Parasitic Resistance Research Articles

Genetic diversity of United States Rambouillet, Katahdin and Dorper sheep

BackgroundManaging genetic diversity is critically important for maintaining species fitness. Excessive homozygosity caused by the loss of genetic diversity can have detrimental effects on the reproduction and production performance of a breed. Analysis of genetic diversity can facilitate the identification of signatures of selection which may contribute to the specific characteristics regarding the health, production and physical appearance of a breed or population. In this study, breeds with well-characterized traits such as fine wool production (Rambouillet, N = 745), parasite resistance (Katahdin, N = 581) and environmental hardiness (Dorper, N = 265) were evaluated for inbreeding, effective population size (Ne), runs of homozygosity (ROH) and Wright’s fixation index (FST) outlier approach to identify differential signatures of selection at 36,113 autosomal single nucleotide polymorphisms (SNPs).ResultsKatahdin sheep had the largest current Ne at the most recent generation estimated with both the GONe and NeEstimator software. The most highly conserved ROH Island was identified in Rambouillet with a signature of selection on chromosome 6 containing 202 SNPs called in an ROH in 50 to 94% of the individuals. This region contained the DCAF16, LCORL and NCAPG genes that have been previously reported to be under selection and have biological roles related to milk production and growth traits. The outlier regions identified through the FST comparisons of Katahdin with Rambouillet and Dorper contained genes with known roles in milk production and mastitis resistance or susceptibility, and the FST comparisons of Rambouillet with Katahdin and Dorper identified genes related to wool growth, suggesting these traits have been under natural or artificial selection pressure in these populations. Genes involved in the cytokine-cytokine receptor interaction pathways were identified in all FST breed comparisons, which indicates the presence of allelic diversity between these breeds in genomic regions controlling cytokine signaling mechanisms.ConclusionsIn this paper, we describe signatures of selection within diverse and economically important U.S. sheep breeds. The genes contained within these signatures are proposed for further study to understand their relevance to biological traits and improve understanding of breed diversity.

Improving CZTS/ZTO solar cell efficiency with inorganic BSF layers

Copper zinc tin sulfide (CZTS) thin-film solar cells have garnered significant attention in the solar energy sector. This study aims to enhance the performance of CZTS solar cells by replacing the conventional, toxic CdS buffer layer with Zn1−xSnxO (ZTO) for x = 0.2. Utilizing the one-dimensional solar cell capacitance simulator (SCAPS-1D) and informed by experimental data on the physical properties of the solar cell layers, we investigated the effects of thickness, doping density, and defect density of the CZTS absorber layer on the cell’s performance. Initially, an efficiency of 14.76% was achieved. To improve this efficiency, an inorganic back surface field (BSF) layer was incorporated to mitigate charge carrier recombination at the absorber/back contact metal interface. Various materials, including CuO, Cu2O , Mo S2 and Mo Se2 , were evaluated as potential BSF layers. Comparative analysis indicated that the inclusion of the BSF layer significantly enhances the solar cell efficiency, achieving up to 27% with Cu2O as the BSF material. Furthermore, the study included an analysis of temperature effects and parasitic resistances to comprehensively assess the solar cell’s performance.

Investigation on Anti‐plasmodial Agents Against wild‐type PfDHFR Through In Silico Computational Tools

AbstractMalaria is the most severe and common parasitic infection, with P. falciparum responsible for the majority of cases and deaths each year. As anti‐malarial drug resistance continues to increase, novel compounds with anti‐ P. falciparum activity must be identified. In search of a new molecule to cure the resistant malarial parasite, a total of 1,70,269 ligands from the Asinex BioDesign library 2021.2 were virtually screened using AutoDock Vina against wild‐type P. falciparum dihydrofolate reductase‐thymidylate synthase (PfDHFR‐TS). The computational molecular modeling investigations indicated the discovery of seventeen new compounds (2‐18) with higher binding energy compared to the PfDHFR‐TS inhibitor, pyrimethamine (1). Furthermore, the study employing drug‐likeness criteria and their ADMET profile suggested that these hits were the most promising drug candidates due to higher absorption and druggability. Furthermore, GROMACS 2023.4 was used to perform the molecular dynamics simulations on the foremost compound (2) having sufficient stability, leading to a key step towards the search of novel PfDHFR‐TS inhibitors against malaria.

Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development.

Malaria drug research and development efforts have resurged in the last decade following the decelerating rate of mortality and malaria cases in endemic regions. The inefficiency of malaria interventions is largely driven by the spreading resistance of the Plasmodium falciparum parasite to current drug regimens and that of the malaria vector, the Anopheles mosquito, to insecticides. In response to the new eradication agenda, drugs that act by breaking the malaria transmission cycle (transmission-blocking drugs), which has been recognized as an important and additional target for intervention, are being developed. These drugs take advantage of the susceptibility of Plasmodium during population bottlenecks before transmission (gametocytes) and in the mosquito vector (gametes, zygotes, ookinetes, oocysts, sporozoites). To date, compounds targeting stage V gametocytes predominate in the chemical library of transmission-blocking drugs, and some of them have entered clinical trials. The targeting of Plasmodium mosquito stages has recently renewed interest in the development of innovative malaria control tools, which hold promise for the application of compounds effective at these stages. In this review, we highlight the major achievements and provide an update on the research of transmission-blocking drugs, with a particular focus on their chemical scaffolds, antiplasmodial activity, and transmission-blocking potential.

Innovative Multistage ML-QSAR Models for Malaria: From Data to Discovery.

Malaria presents a significant challenge to global public health, with around 247 million cases estimated to occur annually worldwide. The growing resistance of Plasmodium parasites to existing therapies underscores the urgent need for new and innovative antimalarial drugs. This study leveraged artificial intelligence (AI) to tackle this complex challenge. We developed multistage Machine Learning Quantitative Structure-Activity Relationship (ML-QSAR) models to effectively analyze large datasets and predict the efficacy of chemical compounds against multiple life cycle stages of Plasmodium parasites. We then selected 16 compounds for experimental evaluation, six of which showed at least dual-stage inhibitory activity and one inhibited all life cycle stages tested. Moreover, explainable AI (XAI) analysis provided insights into critical molecular features influencing model predictions, thereby enhancing our understanding of compound interactions. This study not only empowers the development of advanced predictive AI models but also accelerates the identification and optimization of potential antiplasmodial compounds.

Indepth doping assessment of thick doped GaAs layer by scanning spreading resistance microscopy

Scanning spreading resistance microscopy (SSRM) measurements were performed on GaAs thick films grown by hydride vapor phase epitaxy technology under different growth conditions to evaluate their carrier concentrations. For this purpose, a calibration curve was established based on a multilayer staircase structure grown by molecular beam epitaxy. The dopant calibration range measured by secondary ion mass spectrometry is from 5 × 1016 to 1019 cm−3. An abnormal phenomenon in the calibration process was explained by taking into account the parasitic parallel resistance of the calibration samples. Finally, the calibration curve was used to quantitatively analyze the carriers inside the Zn doping p-type GaAs film from 4 × 1016 to 1018 cm−3 range. We demonstrate here the applicability of SSRM to the in-depth analysis of thick epilayers, providing new inputs for the control of thick film technologies.

Patent characteristics for leishmaniasis treatment as a basis for freedom-to-operate analysis

Among the main zoonoses with the highest morbidity burden is leishmaniasis. The parasite of the genus Leishmania is its etiological agent. There are three forms of the disease: cutaneous, mucocutaneous and visceral. Pentavalent antimonial drugs are used for leishmaniasis treatment, however toxic side effects and parasite resistance have been detected. Intellectual Property Rights (IPRs) protect inventions that promote benefits to society, and patents are particularly notable for preserving advancements in biotechnology. To introduce innovative technologies, it is necessary to analyze the elements and processes involved in the development of products that may be protected by IPRs. This process consists of product deconstruction into its elements for an intellectual property analysis to contemplate commercial viability, and to determine strategies to avoid infringing third party rights (Freedom-to-Operate approach). In this project, a sample of patents protecting treatments directed against leishmaniasis were evaluated in order to know their characteristics, and to establish useful elements for Freedom-to-operate strategies. Open access patent databases were used (The Lens, Google patents, Patentscope, among others), and relevant characteristics such as claims, owners, technology protection region, or year of application for protection were determined. The sample obtained includes patents from 1967 to 2023. The majority of patents were found to be located in countries such as Brazil or the United States, and described developments focused on compounds derived from chemical synthesis, polypeptides, extracts, antigens, or structural components of the parasite. There are several patents that have already expired and whose information can be freely used. The Bolar exemption would allow the use of information from these patents for regulatory compliance purposes. This study provides an overview of what has been patented for leishmaniasis treatment, and information on Freedom-to-operate focus.

