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101.
Zheng C Cao G Xia M Feng H Glenn J Anand R Zhang K Huang T Wang A Kong L Li M Galya L Hughes RO Devraj R Morton PA Rogier DJ Covington M Baribaud F Shin N Scherle P Diamond S Yeleswaram S Vaddi K Newton R Hollis G Friedman S Metcalf B Xue CB 《Bioorganic & medicinal chemistry letters》2011,21(5):1442-1446
We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate. 相似文献
102.
Franklin MC Navarro EC Wang Y Patel S Singh P Zhang Y Persaud K Bari A Griffith H Shen L Balderes P Kussie P 《Structure (London, England : 1993)》2011,19(8):1097-1107
The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches. 相似文献
103.
Physiological responses during interval training with different intensities and duration of exercise
Zuniga JM Berg K Noble J Harder J Chaffin ME Hanumanthu VS 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(5):1279-1284
The purpose of this study was to compare 4 interval training (IT) sessions with different intensities and durations of exercise to determine the effect on mean VO?, total VO?, and duration of exertion ≥95% maximum power output (MPO), and the effects on biomarkers of fatigue such as blood-lactate concentration (BLC) and rating of perceived exertion. The subjects were 12 recreationally competitive male (n = 7, mean ± SD age = 26.2 ± 3.9 years) and female (n = 5, mean ± SD age = 27.6 ± 4.3 years) triathletes. These subjects performed 4 IT sessions on a cycle ergometer varying in intensity (90 and 100% MPO) and duration of exercise (30 seconds and 3 minutes). This study revealed that IT using 30-second duration intervals (30-30 seconds) allows the athlete to perform a longer session, with a higher total and mean VO? HR and lower BLC than 3-minute durations. Similarly, submaximal exertion at 90% of MPO also allows performing longer sessions with a higher total VO? than 100% intensity. Thus, the results of the present study suggested that to increase the total time at high intensity of exercise and total VO? of a single exercise session performed by the athlete, IT protocols of short durations (i.e., 30 seconds) and submaximal intensities (i.e., 90% MPO) should be selected. Furthermore, performing short-duration intervals may allow the athlete to complete a longer IT session with greater metabolic demands (VO?) and lower BLC than longer (i.e., 3 minutes) intervals. 相似文献
104.
Matthew J. Witt Annette C. Broderick John W. Coker Michael S. Coyne Mark Dodd Michael G. Frick Matthew H. Godfrey DuBose B. Griffin Sally R. Murphy Thomas M. Murphy Kris L. Williams Brendan J. Godley 《Diversity & distributions》2011,17(4):624-640
Aim Although satellite tracking has yielded much information regarding the migrations and habitat use of threatened marine species, relatively little has been published about the environmental niche for loggerhead sea turtles Caretta caretta in north‐west Atlantic waters. Location North Carolina, South Carolina and Georgia, USA. Methods We tracked 68 adult female turtles between 1998 and 2008, one of the largest sample sizes to date, for 372.2 ± 210.4 days (mean ± SD). Results We identified two strategies: (1) ‘seasonal’ migrations between summer and winter coastal areas (n = 47), although some turtles made oceanic excursions (n = 4) and (2) occupation of more southerly ‘year‐round’ ranges (n = 18). Seasonal turtles occupied summer home ranges of 645.1 km2 (median, n = 42; using α‐hulls) predominantly north of 35 ° latitude and winter home ranges of 339.0 km2 (n = 24) in a relatively small area on the narrow shelf off North Carolina. We tracked some of these turtles through successive summer (n = 8) and winter (n = 3) seasons, showing inter‐annual home range repeatability to within 14.5 km of summer areas and 10.3 km of winter areas. For year‐round turtles, home ranges were 1889.9 km2. Turtles should be tracked for at least 80 days to reliably estimate the home range size in seasonal habitats. The equivalent minimum duration for ‘year‐round’ turtles is more complex to derive. We define an environmental envelope of the distribution of North American loggerhead turtles: warm waters (between 18.2 and 29.2 °C) on the coastal shelf (in depths of 3.0–89.0 m). Main conclusions Our findings show that adult female loggerhead turtles show predictable, repeatable home range behaviour and do not generally leave waters of the USA, nor the continental shelf (< 200m depth). These data offer insights for future marine management, particularly if they were combined with those from the other management units in the USA. 相似文献
105.
Lander Baeten Gorik Verstraeten Pieter De Frenne Margot Vanhellemont Karen Wuyts Martin Hermy Kris Verheyen 《Plant Ecology》2011,212(5):901-909
The colonization rates of understorey plants into forests growing on former agricultural land differ remarkably among species.
