Notes

2-Heptanone reduces inhibitory control of the particular amygdala on the prelimbic place throughout rodents.
Prenatal Alcohol Exposure (PAE) exerts devastating effects on the Central Nervous System (CNS), which vary as a function of both ethanol load and gestational age of exposure. A growing body of evidence suggests that alcohol exposure profoundly impacts a wide range of cytokines and other inflammation-related genes in the CNS. The olfactory system serves as a critical interface between infectious/inflammatory signals and other aspects of CNS function, and demonstrates long-lasting plasticity in response to alcohol exposure. We therefore utilized transcriptome profiling to identify gene expression patterns for immune-related gene families in the olfactory bulb of Long Evans rats. Pregnant dams received either an ad libitum liquid diet containing 35% daily calories from ethanol (ET), a pair-fed diet (PF) matched for caloric content, or free choice (FCL) access to the liquid diet and water from Gestational Day (GD) 11-20. Offspring were fostered to dams fed the FCL diet, weaned on P21, and then housed with same-seand a decrease in adulthood due to prenatal ethanol exposure, indicating age-specific and long-lasting alterations to immune signaling. These data may provide important insight into the relationship between immune-related signaling cascades and long-term changes in olfactory bulb function after PAE.The study investigated the immediate effect of a moderate interval-running training session on circulating inflammatory cytokines concentration at real conditions of training. Nine recreational runners (5 women and 4 men; 68,33 ± 10,20 kg; 1,65 ± 0,07 m; 28,67 ± 4,24 years) had blood samples collected from antecubital vein before and immediately after a moderate interval-running training session without fasting. Cytokine levels were obtained from blood samples through Multiplex Analysis of Sample Protein Content, performed by Magpix® instrument. The assay detected the cytokines and calculated the plasma cytokine concentrations. Reduced concentration was observed after training session for all cytokines (p less then 0.05), except for IP-10. Moderate effect sizes were identified in IL-6, IL-8, TNF-α, IP-10, MCP1 and GM-CSF. In summary, a single moderate interval-running training session at real conditions of training seems not to be stressing enough to increase cytokine levels as a response to the exercise. Results reinforce that immediate biochemical response and inflammatory modulation related to exercise is dose-dependent and may be influenced by other variables.Living organisms respond to their immediate environment by modulating their genetic programme to perform adapted functions. Eukaryotic organisms that associate with plants (fungi, oomycetes, insects, …) alter their transcriptome in a host-specific manner. Recent comparative transcriptomic studies revealed that host-specialized transcriptomes consist of a limited set of genes. Such a set typically encodes proteins that modulate host structures and functions (predicted effectors and other secreted proteins), control nutrient assimilation (proteases, transporters), and maintain cellular homeostasis (oxidoreductases, detoxification enzymes). We conclude by discussing open mechanistic and evolutionary questions and integrated approaches to move beyond descriptive studies.Faces with typically African features are perceived as darker than they really are. We investigated how early in processing the bias emerges, whether participants are aware of it, and whether it can be altered by explicit instructions. We presented pairs of faces sequentially, manipulated the luminance and morphological features of each, and asked participants which was lighter, and how confident they were in their responses. In Experiment 1, pre-response mouse cursor trajectories showed that morphology affected motor output just as early as luminance did. Furthermore, participants were not slower to respond or less confident when morphological cues drove them to give a response that conflicted with the actual luminance of the faces. read more However, Experiment 2 showed that participants could be instructed to reduce their reliance on morphology, even at early stages of processing. All stimuli used, code to run the experiments reported, raw data, and analyses scripts and their outputs can be found at https//osf.io/brssn.The precise characterization and quantification of oxidative protein damage is a significant challenge due to the low abundance, large variety, and heterogeneity of modifications. Mass spectrometry (MS)-based techniques at the peptide level (proteomics) provide a detailed but limited picture due to incomplete sequence coverage and imperfect enzymatic digestion. This is particularly problematic with oxidatively modified and cross-linked/aggregated proteins. There is a pressing need for methods that can quantify large numbers of modified amino acids, which are often present in low abundance compared to the high background of non-damaged amino acids, in a rapid and reliable fashion. We have developed a protocol using zwitterionic ion-exchange chromatography coupled with LC-MS to simultaneously quantify both parent amino acids and their respective oxidation products. Proteins are hydrolyzed with methanesulfonic acid in the presence of tryptamine and purified by strong cation exchange solid phase extraction. The method was validated for the common amino acids (excluding Gln, Asn, Cys) and the oxidation products 3-chlorotyrosine (3-ClTyr), 3-nitrotyrosine (3-NO2Tyr), di-tyrosine, Nε-(1-carboxymethyl)-l-lysine, o,o'-di-tyrosine, 3,4,-dihydroxyphenylalanine, hydroxy-tryptophan and kynurenine. Linear standard curves were observed over ~3 orders of magnitude dynamic range (2-1000 pmol for parent amino acids, 80 fmol-20 pmol for oxidation products) with limit-of-quantification values as low as 200 fmol (o,o'-di-tyrosine). The validated method was used to quantify Tyr and Trp loss, and formation of 3-NO2Tyr on the isolated protein anastellin treated with peroxynitrous acid, and for 3-ClTyr formation (over a 2 orders of magnitude range) in cell lysates and complex protein mixtures treated with hypochlorous acid.Unfused tetanic contractions evoked in fast motor units exhibit extra-efficient force production at the onset of contraction, an effect called "boost". Boost is diminished in subsequent contractions if there is a short rest period between contractions, but can be re-established with a longer period of rest. We tested the hypothesis that contractile activity and rest could enhance boost-related metrics. Two sets of 3 unfused tetani were evoked 3 min apart in fast fatigable (FF) and fast fatigue-resistant (FR) motor units of the rat medial gastrocnemius. The greatest changes occurred in the first unfused tetanic contractions. Relative to the first contraction in the first set, the first contraction in the second set exhibited higher peak force during boost in a subset of motor units (76% of FF and 48% of FR). Enhanced force during boost was influenced by interaction of slowing of twitch contraction time (up to 20% and 25%, for FF and FR motor units, respectively), half-relaxation time (up to 37% and 49% for FF and FR motor units, respectively), and potentiation of the first twitch (up to 13% and 5% for FF and FR motor units, respectively). Examination of twitches evoked between sets suggested opportunity for greater enhancement of boost with shorter intervening rest periods. The phenomenon of enhanced boost following motor unit activity may interest sports scientists.In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. link2 Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments.Introduction There is little information on the late stages of parkinsonism. Methods We conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less. Results Average disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. link3 Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment. Conclusion These data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients.
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