Head and neck squamous cell carcinoma (HNSCC) remains one of the most common malignancies associated with poor prognosis. DNA methylation has emerged as an important mechanism underlying the radio‑resistance of tumors. Prognostic biomarkers based on radiotherapy‑related aberrant DNA methylation are limited. Methylation profiles of 388 patients with HNSCC were acquired from The Cancer Genome Atlas (TCGA) portal. Genes with differentially methylated CpG sites (DMGs) were screened between patients with a favorable and poor prognosis with or without radiotherapy. A weight gene co‑methylation network was constructed using a Weighted Gene Co‑expression Network Analysis (WGCNA) package. A lasso Cox‑PH model was used to identify the optimal panel of genes with the ability to predict survival in these patients. Prognostic performance of the multi‑gene methylation signature was assessed in a training set and confirmed in a validation set. A total of 976 DMGs were observed between favorable and poor prognostic samples. Four DMG‑enriched co‑methylation modules were identified. A four‑gene methylation signature was determined by the lasso Cox‑PH model that consisted of ZNF10, TMPRSS12, ERGIC2, and RNF215. The risk score based on the four‑gene signature was able to divide the training or validation set into two risk groups with significantly different overall survival. Thus, the present study revealed a radiotherapy‑related four‑gene methylation signature to predict survival outcomes of patients with HNSCC, providing candidate therapeutic targets for novel therapy against HNSCC. However, substantial validation experiments are required.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of autoimmune etiopathogenesis, and is characterized by various neurological symptoms. Glatiramer acetate and interferon‑β are administered as first‑line treatments for this disease. In non‑responsive patients, several second‑line therapies are available, including natalizumab; however, a percentage of MS patients does not respond, or respond partially. Therefore, it is of the utmost importance to develop a diagnostic test for the prediction of drug response in patients suffering from complex diseases, such as MS, where several therapeutic options are already available. By a machine learning approach, the UnCorrelated Shrunken Centroid algorithm was applied to identify a subset of genes of CD4+ T cells that may predict the pharmacological response of relapsing‑remitting MS patients to natalizumab, before the initiation of therapy. The results from the present study may provide a basis for the design of personalized therapeutic strategies for patients with MS.

Compare the efficacy and safety of the 2-drug antiretroviral therapy regimen dolutegravir + lamivudine (DTG + 3TC) with traditional 3-drug regimens in treatment-naive patients with HIV-1.

African trypanosomosis, primarily transmitted by tsetse flies, remains a serious public health and economic challenge in sub-Saharan Africa. Interventions employing natural repellents from non-preferred hosts of tsetse flies represent a promising management approach. Although zebras have been identified as non-preferred hosts of tsetse flies, the basis for this repellency is poorly understood. We hypothesized that zebra skin odors contribute to their avoidance by tsetse flies.

Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.

We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model's energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.

In developing countries, the cost of vaccination limits the use of prophylactic rabies vaccination, especially in cattle. Intradermal vaccination delivers antigen directly to an area with higher number of antigen-presenting cells. Therefore, it could produce equivalent or higher antibody titres than conventional intramuscular vaccination even when a lower dose is given. This study aimed to compare the antibody response in cattle vaccinated intramuscularly with 1mL of inactivated rabies vaccine (Raksharab, Indian Immunologicals) against intradermally vaccinated cattle with 0.2mL of the same vaccine. The study was conducted in Haa province of Bhutan where rabies is not endemic. One hundred cattle from 27 farms were selected for the study. Virus neutralising antibody (VNA) response was measured using the fluorescent antibody virus neutralisation test on the day of vaccination (day 0) and 14, 30, 60 and 90 days later. Overall, 71% of intradermally vaccinated cattle and 89% of the intramuscularly vaccinated cattle produced an adequate response (≥0.5IU/mL). On days 14 and 30 post vaccination fewer cattle (P<0.02) in the intradermal group had adequate titres with 36% and 58%, respectively, having titres ≥0.5 IU/mL compared to the equivalent figures of 78% and 77% in the intramuscular group. The mean VNA titres were lower for the intradermal group than intramuscular group (p<0.001) with the mean difference being > 0.6 IU/mL. Although low dose intradermal vaccination did produce a detectable antibody response, it was inferior to intramuscular vaccination. Thus, although intradermal vaccination has the potential to reduce the cost of vaccination by reducing the dose required, this study showed that a single dose of 0.2 mL intradermally was inferior to an intramuscular dose of 1 mL. Further research evaluating dose and dose regimen is needed before intradermal vaccination using the Raksharab rabies vaccine can be recommended in cattle.

