Direct Profiling the Post-Translational Modification Codes of a Single Protein Immobilized on a Surface Using Cu-free Click Chemistry

Combinatorial post-translational modifications (PTMs), which can serve as dynamic molecular barcodes, have been proposed to regulate distinct protein functions. However, studies of combinatorial PTMs on single protein molecules have been hindered by a lack of suitable analytical methods. Here, we describe erasable single-molecule blotting (eSiMBlot) for combinatorial PTM profiling. This assay is performed in a highly multiplexed manner and leverages the benefits of covalent protein immobilization, cyclic probing with different antibodies, and single molecule fluorescence imaging. Especially, facile and efficient covalent immobilization on a surface using Cu-free click chemistry permits multiple rounds (>10) of antibody erasing/reprobing without loss of antigenicity. Moreover, cumulative detection of coregistered multiple data sets for immobilized single-epitope molecules, such as HA peptide, can be used to increase the antibody detection rate. Finally, eSiMBlot enables direct visualization and quantitative profiling of combinatorial PTM codes at the single-molecule level, as we demonstrate by revealing the novel phospho-codes of ligand-induced epidermal growth factor receptor. Thus, eSiMBlot provides an unprecedentedly simple, rapid, and versatile platform for analyzing the vast number of combinatorial PTMs in biological pathways. Copyright © 2018 American Chemical Societ

The use of chemoprophylaxis in East African Zebu village cattle exposed to trypanosomiasis in Muhaka, Kenya

A study conducted to assess the efficacy of chemoprophylaxis for the improvement of the health and productivity of East African Zebu village cattle exposed to trypanosomiasis. Examines the cost-effectiveness of the treatment. Includes data on calf pre-weaning health and weight traits, weight traits of calves from 12-18 months of age, calf post-weaning health and weight traits, and breeding cow health and production traits - for the non-prophylactic and prophylactic groups

Tidal Venuses: Triggering a Climate Catastrophe via Tidal Heating

Traditionally stellar radiation has been the only heat source considered capable of determining global climate on long timescales. Here we show that terrestrial exoplanets orbiting low-mass stars may be tidally heated at high enough levels to induce a runaway greenhouse for a long enough duration for all the hydrogen to escape. Without hydrogen, the planet no longer has water and cannot support life. We call these planets "Tidal Venuses," and the phenomenon a "tidal greenhouse." Tidal effects also circularize the orbit, which decreases tidal heating. Hence, some planets may form with large eccentricity, with its accompanying large tidal heating, and lose their water, but eventually settle into nearly circular orbits (i.e. with negligible tidal heating) in the habitable zone (HZ). However, these planets are not habitable as past tidal heating desiccated them, and hence should not be ranked highly for detailed follow-up observations aimed at detecting biosignatures. Planets orbiting stars with masses <0.3 solar masses may be in danger of desiccation via tidal heating. We apply these concepts to Gl 667C c, a ~4.5 Earth-mass planet orbiting a 0.3 solar mass star at 0.12 AU. We find that it probably did not lose its water via tidal heating as orbital stability is unlikely for the high eccentricities required for the tidal greenhouse. As the inner edge of the HZ is defined by the onset of a runaway or moist greenhouse powered by radiation, our results represent a fundamental revision to the HZ for non-circular orbits. In the appendices we review a) the moist and runaway greenhouses, b) hydrogen escape, c) stellar mass-radius and mass-luminosity relations, d) terrestrial planet mass-radius relations, and e) linear tidal theories. [abridged]Comment: 59 pages, 11 figures, accepted to Astrobiology. New version includes an appendix on the water loss timescal

Gene-expression analysis of clozapine treatment in whole blood of patients with psychosis

OBJECTIVES: Clozapine is an atypical antipsychotic primarily prescribed for treatment-resistant schizophrenia. We tested the specific effect of clozapine versus other drug treatments on whole-blood gene expression in a sample of patients with psychosis from the UK. METHODS: A total of 186 baseline whole-blood samples from individuals receiving treatment for established psychosis were analysed for gene expression on Illumina HumanHT-12.v4 BeadChips. After standard quality-control procedures, 152 samples remained, including 55 from individuals receiving clozapine. In a within-case study design, weighted gene correlation network analysis was used to identify modules of coexpressed genes. The influence of mood stabilizers, lithium carbonate/lithium citrate and sodium valproate was studied to identify their possible roles as confounders. RESULTS: Individuals receiving clozapine as their only antipsychotic (clozapine monotherapy) had a nominal association with one gene-expression module, whereas no significant change in gene expression was found for other drugs. CONCLUSION: Overall, this study does not provide evidence that clozapine treatment induces medium to large different gene-expression patterns in human whole blood versus other antipsychotic treatments. This does not rule out the possibility of smaller effects as observed for other common antipsychotic treatments

