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Heart failure (HF) is a complex syndrome in which the heart is unable to pump enough blood containing oxygen and nutrients to meet the body’s demands. HF is the leading cause of hospitalization for patients over 65 years of age. After a patient is diagnosed with HF, the mortality rate is 50% within the first five years. Presently, there are no unanimous diagnostic criteria for HF. Bioimpedance (BI) analysis has been proposed in recent years as a technique to detect one of the main symptoms: changes in body volume due to edema. This research presents a portable device (Volum), capable of performing real-time BI measurements in a low-cost and noninvasive way. The goal is to improve patient monitoring at home to ensure rapid intervention in cases of worsening conditions, either with timely hospitalizations or adjustments to a patient’s usual treatment. Volum is a small, wearable, wireless, lightweight, low-power clinical pilot prototype that takes measurements through four electrodes and sends the data via Bluetooth to an Android device.

Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3[UCM-1336, IC50= 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.

In this communication, γ‐phenyl‐γ‐butyrodithiolactone (DTL1) is presented as the first example of a new type of control agent. The styrene polymerization carried out at 60 °C in the presence of DTL1 exhibits living characteristics, without consuming DTL1 during the process. This unprecedented behavior was explained by a mechanism based on the reversible formation of a persistent radical adduct between the DTL1 and the polystyrene macroradicals.

The thermal stability of a Schizolobium parahyba chymotrypsin inhibitor (SPCI) as a function of pH has been investigated using fluorescence, circular dichroism, and differential scanning calorimetry (DSC). The thermodynamic parameters derived from all methods are remarkably similar and strongly suggest the high stability of SPCI under a wide range of pH. The transition temperature (Tm) values ranging from 57 to 85.3°C at acidic, neutral, and alkaline pH are in good agreement with proteins from mesophilic and thermophilic organisms and corroborate previous data regarding the thermal stability of SPCI. All methods gave transitions curves adequately fitted to a two-state model of the unfolding process as judged by the cooperative ratio between the van’t Hoff and the calorimetric enthalpy energies close to unity in all of the pH conditions analyzed, except at pH 3.0. Thermodynamic analysis using all these methods reveals that SPCI is thermally a highly stable protein, over the wide range of pH from 3.0 to 8.8, exhibiting high stability in the pH region of 5.0–7.0. The corresponding maximum stabilities, ΔG25, were obtained at pH 7.0 with values of 15.4kcal mol−1 (combined fluorescence and circular dichroism data), and 15.1kcal mol−1 (DSC), considering a ΔCp of 1.72±0.24kcal mol−1 K−1. The low histidine content (∼1.7%) and the high acidic residue content (∼22.5%) suggests a flat pH dependence of thermal stability in the region 2.0–8.8 and that the decrease in thermal stability at low pH can be due to the differences in pK values of the acidic groups.

ABSTRACTThe unique ability of adeno-associated virus type 2 (AAV) to site-specifically integrate its genome into a defined sequence on human chromosome 19 (AAVS1) makes it of particular interest for use in targeted gene delivery. The objective underlying this study is to provide evidence for the feasibility of retargeting site-specific integration into selected loci within the human genome. Current models postulate that AAV DNA integration is initiated through the interactions of the products of a single viral open reading frame,REP, with sequences present in AAVS1that resemble the minimal origin for AAV DNA replication. Here, we present a cell-free system designed to dissect the Rep functions required to target site-specific integration using functional chimeric Rep proteins derived from AAV Rep78 and Rep1 of the closely related goose parvovirus. We show that amino-terminal domain exchange efficiently redirects the specificity of Rep to the minimal origin of DNA replication. Furthermore, we establish that the amino-terminal 208 amino acids of Rep78/68 constitute a catalytic domain of Rep sufficient to mediate site-specific endonuclease activity.

Addition of the antimitotic drug vinblastine to solutions of purified tubulin induces the formation of helical polymers whose structure and type of aggregation is determined by the concentration of magnesium. While paracrystalline arrangements of single coils are observed at low concentrations of the ion, for concentrations higher than 6 mM free double-coiled spirals are obtained, which are indistinguishable from those obtained in the presence of microtubule-associated proteins (MAPs). This result is consistent with a similar effect of magnesium and MAPs in neutralizing negative charges on the tubulin molecule and so allowing for lateral contacts between protofilaments. The effects that temperature has on the structure of both types of polymers, free spirals or paracrystals, have been monitored using time-resolved X-ray solution scattering. This study shows that a temperature increase: (1) affects the length and lateral aggregation of the spirals in the paracrystalline sample; (2) induces a reversible increase of the helical pitch in both types of polymers that closely follows the temperature change; (3) produces an irreversible aggregation of some of the protein in both types of polymers; and (4) can induce a reversible transformation from one type of structure to the other when the concentration of Mg²⁺is in the boundary between the two ranges. We suggest that the changes in pitch are due to a temperature-induced conformational change of the tubulin molecule. This effect may be related to the structural modifications that result in the temperature-induced assembly of microtubulesin vitrounder normal conditions of assembly.