Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies.     

Sequential Formation of Heteroternary Cucurbit[10]uril (CB[10]) Complexes

The globular and monocationic guest molecule trimethyl-azaphosphatrane ( AZAP , a protonated Verkade superbase) was shown to form a host:guest 1 : 1 complex with the cucurbit[10]uril (CB[10]) macrocycle in water. Molecular dynamics calculations showed that CB[10] adopts an 8-shape with AZAP occupying the majority of the internal space, CB[10] contracting around AZAP and leaving a significant part of the cavity unoccupied. This residual space was used to co-include planar and monocationic co-guest ( CG ) molecules, affording heteroternary CB[10]⋅ AZAP ⋅ CG complexes potentially opening new perspectives in supramolecular chemistry.     

Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5‐HT1A and 5‐HT6 Receptors

Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein‐coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5‐HT_1A and 5‐HT₆ receptors, and we have identified and validated some of their off‐targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease‐relevant systems.     

Robust synchronization of arrays of uncertain nonlinear second-order dynamical systems

A technique to synchronize arrays of dynamical systems is presented. The arrays are formed by uncertain nonlinear second-order systems, called nodes, where only the generalized position is available. The synchronization technique can be applied to many array topologies where the connections can be unidirectional or bidirectional with different weights; this produces a connection matrix that it is not necessarily symmetric. The design of the coupling signals is based on a robust discontinuous controller and on an exact deriver that estimates the velocity of each node. We present experimental results to illustrate the performance of the synchronization technique.     

Pyrolysis kinetics of elephant grass pretreated biomasses

The Elephant Grass (Pennisetum purpureum Schum) was pretreated by two independent processes, through washing with hot water (W-EG) and acid solution (AW-EG) to improve its energy properties to apply it in a thermochemical process conversion into fuel. The biomasses were analyzed by proximate and ultimate analysis; and the pyrolysis kinetics, before and after pretreatments, were evaluated by the apparent activation energy (E _a) for decomposition in the temperature range of greater volatile matter through the Model-free kinetics using thermogravimetric analysis data. The kinetics of the microcrystalline cellulose Avicel PH-101 was performed to evaluate the E _a result of pure cellulose. The pretreatments were efficient in increasing the volatile matter and heating value, decreasing moisture and ash content, and improving its energetic power to the application in fast pyrolysis process for bio-oil production. The TG results have shown that the reduction in ash content facilitates the pyrolysis process, increasing the volatile matter and decreasing the apparent activation energy required to biomasses degradation, due to less diffusional resistances to heat and mass transfer of W-EG and AW-EG. The Avicel PH-101 showed the highest value of apparent activated energy (E _a = 276.2 kJ mol^?1) which could be explained by its crystallinity, suggesting that crystalline cellulose regions are less accessible to heat diffusion than amorphous regions, requiring more energy to its degradation.     

Substituted thienyl stibines and bismuthines: syntheses,structures and cytotoxicity

New stibine and bismuthine substituted thienyl ring compounds, i.e. tris(3‐methyl‐2‐thienyl)stibine (1), tris(3‐methyl‐2‐thienyl)bismuthine (2), tris(3‐thienyl)stibine (3), tris(3‐thienyl)bismuthine (4) and tris(5‐chloro‐2‐thienyl)stibine (5), have been synthesized and characterized by IR, mass, ¹H, ¹³C, COSY, and HETCOR NMR spectroscopy. The metal centres in all compounds are pyramidal, and molecules in the stibine compound (1) and bismuthine compound (2) associate via Sb···S or Bi···S interactions to form supramolecular chains. The cytotoxicity of compounds 1 and 5 was determined. For compound 5, 85% of carcinogenic cell growth inhibition (U, K and H) was observed. Compound 1 shows a significant selectivity (>80%) for carcinogenic cell growth (K and U) inhibition. Both the compounds are highly toxic for the growth of normal lymphocytes with ～95% lethality. Compound 1 is approximately 20 times more toxic than 5 against Artemia salina. Copyright © 2005 John Wiley & Sons, Ltd.     

Tris-(1,2-N,N-dimethylaminomethylferrocenyl)stibine and its heterotrimetallic complex

New tertiary chloro-bis(1,2-N,N-dimethylaminomethylferrocenyl)stibine (1) and tris-(1,2-N,N-dimethylaminomethylferrocenyl)stibine ligand (2) containing CH₂NMe₂ pendenant arm at the ortho-position have been synthesized. Stibine (2) reacts with PtCl₄^2? and hetero trimetallic cis-PtCl₂L (3) complex is obtained, where stibine (2) acts as a bidentate ligand. All these compounds were characterized by various physicochemical methods and their molecular structures were determined by X-ray diffraction analyses. It is to be noted that tris(1,2-aminomethylferrocenyl)stibine represents the first example of a structurally characterized ferrocenyl pnictogen where three 1,2-disubstituted ferrocenyl groups are attached to the central antimony atom and phosphorus analogue of the stibine is missing in the literature. Stibine (1) shows a hypervalent Sb–N interaction while stibine (2) does not show this interaction in solid state.     

Robust output synchronization of phase planar systems

We propose a technique to synchronize, under the master/slave synchronization scheme, two planar systems represented by phase state variables; we name them phase planar systems. The coupling signal has a discontinuous term that produces a closed-loop system having good characteristics of robustness with respect to bounded disturbances and parametric variations, and guarantees exponential convergence to the synchronization state. In general, the coupling signal needs the full state vector of both systems, but because we assume that only the system outputs are available, we include a robust observer. This observer also guarantees exponential convergence to the state of the plant in spite of the existence of bounded disturbances and parametric variations; this characteristic facilitates the stability analysis of the closed-loop system. The performance of the synchronization technique is illustrated with experimental results.     

The evolutionary ecology of technological innovations

Technological evolution has been compared to biological evolution by many authors over the last two centuries. As a parallel experiment of innovation involving economic, historical, and social components, artifacts define a universe of evolving properties that displays episodes of diversification and extinction. Here, we critically review previous work comparing the two types of evolution. Like biological evolution, technological evolution is driven by descent with variation and selection, and includes tinkering, convergence, and contingency. At the same time, there are essential differences that make the two types of evolution quite distinct. Major distinctions are illustrated by current specific examples, including the evolution of cornets and the historical dynamics of information technologies. Due to their fast and rich development, the later provide a unique opportunity to study technological evolution at all scales with unprecedented resolution. Despite the presence of patterns suggesting convergent trends between man‐made systems end biological ones, they provide examples of planned design that have no equivalent with natural evolution.