The high frequency oscillations in the amygdala, hippocampus, and temporal cortex during mesial temporal lobe epilepsy.

The mesial temporal lobe epilepsy (MTLE) seizures are believed to originate from medial temporal structures, including the amygdala, hippocampus, and temporal cortex. Thus, the seizures onset zones (SOZs) of MTLE locate in these regions. However, whether the neural features of SOZs are specific to different medial temporal structures are still unclear and need more investigation. To address this question, the present study tracked the features of two different high frequency oscillations (HFOs) in the SOZs of these regions during MTLE seizures from 10 drug-resistant MTLE patients, who received the stereo electroencephalography (SEEG) electrodes implantation surgery in the medial temporal structures. Remarkable difference of HFOs features, including the proportions of HFOs contacts, percentages of HFOs contacts with significant coupling and firing rates of HFOs, could be observed in the SOZs among three medial temporal structures during seizures. Specifically, we found that the amygdala might contribute to the generation of MTLE seizures, while the hippocampus plays a critical role for the propagation of MTLE seizures. In addition, the HFOs firing rates in SOZ regions were significantly larger than those in NonSOZ regions, suggesting the potential biomarkers of HFOs for MTLE seizure. Moreover, there existed higher percentages of SOZs contacts in the HFOs contacts than in all SEEG contacts, especially those with significant coupling to slow oscillations, implying that specific HFOs features would help identify the SOZ regions. Taken together, our results displayed the features of HFOs in different medial temporal structures during MTLE seizures, and could deepen our understanding concerning the neural mechanism of MTLE.

Biomimetic Cancer-Targeting Nanoplatform Boosting AIEgens-Based Photodynamic Therapy and Ferroptosis by Disrupting Redox-Homeostasis.

Photodynamic therapy (PDT) using aggregation-induced emission photosensitizer (AIE-PS) holds tremendous potential but is limited by its inherent disadvantages and the high concentrations of reduced glutathione (GSH) in tumor cells that can neutralize ROS to weaken PDT. Herein, we designed a nanodelivery system (CM-HSADSP@[PS-Sor]) in which albumin was utilized as a carrier for hydrophobic drug AIE-PS and Sorafenib, cross-linkers with disulfide bonds were introduced to form a nanogel core, and then cancer cell membranes were wrapped on its surface to confer homologous tumor targeting ability. A two-way strategy was employed to disturb redox-homeostasis through blocking GSH synthesis by Sorafenib and consuming excess GSH via abundant disulfide bonds, thereby promoting the depletion of GSH, which in turn increased the ROS levels in cancer cells to amplify the efficacy of ferroptosis and PDT, achieving an efficient in vivo antibreast cancer effect. This study brings a new strategy for ROS-based cancer therapy and expands the application of an albumin-based drug delivery system.

[Research Progress on the Role of Laminin Subunit Alpha 4 in Diseases].

Laminin subunit alpha 4 (LAMA4),a member of the laminin family,is present in the intercellular matrix of adult tissues as a major component of basement membrane.LAMA4 is involved in the adhesion of cells and can bind to corresponding integrins to activate relevant signaling pathways,playing an essential role in the growth,proliferation,and migration of cells.It has been demonstrated that LAMA4 is associated with the occurrence and development of a variety of diseases including tumors,and the expression of LAMA4 can be used as a biomarker of tumor diagnosis and prognosis.This paper summarizes the current research progress in LAMA4 with the focus on the relationship between LAMA4 and diseases,especially tumor,with a view to provide new directions for the future research.

AQP9 (Aquaporin 9) Determines Arsenic Uptake and Tolerance in Human Hepatocellular Carcinoma Cells In Vitro.

