The pan-PPAR agonist lanifibranor reduces development of lung fibrosis and attenuates cardiorespiratory manifestations in a transgenic mouse model of systemic sclerosis

Background: The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype. Methods: PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored. Results: Gene expression data were consistent with the downregulation of the PPAR pathway in the TβRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure. Conclusions: In the TβRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter- individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y ( NPY) is anxiolytic(1,2) and its release is induced by stress(3). NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories(4-6). Here we show that haplotype- driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype- driven NPY expression predicted higher emotion- induced activation of the amygdala, as well as diminished resiliency as assessed by pain/ stress- induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism ( SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter- individual variation in resiliency to stress, a risk factor for many diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62768/1/nature06858.pd

Mortalité embryonnaire chez la chèvre laitière après synchronisation des chaleurs et insémination artificielle à contre saison

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Mortalité embryonnaire chez la chèvre laitière après synchronisation des chaleurs et insémination artificielle à contre saison

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Utilisation des fourrages secs par les caprins

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Parafoveal-on-foveal repetition effects in sentence reading: a co-registered eye-tracking and eeg study

International audienceWhen reading, can the next word in the sentence (word n+1) influence how you read the word you are currently looking at (word n)? Serial models of sentence reading state that this generally should not be the case, whereas parallel models predict that this should be the case. Here we focus on perhaps the simplest and the strongest para-foveal-on-foveal (PoF) manipulation: word n +1 is either the same as word n or a different word. Participants read sentences for comprehension, and when their eyes left word n, the repeated or unrelated word at position n +1 were swapped for a word that provided a syntactically cor-rect continuation of the sentence. We recorded EEG and eye-movements, and time-locked the analysis of fixation-related-potentials (FRPs) to fixation of word n. We found robust PoF repetition effects on gaze durations on word n. Most important is that we also observed significant effects in FRPs, reaching a conservative estimate of significance in a time-window spanning 250-400 ms post-fixation of word n. These effects were marginally significant (after correc-tion) in an earlier 120-250 ms time window and continued into the 400-550 ms time-window. Repetition of the target word n at position n+1 caused a reduced negativity in the FRPs. Given the timing of this effect we argue that it is driven by orthographic processing of word n+1 while read-ers’ eyes are still fixating word n

Reproductive performance of pseudopregnant dairy goats after treatment with prostaglandins

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Chronic blockade of the melanocortin 4 receptor subtype leads to obesity independently of neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes

Neuropeptide Y (NPY) is a powerful orexigenic factor, and alphaMSH is a melanocortin (MC) peptide that induces satiety by activating the MC4 receptor subtype. Genetic models with disruption of MC4 receptor signaling are associated with obesity. In the present study, a 7-day intracerebroventricular infusion to male rats of either the MC receptor antagonist SHU9119 or porcine NPY (10 nmol/day) was shown to strongly stimulate food and water intake and to markedly increase fat pad mass. Very high plasma leptin levels were found in NPY-treated rats (27.1 +/- 1.8 ng/ml compared with 9.9 +/- 0.9 ng/ml in SHU9119-treated animals and 2.1 +/- 0.2 ng/ml in controls). As expected, NPY infusion induced hypogonadism, characterized by an impressive decrease in seminal vesicle and prostate weights. No such effects were seen with the SHU9119 infusion. Similarly, whereas the somatotropic axis of NPY-treated rats was fully inhibited, this axis was normally activated in the obese SHU9119-treated rats. Chronic infusion of SHU9119 strikingly reduced hypothalamic gene expression for NPY (65.2 +/- 3.6% of controls), whereas gene expression for POMC was increased (170 +/- 19%). NPY infusion decreased hypothalamic gene expression for both POMC and NPY (70 +/- 9% and 75.4 +/- 9.5%, respectively). In summary, blockade of the MC4 receptor subtype by SHU9119 was able to generate an obesity syndrome with no apparent side-effects on the reproductive and somatotropic axes. In this situation, it is unlikely that hyperphagia was driven by increased NPY release, because hypothalamic NPY gene expression was markedly reduced, suggesting that hyperphagia mainly resulted from loss of the satiety signal driven by MC peptides. NPY infusion produced hypogonadism and hyposomatotropism in the face of markedly elevated plasma leptin levels and an important reduction in hypothalamic POMC synthesis. In this situation NPY probably acted both by exacerbating food intake through Y receptors and by reducing the satiety signal driven by MC peptides