First report of anthelmintic resistance in Haemonchus contortus in alpacas in Australia

BACKGROUND: Parasitic nematodes can cause substantial clinical and subclinical problems in alpacas and anthelmintics are regularly used to control parasitic nematodes in alpacas. Although anthelmintic resistance has been reported in ruminants worldwide, very little is known about anthelmintic resistance in alpacas. The present study was carried out to confirm a suspected case of anthelmintic resistance in Haemonchus contortus in alpacas in Australia. METHODS: Post mortem examination of an alpaca was conducted to determine the cause of its death. To confirm a suspected case of macrocyclic lactone (ML) resistance in H. contortus in alpacas, a faecal egg count reduction test (FECRT) was performed using closantel (7.5 mg/kg) and ivermectin (0.2 mg/kg). Nematode species were identified by morphological and molecular methods. RESULTS: Post mortem examination of a 1-year-old female alpaca that had died following a brief period of lethargy, anorexia and recumbency revealed severe anaemia, hypoproteinaemia and gastric parasitism by adult Haemonchus contortus, despite recent abamectin (0.2 mg/kg) treatment. Based on these findings and the exclusive use of MLs in the herd over the preceding six years, ML resistance in parasitic nematodes of alpacas on this farm was suspected. FECRT revealed that the efficacy of closantel was 99% (95% CI 93-100), whereas that of ivermectin was 35% (95% CI 0-78), indicating that the treatment failure was likely due to the presence of ML-resistant nematodes. Larval culture of faecal samples collected following ivermectin treatment consisted of 99% H. contortus and 1% Cooperia oncophora, a result confirmed using a PCR assay. CONCLUSIONS: This study provides the first evidence of ML resistance in H. contortus in alpacas in Australia. Based on the extent of anthelmintic resistance in sheep gastrointestinal nematodes in Australia, veterinarians and alpaca owners should be encouraged to implement integrated parasite management strategies to improve nematode control in alpacas

The neurofilament middle molecular mass subunit carboxyl-terminal tail domains is essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate

The phosphorylated carboxyl-terminal “tail” domains of the neurofilament (NF) subunits, NF heavy (NF-H) and NF medium (NF-M) subunits, have been proposed to regulate axon radial growth, neurofilament spacing, and neurofilament transport rate, but direct in vivo evidence is lacking. Because deletion of the tail domain of NF-H did not alter these axonal properties (Rao, M.V., M.L. Garcia, Y. Miyazaki, T. Gotow, A. Yuan, S. Mattina, C.M. Ward, N.S. Calcutt, Y. Uchiyama, R.A. Nixon, and D.W. Cleveland. 2002. J. Cell Biol. 158:681–693), we investigated possible functions of the NF-M tail domain by constructing NF-M tail–deleted (NF-MtailΔ) mutant mice using an embryonic stem cell–mediated “gene knockin” approach that preserves normal ratios of the three neurofilament subunits. Mutant NF-MtailΔ mice exhibited severely inhibited radial growth of both motor and sensory axons. Caliber reduction was accompanied by reduced spacing between neurofilaments and loss of long cross-bridges with no change in neurofilament protein content. These observations define distinctive functions of the NF-M tail in regulating axon caliber by modulating the organization of the neurofilament network within axons. Surprisingly, the average rate of axonal transport of neurofilaments was unaltered despite these substantial effects on axon morphology. These results demonstrate that NF-M tail–mediated interactions of neurofilaments, independent of NF transport rate, are critical determinants of the size and cytoskeletal architecture of axons, and are mediated, in part, by the highly phosphorylated tail domain of NF-M

Trematodes of the Great Barrier Reef, Australia: emerging patterns of diversity and richness in coral reef fishes

The Great Barrier Reef holds the richest array of marine life found anywhere in Australia, including a diverse and fascinating parasite fauna. Members of one group, the trematodes, occur as sexually mature adult worms in almost all Great Barrier Reef bony fish species. Although the first reports of these parasites were made 100 years ago, the fauna has been studied systematically for only the last 25 years. When the fauna was last reviewed in 1994 there were 94 species known from the Great Barrier Reef and it was predicted that there might be 2,270 in total. There are now 326 species reported for the region, suggesting that we are in a much improved position to make an accurate prediction of true trematode richness. Here we review the current state of knowledge of the fauna and the ways in which our understanding of this fascinating group is changing. Our best estimate of the true richness is now a range, 1,100–1,800 species. However there remains considerable scope for even these figures to be incorrect given that fewer than one-third of the fish species of the region have been examined for trematodes. Our goal is a comprehensive characterisation of this fauna, and we outline what work needs to be done to achieve this and discuss whether this goal is practically achievable or philosophically justifiable

The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus

Background: The barber's pole worm, Haemonchus contortus, is one of the most economically important parasites of small ruminants worldwide. Although this parasite can be controlled using anthelmintic drugs, resistance against most drugs in common use has become a widespread problem. We provide a draft of the genome and the transcriptomes of all key developmental stages of H. contortus to support biological and biotechnological research areas of this and related parasites. Results: The draft genome of H. contortus is 320 Mb in size and encodes 23,610 protein-coding genes. On a fundamental level, we elucidate transcriptional alterations taking place throughout the life cycle, characterize the parasite's gene silencing machinery, and explore molecules involved in development, reproduction, host-parasite interactions, immunity, and disease. The secretome of H. contortus is particularly rich in peptidases linked to blood-feeding activity and interactions with host tissues, and a diverse array of molecules is involved in complex immune responses. On an applied level, we predict drug targets and identify vaccine molecules. Conclusions: The draft genome and developmental transcriptome of H. contortus provide a major resource to the scientific community for a wide range of genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological, and epidemiological investigations, and a solid foundation for biotechnological outcomes, including new anthelmintics, vaccines and diagnostic tests. This first draft genome of any strongylid nematode paves the way for a rapid acceleration in our understanding of a wide range of socioeconomically important parasites of one of the largest nematode orders

The Myosin Va Head Domain Binds to the Neurofilament-L Rod and Modulates Endoplasmic Reticulum (ER) Content and Distribution within Axons

The neurofilament light subunit (NF-L) binds to myosin Va (Myo Va) in neurons but the sites of interaction and functional significance are not clear. We show by deletion analysis that motor domain of Myo Va binds to the NF-L rod domain that forms the NF backbone. Loss of NF-L and Myo Va binding from axons significantly reduces the axonal content of ER, and redistributes ER to the periphery of axon. Our data are consistent with a novel function for NFs as a scaffold in axons for maintaining the content and proper distribution of vesicular organelles, mediated in part by Myo Va. Based on observations that the Myo Va motor domain binds to intermediate filament (IF) proteins of several classes, Myo Va interactions with IFs may serve similar roles in organizing organelle topography in different cell types

EZH2 Depletion Blocks the Proliferation of Colon Cancer Cells

The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance

Search for dark matter produced in association with a hadronically decaying vector boson in pp collisions at sqrt (s) = 13 TeV with the ATLAS detector

A search is presented for dark matter produced in association with a hadronically decaying W or Z boson using 3.2 fb−1 of pp collisions at View the MathML sources=13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Events with a hadronic jet compatible with a W or Z boson and with large missing transverse momentum are analysed. The data are consistent with the Standard Model predictions and are interpreted in terms of both an effective field theory and a simplified model containing dark matter