Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons

<p>Abstract</p> <p>Background</p> <p>A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD.</p> <p>Results</p> <p>Here, we performed a large-scale RNA interference screen in <it>C. elegans </it>strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an <it>in vivo </it>model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified.</p> <p>Conclusions</p> <p>Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.</p

Designing effective control of dengue with combined interventions

Viruses transmitted by Aedes mosquitoes, such as dengue, Zika, and chikungunya, have expanding ranges and seem unabated by current vector control programs. Effective control of these pathogens likely requires integrated approaches. We evaluated dengue management options in an endemic setting that combine novel vector control and vaccination using an agent-based model for Yucatán, Mexico, fit to 37 y of data. Our intervention models are informed by targeted indoor residual spraying (TIRS) experiments; trial outcomes and World Health Organization (WHO) testing guidance for the only licensed dengue vaccine, CYD-TDV; and preliminary results for in-development vaccines. We evaluated several implementation options, including varying coverage levels; staggered introductions; and a one-time, large-scale vaccination campaign. We found that CYD-TDV and TIRS interfere: while the combination outperforms either alone, performance is lower than estimated from their separate benefits. The conventional model hypothesized for in-development vaccines, however, performs synergistically with TIRS, amplifying effectiveness well beyond their independent impacts. If the preliminary performance by either of the in-development vaccines is upheld, a one-time, large-scale campaign followed by routine vaccination alongside aggressive new vector control could enable short-term elimination, with nearly all cases avoided for a decade despite continuous dengue reintroductions. If elimination is impracticable due to resource limitations, less ambitious implementations of this combination still produce amplified, longer-lasting effectiveness over single-approach interventions

Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity

Technical document for the implementation of interventions based on generic operational scenarios for Aedes aegypti control

Traditional methods to control the Aedes vector have had only a limited and temporary impact on disease prevention, either because they are not very effective or their coverage is limited. This publication provides a framework for planning and implementing Aedes aegypti surveillance, prevention, and vector control activities through risk stratification to support the development of potential operational scenarios at the local level. A comprehensive table provides a snapshot of “Entomological indicators (available methods) and main entomological indexes for A. aegypti surveillance.

Efficacy of novel indoor residual spraying methods targeting pyrethroid-resistant aedes aegypti within experimental houses

Challenges in maintaining high effectiveness of classic vector control in urban areas has renewed the interest in indoor residual spraying (IRS) as a promising approach for Aedes-borne disease prevention. While IRS has many benefits, application time and intrusive indoor applications make its scalability in urban areas difficult. Modifying IRS to account for Ae. aegypti resting behavior, named targeted IRS (TIRS, spraying walls below 1.5 m and under furniture) can reduce application time; however, an untested assumption is that modifications to IRS will not negatively impact entomological efficacy. We conducted a comparative experimental study evaluating the residual efficacy of classically-applied IRS (as developed for malaria control) compared to two TIRS application methods using a carbamate insecticide against a pyrethroid-resistant, field-derived Ae. aegypti strain. We performed our study within a novel experimental house setting (n = 9 houses) located in Merida (Mexico), with similar layouts and standardized contents. Classic IRS application (insecti-cide applied to full walls and under furniture) was compared to: a) TIRS: insecticide applied to walls below 1.5 m and under furniture, and b) Resting Site TIRS (RS-TIRS): insecticide applied only under furniture. Mosquito mortality was measured eight times post-application (out to six months post-application) by releasing 100 Ae. aegypti females/house and collecting live and dead individuals after 24 hrs exposure. Compared to Classic IRS, TIRS and RS-TIRS took less time to apply (31% and 82% reduction, respectively) and used less insecticide (38% and 85% reduction, respectively). Mortality of pyrethroid-resistant Ae. aegypti did not significantly differ among the three IRS application methods up to two months post application, and did not significantly differ between Classic IRS and TIRS up to four months post application. These data illustrate that optimizing IRS to more efficiently target Ae. aegypti

House screening with insecticide-treated netting provides sustained reductions in domestic populations of Aedes aegypti in Merida, Mexico.

