Hematophagous Culicoides spp. biting midges are of great agricultural importance as livestock, equine, and wildlife pests and as vectors of the orbiviruses bluetongue, epizootic hemorrhagic disease and African horse sickness. To obtain a blood meal, midges deposit saliva containing allergens, proteases, and anti-hemostatic factors, into the dermis to facilitate feeding. Infected midges deposit virus along with the myriad of salivary proteins during feeding. The extreme efficiency with which midges are able to transmit orbiviruses is not clearly understood, as much is still unknown about the physiological trauma of the bite and immune responses to saliva deposited during feeding. Of particular interest are the first few hours and days after the bite; a critical time period for any midge-transmitted virus to quickly establish a localized infection and disseminate, while avoiding the hosts' immune responses.

Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined.

To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.

Herpes simplex virus 1 (HSV-1) latency establishment is tightly controlled by promyelocytic leukemia (PML) nuclear bodies (NBs) (or ND10), although their exact contribution is still elusive. A hallmark of HSV-1 latency is the interaction between latent viral genomes and PML NBs, leading to the formation of viral DNA-containing PML NBs (vDCP NBs), and the complete silencing of HSV-1. Using a replication-defective HSV-1-infected human primary fibroblast model reproducing the formation of vDCP NBs, combined with an immuno-FISH approach developed to detect latent/quiescent HSV-1, we show that vDCP NBs contain both histone H3.3 and its chaperone complexes, i.e., DAXX/ATRX and HIRA complex (HIRA, UBN1, CABIN1, and ASF1a). HIRA also co-localizes with vDCP NBs present in trigeminal ganglia (TG) neurons from HSV-1-infected wild type mice. ChIP and Re-ChIP show that vDCP NBs-associated latent/quiescent viral genomes are chromatinized almost exclusively with H3.3 modified on its lysine (K) 9 by trimethylation, consistent with an interaction of the H3.3 chaperones with multiple viral loci and with the transcriptional silencing of HSV-1. Only simultaneous inactivation of both H3.3 chaperone complexes has a significant impact on the deposition of H3.3 on viral genomes, suggesting a compensation mechanism. In contrast, the sole depletion of PML significantly impacts the chromatinization of the latent/quiescent viral genomes with H3.3 without any overall replacement with H3.1. vDCP NBs-associated HSV-1 genomes are not definitively silenced since the destabilization of vDCP NBs by ICP0, which is essential for HSV-1 reactivation in vivo, allows the recovery of a transcriptional lytic program and the replication of viral genomes. Consequently, the present study demonstrates a specific chromatin regulation of vDCP NBs-associated latent/quiescent HSV-1 through an H3.3-dependent HSV-1 chromatinization involving the two H3.3 chaperones DAXX/ATRX and HIRA complexes. Additionally, the study reveals that PML NBs are major actors in latent/quiescent HSV-1 H3.3 chromatinization through a PML NB/histone H3.3/H3.3 chaperone axis.

Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer's Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases.

The purpose of this meta-analysis from randomized controlled trials (RCTs) was to determine the efficacy and safety of the preoperative use of gabapentin for the treatment of acute and chronic postoperative pain following breast cancer surgery.

To investigate the transmission routes of hepatitis B virus (HBV) in families with clusters of infection and unfavorable prognoses and to analyze the prevalence of liver cirrhosis (LC) or hepatocellular carcinoma (HCC) in the offspring of these families.Families with clusters of HBV infection and unfavorable prognoses were enrolled in the study, and general information and serum samples were collected. The prevalence of LC or HCC was compared in offspring of different genders whose parents were diagnosed with LC or HCC.This analysis comprised 102 probands with 51 siblings, 15 parents, 284 children, and 74 spouses. Interestingly, 88.2% of the siblings and 76.8% of the children of these probands were positive for hepatitis B surface antigen (HBsAg), compared with only 9.5% of the spouses (P < .001). There were 266 nuclear families from 102 clustering families. The prevalence of LC or HCC in sons (44.8%) was higher than that in daughters (8.2%; P < .05) in families with mothers with LC or HCC, but there was no difference in families with fathers with LC or HCC. Moreover, the prevalence of LC or HCC in sons from families with mothers with LC or HCC (44.8%) was higher than in the families with fathers with LC or HCC (21.0%, P = .016).The development of LC or HCC in offspring showed a greater relationship with the adverse outcomes induced by HBV infection in the mother compared with the father, and the prevalence of LC or HCC was much higher in male offspring.

