Citations

A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.

This paper examined the feasibility of using different optimization criteria in inverse dynamic optimization to predict antagonistic muscle forces and joint reaction forces during isokinetic flexion/extension and isometric extension exercises of the knee. Both quadriceps and hamstrings muscle groups were included in this study. The knee joint motion included flexion/extension, varus/valgus, and internal/external rotations. Four linear, nonlinear, and physiological optimization criteria were utilized in the optimization procedure. All optimization criteria adopted in this paper were shown to be able to predict antagonistic muscle contraction during flexion and extension of the knee. The predicted muscle forces were compared in temporal patterns with EMG activities (averaged data measured from five subjects). Joint reaction forces were predicted to be similar using all optimization criteria. In comparison with previous studies, these results suggested that the kinematic information involved in the inverse dynamic optimization plays an important role in prediction of the recruitment of antagonistic muscles rather than the selection of a particular optimization criterion. Therefore, it might be concluded that a properly formulated inverse dynamic optimization procedure should describe the knee joint rotation in three orthogonal planes.

An instrumented wheel system for three-dimensional kinetic analysis of upper extremity during wheelchair propulsion has been designed and validated. This system allows the direct measurements of three-dimensional dynamic forces and moments on the handrim during wheelchair propulsion in a laboratory setting as well as in the field. Static loading tests showed a high linearity and little drift (coefficient of determination, r2 > 0.999). Under dynamic loading, the instrumented wheel provided the well-matched measurement forces and moments with the predicted values from the inverse dynamic method using video-based kinematic data (correlation coefficient, ρ > 0.97). The three-dimensional handrim forces and moments during wheelchair propulsion by a non-disabled subject were demonstrated.

This study evaluated the effects of soft tissue integrity on patellar tracking and patellofemoral joint force after total knee arthroplasty. The results indicate that partial dissection of the soft tissue integrity in the in vitro biomechanical studies of the patellofemoral joint can alter patellar tracking and joint force significantly, leading to improper conclusions.

In 1991 the Clinical Trials Subcommittee of the International Headache Society (IHS) developed and published its first edition of the Guidelines on controlled trials of drugs in episodic migraine because only quality trials can form the basis for international collaboration on drug therapy, and these Guidelines would ‘improve the quality of controlled clinical trials in migraine’. With the current trend for large multinational trials, there is a need for increased awareness of methodological issues in clinical trials of drugs and other treatments for chronic migraine. These Guidelines are intended to assist in the design of well-controlled clinical trials of chronic migraine in adults, and do not apply to studies in children or adolescents.

OBJECTIVE— We assessed the direct (VLDL-triglycerides [VLDL-TG] independent) storage of circulating free fatty acids (FFAs) in visceral and subcutaneous fat in postabsorptive women. RESEARCH DESIGN AND METHODS— Twelve women (BMI 29.6 ± 6.6 kg/m2) received an identical, intravenous bolus dose of [1-14C]oleate followed by timed subcutaneous fat biopsies (abdominal and femoral) and then omental fat biopsy during tubal ligation surgery. Regional fat masses were assessed by combining dual-energy X-ray absorptiometry and computed tomography scanning. Separately, we assessed the fraction of FFA tracer entering VLDL-TG over the time representing the delay in collecting omental fat. RESULTS— Site-specific fat specific activity (SA) (dpm/g lipid) decreased as a function of fat mass in both upper-body subcutaneous (UBSQ) and visceral fat depots. These patterns are consistent with dilution of a relatively fixed amount of FFA tracer within progressively greater amounts of fat. Interestingly, femoral SA did not vary as a function of lower-body subcutaneous (LBSQ) fat mass. [1-14C]oleate storage per million LBSQ adipocytes was positively associated with LBSQ fat mass, but no significant relationships were observed in UBSQ or visceral fat depot. The fraction of [1-14C]oleate stored in UBSQ, LBSQ, and visceral fat was 6.7 ± 3.2, 4.9 ± 3.4, and 1.0 ± 0.3%, respectively. Only ∼4% of the tracer traversed VLDL-TG over 9.5 h. CONCLUSIONS— The increase in FFA tracer storage per adipocyte as a function of LBSQ fat mass implies that LBSQ adipocytes, in contrast to UBSQ and omental adipocytes, store more FFA in women with greater adiposity. The direct FFA storage pathway might play a role in favoring lower-body fat accumulation in women.