A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

The Price of Uncertainty in Present-Biased Planning

The tendency to overestimate immediate utility is a common cognitive bias. As a result people behave inconsistently over time and fail
to reach long-term goals. Behavioral economics tries to help affected individuals
by implementing external incentives. However, designing robust
incentives is often difficult due to imperfect knowledge of the parameter
β ∈ (0, 1] quantifying a person’s present bias. Using the graphical model
of Kleinberg and Oren [8], we approach this problem from an algorithmic
perspective. Based on the assumption that the only information about
β is its membership in some set B ⊂ (0, 1], we distinguish between two
models of uncertainty: one in which β is fixed and one in which it varies
over time. As our main result we show that the conceptual loss of effi-
ciency incurred by incentives in the form of penalty fees is at most 2
in the former and 1 + max B/ min B in the latter model. We also give
asymptotically matching lower bounds and approximation algorithms

Elbow Joint Loads during Simulated Activities of Daily Living:Implications for Formulating Recommendations after Total Elbow Arthroplasty.

Background: Overloading of the elbow joint prosthesis following total elbow arthroplasty can lead to implant failure. Joint moments during daily activities are not well-contextualized for a prosthesis' failure limits and the effect of the current postoperative instruction on elbow joint loading is unclear. This study investigates the difference in elbow joint moments between simulated daily tasks and between flexion-extension, pronation-supination, varus-valgus movement directions. Additionally, the effect of the current postoperative instruction on elbow joint load is examined.Methods: Nine healthy participants (age 45.8 ± 17 years, 3 males) performed eight tasks; driving a car, opening a door, rising from chair, lifting, sliding, combing hair, drinking, emptying cup, without and with the instruction "not lifting more than 1 kg". Upper limb kinematics and hand contact forces were measured. Elbow joint angles and net moments were analyzed using inverse dynamic analysis, where the net moments are estimated from movement data and external forces.Results: Peak elbow joint moments differed significantly between tasks (p &lt; 0.01) and movement directions (p &lt; 0.01). The most and least demanding tasks were, rising from a chair (13.4 Nm extension, 5.0 Nm supination, 15.2 Nm valgus) and sliding (4.3 Nm flexion, 1.7 Nm supination, 2.6 Nm varus). Net moments were significantly reduced after instruction only in the chair task (p &lt; 0.01).Conclusion: This study analyzed elbow joint moments in different directions during daily tasks. The outcomes question whether postoperative instruction can lead to decreasing elbow loads. Future research might focus on reducing elbow loads in the flexion-extension and varus-valgus directions.<br/

Distal and proximal family predictors of adolescents' smoking initiation and development: A longitudinal latent curve model analysis

<p>Abstract</p> <p>Background</p> <p>Studies on adolescent smoking indicate that the smoking behaviours of their parents, siblings and friends are significant micro-level predictors. Parents' socioeconomic status (SES) is an important macro-level predictor. We examined the longitudinal relationships between these predictors and the initiation and development of adolescents' smoking behaviour in Norway.</p> <p>Methods</p> <p>We employed data from <it>The Norwegian Longitudinal Health Behaviour Study (NLHB)</it>, in which participants were followed from the age of 13 to 30. We analysed data from the first 5 waves, covering the age span from 13 to 18, with latent curve modeling (LCM).</p> <p>Results</p> <p>Smoking rates increased from 3% to 31% from age 13 to age 18. Participants' smoking was strongly associated with their best friends' smoking. Parental SES, parents' smoking and older siblings' smoking predicted adolescents' initial level of smoking. Furthermore, the same variables predicted the development of smoking behaviour from age 13 to 18. Parents' and siblings' smoking behaviours acted as mediators of parents' SES on the smoking habits of adolescents.</p> <p>Conclusions</p> <p>Parents' SES was significantly associated, directly and indirectly, with both smoking initiation and development. Parental and older siblings' smoking behaviours were positively associated with both initiation and development of smoking behaviour in adolescents. There were no significant gender differences in these associations.</p

