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Parasitic nematodes pose a significant threat to human and animal health, causing widespread morbidity and substantial socioeconomic losses globally. Despite the utility of anthelmintic drugs in parasite control, the emergence of widespread resistance necessitates the discovery of novel interventions. Advances through the use of whole-organism phenotypic screening have identified some promising nematocidal compounds, including nemacol, tolfenpyrad, UMW-9729, and ABX464. This article summarises efforts in this discovery, with a focus on Haemonchus contortus and Caenorhabditis elegans as model nematodes, and discusses approaches used for drug target deconvolution, including proteomic, chemical and genetic/genomic techniques. Stability-based proteomic assays, such as thermal proteome profiling, have been useful for identifying protein targets for these compounds, shedding light on their mechanisms of action. However, challenges remain in extrapolating findings from C. elegans to parasitic nematodes, emphasising the need for validation studies. Understanding drug–target interactions in nematodes is critical for developing next-generation anthelmintics and for mitigating the growing resistance challenge. This review outlines recent progress in this area and discusses future directions in target validation and anthelmintic development to support parasite control programmes.

Soil-transmitted helminths (STHs) are parasitic nematodes that infect humans, particularly in tropical and subtropical regions, where they contribute substantially to neglected tropical diseases (NTDs). Among them, hookworms (Ancylostoma duodenale, Necator americanus and Ancylostoma ceylanicum) cause substantial morbidity, leading to anaemia, malnutrition, and developmental impairment. Despite the global impact of hookworm disease, genomic research on A. duodenale has lagged behind that of other hookworms, limiting comparative and molecular biological investigations. Here, we report the first chromosome-level reference genome of A. duodenale, assembled from a single adult specimen archived in ethanol at −20 °C for more than 27 years. Using third-generation sequencing (PacBio Revio, Menlo Park, CA, USA, Oxford Nanopore, Oxford, UK), Hi-C scaffolding, and advanced computational tools, we produced a high-quality 319 Mb genome, filling a critical gap in hookworm genomics. Comparative analyses with N. americanus and the related, free-living nematode Caenorhabditis elegans provided new insights into genome organisation, synteny, and specific adaptations. While A. duodenale exhibited strong chromosomal synteny with N. americanus, its limited synteny with C. elegans highlights its distinct parasitic adaptations. We identified 20,015 protein-coding genes, including conserved single-copy orthologues (SCOs) linked to host–pathogen interactions, immune evasion and essential biological processes. The first comprehensive secretome analysis of A. duodenale revealed a diverse repertoire of excretory/secretory (ES) proteins, including immunomodulatory candidates predicted to interact with host structural and immune-related proteins. This study advances hookworm genomics, establishes a basis for the sequencing of archival specimens, and provides fundamental insights into the molecular biology of A. duodenale. The genomic resource for this hookworm species creates new opportunities for diagnostic, therapeutic, and vaccine development within a One Health framework. It complements recent epidemiological work and aligns with the WHO NTD roadmap (2021–2030) and Sustainable Development Goal 3.3.

Background Anoplocephala perfoliata is the most prevalent and pathogenic tapeworm (cestode) of horses worldwide, yet it remains molecularly understudied. Here, we present the mitochondrial and chromosome-scale nuclear genomes and matched somatic proteome for this parasite, establishing the first high-resolution molecular resource for the family Anoplocephalidae. Results This parasite was first characterised morphologically and then by its mitochondrial genome (size: 13,776 bp). Its complete nuclear genome (size: 372.3 Mb) was assembled and characterised; it encodes 9,711 protein-coding genes, 78.2% of which were functionally annotated and ~ 80% supported by transcriptomic evidence. Proteomic analysis confirmed 758 proteins in previously-analysed excretory/secretory (ES) products from adult worms, including highly expressed components of the ubiquitin–proteasome system, stress response families – e.g., translationally controlled tumour proteins (TCTPs) and universal stress proteins (USPs) – and cytoskeletal scaffolds. Approximately 6.5% of the genome contains retroelements, predominantly LINEs. Comparative genomic analyses revealed a relatively conserved synteny with members of the family Taeniidae ( Echinococcus granulosus , E. multilocularis and Taenia multiceps ) and a pronounced structural divergence from Hymenolepis microstoma (Hymenolepididae), reflecting mosaic genome evolution within the order Cyclophyllidea. Classification of proteins inferred from the genome identified GTPases, kinases, peptidases and secretome-associated proteins among the most abundant groups. A subset of proteins exhibited signal peptides or extracellular localisation, suggesting their role as parasite-derived proteins (PDPs) involved in host–parasite communication and immune evasion. Conclusion This integrated genomic and proteomic framework reveals lineage-specific molecular adaptations in A. perfoliata and provides a foundation for future functional and translational investigations of this and closely related cestodes.