Antimalarial efficacy test of the aqueous crude leaf extract of Coriandrum sativum Linn.: an in vivo multiple model experimental study in mice infected with Plasmodium berghei

BackgroundMalaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant’s malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice.MethodsThe plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences.ResultsNo toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract.ConclusionsThe results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended.

Quantitative tests of albendazole resistance in Caenorhabditis elegans beta-tubulin mutants

Benzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in the C. elegans beta-tubulin gene ben-1 and orthologs in parasitic species. However, variants in ben-1 alone do not explain the differences in BZ responses across parasite populations. Here, we examined the roles of five C. elegans beta-tubulin genes (tbb-1, mec-7, tbb-4, ben-1, and tbb-6) in the BZ response as well as to determine if another beta-tubulin acts redundantly with ben-1. We generated C. elegans strains with a loss of each beta-tubulin gene, as well as strains with a loss of tbb-1, mec-7, tbb-4, or tbb-6 in a genetic background that also lacks ben-1. We found that the loss of ben-1 conferred the maximum level of resistance following exposure to a single concentration of albendazole, and the loss of a second beta-tubulin gene did not alter the level of resistance. However, additional traits other than larval development could be affected by the loss of additional beta-tubulins, and the roles of other beta-tubulin genes might be revealed at different albendazole concentrations. Therefore, further work is needed to fully define the possible roles of other beta-tubulin genes in the BZ response.

Wireless Power Transfer System with Constant Voltage/Constant Current Output Performance

Aiming at the problem of unstable output voltage and output current caused by load fluctuation, this paper starts from the perspective of system topology and control strategy for analysis. First, the output characteristics of LCL-S (inductor-capacitor-inductor and series), LCL-P (inductor-capacitor-inductor and parallel), LCL-LCL (inductor-capacitor-inductor and inductor-capacitor-inductor), and LCL-LCC (inductor-capacitor-inductor and inductor-capacitor-capacitor) compensation topologies are analyzed. Combining the advantages of LCL-S and LCL-LCL compensation topology output characteristics, an LCL-LCL/S compensation topology is constructed, and its topology is optimized. Then the influence of parasitic resistance on the output characteristics of LCL-LCL/S compensation topology is derived. A control strategy of primary side regulation is proposed to address the issue of unstable output voltage and current caused by parasitic resistance in the system under variable loads. This method can effectively improve the stability of the output voltage and output current of the wireless power transfer system in the LCL-LCL/S compensation topology under load fluctuations. Finally, a set of experimental prototypes is built to verify the correctness of the theoretical analysis.

Emerging antihelminthic drug resistance: Implications for mass drug administration program

Soil transmitted helminth infections and lymphatic diseases are significant neglected tropical diseases that pose public health challenges in both low and middle economic populations. These parasites live in the human intestine, consuming nutrients intended for the human body. Research findings suggest that the development of resistance to antihelminthic drugs is notably delayed when a combination of medications is used. Antihelminthic tablets are excellent candidates for mass drug administration (MDA) because they are highly effective and safe. Their reliability and safety make them well-suited for widespread distribution among populations at risk of parasitic worm infections. School-based deworming programs have proven successful in providing access to large numbers of children, offering them antihelminthic treatments in various settings. MDA is a key strategy in the global effort to eliminate lymphatic filariasis, with school-based deworming being an integral part of this approach. However, the longer the program lasts, the higher the risk of treatment failure is due to potential parasite resistance. Therefore, there is an urgent call for new methods to monitor and combat the emergence of drug resistance. While MDA has shown significant impact on various helminth infections, the threat of resistance remains a concern. Although there is currently no concrete evidence of resistance to common antihelminthics in humans, experiences from other infectious diseases, particularly in livestock, serve as a cautionary tale against over-reliance on these drugs for controlling lymphatic filariasis.

