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61.
Paula M. Checchi Katherine S. Lawrence Mike V. Van Braden J. Larson JoAnne Engebrecht 《Genetics》2014,197(2):543-560
During meiosis, accurate chromosome segregation relies on homology to mediate chromosome pairing, synapsis, and crossover recombination. Crossovers are dependent upon formation and repair of double-strand breaks (DSBs) by homologous recombination (HR). In males of many species, sex chromosomes are largely hemizygous, yet DSBs are induced along nonhomologous regions. Here we analyzed the genetic requirements for meiotic DSB repair on the completely hemizygous X chromosome of Caenorhabditis elegans males. Our data reveal that the kinetics of DSB formation, chromosome pairing, and synapsis are tightly linked in the male germ line. Moreover, DSB induction on the X is concomitant with a brief period of pseudosynapsis that may allow X sister chromatids to masquerade as homologs. Consistent with this, neither meiotic kleisins nor the SMC-5/6 complex are essential for DSB repair on the X. Furthermore, early processing of X DSBs is dependent on the CtIP/Sae2 homolog COM-1, suggesting that as with paired chromosomes, HR is the preferred pathway. In contrast, the X chromosome is refractory to feedback mechanisms that ensure crossover formation on autosomes. Surprisingly, neither RAD-54 nor BRC-2 are essential for DSB repair on the X, suggesting that unlike autosomes, the X is competent for repair in the absence of HR. When both RAD-54 and the structure-specific nuclease XPF-1 are abrogated, X DSBs persist, suggesting that single-strand annealing is engaged in the absence of HR. Our findings indicate that alteration in sister chromatid interactions and flexibility in DSB repair pathway choice accommodate hemizygosity on sex chromosomes. 相似文献
62.
Roemhildt ML Coughlin KM Peura GD Fleming BC Beynnon BD 《Journal of biomechanics》2006,39(12):2331-2337
The material properties of articular cartilage in the rabbit tibial plateau were determined using biphasic indentation creep tests. Cartilage specimens from matched-pair hind limbs of rabbits approximately 4 months of age and greater than 12 months of age were tested on two locations within each compartment using a custom built materials testing apparatus. A three-way ANOVA was used to determine the effect of leg, compartment, and test location on the material properties (aggregate modulus, permeability, and Poisson's ratio) and thickness of the cartilage for each set of specimens. While no differences were observed in cartilage properties between the left and right legs, differences between compartments were found in each set of specimens. For cartilage from the adolescent group, values for aggregate modulus were 40% less in the medial compartment compared to the lateral compartment, while values for permeability and thickness were greater in the medial compartment compared to the lateral compartment (57% and 30%, respectively). Values for Poisson's ratio were 19% less in the medial compartment compared to the lateral compartment. There was also a strong trend for thickness to differ between test locations. Similar findings were observed for cartilage from the mature group with values for permeability and thickness being greater in the medial compartment compared to the lateral compartment (66% and 34%, respectively). Values for Poisson's ratio were 22% less in the medial compartment compared to the lateral compartment. 相似文献
63.
Maria L. Roemhildt Kathryn M. Coughlin Glenn D. Peura Gary J. Badger Dave Churchill Braden C. Fleming Bruce D. Beynnon 《Journal of biomechanics》2010,43(12):2301-2308
Methods of producing relevant and quantifiable load alterations in vivo with which to study load-induced cartilage degeneration analogous to osteoarthritis are limited. An animal model was used to investigate the effects of increased chronic loads on articular cartilage. Mature rabbits were randomized into one of three experimentally loaded groups and a fourth unoperated control group. A mechanical-loading device was skeletally fixed to the hind limb of animals in the loaded groups. Engaging the device resulted in an additional load of 0%, +22% or +44% body weight to the medial compartment of the experimental knee, while allowing normal joint function. Following a 12-week loading protocol, a creep-indentation test and needle probe test were used to determine the biphasic material properties and thickness of the cartilage at four locations of each femoral and tibial condyle of the experimental and contralateral limbs. Analyses of covariance were performed to compare outcome measures across the treatment groups. The effect of increased load was site and load-level specific with alterations of material properties and thickness most prominent in the posterior region of the medial compartment of the tibia. At this site, permeability increased 128% and thickness increased 28% in the +44% body weight group relative to the 0% body weight group. This model of altered chronic loading initiated changes in the material properties to the articular cartilage at the sites of increased load over 12-weeks that were consistent with early degenerative changes suggesting that increased tibio-femoral loading may be responsible for the alterations. This work begins to elucidate the chronic-load threshold and the time course of cartilage degeneration at different levels of altered loading. 相似文献
64.
Daniel L. Miranda Michael J. Rainbow Evan L. Leventhal Joseph J. Crisco Braden C. Fleming 《Journal of biomechanics》2010,43(8):1623-1626
The combination of three-dimensional (3-D) models with dual fluoroscopy is increasingly popular for evaluating joint function in vivo. Applying these modalities to study knee motion with high accuracy requires reliable anatomical coordinate systems (ACSs) for the femur and tibia. Therefore, a robust method for creating ACSs from 3-D models of the femur and tibia is required. We present and evaluate an automated method for constructing ACSs for the distal femur and proximal tibia based solely on 3-D bone models. The algorithm requires no observer interactions and uses model cross-sectional area, center of mass, principal axes of inertia, and cylindrical surface fitting to construct the ACSs. The algorithm was applied to the femur and tibia of 10 (unpaired) human cadaveric knees. Due to the automated nature of the algorithm, the within specimen variability is zero for a given bone model. The algorithm’s repeatability was evaluated by calculating variability in ACS location and orientation across specimens. Differences in ACS location and orientation between specimens were low (<1.5 mm and <2.5°). Variability arose primarily from natural anatomical and morphological differences between specimens. The presented algorithm provides an alternative method for automatically determining subject-specific ACSs from the distal femur and proximal tibia. 相似文献
65.
