Explore the vast range of titles available.

Differential evolution (DE) is an efficient global optimization algorithm. However, due to its random properties, some individuals may mutate in the direction of deviating from the theoretical global optima, failing to evolve and wasting a lot of computing resources. Moreover, there is an imbalance between exploration and exploitation in mutation strategies. For these shortcomings, we propose an adaptive mutation strategy correction framework (AMSC) for DEs. In this framework, the population is firstly split into superior subpopulation and disadvantaged subpopulation. Two types of auxiliary mutant vectors based on the direction information are designed to respectively enhance the exploration ability and exploitation ability of these two subpopulations, so as to improve the search efficiency. Moreover, for achieving the proper balance between exploration and exploitation in DEs, we propose an adaptive cooperative rule for the above two auxiliary vectors based on the actual crossover rates. This rule controls the relative size of two subgroups to determine the proportion of two types of auxiliary vectors used in the whole population. To evaluate the performance of AMSC framework, we have introduced into eight original DEs and carried out comparative experiments on four practical problems and 59 test functions from CEC 2014 and CEC 2017 benchmark suites. The experiments demonstrate that the AMSC framework can increase DEs’ performance dramatically.

Dengue is the most rapidly expanding arboviral disease in India. Aedes aegypti is the primary vector of dengue fever. Chemical insecticides have long been used in the vector control programmes along with other control measures. However, continuous use of insecticides targeting Ae. aegypti may lead to development of insecticide resistance. Though resistance in Ae. aegypti has been reported, the mutation in ace-1 gene associated with temephos resistance is not reported in natural populations. The present study aims to evaluate the susceptibility/resistance status of Ae. aegypti to temephos from three districts of Tamil Nadu. Ae. aegypti larvae were sampled from different locations in three districts, viz., Dharmapuri, Salem and Namakkal. The standard WHO larval bioassay, biochemical assays and spotting of specific mutation (G119S) in the acetylcholinesterase gene, which is associated with organophosphate resistance, were carried out by PCR and sequencing. The results showed that larvae from Namakkal (NKL) population had an alteration in their susceptibility status (RR = 6.9 fold), while the other populations were moderately susceptible to insecticides. Biochemical assay showed increased activity for α- and β-esterase in NKL, as well as evidence of acetylcholinesterase insensitivity. G119S mutation was detected in this population with high frequency of 0.24. The high activity of esterase, mixed-function oxidase (MFO) and ace-1 mutation frequency were closely associated with temephos resistance. Early detection of resistance alleles in natural vector population could be useful for the successful implementation of insecticide resistance management strategies. The results of this study provide baseline data on temephos resistance in Ae. aegypti populations.

According to the actual requirements, profile and rolling energy consumption are selected as objective functions of rolling schedule optimization for tandem cold rolling. Because of mechanical wear, roll diameter has some uncertainty during the rolling process, ignoring which will cause poor robustness of rolling schedule. In order to solve this problem, a robust multi-objective optimization model of rolling schedule for tandem cold rolling was established. A differential evolution algorithm based on the evolutionary direction was proposed. The algorithm calculated the horizontal angle of the vector, which was used to choose mutation vector. The chosen vector contained converging direction and it changed the random mutation operation in differential evolution algorithm. Efficiency of the proposed algorithm was verified by two benchmarks. Meanwhile, in order to ensure that delivery thicknesses have descending order like actual rolling schedule during evolution, a modified Latin Hypercube Sampling process was proposed. Finally, the proposed algorithm was applied to the model above. Results showed that profile was improved and rolling energy consumption was reduced compared with the actual rolling schedule. Meanwhile, robustness of solutions was ensured.

Although dendritic cell (DC)-based immunotherapy is considered a promising approach for cancer treatment, a large quantity of DC vaccine is required for effective sensitization/activation of immune cells because of the poor migratory ability of administered DCs into regional lymphoid tissue. In this study, we created a DC vaccine sufficiently transduced with CC chemokine receptor-7 gene (CCR7/DCs) by applying RGD fiber-mutant adenovirus vector (AdRGD), and investigated its immunological characteristics and therapeutic efficacy. CCR7/DCs acquired strong chemotactic activity for CC chemokine ligand-21 (CCL21) and exhibited an immunophenotype similar to mature DCs but not immature DCs with regard to major histocompatibility complex/costimulatory molecule-expression levels and allogenic T cell proliferation-stimulating ability, while maintaining inherent endocytotic activity. Importantly, CCR7/DCs injected intradermally into mice could accumulate in draining lymph nodes about 5.5-fold more efficiently than control AdRGD-applied DCs. Reflecting these properties of CCR7/DCs, DC vaccine genetically engineered to simultaneously express endogenous antigen and CCR7 could elicit more effective antigen-specific immune response in vivo using a lower dosage than DC vaccine transduced with antigen alone. Therefore, the application of CCR7/DCs having positive migratory ability to lymphoid tissues may contribute to reduction of efforts and costs associated with DC vaccine preparation by considerably reducing the DC vaccine dosage needed to achieve effective treatment by DC-based immunotherapy.

