Durability monitoring of long-lasting insecticidal (mosquito) nets (LLINs) in Madagascar: physical integrity and insecticidal activity

Abstract Background Long-lasting insecticidal mosquito nets (LLINs) are highly effective for malaria prevention. However, it is also clear that durability monitoring is essential to predict when, post-distribution, a net population, no longer meets minimum WHO standards and needs to be replaced. Following a national distribution campaign in 2013, we tracked two durability indicators, physical integrity and bio-efficacy at six and 12 months post-distribution. While the loss of net integrity during this period was in line with expectations for a one-year net life, bio-efficacy results suggested that nets were losing insecticidal effect faster than expected. The rate of bio-efficacy loss varied significantly between different net brands. Methods We tested 600 randomly selected LLINs, 200 from each of three net brands. Each brand came from different eco-epidemiological zones reflecting the original distribution scheme. Fabric integrity (size and number of holes) was quantified using the proportional hole index (pHI). A subsample of the nets, 134 new nets, 150 at six months and 124 at 12 months, were then tested for bio-efficacy using the World Health Organization (WHO) recommended method. Results Three net types, Netprotect®, Royalsentry® and Yorkool®, were followed. After six months, 54%, 39% and 45%, respectively, showed visible loss of integrity. The median pHI by type was estimated to be one, zero and one respectively. The percentage of damaged nets increased after 12 months such that 83.5%, 74% and 68.5%, had holes. The median pHI for each brand of nets was 47.5, 47 and 23. No significant difference in the estimated pHI at either six or 12 months was observed. There was a statistically significant difference in the proportion of hole size category between the three brands (χ 2 = 15.761, df = 4, P = 0.003). In cone bio-assays, mortality of new Yorkool® nets was surprisingly low (48.6%), mortality was 90.2% and 91.3% for Netprotect® and Royalsentry® (F (2, 131) = 81.59, P < 0.0001), respectively. At 12 month use, all tested nets were below the WHO threshold for replacement. Conclusion These findings suggest that there is a need for better net quality control before distribution. More frequent replacement of LLINs is probably not an option programmatically. Regardless of prior approval, LLIN durability monitoring for quality assessment as well as net loss following distribution is necessary to improve malaria control efforts

Substrate-Assisted Catalysis Unifies Two Families of Chitinolytic Enzymes

Hen egg-white lysozyme has long been the paradigm for enzymatic glycosyl hydrolysis with retention of configuration, with a protonated carboxylic acid and a deprotonated carboxylate participating in general acid-base catalysis. In marked contrast, the retaining chitin degrading enzymes from glycosyl hydrolase families 18 and 20 all have a single glutamic acid as the catalytic acid but lack a nucleophile on the enzyme. Both families have a catalytic (βα)8-barrel domain in common. X-ray structures of three different chitinolytic enzymes complexed with substrates or inhibitors identify a retaining mechanism involving a protein acid and the carbonyl oxygen atom of the substrate’s C2 N-acetyl group as the nucleophile. These studies unambiguously demonstrate the distortion of the sugar ring toward a sofa conformation, long postulated as being close to that of the transition state in glycosyl hydrolysis.

Encompassing new use cases - level 3.0 of the HUPO-PSI format for molecular interactions.

BACKGROUND: Systems biologists study interaction data to understand the behaviour of whole cell systems, and their environment, at a molecular level. In order to effectively achieve this goal, it is critical that researchers have high quality interaction datasets available to them, in a standard data format, and also a suite of tools with which to analyse such data and form experimentally testable hypotheses from them. The PSI-MI XML standard interchange format was initially published in 2004, and expanded in 2007 to enable the download and interchange of molecular interaction data. PSI-XML2.5 was designed to describe experimental data and to date has fulfilled this basic requirement. However, new use cases have arisen that the format cannot properly accommodate. These include data abstracted from more than one publication such as allosteric/cooperative interactions and protein complexes, dynamic interactions and the need to link kinetic and affinity data to specific mutational changes. RESULTS: The Molecular Interaction workgroup of the HUPO-PSI has extended the existing, well-used XML interchange format for molecular interaction data to meet new use cases and enable the capture of new data types, following extensive community consultation. PSI-MI XML3.0 expands the capabilities of the format beyond simple experimental data, with a concomitant update of the tool suite which serves this format. The format has been implemented by key data producers such as the International Molecular Exchange (IMEx) Consortium of protein interaction databases and the Complex Portal. CONCLUSIONS: PSI-MI XML3.0 has been developed by the data producers, data users, tool developers and database providers who constitute the PSI-MI workgroup. This group now actively supports PSI-MI XML2.5 as the main interchange format for experimental data, PSI-MI XML3.0 which additionally handles more complex data types, and the simpler, tab-delimited MITAB2.5, 2.6 and 2.7 for rapid parsing and download

Commencement Program, December (1998)

https://red.mnstate.edu/commencement/1169/thumbnail.jp

Phage T4 SegB protein is a homing endonuclease required for the preferred inheritance of T4 tRNA gene region occurring in co-infection with a related phage

