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101.
Stanger K Steffek M Zhou L Pozniak CD Quan C Franke Y Tom J Tam C Elliott JM Lewcock JW Zhang Y Murray J Hannoush RN 《Nature chemical biology》2012,8(7):655-660
The caspases are a family of cytosolic proteases with essential roles in inflammation and apoptosis. Drug discovery efforts have focused on developing molecules directed against the active sites of caspases, but this approach has proved challenging and has not yielded any approved therapeutics. Here we describe a new strategy for generating inhibitors of caspase-6, a potential therapeutic target in neurodegenerative disorders, by screening against its zymogen form. Using phage display to discover molecules that bind the zymogen, we report the identification of a peptide that specifically impairs the function of caspase-6 in vitro and in neuronal cells. Remarkably, the peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization. Our data illustrate that screening against the zymogen holds promise as an approach for targeting caspases in drug discovery. 相似文献
102.
103.
Gundermann DM Fry CS Dickinson JM Walker DK Timmerman KL Drummond MJ Volpi E Rasmussen BB 《Journal of applied physiology (Bethesda, Md. : 1985)》2012,112(9):1520-1528
Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism(s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism(s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise. 相似文献
104.
Kumara TK Disney RH Abu Hassan A Flores M Hwa TS Mohamed Z CheSalmah MR Bhupinder S 《Journal of vector ecology》2012,37(1):62-68
Flies attracted to human remains during death investigations were surveyed in north Peninsular Malaysia. Six families, eight genera, and 16 species were identified from human remains, with the greatest fly diversity occurring on remains recovered indoors. The total relative frequency of species was led by Chrysomya megacephala (Fabricius, 1794) (46%), followed by Chrysomya rufifacies (Macquart, 1842) (22%), Sarcophaga (Liopygia) ruficornis (Fabricius, 1974) (5%), Sarcophaga spp. (4%), Synthesiomyia nudiseta Wulp, 1883 (6%), Megaselia spp. (3%), Megaselia scalaris (Loew, 1866), (2%), Megaselia spiracularis Schmitz, 1938 (2%), and Chrysomya villeneuvi Patton, 1922 (2%). Hemipyrellia tagaliana (Bigot, 1877), Desmometopa sp., Megaselia curtineura (Brues, 1909), Hemipyrellia ligurriens Wiedemann 1830, Ophyra sp., Sarcophaga princeps Wiedemann 1830, Piophila casei (Linnaeus, 1758), and unidentified pupae each represented 1%, respectively. 相似文献
105.
When a long DNA molecule is stretched beyond its B-form contour length, a transition occurs in which its length increases by a factor of 1.7, with very little force increase. A quantitative model was proposed to describe this transition as force-induced melting, where double-stranded DNA is converted into single-stranded DNA. The force-induced melting model accurately describes the thermodynamics of DNA overstretching as a function of solution conditions and in the presence of DNA binding ligands. An alternative explanation suggests a transformation into S-DNA, a double-stranded form which preserves the interstrand base pairing. To determine the extent to which DNA base pairs are exposed to solution during the transition, we held DNA overstretched to different lengths within the transition in the presence of glyoxal. If overstretching involved strand separation, then force-melted basepairs would be glyoxal-modified, thus essentially permanently single-stranded. Subsequent stretches confirm that a significant fraction of the DNA melted by force is permanently melted. This result demonstrates that DNA overstretching is accompanied by a disruption of the DNA helical structure, including a loss of hydrogen bonding. 相似文献
106.
Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL 总被引:3,自引:0,他引:3
Benson MJ Dillon SR Castigli E Geha RS Xu S Lam KP Noelle RJ 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(6):3655-3659
Memory B (B(MEM)) cells and long-lived bone marrow plasma cells (BM-PCs) persist within local environmental survival niches that afford cellular longevity. However, the factors supporting B(MEM) cell survival within the secondary lymphoid organs and allowing BM-PC persistence in the bone marrow remain poorly characterized. We report herein that long-lived B(MEM) cell survival and function are completely independent of BAFF (B cell-activating factor of the TNF family) or APRIL (a proliferation-inducing ligand). Thus, B(MEM) cells represent the only mature B2 lineage subset whose survival is independent of these ligands. We have previously shown that the TNFR family member receptor BCMA (B cell maturation Ag) is a critical survival receptor for BM-PC survival in vivo. We identify in this study the ligands critical for BM-PC survival and show that either BAFF or APRIL supports the survival of BM-PCs in vivo. These data define the BAFF/APRIL-dependent and -independent components of long-lived humoral immunity. 相似文献
107.
Bridges TM Brady AE Kennedy JP Daniels RN Miller NR Kim K Breininger ML Gentry PR Brogan JT Jones CK Conn PJ Lindsley CW 《Bioorganic & medicinal chemistry letters》2008,18(20):5439-5442
This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably. 相似文献
108.
The ciliate class Colpodea provides a powerful case in which a molecular genealogy can be compared to a detailed morphological taxonomy of a microbial group. Previous analyses of the class using the small-subunit rDNA are based on sparse taxon sampling, and are therefore of limited use in comparisons with morphologically-based classifications. Taxon sampling is increased here to include all orders within the class, and more species within previously sampled orders and in the species rich genus Colpoda. Results indicate that the Colpodea may be paraphyletic, although there is no support for deep nodes. The orders Bursariomorphida, Grossglockneriida, and Sorogenida are monophyletic. The orders Bryometopida, Colpodida, and Cyrtolophosidida, and the genus Colpoda, are not monophyletic. Although congruent in many aspects, the conflict between some nodes on this single gene genealogy and morphology-based taxonomy suggests the need for additional markers as well as a reassessment of the Colpodea taxonomy. 相似文献
109.
Host-bacterial coevolution and the search for new drug targets 总被引:1,自引:0,他引:1
Zaneveld J Turnbaugh PJ Lozupone C Ley RE Hamady M Gordon JI Knight R 《Current opinion in chemical biology》2008,12(1):109-114
Understanding the coevolution between humans and our microbial symbionts and pathogens requires complementary approaches, ranging from community analysis to in-depth analysis of individual genomes. Here we review the evidence for coevolution between symbionts and their hosts, the role of horizontal gene transfer in coevolution, and genomic and metagenomic approaches to identify drug targets. Recent studies have shown that our symbiotic microbes confer many metabolic capabilities that our mammalian genomes lack, and that targeting mechanisms of horizontal gene transfer is a promising new direction for drug discovery. Gnotobiotic ('germ-free') mice are an especially exciting new tool for unraveling the function of microbes, whether individually or in the context of complex communities. 相似文献
110.
Reduced sterol regulatory element‐binding protein (SREBP) processing through site‐1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro 下载免费PDF全文