SRSF1-dependent alternative splicing attenuates BIN1 expression in non–small cell lung cancer

Decreased bridging integrator 1 (BIN1) expression has great significance in promoting the progression of malignant tumors. Reduced messenger RNA expression is partly due to aberrant alternative splicing (AS). However, the AS status of BIN1 and its correlation with BIN1 inactivation in non–small cell lung cancer (NSCLC) remains poorly defined. Here we reported that BIN1 inactivation was not related to DNA methylation in NSCLC. Importantly, BIN1 with exon 12A inclusion (BIN1+12A isoform), the most frequent aberrant splicing variant in tumors was also observed in NSCLC, and might be accounted for BIN1 inactivation. Furthermore, we showed that the aberrant splicing of BIN1 was under the control of serine and arginine-rich factor 1 (SRSF1) in NSCLC. In addition, colony formation assay showed that BIN1+12A isoform could abolish the tumor-inhibiting ability of BIN1 in NSCLC cells. Meanwhile, transwell, wound healing and apoptosis experiments demonstrated that the occurrence of BIN1+12A could abrogate the invasion suppressing activity and proapoptotic property of BIN1 in NSCLC. Significantly, we also found that BIN1+12A isoform neutralized the tumor-suppressing functions of BIN1 via affecting its subcellular localization. Altogether, these data revealed an aberrant splicing phenomenon which abated the expression and tumor-inhibiting activity of BIN1 in NSCLC, and the related mechanisms were associated with SRSF1.     

Modeling the role of macrophages in HIV persistence during antiretroviral therapy

HIV preferentially infects activated CD4+ T cells. Current antiretroviral therapy cannot eradicate the virus. Viral infection of other cells such as macrophages may contribute to viral persistence during antiretroviral therapy. In addition to cell-free virus infection, macrophages can also get infected when engulfing infected CD4+ T cells as innate immune sentinels. How macrophages affect the dynamics of HIV infection remains unclear. In this paper, we develop an HIV model that includes the infection of CD4+ T cells and macrophages via cell-free virus infection and cell-to-cell viral transmission. We derive the basic reproduction number and obtain the local and global stability of the steady states. Sensitivity and viral dynamics simulations show that even when the infection of CD4+ T cells is completely blocked by therapy, virus can still persist and the steady-state viral load is not sensitive to the change of treatment efficacy. Analysis of the relative contributions to viral replication shows that cell-free virus infection leads to the majority of macrophage infection. Viral transmission from infected CD4+ T cells to macrophages during engulfment accounts for a small fraction of the macrophage infection and has a negligible effect on the total viral production. These results suggest that macrophage infection can be a source contributing to HIV persistence during suppressive therapy. Improving drug efficacies in heterogeneous target cells is crucial for achieving HIV eradication in infected individuals.

     

HAP1 Modulates Epileptic Seizures by Regulating GABAAR Function in Patients with Temporal Lobe Epilepsy and in the PTZ-Induced Epileptic Model

Neurochemical Research - The number of γ-aminobutyric acid type A receptors (GABAARs) expressed on the surface membrane and at synaptic sites is implicated in the enhanced excitation of...     

Toll-like receptor 4 contributes to uterine activation by upregulating pro-inflammatory cytokine and CAP expression via the NF-κB/P38MAPK signaling pathway during pregnancy

Evidence indicates that inflammatory response is significant during the physiological process of human parturition; however, the specific signaling pathway that triggers inflammation is undefined. Toll-like receptors (TLRs) are key upstream gatekeepers that control inflammatory activation before preterm delivery. Our previous study showed that TLR4 expression was significantly increased in human pregnancy tissue during preterm and term labor. Therefore, we explore whether TLR4 plays a role in term labor by initiating inflammatory responses, therefore promoting uterine activation. The results showed that expression of TLR4, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), CC chemokine ligand 2 (CCL-2), and uterine contraction-associated proteins (CAPs) was upregulated in the human and mice term labor (TL) group compared with the not-in-labor (TNL) group, and the TLR4 level positively correlated with CAP expression. In pregnant TLR4-knockout (TLR4^−/−) mice, gestation length was extended by 8 hr compared with the wild-type group, and the expression of IL-1β, IL-6, TNF-α, CCL-2, and CAPs was decreased in TLR4^−/− mice. Furthermore, nuclear factor-κB (NF-κB) and P38MAPK activation is involved in the initiation of labor but was inhibited in TLR4^−/− mice. In uterine smooth muscle cells, the expression of inflammatory cytokines and CAPs decreased when the NF-κB and P38MAPK pathway was inhibited. Our data suggest that TLR4 is a key factor in regulating the inflammatory response that drives uterine activation and delivery initiation via activating the NF-κB/P38MAPK pathway.     