Arsenic-based therapeutic strategies, even though promising for acute promyelocytic leukemia (APL), are limited by arsenic-related toxic effect and resistance with unknown mechanisms. The purpose of this study is to better understand the different sensitivities of hepatocellular carcinoma cells to arsenic and its mechanism. Arsenic-sensitive liver cancer cell line (HepG2) and arsenic-resistant HepG2 (AsHepG2) cells are employed to study the role of aquaporin 9 (AQP9) in arsenic uptake and tolerance. The half-maximal inhibitory concentration (IC50) value of arsenic in AsHepG2 cells (15.59 ± 1.36 µM) is significantly higher than that in HepG2 cells (7.33 ± 0.93 µM; p= 0.0288). We demonstrated that, with the treatment of sodium arsenite (NaAsO2), arsenic was accumulated at a significantly lower level in AsHepG2 cells in comparison with HepG2 cells (p= 0.00549). Further, arsenic level in AsHepG2 cells reaches a plateau after six hours of treatment, whereas arsenic continues to increase in HepG2 cells during the entire experimental period. Mechanistic study showed that the expression of AQP9 is decreased in a dose-dependent manner in AsHepG2 cells, but no significant difference in HepG2 cells. Furthermore, NaAsO2 dramatically increases AQP9 and p38 phosphorylation, which may partially regulate arsenic sensitivity in both cell lines. In conclusion, the expression and phosphorylation of AQP9 regulated by p38 kinase are involved in the arsenic uptake, thus regulating cellular arsenic sensitivity.

MicroRNA-191 modulates cisplatin-induced DNA damage response by targeting RCC2.

Cisplatin is a first-line chemotherapeutic agent for the treatment of many types of cancer, but the emergence of chemoresistance hinders its application. Thus, a better understanding of cisplatin-induced DNA damage response (DDR) would help to overcome this problem. Previously, we have identified a panel of microRNAs with altered expression after cisplatin treatment in HeLa cells. In the current study, we focused on one of them, miR-191, and investigated its function in cisplatin-induced DDR. We found that overexpression of miR-191 sensitized HeLa cells to the cytotoxic effects of cisplatin, resulted in decreased viable cells. However, overexpression of miR-191 did not cause changes in apoptotic cell ratio but rather induced significant G2/M arrest in HeLa cell treated with cisplatin. Additionally, enhanced cisplatin-induced DNA damage was observed. Through bioinformatic analysis and verified by dual-luciferase assay, it was demonstrated that the chromosome condensation 2 regulator (RCC2) gene is a target for miR-191 regulation. Furthermore, the downregulation of RCC2 by siRNA mimics the effects of miR-191, in which greater DNA damage was observed upon cisplatin treatment. Taken together, our study indicates that miR-191 may be an important player in cisplatin-induced DDR, and it elicits its function, at least partially, through the regulation of RCC2.

Effects of ingested polystyrene microplastics on brine shrimp, Artemia parthenogenetica.

Microplastics are a contaminant of emerging concern which enter the marine environment from a variety of sources. The ingestion and toxic effects of microplastics on marine life, especially for filter feeders, are a cause of concern in view of their ubiquitous nature and their similar size as food sources. To assess the toxic effects of microspheres ingested by brine shrimp larvae, we exposed Artemia parthenogenetica to 10 µm polystyrene microspheres at different concentrations. These concentrations were approximate to the extrapolated marine aquatic environmentally relevant concentrations. The lowest polystyrene concentrations at which ingestion was visualized in A. parthenogenetica were 12 ±â€¯0.57 particles/mL (6.7 ±â€¯0.32 µg/L) and 1.1 ±â€¯0.16 particles/mL (0.61 ±â€¯0.088 µg/L), respectively. There were no significant impacts on the survival, growth or development in A. parthenogenetica occurring over the 14-d exposure across a range of polystyrene nominal concentrations (1-1000 particles/mL or 0.55-550 µg/L). However, abnormal ultrastructures of intestinal epithelial cells were observed upon exposure to polystyrene microspheres, including fewer and disordered microvilli, an increased number of mitochondrion and the appearance of autophagosome. These phenomena could affect nutrition absorption and energy metabolism. Although no major acute or chronic toxicity effects on A. parthenogenetica were observed over 24-h or 14-d exposures, this study provides evidence that the ingestion of polystyrene microplastics at extrapolated environmentally relevant concentrations can be visualized through a microscope to be causing a series of responses in intestinal epithelial cells.

Depletion of Paraspeckle Protein 1 Enhances Methyl Methanesulfonate-Induced Apoptosis through Mitotic Catastrophe.