Efficiency enhancement of novel ITO/ZnSe/CNTs thin film solar cell

This study presents a novel photovoltaic cell design utilizing a layered structure of Indium Tin Oxide (ITO), Zinc Selenide (ZnSe), and Carbon Nanotubes (CNTs) for enhanced solar energy conversion. We employed the Solar Cell Capacity Simulator (SCAPS-1D) to model and optimize the device under AM 1.5 spectrum conditions. Our simulations systematically investigated the influence of key parameters including layer thicknesses, doping concentrations, temperature, back contact work function, and parasitic resistances on cell performance. The optimized structure demonstrated a theoretical power conversion efficiency of 29.91%, with an open-circuit voltage (Voc) of 799 mV, a short-circuit current density (Jsc) of 43.49 mA/cm², and a fill factor (FF) of 86.02%. These promising results are attributed to the synergistic combination of CNTs' broad spectral absorption, ZnSe's effective charge separation, and optimized layer properties. We found that the CNT absorber layer's doping concentration significantly impacted cell performance, with an optimal value of 10¹⁷ cm⁻³. The ZnSe buffer layer thickness showed minimal effect on efficiency within the studied range. Temperature increases from 300 K to 400 K led to a significant efficiency drop from 33.97% to 24.65%, primarily due to Voc reduction. While these results represent idealized conditions and upper theoretical limits, they provide valuable insights for the potential of CNT-based solar cells. This study offers a roadmap for future experimental work in high-efficiency thin-film photovoltaics, highlighting the promise of novel material combinations and the importance of device architecture optimization.

Empirical design and comprehensive analysis of multiport converter in distributed generation enabled microgrids

Distributed generation-enabled microgrids are a revolutionary approach for the energy paradigms that will transform the ways of generation, distribution, and utilization. A decentralized approach to energy generation in microgrids results in the robustness and independence of energy networks. Empowerment of the communities to take control of energy requirements with multiport converter-based microgrids promotes sustainability, efficiency, reduced losses, and increased resilience against the evolving trends of the energy sector. In this research, a hybrid energy-integrated multiport converter is designed and analyzed under its various modes of operation. Rapid transitions from one energy source to another are attained within 0.4μs to feed the load at a steady state voltage of 400 V, and within 0.15μs to charge the energy storage system at a steady state voltage of 48 V which indicates the robustness and independence of energy systems via this proposed approach. The resilience of the microgrid is obtained because of this rapid trans Moreover, the proposed converter offers a voltage gain of 8.3 with 96 % efficiency making it sustainable for maximization of renewable energy. In addition, the resilience of the proposed converter is exhibited through high power densities at power losses of not more than 7.5 % making it an innovative candidate for hybrid energy systems as compared to existing technologies. Simulation scenarios are validated through mathematical analysis, proving their effectiveness in distributed generation-enabled microgrids. The proposed research model is effective in a real environment because of the minimal effects of parasitic resistance, reduced total harmonic distortion under different loads, and negligible electromagnetic interferences, demonstrated through simulations.

Effect of Si substrate conductivity on surface acoustic wave resonator

A surface acoustic wave (SAW) filter’s bandwidth and quality are determined by its resonators’ electromechanical coupling coefficient (k2) and impedance ratio (IR). Research commonly focuses on the effects of piezoelectric material and cutting direction on these parameters. This paper investigates the effect of the conductivity of the Si substrate on k2 and IR through finite element method (FEM) simulations. A new model based on the modified Butterworth-van-Dyke (MBVD) model is presented. This new model takes into account the substrate parasitic capacitance and resistance to predict resonator performance on low resistivity (LR) Si piezoelectric on insulator (POI) substrates. Both high resistivity (HR) Si and LR-Si are utilized to fabricate POI SAW resonators, which are subsequently tested. The high conductivity of the Si support layer leads to a decrease in both k2 and IR. By employing Si substrates with different resistances during fabrication, it becomes possible to manufacture resonators with varying k2 values, thus meeting diverse bandwidth requirements for filters.

Genomic Regions Associated with Resistance to Gastrointestinal Parasites in Australian Merino Sheep.