Dominant intermediate Charcot-Marie-Tooth disease type C（DI-CMTC） is a dominantly inherited neuropathy that has been classified primarily based on motor conduction velocity tests but is now known to involve axonal and demyelination features.DI-CMTC is linked to tyrosyl-t RNA synthetase（YARS）-associated neuropathies,which are caused by E196 K and G41 R missense mutations and a single de novo deletion（153-156 del VKQV）.It is well-established that these YARS mutations induce neuronal dysfunction,morphological symptoms involving axonal degeneration,and impaired motor performance.The present study is the first to describe a novel mouse model of YARS-mutation-induced neuropathy involving a neuron-specific promoter with a deleted mitochondrial targeting sequence that inhibits the expression of YARS protein in the mitochondria.An adenovirus vector system and in vivo techniques were utilized to express YARS fusion proteins with a Flag-tag in the spinal cord,peripheral axons,and dorsal root ganglia.Following transfection of YARS-expressing viruses,the distributions of wild-type（WT） YARS and E196 K mutant proteins were compared in all expressed regions; G41 R was not expressed.The proportion of Flag/green fluorescent protein（GFP） double-positive signaling in the E196 K mutant-type mice did not significantly differ from that of WT mice in dorsal root ganglion neurons.All adenovirus genes,and even the empty vector without the YARS gene,exhibited GFP-positive signaling in the ventral horn of the spinal cord because GFP in an adenovirus vector is driven by a cytomegalovirus promoter.The present study demonstrated that anatomical differences in tissue can lead to dissimilar expressions of YARS genes.Thus,use of this novel animal model will provide data regarding distributional defects between mutant and WT genes in neurons,the DICMTC phenotype,and potential treatment approaches for this disease.

Semliki Forest virus vectors (SFV) have been developed for efficient transgene expression to result in high receptor yields(50-200 pmol receptor/mg protein) in a variety of mammalian host cells. Transfer of the SFV technology to mammalian cells growing in suspension cultures has made it feasible to produce hundreds of milligrams of receptor proteins in a short time. Large-scale production, however, raises the questions of the safety of handling virally infected cells for down-stream processing. Analysis of cell culture medium and SFV-infected cells revealed that some infectious particles were still present. Replacement of virus-containing medium at 2 h post-infection efficiently removed the majority of infectious replication-deficient SFV particles. Washes with PBS further reduced the number of infectious particles significantly both in the medium and associated with cells to levels that allowed safe handling of SFV-infected cells outside the cell culture facility for biochemical, pharmacological, or electrophysiological assays or down-stream processes in connection to receptor purification. Furthermore, engineering of novel temperature-sensitive mutant SFV vectors resulted in temperature-controlled transgene expression, which completely eliminates the risk of contaminating laboratory personnel.

Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which dominant diseases exert their effects is often experimentally challenging and resource intensive, but is essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated by conventional gene therapy, whereas DN and GOF mechanisms may require gene editing or targeting by small molecules. Moreover, pathogenic missense mutations that act via DN and GOF mechanisms are more difficult to identify than those that act via LOF using nearly all currently available variant effect predictors. Here, we introduce a tripartite statistical model made up of support vector machine binary classifiers trained to predict whether human protein coding genes are likely to be associated with DN, GOF, or LOF molecular disease mechanisms. We test the utility of the predictions by examining biologically and clinically meaningful properties known to be associated with the mechanisms. Our results strongly support that the models are able to generalise on unseen data and offer insight into the functional attributes of proteins associated with different mechanisms. We hope that our predictions will serve as a springboard for researchers studying novel variants and those of uncertain clinical significance, guiding variant interpretation strategies and experimental characterisation. Predictions for the human UniProt reference proteome are available at https://osf.io/z4dcp/ .