Search for QTL affecting the shape of the egg laying curve of the Japanese quail

BACKGROUND: Egg production is of critical importance in birds not only for their reproduction but also for human consumption as the egg is a highly nutritive and balanced food. Consequently, laying in poultry has been improved through selection to increase the total number of eggs laid per hen. This number is the cumulative result of the oviposition, a cyclic and repeated process which leads to a pattern over time (the egg laying curve) which can be modelled and described individually. Unlike the total egg number which compounds all variations, the shape of the curve gives information on the different phases of egg laying, and its genetic analysis using molecular markers might contribute to understand better the underlying mechanisms. The purpose of this study was to perform the first QTL search for traits involved in shaping the egg laying curve, in an F(2 )experiment with 359 female Japanese quail. RESULTS: Eight QTL were found on five autosomes, and six of them could be directly associated with egg production traits, although none was significant at the genome-wide level. One of them (on CJA13) had an effect on the first part of the laying curve, before the production peak. Another one (on CJA06) was related to the central part of the curve when laying is maintained at a high level, and the four others (on CJA05, CJA10 and CJA14) acted on the last part of the curve where persistency is determinant. The QTL for the central part of the curve was mapped at the same position on CJA06 than a genome-wide significant QTL for total egg number detected previously in the same F(2). CONCLUSION: Despite its limited scope (number of microsatellites, size of the phenotypic data set), this work has shown that it was possible to use the individual egg laying data collected daily to find new QTL which affect the shape of the egg laying curve. Beyond the present results, this new approach could also be applied to longitudinal traits in other species, like growth and lactation in ruminants, for which good marker coverage of the genome and theoretical models with a biological significance are available

A Randomised Experiment Evaluating the Mindful Raisin Practice as a Method of Reducing Chocolate Consumption During and After a Mindless Activity

The present study investigated the impact of the mindful raisin exercise on overeating during and after the experiment while controlling for wellbeing. One-hundred and twenty-eight participants were recruited and completed a questionnaire on wellbeing (i.e. depression, anxiety and stress) and state mindfulness. Participants were randomly allocated to either the mindful raisin exercise or a newspaper reading control condition. The State Mindfulness Scale was then completed again, and participants watched a neutral video while exposed to chocolate for 10 min. For those 10 min, results showed that the mindfulness condition translated into lower food consumption during the mindless activity when compared to the control condition. Post experiment, participants were asked to wait for 5 min, and any extra chocolate consumption during this time was recorded. Post-consumption was non-significantly different between the two groups, with those in the mindfulness condition consuming 1.3 g less than those in the control group. Controlling for wellbeing did not alter the impact of the mindfulness intervention on consumption. Implications for future work and practical applications for weight regulation are discussed

The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population

Contains fulltext : 81191.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: In selected populations, pelvic organ prolapse (POP) was associated with bladder/bowel symptoms, but data on the general female population are lacking. Our aim was to obtain normative data on the prevalence of POP and pelvic floor dysfunction (PFD) symptoms and signs and to identify associations. METHODS: Validated questionnaires on POP and PFD (urogenital distress inventory, (UDI) and defaecation distress inventory (DDI)) were sent to a general population of 2,979 women (aged 45-85 years). Data were analysed using the Kruskal-Wallis test, chi square test and Spearman's rank correlation coefficient. RESULTS: Response rate was 62.7%. Associations between POP stage and parity (0.002) and vaginal bulging (<0.001) are significant. Anatomical locations of POP and PFD symptoms correlated significantly with incontinence of flatus, feeling anal prolapse, manual evacuation of stool, vaginal bulging, constipation and pain during faecal urge (p < or = 0.005). CONCLUSIONS: Strategies should be developed to alleviate obstructive bowel disorders associated with POP

Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany

BACKGROUND: Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany. METHODS: One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry. RESULTS: The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001). CONCLUSION: The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m(2 )have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones

One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke

Previous studies conducted between 1997 and 2003 estimated that the risk of stroke or an acute coronary syndrome was 12 to 20% during the first 3 months after a transient ischemic attack (TIA) or minor stroke. The TIAregistry.org project was designed to describe the contemporary profile, etiologic factors, and outcomes in patients with a TIA or minor ischemic stroke who receive care in health systems that now offer urgent evaluation by stroke specialists.We recruited patients who had had a TIA or minor stroke within the previous 7 days. Sites were selected if they had systems dedicated to urgent evaluation of patients with TIA. We estimated the 1-year risk of stroke and of the composite outcome of stroke, an acute coronary syndrome, or death from cardiovascular causes. We also examined the association of the ABCD(2) score for the risk of stroke (range, 0 [lowest risk] to 7 [highest risk]), findings on brain imaging, and cause of TIA or minor stroke with the risk of recurrent stroke over a period of 1 year.From 2009 through 2011, we enrolled 4789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan-Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan-Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD(2) score of 6 or 7 were each associated with more than a doubling of the risk of stroke.We observed a lower risk of cardiovascular events after TIA than previously reported. The ABCD(2) score, findings on brain imaging, and status with respect to large-artery atherosclerosis helped stratify the risk of recurrent stroke within 1 year after a TIA or minor stroke