Homing endonucleases initiate nonreciprocal transfer of DNA segments containing their own genes and the flanking sequences by cleaving the recipient DNA. Bacteriophage T4 segB gene, which is located in a cluster of tRNA genes, encodes a protein of unknown function, homologous to homing endonucleases of the GIY-YIG family. We demonstrate that SegB protein is a site-specific endonuclease, which produces mostly 3′ 2-nt protruding ends at its DNA cleavage site. Analysis of SegB cleavage sites suggests that SegB recognizes a 27-bp sequence. It contains 11-bp conserved sequence, which corresponds to a conserved motif of tRNA TψC stem-loop, whereas the remainder of the recognition site is rather degenerate. T4-related phages T2L, RB1 and RB3 contain tRNA gene regions that are homologous to that of phage T4 but lack segB gene and several tRNA genes. In co-infections of phages T4 and T2L, segB gene is inherited with nearly 100% of efficiency. The preferred inheritance depends absolutely on the segB gene integrity and is accompanied by the loss of the T2L tRNA gene region markers. We suggest that SegB is a homing endonuclease that functions to ensure spreading of its own gene and the surrounding tRNA genes among T4-related phages

Capturing variation impact on molecular interactions in the IMEx Consortium mutations data set

The current wealth of genomic variation data identified at nucleotide level presents the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Physical interactions between molecules are the linking steps underlying most, if not all, cellular processes. Understanding the effects that sequence variation has on a molecule's interactions is a key step towards connecting mechanistic characterization of nonsynonymous variation to phenotype. We present an open access resource created over 14 years by IMEx database curators, featuring 28,000 annotations describing the effect of small sequence changes on physical protein interactions. We describe how this resource was built, the formats in which the data is provided and offer a descriptive analysis of the data set. The data set is publicly available through the IntAct website and is enhanced with every monthly release

Sugar-fermenting yeast as an organic source of carbon dioxide to attract the malaria mosquito Anopheles gambiae s.s.

<p>Abstract</p> <p>Background</p> <p>Carbon dioxide (CO₂) plays an important role in the host-seeking process of opportunistic, zoophilic and anthropophilic mosquito species and is, therefore, commonly added to mosquito sampling tools. The African malaria vector <it>Anopheles gambiae sensu stricto </it>is attracted to human volatiles augmented by CO₂. This study investigated whether CO₂, usually supplied from gas cylinders acquired from commercial industry, could be replaced by CO₂derived from fermenting yeast (yeast-produced CO₂).</p> <p>Methods</p> <p>Trapping experiments were conducted in the laboratory, semi-field and field, with <it>An. gambiae s.s</it>. as the target species. MM-X traps were baited with volatiles produced by mixtures of yeast, sugar and water, prepared in 1.5, 5 or 25 L bottles. Catches were compared with traps baited with industrial CO₂. The additional effect of human odours was also examined. In the laboratory and semi-field facility dual-choice experiments were conducted. The effect of traps baited with yeast-produced CO₂on the number of mosquitoes entering an African house was studied in the MalariaSphere. Carbon dioxide baited traps, placed outside human dwellings, were also tested in an African village setting. The laboratory and semi-field data were analysed by a χ²-test, the field data by GLM. In addition, CO₂concentrations produced by yeast-sugar solutions were measured over time.</p> <p>Results</p> <p>Traps baited with yeast-produced CO₂caught significantly more mosquitoes than unbaited traps (up to 34 h post mixing the ingredients) and also significantly more than traps baited with industrial CO₂, both in the laboratory and semi-field. Adding yeast-produced CO₂to traps baited with human odour significantly increased trap catches. In the MalariaSphere, outdoor traps baited with yeast-produced or industrial CO₂+ human odour reduced house entry of mosquitoes with a human host sleeping under a bed net indoors. <it>Anopheles gambiae s.s</it>. was not caught during the field trials. However, traps baited with yeast-produced CO₂caught similar numbers of <it>Anopheles arabiensis </it>as traps baited with industrial CO₂. Addition of human odour increased trap catches.</p> <p>Conclusions</p> <p>Yeast-produced CO₂can effectively replace industrial CO₂for sampling of <it>An. gambiae s.s</it>.. This will significantly reduce costs and allow sustainable mass-application of odour-baited devices for mosquito sampling in remote areas.</p

Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women

BACKGROUND The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P = 0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P = 0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo.Supported by the International Partnership for Microbicides (a not-for-profit product-development partnership), which receives support from the Bill and Melinda Gates Foundation, Irish Aid, the Ministry of Foreign Affairs of Denmark, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation, the U.K. Department for International Development, the American people through the U.S. Agency for International Development, and the President’s Emergency Plan for AIDS Relief.http://www.nejm.org2017-06-01am2017Family Medicin

Learning to live together: mutualism between self-splicing introns and their hosts

Group I and II introns can be considered as molecular parasites that interrupt protein-coding and structural RNA genes in all domains of life. They function as self-splicing ribozymes and thereby limit the phenotypic costs associated with disruption of a host gene while they act as mobile DNA elements to promote their spread within and between genomes. Once considered purely selfish DNA elements, they now seem, in the light of recent work on the molecular mechanisms regulating bacterial and phage group I and II intron dynamics, to show evidence of co-evolution with their hosts. These previously underappreciated relationships serve the co-evolving entities particularly well in times of environmental stress