Molecular and biochemical parasitology最新文献

{"title":"Transient expression of a luciferase mRNA in plant-parasitic and free-living nematodes by electroporation","authors":"Thanuja Thekke-Veetil ,&nbsp;Nancy K. McCoppin ,&nbsp;Leslie L. Domier ,&nbsp;M.R. Hajimorad ,&nbsp;Kris N. Lambert ,&nbsp;Hyoun-Sub Lim ,&nbsp;Glen L. Hartman","doi":"10.1016/j.molbiopara.2022.111489","DOIUrl":"10.1016/j.molbiopara.2022.111489","url":null,"abstract":"<div><p><span><span>Despite their economic significance in agricultural cropping systems, a lack of suitable molecular tools for manipulating gene expression has hindered progress in the functional genomics of plant </span>parasitic nematodes (PPN). Obligate sexual reproduction and the obligate nature of PPN-host interactions further complicate the development of </span><em>in vivo</em><span> gene delivery and expression systems in these pests. Methods such as microinjection<span> and microprojectile bombardment have been developed for introducing gene constructs into the free-living nematode, </span></span><span><em>Caenorhabditis elegans</em></span><span><span>. However, these procedures can be laborious and inefficient. Electroporation<span><span> has been used extensively to introduce macromolecules, including single-stranded </span>RNAs, into eukaryotic and </span></span>prokaryotic cells<span><span>. The technique has also been used for the delivery of DNA and double-stranded RNA constructs into nematodes by whole-animal electroporation. Here, we describe methods for the expression of a nematode-optimized NanoLuc </span>luciferase mRNA in the form of </span></span><em>in vitro</em> transcripts following whole-animal electroporation of <span><em>Heterodera glycines</em></span>, <span><em>Meloidogyne incognita</em></span>, and <em>C. elegans</em>. The ability to transiently express single-stranded RNA constructs in economically important PPN provides a rapid means to evaluate nematode and/or foreign genes for their biological significance and potential role in nematode management.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83851200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of nanoparticles with 5-fluorouracil and chloroquine on Acanthamoeba castellanii activity","authors":"Balsam Qubais Saeed ,&nbsp;Mutasem Rawas Qalaji ,&nbsp;Noor Akbar ,&nbsp;Ruqaiyyah Siddiqui ,&nbsp;Cagliani Roberta ,&nbsp;Shaista Manzoor ,&nbsp;Jibran Sualeh Muhammad ,&nbsp;Ahmed Omar Adrees ,&nbsp;Rula Al-Shahrabi ,&nbsp;Naveed Ahmed Khan","doi":"10.1016/j.molbiopara.2022.111492","DOIUrl":"10.1016/j.molbiopara.2022.111492","url":null,"abstract":"<div><p><span><em>Acanthamoeba</em></span> is opportunistic pathogens that cause vision-threatening <em>Acanthamoeba</em><span><span> keratitis (AK). Previous studies proposed the use of </span>chloroquine (CQ) and 5-fluorouracil (5FU) as anti-</span><em>Acanthamoeba</em> agents. The objective of this study was to determine the benefit of using 5FU and CQ nanoparticles (NP) formulations against <em>A. castellanii</em><span> that belonging to the T4 genotype and evaluate their anti-Acanthamoebic characteristic. Triplicate batches of 5FU nanoparticles (5FU-NP) were synthesized by using a modified nanoprecipitation method, while CQ nanoparticles (CQ-NP) synthesized using a modified double emulsion method. The synthesized nanoparticles were subjected to biological assays to investigate their amoebicidal, amoebistatic, anti-encystation, and anti-excystation effects against </span><em>A. castellanii</em><span><span>, as well as cell cytotoxicity. Cytotoxicity assays were performed using human </span>keratinocyte<span><span> cells (HaCaT) to determine the effect of CQ and 5FU nanoformulations on host cells. 5FU-NP with a concentration of 60 µM showed significant inhibition to amoeba binding into human cell lines and remarkable prevention mainly during the encystation stage. Moreover, 5FU-NP resulted in less cytotoxicity and </span>pathogenicity when compared with the free 5FU. On the other hand, CQ and CQ-NP, at the same concentration, showed poor inhibition to amoeba binding into human cells and insignificant prevention to encystation stage. Moderate human cells damage was resulted following their treatment with CQ and CQ-NP. In conclusion, 5FU may have the potential as an antiamoebic agent against </span></span><em>Acanthamoeba</em> spp. preferably as a nanoformulation to enhance its activity and reduce its cytoxicity.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74473016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single amino acid substitution alters activity and specificity in Plasmodium falciparum aspartyl & asparaginyl-tRNA synthetases","authors":"Vivek Kumar Sharma ,&nbsp;Swati Gupta ,&nbsp;Jyoti Chhibber-Goel ,&nbsp;Manickam Yogavel ,&nbsp;Amit Sharma","doi":"10.1016/j.molbiopara.2022.111488","DOIUrl":"10.1016/j.molbiopara.2022.111488","url":null,"abstract":"<div><p><span><span><span>The specificity of each aminoacyl-tRNA synthetase (aaRS) for its cognate amino acid ensures correct tRNA </span>esterification and allows fidelity in </span>protein synthesis. The aaRSs discriminate based on the chemical properties of their amino acid substrates and structural features of the binding pockets. In this study, we characterized aspartyl-(DRS) and asparaginyl-tRNA synthetase (NRS) from </span><span><em>Plasmodium falciparum</em></span> to determine the basis of their specificity towards <span>L</span>-asp and <span>L</span>-asn respectively. The negatively charged <span>L</span>-asp and its analogue <span>L</span>-asn differ only in their side-chain groups i.e., -OH and -NH₂<span>. Further, the amino acid binding sites are highly conserved within these two enzymes. Analysis of the substrate (</span><span>L</span>-asp/<span>L</span>-asn) binding sites across species revealed two highly conserved residues in <em>Pf</em><span>DRS (D408 and K372) and </span><em>Pf</em>NRS (E395 and L360) that are involved in recognition of the O^δ2/N^δ2 of <span>L</span>-asp/<span>L</span>-asn respectively. These residues were mutated and swapped between the D408→E in <em>Pf</em>DRS and the corresponding E395→D in <em>Pf</em>NRS. A similar approach was employed for residue number K372→L in <em>Pf</em>DRS and L360→K in <em>Pf</em>NRS. The mutated <em>Pf</em>DRS^D408E<span> retained its enzymatic activity<span> during step 1 of aminoacylation reaction towards </span></span><span>L</span>-asp and <span>L</span>-asn and esterified tRNA^Asp with <span>L</span>-asp like wild type enzyme, while the <em>Pf</em>DRS^K372L was rendered enzymatically inactive. The correspondingly mutated <em>Pf</em>NRS^E395D was enzymatically inactive. The mutated <em>Pf</em>NRS^L360K had an altered specificity and esterified tRNA^Asn with non-cognate amino acid <span>L</span>-asp and not <span>L</span>-asn. These data suggest that the residue K372 is crucial for the enzymatic activity of <em>Pf</em>DRS while the residue L360 in <em>Pf</em>NRS imparts specificity towards <span>L</span>-asn.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86479495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Plasmodium research, an update: Highlights from the Malaria in Melbourne 2021 conference","authors":"Jack Adderley ,&nbsp;Coralie Boulet ,&nbsp;Kirsty McCann ,&nbsp;Emma McHugh ,&nbsp;Lisa J. Ioannidis ,&nbsp;Lee M. Yeoh","doi":"10.1016/j.molbiopara.2022.111487","DOIUrl":"10.1016/j.molbiopara.2022.111487","url":null,"abstract":"<div><p><span>The Malaria in Melbourne 2021 conference was held online in October. This conference aims to provide a platform for students and early career researchers to share their research and develop new collaborative networks. The program covered a broad range of topics including antimalarial drug development, epidemiology, immunology, molecular and cellular biology, and other emerging technologies. This article summarises recent advances in </span><em>Plasmodium</em> research presented at the Malaria in Melbourne 2021 conference.