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91.
In the field of evolutionary structural genomics, methods are needed to evaluate why genomes evolved to contain the fold distributions that are observed. In order to study the effects of population dynamics in the evolved genomes we need fast and accurate evolutionary models which can analyze the effects of selection, drift and fixation of a protein sequence in a population that are grounded by physical parameters governing the folding and binding properties of the sequence. In this study, various knowledge-based, force field, and statistical methods for protein folding have been evaluated with four different folds: SH2 domains, SH3 domains, Globin-like, and Flavodoxin-like, to evaluate the speed and accuracy of the energy functions. Similarly, knowledge-based and force field methods have been used to predict ligand binding specificity in SH2 domain. To demonstrate the applicability of these methods, the dynamics of evolution of new binding capabilities by an SH2 domain is demonstrated. 相似文献
92.
Nathalie Fenner Robert Williams Hannah Toberman Steve Hughes Brian Reynolds Chris Freeman 《Hydrobiologia》2011,665(1):51-66
The hypothesis that specific components of seawater, such as particulate, dissolved and colloidal organic and inorganic material,
render virions non-infective has long been postulated, but never rigorously tested. To address this hypothesis, the plaque
assay method was used to derive infective decay rates, k, of two bacteriophages—P1 (marine host: PWH3a) and T4 (enteric host: E. coli B). We compared k values of bacteriophage suspended in serial filtrations of seawater, with and without autoclaving and UV oxidation. Both
phages exhibited reduced decay rates in particle-free water (<0.2 μm) compared to <10 μm filtrate. The largest decrease in
virion decay rates was achieved by autoclaving the 0.2 μm filtrate. UV oxidation of <0.2 μm filtrate, however, yielded higher
decay rates than observed in autoclaved treatments. The lowest k values were seen in ultra-filtered seawater (<10 kDa). Exposure to a wide range of concentrations of Pronase E (a proteolytic
enzyme), inorganic clay (kaolinite or montmorillonite), and organic particles (phytoplankton debris) did not promote phage
inactivation. P1 infective titers were also not consistently reduced by exposures to axenic cultures of a resistant host mutant
(PWH3a-R) and a non-host marine bacterium (MB-5). Finally, phage were exposed to a range of temperatures to derive activation
energies required for phage inactivation. Application of the Arrhenius model to inactivation of T4 and P1 yielded activation
energies (E
a) of 49 and 40 kJ mol−1, respectively. This is the first comprehensive analysis in which specific seawater components were assayed for their ability
to inactivate bacteriophage. Inactivation of these phage does not appear to depend on capsomere denaturation, proteolytic
extracellular enzymes, sorption to non-host bacteria, clay particles or particulate organic debris, but is accelerated by
naturally occurring particles, which include living organisms, and heat-labile colloids and macromolecules >10 kDa. 相似文献
93.
Konyukh M Delorme R Chaste P Leblond C Lemière N Nygren G Anckarsäter H Rastam M Ståhlberg O Amsellem F Gillberg IC Mouren-Simeoni MC Herbrecht E Fauchereau F Toro R Gillberg C Leboyer M Bourgeron T 《PloS one》2011,6(3):e17289
Background
Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate.Methodology/Principal Findings
We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls.Conclusions/Significance
Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD. 相似文献94.
Nicoll-Griffith DA Seto C Aubin Y Lévesque JF Chauret N Day S Silva JM Trimble LA Truchon JF Berthelette C Lachance N Wang Z Sturino C Braun M Zamboni R Young RN 《Bioorganic & medicinal chemistry letters》2007,17(2):301-304
Metabolites of the potent DP antagonist, MK-0524, were generated using in vitro systems including hepatic microsomes and hepatocytes. Four metabolites (two hydroxylated diastereomers, a ketone and an acyl glucuronide) were characterized by LC-MS/MS and 1H NMR. Larger quantities of these metabolites were prepared by either organic synthesis or biosynthetically to be used as standards in other studies. The propensity for covalent binding was assessed and was found to be acceptable (<50 pmol-equiv/mg protein). 相似文献
95.
Chu GH Gu M Cassel JA Belanger S Stabley GJ DeHaven RN Conway-James N Koblish M Little PJ DeHaven-Hudkins DL Dolle RE 《Bioorganic & medicinal chemistry letters》2006,16(3):645-648
A novel series of phenylamino acetamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists. 相似文献
96.
97.
Nahon P Charnaux N Friand V Prost-Squarcioni C Ziol M Lièvre N Trinchet JC Beaugrand M Gattegno L Pessayre D Sutton A 《Free radical biology & medicine》2008,45(9):1308-1317
The Ala/16Val dimorphism incorporates alanine (Ala) or valine (Val) in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD), modifying MnSOD mitochondrial import and activity. In alcoholic cirrhotic patients, the Ala-MnSOD allele is associated with hepatic iron accumulation and an increased risk of hepatocellular carcinoma. The Ala-MnSOD variant could modulate the expression of proteins involved in iron storage (cytosolic ferritin), uptake (transferrin receptors, TfR-1 and-2), extrusion (hepcidin), and intracellular distribution (frataxin) to trigger hepatic iron accumulation. We therefore assessed the Ala/Val-MnSOD genotype and the hepatic iron score in 162 alcoholic cirrhotic patients. In our cohort, this hepatic iron score increased with the number of Ala-MnSOD alleles. We also transfected Huh7 cells with Ala-MnSOD-or Val-MnSOD-encoding plasmids and assessed cellular iron, MnSOD activity, and diverse mRNAs and proteins. In Huh7 cells, MnSOD activity was higher after Ala-MnSOD transfection than after Val-MnSOD transfection. Additionally, iron supplementation decreased transfected MnSOD proteins and activities. Ala-MnSOD transfection increased the mRNAs and proteins of ferritin, hepcidin, and TfR2, decreased the expression of frataxin, and caused cellular iron accumulation. In contrast, Val-MnSOD transfection had limited effects. In conclusion, the Ala-MnSOD variant favors hepatic iron accumulation by modulating the expression of proteins involved in iron homeostasis. 相似文献
98.
99.
Nathalie Vrielynck Katja Schneider Marion Rodriguez Jason Sims Aurlie Chambon Aurlie Hurel Arnaud De
Muyt Arnaud Ronceret Ondrej Krsicka Christine Mzard Peter Schlgelhofer Mathilde Grelon 《Nucleic acids research》2021,49(17):9821
In the current meiotic recombination initiation model, the SPO11 catalytic subunits associate with MTOPVIB to form a Topoisomerase VI-like complex that generates DNA double strand breaks (DSBs). Four additional proteins, PRD1/AtMEI1, PRD2/AtMEI4, PRD3/AtMER2 and the plant specific DFO are required for meiotic DSB formation. Here we show that (i) MTOPVIB and PRD1 provide the link between the catalytic sub-complex and the other DSB proteins, (ii) PRD3/AtMER2, while localized to the axis, does not assemble a canonical pre-DSB complex but establishes a direct link between the DSB-forming and resection machineries, (iii) DFO controls MTOPVIB foci formation and is part of a divergent RMM-like complex including PHS1/AtREC114 and PRD2/AtMEI4 but not PRD3/AtMER2, (iv) PHS1/AtREC114 is absolutely unnecessary for DSB formation despite having a conserved position within the DSB protein network and (v) MTOPVIB and PRD2/AtMEI4 interact directly with chromosome axis proteins to anchor the meiotic DSB machinery to the axis. 相似文献