The objective of this study was to identify genomic regions and genes associated with resistance to gastrointestinal nematodes in Australian Merino sheep in Uruguay, using the single-step GWAS methodology (ssGWAS), which is based on genomic estimated breeding values (GEBVs) obtained from a combination of pedigree, genomic, and phenotypic data. This methodology converts GEBVs into SNP effects. The analysis included 26,638 animals with fecal egg count (FEC) records obtained in two independent parasitic cycles (FEC1 and FEC2) and 1700 50K SNP genotypes. The comparison of genomic regions was based on genetic variances (gVar(%)) explained by non-overlapping regions of 20 SNPs. For FEC1 and FEC2, 18 and 22 genomic windows exceeded the significance threshold (gVar(%) ≥ 0.22%), respectively. The genomic regions with strong associations with FEC1 were located on chromosomes OAR 2, 6, 11, 21, and 25, and for FEC2 on OAR 5, 6, and 11. The proportion of genetic variance attributed to the top windows was 0.83% and 1.9% for FEC1 and FEC2, respectively. The 33 candidate genes shared between the two traits were subjected to enrichment analysis, revealing a marked enrichment in biological processes related to immune system functions. These results contribute to the understanding of the genetics underlying gastrointestinal parasite resistance and its implications for other productive and welfare traits in animal breeding programs.

Trombos de Strongylus vulgaris aderidos na valva semilunar aórtica e aorta em equino

Intestinal parasitic infections are one of the main debilitating conditions that affect horses. Grazing, natural habits, breeding methods and the unrestrained use of dewormers favor the development of parasites, make their control difficult and cause parasite resistance to commonly used active ingredients. Parasites, in addition to causing economic losses directly related to pathologies and clinical manifestations such as reduced performance and development of the affected animals, can favor the development of other conditions such as colic syndrome, among others. Among the species that affect the equines, the most prominent parasite is Strongylus vulgaris, which, during its evolutionary cycle, migrates through the animal’s body through blood vessels, and can affect different systems, explaining its important pathogenesis. The formation of thrombi in important vessels within the organism of parasitized animals is notable, which is sufficient for the development of other pathologies.

Mutation of the Plasmodium falciparum Flavokinase Confers Resistance to Roseoflavin and 8-Aminoriboflavin.

The riboflavin analogues, roseoflavin and 8-aminoriboflavin, inhibit malaria parasite proliferation by targeting riboflavin utilization. To determine their mechanism of action, we generated roseoflavin-resistant parasites by in vitro evolution. Relative to wild-type, these parasites were 4-fold resistant to roseoflavin and cross-resistant to 8-aminoriboflavin. Whole genome sequencing of the resistant parasites revealed a missense mutation leading to an amino acid change (L672H) in the gene coding for a putative flavokinase (PfFK), the enzyme responsible for converting riboflavin into the cofactor flavin mononucleotide (FMN). To confirm that the L672H mutation is responsible for the phenotype, we generated parasites with the missense mutation incorporated into the PfFK gene. The IC50 values for roseoflavin and 8-aminoriboflavin against the roseoflavin-resistant parasites created through in vitro evolution were indistinguishable from those against parasites in which the missense mutation was introduced into the native PfFK. We also generated two parasite lines episomally expressing GFP-tagged versions of either the wild-type or mutant forms of PfFK. We found that PfFK-GFP localizes to the parasite cytosol and that immunopurified PfFK-GFP phosphorylated riboflavin, roseoflavin, and 8-aminoriboflavin. The L672H mutation increased the KM for roseoflavin, explaining the resistance phenotype. Mutant PfFK is no longer capable of phosphorylating 8-aminoriboflavin, but its antiplasmodial activity against resistant parasites can still be antagonized by increasing the extracellular concentration of riboflavin, consistent with it also inhibiting parasite growth through competitive inhibition of PfFK. Our findings, therefore, are consistent with roseoflavin and 8-aminoriboflavin inhibiting parasite proliferation by inhibiting riboflavin phosphorylation and via the generation of toxic flavin cofactor analogues.

