Systematic Identification of Genes that Regulate Neuronal Wiring in the Drosophila Visual System

Forward genetic screens in model organisms are an attractive means to identify those genes involved in any complex biological process, including neural circuit assembly. Although mutagenesis screens are readily performed to saturation, gene identification rarely is, being limited by the considerable effort generally required for positional cloning. Here, we apply a systematic positional cloning strategy to identify many of the genes required for neuronal wiring in the Drosophila visual system. From a large-scale forward genetic screen selecting for visual system wiring defects with a normal retinal pattern, we recovered 122 mutations in 42 genetic loci. For 6 of these loci, the underlying genetic lesions were previously identified using traditional methods. Using SNP-based mapping approaches, we have now identified 30 additional genes. Neuronal phenotypes have not previously been reported for 20 of these genes, and no mutant phenotype has been previously described for 5 genes. The genes encode a variety of proteins implicated in cellular processes such as gene regulation, cytoskeletal dynamics, axonal transport, and cell signalling. We conducted a comprehensive phenotypic analysis of 35 genes, scoring wiring defects according to 33 criteria. This work demonstrates the feasibility of combining large-scale gene identification with large-scale mutagenesis in Drosophila, and provides a comprehensive overview of the molecular mechanisms that regulate visual system wiring

Exercise interventions for smoking cessation

Background Taking regular exercise, whether cardiovascular‐type exercise or resistance exercise, may help people to give up smoking, particularly by reducing cigarette withdrawal symptoms and cravings, and by helping to manage weight gain. Objectives To determine the effectiveness of exercise‐based interventions alone, or combined with a smoking cessation programme, for achieving long‐term smoking cessation, compared with a smoking cessation intervention alone or other non‐exercise intervention. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register for studies, using the term 'exercise' or 'physical activity' in the title, abstract or keywords. The date of the most recent search was May 2019. Selection criteria We included randomised controlled trials that compared an exercise programme alone, or an exercise programme as an adjunct to a cessation programme, with a cessation programme alone or another non‐exercise control group. Trials were required to recruit smokers wishing to quit or recent quitters, to assess abstinence as an outcome and have follow‐up of at least six months. Data collection and analysis We followed standard Cochrane methods. Smoking cessation was measured after at least six months, using the most rigorous definition available, on an intention‐to‐treat basis. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for smoking cessation for each study, where possible. We grouped eligible studies according to the type of comparison, as either smoking cessation or relapse prevention. We carried out meta‐analyses where appropriate, using Mantel‐Haenszel random‐effects models. Main results We identified 24 eligible trials with a total of 7279 adult participants randomised. Two studies focused on relapse prevention among smokers who had recently stopped smoking, and the remaining 22 studies were concerned with smoking cessation for smokers who wished to quit. Eleven studies were with women only and one with men only. Most studies recruited fairly inactive people. Most of the trials employed supervised, group‐based cardiovascular‐type exercise supplemented by a home‐based exercise programme and combined with a multi‐session cognitive behavioural smoking cessation programme. The comparator in most cases was a multi‐session cognitive behavioural smoking cessation programme alone. Overall, we judged two studies to be at low risk of bias, 11 at high risk of bias, and 11 at unclear risk of bias. Among the 21 studies analysed, we found low‐certainty evidence, limited by potential publication bias and by imprecision, comparing the effect of exercise plus smoking cessation support with smoking cessation support alone on smoking cessation outcomes (RR 1.08, 95% CI 0.96 to 1.22; I2 = 0%; 6607 participants). We excluded one study from this analysis as smoking abstinence rates for the study groups were not reported. There was no evidence of subgroup differences according to the type of exercise promoted; the subgroups considered were: cardiovascular‐type exercise alone (17 studies), resistance training alone (one study), combined cardiovascular‐type and resistance exercise (one study) and type of exercise not specified (two studies). The results were not significantly altered when we excluded trials with high risk of bias, or those with special populations, or those where smoking cessation intervention support was not matched between the intervention and control arms. Among the two relapse prevention studies, we found very low‐certainty evidence, limited by risk of bias and imprecision, that adding exercise to relapse prevention did not improve long‐term abstinence compared with relapse prevention alone (RR 0.98, 95% CI 0.65 to 1.47; I2 = 0%; 453 participants). Authors' conclusions There is no evidence that adding exercise to smoking cessation support improves abstinence compared with support alone, but the evidence is insufficient to assess whether there is a modest benefit. Estimates of treatment effect were of low or very low certainty, because of concerns about bias in the trials, imprecision and publication bias. Consequently, future trials may change these conclusions.PLAIN LANGUAGE SUMMARY: Can exercise help people quit smoking? Background We reviewed the evidence about whether exercise helps people who want to quit smoking, or have recently stopped smoking, to stop smoking for at least six months. Taking regular exercise may help people give up smoking by helping with cigarette withdrawal and cravings, and by helping them to manage weight gain, which can be a concern among people trying to quit. Study characteristics We found 24 studies with a total of 7279 people. Two studies focused on helping those who had recently stopped smoking and the rest of the studies included current smokers who wished to quit. All the studies were conducted with adults. Eleven studies were with women only and one with men only. Most studies recruited fairly inactive people. Most studies offered supervised and group‐based, aerobic‐type exercise. The evidence is up‐to‐date to May 2019. Key results When we combined the results of 21 studies (6607 participants) which compared exercise and smoking‐cessation programmes to smoking cessation programmes alone, there was no evidence that exercise increased quit rates at six months or longer. There was no evidence that the effect was different for different types of exercise. When we combined results from two studies (453 participants), there was no evidence that exercise helped people who had recently quit to stay quit. Quality of evidence We judged the quality of evidence for whether exercise programmes help people quit smoking as low certainty, suggesting that future research could change these results. The low certainty is because we cannot rule out chance as an explanation for the suggested slight benefit. It could be that exercise may not help at all, or it could be that supporting people to do exercise modestly increases quit rates. We do not know which of these is true. We also consider that a good number of the trials may be biased. We have concerns that small studies which found smaller effects were less likely to be published than small studies which found bigger effects, making the average result misleading. We judged the evidence from two studies examining whether exercise helps people to avoid relapse to smoking to be of very low certainty, again suggesting that more research is needed. This is due to imprecision of the estimated effects and a high risk of bias in the methods used by one of the studies

Immunotherapy of type-1 allergies with virus-like particles and CpG-motifs

Immunotherapy of type-I-allergies is regarded as the most efficient treatment option besides allergen avoidance. Different forms of allergen preparations are used as well as different routes of application. Virus-like particles represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances immune cell activation. This article will focus on the function of virus-like particles loaded with DNA rich in CpG-motifs and discuss clinical experience in treatment of allergic rhinitis. Evidence will be presented that clinically effective treatment can be obtained even in the absence of allergens. Results encourage further investigation of virus-like particles and CpG-motifs in immunotherapy, either as a stand alone product, or as adjuvants for allergen-specific immunotherapy

Is The Allergen Really Needed in Allergy Immunotherapy?

Immunotherapy for type I allergies is well established and is regarded to be the most efficient treatment option besides allergen avoidance. As of today, different forms of allergen preparations are used in this regard, as well as different routes of application. Virus-like particles (VLPs) represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances activation of innate as well as adaptive immune responses. CpG motifs represent intensively investigated and potent direct stimulators of plasmacytoid dendritic cells and B cells, while T cell responses are enhanced indirectly through increased antigen presentation and cytokine release. This article will focus on the function of VLPs loaded with DNA rich in nonmethylated CG motifs (CpGs) and the clinical experience gained in the treatment of allergic rhinitis, demonstrating clinical efficacy also if administered without allergens. Several published studies have demonstrated a beneficial impact on allergic symptoms by treatment with CpG-loaded VLPs. Subcutaneous injection of VLPs loaded with CpGs was tested with or without the adjuvant alum in the presence or absence of an allergen. The results encourage further investigation of VLPs and CpG motifs in immunotherapy, either as a stand-alone product or as adjuvants for allergen-specific immunotherapy

Cathodal HD-tDCS on the right V5 improves motion perception in humans

Brain lesions in the visual associative cortex are known to impair visual perception, i.e., the capacity to correctly perceive different aspects of the visual world, such as motion, color, or shapes. Visual perception can be influenced by non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). In a recently developed technique called high definition (HD) tDCS, small HD-electrodes are used instead of the sponge electrodes in the conventional approach. This is believed to achieve high focality and precision over the target area. In this paper we tested the effects of cathodal and anodal HD-tDCS over the right V5 on motion and shape perception in a single blind, within-subject, sham controlled, cross-over trial. The purpose of the study was to prove the high focality of the stimulation only over the target area. Twenty one healthy volunteers received 20 min of 2 mA cathodal, anodal and sham stimulation over the right V5 and their performance on a visual test was recorded. The results showed significant improvement in motion perception in the left hemifield after cathodal HD-tDCS, but not in shape perception. Sham and anodal HD-tDCS did not affect performance. The specific effect of influencing performance of visual tasks by modulating the excitability of the neurons in the visual cortex might be explained by the complexity of perceptual information needed for the tasks. This provokes a "noisy" activation state of the encoding neuronal patterns. We speculate that in this case cathodal HD-tDCS may focus the correct perception by decreasing global excitation and thus diminishing the "noise" below threshold