Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission

Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal anti- bodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins rep- resenting the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell trans- mission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver

Dietary patterns and their sociodemographic and lifestyle determinants in Switzerland : results from the national nutrition survey menuCH

From a public health perspective, determinants of diets are crucial to identify, but they remain unclear in Switzerland. Hence, we sought to define current dietary patterns and their sociodemographic and lifestyle determinants using the national nutrition survey menuCH (2014⁻2015, n = 2057). First, we applied multiple factorial analysis and hierarchical clustering on the energy-standardised daily consumption of 17 food categories. Four dietary patterns were identified ("Swiss traditional": high intakes of dairy products and chocolate, n = 744; "Western 1": soft drinks and meat, n = 383; "Western 2": alcohol, meat and starchy, n = 444; and "Prudent": n = 486). Second, we used multinomial logistic regression to examine the determinants of the four dietary patterns: ten sociodemographic or lifestyle factors (sex, age, body mass index, language region, nationality, marital status, income, physical activity, smoking status, and being on a weight-loss diet) were significantly associated with the dietary patterns. Notably, belonging to the French- and Italian-speaking regions of Switzerland increased the odds of following a "Prudent" diet (Odds ratio [95% confidence interval]: 1.92 [1.45⁻2.53] and 1.68 [0.98⁻2.90], respectively) compared to the German-speaking regions. Our findings highlight the influence of sociodemographic and lifestyle parameters on diet and the particularities of the language regions of Switzerland. These results provide the basis for public health interventions targeted for population subgroups

Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome

Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucosestimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-βH3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-βH3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker γ-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of β cell-specific endocrinopathies in FA patients

Dietary Patterns and Their Sociodemographic and Lifestyle Determinants in Switzerland: Results from the National Nutrition Survey menuCH.

From a public health perspective, determinants of diets are crucial to identify, but they remain unclear in Switzerland. Hence, we sought to define current dietary patterns and their sociodemographic and lifestyle determinants using the national nutrition survey menuCH (2014–2015, n = 2057). First, we applied multiple factorial analysis and hierarchical clustering on the energy-standardised daily consumption of 17 food categories. Four dietary patterns were identified (“Swiss traditional”: high intakes of dairy products and chocolate, n = 744; “Western 1”: soft drinks and meat, n = 383; “Western 2”: alcohol, meat and starchy, n = 444; and “Prudent”: n = 486). Second, we used multinomial logistic regression to examine the determinants of the four dietary patterns: ten sociodemographic or lifestyle factors (sex, age, body mass index, language region, nationality, marital status, income, physical activity, smoking status, and being on a weight-loss diet) were significantly associated with the dietary patterns. Notably, belonging to the French- and Italian-speaking regions of Switzerland increased the odds of following a “Prudent” diet (Odds ratio [95% confidence interval]: 1.92 [1.45–2.53] and 1.68 [0.98–2.90], respectively) compared to the German-speaking regions. Our findings highlight the influence of sociodemographic and lifestyle parameters on diet and the particularities of the language regions of Switzerland. These results provide the basis for public health interventions targeted for population subgroups

Pursuing the diffraction limit with nano-led scanning transmission optical microscopy

Recent research into miniaturized illumination sources has prompted the development of alternative microscopy techniques. Although they are still being explored, emerging nano-light-emitting-diode (nano-LED) technologies show promise in approaching the optical resolution limit in a more feasible manner. This work presents the exploration of their capabilities with two different prototypes. In the first version, a resolution of less than 1 µm was shown thanks to a prototype based on an optically downscaled LED using an LED scanning transmission optical microscopy (STOM) technique. This research demonstrates how this technique can be used to improve STOM images by oversampling the acquisition. The second STOM-based microscope was fabricated with a 200 nm GaN LED. This demonstrates the possibilities for the miniaturization of on-chip-based microscopes.This work was partially supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 737089—ChipScope

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip

DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken

Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma

BACKGROUND: The CCND1 gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of a common A/G polymorphism. Cyclin D1a and b proteins differ in their C-terminus, a region involved in protein degradation and sub-cellular localization. Recent data have suggested that cyclin D1b could be a nuclear oncogene. The presence of cyclin D1b mRNA and protein has been studied in two hemopathies in which cyclin D1 could be present: multiple myeloma (MM) and mantle cell lymphoma (MCL). The A/G polymorphism of CCND1 has also been verified in a series of patients. METHODS: The expression of cyclin D1 mRNA isoforms has been studied by real-time quantitative PCR; protein isoforms expression, localization and degradation by western blotting. The CCND1 polymorphism was analyzed after sequencing genomic DNA. RESULTS: Cyclin D1 mRNA isoforms a and b were expressed in mantle cell lymphoma (MCL) and multiple myeloma (MM). Cyclin D1b proteins were present in MCL, rarely in MM. Importantly, both protein isoforms localized the nuclear and cytoplasmic compartments. They displayed the same short half-life. Thus, the two properties of cyclin D1b recognized as necessary for its transforming activity are missing in MCL. Moreover, CCND1 polymorphism at the exon/intron boundary had no influence on splicing regulation in MCL cells. CONCLUSION: Our results support the notion that cyclin D1b is not crucial for the pathogenesis of MCL and MM

A Comparison of Four Probability-Based Online and Mixed-Mode Panels in Europe

Inferential statistics teach us that we need a random probability sample to infer from a sample to the general population. In online survey research, however, volunteer access panels, in which respondents self-select themselves into the sample, dominate the landscape. Such panels are attractive due to their low costs. Nevertheless, recent years have seen increasing numbers of debates about the quality, in particular about errors in the representativeness and measurement, of such panels. In this article, we describe four probability-based online and mixed-mode panels for the general population, namely, the Longitudinal Internet Studies for the Social Sciences (LISS) Panel in the Netherlands, the German Internet Panel (GIP) and the GESIS Panel in Germany, and the Longitudinal Study by Internet for the Social Sciences (ELIPSS) Panel in France. We compare them in terms of sampling strategies, offline recruitment procedures, and panel characteristics. Our aim is to provide an overview to the scientific community of the availability of such data sources to demonstrate the potential strategies for recruiting and maintaining probability-based online panels to practitioners and to direct analysts of the comparative data collected across these panels to methodological differences that may affect comparative estimates

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification