Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive (1)H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (R(d)) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body R(d) and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body R(d) (r = -0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.     

Reliable simulations of the human proximal femur by high-order finite element analysis validated by experimental observations

Background: The mechanical response of patient-specific bone to various load conditions is of major clinical importance in orthopedics. Herein we enhance the methods presented in Yosibash et al. [2007. A CT-based high-order finite element analysis of the human proximal femur compared to in-vitro experiments. ASME Journal of Biomechanical Engineering 129(3), 297–309.] for the reliable simulations of the human proximal femur by high-order finite elements (FEs) and validate the simulations by experimental observations.

Method of approach: A fresh-frozen human femur was scanned by quantitative computed tomography (QCT) and thereafter loaded (in vitro experiments) by a quasi-static force of up to 1250 N. QCT scans were manipulated to generate a high-order FE bone model with distinct cortical and trabecular regions having inhomogeneous isotropic elastic properties with Young's modulus represented by continuous spatial functions. Sensitivity analyses were performed to quantify parameters that mostly influence the mechanical response. FE results were compared to displacements and strains measured in the experiments.

Results: Young moduli correlated to QCT Hounsfield Units by relations in Keyak and Falkinstein [2003. Comparison of in situ and in vitro CT scan-based finite element model predictions of proximal femoral fracture load. Medical Engineering and Physics 25, 781–787.] were found to provide predictions that match the experimental results closely. Excellent agreement was found for both the displacements and strains. The presented study demonstrates that reliable and validated high-order patient-specific FE simulations of human femurs based on QCT data are achievable for clinical computer-aided decision making.     

Coupling between neuronal firing rate, gamma LFP, and BOLD fMRI is related to interneuronal correlations

BACKGROUND: To what extent is activity of individual neurons coupled to the local field potential (LFP) and to blood-oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI)? This issue is of high significance for understanding brain function and for relating animal studies to fMRI, yet it is still under debate. RESULTS: Here we report data from simultaneous recordings of isolated unit activity and LFP by using multiple electrodes in the human auditory cortex. We found a wide range of coupling levels between the activity of individual neurons and gamma LFP. However, this large variability could be predominantly explained (r = 0.66) by the degree of firing-rate correlations between neighboring neurons. Importantly, this phenomenon occurred during both sensory stimulation and spontaneous activity. Concerning the coupling of neuronal activity to BOLD fMRI, we found that gamma LFP was well coupled to BOLD measured across different individuals (r = 0.62). By contrast, the coupling of single units to BOLD was highly variable and, again, tightly related to interneuronal-firing-rate correlations (r = 0.70). CONCLUSIONS: Our results offer a resolution to a central controversy regarding the coupling between neurons, LFP, and BOLD signals by demonstrating, for the first time, that the coupling of single units to the other measures is variable yet it is tightly related to the degree of interneuronal correlations in the human auditory cortex.     

Cortactin releases the brakes in actin- based motility by enhancing WASP-VCA detachment from Arp2/3 branches

Cortactin is involved in invadopodia and podosome formation [1], pathogens and endosome motility [2], and persistent lamellipodia protrusion [ [3] and [4] ]; its overexpression enhances cellular motility and metastatic activity [ [5] , [6] , [7] and [8] ]. Several mechanisms have been proposed to explain cortactin's role in Arp2/3-driven actin polymerization [ [9] and [10] ], yet its direct role in cell movement remains unclear. We use a biomimetic system to study the mechanism of cortactin-mediated regulation of actin-driven motility [11]. We tested the role of different cortactin variants that interact with Arp2/3 complex and actin filaments distinctively. We show that wild-type cortactin significantly enhances the bead velocity at low concentrations. Single filament experiments show that cortactin has no significant effect on actin polymerization and branch stability, whereas it strongly affects the branching rate driven by Wiskott-Aldrich syndrome protein (WASP)-VCA fragment and Arp2/3 complex. These results lead us to propose that cortactin plays a critical role in translating actin polymerization at a bead surface into motion, by releasing WASP-VCA from the new branching site. This enhanced release has two major effects: it increases the turnover rate of branching per WASP molecule, and it decreases the friction-like force caused by the binding of the moving surface with respect to the growing actin network.     

Mitochondrial biogenesis related endurance genotype score and sports performance in athletes

We determined the probability of individuals having the ‘optimal’ mitochondrial biogenesis related endurance polygenic profile, and compared the endurance polygenic profile of Israeli (Caucasian) endurance athletes (n = 74), power athletes (n = 81), and non-athletes (n = 240). We computed a mitochondrial biogenesis related ‘endurance genotype score’ (EGS, scoring from 0 to 100) from the accumulated combination of six polymorphisms in the PPARGC1A-NRF-TFAM pathway. Some of the variant alleles of the polymorphisms studied were so infrequent, that the probability of possessing an ‘optimal’ EGS (= 100) was 0% in the entire study population. However, the EGS was significantly higher (P < 0.001) in endurance athletes (38.9 ± 17.1) compared with controls (30.6 ± 12.4) or power athletes (29.0 ± 11.2). In summary, although the probability of an individual possessing a theoretically ‘optimal’ genetic background for endurance sports is very low, in general endurance athletes have a polygenic profile that is more suitable for mitochondrial biogenesis.