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排序方式: 共有248条查询结果,搜索用时 15 毫秒
131.
Tao Wu Advait Nagle Tomoyo Sakata Kerstin Henson Rachel Borboa Zhong Chen Kelli Kuhen David Plouffe Elizabeth Winzeler Francisco Adrian Tove Tuntland Jonathan Chang Susan Simerson Steven Howard Jared Ek John Isbell Xianming Deng Nathanael S. Gray David C. Tully Arnab K. Chatterjee 《Bioorganic & medicinal chemistry letters》2009,19(24):6970-6974
Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter. 相似文献
132.
Glen Spraggon Michael Hornsby Aaron Shipway David C. Tully Badry Bursulaya Henry Danahay Jennifer L. Harris Scott A. Lesley 《Protein science : a publication of the Protein Society》2009,18(5):1081-1094
Prostasin or human channel‐activating protease 1 has been reported to play a critical role in the regulation of extracellular sodium ion transport via its activation of the epithelial cell sodium channel. Here, the structure of the extracellular portion of the membrane associated serine protease has been solved to high resolution in complex with a nonselective d‐FFR chloromethyl ketone inhibitor, in an apo form, in a form where the apo crystal has been soaked with the covalent inhibitor camostat and in complex with the protein inhibitor aprotinin. It was also crystallized in the presence of the divalent cation Ca+2. Comparison of the structures with each other and with other members of the trypsin‐like serine protease family reveals unique structural features of prostasin and a large degree of conformational variation within specificity determining loops. Of particular interest is the S1 subsite loop which opens and closes in response to basic residues or divalent ions, directly binding Ca+2 cations. This induced fit active site provides a new possible mode of regulation of trypsin‐like proteases adapted in particular to extracellular regions with variable ionic concentrations such as the outer membrane layer of the epithelial cell. 相似文献
133.
Eric A. Moulton Rami Burstein Shannon Tully Richard Hargreaves Lino Becerra David Borsook 《PloS one》2008,3(11)
Background
The brainstem contains descending circuitry that can modulate nociceptive processing (neural signals associated with pain) in the dorsal horn of the spinal cord and the medullary dorsal horn. In migraineurs, abnormal brainstem function during attacks suggest that dysfunction of descending modulation may facilitate migraine attacks, either by reducing descending inhibition or increasing facilitation. To determine whether a brainstem dysfunction could play a role in facilitating migraine attacks, we measured brainstem function in migraineurs when they were not having an attack (i.e. the interictal phase).Methods and Findings
Using fMRI (functional magnetic resonance imaging), we mapped brainstem activity to heat stimuli in 12 episodic migraine patients during the interictal phase. Separate scans were collected to measure responses to 41°C and noxious heat (pain threshold+1°C). Stimuli were either applied to the forehead on the affected side (as reported during an attack) or the dorsum of the hand. This was repeated in 12 age-gender-matched control subjects, and the side tested corresponded to that in the matched migraine patients. Nucleus cuneiformis (NCF), a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs. 3 out of the 4 thermal stimulus conditions showed significantly greater NCF activation in control subjects than the migraine patients.Conclusions
Altered descending modulation has been postulated to contribute to migraine, leading to loss of inhibition or enhanced facilitation resulting in hyperexcitability of trigeminovascular neurons. NCF function could potentially serve as a diagnostic measure in migraine patients, even when not experiencing an attack. This has important implications for the evaluation of therapies for migraine. 相似文献134.
