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101.
102.
Agustin Casimiro-Garcia Christopher F. Bigge Jo Ann Davis Teresa Padalino James Pulaski Jeffrey F. Ohren Patrick McConnell Christopher D. Kane Lori J. Royer Kimberly A. Stevens Bruce Auerbach Wendy Collard Christine McGregor Kun Song 《Bioorganic & medicinal chemistry》2009,17(20):7113-7125
The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the α-position and their evaluation for binding and activation of PPARα and PPARγ are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARα/γ dual agonist (EC50 = 0.013 and 0.061 μM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies. 相似文献
103.
Emam ElHak Abdel Fatah Natalie R. Shirley Mohamed R. Mahfouz Benjamin M. Auerbach 《American journal of physical anthropology》2012,149(4):547-559
This study presents a novel three‐dimensional analysis using statistical atlases and automated measurements to assess diaphyseal morphology of the clavicle and its relationship to muscle asymmetry. A sample of 505 individuals (285 males, 220 females) from the William McCormick Clavicle Collection was CT scanned, segmented, and added to a statistical bone atlas that captures correspondence between homologous points on the bone surfaces. Muscle attachment sites were localized on the atlas and then propagated across the entire population. Cross‐sectional contours were extracted at 5% increments along the entire bone, as well as at muscle attachment sites and the clavicle waist; maximum and minimum dimensions of each cross‐sectional contour were calculated. In addition, the entire three‐dimensional surface was examined for asymmetry by analyzing the magnitude and directional differences between homologous points across all bone surfaces in the dataset. The results confirm the existing studies on clavicle asymmetry, namely that the left clavicle is longer than the right, but the right is more robust than the left. However, the patterns of asymmetry are sexually dimorphic. Males are significantly asymmetric in all dimensions and at muscle and ligament attachment sites (P < 0.05), whereas female asymmetry is more variable. We hypothesize that this is related to absolute and relative differences in male muscle strength compared to females. However, an area with no muscle attachments on the posterior midshaft was significantly asymmetric in both sexes. We suggest that this is a curvature difference caused by opposing muscle actions at the medial and lateral ends of the bone. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc. 相似文献
104.
Humans demonstrate species-wide bilateral asymmetry in long bone dimensions. Previous studies have documented greater right-biases in upper limb bone dimensions--especially in length and diaphyseal breadth--as well as more asymmetry in the upper limb when compared with the lower limb. Some studies have reported left-bias in lower limb bone dimensions, which, combined with the contralateral asymmetry in upper limbs, has been termed "crossed symmetry." The examination of sexual dimorphism and population variation in asymmetry has been limited. This study re-examines these topics in a large, geographically and temporally diverse sample of 780 Holocene adult humans. Fourteen bilateral measures were taken, including maximum lengths, articular and peri-articular breadths, and diaphyseal breadths of the femur, tibia, humerus, and radius. Dimensions were converted into percentage directional (%DA) and absolute (%AA) asymmetries. Results reveal that average diaphyseal breadths in both the upper and lower limbs have the greatest absolute and directional asymmetry among all populations, with lower asymmetry evident in maximum lengths or articular dimensions. Upper limb bones demonstrate a systematic right-bias in all dimensions, while lower limb elements have biases closer to zero %DA, but with slight left-bias in diaphyseal breadths and femoral length. Crossed symmetry exists within individuals between similar dimensions of the upper and lower limbs. Females have more asymmetric and right-biased upper limb maximum lengths, while males have greater humeral diaphyseal and head breadth %DAs. The lower limb demonstrates little sexual dimorphism in asymmetry. Industrial groups exhibit relatively less asymmetry than pre-industrial humans and less dimorphism in asymmetry. A mixture of influences from both genetic and behavioral factors is implicated as the source of these patterns. 相似文献
105.
Acetylcholine receptor channels switch between conformations that have a low versus high affinity for the transmitter and conductance for ions (R↔R*; gating). The forward isomerization, which begins at the transmitter binding sites and propagates ∼50 Å to the narrow region of the pore, occurs by approximately the same sequence of molecular events with or without agonists present at the binding sites. To pinpoint the forces that govern the R versus R* agonist affinity ratio, we measured single-channel activation parameters for apo-receptors having combinations of mutations of 10 transmitter binding site residues in the α (Y93, G147, W149, G153, Y190, C192, and Y198), ε (W55 and P121), or δ (W57) subunit. Gating energy changes were largest for the tryptophan residues. The αW149 energy changes were coupled with those of the other aromatic amino acids. Mutating the aromatic residues to Phe reduces the R/R* equilibrium dissociation constant ratio, with αY190 and αW149 being the most sensitive positions. Most of the mutations eliminated long-lived spontaneous openings. The results provide a foundation for understanding how ligands trigger protein conformational change. 相似文献
106.
S M Auerbach 《Journal of biomechanics》1984,17(11):861-866
An axisymmetric finite element model of cuff on limb was developed. The model was used to simulate a clinical experiment by others in which the fluid pressure was measured at various points under a blood pressure cuff; the distribution of calculated hydrostatic stress was consistent with the clinical results. Simulations involving varying degrees of rounding at the edges of a tourniquet suggested that ensuring such rounding decreases maximum octahedral shear stress; this finding was consistent with studies by others using a two-dimensional physical model. The calculated stresses were highest at the tourniquet edges; this was consistent with nerve conduction and photomicrographic studies by others of damage caused by tourniquet use. 相似文献
107.
108.
Summary In the strain ad 3A 38701 inos 37401, UV usually produces about twice as many inositol-as adenine-reversions. We have shown previously that this inositol-specificity of UV can be reversed into adenine-specificity by pre- or post-treatment with low doses of the adenine-specific DEB. We now have tested two more adenine-specific mutagens, nitrous acid (NA) and a mixture of hydrogen peroxide and formaldehyde (HF) and one inositolspecific mutagen nitrosoethylurethane (NEU) for interaction with UV. The former two substances behaved like DEB in reversing the inositol-specificity of UV when given as pre-or post-treatment. Pre-treatment with NEU always enhanced the frequency of inositol-reversions beyond additivity. At low doses, it also enhanced the frequency of adenine-reversions. The results are discussed in relation to mutagen specificity. They indicate that specificity may arise from the effects of treatment on cellular events in any one of the three major parts of the mutational pathway: repair, expression, growth of completed mutants into clones. 相似文献
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110.