Cutaneous and Mucosal Phaeohyphomycosis Caused by Exophiala spinifera in a Pregnant Patient: Case Report and Literature Review

We report a case of mucocutaneous phaeohyphomycosis caused by Exophiala spinifera. Crusty plaques and nodules were major clinical features. Histological examination revealed brown yeast-like cells and hyphae. Mycological and molecular data identified E. spinifera as etiologic agent. Oral itraconazole was effective, which was in accordance with the results of in vitro susceptibility testing. We speculated that her pregnancy may play a role of risk factor in the infection by E. spinifera.     

In vitro antifungal activity and mode of action of selected polyphenolic antioxidants on Botrytis cinerea

Six selected antioxidants (catechin, quercetin-3-galactoside, cyanidin-3-glucoside, pelargonidin-3-glucoside, ellagic and gallic acids) were evaluated in vitro for their antifungal activities and mode of action on Botrytis cinerea Pers., one of the most important pathogens of strawberries. Inhibitory effects were found for all the tested antioxidants, but varied at different fungal developmental stages. Catechin and quercetin-3-galactoside showed linear inhibitory effects on germ tube elongation, with the highest suppression ratios of 54.8% and 58.8% respectively. No significant effect was found on spore germination between treatments and control. Gallic acid showed very strong and linear inhibition on spore germination (r = ?0.95), but the effect diminished after spore germination. Cyanidin-3-glucoside and pelargonidin-3-glucoside provided effective control on the fungi as concentrations increased. The arresting effect of ellagic acid on development of B. cinerea was quadratic. Ellagic acid inhibited germ tube elongation and mycelial growth at its highest and lowest concentrations, while no effects were observed at its medium concentration used in this study.     

The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis

Monocyte differentiation antigen CD14 is considered an important cell-activating mediator of inflammatory responses that may result in atherosclerosis, coronary heart disease (CHD), thrombus formation, and myocardial infarction (MI). A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with CHD. To investigate this inconsistency, we performed a meta-analysis of 28 studies involving a total of 13,335 CHD cases and 7,979 controls for C-260T of the CD14 gene to evaluate the effect of CD14 on genetic susceptibility for CHD. An overall random effects odds ratio of 1.24 (95 % CI: 1.12–1.36, P < 10^?5) was found for T allele. Significant results were also observed using dominant (OR = 1.34, 95 % CI: 1.17–1.54, P < 10^?4) or recessive genetic model (OR = 1.25, 95 % CI: 1.10–1.41, P = 0.0004). There was strong evidence of heterogeneity (P < 10^?5), which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant results were found in East Asians; whereas no significant associations were found among Caucasians and other ethnic populations in all genetic models. In the stratified analysis according to sample size, CHD endpoints, and HWE status, significantly increased risks for the polymorphism were found in all genetic models. In conclusion, our results indicate that the CD14 C-260T polymorphism is a risk factor of CHD, especially in East Asians. However, additional very large-scale studies are warranted to confirm our results.     

Concepts and analysis of mass extinction with the late Ordovician event as an example

Twelve groups of fossils, including graptolites, brachiopods, nautiloids, trilobites, corals, crinoids, bryozoans, conodonts, ostracods, gastropods, chitinozoans, and acritarchs expired in different but substantial magnitude and global extent during the late Caradoc to latest Ashgill. It indicates a multiple‐episodic mass extinction containing the possible Prologue (late Caradoc), Climax episode (Rawtheyan) and Epilogue (late Hirnantian). The main causes of this mass extinction are recognized as a global sea‐level lowering in the climax and remarkable rapid rise at the final, and global cooling. The Chinese data, especially from the South China Paleoplate, are evaluated first. They are significant for explaining this global bioevent.