Chiang AS Blum A Barditch J Chen YH Chiu SL Regulski M Armstrong JD Tully T Dubnau J 《Current biology : CB》2004,14(4):263-272
BACKGROUND: In both vertebrate and invertebrate animals, anesthetic agents cause retrograde amnesia for recently experienced events. In contrast, older memories are resistant to the same treatments. In Drosophila, anesthesia-resistant memory (ARM) and long-term memory (LTM) are genetically distinct forms of long-lasting memory that exist in parallel for at least a day after training. ARM is disrupted in radish mutants but is normal in transgenic flies overexpressing a CREB repressor transgene. In contrast, LTM is normal in radish mutants but is disrupted in CREB repressor transgenic flies. To date, nothing is known about the molecular, genetic, or cell biological pathways underlying ARM. RESULTS: Here, we report the molecular identification of radish as a phospholipase-A2, providing the first clue about signaling pathways underlying ARM in any animal. An enhancer-trap allele of radish (C133) reveals expression in a novel anatomical pathway. Transgenic expression of PLA2 under control of C133 restores normal levels of ARM to radish mutants, whereas transient disruption of neural activity in C133 neurons inhibits memory retention. Notably, expression of C133 is not in mushroom bodies, the primary anatomical focus of olfactory memory research in Drosophila. CONCLUSIONS: Identification of radish as a phospholipase-A2 and the neural expression pattern of an enhancer-trap allele significantly broaden our understanding of the biochemistry and anatomy underlying olfactory memory in Drosophila. 相似文献
135.
Enzymatic synthesis of chiral intermediates for pharmaceuticals 总被引:1,自引:0,他引:1
Patel R Hanson R Goswami A Nanduri V Banerjee A Donovan MJ Goldberg S Johnston R Brzozowski D Tully T Howell J Cazzulino D Ko R 《Journal of industrial microbiology & biotechnology》2003,30(5):252-259
There has been an increasing awareness of the enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enatioselective manner. Chiral intermediates are in high demand by pharmaceutical industries for the preparation bulk drug substances. In this review article, microbial/enzymatic processes for the synthesis of chiral intermediates for antihypertensive drugs, melatonin receptor agonists, and beta3-receptor receptor agonists are described. 相似文献
136.
A sensitive denaturing gradient-Gel electrophoresis assay reveals a high frequency of heteroplasmy in hypervariable region 1 of the human mtDNA control region 总被引:19,自引:0,他引:19 下载免费PDF全文
Tully LA Parsons TJ Steighner RJ Holland MM Marino MA Prenger VL 《American journal of human genetics》2000,67(2):432-443
A population study of heteroplasmy in the hypervariable region 1 (HV1) portion of the human mtDNA control region was performed. Blood samples from 253 randomly chosen individuals were examined using a sensitive denaturing gradient-gel electrophoresis (DGGE) system. This method is capable of detecting heteroplasmic proportions as low as 1% and virtually all heteroplasmy where the minor component is > or = 5%. Heteroplasmy was observed in 35 individuals (13.8%; 95% confidence interval [CI] 9.6-18.0). Of these individuals, 33 were heteroplasmic at one nucleotide position, whereas 2 were heteroplasmic at two different positions (a condition known as "triplasmy"). Although heteroplasmy occurred at a total of 16 different positions throughout HV1, it was most frequently observed at positions 16093 (n=13) and 16129 (n=6). In addition, the majority of heteroplasmic variants occurred at low proportions and could not be detected by direct sequencing of PCR products. This study indicates that low-level heteroplasmy in HV1 is relatively common and that it occurs at a broad spectrum of sites. Our results corroborate those of other recent reports indicating that heteroplasmy in the control region is more common than was previously believed-a finding that is of potential importance to evolutionary studies and forensic applications that are based on mtDNA variation. 相似文献
137.
Mauricio A. Martins Damien C. Tully Michael A. Cruz Karen A. Power Marlon G. Veloso de Santana David J. Bean Colin B. Ogilvie Rujuta Gadgil Noemia S. Lima Diogo M. Magnani Keisuke Ejima David B. Allison Michael Piatak Jr. John D. Altman Christopher L. Parks Eva G. Rakasz Saverio Capuano III Ricardo Galler Myrna C. Bonaldo Jeffrey D. Lifson Todd M. Allen David I. Watkins 《Journal of virology》2015,89(21):10802-10820
138.
