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排序方式: 共有250条查询结果,搜索用时 15 毫秒
71.
Federica Lombardi Kalyan Golla Darren J. Fitzpatrick Fergal P. Casey Niamh Moran Denis C. Shields 《PLoS computational biology》2015,11(4)
Identifying effective therapeutic drug combinations that modulate complex
signaling pathways in platelets is central to the advancement of effective
anti-thrombotic therapies. However, there is no systems model of the platelet
that predicts responses to different inhibitor combinations. We developed an
approach which goes beyond current inhibitor-inhibitor combination screening to
efficiently consider other signaling aspects that may give insights into the
behaviour of the platelet as a system. We investigated combinations of platelet
inhibitors and activators. We evaluated three distinct strands of information,
namely: activator-inhibitor combination screens (testing a panel of inhibitors
against a panel of activators); inhibitor-inhibitor synergy screens; and
activator-activator synergy screens. We demonstrated how these analyses may be
efficiently performed, both experimentally and computationally, to identify
particular combinations of most interest. Robust tests of activator-activator
synergy and of inhibitor-inhibitor synergy required combinations to show
significant excesses over the double doses of each component. Modeling
identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and
complementarity between inhibitor-inhibitor synergy effects and
activator-inhibitor combination effects. This approach accelerates the mapping
of combination effects of compounds to develop combinations that may be
therapeutically beneficial. We integrated the three information sources into a
unified model that predicted the benefits of a triple drug combination targeting
ADP, thromboxane and thrombin signaling. 相似文献
72.
Almeida CA Bronke C Roberts SG McKinnon E Keane NM Chopra A Kadie C Carlson J Haas DW Riddler SA Haubrich R Heckerman D Mallal S John M 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(5):2502-2513
Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 individuals from the same cohort, which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-γ responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA-HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design. 相似文献
73.
74.
75.
Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism
Smith P Mangan NE Walsh CM Fallon RE McKenzie AN van Rooijen N Fallon PG 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(7):4557-4566
The propensity of a range of parasitic helminths to stimulate a Th2 or regulatory cell-biased response has been proposed to reduce the severity of experimental inflammatory bowel disease. We examined whether infection with Schistosoma mansoni, a trematode parasite, altered the susceptibility of mice to colitis induced by dextran sodium sulfate (DSS). Mice infected with schistosome worms were refractory to DSS-induced colitis. Egg-laying schistosome infections or injection of eggs did not render mice resistant to colitis induced by DSS. Schistosome worm infections prevent colitis by a novel mechanism dependent on macrophages, and not by simple modulation of Th2 responses, or via induction of regulatory CD4+ or CD25+ cells, IL-10, or TGF-beta. Infected mice had marked infiltration of macrophages (F4/80+CD11b+CD11c(-)) into the colon lamina propria and protection from DSS-induced colitis was shown to be macrophage dependent. Resistance from colitis was not due to alternatively activated macrophages. Transfer of colon lamina propria F4/80+ macrophages isolated from worm-infected mice induced significant protection from colitis in recipient mice treated with DSS. Therefore, we propose a new mechanism whereby a parasitic worm suppresses DSS-induced colitis via a novel colon-infiltrating macrophage population. 相似文献
76.
77.
O'Reilly M Palfi A Chadderton N Millington-Ward S Ader M Cronin T Tuohy T Auricchio A Hildinger M Tivnan A McNally N Humphries MM Kiang AS Humphries P Kenna PF Farrar GJ 《American journal of human genetics》2007,81(1):127-135
Mutational heterogeneity represents a significant barrier to development of therapies for many dominantly inherited diseases. For example, >100 mutations in the rhodopsin gene (RHO) have been identified in patients with retinitis pigmentosa (RP). The development of therapies for dominant disorders that correct the primary genetic lesion and overcome mutational heterogeneity is challenging. Hence, therapeutics comprising two elements--gene suppression in conjunction with gene replacement--have been investigated. Suppression is targeted to a site independent of the mutation; therefore, both mutant and wild-type alleles are suppressed. In parallel with suppression, a codon-modified replacement gene refractory to suppression is provided. Both in vitro and in vivo validation of suppression and replacement for RHO-linked RP has been undertaken in the current study. RNA interference (RNAi) has been used to achieve ~90% in vivo suppression of RHO in photoreceptors, with use of adeno-associated virus (AAV) for delivery. Demonstration that codon-modifed RHO genes express functional wild-type protein has been explored transgenically, together with in vivo expression of AAV-delivered RHO-replacement genes in the presence of targeting RNAi molecules. Observation of potential therapeutic benefit from AAV-delivered suppression and replacement therapies has been obtained in Pro23His mice. Results provide the first in vivo indication that suppression and replacement can provide a therapeutic solution for dominantly inherited disorders such as RHO-linked RP and can be employed to circumvent mutational heterogeneity. 相似文献
78.