66.
An important indicator of osteoarthritis (OA) progression is the loss of proteoglycan (PG) aggregates from the cartilage tissue. Using the indentation creep test, two analytical methods, as previously developed by Lu et al. [Lu, X. L., Miller, C., Chen, F. H., Guo, X. E., Mow, V. C., 2007. The generalized triphasic correspondence principle for simultaneous determination of the mechanical properties and proteoglycan content of articular cartilage by indentation. Journal of Biomechanics 40, 2434-2441 (EPub).], for predicting the fixed charge density (FCD) of goat knee articular cartilage in the normal (control) and degenerated states were compared: (1) a "dual-stage" method to calculate FCD from the mechanical properties of the tissue when tested in isotonic and hypertonic solutions; and (2) a "single-stage" method to predict FCD (as in (1)) assuming an intrinsic Poisson's ratio of 0.05 in the hypertonic state. A biochemical analysis using 1,9-dimethylmethylene blue (DMMB) assay was conducted to directly measure PG content, and hence FCD. The association between the FCD and the aggregate modulus of the tissue was also explored. The mean (+/-S.D.) FCD values measured using the dual-stage method were the closest (control: 0.129+/-0.039, degenerated: 0.046+/-029) to the DMMB results (control: 0.125+/-0.034, degenerated: 0.057+/-0.024) as compared to those of the single-stage method (control: 0.147+/-0.035, degenerated: 0.063+/-0.026). The single-stage method was more reliable (r(2)=0.81) when compared to the dual-stage method (r(2)=0.79). A prediction of FCD from the aggregate modulus generated the least reliable FCD prediction (r(2)=0.68). Because both the dual- and single-stage methods provided reliable FCD estimates for normal and degenerated tissue, the less time-consuming single-stage method was concluded to be the ideal technique for predicting FCD and hence PG content of the tissue. 相似文献
67.
Magnetic resonance imaging has been used to monitor the diffusion of water at 310 K into a series of semi-IPNs of poly(ethyl methacrylate), PEM, and copolymers of 2-hydroxyethyl methacrylate, HEMA, and tetrahydrofurfuryl methacrylate, THFMA. The diffusion was found to be well described by a Fickian kinetic model in the early stages of the water sorption process, and the diffusion coefficients were found to be slightly smaller than those for the copolymers of HEMA and THFMA, P(HEMA-co-THFMA), containing the same mole fraction of HEMA in the matrix. A second stage sorption process was identified in the later stage of water sorption by the PEM/PTHFMA semi-IPN and for the systems containing a P(HEMA-co-THFMA) component with a mole fraction HEMA of 0.6 or less. This was characterized by the presence of water near the surface of the cylinders with a longer NMR T(2) relaxation time, which would be characteristic of mobile water, such as water present in large pores or surface fissures. The presence of the drug chlorhexidine in the polymer matrixes at a concentration of 5.625 wt % was found not to modify the properties significantly, but the diffusion coefficients for the water sorption were systematically smaller when the drug was present. 相似文献
68.
Mark S. Plummer Joseph Cornicelli Howard Roark Donald J. Skalitzky Charles J. Stankovic Susan Bove Jayvardhan Pandit Annise Goodman James Hicks Aurash Shahripour David Beidler Xiao Kang Lu Brian Sanchez Christopher Whitehead Ron Sarver Timothy Braden Richard Gowan Xi Qiang Shen Sandra Lightle 《Bioorganic & medicinal chemistry letters》2013,23(11):3443-3447
Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F = 78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3 h after a single, 10 mg/kg, subcutaneous dose. 相似文献
69.
70.
Andrew J. Link Xinnan Niu Connie M. Weaver Jennifer L. Jennings Dexter T. Duncan K. Jill McAfee Morgan Sammons Vince R. Gerbasi Adam R. Farley Tracey C. Fleischer Christopher M. Browne Parimal Samir Allison Galassie Braden Boone 《Proteomics》2020,20(7)
To identify protein–protein interactions and phosphorylated amino acid sites in eukaryotic mRNA translation, replicate TAP‐MudPIT and control experiments are performed targeting Saccharomyces cerevisiae genes previously implicated in eukaryotic mRNA translation by their genetic and/or functional roles in translation initiation, elongation, termination, or interactions with ribosomal complexes. Replicate tandem affinity purifications of each targeted yeast TAP‐tagged mRNA translation protein coupled with multidimensional liquid chromatography and tandem mass spectrometry analysis are used to identify and quantify copurifying proteins. To improve sensitivity and minimize spurious, nonspecific interactions, a novel cross‐validation approach is employed to identify the most statistically significant protein–protein interactions. Using experimental and computational strategies discussed herein, the previously described protein composition of the canonical eukaryotic mRNA translation initiation, elongation, and termination complexes is calculated. In addition, statistically significant unpublished protein interactions and phosphorylation sites for S. cerevisiae’s mRNA translation proteins and complexes are identified. 相似文献