The effects of subcurative praziquantel treatment on life-history traits and trade-offs in drug-resistant Schistosoma mansoni

Natural selection acts on all organisms, including parasites, to maximize reproductive fitness. Drug resistance traits are often associated with life-history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian state-space models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma mansoni may be limited by life-history costs not present in susceptible counterparts. S. mansoni parasites from a praziquantel-susceptible (S), a praziquantel-resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life-history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade-offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade-offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life-history traits within the molluscan host were complex, but trade-offs were demonstrated between parasite establishment and cercarial output. The observed trade-offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life-history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life-history parameters, aiding our understanding of costs and trade-offs of resistant parasites within this system and beyond

The laboratory millimeter-wave spectrum of methyl formate in its ground torsional E state

Over 250 rotational transitions of the internal rotor methyl formate (HCOOCH_3) in its ground v_t = 0 degenerate (E) torsional substate have been measured in the millimeter-wave spectral region. These data and a number of E-state lines identified by several other workers have been analyzed using an extension of the classical principal-axis method in the high barrier limit. The resulting rotational constants allow accurate prediction of the v_t = 0 E substate methyl formate spectrum below 300 GHz between states with angular momentum J ≤ 30 and rotational energy E_(rot)≤ 350cm^(-1). The calculated transition frequencies for the E state, when combined with the results of the previous analysis of the ground-symmetric, nondegenerate state, account for over 200 of the emission lines observed toward Orion in a recent survey of the 215-265 GHz band

Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

Background Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen‐activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance. Objectives To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy. Methods Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib‐induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib‐resistant melanoma cell survival and invasion, respectively. Results CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF‐mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271‐expressing subpopulations. Trametinib‐induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271‐expressing melanoma subpopulations with RNA interference and small‐molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents – including Δ9‐tetrahydrocannabinol and Vps34 – reduced survival of MEKi‐resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi‐resistant cells in an in vivo zebrafish xenograft. Conclusions These results highlight a novel mechanism of MEKi‐induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug‐resistant melanoma cells to the cytotoxic effects of MEKi

Automatic speech recognition research at NASA-Ames Research Center

A trainable acoustic pattern recognizer manufactured by Scope Electronics is presented. The voice command system VCS encodes speech by sampling 16 bandpass filters with center frequencies in the range from 200 to 5000 Hz. Variations in speaking rate are compensated for by a compression algorithm that subdivides each utterance into eight subintervals in such a way that the amount of spectral change within each subinterval is the same. The recorded filter values within each subinterval are then reduced to a 15-bit representation, giving a 120-bit encoding for each utterance. The VCS incorporates a simple recognition algorithm that utilizes five training samples of each word in a vocabulary of up to 24 words. The recognition rate of approximately 85 percent correct for untrained speakers and 94 percent correct for trained speakers was not considered adequate for flight systems use. Therefore, the built-in recognition algorithm was disabled, and the VCS was modified to transmit 120-bit encodings to an external computer for recognition

Parent-infant interaction in infant siblings at risk of autism

Recent models of the early emergence of autism spectrum disorder (ASD) propose an interaction between risk susceptibility and the infant's social environment, resulting in a progressively atypical developmental trajectory. The infant's early social environmental experience consists mostly of interaction with caregivers, yet there has been little systematic study of early parent-infant interaction in infants at risk of ASD. This study examined the global characteristics of parent-infant interaction in 6- to 10-month-old infants with an older sibling diagnosed with ASD (at-risk sibs), in comparison with a group of infants with no family history of ASD (low-risk sibs). As part of the British Autism Study of Infant Siblings (BASIS), 6-min videotaped unstructured play interactions of mother-infant dyads (45 at-risk sibs and 47 low-risk sibs) were rated on global aspects of parent-infant interaction, blind to participant information. Differences in global characteristics of interaction were observed in both infant and parent contributions in the at-risk group compared to low-risk controls. In analyses adjusted for age and developmental level, at-risk sib infants were less lively, and their parents showed higher directiveness, and lower sensitive responding (as a trend after adjustment). Level of infant liveliness was independent of other interactive behaviour. Consistent with reports in previous literature in older children with autism and in other neurodevelopmental disorders, our findings may suggest that infants at genetic risk are exposed to a more directive interactive style relatively early in infancy. We discuss possible explanations for these findings and implications for further developmental study and intervention. (C) 2012 Elsevier Ltd. All rights reserved.</p

Conditional Image-Text Embedding Networks

This paper presents an approach for grounding phrases in images which jointly learns multiple text-conditioned embeddings in a single end-to-end model. In order to differentiate text phrases into semantically distinct subspaces, we propose a concept weight branch that automatically assigns phrases to embeddings, whereas prior works predefine such assignments. Our proposed solution simplifies the representation requirements for individual embeddings and allows the underrepresented concepts to take advantage of the shared representations before feeding them into concept-specific layers. Comprehensive experiments verify the effectiveness of our approach across three phrase grounding datasets, Flickr30K Entities, ReferIt Game, and Visual Genome, where we obtain a (resp.) 4%, 3%, and 4% improvement in grounding performance over a strong region-phrase embedding baseline.Comment: ECCV 2018 accepted pape

The millimeter and submillimeter laboratory spectrum of methyl formate in its ground symmetric torsional state

Over 200 rotational lines of methyl formate in its ground (v-t = 0), symmetric (A) torsional state have been measured in the frequency range 140-550 GHz. Analysis of these and lower frequency transitions permits accurate prediction (≤0.1 MHz) of over 10,000 transitions at frequencies below 600 GHz with angular momentum J ≤ 50. The measured spectral lines have permitted identification of over 100 new methyl formate lines in Orion

Direct Dark Matter Detection with Velocity Distribution in the Eddington approach

Exotic dark matter together with the vacuum energy (associated with the cosmological constant) seem to dominate the Universe. Thus its direct detection is central to particle physics and cosmology. Supersymmetry provides a natural dark matter candidate, the lightest supersymmetric particle (LSP). One essential ingredient in obtaining the direct detection rates is the density and the velocity distribution of the LSP in our vicinity. In the present paper we study simultaneously density profiles and velocity distributions in the context of the Eddington approach. In such an approach, unlike the commonly assumed Maxwell-Boltzmann (M-B) distribution, the upper bound of the velocity arises naturally from the potential.Comment: 21 LaTex pages, 27 figure