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Small-Scale Food Animal Production and Antimicrobial Resistance: Mountain, Molehill, or Something in-between?
SummarySmall-scale food animal production is widely practiced around the globe, yet it is often overlooked in terms of the environmental health risks. Evidence suggests that small-scale food animal producers often employ the use of antimicrobials to improve the survival and growth of their animals, and that this practice leads to the development of antimicrobial resistance (AMR) that can potentially spread to humans. The nature of human-animal interactions in small-scale food animal production systems, generally practiced in and around the home, likely augments spillover events of AMR into the community on a scale that is currently unrecognized and deserves greater attention. https://doi.org/10.1289/EHP2116
ActivityNET: Neural networks to predict public transport trip purposes from individual smart card data and POIs
Predicting trip purpose from comprehensive and continuous smart card data is beneficial for transport and city planners in investigating travel behaviors and urban mobility. Here, we propose a framework, ActivityNET, using Machine Learning (ML) algorithms to predict passengersâ trip purpose from Smart Card (SC) data and Points-of-Interest (POIs) data. The feasibility of the framework is demonstrated in two phases. Phase I focuses on extracting activities from individualsâ daily travel patterns from smart card data and combining them with POIs using the proposed âactivity-POIs consolidation algorithmâ. Phase II feeds the extracted features into an Artificial Neural Network (ANN) with multiple scenarios and predicts trip purpose under primary activities (home and work) and secondary activities (entertainment, eating, shopping, child drop-offs/pick-ups and part-time work) with high accuracy. As a case study, the proposed ActivityNET framework is applied in Greater London and illustrates a robust competence to predict trip purpose. The promising outcomes demonstrate that the cost-effective framework offers high predictive accuracy and valuable insights into transport planning
A three amino acid deletion in the transmembrane domain of the nicotinic acetylcholine receptor α6 subunit confers high-level resistance to spinosad in Plutella xylostella
Spinosad is a macrocyclic lactone insecticide that acts primarily at the nicotinic acetylcholine receptors (nAChRs) of target insects. Here we describe evidence that high levels of resistance to spinosad in the diamondback moth (Plutella xylostella) are associated with a three amino acid (3-aa) deletion in the fourth transmembrane domain (TM4) of the nAChR α6 subunit (Pxα6). Following laboratory selection with spinosad, the SZ-SpinR strain of P. xylostella exhibited 940-fold resistance to spinosad. In addition, the selected insect population had 1060-fold cross-resistance to spinetoram but, in contrast, no cross-resistance to abamectin was observed. Genetic analysis indicates that spinosad resistance in SZ-SpinR is inherited as a recessive and autosomal trait, and that the 3-aa deletion (IIA) in TM4 of Pxα6 is tightly linked to spinosad resistance. Because of well-established difficulties in functional expression of cloned insect nAChRs, the analogous resistance-associated deletion mutation was introduced into a prototype nAChR (the cloned human α7 subunit). Two-electrode voltage-clamp recording with wild-type and mutated nAChRs expressed in Xenopus laevis oocytes indicated that the mutation causes a complete loss of agonist activation. In addition, radioligand binding studies indicated that the 3-aa deletion resulted in significantly lower-affinity binding of the extracellular neurotransmitter-binding site. These findings are consistent with the 3-amino acid (IIA) deletion within the transmembrane domain of Pxα6 being responsible for target-site resistance to spinosad in the SZ-SpinR strain of P. xylostella
Synergistic and compensatory effects of two point mutations conferring target-site resistance to fipronil in the insect GABA receptor RDL
Insecticide resistance can arise from a variety of mechanisms, including changes to the target site, but is often associated with substantial fitness costs to insects. Here we describe two resistance-associated target-site mutations that have synergistic and compensatory effects that combine to produce high and persistent levels of resistance to fipronil, an insecticide targeting on Îł-aminobytyric acid (GABA) receptors. In Nilaparvata lugens, a major pest of rice crops in many parts of Asia, we have identified a single point mutation (A302S) in the GABA receptor RDL that has been identified previously in other species and which confers low levels of resistance to fipronil (23-fold) in N. lugans. In addition, we have identified a second resistance-associated RDL mutation (R300Q) that, in combination with A302S, is associated with much higher levels of resistance (237-fold). The R300Q mutation has not been detected in the absence of A302S in either laboratory-selected or field populations, presumably due to the high fitness cost associated with this mutation. Significantly, it appears that the A302S mutation is able to compensate for deleterious effects of R300Q mutation on fitness cost. These findings identify a novel resistance mechanism and may have important implications for the spread of insecticide resistance