Different dispersal and recruitment largely account for the contrasting colonization rates, but different effects of the soil
legacies of former agricultural land use on plant performance may also play a role. Seven herbaceous forest species were sampled
in paired post-agricultural and ancient forest stands to study whether land-use history has an effect on the aboveground nutrient
concentrations (N, P and N:P ratios) and biomass of forest herbs and, if so, whether slow and fast colonizing species respond
differently. Results showed that P concentrations were significantly affected by former land use with higher concentrations
in the post-agricultural stands. N concentrations were unaffected and N:P ratios were significantly higher in the ancient
stands. Nutrient concentrations varied considerably among species, but the variation was unrelated to their colonization capacity.
Six out of the seven species had higher biomass in the post-agricultural stands relative to the ancient stands, and the degree
to which the species increased biomass was positively related to their colonization capacity, i.e., the fast colonizing species
showed the strongest increase. Such differential responses to past land use may contribute to the contrasting colonization
capacity of forest plants. Land-use history thus affected both the nutrient concentrations and biomass of forest herbs, and
only the biomass response was related to colonization capacity. 相似文献
106.
The advent of algorithms for fragmentation spectrum-based label-free quantitative proteomics has enabled straightforward quantification of shotgun proteomic experiments. Despite the popularity of these approaches, few studies have been performed to assess their performance. We have therefore profiled the precision and the accuracy of three distinct relative label-free methods on both the protein and the proteome level. We derived our test data from two well-characterized publicly available quantitative data sets. 相似文献
107.
Tyrosine nitration is the consequence of a complex machinery of formation and merging of oxygen and nitrogen radicals, and has been associated with both physiological pathways as well as with several human diseases. The latter turned this posttranslational protein modification into an interesting biomarker, being either a consequence of the disease or a factor contributing to the disease onset. However, the interpretation of MS and MS/MS data of peptides containing nitrotyrosine has proven to be very challenging and consequently, the risk of linking MS/MS spectra to incorrect peptide sequences exists and has been reported. Here, we discuss the causes of data misinterpretation and describe a general method to avoid mistakes of MS/MS spectrum misinterpretation. Central in our approach is the reduction of nitrotyrosine into aminotyrosine and the use of the Peptizer algorithm to inspect MS/MS quality-related assumptions. 相似文献
108.
After infection, extralymphoid tissues are enriched with effector and memory T cells of a highly activated phenotype. The capacity for rapid effector cytokine response from extralymphoid tissue-memory T cells suggests these cells may perform a 'sentinel' function in the tissue. While it has been demonstrated that extralymphoid CD4+ T cells can directly respond to secondary infection, little is known about how rapidly this response is initiated, and how early activation of T cells in the tissue may affect the innate response to infection. Here we use a mouse model of secondary heterosubtypic influenza infection to show that CD4(+) T cells in the lung airways are reactivated within 24 hours of secondary challenge. Airway CD4(+) T cells initiate an inflammatory cytokine and chemokine program that both alters the composition of the early innate response and contributes to the reduction of viral titers in the lung. These results show that, unlike a primary infection, extralymphoid tissue-memory CD4(+) T cells respond alongside the innate response during secondary infection, thereby shaping the overall immune profile in the airways. These data provide new insights into the role of extralymphoid CD4(+) T cells during secondary immune responses. 相似文献
109.
110.
Matsuzaki I Chatterjee S Debolt K Manevich Y Zhang Q Fisher AB 《American journal of physiology. Heart and circulatory physiology》2005,289(1):H336-H343
Vascular endothelial growth factor (VEGF) is considered to be important in promotion of capillary growth in skeletal muscles exposed to increased activity. We studied its interactions with nitric oxide (NO) by examining the expression of endothelial NO synthase (NOS), VEGF, and VEGF receptor-2 (VEGFR-2) proteins in relation to capillary growth in rat extensor digitorum longus muscles electrically stimulated for 2, 4, or 7 days with and without NOS inhibition by N(omega)-nitro-L-arginine (L-NNA, 3 mg/day). Stimulation increased all proteins from 2 days onward, concomitantly with capillary proliferation (labeling for proliferating cell nuclear antigen). Capillary-to-fiber ratio was elevated by 25% after 7 days. Concurrent oral administration of L-NNA did not affect the increase in endothelial NOS but depressed its activity, as shown by increased blood pressure and decreased arteriolar diameters in 2-day-stimulated muscles. NOS inhibition eliminated the increased expression of VEGFR-2 and VEGF proteins in muscles stimulated for 2 and 4 days but not for 7 days. However, it depressed capillary proliferation and the increase in C/F at all time points. We conclude that, in stimulated muscles, NO, generated by activation of neuronal NOS by muscle activity or endothelial NOS by increased blood flow and capillary shear stress, may increase capillary proliferation in the early stages of stimulation through upregulation of VEGFR-2 and VEGF. With longer stimulation, capillary growth appears to require NO, and high levels of VEGF and VEGFR-2 may be contributing to maintenance of the increased capillary bed. 相似文献