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排序方式: 共有4071条查询结果,搜索用时 15 毫秒
31.
Steven T. Staben Timothy P. Heffron Daniel P. Sutherlin Seema R. Bhat Georgette M. Castanedo Irina S. Chuckowree Jenna Dotson Adrian J. Folkes Lori S. Friedman Leslie Lee John Lesnick Cristina Lewis Jeremy M. Murray Jim Nonomiya Alan G. Olivero Emile Plise Jodie Pang Wei Wei Prior Laurent Salphati Lionel Rouge Bing-Yan Zhu 《Bioorganic & medicinal chemistry letters》2010,20(20):6048-6051
Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model. 相似文献
32.
Olga A. Grishina Irina V. Kirillova Olga E. Glukhova 《Computer methods in biomechanics and biomedical engineering》2016,19(3):297-305
The biomechanical model of human coronary arteries was modified for improving the quality of diagnosis and surgical treatment for coronary heart disease. The problem of hemodynamics in the left coronary artery with multivessel bed disease – 45% stenosis of the anterior descending branch and 75% stenosis of the circumflex branch – was particularly considered. Numerical simulation of the coronary arterial bypass of the main trunk was carried out to estimate the functional condition of the coronary arteries after restoring myocardial blood supply by surgery. 相似文献
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34.
Dung beetles (subfamily Scarabaeinae) are popular model organisms in ecology and developmental biology, and for the last two decades they have experienced a systematics renaissance with the adoption of modern phylogenetic approaches. Within this period 16 key phylogenies and numerous additional studies with limited scope have been published, but higher-level relationships of this pivotal group of beetles remain contentious and current classifications contain many unnatural groupings. The present study provides a robust phylogenetic framework and a revised classification of dung beetles. We assembled the so far largest molecular dataset for dung beetles using sequences of 8 gene regions and 547 terminals including the outgroup taxa. This dataset was analyzed using Bayesian, maximum likelihood and parsimony approaches. In order to test the sensitivity of results to different analytical treatments, we evaluated alternative partitioning schemes based on secondary structure, domains and codon position. We assessed substitution models adequacy using Bayesian framework and used these results to exclude partitions where substitution models did not adequately depict the processes that generated the data. We show that exclusion of partitions that failed the model adequacy evaluation has a potential to improve phylogenetic inference, but efficient implementation of this approach on large datasets is problematic and awaits development of new computationally advanced software. In the class Insecta it is uncommon for the results of molecular phylogenetic analysis to lead to substantial changes in classification. However, the results presented here are congruent with recent morphological studies and support the largest change in dung beetle systematics for the last 50 years. Here we propose the revision of the concepts for the tribes Deltochilini (Canthonini), Dichotomiini and Coprini; additionally, we redefine the tribe Sisyphini. We provide and illustrate synapomorphies and diagnostic characters supporting the new concepts to facilitate diagnosability of the redefined tribes. As a result of the proposed changes a large number of genera previously assigned to these tribes are now left outside the redefined tribes and are treated as incertae sedis. The present study redefines dung beetles classification and gives new insight into their phylogeny. It has broad implications for the systematics as well as for various ecological and evolutionary analyses in dung beetles. 相似文献
35.
Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS 总被引:1,自引:0,他引:1
Garbuzova-Davis S Saporta S Haller E Kolomey I Bennett SP Potter H Sanberg PR 《PloS one》2007,2(11):e1205
Background
The blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (BCSFB) control cerebral/spinal cord homeostasis by selective transport of molecules and cells from the systemic compartment. In the spinal cord and brain of both ALS patients and animal models, infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells, and IgG deposits have been observed that may have a critical role in motor neuron damage. Additionally, increased levels of albumin and IgG have been found in the cerebrospinal fluid in ALS patients. These findings suggest altered barrier permeability in ALS. Recently, we showed disruption of the BBB and BSCB in areas of motor neuron degeneration in the brain and spinal cord in G93A SOD1 mice modeling ALS at both early and late stages of disease using electron microscopy. Examination of capillary ultrastructure revealed endothelial cell degeneration, which, along with astrocyte alteration, compromised the BBB and BSCB. However, the effect of these alterations upon barrier function in ALS is still unclear. The aim of this study was to determine the functional competence of the BSCB in G93A mice at different stages of disease.Methodology/Principal Findings
Evans Blue (EB) dye was intravenously injected into ALS mice at early or late stage disease. Vascular leakage and the condition of basement membranes, endothelial cells, and astrocytes were investigated in cervical and lumbar spinal cords using immunohistochemistry. Results showed EB leakage in spinal cord microvessels from all G93A mice, indicating dysfunction in endothelia and basement membranes and confirming our previous ultrastructural findings on BSCB disruption. Additionally, downregulation of Glut-1 and CD146 expressions in the endothelial cells of the BSCB were found which may relate to vascular leakage.Conclusions/Significance
Results suggest that the BSCB is compromised in areas of motor neuron degeneration in ALS mice at both early and late stages of the disease. 相似文献36.