Alexis E. Cullen Amelia Jewell John Tully Suzanne Coghlan Kimberlie Dean Tom Fahy 《PloS one》2015,10(9)
Background
Incidents of absconsion in forensic psychiatric units can have potentially serious consequences, yet surprisingly little is known about the characteristics of patients who abscond from these settings. The few previous studies conducted to date have employed retrospective designs, and no attempt has been made to develop an empirically-derived risk assessment scale. In this prospective study, we aimed to identify predictors of absconsion over a two-year period and investigate the feasibility of developing a brief risk assessment scale.Methods
The study examined a representative sample of 135 patients treated in forensic medium- and low-secure wards. At baseline, demographic, clinical, treatment-related, and offending/behavioural factors were ascertained from electronic medical records and the treating teams. Incidents of absconsion (i.e., failure to return from leave, incidents of escape, and absconding whilst on escorted leave) were assessed at a two-year follow-up. Logistic regression analyses were used to determine the strongest predictors of absconsion which were then weighted according to their ability to discriminate absconders and non-absconders. The predictive utility of a brief risk assessment scale based on these weighted items was evaluated using receiver operator characteristics (ROC).Results
During the two-year follow-up period, 27 patients (20%) absconded, accounting for 56 separate incidents. In multivariate analyses, four factors relating to offending and behaviour emerged as the strongest predictors of absconsion: history of sexual offending, previous absconsion, recent inpatient verbal aggression, and recent inpatient substance use. The weighted risk scale derived from these factors had moderate-to-good predictive accuracy (ROC area under the curve: 0.80; sensitivity: 067; specificity: 0.71), a high negative predictive value (0.91), but a low positive predictive value (0.34).Conclusion
Potentially-targetable recent behaviours, such as inpatient verbal aggression and substance use, are strong predictors of absconsion in forensic settings; the absence of these factors may enable clinical teams to identify unnecessarily restricted low-risk individuals. 相似文献139.
The env gene of human immunodeficiency virus (HIV) is a functionally important gene responsible for the production of protein products (gp120 and gp41) involved in host cell recognition, binding, and entry. This occurs through a complex and, as yet, not fully understood process of protein-protein interaction and within and between protein functional communication. Exposure on the surface of active HIV virions means the gp120-gp41 complexes are subjected to intense immune system pressure and have, therefore, evolved mechanisms to avoid neutralization. Using protein-coding sequences representing all the HIV type-1 (HIV-1) group M subtypes, we have identified amino acids within the env gene whose evolution is inextricably linked over the entire HIV-1 group M epidemic. We identified 848 pairs of coevolving residues (involving 263 out of 764 amino acid sites), which represent 0.29% of all possible pairs. Of the coevolving pairs, 68% were significantly correlated by hydrophobicity, molecular weight, or both hydrophobicity and molecular weight. Subsequent grouping of coevolving pairs resulted in the identification of 290 groups of amino acid residues, with the size of these groups ranging from 2 to 10 amino acid residues. Many of these dependencies are correlated by function including CD4 binding, coreceptor binding, glycosylation, and protein-protein interaction. This analysis provides important information regarding the functional dependencies observed within all the HIV-1 group M subtypes and may assist in the identification of functional protein domains and therapeutic targets within the HIV-1 env gene. 相似文献
140.
When environmental conditions exert sex-specific selection on offspring, mothers should benefit from biasing their sex allocation
towards the sex with the highest fitness in a given environment. Yet, studies show mixed support for such adaptive strategies
in vertebrates, which may be due to mechanistic constraints and/or weak selection on facultative sex allocation. In an attempt
to disentangle these alternatives, we quantified sex-specific fitness returns and sex allocation (sex ratio and sex-specific
mass at birth) according to maternal factors (body size, age, birth date, and litter size), habitat, and year in a viviparous
snake with genotypic sex determination. We used data on 106 litters from 19 years of field survey in two nearby habitats occupied
by the meadow viper Vipera ursinii ursinii in south-eastern France. Maternal reproductive investment and habitat quality had no differential effects on the growth and
survival of sons and daughters. Sex ratio at birth was balanced despite a slight female-biased mortality before birth. No
sexual mass dimorphism between offspring was evident. Sex allocation was almost random apart for a trend towards more male-biased
litters as females grew older, which could be explained by an inbreeding avoidance strategy. Thus, a weak selection for facultative
sex allocation seems sufficient to explain the almost equal sex allocation in the meadow viper. 相似文献