Previously, we have shown that paraspeckle protein 1 (PSPC1), a protein component of paraspeckles that was involved in cisplatin-induced DNA damage response (DDR), probably functions at the G1/S checkpoint. In the current study, we further examined the role of PSPC1 in another DNA-damaging agent, methyl methanesulfonate (MMS)-induced DDR, in particular, focusing on MMS-induced apoptosis in HeLa cells. First, it was found that MMS treatment induced the expression of PSPC1. While MMS treatment alone can induce apoptosis, depletion of PSPC1 expression using siRNA significantly increased the level of apoptosis following MMS exposure. In contrast, overexpressing PSPC1 decreased the number of apoptotic cells. Interestingly, morphological observation revealed that many of the MMS-treated PSPC1-knockdown cells contained two or more nuclei, indicating the occurrence of mitotic catastrophe. Cell cycle analysis further showed that depletion of PSPC1 caused more cells entering the G2/M phase, a prerequisite of mitosis catastrophe. On the other hand, over-expressing PSPC1 led to more cells accumulating in the G1/S phase. Taken together, these observations suggest an important role for PSPC1 in MMS-induced DDR, and in particular, depletion of PSPC1 can enhance MMS-induced apoptosis through mitotic catastrophe.

Prevalence of Kaposi's sarcoma associated herpesvirus among men attending sexually transmitted infections clinics in Anhui, China.

Kaposi's sarcoma-associated herpesvirus (KSHV) may be transmitted via sexual contacts, but limited information is available on KSHV infection status among sexually transmitted infection (STI) patients in China. The main objective of the present study was to determine the KSHV seroprevalence and its risk factors among male STI patients. A cross-sectional survey was conducted in three prefectures of Anhui province, China, between June and September 2013. A total of 1,600 male patients who visited an STI clinic were invited, and 1,372 participated in the study. Data were abstracted from the medical records for all the patients. Blood samples were collected and tested for antibodies to KSHV, HIV, HCV, and syphilis. Factors associated with KSHV seropositivity were examined using multivariable logistic regression analysis. The overall prevalence of KSHV, HIV, HCV, and syphilis was 13.3%, 0.7%, 0.6%, and 12.5%, respectively. After adjusting for potential confounders, KSHV infection was significantly associated with ever having anal sex with men (19 out of 30 males, OR: 8.64, 95%CI: 1.92-38.79) and HIV infection (six out of nine HIV-positive individuals, OR: 8.39, 95%CI: 1.80-39.04). There were no significant associations of KSHV infection with drug use, heterosexual sex behaviors, syphilis, and HCV. Our finding has shown that a relatively moderate prevalence of KSHV was found among male STI patients. While an increased risk for KSHV infection was observed among participants with homosexual contacts. Routine KSHV testing is recommended for male individuals attending STI clinics.

Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways.

BACKGROUND: Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the etiologic agent of KS, the most common AIDS-related malignancy. The majority of KS tumor cells harbor latent KSHV virus but only a small percentage undergoes spontaneous lytic replication. Viral reactivation from latency is crucial for the pathogenesis and development of KS, but the cellular mechanisms underlying the switch between viral latency and replication are not well understood. METHODS: The level of let-7 miRNAs and MAP4K4 in KSHV infected 293T cells were quantified by real-time PCRs. Let-7 expression was silenced by the miRNA sponge technique. In let-7a transfected 293T cells, the expression of MAP4K4 was measured by real-time PCR and western blot. Luciferease expression was employed to examine the effect of let-7a on the 3'-untranslated region (UTR) of the MAP4K4 gene in 293T cells. Real-time PCR was used to quantify the KSHV copy numbers in BC-3 cells in which the expression of let-7a and/or MAP4K4 were altered. Finally, ERK, JNK and p38 protein production and their phosphorylation status were detected by western blots in let-7a or MAP4K4 transfected BCBL-1 cells. RESULTS: The expression of microRNA let-7 was dramatically decreased in KSHV infected 293T cells, but that of MAP4K4 was increased significantly. Let-7a is physically associated with and targets the MAP4K4 3'UTR, and inhibits MAP4K4 expression at both mRNA and protein levels. MAP4K4 stimulates KSHV reactivation from latency, whereas let-7a inhibits the function of MAP4K4 by reversing the function of MAP4K4 on JNK, phospho-JNK and phospho-ERK1/2 levels. CONCLUSION: Our results establish that let-7a specifically suppresses MAP4K4 expression, and further inhibits KSHV reactivation by interfering with the function of MAP4K4 on the MAPK pathway, highlighting let-7a as a potential treatment for KS.

Increased Neutrophil Gelatinase-Associated Lipocalin is Associated with Mortality and Multiple Organ Dysfunction Syndrome in Severe Sepsis and Septic Shock.

