Transcriptional profiling of cattle infected with Trypanosoma congolense highlights gene expression signatures underlying trypanotolerance and trypanosusceptibility

<p>Abstract</p> <p>Background</p> <p>African animal trypanosomiasis (AAT) caused by tsetse fly-transmitted protozoa of the genus <it>Trypanosoma </it>is a major constraint on livestock and agricultural production in Africa and is among the top ten global cattle diseases impacting on the poor. Here we show that a functional genomics approach can be used to identify temporal changes in host peripheral blood mononuclear cell (PBMC) gene expression due to disease progression. We also show that major gene expression differences exist between cattle from trypanotolerant and trypanosusceptible breeds. Using bovine long oligonucleotide microarrays and real time quantitative reverse transcription PCR (qRT-PCR) validation we analysed PBMC gene expression in naïve trypanotolerant and trypanosusceptible cattle experimentally challenged with <it>Trypanosoma congolense </it>across a 34-day infection time course.</p> <p>Results</p> <p>Trypanotolerant N'Dama cattle displayed a rapid and distinct transcriptional response to infection, with a ten-fold higher number of genes differentially expressed at day 14 post-infection compared to trypanosusceptible Boran cattle. These analyses identified coordinated temporal gene expression changes for both breeds in response to trypanosome infection. In addition, a panel of genes were identified that showed pronounced differences in gene expression between the two breeds, which may underlie the phenomena of trypanotolerance and trypanosusceptibility. Gene ontology (GO) analysis demonstrate that the products of these genes may contribute to increased mitochondrial mRNA translational efficiency, a more pronounced B cell response, an elevated activation status and a heightened response to stress in trypanotolerant cattle.</p> <p>Conclusion</p> <p>This study has revealed an extensive and diverse range of cellular processes that are altered temporally in response to trypanosome infection in African cattle. Results indicate that the trypanotolerant N'Dama cattle respond more rapidly and with a greater magnitude to infection compared to the trypanosusceptible Boran cattle. Specifically, a subset of the genes analyzed by real time qRT-PCR, which display significant breed differences, could collectively contribute to the trypanotolerance trait in N'Dama.</p

Transcriptional adaptations following exercise in Thoroughbred horse skeletal muscle highlights molecular mechanisms that lead to muscle hypertrophy

<p>Abstract</p> <p>Background</p> <p>Selection for exercise-adapted phenotypes in the Thoroughbred racehorse has provided a valuable model system to understand molecular responses to exercise in skeletal muscle. Exercise stimulates immediate early molecular responses as well as delayed responses during recovery, resulting in a return to homeostasis and enabling long term adaptation. Global mRNA expression during the immediate-response period has not previously been reported in skeletal muscle following exercise in any species. Also, global gene expression changes in equine skeletal muscle following exercise have not been reported. Therefore, to identify novel genes and key regulatory pathways responsible for exercise adaptation we have used equine-specific cDNA microarrays to examine global mRNA expression in skeletal muscle from a cohort of Thoroughbred horses (<it>n = </it>8) at three time points (before exercise, immediately post-exercise, and four hours post-exercise) following a single bout of treadmill exercise.</p> <p>Results</p> <p>Skeletal muscle biopsies were taken from the <it>gluteus medius </it>before (T₀), immediately after (T₁) and four hours after (T₂) exercise. Statistically significant differences in mRNA abundance between time points (T₀<it>vs </it>T₁and T₀<it>vs </it>T₂) were determined using the empirical Bayes moderated <it>t</it>-test in the Bioconductor package Linear Models for Microarray Data (LIMMA) and the expression of a select panel of genes was validated using real time quantitative reverse transcription PCR (qRT-PCR). While only two genes had increased expression at T₁(<it>P </it>< 0.05), by T₂932 genes had increased (<it>P </it>< 0.05) and 562 genes had decreased expression (<it>P </it>< 0.05). Functional analysis of genes differentially expressed during the recovery phase (T₂) revealed an over-representation of genes localized to the actin cytoskeleton and with functions in the MAPK signalling, focal adhesion, insulin signalling, mTOR signaling, p53 signaling and Type II diabetes mellitus pathways. At T₁, using a less stringent statistical approach, we observed an over-representation of genes involved in the stress response, metabolism and intracellular signaling. These findings suggest that protein synthesis, mechanosensation and muscle remodeling contribute to skeletal muscle adaptation towards improved integrity and hypertrophy.</p> <p>Conclusions</p> <p>This is the first study to characterize global mRNA expression profiles in equine skeletal muscle using an equine-specific microarray platform. Here we reveal novel genes and mechanisms that are temporally expressed following exercise providing new knowledge about the early and late molecular responses to exercise in the equine skeletal muscle transcriptome.</p