Prefoldins are novel regulators of the unfolded protein response in artemisinin resistant Plasmodium falciparum malaria

Emerging Artemisinin (ART) resistance in Plasmodium falciparum (Pf) poses challenges for the discovery of novel drugs to tackle ART-resistant parasites. Concentrated efforts toward the ART resistance mechanism indicated a strong molecular link of ART resistance with upregulated expression of unfolded protein response pathways involving Prefoldins (PFDs). However, a complete characterization of PFDs as molecular players taking part in ART resistance mechanism, and discovery of small molecule inhibitors to block this process have not been identified to date. Here, we functionally characterized all Pf Prefoldin subunits (PFD1-6) and established a causative role played by PFDs in ART resistance by demonstrating their expression in intra-erythrocytic parasites along with their interactions with Kelch13 protein through immunoprecipitation coupled MS/MS analysis. Systematic biophysical interaction analysis between all subunits of PFDs revealed their potential to form a complex. The role of PFDs in ART resistance was confirmed in orthologous yeast PFD6 mutants, where PfPFD6 expression in yeast mutants reverted phenotype to ART resistance. We identified an FDA-approved drug "Biperiden" that restricts the formation of Prefoldin complex and inhibits its interaction with its key parasite protein substrates, MSP-1 and α-tubulin-I. Moreover, Biperiden treatment inhibits the parasite growth in ART-sensitive Pf3D7 and resistant Pf3D7k13R539T strains. Ring survival assays that are clinically relevant to analyze ART resistance in Pf3D7k13R539T parasites demonstrate the potency of BPD to inhibit the growth of survivor parasites. Overall, our study provides the first evidence of the role of PfPFDs in ART resistance mechanisms and opens new avenues for the management of resistant parasites.

Effect of Phlebotomus papatasi on the fitness, infectivity and antimony-resistance phenotype of antimony-resistant Leishmania major Mon-25

Leishmania major is responsible for zoonotic cutaneous leishmaniasis. Therapy is mainly based on the use of antimony-based drugs; however, treatment failures and illness relapses were reported. Although studies were developed to understand mechanisms of drug resistance, the interactions of resistant parasites with their reservoir hosts and vectors remain poorly understood. Here we compared the development of two L. major MON-25 trivalent antimony-resistant lines, selected by a stepwise in vitro Sb(III)-drug pressure, to their wild-type parent line in the natural vector Phlebotomus papatasi. The intensity of infection, parasite location and morphological forms were compared by microscopy. Parasite growth curves and IC50 values have been determined before and after the passage in Ph. papatasi. qPCR was used to assess the amplification rates of some antimony-resistance gene markers. In the digestive tract of sand flies, Sb(III)-resistant lines developed similar infection rates as the wild-type lines during the early-stage infections, but significant differences were observed during the late-stage of the infections. Thus, on day 7 p. i., resistant lines showed lower representation of heavy infections with colonization of the stomodeal valve and lower percentage of metacyclic promastigote forms in comparison to wild-type strains. Observed differences between both resistant lines suggest that the level of Sb(III)-resistance negatively correlates with the quality of the development in the vector. Nevertheless, both resistant lines developed mature infections with the presence of infective metacyclic forms in almost half of infected sandflies. The passage of parasites through the sand fly guts does not significantly influence their capacity to multiply in vitro. The IC50 values and molecular analysis of antimony-resistance genes showed that the resistant phenotype of Sb(III)-resistant parasites is maintained after passage through the sand fly. Sb(III)-resistant lines of L. major MON-25 were able to produce mature infections in Ph. papatasi suggesting a possible circulation in the field using this vector.

Exploring Genetic Silencing: RNAi and CRISPR-Cas Potential Against Drug Resistance in Malaria

Abstract: Malaria has been one of the most lethal infectious diseases throughout history, claiming a high number of human lives. The genomic plasticity of Plasmodium falciparum, the causative agent of the most severe and deadly form of malaria, gives the parasite a constant resistance to drugs developed for its control. Despite efforts to control and even eradicate the disease, these have largely been unsuccessful due to the parasite's continuous adaptations. This study aims to examine the key genes involved in parasite resistance and propose a shift in the combat strategy. Gene silencing techniques offer promise in combating malaria, yet further research is needed to harness their potential for disease control fully. Although there is still a long way to go for the implementation of gene silencing-based therapeutic strategies, this review addresses examples of the use of such techniques in various human diseases and how they could be extrapolated for malaria treatment.