly attenuated TGF-β-induced up-regulation of NKG2DLs in PC3 and HepG2 cells, suggesting that SP1 plays a key role in TGF-β-induced up-regulation of NKG2DLs. TGF-β treatment rapidly increased SP1 protein expression while not mRNA level. It might be due to that TGF-β can elevate SP1 stability by activating PI3K/AKT signalling pathway, subsequently inhibiting GSK-3β activity and decreasing the association between SP1 and GSK-3β. Knockdown of GSK-3β further verified our findings. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of SP1 is required for TGF-β induced up-regulation of NKG2DLs. Our study provided valuable evidence for exploring the tumour immune modulation function of TGF-β.

Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells.

To investigate the effects of dietary starch structure (amylose/amylopectin ratio, AR) on serum glucose absorption metabolism and intestinal health, a total of ninety weaned piglets (Duroc × (Yorkshire × Landrace)) were randomly assigned to 5 dietary treatments and fed with a diet containing different AR (2.90, 1.46, 0.68, 0.31, and 0.14). The trial lasted for 21 d. In this study, the growth performance was not affected by the dietary starch structure (p > 0.05). Diets with higher amylose ratios (i.e., AR 2.90 and 1.46) led to a significant reduction of the serum glucose concentration at 3 h post-prandium (p < 0.01), while high amylopectin diets (AR 0.31 and 0.14) significantly elevated The expression of gene s at this time point (p < 0.01). High amylopectin diets also increased the apparent digestibility of crude protein (CP), ether extract (EE), dry matter (DM), gross energy (GE), and crude ash (p < 0.001). Interestingly, diet rich in amylose (AR 2.90) significantly elevated the butyric acid content (p < 0.05) and decreased the pH value (p < 0.05) in the cecal digesta. In contrast, diet rich in amylopectin (i.e., AR 0.14) significantly elevated the total bacteria populations in the cecal digesta (p < 0.001). Moreover, a high amylopectin diet (AR 0.14) tended to elevate the mRNA level of fatty acid synthase (FAS, p = 0.083), but significantly decreased the mRNA level of sodium-dependent glucose transporter 1 (SGLT1, p < 0.05) in the duodenal and jejunal mucosa, respectively. These results suggested that blood glucose and insulin concentrations were improved in high AR diets, and the diet also helped to maintain the intestinal health.

Breast cancer is the leading cause of cancer-related deaths in females worldwide. Formin-like protein 2 (FMNL2) is a member of formin family that governs cytokinesis, cell polarity, morphogenesis and cell division. To our knowledge, the function of FMNL2 in breast cancer proliferation still remains uncovered.

Bisphenol A (BPA)-free plastic products are widely available. Transient BPA release has been reported in Tritan drinking bottles. This study assessed the effectiveness of common consumer washing methods in removing BPA contamination in Tritan bottles using both ELISA and HPLC-MS/MS assays. BPA release was detected in 2 out of 10 kinds of Tritan drinking bottles tested. Average BPA level was 0.493 μg/L in water samples from a type of Tritan kid drinking bottle following 24-hour incubation at room temperature, corresponding to a release rate of 0.015 ng/cm2/h. Of the common consumer cleaning methods identified in an informal survey, dishwashing was the most effective method that significantly reduced, even eliminated BPA release from the tested BPA-positive Tritan bottles, while rinsing with water and handwashing with soap and water were ineffective. The bioactivity of the leached BPA was confirmed using a rodent cardiac myocyte acute exposure model and an invertebrate 7-day exposure model. The BPA release is possibly the result of surface contamination in the manufacturing process. As a case study, our result may be informative for general consumer practice and for better quality control by the manufactures.

Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.