Field Theory And Second Renormalization Group For Multifractals In Percolation

The field-theory for multifractals in percolation is reformulated in such a way that multifractal exponents clearly appear as eigenvalues of a second renormalization group. The first renormalization group describes geometrical properties of percolation clusters, while the second-one describes electrical properties, including noise cumulants. In this context, multifractal exponents are associated with symmetry-breaking fields in replica space. This provides an explanation for their observability. It is suggested that multifractal exponents are ''dominant'' instead of ''relevant'' since there exists an arbitrary scale factor which can change their sign from positive to negative without changing the Physics of the problem.Comment: RevTex, 10 page

Diluted Networks of Nonlinear Resistors and Fractal Dimensions of Percolation Clusters

We study random networks of nonlinear resistors, which obey a generalized Ohm's law, $V\sim I^r$. Our renormalized field theory, which thrives on an interpretation of the involved Feynman Diagrams as being resistor networks themselves, is presented in detail. By considering distinct values of the nonlinearity r, we calculate several fractal dimensions characterizing percolation clusters. For the dimension associated with the red bonds we show that $d_{\scriptsize red} = 1/\nu$ at least to order {\sl O} (\epsilon^4), with $\nu$ being the correlation length exponent, and $\epsilon = 6-d$, where d denotes the spatial dimension. This result agrees with a rigorous one by Coniglio. Our result for the chemical distance, d_{\scriptsize min} = 2 - \epsilon /6 - [ 937/588 + 45/49 (\ln 2 -9/10 \ln 3)] (\epsilon /6)^2 + {\sl O} (\epsilon^3) verifies a previous calculation by one of us. For the backbone dimension we find D_B = 2 + \epsilon /21 - 172 \epsilon^2 /9261 + 2 (- 74639 + 22680 \zeta (3))\epsilon^3 /4084101 + {\sl O} (\epsilon^4), where $\zeta (3) = 1.202057...$, in agreement to second order in $\epsilon$ with a two-loop calculation by Harris and Lubensky.Comment: 29 pages, 7 figure

Noisy random resistor networks: renormalized field theory for the multifractal moments of the current distribution

We study the multifractal moments of the current distribution in randomly diluted resistor networks near the percolation treshold. When an external current is applied between to terminals $x$ and $x^\prime$ of the network, the $l$th multifractal moment scales as $M_I^{(l)} (x, x^\prime) \sim | x - x^\prime |^{\psi_l /\nu}$, where $\nu$ is the correlation length exponent of the isotropic percolation universality class. By applying our concept of master operators [Europhys. Lett. {\bf 51}, 539 (2000)] we calculate the family of multifractal exponents $\{\psi_l \}$ for $l \geq 0$ to two-loop order. We find that our result is in good agreement with numerical data for three dimensions.Comment: 30 pages, 6 figure

Effects of surfaces on resistor percolation

We study the effects of surfaces on resistor percolation at the instance of a semi-infinite geometry. Particularly we are interested in the average resistance between two connected ports located on the surface. Based on general grounds as symmetries and relevance we introduce a field theoretic Hamiltonian for semi-infinite random resistor networks. We show that the surface contributes to the average resistance only in terms of corrections to scaling. These corrections are governed by surface resistance exponents. We carry out renormalization group improved perturbation calculations for the special and the ordinary transition. We calculate the surface resistance exponents \phi_{\mathcal S \mathnormal} and \phi_{\mathcal S \mathnormal}^\infty for the special and the ordinary transition, respectively, to one-loop order.Comment: 19 pages, 3 figure

Critical Exponents for Diluted Resistor Networks

An approach by Stephen is used to investigate the critical properties of randomly diluted resistor networks near the percolation threshold by means of renormalized field theory. We reformulate an existing field theory by Harris and Lubensky. By a decomposition of the principal Feynman diagrams we obtain a type of diagrams which again can be interpreted as resistor networks. This new interpretation provides for an alternative way of evaluating the Feynman diagrams for random resistor networks. We calculate the resistance crossover exponent $\phi$ up to second order in $\epsilon=6-d$, where $d$ is the spatial dimension. Our result $\phi=1+\epsilon /42 +4\epsilon^2 /3087$ verifies a previous calculation by Lubensky and Wang, which itself was based on the Potts--model formulation of the random resistor network.Comment: 27 pages, 14 figure

Microbiota and host determinants of behavioural phenotype in maternally separated mice

Early-life stress is a determinant of vulnerability to a variety of disorders that include dysfunction of the brain and gut. Here we exploit a model of early-life stress, maternal separation (MS) in mice, to investigate the role of the intestinal microbiota in the development of impaired gut function and altered behaviour later in life. Using germ-free and specific pathogen-free mice, we demonstrate that MS alters the hypothalamic-pituitary-adrenal axis and colonic cholinergic neural regulation in a microbiota-independent fashion. However, microbiota is required for the induction of anxiety-like behaviour and behavioural despair. Colonization of adult germ-free MS and control mice with the same microbiota produces distinct microbial profiles, which are associated with altered behaviour in MS, but not in control mice. These results indicate that MS-induced changes in host physiology lead to intestinal dysbiosis, which is a critical determinant of the abnormal behaviour that characterizes this model of early-life stress

Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria