A Study of Host Factors that Affect Herpes Simplex Virus 1 Pathogenesis: The Role of Cold Sore Susceptibility Gene 1 (CSSG1) in HSV1 Replication

Numerous factors that affect herpes simplex virus 1 (HSV1)-mediated pathogenesis have been identified. Such factors directly impact the replication of HSV1 as well as modulate host immune responses following HSV1 infection. In this work, I characterize how HSV1 replication is impacted by expression of the protein encoded by C21orf91, or “Cold Sore Susceptibility Gene” (CSSG1), that has been linked to HSV1 reactivation in humans. I investigated expression of CSSG1 mRNA expression in various tissues and found that CSSG1 mRNA was present in several tissues of importance in HSV1 disease, including brain, trigeminal ganglia (TG), cornea and spleen. Western blot analysis demonstrated that CSSG1 protein is expressed in human cells. Subcellular fractionation analysis reveals that CSSG1 is predominantly found in the cell nucleus, where it colocalizes with chromatin and with Tip60, a chromatin-binding histone modifying protein that has been shown to be essential for the replication of herpesviruses. I also discovered that CSSG1 is present in the cytosol of cells where it forms large cytosolic aggregates in presence of TRAF6, a downstream adapter that plays an important role in innate immune receptor signaling. To determine if CSSG1 directly impacts viral replication, I generated CSSG1 knockdown human cell lines. I found that HSV1 replication was reduced in CSSG1 knockdown cells compared to control cells, whereas replication of the unrelated virus, vesicular stomatitis virus (VSV), was not affected by knockdown of CSSG1. I demonstrate that CSSG1 was necessary for efficient expression of HSV1 viral proteins during infection. Western blot analysis and measurement of expression of HSV1 proteins expressed at various stages of viral replication illustrates that CSSG1 was required for HSV1 replication at very early stage of infection. I also noted that CSSG1 expression impacted the DNA damage response in HSV1 infected cells. Levels of H2AX phosphorylation, a marker of the DNA damage response, were increased in HSV1-infected CSSG1 knockdown cells compared to control cells. DNA damage responses are thought to promote HSV1 reactivation from latency and HSV1 gene expression, indicating a potential mechanism for role of CSSG1 in HSV1 replication through modulating the DNA damage response. Overall, my work demonstrates that CSSG1 affects HSV1 replication and provides insight on how CSSG1 polymorphisms in humans could affect HSV1 reactivation and replication to promote cold sores. These discoveries may also lead to a better understanding of pathogenesis of other herpesviruses in humans

Challenges in path planning of high energy density beams for additive manufacturing

As there are no cutting forces in High Energy Density (HED) beams like lasers and Electron Beam (EB), their speeds are limited only by their positioning systems. On the other hand, as the entire matrix of the 3D printed part has to be addressed by the thin beam in multiple passes in multiple layers, they have to travel several kilometers in tiny motions. Therefore, the acceleration of the motion system becomes the limiting factor than velocity or precision. The authors have proposed an area-filling strategy for EB to fill the layer with optimal squares to exploit analog and hardware computing. 3D printing requires uniform intensity slanged as flat hat shape whereas the default is Gaussian. The authors have proposed an optimal algorithm that takes into account the maximum velocity and acceleration for achieving a flat hat without any compromise on productivity

Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode. © 2014 Agassandian et al

Anthropometric measures in relation to Basal Cell Carcinoma: a longitudinal study

BACKGROUND: The relationship between anthropometric indices and risk of basal cell carcinoma (BCC) is largely unknown. We aimed to examine the association between anthropometric measures and development of BCC and to demonstrate whether adherence to World Health Organisation guidelines for body mass index, waist circumference, and waist/hip ratio was associated with risk of BCC, independent of sun exposure. METHODS: Study participants were participants in a community-based skin cancer prevention trial in Nambour, a town in southeast Queensland (latitude 26°S). In 1992, height, weight, and waist and hip circumferences were measured for all 1621 participants and weight was remeasured at the end of the trial in 1996. Prevalence proportion ratios were calculated using a log-binomial model to estimate the risk of BCC prior to or prevalent in 1992, while Poisson regression with robust error variances was used to estimate the relative risk of BCC during the follow-up period. RESULTS: At baseline, 94 participants had a current BCC, and 202 had a history of BCC. During the 5-year follow-up period, 179 participants developed one or more new BCCs. We found no significant association between any of the anthropometric measures or indices and risk of BCC after controlling for potential confounding factors including sun exposure. There was a suggestion that short-term weight gain may increase the risk of developing BCC for women only. CONCLUSION: Adherence to World Health Organisation guidelines for body mass index, waist circumference and waist/hip ratio is not significantly associated with occurrence of basal cell carcinomas of the skin

A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study.

Funder: Centre International de Recherche sur le Cancer; doi: http://dx.doi.org/10.13039/100008700PURPOSE: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive. METHODS: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS). RESULTS: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS. CONCLUSIONS: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London