Exploring the relationship between travel pattern and social-demographics using smart card data and household survey
Understanding social-demographics of passengers in public transit systems is significant for transportation operators and city planners in many real applications, such as forecasting travel demand and providing personalised transportation service. This paper develops an entire framework to analyse the relationship between passengersâ movement patterns and social-demographics by using smart card (SC) data with a household survey. The study first extracts various novel travel features of passengers from SC data, including spatial, temporal, travel mode and travel frequency features, to identify long-term travel patterns and their seasonality, for the in-depth understanding of âhowâ people travel in cities. Leveraging household survey data, we then classify passengers into several groups based on their social-demographic characteristics, such as age, and working status, to identify the homogeneity of travellers for understanding âwhoâ travels using public transit. Finally, we explore the significant relationships between the travel patterns and demographic clusters. This research reveals explicit semantic explanations of âwhyâ passengers exhibit these travel patterns
Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens
Several human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.postprin
ProteoMirExpress: inferring microRNA-centered regulatory networks from high-throughput proteomic and transcriptome data
MicroRNAs (miRNAs) regulate gene expression through translational repression and RNA degradation. Recently developed high-throughput proteomic methods measure gene expression changes at protein levels, and therefore can reveal the direct effects of miRNAsâ translational repression. Here, we present a web server, ProteoMirExpress that integrates proteomic and mRNA expression data together to infer miRNA-centered regulatory networks. With both high throughput data from the users, ProteoMirExpress is able to discover not only miRNA targets that have mRNA decreased, but also subgroups of targets whose proteins are suppressed but mRNAs are not significantly changed or whose mRNAs are decreased but proteins are not significantly changed, which were usually ignored by most current methods. Furthermore, both direct and indirect targets of miRNAs can be detected. Therefore ProteoMirExpress provides more comprehensive miRNA-centered regulatory networks. We use several published data to assess the quality of our inferred networks and prove the value of our server. ProteoMirExpress is available at http://jjwanglab.org/ProteoMirExpress, with free access to academic users.postprin
Brain penetrant LRRK2 inhibitor
This is the author accepted manuscript. The final version is available from ACS via the DOI in this record.âŻActivating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5- chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 ÎŒM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg. © 2012 American Chemical Society.NIHMedical Research CouncilMichael J Fox foundation for Parkinsonâs disease researchPharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer
T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells
Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al
Decoherence induced deformation of the ground state in adiabatic quantum computation
Despite more than a decade of research on adiabatic quantum computation
(AQC), its decoherence properties are still poorly understood. Many theoretical
works have suggested that AQC is more robust against decoherence, but a
quantitative relation between its performance and the qubits' coherence
properties, such as decoherence time, is still lacking. While the thermal
excitations are known to be important sources of errors, they are predominantly
dependent on temperature but rather insensitive to the qubits' coherence. Less
understood is the role of virtual excitations, which can also reduce the ground
state probability even at zero temperature. Here, we introduce normalized
ground state fidelity as a measure of the decoherence-induced deformation of
the ground state due to virtual transitions. We calculate the normalized
fidelity perturbatively at finite temperatures and discuss its relation to the
qubits' relaxation and dephasing times, as well as its projected scaling
properties.Comment: 10 pages, 3 figure
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