MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate.

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear.

Investigating Cryptic Binding Sites by Molecular Dynamics Simulations.

This Account highlights recent advances and discusses major challenges in investigations of cryptic (hidden) binding sites by molecular simulations. Cryptic binding sites are not visible in protein targets crystallized without a ligand and only become visible crystallographically upon binding events. These sites have been shown to be druggable and might provide a rare opportunity to target difficult proteins.

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH).

Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor.

Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fields against our set of nuclear magnetic resonance (NMR) observables for a complex and medically relevant system, the major factor VIII binding region on the von Willebrand factor. This biomedically important region comprises both a folded and a partially structured domain.

The architecture of EGFR's basal complexes reveals autoinhibition mechanisms in dimers and oligomers.

Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation.

Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations.

p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity.

Dependence of protein crystal stability on residue charge states and ion content of crystal solvent.

Protein crystallization is frequently induced by the addition of various precipitants, which directly affect protein solubility. In addition to organic cosolvents and long-chain polymers, salts belong to the most widely used precipitants in protein crystallography. However, despite such widespread usage, their mode of action at the atomistic level is still largely unknown.

X-ray refinement significantly underestimates the level of microscopic heterogeneity in biomolecular crystals.

Biomolecular X-ray structures typically provide a static, time- and ensemble-averaged view of molecular ensembles in crystals. In the absence of rigid-body motions and lattice defects, B-factors are thought to accurately reflect the structural heterogeneity of such ensembles. In order to study the effects of averaging on B-factors, we employ molecular dynamics simulations to controllably manipulate microscopic heterogeneity of a crystal containing 216 copies of villin headpiece.

On the Contribution of Linear Correlations to Quasi-harmonic Conformational Entropy in Proteins.

We study the contribution of linear, pairwise atom-positional correlations (covariances) to absolute and relative conformational entropy as calculated by quasi-harmonic analysis of molecular dynamics (MD) trajectories (SQH and ΔSQH). By analyzing a total of 25 μs of MD simulations of ubiquitin and six of its binding partners in bound and unbound states, and 2.4 μs of simulations of eight different proteins in phosphorylated and unphosphorylated states, we show that ΔSQH represents a remarkably constant fraction of a quasi-harmonic entropy change obtained if one ignores the contribution of covariance terms and uses mass-weighted atom-positional variances only (ΔSVAR).

Dynamics may significantly influence the estimation of interatomic distances in biomolecular X-ray structures.

Atomic positions obtained by X-ray crystallography are time and space averages over many molecules in the crystal. Importantly, interatomic distances, calculated between such average positions and frequently used in structural and mechanistic analyses, can be substantially different from the more appropriate time-average and ensemble-average interatomic distances. Using crystallographic B-factors, one can deduce corrections, which have so far been applied exclusively to small molecules, to obtain correct average distances as a function of the type of atomic motion.

Determination of ensemble-average pairwise root mean-square deviation from experimental B-factors.

Root mean-square deviation (RMSD) after roto-translational least-squares fitting is a measure of global structural similarity of macromolecules used commonly. On the other hand, experimental x-ray B-factors are used frequently to study local structural heterogeneity and dynamics in macromolecules by providing direct information about root mean-square fluctuations (RMSF) that can also be calculated from molecular dynamics simulations. We provide a mathematical derivation showing that, given a set of conservative assumptions, a root mean-square ensemble-average of an all-against-all distribution of pairwise RMSD for a single molecular species, (1/2), is directly related to average B-factors () and (1/2).

[Clinical experience with an alpha glucosidase inhibitor (acarbose) in the treatment of non-insulin-dependent diabetes. Multicenter study].

Background: Acarbose, an alpha glucosidase inhibitor is a drug used in the treatment of non insulin dependent diabetes mellitus, that interferes with the intestinal absorption of monosaccharides.

Aim: To study the effect of acarbose in non insulin dependent diabetic patients that had an inadequate metabolic control with diet and sulphonylureas.

Patients And Methods: Diabetic patients received acarbose, 150 mg/day during four weeks and this dose was increased to 300 mg/day during 3 months.

Triggers of acute myocardial infarction regarding its site.

We have studied the incidence of possible triggers of the myocardial infarction regarding its site in 750 patients with anterior and 731 patients with inferior infarction. Infarctions occurred most frequently without recalling any triggering activity, especially in patients with anterior infarction (67 vs. 44%).

[Comparison of auscultation findings using a classic stethoscope (Litmann 2120) and electronically amplified stethoscope (Medmax2)].

Heart auscultation has one of the key roles in beside diagnosis, especially in patients with cardiovascular diseases. Sometimes, because of the human cars' low sensitivity, a problem emerges in the proper evaluation of heart sounds and murmurs of lower frequencies. Our study compared two stethoscopes, the classic acoustic stethoscope (Littmann 2120) and an electronic one with the sound amplifier and the noise filtering system (Medmax2) in 10 patients examined by 10 physicians.

[Anterior septal myocardial infarct impairs cardiovascular function more than inferior septal myocardial infarct].

The functional ability, expressed as percentage of expected oxygen uptake, measured on the tread-mill according to the Bruce protocol, was assessed in 30 patients with anteroseptal, and in 30 patients with inferior myocardial infarction (MI), 4 months after the incident. In comparison to those with inferior MI, the patients with anteroseptal localization exhibited significantly lower values of functional ability (68.37% +/- 14% versus 75.

[Controlled comparison of nicardipine and propranolol in the treatment of arterial hypertension].

A randomized collective comparative study between nicardipine (N) and propranolol (P) was conducted over a period of 7 weeks in thirty hypertensive patients of both sexes, aged from 20 to 65 years, with the diastolic pressure over 100, but below 120 mmHg. Thirteen examinees were given N (60-120 mg daily) and seventeen P (120-240 mg daily); the groups were comparable according to a series of relevant parameters. In the placebo-period the mean arterial pressure (MAP) was slightly lowered, by 4.

[The role of the diagonal ear lobe crease in the clinical evaluation of coronary risk].

Two hundred and forty-three prospective patients (143 with proved coronary heart disease and 100 without coronary disease) were analysed for the presence or absence of ear lobe crease, a possible aural sign of coronary artery disease. The crease was present in 72.7% of the coronary and 48% of the noncoronary examinees (p less than 0.

[Comparison of the antihypertensive effects of bopindolol and metoprolol in the treatment of arterial hypertension].

A randomized, double blind clinical trial included 40 hypertension patients of both sexes, aged 18-70 years, with diastolic blood pressure persistently above 100 (13.33 kPa) and below 120 mm Hg (15.99 kPa).