Due to the rapidly increasing life-expectancy, the prevalence of glaucoma has increased steadily in recent years. We aimed to evaluate the patterns of care and primary treatment strategy patterns in Korea according to glaucoma subtypes to assess the quality of care for glaucoma patients.In this serial cross-sectional survey, the claims data from the Korean National Health Insurance Service was used to identify and group glaucoma patients into primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), other types of glaucoma, and ocular hypertension from 2002 to 2013. Records for outpatient visits, hospitalizations, drug prescriptions, admissions, and surgical interventions were used to determine the patterns of care and identify primary treatment strategies.Both the prevalence (0.11% in 2002 to 0.43% in 2013) and incidence rates (0.06% in 2003 to 0.11% in 2013) for glaucoma increased over time. The mean number of outpatient visits increased (4.9-6.0 visits per year), while the proportion of hospitalized patients (2.3-1.0% of patients) and duration of hospital stay (4.5-3.4 days among hospitalized patients) decreased between 2002 and 2013 for patients with POAG. The proportion of patients not being managed by medication or surgery decreased, with POAG and PACG patients receiving medications increasing from 70.9% and 59.2% in 2002 to 88.4% and 63.3% in 2013, respectively. Finally, while the proportion of trabeculectomy decreased (22.2% to 10.0% of surgical procedures in 2002 and 2013, respectively), more patients with PACG have received iridectomy (59.3% to 86.0% of surgical procedures in 2002 and 2013, respectively).Between 2002 and 2013, the pattern of care for both patients with POAG and PACG has shifted toward management by outpatient visits and intervention with anti-glaucoma medications in Korea.

We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings.

This study aims to compare the effect of repaglinide and metformin among Chinese patients with newly diagnosed diabetes, and explore the possible mechanisms by which repaglinide alters insulin secretion.Sixty subjects with glycated hemoglobin (HbA1c) < 10.0% were randomly selected to receive repaglinide or metformin monotherapy for 15 weeks. Blood glucose levels, glycemic variability, β-cell function, and first-phase insulin secretion were compared between these 2 groups at baseline and at 15 weeks. Mouse insulinoma (MIN-6) cells were divided into 3 groups: low glucose, high glucose, and repaglinide 50 nm groups. Cells and cell culture mediums were collected at different timepoints. The expression of pericentrin (PCNT), F-actin, and insulin were tested with immunofluorescence and enzyme-linked immunosorbent assay.All glycemic parameters and variability indexes significantly decreased from baseline to 15 weeks, while no significant difference was found between these 2 groups at baseline or at 15 weeks. Furthermore, there was no significant difference found in fasting insulin and postprandial insulin at baseline and at 15 weeks, while homeostasis model assessment β significantly increased. The first-phase glucose and insulin secretion of the intravenous glucose tolerance test improved in both groups, especially in the repaglinide group. Insulin, PCNT, and F-actin expression in MIN-6 cells decreased after 15 minutes of stimulation with repaglinide, while no difference was observed at 2, 6, and 12 hours. The insulin levels of the cell medium in the repaglinide group remained significantly higher at all timepoints.This study manifests that repaglinide has a noninferiority effect on the glycemic parameters of Chinese patients with newly diagnosed diabetes, when compared with metformin. The PCNT-F-actin pathway plays an important role in the repaglinide regulation process of on-demand insulin secretion.

Chronic inflammation has been regarded as one of the causes of idiopathic sudden sensorineural hearing loss (ISSHL). Several individual studies have reported the association between neutrophil-to-lymphocyte ratio (NLR) and ISSHL. However, the findings have been inconsistent, and these data have not been systematically evaluated. Thus, we conducted this meta-analysis to further explore the predictive value of NLR on formation and prognosis of ISSHL.

Theranostic platforms integrating imaging diagnostic and therapeutic interventions into a single nanoplatform have attracted considerable attention for cancer-individualized therapies. However, their uncertain stability, complex pharmacokinetics, and intrinsic toxicology of multiple components hinder their practical application in clinical research. In this paper, stable and high-concentration molybdenum carbide quantum dots (Mo₂C QDs) with a diameter of approximately 6 nm and a topographic height of about 1.5 nm were synthesized using a facile sonication-assisted liquid-phase exfoliation approach. The prepared Mo₂C QDs exhibited a strong near-infrared (NIR) absorbance with a high molar extinction coefficient of 4.424 Lg-1cm-1 at 808 nm, a high photothermal conversion efficiency of 42.9%, and showed excellent performance on photoacoustic imaging. The Mo₂C QDs had high stability and highly biocompatibility, with low cytotoxicity. Under NIR irradiation, a remarkable in vitro and in vivo therapeutic effect was obtained. Such a stable and biocompatible all-in-one theranostic nanoagent generated by facile synthesis that combines promising imaging guidance and effective tumor ablation properties may hold great potential for theranostic nanomedicine.

'Rama and the Worm' is a shadow puppet production targeting neglected diseases in Central Java. It is an entertainment-based intervention study to promote health by reducing the impact of parasitic diseases such as soil-transmitted helminths (STH). The study uses traditional Javanese shadow puppetry (wayang kulit) as a vehicle in village communities to disseminate health messages and promote behaviour change to prevent diseases caused, primarily, by inadequate sanitation and poor hygiene. The health education messages contained in the play, although using traditional characters and themes, required the creation of a completely new narrative script, using characters and plot lines familiar to the wayang kulit repertoire, but placing them in new situations that relate specifically to health promotion objectives. The intervention was piloted in a village in Central Java, Indonesia using a pre/post design with both qualitative and quantitative analysis. A total of 96 male and female villagers, aged between 7 and 87 years, provided both baseline and follow up data. Participant knowledge and behaviours related to gastrointestinal and helminth-related disease were assessed before and after the intervention through a questionnaire administered by interview. Results revealed statistically significant improvements in both knowledge (48.6% pre-intervention score vs. 62.8% post-intervention score, p < 0.001) and behaviour (77.4% vs. 80.6%, p = 0.004) related to gastrointestinal and helminth disease. Findings of the study indicate the wayang kulit performance is an effective health education tool. The results provide proof of concept with scaling up the next step forward. The wayang kulit production provides a significant additional component for an integrated, comprehensive approach to reduction and elimination of STH infection.

Cancer cells undergo uncontrolled proliferation resulting from aberrant activity of various cell-cycle proteins. Therefore, despite recent advances in intensive chemotherapy, it is difficult to cure cancer completely. Recently, cell-cycle regulators became attractive targets in cancer therapy. Zingerone, a phenolic compound isolated from ginger, is a nontoxic and inexpensive compound with varied pharmacological activities. In this study, the therapeutic effect of zingerone as an anti-mitotic agent in human neuroblastoma cells was investigated. Following treatment of BE(2)-M17 cells with zingerone, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and colony-formation assay to evaluate cellular proliferation, in addition to immunofluorescence cytochemistry and flow cytometry to examine the mitotic cells. The association of gene expression with tumor stage and survival was analyzed. Furthermore, to examine the anti-cancer effect of zingerone, we applied a BALB/c mouse-tumor model using a BALB/c-derived adenocarcinoma cell line. In human neuroblastoma cells, zingerone inhibited cellular viability and survival. Moreover, the number of mitotic cells, particularly those in prometaphase, increased in zingerone-treated neuroblastoma cells. Regarding specific molecular mechanisms, zingerone decreased cyclin D1 expression and induced the cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The decrease in cyclin D1 and increase in histone H3 phosphorylated (p)-Ser10 were confirmed by immunohistochemistry in tumor tissues administered with zingerone. These results suggest that zingerone induces mitotic arrest followed by inhibition of growth of neuroblastoma cells. Collectively, zingerone may be a potential therapeutic drug for human cancers, including neuroblastoma.

