Application of small RNA technology for improved control of parasitic helminths

Over the last decade microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as important regulators of post-transcriptional gene expression. miRNAs are short, non-coding RNAs that regulate a variety of processes including cancer, organ development and immune function. This class of small RNAs bind with partial complementarity to their target mRNA sequences, most often in the 3′UTR, to negatively regulate gene expression. In parasitic helminths, miRNAs are being increasingly studied for their potential roles in development and host-parasite interactions. The availability of genome data, combined with small RNA sequencing, has paved the way to profile miRNAs expressed at particular developmental stages for many parasitic helminths. While some miRNAs are conserved across species, others appear to be unique to specific parasites, suggesting important roles in adaptation and survival in the host environment. Some miRNAs are released from parasites, in exosomes or in protein complexes, and the potential effects of these on host immune function are being increasingly studied. In addition, release of miRNAs from schistosome and filarial parasites into host plasma can be exploited for the development of specific and sensitive diagnostic biomarkers of infection. Interfering with miRNA function, as well as silencing key components of the pathways they regulate, will progress our understanding of parasite development and provide a novel approach to therapeutic control. RNA interference (RNAi) by siRNAs has proven to be inconsistent in parasitic nematodes. However, the recent successes reported for schistosome and liver fluke RNAi, encourage further efforts to enhance delivery of RNA and improve in vitro culture systems and assays to monitor phenotypic effects in nematodes. These improvements are important for the establishment of reliable functional genomic platforms for novel drug and vaccine development. In this review we focus on the important roles of miRNAs and siRNAs in post-transcriptional gene regulation in veterinary parasitic helminths and the potential value of these in parasite diagnosis and control

Early Years and Key Stage 1 Mathematics Teaching: Evidence Review

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Increased expression of a microRNA correlates with anthelmintic resistance in parasitic nematodes

Resistance to anthelmintic drugs is a major problem in the global fight against parasitic nematodes infecting humans and animals. While previous studies have identified mutations in drug target genes in resistant parasites, changes in the expression levels of both targets and transporters have also been reported. The mechanisms underlying these changes in gene expression are unresolved. Here, we take a novel approach to this problem by investigating the role of small regulatory RNAs in drug resistant strains of the important parasite Haemonchus contortus. microRNAs (miRNAs) are small (22 nt) non-coding RNAs that regulate gene expression by binding predominantly to the 3′ UTR of mRNAs. Changes in miRNA expression have been implicated in drug resistance in a variety of tumor cells. In this study, we focused on two geographically distinct ivermectin resistant strains of H. contortus and two lines generated by multiple rounds of backcrossing between susceptible and resistant parents, with ivermectin selection. All four resistant strains showed significantly increased expression of a single miRNA, hco-miR-9551, compared to the susceptible strain. This same miRNA is also upregulated in a multi-drug-resistant strain of the related nematode Teladorsagia circumcincta. hco-miR-9551 is enriched in female worms, is likely to be located on the X chromosome and is restricted to clade V parasitic nematodes. Genes containing predicted binding sites for hco-miR-9551 were identified computationally and refined based on differential expression in a transcriptomic dataset prepared from the same drug resistant and susceptible strains. This analysis identified three putative target mRNAs, one of which, a CHAC domain containing protein, is located in a region of the H. contortus genome introgressed from the resistant parent. hco-miR-9551 was shown to interact with the 3′ UTR of this gene by dual luciferase assay. This study is the first to suggest a role for miRNAs and the genes they regulate in drug resistant parasitic nematodes. miR-9551 also has potential as a biomarker of resistance in different nematode species

On Essentiality and the World Health Organization's Model List of Essential Medicines

BackgroundIn 1977 the World Health Organization created its first Model List of Essential Medicines—a list designed to aid countries in determining which medicines to prioritize on their National Essential Medicines Lists. In classifying drugs as “essential,” the World Health Organization has historically stressed drugs' ability to meet priority health needs of populations and cost.ObjectivesIn this paper we trace the fluctuations in the application of cost and priority status of disease as criteria for essential medicines throughout the reports published by the WHO Expert Committee on Selection and Use of Essential Medicines since 1977.MethodsWe analyzed essential medicines lists published on the World Health Organization website since 1977 for trends in criteria concerning cost and priority status of disease. Where, available, analyzed the World Health Organization Expert Committee analysis rationalizing why certain medicines were or were not added and were or were not removed.ResultsThe application of the criteria of cost and priority status of essential medicines has fluctuated dramatically over the years.ConclusionsThe definition of essential medicines has shifted and now necessitates a new consensus on normative definitions and criteria. A more standardized and transparent set of procedures for choosing essential medicines is required

Education for a Future in Crisis: Developing a Humanities-Informed STEM Curriculum

In the popular imagination, science and technology are often seen as fields of knowledge production critical to social progress and a cooperative future. This optimistic portrayal of technological advancement also features prominently in internal discourses amongst scientists, industry leaders, and STEM students alike. Yet, an overwhelming body of research, investigation, and first-person accounts highlight the varying ways modern science, technology, and engineering industries contribute to the degradation of our changing environments and exploit and harm global low-income and marginalized populations. By and large, siloed higher-education STEM curricula provide inadequate opportunities for undergraduate and graduate students to critically analyze the historical and epistemological foundations of scientific knowledge production and even fewer tools to engage with and respond to modern community-based cases. Here, we describe the development of a humanities- and social sciences-informed curriculum designed to address the theory, content, and skill-based needs of traditional STEM students considering technoscientific careers. In essence, this course is designed to foster behavior change, de-center dominant ways of knowing in the sciences, and bolster self-reflection and critical-thinking skills to equip the developing STEM workforce with a more nuanced and accurate understanding of the social, political, and economic role of science and technology. This curriculum has the potential to empower STEM-educated professionals to contribute to a more promising, inclusive future. Our framework foregrounds key insights from science and technology studies, Black and Native feminisms, queer theory, and disability studies, alongside real-world case studies using critical pedagogies.Comment: 25 pages, 1 figure, 4 table

Profiling microRNAs through development of the parasitic nematode Haemonchus identifies nematode-specific miRNAs that suppress larval development

Parasitic nematodes transition between dramatically different free-living and parasitic stages, with correctly timed development and migration crucial to successful completion of their lifecycle. However little is known of the mechanisms controlling these transitions. microRNAs (miRNAs) negatively regulate gene expression post-transcriptionally and regulate development of diverse organisms. Here we used microarrays to determine the expression profile of miRNAs through development and in gut tissue of the pathogenic nematode Haemonchus contortus. Two miRNAs, mir-228 and mir-235, were enriched in infective L3 larvae, an arrested stage analogous to Caenorhabditis elegans dauer larvae. We hypothesized that these miRNAs may suppress development and maintain arrest. Consistent with this, inhibitors of these miRNAs promoted H. contortus development from L3 to L4 stage, while genetic deletion of C. elegans homologous miRNAs reduced dauer arrest. Epistasis studies with C. elegans daf-2 mutants showed that mir-228 and mir-235 synergise with FOXO transcription factor DAF-16 in the insulin signaling pathway. Target prediction suggests that these miRNAs suppress metabolic and transcription factor activity required for development. Our results provide novel insight into the expression and functions of specific miRNAs in regulating nematode development and identify miRNAs and their target genes as potential therapeutic targets to limit parasite survival within the host