The Potential Impact of Density Dependent Fecundity on the Use of the Faecal Egg Count Reduction Test for Detecting Drug Resistance in Human Hookworms

Current efforts to control human soil-transmitted helminth (STH) infections involve the periodic mass treatment of people, particularly children, in all endemic areas, using benzimidazole and imidothiazole drugs. Given the fact that high levels of resistance have developed to these same drugs in roundworms of livestock, there is a need to monitor drug efficacy in human STHs. The faecal egg count reduction test (FECRT), in which faecal egg output is measured pre- and post-drug treatment, is presently under examination by WHO as a means of detecting the emergence of resistance. We have examined the potential impact of density dependent fecundity on FECRT data. Recent evidence with the canine hookworm indicates that the density dependent egg production phenomenon shows dynamic properties in response to drug treatment. This will impact on measurements of drug efficacy, and hence drug resistance. It is likely that the female worms that survive a FECRT drug treatment in some human cases will respond to the relaxation of density dependent constraints on egg production by increasing their egg output significantly compared to their pre-treatment levels. These cases will therefore underestimate drug efficacy in the FECRT. The degree of underestimation will depend on the ability of the worms within particular hosts to increase their egg output, which will in turn depend on the extent to which their egg output is constrained prior to the drug treatment. As worms within different human cases will likely be present at quite different densities prior to a proposed FECRT, there is potential for the effects of this phenomenon on drug efficacy measurements to vary considerably within any group of potential FECRT candidates. Measurement of relative drug efficacy may be improved by attempting to ensure a consistent degree of underestimation in groups of people involved in separate FECRTs. This may be partly achieved by omission of cases with the heaviest infections from a FECRT, as these cases may have the greatest potential to increase their egg output upon removal of density dependent constraints. The potential impact of worm reproductive biology on the utility of the FECRT as a resistance detection tool highlights the need to develop new drug resistance monitoring methods which examine either direct drug effects on isolated worms with in vitro phenotypic assays, or changes in worm genotypes

Synergism between ivermectin and the tyrosine kinase/P-glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Anthelmintic resistance is a major problem in parasitic nematodes of livestock worldwide. One means to counter resistance is to use synergists that specifically inhibit resistance mechanisms in order to restore the toxicity, and hence preserve the usefulness, of currently available anthelmintics. P-glycoproteins (P-gps) eliminate a wide variety of structurally unrelated xenobiotics from cells, and have been implicated in anthelmintic resistance. Crizotinib is a tyrosine kinase inhibitor under development as a cancer therapeutic. The compound also inhibits P-gps, and has been shown to reverse multidrug resistance in cancer cells. We were therefore interested in determining if the compound was able to increase the sensitivity of Haemonchus contortus larvae to ivermectin, as measured by in vitro larval development and migration assays with a drug-resistant and a –susceptible isolate. In migration assays, co-administration of crizotinib increased the toxicity of ivermectin to resistant larvae (up to 5.7-fold decrease in ivermectin IC), and rendered the resistant larvae equally or more sensitive to ivermectin than the susceptible isolate. On the other hand, co-administration of crizotinib had no effect on ivermectin sensitivity in the susceptible isolate. In development assays, significant increases in the sensitivity of both the resistant (up to 1.9-fold) and susceptible (up to 1.6-fold) larvae to ivermectin were observed, although the magnitude of the observed synergism was less than seen in migration assays, and the resistant larvae retained significant levels of ivermectin resistance. By highlighting the ability of the P-gp inhibitor crizotinib to increase the sensitivity of H. contortus larvae to ivermectin, this study provides further evidence that P-gp inhibitors are potential tools for modulating the efficacy of anthelmintics. In addition, the differences in the outcomes of the two assays, with ‘resistance-breaking’ effects being much more marked in migration assays, suggest that some life-stage-specific aspects may exist in the interaction of ivermectin with P-gps in the two worm isolates

Drug-efflux and target-site gene expression patterns in Haemonchus contortus larvae able to survive increasing concentrations of levamisole in vitro

While there is some evidence that changes in nicotinic acetylcholine receptor (nAChR) subunits confer resistance to levamisole in gastrointestinal helminth parasites, the exact nature of the resistance mechanism(s) is unclear. We utilised the presence of a resistant fraction within the Wallangra 2003 isolate of Haemonchus contortus larvae in order to subdivide the population into three subpopulations of larvae able to survive increasing concentrations of the drug. We then measured gene expression levels in the subpopulations and the larval population as a whole, focusing on genes encoding the subunit components of levamisole-sensitive receptors, genes encoding ancillary proteins involved in receptor assembly, and P-glycoprotein (P-gp) genes. The subpopulation surviving the lowest levamisole concentration showed increases of 1.5- to 3-fold in a number of P-gp genes (Hco-pgp-3, -4, -10, and -14) alongside unchanged receptor genes, compared to the whole Wallangra larval population. On the other hand, the subpopulation surviving the intermediate levamisole concentration showed an increase in only a single P-gp (Hco-pgp-14), alongside decreases in some receptor subunit (Hco-unc-63a) and ancillary protein genes (Hco-unc-50, Hco-ric-3.1 and 3.1). The subpopulation surviving the highest levamisole concentration showed further decreases in receptor subunit genes (Hco-unc-63a and Hco-unc-29 paralogs) as well as genes involved in receptor assembly (Hco-unc-74, Hco-unc-50, Hco-ric-3.1 and 3.1), alongside no increased P-gp gene levels. This suggests a biphasic pattern of drug resistance in the larvae of this worm isolate, in which a non-specific P-gp-mediated mechanism confers low levels of resistance, while higher level resistance is due to altered receptor subunit composition as a result of changes in both subunit composition and in the levels of proteins involved in receptor assembly

