A target repurposing approach identifies N-myristoyltransferase as a new candidate drug target in filarial nematodes

Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5-10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis

Adverse Pregnancy Outcomes Following Motor Vehicle Crashes

Motor vehicle crashes are a leading cause of serious trauma during pregnancy, but little is known about their relationships with pregnancy outcomes

2dFLenS and KiDS: determining source redshift distributions with cross-correlations

We develop a statistical estimator to infer the redshift probability distribution of a photometric sample of galaxies from its angular cross-correlation in redshift bins with an overlapping spectroscopic sample. This estimator is a minimum-variance weighted quadratic function of the data: a quadratic estimator. This extends and modifies the methodology presented by McQuinn & White. The derived source redshift distribution is degenerate with the source galaxy bias, which must be constrained via additional assumptions. We apply this estimator to constrain source galaxy redshift distributions in the Kilo-Degree imaging survey through cross-correlation with the spectroscopic 2-degree Field Lensing Survey, presenting results first as a binned step-wise distribution in the range z < 0.8, and then building a continuous distribution using a Gaussian process model. We demonstrate the robustness of our methodology using mock catalogues constructed from N-body simulations, and comparisons with other techniques for inferring the redshift distribution

Differential susceptibility of Onchocerca volvulus microfilaria to ivermectin in two areas of contrasting history of mass drug administration in Cameroon: relevance of microscopy and molecular techniques for the monitoring of skin microfilarial repopulation within six months of direct observed treatment

Background Ivermectin is an excellent microfilaricide against Onchocerca volvulus. However, in some regions, long term use of ivermectin has resulted in sub-optimal responses to the treatment. More data to properly document the phenomenon in various contexts of ivermectin mass drug administration (IVM-MDA) is needed. Also, there is a need to accurately monitor a possible repopulation of skin by microfilariae following treatment. Skin snip microscopy is known to have a low sensitivity in individuals with light infections, which can be the case following treatment. This study was designed with two complementary objectives: (i) to assess the susceptibility of O. volvulus microfilariae to ivermectin in two areas undergoing IVM-MDA for different lengths of time, and (ii) to document the repopulation of skin by the O. volvulus microfilariae following treatment, using 3 independent diagnostic techniques. Method Identified microfilaridermic individuals were treated with ivermectin and re-examined after 1, 3, and 6 months using microscopy, actin real-time PCR (actin-qPCR) and O-150 LAMP assays. Susceptibility to ivermectin and trends in detecting reappearance of skin microfilariae were determined using three techniques. Microscopy was used as an imperfect gold standard to determine the performance of actin-qPCR and LAMP. Results In Bafia with over 20 years of IVM-MDA, 11/51 (21.6%) direct observe treated microfilaridemic participants were still positive for skin microfilariae after 1 month. In Melong, with 10 years of IVM-MDA, 2/29 (6.9%) treated participants were still positive. The microfilarial density reduction per skin biopsy within one month following treatment was significantly lower in participants from Bafia. In both study sites, the molecular techniques detected higher proportions of infected individuals than microscopy at all monitoring time points. LAMP demonstrated the highest levels of sensitivity and real-time PCR was found to have the highest specificity. Conclusion Patterns in skin mirofilariae clearance and repopulation were established. O. volvulus worms from Bafia with higher number of annual MDA displayed a lower clearance and higher repopulation rate after treatment with ivermectin. Molecular assays displayed higher sensitivity in monitoring O. volvulus microfilaridemia within six months following treatment

Loss and dispersion of superficial white matter in Alzheimer's disease: a diffusion MRI study.

