92 research outputs found
Deuterium isotope effects on 15N backbone chemical shifts in proteins
Quantum mechanical calculations are presented that predict that one-bond deuterium isotope effects on the 15N chemical shift of backbone amides of proteins, 1Î15N(D), are sensitive to backbone conformation and hydrogen bonding. A quantitative empirical model for 1Î15N(D) including the backbone dihedral angles, ÎŚ and Ψ, and the hydrogen bonding geometry is presented for glycine and amino acid residues with aliphatic side chains. The effect of hydrogen bonding is rationalized in part as an electric-field effect on the first derivative of the nuclear shielding with respect to NâH bond length. Another contributing factor is the effect of increased anharmonicity of the NâH stretching vibrational state upon hydrogen bonding, which results in an altered NâH/NâD equilibrium bond length ratio. The NâH stretching anharmonicity contribution falls off with the cosine of the NâH¡¡¡O bond angle. For residues with uncharged side chains a very good prediction of isotope effects can be made. Thus, for proteins with known secondary structures, 1Î15N(D) can provide insights into hydrogen bonding geometries
Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis
Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline
Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65
Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimerâs disease
BACKGROUND: Treatment of mild-moderate Alzheimerâs disease (AD) subjects (Nâ=â119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. METHODS: For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (Nâ=â19 resveratrol-treated and Nâ=â19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. RESULTS: Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels. CONCLUSIONS: Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT0150485
NâHâŻO versus OâHâŻO: density functional calculation and first principle molecular dynamics study on a quinoline-2-carboxamide N-oxide
Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS
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