Paleogeodetic records of seismic and aseismic subduction from central Sumatran microatolls, Indonesia

We utilize coral microatolls in western Sumatra to document vertical deformation associated with subduction. Microatolls are very sensitive to fluctuations in sea level and thus act as natural tide gauges. They record not only the magnitude of vertical deformation associated with earthquakes (paleoseismic data), but also continuously track the long-term aseismic deformation that occurs during the intervals between earthquakes (paleogeodetic data). This paper focuses on the twentieth century paleogeodetic history of the equatorial region. Our coral paleogeodetic record of the 1935 event reveals a classical example of deformations produced by seismic rupture of a shallow subduction interface. The site closest to the trench rose 90 cm, whereas sites further east sank by as much as 35 cm. Our model reproduces these paleogeodetic data with a 2.3 m slip event on the interface 88 to 125 km from the trench axis. Our coral paleogeodetic data reveal slow submergence during the decades before and after the event in the areas of coseismic emergence. Likewise, interseismic emergence occurred before and after the 1935 event in areas of coseismic submergence. Among the interesting phenomenon we have discovered in the coral record is evidence of a large aseismic slip or “silent event” in 1962, 27 years after the 1935 event. Paleogeodetic deformation rates in the decades before, after, and between the 1935 and 1962 events have varied both temporally and spatially. During the 25 years following the 1935 event, submergence rates were dramatically greater than in prior decades. During the past four decades, however, rates have been lower than in the preceding decades, but are still higher than they were prior to 1935. These paleogeodetic records enable us to model the kinematics of the subduction interface throughout the twentieth century

Ocean mass, sterodynamic effects, and vertical land motion largely explain US coast relative sea level rise

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Harvey, T., Hamlington, B. D., Frederikse, T., Nerem, R. S., Piecuch, C. G., Hammond, W. C., Blewitt, G., Thompson, P. R., Bekaert, D. P. S., Landerer, F. W., Reager, J. T., Kopp, R. E., Chandanpurkar, H., Fenty, I., Trossman, D. S., Walker, J. S., & Boening, C. W. Ocean mass, sterodynamic effects, and vertical land motion largely explain US coast relative sea level rise. Communications Earth & Environment, 2(1), (2021): 233, https://doi.org/10.1038/s43247-021-00300-w.Regional sea-level changes are caused by several physical processes that vary both in space and time. As a result of these processes, large regional departures from the long-term rate of global mean sea-level rise can occur. Identifying and understanding these processes at particular locations is the first step toward generating reliable projections and assisting in improved decision making. Here we quantify to what degree contemporary ocean mass change, sterodynamic effects, and vertical land motion influence sea-level rise observed by tide-gauge locations around the contiguous U.S. from 1993 to 2018. We are able to explain tide gauge-observed relative sea-level trends at 47 of 55 sampled locations. Locations where we cannot explain observed trends are potentially indicative of shortcomings in our coastal sea-level observational network or estimates of uncertainty.The research was carried out in part at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. C.G.P. was supported by NASA grant 80NSSC20K1241. B.D.H., T.C.H., and T.F. were supported by NASA JPL Task 105393.281945.02.25.04.59. R.E.K. and J.S.W. were supported by U.S. National Aeronautics and Space Administration (grants 80NSSC17K0698, 80NSSC20K1724 and JPL task 105393.509496.02.08.13.31) and U.S. National Science Foundation (grant ICER-1663807). P.R.T. acknowledges financial support from the NOAA Global Ocean Monitoring and Observing program in support of the University of Hawaii Sea Level Center (NA11NMF4320128). The ECCO project is funded by the NASA Physical Oceanography; Modeling, Analysis, and Prediction; and Cryosphere Programs

Molecular evidence of Rickettsia felis infection in dogs from northern territory, Australia

The prevalence of spotted fever group rickettsial infection in dogs from a remote indigenous community in the Northern Territory (NT) was determined using molecular tools. Blood samples collected from 130 dogs in the community of Maningrida were subjected to a spotted fever group (SFG)-specific PCR targeting the ompB gene followed by a Rickettsia felis-specific PCR targeting the gltA gene of R. felis. Rickettsia felis ompB and gltA genes were amplified from the blood of 3 dogs. This study is the first report of R. felis infection in indigenous community dogs in NT

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts