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151.
Howl J Matou-Nasri S West DC Farquhar M Slaninová J Ostenson CG Zorko M Ostlund P Kumar S Langel U McKeating J Jones S 《Cellular and molecular life sciences : CMLS》2012,69(17):2951-2966
Cell-penetrating peptides (CPPs) have proven utility for the highly efficient intracellular delivery of bioactive cargoes that include peptides, proteins, and oligonucleotides. The many strategies developed to utilize CPPs solely as pharmacokinetic modifiers necessarily requires them to be relatively inert. Moreover, it is feasible to combine one or multiple CPPs with bioactive cargoes either by direct chemical conjugation or, more rarely, as non-covalent complexes. In terms of the message-address hypothesis, this combination of cargo (message) linked to a CPP (address) as a tandem construct conforms to the sychnological organization. More recently, we have introduced the term bioportide to describe monomeric CPPs that are intrinsically bioactive. Herein, we describe the design and biochemical properties of two rhegnylogically organized monometic CPPs that collectively modulate a variety of biological and pathophysiological phenomena. Thus, camptide, a cell-penetrant sequence located within the first intracellular loop of a human calcitonin receptor, regulates cAMP-dependent processes to modulate insulin secretion and viral infectivity. Nosangiotide, a bioportide derived from endothelial nitric oxide synthase, potently inhibits many aspects of the endothelial cell morphology and movement and displays potent anti-angiogenic activity in vivo. We conclude that, due to their capacity to translocate and target intracellular signaling events, bioportides represent an innovative generic class of bioactive agents. 相似文献
152.
153.
Mishra SK Ammon T Popowicz GM Krajewski M Nagel RJ Ares M Holak TA Jentsch S 《Nature》2011,474(7350):173-178
Alternative splicing of pre-messenger RNAs diversifies gene products in eukaryotes and is guided by factors that enable spliceosomes to recognize particular splice sites. Here we report that alternative splicing of Saccharomyces cerevisiae SRC1 pre-mRNA is promoted by the conserved ubiquitin-like protein Hub1. Structural and biochemical data show that Hub1 binds non-covalently to a conserved element termed HIND, which is present in the spliceosomal protein Snu66 in yeast and mammals, and Prp38 in plants. Hub1 binding mildly alters spliceosomal protein interactions and barely affects general splicing in S. cerevisiae. However, spliceosomes that lack Hub1, or are defective in Hub1-HIND interaction, cannot use certain non-canonical 5' splice sites and are defective in alternative SRC1 splicing. Hub1 confers alternative splicing not only when bound to HIND, but also when experimentally fused to Snu66, Prp38, or even the core splicing factor Prp8. Our study indicates a novel mechanism for splice site utilization that is guided by non-covalent modification of the spliceosome by an unconventional ubiquitin-like modifier. 相似文献
154.
Chambers JC Zhang W Sehmi J Li X Wass MN Van der Harst P Holm H Sanna S Kavousi M Baumeister SE Coin LJ Deng G Gieger C Heard-Costa NL Hottenga JJ Kühnel B Kumar V Lagou V Liang L Luan J Vidal PM Mateo Leach I O'Reilly PF Peden JF Rahmioglu N Soininen P Speliotes EK Yuan X Thorleifsson G Alizadeh BZ Atwood LD Borecki IB Brown MJ Charoen P Cucca F Das D de Geus EJ Dixon AL Döring A Ehret G Eyjolfsson GI Farrall M Forouhi NG Friedrich N Goessling W Gudbjartsson DF Harris TB Hartikainen AL Heath S 《Nature genetics》2011,43(11):1131-1138
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. 相似文献
155.
Loveday C Turnbull C Ramsay E Hughes D Ruark E Frankum JR Bowden G Kalmyrzaev B Warren-Perry M Snape K Adlard JW Barwell J Berg J Brady AF Brewer C Brice G Chapman C Cook J Davidson R Donaldson A Douglas F Greenhalgh L Henderson A Izatt L Kumar A Lalloo F Miedzybrodzka Z Morrison PJ Paterson J Porteous M Rogers MT Shanley S Walker L;Breast Cancer Susceptibility Collaboration 《Nature genetics》2011,43(9):879-882
Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers. 相似文献
156.
Gudbjartsson DF Sulem P Stacey SN Goldstein AM Rafnar T Sigurgeirsson B Benediktsdottir KR Thorisdottir K Ragnarsson R Sveinsdottir SG Magnusson V Lindblom A Kostulas K Botella-Estrada R Soriano V Juberías P Grasa M Saez B Andres R Scherer D Rudnai P Gurzau E Koppova K Kiemeney LA Jakobsdottir M Steinberg S Helgason A Gretarsdottir S Tucker MA Mayordomo JI Nagore E Kumar R Hansson J Olafsson JH Gulcher J Kong A Thorsteinsdottir U Stefansson K 《Nature genetics》2008,40(7):886-891
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation. 相似文献
157.
Five new species of Homalotylus Mayr (Hymenoptera: Encyrtidae) – H. noyesi sp. nov., H. biharensis sp. nov., H. varicolorus sp. nov. (from Bihar province), H. montanus sp. nov. (from Tamil Nadu province) and H. insularis sp. nov. (from Andaman and Nicobar Island) – are described from India. A revised key to the Indian species of Homalotylus is provided.
http://zoobank.org/urn:lsid:zoobank.org:pub:9209CC16-7A20-49BF-B4C6-95EF0F5567DF 相似文献
158.
Sudhir Kumar Singh Himanshu Pandey Jawdat Al-Bassam Larisa Gheber 《Cellular and molecular life sciences : CMLS》2018,75(10):1757-1771
Mitotic kinesin-5 bipolar motor proteins perform essential functions in mitotic spindle dynamics by crosslinking and sliding antiparallel microtubules (MTs) apart within the mitotic spindle. Two recent studies have indicated that single molecules of Cin8, the Saccharomyces cerevisiae kinesin-5 homolog, are minus end-directed when moving on single MTs, yet switch directionality under certain experimental conditions (Gerson-Gurwitz et al., EMBO J 30:4942–4954, 2011; Roostalu et al., Science 332:94–99, 2011). This finding was unexpected since the Cin8 catalytic motor domain is located at the N-terminus of the protein, and such kinesins have been previously thought to be exclusively plus end-directed. In addition, the essential intracellular functions of kinesin-5 motors in separating spindle poles during mitosis can only be accomplished by plus end-directed motility during antiparallel sliding of the spindle MTs. Thus, the mechanism and possible physiological role of the minus end-directed motility of kinesin-5 motors remain unclear. Experimental and theoretical studies from several laboratories in recent years have identified additional kinesin-5 motors that are bidirectional, revealed structural determinants that regulate directionality, examined the possible mechanisms involved and have proposed physiological roles for the minus end-directed motility of kinesin-5 motors. Here, we summarize our current understanding of the remarkable ability of certain kinesin-5 motors to switch directionality when moving along MTs. 相似文献
159.
160.
Three dimensional Couette flow and heat transfer through a porous medium with variable permeability 总被引:1,自引:0,他引:1
This paper reports research on the effects of variations in injection velocity and permeability on the heat transfer and flow through a highly porous medium between two horizontal parallel plates situated at constant distance with constant suction by the upper plate.Due to this type of variation in injection velocity and in permeability the flow becomes three dimensional.The governing equstions are solved by adopting complex variable notations to obtain the expressions for the velocity and temperature field.The skin-friction along the main flow direction and rate of heat transfer are discussed with the help of graphs. 相似文献