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81558580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ‘nuclear option’ revisited: Confirmation of Ss-daf-12 function and therapeutic potential in Strongyloides stercoralis and other parasitic nematode infections","authors":"James B. Lok ,&nbsp;Steven A. Kliewer ,&nbsp;David J. Mangelsdorf","doi":"10.1016/j.molbiopara.2022.111490","DOIUrl":"https://doi.org/10.1016/j.molbiopara.2022.111490","url":null,"abstract":"<div><p><span><span>Mechanisms governing morphogenesis and development of infectious third-stage larvae (L3i) of </span>parasitic nematodes have been likened to those regulating dauer development in </span><span><em>Caenorhabditis elegans</em></span><span><span>. Dauer regulatory signal transduction comprises initial G protein-coupled receptor (GPCR) signaling in chemosensory neurons of the amphidial complex that regulates parallel insulin- and TGFβ-like signaling in the tissues. Insulin- and TGFβ-like signals converge to co-regulate steroid signaling through the </span>nuclear receptor<span> (NR) DAF-12. Discovery of the steroid ligands of DAF-12 opened a new avenue of small molecule physiology in </span></span><em>C. elegans</em>. These signaling pathways are conserved in parasitic nematodes and an increasing body of evidence supports their function in formation and developmental regulation of L3i during the infectious process in soil transmitted species. This review presents these lines of evidence for G protein-coupled receptor (GPCR), insulin- and TGFβ-like signaling in brief and focuses primarily on signaling through parasite orthologs of DAF-12. We discuss in some depth the deployment of sensitive analytical techniques to identify Δ7-dafachronic acid as the natural ligand of DAF-12 homologs in <span><em>Strongyloides stercoralis</em></span> and <span><em>Haemonchus contortus</em></span><span> and of targeted mutagenesis by CRISPR/Cas9 to assign dauer-like regulatory function to the NR </span><em>Ss-</em>DAF-12, its coactivator <em>Ss-</em><span>DIP-1 and the key ligand biosynthetic enzyme </span><em>Ss-</em>CYP-22a9. Finally, we present published evidence of the potential of <em>Ss-</em>DAF-12 signaling as a chemotherapeutic target in human strongyloidiasis.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137042693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiamoebic properties of salicylic acid-based deep eutectic solvents for the development of contact lens disinfecting solutions against Acanthamoeba","authors":"Ruqaiyyah Siddiqui ,&nbsp;Zinb Makhlouf ,&nbsp;Noor Akbar ,&nbsp;Mustafa Khamis ,&nbsp;Taleb Ibrahim ,&nbsp;Amir Sada Khan ,&nbsp;Naveed Ahmed Khan","doi":"10.1016/j.molbiopara.2022.111493","DOIUrl":"10.1016/j.molbiopara.2022.111493","url":null,"abstract":"<div><p><span><em>Acanthamoeba castellanii</em></span><span><span><span> is a protist pathogen that can cause sight-threatening </span>keratitis and a fatal infection of the central nervous system, known as </span>granulomatous amoebic encephalitis<span>. In this study, effects of five malonic acid and salicylic acid-based deep eutectic solvents (DES) on </span></span><em>A. castellanii</em> were investigated<em>.</em><span><span> These are salicylic acid-trioctylphosphine (DES 1), salicylic acid- trihexylamine (DES 2), salicylic acid-trioctylamine (DES 3), malonic acid-trioctylphosphine (DES 4) and malonic acid-trihexylamine (DES 5). The experiments were done by performing amoebicidal, encystment, excystment, cytopathogenicity, and </span>cytotoxicity assays. At micromolar dosage, the solvents DES 2 and DES 3 displayed significant amoebicidal effects (P &lt; 0.05), inhibited encystment and excystment, undermined the cell-mediated cytopathogenicity of </span><em>A. castellanii,</em><span> and also displayed minimal cytotoxicity to human cells. Conversely, the chemical components of these solvents: salicylic acid<span>, trihexylamine, and trioctylamine showed minimal effects when tested individually. These results are very promising and to the best of our knowledge, are reported for the first time on the effects of deep eutectic solvents on amoebae. These results can be applied in the development of new formulations of novel contact lens disinfectants against </span></span><em>Acanthamoeba castellanii.