The filarioid nematode Dirofilaria immitis is the causative agent of heartworm disease, a major parasitic infection of canids, felids and occasionally humans. Current prevention relies on macrocyclic lactone-based chemoprophylaxis, but the emergence of drug resistance highlights the need for new intervention strategies. Here, we applied a machine learning (ML)-based framework to predict and prioritise essential genes in D. immitis in silico, using genomic, transcriptomic and functional datasets from the model organisms Caenorhabditis elegans and Drosophila melanogaster. With a curated set of 26 predictive features, we trained and evaluated multiple ML models and, using a defined threshold, we predicted 406 ‘high-priority’ essential genes. These genes showed strong transcriptional activity across developmental stages and were inferred to be enriched in pathways related to ribosome biogenesis, translation, RNA processing and signalling, underscoring their potential as anthelmintic targets. Transcriptomic analyses suggested that these genes are associated with key reproductive and neural tissues, while chromosomal mapping revealed a relatively even genomic distribution, in contrast to patterns observed in C. elegans and Dr. melanogaster. In addition, initial evidence suggested structural variation in the X chromosome compared with a recently published D. immitis assembly, indicating the importance of integrating long-read sequencing with high-throughput chromosome conformation capture (Hi-C) mapping. Overall, this study reinforces the potential of ML-guided approaches for essential gene discovery in parasitic nematodes and provides a foundation for downstream validation and therapeutic target development.

A high-throughput platform for assessing the activity of synthetic or natural compounds on the motility and development of Haemonchus contortus larvae has been established for identifying new anthelmintic compounds active against strongylid nematodes. This study evaluated the impact of serum supplementation on larval development, motility and survival in vitro and its implications for phenotypic compound screening. Of five blood components assessed, 7.5% sheep serum significantly enhanced larval development, motility and survival compared to the original medium (LB*), leading to the formulation of an improved medium (LBS*). Proteomic analysis revealed marked differences in protein expression in larvae cultured in LBS* versus LB*, including molecules associated with structural integrity and metabolic processes. The phenotypic screening of 240 compounds (“Global Priority Box” from Medicines Malaria Venture) using LBS* yielded results distinct from those in LB*, highlighting the effect of culture conditions on screening assessments. These findings indicate/emphasise the critical need to evaluate and optimise culture media for physiologically relevant conditions in screening platforms, improving the reliability of anthelmintic discovery.

Long non-coding, tandem-repetitive regions in mitochondrial (mt) genomes of many metazoans have been notoriously difficult to characterise accurately using conventional sequencing methods. Here, we show how the use of a third-generation (long-read) sequencing and informatic approach can overcome this problem. We employed Oxford Nanopore technology to sequence genomic DNAs from a pool of adult worms of the carcinogenic parasite, Schistosoma haematobium, and used an informatic workflow to define the complete mt non-coding region(s). Using long-read data of high coverage, we defined six dominant mt genomes of 33.4 kb to 22.6 kb. Although no variation was detected in the order or lengths of the protein-coding genes, there was marked length (18.5 kb to 7.6 kb) and structural variation in the non-coding region, raising questions about the evolution and function of what might be a control region that regulates mt transcription and/or replication. The discovery here of the largest tandem-repetitive, non-coding region (18.5 kb) in a metazoan organism also raises a question about the completeness of some of the mt genomes of animals reported to date, and stimulates further explorations using a Nanopore-informatic workflow.

Alveolar echinococcosis (AE) in humans is caused by the larval (metacestode) stage of Echinococcus multilocularis, commonly known as the ‘fox tapeworm’. This disease predominantly targets the liver and has an invasive growth pattern, allowing it to spread to adjacent and distant tissues. Due to its gradual progression and tumour-like characteristics, early diagnosis and prompt intervention are crucial, particularly as there are currently no highly effective vaccines or chemotherapeutics against AE. Current estimates suggest that ~10,500 new infections occur annually worldwide; however, more research is required to refine the prevalence and incidence data for both human and animal hosts in endemic areas of the world. This article discusses the biology of E. multilocularis, outlines aspects of the pathogenesis, diagnosis, treatment, and management of AE, reviews its global distribution, annual incidence, and prevalence, highlights the role of molecular parasitology in advancing therapeutic strategies, and presents recommendations for improving the prevention and control of AE in human populations.

Relapse remains the major cause of mortality for patients with Acute Myeloid Leukemia (AML). Improved tracking of minimal residual disease (MRD) holds the promise of timely treatment adjustments to preempt relapse. Current surveillance techniques detect circulating blasts that coincide with advanced disease and poorly reflect MRD during early relapse. Here, we investigate exosomes as a minimally invasive platform for a microRNA (miRNA) biomarker. We identify a set of miRNA enriched in AML exosomes and track levels of circulating exosome miRNA that distinguish leukemic xenografts from both non-engrafted and human CD34+ controls. We develop biostatistical models that reveal circulating exosomal miRNA at low marrow tumor burden and before circulating blasts can be detected. Remarkably, both leukemic blasts and marrow stroma contribute to serum exosome miRNA. We propose development of serum exosome miRNA as a platform for a novel, sensitive compartment biomarker for prospective tracking and early detection of AML recurrence.

Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

Trichinellosis is a globally important food-borne parasitic disease of humans caused by roundworms of the Trichinella complex. Extensive biological diversity is reflected in substantial ecological and genetic variability within and among Trichinella taxa, and major controversy surrounds the systematics of this complex. Here we report the sequencing and assembly of 16 draft genomes representing all 12 recognized Trichinella species and genotypes, define protein-coding gene sets and assess genetic differences among these taxa. Using thousands of shared single-copy orthologous gene sequences, we fully reconstruct, for the first time, a phylogeny and biogeography for the Trichinella complex, and show that encapsulated and non-encapsulated Trichinella taxa diverged from their most recent common ancestor ∼21 million years ago (mya), with taxon diversifications commencing ∼10−7 mya. Trichinellosis is a globally important food-borne disease caused by roundworms of the Trichinella complex. Here the authors present genomic sequences representing all 12 recognized Trichinella species and genotypes, and reconstruct their phylogeny and biogeography.