Companies need to ensure that customers perceive their brands as intended, with strong and unique associations, when facing a competitive market. Traditionally, brand associations are measured using conventional techniques such as surveys and questionnaires albeit both conscious and unconscious factors can influence the collected data and the outcome of a campaign. Neuromarketing can shed light on how the customer's brain processes marketing stimuli. We report here on an EEG study aimed at gauging mental associations with brands. We focus on the N400 event-related potential, an EEG component most strongly elicited in response to a concept unrelated to a preceding concept. We considered two video on demand brands, Netflix and Rex&Rio, and selected a set of words grouped in 4 categories that were either related (Television, Relaxation, and Price), in varying degrees, or unrelated (Unrelated) to the said brands. The experiment started with both brands' TV commercials, as a common reference for our participants. We then applied a semantic priming paradigm in which a brand logo ("prime") was followed by a word ("target"), and the strength of the N400 response to the word used as an inverted measure of the association strength with the brand logo. We clustered N400 responses to identify, for each brand, natural groups of associated words. As a result, for Netflix the cluster with the smallest N400 responses (i.e., strongest associations) consisted of words related to Television but for Rex&Rio it consisted of words related to Relaxation. We also evaluated the relationship between the two brands and determined which associations they share or which ones not. It turned out that associations related to Relaxation and Television distinguish the two brands. Interestingly, survey data did not show any difference between the two brands as they were equally associated with Television and Relaxation. These findings show that our N400 technique can reveal brand associations, and natural categories thereof, that would otherwise go unnoticed when using conventional surveys.

The objective of this study was to examine whether exposure to Intimate Partner Violence (IPV) is associated with premature termination of Exclusive Breastfeeding (EB). Per WHO recommendations, this was defined as ceasing breastfeeding or supplementing with other foods or liquids before the child was 6 months old.

Gastrointestinal parasites are neglected infections, yet they cause significant burden to animal and human health globally. To date, most studies of gastrointestinal parasites focus on host-parasite systems that involve either a single parasite or a host species. However, when hosts share habitat and resources, they may also cross-transmit generalist gastrointestinal parasites. Here we explore multi-host-parasite interactions in a single ecosystem to understand the infection patterns, especially those linked to livestock-wildlife interfaces and zoonotic risk.

We analyzed the preference of three psychological intervention formats-individual, group, and online-in a sample of 267 patients with a primary diagnosis of emotional disorder in Spanish public mental health settings.

Streptococcus agalactiae (Group B Streptococcus, GBS) normally colonizes healthy adults but can cause invasive disease, such as meningitis, in the newborn. To gain access to the central nervous system, GBS must interact with and penetrate brain or meningeal blood vessels; however, the exact mechanisms are still being elucidated. Here, we investigate the contribution of BspC, an antigen I/II family adhesin, to the pathogenesis of GBS meningitis. Disruption of the bspC gene reduced GBS adherence to human cerebral microvascular endothelial cells (hCMEC), while heterologous expression of BspC in non-adherent Lactococcus lactis conferred bacterial attachment. In a murine model of hematogenous meningitis, mice infected with ΔbspC mutants exhibited lower mortality as well as decreased brain bacterial counts and inflammatory infiltrate compared to mice infected with WT GBS strains. Further, BspC was both necessary and sufficient to induce neutrophil chemokine expression. We determined that BspC interacts with the host cytoskeleton component vimentin and confirmed this interaction using a bacterial two-hybrid assay, microscale thermophoresis, immunofluorescent staining, and imaging flow cytometry. Vimentin null mice were protected from WT GBS infection and also exhibited less inflammatory cytokine production in brain tissue. These results suggest that BspC and the vimentin interaction is critical for the pathogenesis of GBS meningitis.

Diaphorin is a polyketide produced by Candidatus Profftella armatura (Betaproteobacteria), an organelle-like defensive symbiont harbored by a plant sap-sucking insect, Asian citrus psyllid Diaphorina citri (Hemiptera: Liviidae). Diaphorin belongs to the pederin family, a group of compounds that share much of their core structure with that of pederin, which is characterized by two dihydropyran rings bridged by an N-acyl aminal. Most members of this family have potent antitumor activity, making them promising anticancer drug candidates. The present study assessed the therapeutic potential of diaphorin for its antitumor activity against 39 human cancer cell lines including those from breast, brain, colon, lung, skin, ovary, kidney, stomach, and prostate. The results showed that diaphorin had inhibitory activity against all 39 cancer cell lines tested. The GI50, TGI, and LC50 values ranged from 0.28 μM- 2.4 μM, 1.6 μM -11 μM, and 7.5 μM-> 100 μM, respectively. These values are among the highest in the pederin family, indicating that the anticancer activity of diaphorin is milder than those of other pederin congeners. The inhibitory effects of diaphorin significantly differed among the distinct cancer types. The maximum difference was about 10-fold, which was similar to those of most other pederin congeners.

Evaluation of an external color coded perfusion quantification software with CEUS for the post-interventional success control following TACE in patients with HCC.

Reduced oxygenation of the outer retina in the aging eye may activate a chronic hypoxic response in RPE and photoreceptor cells and is considered as a risk factor for the development of age-related macular degeneration (AMD). In mice, a chronically active hypoxic response in the retinal pigment epithelium (RPE) or photoreceptors leads to age-dependent retinal degeneration. To identify proteins that may serve as accessible markers for a chronic hypoxic insult to photoreceptors, we used proteomics to determine the protein composition of the vitreous humor in genetically engineered mice that lack the von Hippel-Lindau tumor suppressor (Vhl) specifically in rods (rodΔVhl) or cones (all-coneΔVhl). Absence of VHL leads to constitutively active hypoxia-inducible transcription factors (HIFs) and thus to a molecular response to hypoxia even in normal room air. To discriminate between the consequences of a local response in photoreceptors and systemic hypoxic effects, we also evaluated the vitreous proteome of wild type mice after exposure to acute hypoxia. 1'043 of the identified proteins were common to all three hypoxia models. 257, 258 and 356 proteins were significantly regulated after systemic hypoxia, in rodΔVhl and in all-coneΔVhl mice, respectively, at least at one of the analyzed time points. Only few of the regulated proteins were shared by the models indicating that the vitreous proteome is differentially affected by systemic hypoxia and the rod or cone-specific hypoxic response. Similarly, the distinct protein compositions in the individual genetic models at early and late time points suggest regulated, cell-specific and time-dependent processes. Among the proteins commonly regulated in the genetic models, guanylate binding protein 2 (GBP2) showed elevated levels in the vitreous that were accompanied by increased mRNA expression in the retina of both rodΔVhl and all-coneΔVhl mice. We hypothesize that some of the differentially regulated proteins at early time points may potentially be used as markers for the detection of a chronic hypoxic response of photoreceptors.

Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or sham VNS after successful trials. After five days of pairing intracortical microstimulation (ICMS) was performed in the motor cortex contralateral to the trained limb. VNS paired with training more than doubled cortical representations of proximal forelimb movements. Depletion of either cortical norepinephrine or serotonin prevented this effect. The requirement of multiple neuromodulators is consistent with earlier studies showing that these neuromodulators regulate synaptic plasticity in a complimentary fashion.

Metformin has been widely used to alleviate hyperglycemia in patients with type 2 diabetes mainly via suppressing hepatic gluconeogenesis. However, the underlying mechanism remains incompletely clear. Here, we aimed to explore the role of PPP1R3C in metformin-mediated inhibition of hepatic gluconeogenesis.

Polycyclic aromatic hydrocarbons (PAHs) are a class of pervasive global environmental pollutants and adversely affect human health. Among PAHs, phenanthrene and anthracene are isomers consisting of three benzene rings. In the present study, we have made comparisons of constitutive androstane receptor (CAR) activation and toxic effects on the liver between these two isomers. Phenanthrene, but not anthracene, significantly induced promoter activity and gene expression of human drug metabolizing enzyme CYP2B6 in HepG2 cells and human primary hepatocytes, respectively. Phenanthrene, but not anthracene, significantly increased CYP2B10 expression levels and caused hepatotoxicity in mice. Phenanthrene induced the nuclear accumulation of CAR in the liver of wild-type mice, but not CAR-/- mice. Hepatocellular necrosis, elevated expression levels of some CAR-related genes such as CYP2B10, CYP3A11, UGT1A1, SULT2A1 and GSTM3, and lower hepatic glutathione levels were found in phenanthrene-exposed wild-type mice but not CAR-/- mice. Additionally, phenanthrene and anthracene were detected in both raw and grilled lamb samples. The average concentrations of phenanthrene were much higher than those of anthracene in these samples. This study is the first to demonstrate that phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor CAR, and CAR plays a crucial role in phenanthrene-induced mouse hepatotoxicity. Compared with anthracene, K region may be an important electronic structure of phenanthrene for activation of CAR. Dietary consumption of PAHs-contaminated food is an important exposure route for humans. Exposure to phenanthrene may affect human health especially associated with liver.

Chondroitin sulfate (CS) chains are prominent extra/pericellular matrix components in the central nervous system (CNS) and can exert positive or negative regulatory effects on neurite outgrowth, depending on the CS structure and the amount. Despite the remarkable abilities of highly sulfated forms of CS chains to enhance neurite outgrowth, the neuronal recognition systems for such promotional CS chains, including CS-D polysaccharide, remain to be fully elucidated.

CuATSM is a PET-imaging agent that has recently received attention for its success in extending the lifespan in animals in several neurodegenerative disease models. In the SOD1G93A model of ALS, CuATSM prolonged mouse longevity far longer than any previously tested therapeutic agents. The mechanism underlying this outcome has not been fully understood, but studies suggest that this copper complex contributes to maintaining copper homeostasis in mitochondria. More specifically for the SOD1 model, the molecule supplies copper back to the SOD1 protein. Additionally, CuATSM demonstrated similar protective effects in various in vivo Parkinson's disease mouse models. In the current pilot study, we utilized a neurodegenerative mouse model of motor neuron degeneration induced by the neurotoxin β-sitosterol β-D-glucoside. In this model, slow but distinct and progressive features of sporadic ALS occur. Treatment with CuATSM kept animal behavioural performance on par with the controls and prevented the extensive motor neuron degeneration and microglia activation seen in the untreated animals. These outcomes support a broader neuroprotective role for CuATSM beyond mutant SOD models of ALS.