Two new tetrahedral tungsten cyanide cluster compounds, [Cu(dien)]3[W4Te4(CN)12] · 9H2O (1) (dien=diethylenetriamine) and [Ni(en)(NH3)]3[W4Se4(CN)12] · 7.5H2O (2) (en=ethylenediamine), were synthesized by treating aqueous solutions of the saltlike cluster compound K6[W4Te4(CN)12] · 5H2O/K6[W4Se4(CN)12] · 6H2O with copper(II)/nickel(II) chloride in aqueous ammonia containing dien/en. The cyano-bridged layered coordination polymeric compounds were characterized by single-crystal X-ray diffraction analysis: monoclinic, space group P21 for 1; trigonal, space group for 2. Structures of 1 and 2 consist of infinite neutral layers of cluster components {W4Te4(CN)12}/{W4Se4(CN)12} connected, one another by {Cu(dien)} or {Ni(en)(NH3)} fragments, respectively. 相似文献
37.
Konstantin Byrgazov Irina Grishkovskaya Stefan Arenz Nicolas Coudevylle Hannes Temmel Daniel N. Wilson Kristina Djinovic-Carugo Isabella Moll 《Nucleic acids research》2015,43(1):661-673
In Gram-negative bacteria, the multi-domain protein S1 is essential for translation initiation, as it recruits the mRNA and facilitates its localization in the decoding centre. In sharp contrast to its functional importance, S1 is still lacking from the high-resolution structures available for Escherichia coli and Thermus thermophilus ribosomes and thus the molecular mechanism governing the S1–ribosome interaction has still remained elusive. Here, we present the structure of the N-terminal S1 domain D1 when bound to the ribosome at atomic resolution by using a combination of NMR, X-ray crystallography and cryo-electron microscopy. Together with biochemical assays, the structure reveals that S1 is anchored to the ribosome primarily via a stabilizing π-stacking interaction within the short but conserved N-terminal segment that is flexibly connected to domain D1. This interaction is further stabilized by salt bridges involving the zinc binding pocket of protein S2. Overall, this work provides one hitherto enigmatic piece in the ′ribosome puzzle′, namely the detailed molecular insight into the topology of the S1–ribosome interface. Moreover, our data suggest novel mechanisms that have the potential to modulate protein synthesis in response to environmental cues by changing the affinity of S1 for the ribosome. 相似文献
38.
Breitbach N Tillmann S Schleuning M Grünewald C Laube I Steffan-Dewenter I Böhning-Gaese K 《Oecologia》2012,168(2):425-437
Land-use intensification is a major cause for the decline in species diversity in human-modified landscapes. The loss of functionally
important species can reduce a variety of ecosystem functions, such as pollination and seed dispersal, but the intricate relationships
between land-use intensity, biodiversity and ecosystem functioning are still contentious. Along a gradient from forest to
intensively used farmland, we quantified bee species richness, visitation rates of bees and pollination success of wild cherry
trees (Prunus avium). We analysed the effects of structural habitat diversity at a local scale and of the proportion of suitable habitat around
each tree at a landscape scale. We compared these findings with those from previous studies of seed-dispersing birds and mammals
in the same model system and along the same land-use gradient. Bee species richness and visitation rates were found to be
highest in structurally simple habitats, whereas bird species richness—but not their visitation rates—were highest in structurally
complex habitats. Mammal visitation rates were only influenced at the landscape scale. These results show that different functional
groups of animals respond idiosyncratically to gradients in habitat and landscape structure. Despite strong effects on bees
and birds, pollination success and bird seed removal did not differ along the land-use gradient at both spatial scales. These
results suggest that mobile organisms, such as bees and birds, move over long distances in intensively used landscapes and
thereby buffer pollination and seed-dispersal interactions. We conclude that measures of species richness and interaction
frequencies are not sufficient on their own to understand the ultimate consequences of land-use intensification on ecosystem
functioning. 相似文献
39.
Shalova IN Kajiji T Lim JY Gómez-Piña V Fernández-Ruíz I Arnalich F Iau PT López-Collazo E Wong SC Biswas SK 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(8):3584-3593
Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16(+)) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R-associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16(+) monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis. 相似文献
40.