BACKGROUND: This study examines the clinical utility of increased neutrophil gelatinase-associated lipocalin (NGAL) as an indicator of mortality and multiple organ dysfunction syndrome (MODS) in severe sepsis and septic shock. METHODS: We designed a prospective cohort study in an intensive care unit, and 123 patients with severe sepsis or septic shock were included. Data were used to determine a relationship between NGAL and the development of MODS and mortality. These associations were determined by the Mann-Whitney U test, log-rank test, Cox proportional hazards regression analyses, and plotting the receiver operating characteristic curve. RESULTS: Patients with high NGAL (75th percentile) had increased risk of mortality and MODS compared with patients with low NGAL (log-rank test, P < 0.05). There were 39 patients (32%) with mortality during follow-up at 12 months, 10 patients (8%) with MODS on day 1, and 37 patients (30%) on day 7. The area under the receiver operating characteristic curve showed that high NGAL could predict mortality (0.6385) during intensive care unit stay. After adjustment for confounding risk factors chosen by backward elimination by Cox regression analysis, high NGAL remained an independent predictor of mortality and MODS (hazard ratios, 2.128 [95% confidence interval, 1.078-4.203; P = 0.030] and 1.896 [95% confidence interval, 1.012-3.552; P = 0.046], respectively). CONCLUSIONS: High plasma NGAL independently predicts mortality and MODS in severe sepsis and septic shock.

Overexpression of a rice defense-related F-box protein gene OsDRF1 in tobacco improves disease resistance through potentiation of defense gene expression.

F-box proteins play important roles in plant growth/development and responses to environmental stimuli through targeting substrates into degradation machinery. A rice defense-related F-box protein gene, OsDRF1, was cloned and identified during a course of study aimed at elucidating the molecular basis of induced immunity in rice. OsDRF1 encodes a protein of 328 amino acids, containing a highly conserved F-box domain. Expression of OsDRF1 was induced upon treatment with benzothiadiazole (BTH), a chemical inducer of defense responses in rice. Moreover, in BTH-treated rice seedlings, expression of OsDRF1 was further induced by infection with Magnaporthe grisea, the rice blast fungus, compared with those in water-treated seedlings. OsDRF1 was also upregulated in rice seedlings after treatment with ABA. Overexpression of OsDRF1 in transgenic tobacco resulted in enhanced disease resistance against tomato mosaic virus (ToMV) and Pseudomonas syringae pv. tabaci and strengthened expression of defense-related genes after salicylic acid treatment or ToMV infection. Root elongation of the OsDRF1-overexpressing transgenic seedlings was significantly inhibited by ABA, indicating that overexpression of OsDRF1 resulted in increased ABA sensitivity. The results suggest that OsDRF1 plays a role in disease resistance via upregulating defense-related gene expression and that OsDRF1 may also be involved in the response to ABA.

Molecular characterization of four rice genes encoding ethylene-responsive transcriptional factors and their expressions in response to biotic and abiotic stress.

We isolated and identified four rice genes, OsBIERF1 to OsBIERF4 (Oryza sativa benzothiadiazole (BTH)-induced ethylene responsive transcriptional factors (ERF)) and analyzed their expressions in rice disease resistance response and under various abiotic stress conditions. The OsBIERF1-4 proteins contain conserved ERF domains, but are categorized into different classes of the previously characterized ERF proteins based on their structural organizations. OsBIERF3 and OsBIERF2 belong to Classes I and II, respectively; while OsBIRERF1 and OsBIERF4 are members of Class IV. OsBIERF3 could bind specifically to the GCC box sequence and was targeted to nucleus when transiently expressed in onion epidermis cells. Expression of OsBIERF1, OsBIERF3 and OsBIERF4 was induced by treatments with BTH and salicylic acid, chemical inducers capable of inducing disease resistance response in rice. In the BTH-treated rice seedlings, expression of OsBIERF1, OsBIERF3 and OsBIERF4 was further induced by infection with Magnaporthe grisea, the rice blast fungus, as compared with those in water-treated seedlings. OsBIERF1 and OsBIERF3 were activated in an incompatible interaction but not in compatible interaction between rice and M. grisea. Moreover, OsBIERF1, OsBIERF3 and OsBIERF4 were also up-regulated by salt, cold, drought and wounding. These results suggest that OsBIERF proteins may participate in different signaling pathways that mediate disease resistance response and stress responses to abiotic factors.