</em></p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40399918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using newly optimized genetic tools to probe Strongyloides sensory behaviors","authors":"Patricia Mendez ,&nbsp;Breanna Walsh ,&nbsp;Elissa A. Hallem","doi":"10.1016/j.molbiopara.2022.111491","DOIUrl":"10.1016/j.molbiopara.2022.111491","url":null,"abstract":"<div><p>The oft-neglected human-parasitic threadworm, <em>Strongyloides stercoralis</em>, infects roughly eight percent of the global population, placing disproportionate medical and economic burden upon marginalized communities. While current chemotherapies treat strongyloidiasis, disease recrudescence and the looming threat of anthelminthic resistance necessitate novel strategies for nematode control. Throughout its life cycle, <em>S. stercoralis</em> relies upon sensory cues to aid in environmental navigation and coordinate developmental progression. Odorants, tastants, gases, and temperature have been shown to shape parasite behaviors that drive host seeking and infectivity; however, many of these sensory behaviors remain poorly understood, and their underlying molecular and neural mechanisms are largely uncharacterized. Disruption of sensory circuits essential to parasitism presents a promising strategy for future interventions. In this review, we describe our current understanding of sensory behaviors – namely olfactory, gustatory, gas sensing, and thermosensory behaviors – in <em>Strongyloides</em> spp. We also highlight the ever-growing cache of genetic tools optimized for use in <em>Strongyloides</em> that have facilitated these findings, including transgenesis, CRISPR/Cas9-mediated mutagenesis, RNAi, chemogenetic neuronal silencing, and the use of fluorescent biosensors to measure neuronal activity. Bolstered by these tools, we are poised to enter an era of rapid discovery in <em>Strongyloides</em> sensory neurobiology, which has the potential to shape pioneering advances in the prevention and treatment of strongyloidiasis.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9301051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 'Nuclear Option' Revisited: Confirmation of Ss-daf-12 Function and Therapeutic Potential in Strongyloides stercoralis and Other Parasitic Nematode Infections.","authors":"J. Lok, S. Kliewer, D. Mangelsdorf","doi":"10.2139/ssrn.4040621","DOIUrl":"https://doi.org/10.2139/ssrn.4040621","url":null,"abstract":"Mechanisms governing morphogenesis and development of infectious third-stage larvae (L3i) of parasitic nematodes have been likened to those regulating dauer development in Caenorhabditis elegans. Dauer regulatory signal transduction comprises initial G protein-coupled receptor (GPCR) signaling in chemosensory neurons of the amphidial complex that regulates parallel insulin- and TGFβ-like signaling in the tissues. Insulin- and TGFβ-like signals converge to co-regulate steroid signaling through the nuclear receptor (NR) DAF-12. Discovery of the steroid ligands of DAF-12 opened a new avenue of small molecule physiology in C. elegans. These signaling pathways are conserved in parasitic nematodes and an increasing body of evidence supports their function in formation and developmental regulation of L3i during the infectious process in soil transmitted species. This review presents these lines of evidence for G protein-coupled receptor (GPCR), insulin- and TGFβ-like signaling in brief and focuses primarily on signaling through parasite orthologs of DAF-12. We discuss in some depth the deployment of sensitive analytical techniques to identify Δ7-dafachronic acid as the natural ligand of DAF-12 homologs in Strongyloides stercoralis and Haemonchus contortus and of targeted mutagenesis by CRISPR/Cas9 to assign dauer-like regulatory function to the NR Ss-DAF-12, its coactivator Ss-DIP-1 and the key ligand biosynthetic enzyme Ss-CYP-22a9. Finally, we present published evidence of the potential of Ss-DAF-12 signaling as a chemotherapeutic target in human strongyloidiasis.","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89076872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transporter