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61.
Xiang MA Rybczynski PJ Patel M Chen RH McComsey DF Zhang HC Gunnet JW Look R Wang Y Minor LK Zhong HM Villani FJ Demarest KT Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2007,17(23):6623-6628
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation. 相似文献
62.
Zuo Y Zheng H Wang Y Chruszcz M Cymborowski M Skarina T Savchenko A Malhotra A Minor W 《Structure (London, England : 1993)》2007,15(4):417-428
The 3' processing of most bacterial precursor tRNAs involves exonucleolytic trimming to yield a mature CCA end. This step is carried out by RNase T, a member of the large DEDD family of exonucleases. We report the crystal structures of RNase T from Escherichia coli and Pseudomonas aeruginosa, which show that this enzyme adopts an opposing dimeric arrangement, with the catalytic DEDD residues from one monomer closely juxtaposed with a large basic patch on the other monomer. This arrangement suggests that RNase T has to be dimeric for substrate specificity, and agrees very well with prior site-directed mutagenesis studies. The dimeric architecture of RNase T is very similar to the arrangement seen in oligoribonuclease, another bacterial DEDD family exoribonuclease. The catalytic residues in these two enzymes are organized very similarly to the catalytic domain of the third DEDD family exoribonuclease in E. coli, RNase D, which is monomeric. 相似文献
63.
Grabowski M Joachimiak A Otwinowski Z Minor W 《Current opinion in structural biology》2007,17(3):347-353
Structural characterization of the protein universe is the main mission of Structural Genomics (SG) programs. However, progress in gene sequencing technology, set in motion in the 1990s, has resulted in rapid expansion of protein sequence space--a twelvefold increase in the past seven years. For the SG field, this creates new challenges and necessitates a re-assessment of its strategies. Nevertheless, despite the growth of sequence space, at present nearly half of the content of the Swiss-Prot database and over 40% of Pfam protein families can be structurally modeled based on structures determined so far, with SG projects making an increasingly significant contribution. The SG contribution of new Pfam structures nearly doubled from 27.2% in 2003 to 51.6% in 2006. 相似文献
64.
The spotted owl (Strix occidentalis) is a threatened species in many areas of its western North American range. Concomitant with its decline has been a rapid
invasion of its range and habitat by barred owls (Strix varia), a native species that was restricted, until relatively recently, to eastern North America. We assess the theoretical potential
for negative interactions between these two owls by examining size dimorphism and ecological relationships within various
owl assemblages throughout the world. We then review the anecdotal, natural history, modeling, and experimental evidence that
suggest barred owls may negatively affect spotted owls with at least a potential for the competitive exclusion of spotted
owls by barred owls throughout all or part of the former’2019;s range. While it is widely accepted that barred owls are either
causing or exacerbating declines of spotted owl populations, there are confounding factors, such as habitat loss and bad weather
that also may contribute to declines of spotted owls. Both theory and empirical information suggest that barred owls are likely
to have negative effects on spotted owl range and density, but the degree of the impact is not predictable. There is a conservation
conundrum here, in that the barred owl is a native species that has expanded its range westwards, either naturally or with
a degree of human facilitation, and now constitutes a major threat to the viability of another native species, the threatened
spotted owl. We propose that only through carefully designed experiments involving removal of barred owls will we be able
to determine if recent declines in spotted owl populations are caused by barred owls or by other factors. It is rare in conservation
science that replicate study areas exist for which we also have long-standing demographic information, as is the case with
the spotted owl. Removal experiments would take advantage of the wealth of data on spotted owls, and allow ecologists to assess
formally the impacts of an invasive species on a threatened species, as well as to suggest mitigation measures. 相似文献
65.