Pathological cerebral white matter changes in Alzheimer's disease have been shown using diffusion tensor imaging. Superficial white matter changes are relatively understudied despite their importance in cortico-cortical connections. Measuring superficial white matter degeneration using diffusion tensor imaging is challenging due to its complex organizational structure and proximity to the cortex. To overcome this, we investigated diffusion MRI changes in young-onset Alzheimer's disease using standard diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging to distinguish between disease-related changes that are degenerative (e.g. loss of myelinated fibres) and organizational (e.g. increased fibre dispersion). Twenty-nine young-onset Alzheimer's disease patients and 22 healthy controls had both single-shell and multi-shell diffusion MRI. We calculated fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index and tissue fraction (1-free water fraction). Diffusion metrics were sampled in 15 a priori regions of interest at four points along the cortical profile: cortical grey matter, grey/white boundary, superficial white matter (1 mm below grey/white boundary) and superficial/deeper white matter (2 mm below grey/white boundary). To estimate cross-sectional group differences, we used average marginal effects from linear mixed effect models of participants' diffusion metrics along the cortical profile. The superficial white matter of young-onset Alzheimer's disease individuals had lower neurite density index compared to controls in five regions (superior and inferior parietal, precuneus, entorhinal and parahippocampus) (all P < 0.05), and higher orientation dispersion index in three regions (fusiform, entorhinal and parahippocampus) (all P < 0.05). Young-onset Alzheimer's disease individuals had lower fractional anisotropy in the entorhinal and parahippocampus regions (both P < 0.05) and higher fractional anisotropy within the postcentral region (P < 0.05). Mean diffusivity was higher in the young-onset Alzheimer's disease group in the parahippocampal region (P < 0.05) and lower in the postcentral, precentral and superior temporal regions (all P < 0.05). In the overlying grey matter, disease-related changes were largely consistent with superficial white matter findings when using neurite density index and fractional anisotropy, but appeared at odds with orientation dispersion and mean diffusivity. Tissue fraction was significantly lower across all grey matter regions in young-onset Alzheimer's disease individuals (all P < 0.001) but group differences reduced in magnitude and coverage when moving towards the superficial white matter. These results show that microstructural changes occur within superficial white matter and along the cortical profile in individuals with young-onset Alzheimer's disease. Lower neurite density and higher orientation dispersion suggests underlying fibres undergo neurodegeneration and organizational changes, two effects previously indiscernible using standard diffusion tensor metrics in superficial white matter

2dFLenS and KiDS: Determining source redshift distributions with cross-correlations

We develop a statistical estimator to infer the redshift probability distribution of a photometric sample of galaxies from its angular cross-correlation in redshift bins with an overlapping spectroscopic sample. This estimator is a minimum-variance weighted quadratic function of the data: a quadratic estimator. This extends and modifies the methodology presented by McQuinn & White. The derived source redshift distribution is degenerate with the source galaxy bias, which must be constrained via additional assumptions. We apply this estimator to constrain source galaxy redshift distributions in theKilo-Degree imaging survey through crosscorrelation with the spectroscopic 2-degree Field Lensing Survey, presenting results first as a binned step-wise distribution in the range z < 0.8, and then building a continuous distribution using a Gaussian process model. We demonstrate the robustness of our methodology using mock catalogues constructed from N-body simulations, and comparisons with other techniques for inferring the redshift distribution.CB acknowledges the support of the Australian Research Council through the award of a Future Fellowship. JHD acknowledges support from the European Commission under a Marie-SkłodwoskaCurie European Fellowship (EU project 656869) and from the NSERC of Canada. CH acknowledges funding from the European Research Council under grant number 647112. HH and CBM are supported by an Emmy Noether grant (No. Hi 1495/2-1) of the Deutsche Forschungsgemeinschaft. DK is supported by the Deutsche Forschungsgemeinschaft in the framework of the TR33 ‘The Dark Universe’. KK acknowledges support by the Alexander von Humboldt Foundatio

The 2-degree Field Lensing Survey: design and clustering measurements

We present the 2-degree Field Lensing Survey (2dFLenS), a new galaxy redshift survey performed at the Anglo-Australian Telescope. 2dFLenS is the first wide-area spectroscopic survey specifically targeting the area mapped by deep-imaging gravitational lensing fields, in this case the Kilo-Degree Survey. 2dFLenS obtained 70 079 redshifts in the range z < 0.9 over an area of 731 deg2, and is designed to extend the data sets available for testing gravitational physics and promote the development of relevant algorithms for joint imaging and spectroscopic analysis. The redshift sample consists first of 40 531 Luminous Red Galaxies (LRGs), which enable analyses of galaxy–galaxy lensing, redshift-space distortion, and the overlapping source redshift distribution by cross-correlation. An additional 28 269 redshifts form a magnitude-limited (r < 19.5) nearly complete subsample, allowing direct source classification and photometric-redshift calibration. In this paper, we describe the motivation, target selection, spectroscopic observations, and clustering analysis of 2dFLenS. We use power spectrum multipole measurements to fit the redshift-space distortion parameter of the LRG sample in two redshift ranges 0.15 < z < 0.43 and 0.43 < z < 0.7 as β = 0.49 ± 0.15 and β = 0.26 ± 0.09, respectively. These values are consistent with those obtained from LRGs in the Baryon Oscillation Spectroscopic Survey. 2dFLenS data products will be released via our website http://2dflens.swin.edu.au