Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection

<p>Abstract</p> <p>Background</p> <p>West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus.</p> <p>Results</p> <p>Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19⁺B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4⁺and CD8⁺T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8⁺T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease.</p> <p>Conclusions</p> <p>Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi.</p

Contribution of chronic diseases to the mild and severe disability burden in Belgium

Background: Population aging accompanied by an increased longevity with disability has raised international concern, especially due to its costs to the health care systems. Chronic diseases are the main causes of physical disability and their simultaneous occurrence in the population can impact the disablement process, resulting in different severity levels. In this study, the contribution of chronic diseases to both mild and severe disability burden in Belgium was investigated. Methods: Data on 21 chronic diseases and disability from 35,799 individuals aged 15years or older who participated in the 1997, 2001, 2004, or 2008 Belgian Health Interview Surveys were analysed. Mild and severe disability were defined based on questions related to six activities of daily living and/or mobility limitations. To attribute disability by severity level to selected chronic diseases, multiple additive hazard models were fitted to each disability outcome, separately for men and women. Results: A stable prevalence of mild (5%) and severe (2-3%) disability was observed for the Belgian population aged 15years or older between 1997 and 2008. Arthritis was the most important contributor in women with mild and severe disability. In men, low back pain and chronic respiratory diseases contributed most to the mild and severe disability burden, respectively. The contribution also differed by age: for mild disability, depression and chronic respiratory diseases were important contributors among young individuals, while heart attack had a large contribution for older individuals. For severe disability, neurological diseases and stroke presented a large contribution in young and elderly individuals, respectively. Conclusions: Our results indicate that the assessment of the contribution of chronic diseases on disability is more informative if different levels of disability are taken into consideration. The identification of diseases which are related to different levels of disability - mild and severe - can assist policymakers in the definition and prioritisation of strategies to tackle disability, involving prevention, rehabilitation programs, support services, and training for disabled individuals

PHIL photoinjector test line

LAL is now equiped with its own platform for photoinjectors tests and Research and Developement, named PHIL (PHotoInjectors at LAL). This facility has two main purposes: push the limits of the photoinjectors performances working on both the design and the associated technology and provide a low energy (MeV) short pulses (ps) electron beam for the interested users. Another very important goal of this machine will be to provide an opportunity to form accelerator physics students, working in a high technology environment. To achieve this goal a test line was realised equipped with an RF source, magnets and beam diagnostics. In this article we will desrcibe the PHIL beamline and its characteristics together with the description of the first two photoinjector realised in LAL and tested: the ALPHAX and the PHIN RF Guns

The effect of smoking on the duration of life with and without disability, Belgium 1997-2011

Background: Smoking is the single most important health threat yet there is no consistency as to whether non-smokers experience a compression of years lived with disability compared to (ex-)smokers. The objectives of the manuscript are (1) to assess the effect of smoking on the average years lived without disability (Disability Free Life Expectancy (DFLE)) and with disability (Disability Life Expectancy (DLE)) and (2) to estimate the extent to which these effects are due to better survival or reduced disability in never smokers. Methods. Data on disability and mortality were provided by the Belgian Health Interview Survey 1997 and 2001 and a 10 years mortality follow-up of the survey participants. Disability was defined as difficulties in activities of daily living (ADL), in mobility, in continence or in sensory (vision, hearing) functions. Poisson and multinomial logistic regression models were fitted to estimate the probabilities of death and the prevalence of disability by age, gender and smoking status adjusted for socioeconomic position. The Sullivan method was used to estimate DFLE and DLE at age 30. The contribution of mortality and of disability to smoking related differences in DFLE and DLE was assessed using decomposition methods. Results: Compared to never smokers, ex-smokers have a shorter life expectancy (LE) and DFLE but the number of years lived with disability is somewhat larger. For both sexes, the higher disability prevalence is the main contributing factor to the difference in DFLE and DLE. Smokers have a shorter LE, DFLE and DLE compared to never smokers. Both higher mortality and higher disability prevalence contribute to the difference in DFLE, but mortality is more important among males. Although both male and female smokers experience higher disability prevalence, their higher mortality outweighs their disability disadvantage resulting in a shorter DLE. Conclusion: Smoking kills and shortens both life without and life with disability. Smoking related disability can however not be ignored, given its contribution to the excess years with disability especially in younger age groups

Probing the urea dependence of residual structure in denatured human α-lactalbumin

Backbone 15N relaxation parameters and 15N–1HN residual dipolar couplings (RDCs) have been measured for a variant of human α-lactalbumin (α-LA) in 4, 6, 8 and 10 M urea. In the α-LA variant, the eight cysteine residues in the protein have been replaced by alanines (all-Ala α-LA). This protein is a partially folded molten globule at pH 2 and has been shown previously to unfold in a stepwise non-cooperative manner on the addition of urea. 15N R2 values in some regions of all-Ala α-LA show significant exchange broadening which is reduced as the urea concentration is increased. Experimental RDC data are compared with RDCs predicted from a statistical coil model and with bulkiness, average area buried upon folding and hydrophobicity profiles in order to identify regions of non-random structure. Residues in the regions corresponding to the B, D and C-terminal 310 helices in native α-LA show R2 values and RDC data consistent with some non-random structural propensities even at high urea concentrations. Indeed, for residues 101–106 the residual structure persists in 10 M urea and the RDC data suggest that this might include the formation of a turn-like structure. The data presented here allow a detailed characterization of the non-cooperative unfolding of all-Ala α-LA at higher concentrations of denaturant and complement previous studies which focused on structural features of the molten globule which is populated at lower concentrations of denaturant

Systems Analysis Implicates WAVE2&nbsp;Complex in the Pathogenesis of&nbsp;Developmental Left-Sided Obstructive&nbsp;Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/1/epi13937_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/2/epi13937.pd

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al