There is a need for effective methods to control Aedes aegypti and prevent the transmission of dengue, chikungunya, yellow fever and Zika viruses. Insecticide treated screening (ITS) is a promising approach, particularly as it targets adult mosquitoes to reduce human-mosquito contact. A cluster-randomised controlled trial evaluated the entomological efficacy of ITS based intervention, which consisted of the installation of pyrethroid-impregnated long-lasting insecticide-treated netting material fixed as framed screens on external doors and windows. A total of 10 treatment and 10 control clusters (100 houses/cluster) were distributed throughout the city of Merida, Mexico. Cross-sectional entomological surveys quantified indoor adult mosquito infestation at baseline (pre-intervention) and throughout four post-intervention (PI) surveys spaced at 6-month intervals corresponding to dry/rainy seasons over two years (2012-2014). A total of 844 households from intervention clusters (86% coverage) were protected with ITS at the start of the trial. Significant reductions in the indoor presence and abundance of Ae. aegypti adults (OR = 0.48 and IRR = 0.45, P<0.05 respectively) and the indoor presence and abundance of Ae. aegypti female mosquitoes (OR = 0.47 and IRR = 0.44, P<0.05 respectively) were detected in intervention clusters compared to controls. This high level of protective effect was sustained for up to 24 months PI. Insecticidal activity of the ITS material declined with time, with ~70% mortality being demonstrated in susceptible mosquito cohorts up to 24 months after installation. The strong and sustained entomological impact observed in this study demonstrates the potential of house screening as a feasible, alternative approach to a sustained long-term impact on household infestations of Ae. aegypti. Larger trials quantifying the effectiveness of ITS on epidemiological endpoints are warranted and therefore recommended

Deltamethrin resistance in Aedes aegypti results in treatment failure in Merida, Mexico

The operational impact of deltamethrin resistance on the efficacy of indoor insecticide applications to control Aedes aegypti was evaluated in Merida, Mexico. A randomized controlled trial quantified the efficacy of indoor residual spraying (IRS) against adult Ae. aegypti in houses treated with either deltamethrin (to which local Ae. aegypti expressed a high degree of resistance) or bendiocarb (to which local Ae. aegypti were fully susceptible) as compared to untreated control houses. All adult Ae. aegypti infestation indices during 3 months post-spraying were significantly lower in houses treated with bendiocarb compared to untreated houses (odds ratio < 0.75; incidence rate ratio < 0.65) whereas no statistically significant difference was detected between the untreated and the deltamethrin-treated houses. On average, bendiocarb spraying reduced Ae. aegypti abundance by 60% during a 3-month period. Results demonstrate that vector control efficacy can be significantly compromised when the insecticide resistance status of Ae. aegypti populations is not taken into consideration

Estimating absolute indoor density of Aedes aegypti using removal sampling

Exhaustive removal sampling represents a promising method for quantification of absolute indoor Aedes aegypti density, leading to improved entomological estimates of mosquito distribution. The study describes the use of sequential removal sampling to estimate absolute numbers of indoor resting Aedes in the city of Merida, Mexico. The study was performed in 200 houses based on recent occurrence of Aedes-borne viral illness in residents. The lack of a numerical association between relative and absolute density of adult Ae. aegypti represent a significant gap in vector surveillance. Merida is highly endemic for dengue and other Aedes-borne viruses.Bureau for Global HealthU.S Agency for International Development (USAID)US Centers for Disease Control and Prevention (CDC)Canadian Institutes of Health Research (CIHR

Insecticide-Treated House Screens to Reduce Infestations of Dengue Vectors

The public health importance of the endophilic mosquito Aedes aegypti increased dramatically in the recent decade, because it is the vector of dengue, chikungunya, Zika and yellow fever. The use of long-lasting insecticidal nets (LLINs) fixed on doors and windows, as insecticide-treated screening (ITS), is one innovative approach recently evaluated for Aedes control in South Mexico. From 2009 to 2014, cluster-randomised controlled trials were conducted in Acapulco and Merida. Intervention clusters received Aedes-proof houses (‘Casas a prueba de Aedes’) with ITS and were followed up during 2 years. Overall, results showed significant and sustained reductions on indoor adult vector densities in the treated clusters with ITS after 2 years: ca. 50% on the presence (OR ≤ 0.62, P < 0.05) and abundance (IRR ≤ 0.58, P < 0.05). ITS on doors and windows are ‘user-friendly’ tool, with high levels of acceptance, requiring little additional work or behavioural change by householders. Factors that favoured these interventions were (a) house construction, (b) high coverage achieved due to the excellent acceptance by the community and (c) collaboration of the vector control services; and only some operational complaints relating to screen fragility and the installation process. ITS is a housing improvement that should be part of the current paradigms for urban vector-borne disease control