Ringspot, caused by the fungus Mycosphaerella brassicicola, is a serious disease of Brassica crops worldwide. Despite noteworthy progress to reveal the role of glucosinolates in pathogen defense, the host⁻pathogen interaction between cabbage (Brassica oleracea) and M. brassicicola has not been fully explored. Here, we investigated the glucosinolate profiles and expression of glucosinolate biosynthesis genes in the ringspot-resistant (R) and susceptible (S) lines of cabbage after infection with M. brassicicola. The concomitant rise of aliphatic glucoiberverin (GIV) and indolic glucobrassicin (GBS) and methoxyglucobrassicin (MGBS) was linked with ringspot resistance in cabbage. Pearson's correlation and principle component analysis showed a significant positive association between GIV contents and the expression of the glucosinolate biosynthesis gene ST5b-Bol026202 and between GBS contents and the expression of the glucosinolate biosynthesis gene MYB34-Bol017062. Our results confirmed that M. brassicicola infection induces the expression of glucosinolate biosynthesis genes in cabbage, which alters the content of individual glucosinolates. This link between the expression of glucosinolate biosynthesis genes and the accumulation of their respective glucosinolates with the resistance to ringspot extends our molecular sense of glucosinolate-negotiated defense against M. brassicicola in cabbage.

The interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR) is a promising target for the treatment of hyperc-holesterolemia. In this study, a new method based on competitive affinity and tag detection was developed, which aimed to evaluate potent natural inhibitors preventing the interaction of PCSK9/LDLR directly. Herein, natural compounds with efficacy in the treatment of hypercholesterolemia were chosen to investigate their inhibitory activities on the PCSK9/LDLR interaction. Two of them, polydatin (1) and tetrahydroxydiphenylethylene-2-O-glucoside (2), were identified as potential inhibitors for the PCSK9/LDLR interaction and were proven to prevent PCSK9-mediated LDLR degradation in HepG2 cells. The results suggested that this strategy could be applied for evaluating potential bioactive compounds inhibiting the interaction of PCSK9/LDLR and this strategy could accelerate the discovery of new drug candidates for the treatment of PCSK9-mediated hypercholesterolemia.

This study investigated peripheral and central metabolites affecting depression, anxiety, suicidal ideation, and anger in complex regional pain syndrome (CRPS) patients.

Antisense transcription emerges as a key regulator of important biological processes in the human malaria parasite Plasmodium falciparum. RNA-processing factors, however, remain poorly characterized in this pathogen. Here, we purified the multiprotein RNA exosome complex of malaria parasites by affinity chromatography, using HA-tagged PfRrp4 and PfDis3 as the ligands. Seven distinct core exosome subunits (PfRrp41, PfMtr3, PfRrp42, PfRrp45, PfRrp4, PfRrp40, PfCsl4) and two exoribonuclease proteins PfRrp6 and PfDis3 are identified by mass spectrometry. Western blot analysis detects Dis3 and Rrp4 predominantly in the cytoplasmic fraction during asexual blood stage development. An inducible gene knock out of the PfDis3 subunit reveals the upregulation of structural and coding RNA, but the vast majority belongs to antisense RNA. Furthermore, we detect numerous types of cryptic unstable transcripts (CUTs) linked to virulence gene families including antisense RNA in the rif gene family. Our work highlights the limitations of steady-state RNA analysis to predict transcriptional activity and link the RNA surveillance machinery directly with post-transcriptional control and gene expression in malaria parasites.

This study mainly investigated the effects of matrine on cell apoptosis and the effects of anticancer drugs in non-small cell lung cancer (NSCLC) cell lines (A549 and LK2 cells). The results showed that matrine (≥10 μM) caused a significant inhibition on cell viability and 10 and 100 μM matrine induced cell apoptosis via influencing p53, bax, casp3, and bcl-2 expressions in A549 cells. In addition, matrine significantly down-regulated C-C chemokine receptor type 7 (CCR7) expression, and blocking the down-regulation of CCR7 by exogenous chemokine ligand 21 (CCL21) treatment alleviated matrine-caused effects of apoptosis genes in A549 cells. The results were further validated in LK2 cells that matrine regulated apoptosis gene expressions, which were reversed by CCL21 treatment. Furthermore, matrine enhances the effects of cisplatin, 5-fluorouracil, and paclitaxel in A549 cells, and the anticancer effects exhibit a dosage-dependent manner. In summary, matrine induced cell apoptosis and enhanced the effects of anticancer drugs in NSCLC cells; the mechanism might be associated with the CCR7 signal.

The emerging roles of rhizobacteria in improving plant nutrition and stress protection have great potential for sustainable use in saline soils. We evaluated the function of the salt-tolerant strain Azotobacter chroococcum 76A as stress protectant in an important horticultural crop, tomato. Specifically we hypothesized that treatment of tomato plants with A. chroococcum 76A could improve plant performance under salinity stress and sub-optimal nutrient regimen.