Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity

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Mechanical,histological, and functional properties remain inferior in conservatively treated Achilles tendons in rodents: Long term evaluation

Conservative treatment (non-operative) of Achilles tendon ruptures is suggested to produce equivalent capacity for return to function; however, long term results and the role of return to activity (RTA) for this treatment paradigm remain unclear. Therefore, the objective of this study was to evaluate the long term response of conservatively treated Achilles tendons in rodents with varied RTA. Sprague Dawley rats (n = 32) received unilateral blunt transection of the Achilles tendon followed by randomization into groups that returned to activity after 1-week (RTA1) or 3-weeks (RTA3) of limb casting in plantarflexion, before being euthanized at 16-weeks post-injury. Uninjured age-matched control animals were used as a control group (n = 10). Limb function, passive joint mechanics, tendon properties (mechanical, histological), and muscle properties (histological, immunohistochemical) were evaluated. Results showed that although hindlimb ground reaction forces and range of motion returned to baseline levels by 16-weeks post-injury regardless of RTA, ankle joint stiffness remained altered. RTA1 and RTA3 groups both exhibited no differences in fatigue properties; however, the secant modulus, hysteresis, and laxity were inferior compared to uninjured age-matched control tendons. Despite these changes, tendons 16-weeks post-injury achieved secant stiffness levels of uninjured tendons. RTA1 and RTA3 groups had no differences in histological properties, but had higher cell numbers compared to control tendons. No changes in gastrocnemius fiber size or type in the superficial or deep regions were detected, except for type 2x fiber fraction. Together, this work highlights RTA-dependent deficits in limb function and tissue-level properties in long-term Achilles tendon and muscle healing.     

Impacts of maturation on the micromechanics of the meniscus extracellular matrix

To elucidate how maturation impacts the structure and mechanics of meniscus extracellular matrix (ECM) at the length scale of collagen fibrils and fibers, we tested the micromechanical properties of fetal and adult bovine menisci via atomic force microscopy (AFM)-nanoindentation. For circumferential fibers, we detected significant increase in the effective indentation modulus, E_ind, with age. Such impact is in agreement with the increase in collagen fibril diameter and alignment during maturation, and is more pronounced in the outer zone, where collagen fibrils are more aligned and packed. Meanwhile, maturation also markedly increases the E_ind of radial tie fibers, but not those of intact surface or superficial layer. These results provide new insights into the effect of maturation on the assembly of meniscus ECM, and enable the design of new meniscus repair strategies by modulating local ECM structure and mechanical behaviors.     

Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities

Although several p53–Mdm2-binding disruptors have been identified to date, few studies have been published on p53–Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200–300 selectively inhibited the p53–Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53–Mdmx interaction over the p53–Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53–Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100 mg/kg and 150 mg/kg, respectively, in 40 days.     

Analysis of genetic changes in radiated and non-radiated bulk oat (Avena sativa L.) populations

Summary In both radiated and non-radiated oat populations inbreeding coefficients increased more slowly than was expected on the assumption of full selfing and equal selective values for homozygotes and heterozygotes. Assuming 1% outcrossing for oats and a selective value of 1.0 for the mean, the heterozygotes for two loci governing crown rust reaction have an advantage of 50% over the homozygotes. This study supports previous observations that the heterozygote often has a decided advantage in predominantly self-pollinated crops.     

Comparing Stochastically Restricted Linear Estimators in a Regression Model

Conditions for superiority of the minimum dispersion estimator over another with respect to the covariance matrix are derived when the vector parameter of a regression model is subject to competing stochastic restrictions. The restrictions may also consist both of a deterministic part and a stochastic part.