Age‐related changes to the satellite cell niche are associated with reduced activation following exercise

Skeletal muscle satellite cell (SC) function and responsiveness is regulated, in part, through interactions within the niche, in which they reside. Evidence suggests that structural changes occur in the SC niche as a function of aging. In the present study, we investigated the impact of aging on SC niche properties. Muscle biopsies were obtained from the vastus lateralis of healthy young (YM; 21 ± 1 yr; n = 10) and older men (OM; 68 ± 1 yr; n = 16) at rest. A separate group of OM performed a single bout of resistance exercise and additional muscle biopsies were taken 24 and 48 hours post‐exercise; this was performed before and following 12 wks of combined exercise training (OM‐Ex; 73 ± 1; n = 24). Muscle SC niche measurements were assessed using high resolution immunofluorescent confocal microscopy. Type II SC niche laminin thickness was greater in OM (1.86 ± 0.06 µm) as compared to YM (1.55 ± 0.09 µm, P < .05). The percentage of type II‐associated SC that were completely surrounded by laminin was greater in OM (13.6%±4.2%) as compared to YM (3.5%±1.5%; P < .05). In non‐surrounded SC, the proportion of active MyoD+/Pax7+ SC were higher compared to surrounded SC (P < .05) following a single bout of exercise. This “incarceration” of the SC niche by laminin appears with aging and may inhibit SC activation in response to exercise

Dynamic model of supercritical Organic Rankine Cycle waste heat recovery system for internal combustion engine

The supercritical Organic Rankine Cycle (ORC) for the Waste Heat Recovery (WHR) from Internal Combustion (IC) engines has been a growing research area in recent years, driven by the aim to enhance the thermal efficiency of the ORC and engine. Simulation of a supercritical ORC-WHR system before a real-time application is important as high pressure in the system may lead to concerns about safety and availability of components. In the ORC-WHR system, the evaporator is the main contributor to thermal inertia of the system and is considered to be the critical component since the heat transfer of this device influences the efficiency of the system. Since the thermo-physical properties of the fluid at supercritical pressures are dependent on temperature, it is necessary to consider the variations in properties of the working fluid. The wellknown Finite Volume (FV) discretization method is generally used to take those property changes into account. However, a FV model of the evaporator in steady state condition cannot be used to predict the thermal inertia of the cycle when it is subjected to transient heat sources. In this paper, a dynamic FV model of the evaporator has been developed and integrated with other components in the ORC-WHR system. The stability and transient responses along with the performance of the ORC-WHR system for the transient heat source are investigated and are also included in this paper

Characterization of Type I and IV Collagens by Raman Microspectroscopy: Identification of Spectral Markers of the Dermo-Epidermal Junction

Abstract. Type I and IV collagens are important constituents of the skin. Type I collagen is found in all dermal layers in high proportion, while type IV collagen is localized in the basement membrane of the dermo-epidermal junction (DEJ). These proteins are strongly altered during aging or cancer progression. Although they possess amino acid compositions which, are close, they present also important structural differences inducing specific physicochemical properties. Raman spectroscopy is based on a nondestructive interaction of the light with the matter. This technique permits to probe the intrinsic molecular composition of the samples without staining or particular preparation. The aim of our research is to study the correlation between the molecular conformations of type I and IV collagens and their Raman features. We showed that signals specific of each protein can be revealed and that they translate structural differences between the two collagens. From this collagens spectral characterization, the analysis of skin sections also permitted to identify spectral markers of dermis, epidermis, and epidermis/dermis interface. These preliminary results represent basic data for further studies, particularly to probe skin molecular alterations induced by chronologic aging

The origin of potency and mutant-selective inhibition by bivalent ATP-allosteric EGFR inhibitors

Targeted small-molecule therapies in mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) have undergone several generations of development in response to acquired drug resistance. With the emergence of the highly prevalent T790M and C797S drug-resistant mutations, a diverse arsenal of ATP-competitive molecules has led to the front-line drug AZD9291 (osimertinib) and several in clinical development. Several allosteric inhibitors bind a site adjacent to the ATP-binding site and exhibit synergy when dosed in combination with certain ATP-competitive inhibitors. Structure-guided design of molecules that anchor to both sites simultaneously, namely ATP-allosteric bivalent inhibitors, have been reported as proof-of-concept EGFR mutant-selective compounds, however their properties are underexplored and currently exhibit modest activity in human cancer cell lines. To better understand the structural and functional properties of such molecules, we have carried out structure-activity relationships (SAR) defining the groups of the allosteric pocket that are responsible for enabling mutant selectivity and potency of this series. We find that the back pocket phenol ring enables stronger binding while the methylisoindolinone is responsible for enabling selectivity for the oncogenic mutations. An optimized allosteric site-binding group and a C797-targeting ATP-site scaffold exhibit inhibitory effects in a variety of EGFR mutant cell lines, which is improved over earlier examples. Additionally, a closely related reversible-binding analogue exhibits mutant-selective activity and ~1 nM biochemical potency against L858R/T790M/C797S and promising antiproliferative effects in human cancer cells indicating that ATP-allosteric bivalent kinase inhibitors may serve as tool compounds in understanding overcoming these important resistance mechanisms. These results highlight the utility of bivalent ATP-allosteric compounds in understanding the impact certain functional groups have in the potency and mutant-selectivity enabled by allosteric pocket binding. The results of this study incentivize further investigations of compounds that bind within an exit vector made accessible in the inactive αC-helix “out” conformation as a novel approach for kinase inhibitors