Long-lasting insecticidal nets (LLINs) are the primary malaria prevention tool, but their effectiveness is threatened by pyrethroid resistance. We embedded a pragmatic cluster-randomised trial into Uganda's national LLIN campaign to compare conventional LLINs with those containing piperonyl butoxide (PBO), a synergist that can partially restore pyrethroid susceptibility in mosquito vectors. 104 health sub-districts, from 48 districts in Uganda, were randomly assigned to LLINs with PBO (PermaNet 3.0 and Olyset Plus) and conventional LLINs (PermaNet 2.0 and Olyset Net) by proportionate randomisation using an iterative process. At baseline 6, 12, and 18 months after LLIN distribution, cross-sectional surveys were done in 50 randomly selected households per cluster (5200 per survey); a subset of ten households per cluster (1040 per survey) were randomly selected for entomological surveys. The primary outcome was parasite prevalence by microscopy in children aged 2–10 years, assessed in the as-treated population at 6, 12, and 18 months. This trial is registered with ISRCTN, ISRCTN17516395. LLINs were delivered to households from March 25, 2017, to March 18, 2018, 32 clusters were randomly assigned to PermaNet 3.0, 20 to Olyset Plus, 37 to PermaNet 2.0, and 15 to Olyset Net. In the as-treated analysis, three clusters were excluded because no dominant LLIN was received, and four clusters were reassigned, resulting in 49 PBO LLIN clusters (31 received PermaNet 3.0 and 18 received Olyset Plus) and 52 non-PBO LLIN clusters (39 received PermaNet 2.0 and 13 received Olyset Net). At 6 months, parasite prevalence was 11% (386/3614) in the PBO group compared with 15% (556/3844) in the non-PBO group (prevalence ratio [PR] adjusted for baseline values 0·74, 95% CI 0·62–0·87; p=0·0003). Parasite prevalence was similar at month 12 (11% vs 13%; PR 0·73, 95% CI 0·63–0·85; p=0·0001) and month 18 (12% vs 14%; PR 0·84, 95% CI 0·72–0·98; p=0·029). In Uganda, where pyrethroid resistance is high, PBO LLINs reduced parasite prevalence more effectively than did conventional LLINs for up to 18 months. This study provides evidence needed to support WHO's final recommendation on use of PBO LLINs. The Against Malaria Foundation, UK Department for International Development, Innovative Vector Control Consortium, and Bill and Melinda Gates Foundation.

Background There is evidence that the knockdown resistance gene ( Kdr ) L1014F and acetylcholinesterase-1 gene ( Ace-1 R ) G119S mutations involved in pyrethroid and carbamate resistance in Anopheles gambiae influence malaria transmission in sub-Saharan Africa. This is likely due to changes in the behaviour, life history and vector competence and capacity of An. gambiae . In the present study, performed as part of a two-arm cluster randomized controlled trial evaluating the impact of household screening plus a novel insecticide delivery system (In2Care Eave Tubes), we investigated the distribution of insecticide target site mutations and their association with infection status in wild An. gambiae sensu lato (s.l.) populations. Methods Mosquitoes were captured in 40 villages around Bouaké by human landing catch from May 2017 to April 2019. Randomly selected samples of An. gambiae s.l. that were infected or not infected with Plasmodium sp. were identified to species and then genotyped for Kdr L1014F and Ace-1 R G119S mutations using quantitative polymerase chain reaction assays. The frequencies of the two alleles were compared between Anopheles coluzzii and Anopheles gambiae and then between infected and uninfected groups for each species . Results The presence of An. gambiae (49%) and An. coluzzii (51%) was confirmed in Bouaké. Individuals of both species infected with Plasmodium parasites were found. Over the study period, the average frequency of the Kdr L1014F and Ace-1 R G119S mutations did not vary significantly between study arms. However, the frequencies of the Kdr L1014F and Ace-1 R G119S resistance alleles were significantly higher in An. gambiae than in An. coluzzii [odds ratio (95% confidence interval): 59.64 (30.81–131.63) for Kdr , and 2.79 (2.17–3.60) for Ace-1 R ]. For both species, there were no significant differences in Kdr L1014F or Ace-1 R G119S genotypic and allelic frequency distributions between infected and uninfected specimens ( P  > 0.05). Conclusions Either alone or in combination, Kdr L1014F and Ace-1 R G119S showed no significant association with Plasmodium infection in wild An. gambiae and An. coluzzii , demonstrating the similar competence of these species for Plasmodium transmission in Bouaké. Additional factors including behavioural and environmental ones that influence vector competence in natural populations, and those other than allele measurements (metabolic resistance factors) that contribute to resistance, should be considered when establishing the existence of a link between insecticide resistance and vector competence. Graphical Abstract

Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and mosquito-borne diseases, including malaria and dengue. They exert toxic effects by altering the function of voltage-gated sodium channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of pyrethroids for vector control is the emergence of mosquito resistance to pyrethroids worldwide. Here, we report the successful expression of a sodium channel, AaNa ᵥ1–1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine sodium channel mutations that are associated with pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNa ᵥ1–1 sensitivity to pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed pyrethroid-receptor site in the house fly sodium channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of pyrethroid action and resistance as well as the high selectivity of pyrethroids on insect vs. mammalian sodium channels. Results from this study could impact future prediction and monitoring of pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.