A population biological model with a singular nonlinearity

summary:We consider the existence of positive solutions of the singular nonlinear semipositone problem of the form $$\begin {cases} -{\rm div}(|x|^{-\alpha p}|\nabla u|^{p-2}\nabla u)=|x|^{-(\alpha +1)p+\beta } \Big (a u^{p-1}-f(u)-\dfrac {c}{u^{\gamma }}\Big ), \quad x\in \Omega ,\\ u=0, \quad x\in \partial \Omega , \end {cases}$$ where $\Omega$ is a bounded smooth domain of ${\mathbb R}^N$ with $0\in \Omega$, $1<p<N$, $0\leq \alpha < {(N-p)}/{p}$, $\gamma \in (0,1)$, and $a$, $\beta$, $c$ and $\lambda$ are positive parameters. Here $f\colon [0,\infty )\to {\mathbb R}$ is a continuous function. This model arises in the studies of population biology of one species with $u$ representing the concentration of the species. We discuss the existence of a positive solution when $f$ satisfies certain additional conditions. We use the method of sub-supersolutions to establish our results

Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter

Mammals are coinfected by multiple pathogens that interact through unknown mechanisms. We found that helminth infection, characterized by the induction of the cytokine interleukin-4 (IL-4) and the activation of the transcription factor Stat6, reactivated murine γ-herpesvirus infection in vivo. IL-4 promoted viral replication and blocked the antiviral effects of interferon-γ (IFNγ) by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. IL-4 also reactivated human Kaposi's sarcoma-associated herpesvirus from latency in cultured cells. Exogenous IL-4 plus blockade of IFNγ reactivated latent murine γ-herpesvirus infection in vivo, suggesting a "two-signal" model for viral reactivation. Thus, chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status

Self-optimization, community stability, and fluctuations in two individual-based models of biological coevolution

We compare and contrast the long-time dynamical properties of two individual-based models of biological coevolution. Selection occurs via multispecies, stochastic population dynamics with reproduction probabilities that depend nonlinearly on the population densities of all species resident in the community. New species are introduced through mutation. Both models are amenable to exact linear stability analysis, and we compare the analytic results with large-scale kinetic Monte Carlo simulations, obtaining the population size as a function of an average interspecies interaction strength. Over time, the models self-optimize through mutation and selection to approximately maximize a community fitness function, subject only to constraints internal to the particular model. If the interspecies interactions are randomly distributed on an interval including positive values, the system evolves toward self-sustaining, mutualistic communities. In contrast, for the predator-prey case the matrix of interactions is antisymmetric, and a nonzero population size must be sustained by an external resource. Time series of the diversity and population size for both models show approximate 1/f noise and power-law distributions for the lifetimes of communities and species. For the mutualistic model, these two lifetime distributions have the same exponent, while their exponents are different for the predator-prey model. The difference is probably due to greater resilience toward mass extinctions in the food-web like communities produced by the predator-prey model.Comment: 26 pages, 12 figures. Discussion of early-time dynamics added. J. Math. Biol., in pres

The Effect of Nutrient Intake on Bone Mineral Status in Young Adults: The Northern Ireland Young Hearts Project

Aunque hemos hablado de ello, no estará de más recordar que uno de los mejores blogs de historia es el de la Historical Society. Este recién empezado año lo han inaugurado con un repaso al número que su revista, Historically Speaking, publicó a principios de 2009. Ha pasado cierto tiempo, es evidente, pero conviene detenerse en su contenido, porque no es habitual: la forma en la que escribimos  la historia. En efecto, la citada publicación dedicó una mesa redonda a debatir sobre "Teaching the..

Parental attendance in two early-childhood training programmes to improve nurturing care: a randomized controlled trial

Parent training programmes have significant potential to improve the quality of children's early environments and thereby their development and life-course outcomes. The aim of this study was to identify and explain the extent to which parents engaged in two group-based training programmes, offered to high-risk families enrolled in a randomized controlled trial study called PIÁ in Southern Brazil. The programmes were: (1) ACT: Raising Safe Kids, a 9-week programme aiming to reduce harsh parenting and maltreatment and improve positive parenting practices; (2) Dialogic book-sharing (DBS), an 8-week programme aiming to promote parental sensitivity and improve child cognitive development and social understanding. Of the 123 mothers randomly allocated to the ACT programme, 64.2% (n = 79) completed the course, and of 124 mothers allocated to DBS, 76.6% (n = 95) completed the course. After the interventions, mothers were very positive about the experience of both programmes but highlighted practical difficulties in attending. In adjusted regression analyses, only two variables significantly predicted ACT course completion (maternal age and distance between the intervention site and household); no significant predictor was found for DBS attendance. We conclude that although high completion rates are possible, there are important challenges to engaging parents of young children in training programmes, and practical difficulties occurring during training courses may be more important for attendance than baseline participant characteristics

The status of GEO 600

The GEO 600 laser interferometer with 600m armlength is part of a worldwide network of gravitational wave detectors. GEO 600 is unique in having advanced multiple pendulum suspensions with a monolithic last stage and in employing a signal recycled optical design. This paper describes the recent commissioning of the interferometer and its operation in signal recycled mode