Brittany L. Wagler Rachel A. Smiley Alyson B. Courtemanch Gregory Anderson Daryl Lutz Doug McWhirter Doug Brimeyer Patrick Hnilicka Cody P. Massing David W. German Thomas R. Stephenson Kevin L. Monteith 《The Journal of wildlife management》2022,86(3):e22181
Wildlife capture, and the data collection associated with it, has led to major advancements in ecology that are integral to decision making pertaining to wildlife conservation. Capturing wildlife, however, can cause lethal and non-lethal risks to animals. Understanding the factors that contribute to the level of risk involved in wildlife capture is therefore important for the development and implementation of the safest and most effective methodologies. We used data from 736 animal captures of 389 individuals for 2 subspecies of female bighorn sheep (Rocky Mountain bighorn [Ovis canadensis canadensis], Sierra Nevada bighorn sheep [O. c. sierrae]) in Wyoming and California, USA, in 2002–2020 to evaluate the degree and extent of time that capture via helicopter net-gunning affects survival. We compared pre- and post-capture survival during a 10-week window centered on a capture event, and post-capture survival between captured animals and animals that were monitored but not captured during the 10-week window. Additionally, we evaluated the effects of handling techniques (number of times captured, season of capture event, handling time, chase time, and body temp) and biological factors (age and nutritional condition) on probability of capture mortality. Mean daily survival was 0.9992 during a 5-week pre-capture window, dropped to 0.9864 on the day of capture, and rebounded within 3 days of capture to pre-capture levels and that of sheep that were not captured. Overall, direct mortality resulting from capture was 1.36%, with 0.54% mortality occurring within the 3 days following a capture event for an overall 1.90% capture-related mortality. The only handling and biological metrics that influenced the probability of capture mortality were rectal temperature and nutritional condition; high initial rectal temperatures and poor body condition were associated with increased risk of mortality in the days following capture. Overall, helicopter net-gunning imposed low and short-term risk to survival of female bighorn sheep. To reduce bias in survival estimates, we recommend using a 3-day censorship window for post-capture mortalities as opposed to the common practice of a 2–5-week censor window. Helicopter net-gunning, including annual or seasonal recaptures, remains an effective and comparatively safe technique for capture and associated data collection of bighorn sheep. 相似文献
66.
Two new species of oribatid mites of the genus Scapheremaeus (Oribatida, Cymbaeremaeidae), Scapheremaeus
gibbus
sp. n. and Scapheremaeus
luxtoni
sp. n., are described from New Zealand. Scapheremaeus
gibbus
sp. n. is morphologically most similar to Scapheremaeus
humeratus Balogh & Mahunka, 1967, but differs from the latter by the number of notogastral, genital and adanal setae, morphology of bothridial setae, position of adanal lyrifissures and absence of humeral processes. Scapheremaeus
luxtoni
sp. n. is morphologically most similar to Scapheremaeus
yamashitai Aoki, 1970, but differs from the latter by the morphology of notogastral and rostral setae, morphology of leg solenidia φ2 and development of humeral processes. The species Scapheremaeus
zephyrus Colloff, 2010 is recorded for the first time in New Zealand. An identification key to the known New Zealand species of Scapheremaeus is provided. 相似文献
67.
68.
Minor RK López M Younts CM Jones B Pearson KJ Anson RM Diéguez C de Cabo R 《Aging cell》2011,10(3):483-492
Calorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR's antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate-injected mice. While CR was protective in control mice challenged with a two-stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the monosodium glutamate-treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite-suppressed mice. We propose that some of CR's beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the arcuate nucleus of the hypothalamus are involved in the translation of reduced intake to downstream physiological and functional benefits. 相似文献
69.
Kraemer BF Campbell RA Schwertz H Cody MJ Franks Z Tolley ND Kahr WH Lindemann S Seizer P Yost CC Zimmerman GA Weyrich AS 《PLoS pathogens》2011,7(11):e1002355
Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria. 相似文献
70.
The Structural Biology Knowledgebase: a portal to protein structures,sequences, functions,and methods 总被引:1,自引:0,他引:1