Jubao Duan Jianxin Shi Alessia Fiorentino Catherine Leites Xiangning Chen Winton Moy Jingchun Chen Boian?S. Alexandrov Anny Usheva Deli He Jessica Freda Niamh?L. O’Brien MGS GPC Andrew McQuillin Alan?R. Sanders Elliot?S. Gershon Lynn?E. DeLisi Alan?R. Bishop Hugh?M.D. Gurling Michele?T. Pato Douglas?F. Levinson Kenneth?S. Kendler Carlos?N. Pato Pablo?V. Gejman 《American journal of human genetics》2014,95(6):744-753
79.
Joint morphogenesis is the process in which prenatal joints acquire their reciprocal and interlocking shapes. Despite the clinical importance of the process, it remains unclear how joints acquire their shapes. In this study, we simulate 3D mechanobiological joint morphogenesis for which the effects of a range of movements (or lack of movement) and different initial joint shapes are explored. We propose that static hydrostatic compression inhibits cartilage growth while dynamic hydrostatic compression promotes cartilage growth. Both pre-cavitational (no muscle contractions) and post-cavitational (with muscle contractions) phases of joint development were simulated. Our results showed that for hinge type motion (planar motion from 45° to 120°) the proximal joint surface developed a convex profile in the posterior region and the distal joint surface developed a slightly concave profile. When 3D movements from 40° to −40° in two planes were applied, simulating a rotational movement, the proximal joint surface developed a concave profile whereas the distal joint surface rudiment acquire a rounded convex profile, showing an interlocking shape typical of a ball and socket joint. The significance of this research is that it provides new and important insights into normal and abnormal joint development, and contributes to our understanding of the mechanical factors driving very early joint morphogenesis. An enhanced understanding of how prenatal joints form is critical for developing strategies for early diagnosis and preventative treatments for congenital musculoskeletal abnormalities such as developmental dysplasia of the hip. 相似文献
80.
Kilcoyne M Sharma S McDevitt N O'Leary C Joshi L McMahon SS 《Biochemical and biophysical research communications》2012,420(3):616-622
Glycosylation is found ubiquitously throughout the central nervous system (CNS). Chondroitin sulphate proteoglycans (CSPGs) are a group of molecules heavily substituted with glycosaminoglycans (GAGs) and are found in the extracellular matrix (ECM) and cell surfaces. Upon CNS injury, a glial scar is formed, which is inhibitory for axon regeneration. Several CSPGs are up-regulated within the glial scar, including NG2, and these CSPGs are key inhibitory molecules of axonal regeneration. Treatment with chondroitinase ABC (ChABC) can neutralise the inhibitory nature of NG2. A gene expression dataset was mined in silico to verify differentially regulated glycosylation-related genes in neurons after spinal cord injury and identify potential targets for further investigation. To establish the glycosylation differential of neurons that grow in a healthy, inhibitory and ChABC-treated environment, we established an indirect co-culture system where PC12 neurons were grown with primary astrocytes, Neu7 astrocytes (which overexpress NG2) and Neu7 astrocytes treated with ChABC. After 1, 4 and 8 days culture, lectin cytochemistry of the neurons was performed using five fluorescently-labelled lectins (ECA MAA, PNA, SNA-I and WFA). Usually α-(2,6)-linked sialylation scarcely occurs in the CNS but this motif was observed on the neurons in the injured environment only at day 8. Treatment with ChABC was successful in returning neuronal glycosylation to normal conditions at all timepoints for MAA, PNA and SNA-I staining, and by day 8 in the case of WFA. This study demonstrated neuronal cell surface glycosylation changes in an inhibitory environment and indicated a return to normal glycosylation after treatment with ChABC, which may be promising for identifying potential therapies for neuronal regeneration strategies. 相似文献