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161.
Lebsack AD Rech JC Branstetter BJ Hawryluk NA Merit JE Allison B Rynberg R Buma J Rizzolio M Swanson N Ao H Maher MP Herrmann M Freedman J Scott BP Luo L Bhattacharya A Wang Q Chaplan SR Wickenden AD Breitenbucher JG 《Bioorganic & medicinal chemistry letters》2010,20(23):7142-7146
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 μg/mL and SIF=11 μg/mL) was significantly improved over compound 1 (pH 2=5 μg/mL and SIF=0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats. 相似文献
162.
Justin C. Meissen Alec J. Glidden Mark E. Sherrard Kenneth J. Elgersma Laura L. Jackson 《Restoration Ecology》2020,28(4):807-816
Agricultural intensification continues to diminish many ecosystem services in the North American Corn Belt. Conservation programs may be able to combat these losses more efficiently by developing initiatives that attempt to balance multiple ecological benefits. In this study, we examine how seed mix design and first year management influence three ecosystem services commonly provided by tallgrass prairie reconstructions (erosion control, weed resistance, and pollinator resources). We established research plots with three seed mixes, with and without first year mowing. The grass‐dominated “Economy” mix had 21 species and a 3:1 grass‐to‐forb seeding ratio. The forb‐dominated “Pollinator” mix had 38 species and a 1:3 grass‐to‐forb seeding ratio. The grass:forb balanced “Diversity” mix, which was designed to resemble regional prairie remnants, had 71 species and a 1:1 grass‐to‐forb ratio. To assess ecosystem services, we measured native stem density, cover, inflorescence production, and floral richness from 2015 to 2018. The Economy mix had high native cover and stem density, but produced few inflorescences and had low floral richness. The Pollinator mix had high inflorescence production and floral richness, but also had high bare ground and weed cover. The Diversity mix had high inflorescence production and floral richness (comparable to the Pollinator mix) and high native cover and stem density (comparable to the Economy mix). First year mowing accelerated native plant establishment and inflorescence production, enhancing the provisioning of ecosystem services during the early stages of a reconstruction. Our results indicate that prairie reconstructions with thoughtfully designed seed mixes can effectively address multiple conservation challenges. 相似文献
163.
Steve Wiseman Even H. J?rgensen Alec G. Maule Mathilakath M. Vijayan 《Polar Biology》2011,34(6):933-937
The remote Arctic lakes on Bj?rn?ya Island, Norway, offer a unique opportunity to study possible affect of lifelong contaminant
exposure in wild populations of landlocked Arctic charr (Salvelinus alpinus). This is because Lake Ellasj?en has persistent organic pollutant (POP) levels that are significantly greater than in the
nearby Lake ?yangen. We examined whether this differential contaminant loading was reflected in the expression of protein
markers of exposure and effect in the native fish. We assessed the expressions of cellular stress markers, including cytochrome
P4501A (Cyp1A), heat shock protein 70 (hsp70), and glucocorticoid receptor (GR) in feral charr from the two lakes. The average
polychlorinated biphenyl (PCB) load in the charr liver from Ellasj?en was approximately 25-fold higher than in individuals
from ?yangen. Liver Cyp1A protein expression was significantly higher in individuals from Ellasj?en compared with ?yangen,
confirming differential PCB exposure. There was no significant difference in hsp70 protein expression in charr liver between
the two lakes. However, brain hsp70 protein expression was significantly elevated in charr from Ellasj?en compared with ?yangen.
Also, liver GR protein expression was significantly higher in the Ellasj?en charr compared with ?yangen charr. Taken together,
our results suggest changes to cellular stress-related protein expression as a possible adaptation to chronic-contaminant
exposure in feral charr in the Norwegian high-Arctic. 相似文献
164.
Why do people often choose to cooperate when they can better serve their interests by acting selfishly? One potential mechanism is that the anticipation of guilt can motivate cooperative behavior. We utilize a formal model of this process in conjunction with fMRI to identify brain regions that mediate cooperative behavior while participants decided whether or not to honor a partner's trust. We observed increased activation in the insula, supplementary motor area, dorsolateral prefrontal cortex (PFC), and temporal parietal junction when participants were behaving consistent with our model, and found increased activity in the ventromedial PFC, dorsomedial PFC, and nucleus accumbens when they chose to abuse trust and maximize their financial reward. This study demonstrates that a neural system previously implicated in expectation processing plays a critical role in assessing moral sentiments that in turn can sustain human cooperation in the face of temptation. VIDEO ABSTRACT: 相似文献
165.
166.
167.
B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies 总被引:2,自引:0,他引:2
Winer DA Winer S Shen L Wadia PP Yantha J Paltser G Tsui H Wu P Davidson MG Alonso MN Leong HX Glassford A Caimol M Kenkel JA Tedder TF McLaughlin T Miklos DB Dosch HM Engleman EG 《Nature medicine》2011,17(5):610-617
Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease. 相似文献
168.
Human sweat, liquid ammonia, and bovine blood are known to be attractive to some hematophagous flies. These materials were evaluated with and without carbon dioxide (CO2) for their ability to increase capture of female “canyon flies” (Fannia conspicua Malloch) using CDC‐type suction traps (without light). Ammonia acted synergistically with CO2 to increase trap catch 89.9% over CO2 alone. There was no synergistic effect of human sweat or bovine blood with CO2. In the absence of CO2, none of the three materials increased trap catch of female canyon flies relative to non‐baited traps. Implications for canyon fly control and further trap improvement are discussed. 相似文献
169.
D. P. Gladue V. O'Donnell R. Baker-Branstetter L. G. Holinka J. M. Pacheco I. Fernandez-Sainz Z. Lu E. Brocchi B. Baxt M. E. Piccone L. Rodriguez M. V. Borca 《Journal of virology》2012,86(22):12080-12090
Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an Apthovirus within the Picornaviridae family. Replication of the virus occurs in association with replication complexes that are formed by host cell membrane rearrangements. The largest viral protein in the replication complex, 2C, is thought to have multiple roles during virus replication. However, studies examining the function of FMDV 2C have been rather limited. To better understand the role of 2C in the process of virus replication, we used a yeast two-hybrid approach to identify host proteins that interact with 2C. We report here that cellular Beclin1 is a specific host binding partner for 2C. Beclin1 is a regulator of the autophagy pathway, a metabolic pathway required for efficient FMDV replication. The 2C-Beclin1 interaction was further confirmed by coimmunoprecipitation and confocal microscopy to actually occur in FMDV-infected cells. Overexpression of either Beclin1 or Bcl-2, another important autophagy factor, strongly affects virus yield in cell culture. The fusion of lysosomes to autophagosomes containing viral proteins is not seen during FMDV infection, a process that is stimulated by Beclin1; however, in FMDV-infected cells overexpressing Beclin1 this fusion occurs, suggesting that 2C would bind to Beclin1 to prevent the fusion of lysosomes to autophagosomes, allowing for virus survival. Using reverse genetics, we demonstrate here that modifications to the amino acids in 2C that are critical for interaction with Beclin1 are also critical for virus growth. These results suggest that interaction between FMDV 2C and host protein Beclin1 could be essential for virus replication. 相似文献
170.
Rebecca N. D'Amico Alec M. Murray David D. Boehr 《BioEssays : news and reviews in molecular, cellular and developmental biology》2020,42(9):2000092
A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free-energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free-energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. 相似文献