gene expression and Wolbachia quantification in adults of Dirofilaria immitis treated in vitro with ivermectin or moxidectin alone or in combination with doxycycline for 12 h","authors":"Chiara Bazzocchi ,&nbsp;Marco Genchi ,&nbsp;Chiara Lucchetti ,&nbsp;Alessandra Cafiso ,&nbsp;Lavinia Ciuca ,&nbsp;John McCall ,&nbsp;Laura Helen Kramer ,&nbsp;Alice Vismarra","doi":"10.1016/j.molbiopara.2022.111475","DOIUrl":"https://doi.org/10.1016/j.molbiopara.2022.111475","url":null,"abstract":"<div><p><span>Due to their marked larvicidal activity, macrocyclic lactones (MLs) are used for the prevention of heartworm disease ( </span><em>Dirofilaria immitis)</em><span> in dogs. They have also been shown to eliminate adult parasites after long-term administration, with a so-called “slow-kill” effect. In addition, recent studies have established that a combination of doxycycline, which eliminates the endosymbiont </span><span><em>Wolbachia</em></span>, and MLs has superior adulticide effects when compared to MLs alone. It has been hypothesized that the apparent synergism between doxycycline/MLs may be due to interaction with drug efflux transport proteins. The aim of the present study was to evaluate gene expression of several transport proteins in <em>D. immitis</em><span> adults treated in vitro either with doxycycline alone, ivermectin alone, moxidectin alone, or a combination of ivermectin or moxidectin with doxycycline for 12 h. Quantitative PCR analysis showed a sex-dependent response to treatments. In female worms, Dim</span><em>-pgp-10</em>, Dim<em>-haf-</em>1 and Dim<em>-haf-</em>5 were upregulated compared to controls with doxycycline alone and when combined with ivermectin. Moxidectin did not induce any changes in gene expression. In males, moxidectin administered alone induced a slight increase in Dim<em>-pgp-10</em>, Dim<em>-pgp-11</em>and <em>Di-avr-14</em>, while ivermectin in combination with doxycycline produced significant upregulation of the ML receptor <em>Di-avr-14</em>. These results suggest possible synergism between the two drug classes and different susceptibility of males vs. females to adulticide effects.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91958343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Approaches to studying the developmental switch of Strongyloides – Moving beyond the dauer hypothesis","authors":"Mark Viney,&nbsp;Robert Morris","doi":"10.1016/j.molbiopara.2022.111477","DOIUrl":"10.1016/j.molbiopara.2022.111477","url":null,"abstract":"<div><p><em>Strongyloides’</em> developmental switch between direct, parasitic and indirect, free-living development has intrigued, confused, and fascinated biologists since it was first discovered more than 100 years ago. Proximately, the switch is controlled by environmental conditions that developing larvae are exposed to, but genotypes differ in their sensitivity to these cues. Ultimately, selection will act on this switch to generate a direct <em>vs.</em> indirect phenotype that maximises a genotype’s fitness, but we have a poor understanding of the relative fitness advantages of these different routes of development. Mechanistically, the switch senses and transduces environmental cues, integrates signals that are then used to make a developmental decision which is then enacted. Seeking to understand the molecular form of this process has focussed on the <em>C. elegans</em> dauer hypothesis, but this has been found to be wanting. So, we argue that the time has come to move beyond the dauer hypothesis and better refine our question to ask: What is it that controls the variation in developmental switching among <em>Strongyloides</em> genotypes? We discuss approaches to achieve this research aim that now lies within our grasp.</p></div>","PeriodicalId":18721,"journal":{"name":"Molecular and biochemical parasitology","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166685122000317/pdfft?md5=feb5dbcc611e908655b3067dd921f450&pid=1-s2.0-S0166685122000317-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73342760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}