The Isotonic Velocity Transient Following a Sudden Rise in Force Imposed on the Muscle Sarcomere During Unloaded Shortening Reveals a Rate Limiting Step in Detached Myosin Motors

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Gaussian Process Prior Variational Autoencoders

Variational autoencoders (VAE) are a powerful and widely-used class of models to learn complex data distributions in an unsupervised fashion. One important limitation of VAEs is the prior assumption that latent sample representations are independent and identically distributed. However, for many important datasets, such as time-series of images, this assumption is too strong: accounting for covariances between samples, such as those in time, can yield to a more appropriate model specification and improve performance in downstream tasks. In this work, we introduce a new model, the Gaussian Process (GP) Prior Variational Autoencoder (GPPVAE), to specifically address this issue. The GPPVAE aims to combine the power of VAEs with the ability to model correlations afforded by GP priors. To achieve efficient inference in this new class of models, we leverage structure in the covariance matrix, and introduce a new stochastic backpropagation strategy that allows for computing stochastic gradients in a distributed and low-memory fashion. We show that our method outperforms conditional VAEs (CVAEs) and an adaptation of standard VAEs in two image data applications.Comment: Accepted at 32nd Conference on Neural Information Processing Systems (NIPS 2018), Montr\'eal, Canad

Activation of skeletal muscle is controlled by a dual-filament mechano-sensing mechanism

Contraction of skeletal muscle is triggered by a transient rise in intracellular calcium concentration leading to a structural change in the actin-containing thin filaments that allows binding of myosin motors from the thick filaments. Most myosin motors are unavailable for actin binding in resting muscle because they are folded back against the thick filament backbone. Release of the folded motors is triggered by thick filament stress, implying a positive feedback loop in the thick filaments. However, it was unclear how thin and thick filament activation mechanisms are coordinated, partly because most previous studies of the thin filament regulation were conducted at low temperatures where the thick filament mechanisms are inhibited. Here, we use probes on both troponin in the thin filaments and myosin in the thick filaments to monitor the activation states of both filaments in near-physiological conditions. We characterize those activation states both in the steady state, using conventional titrations with calcium buffers, and during activation on the physiological timescale, using calcium jumps produced by photolysis of caged calcium. The results reveal three activation states of the thin filament in the intact filament lattice of a muscle cell that are analogous to those proposed previously from studies on isolated proteins. We characterize the rates of the transitions between these states in relation to thick filament mechano-sensing and show how thin- and thick-filament-based mechanisms are coupled by two positive feedback loops that switch on both filaments to achieve rapid cooperative activation of skeletal muscle

New trends in platinum and palladium complexes as antineoplastic agents

The discovery of cisplatin (cis-Pt(NH3)2Cl2) as an antineoplastic agent has focused attention on the rational design of metal complexes that can be potentially used in cancer chemotherapy. Today, the pharmaceutical industry invests more than $1 billion each year in the development of new metal-based drugs to improve biological activities, in terms of cellular selectivity, therapeutic efficiency and minimization of side effects. Chemotherapies based on transition metals play a key role in cancer treatment, and among them platinum and palladium are the most fruitful. This article reviews the main recent advances in the design and synthesis of platinum- and palladium-based drugs, their structural features and biological studies of them. The rationale for the choice of the ligand, related to leaving groups, the geometry of the complex and the oxidation state of the metal ion, is discussed. An overview of the main biological techniques and approaches for testing the interaction of these molecules with the biological environment, mainly DNA, to validate the effect is also provided

Structural Changes in Myosin Heads and Filaments during Unloaded Shortening and Force Redevelopment

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An in vitro comparative study of the antioxidant activity and SIRT1 modulation of natural compounds

Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK. Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay. No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK. Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation