Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.

Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1.

Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.

Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK).

On the systematic placement of Montezumellidae Ossó amp; Domínguez, 2013 (Decapoda: Brachyura: Eubrachyura).

Recovery of new samples of Montezumella amenosi Vía, 1959 and Moianella cervantesi Ossó Domínguez, 2013, with preserved cephalic appendages and ventral features, now allows for new and complete revision of Montezumellidae, an extinct eubrachyuran family that appeared in the Middle Eocene and lived until the Neogene. New data on antennular and antennal features, as well as additional data on the sternal and pleonal features of the females, have been analyzed. As a result, Montezumellidae is removed from Cancroidea, where it was previously placed.

How peptide/MHC presence affects the dynamics of the LC13 T-cell receptor.

The interaction between T-cell receptors (TCRs) of T-cells and potentially immunogenic peptides presented by MHCs of antigen presenting cells is one of the most important mechanisms of the adaptive human immune system. A large number of structural simulations of the TCR/peptide/MHC system have been carried out. However, to date no study has investigated the differences of the dynamics between free TCRs and pMHC bound TCRs on a large scale.

Analysis of tolerance and security of chemo hyperthermia with Mitomycin C for the treatment of non-muscle invasive bladder cancer.

Objectives: The treatment of non muscle invasive bladder cancer (NMIBC) continues to be a challenge. Hyperthermia (HT) combined with intravesical chemotherapy is used to enhance the effects of chemotherapy.

Methods: A review of the publications was carried out to synthesize the adverse effects (AE) reported by the use of chemohyperthermia (QHT) with Mitomycin-C (MMC).

A new dromiid crab (Crustacea, Brachyura, Dromioidea) from the Upper Eocene of Huesca (Aragón, northern Spain).

A new genus and species of brachyuran crab from the Upper Eocene (Priabonian) strata in Basa Valley (Huesca, northern Spain) assignable to the superfamily Dromioidea, Basadromia longifrons n. gen., n.

Computer-aided structure-based design of multitarget leads for Alzheimer's disease.

Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates.

Two-week, high-dose proton pump inhibitor, moxifloxacin triple Helicobacter pylori therapy after failure of standard triple or non-bismuth quadruple treatments.

Background: Aim was to evaluate the efficacy and tolerability of a moxifloxacin-containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed.

Methods: Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days.

Effect of pH and ligand charge state on BACE-1 fragment docking performance.

In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities.

On the active site protonation state in aspartic proteases: implications for drug design.

Aspartic proteases (AP) are a family of important hydrolytic enzymes in medicinal chemistry, since many of its members have become therapeutical targets for a wide variety of diseases from AIDS to Alzheimer. The enzymatic activity of these proteins is driven by the Asp dyad, a pair of active site Asp residues that participate in the hydrolysis of peptides. Hence, the protonation state of these and other acidic residues present in these enzymes determines the catalytic rate and the affinity for an inhibitor at a given pH.

Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.

The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations.

On a possible neutral charge state for the catalytic dyad in β-secretase when bound to hydroxyethylene transition state analogue inhibitors.

β-Secretase is one of the aspartic proteases involved in the formation of amyloid plaques in Alzheimer's disease patients. Our previous results using a combination of surface plasmon resonance experiments with molecular modeling calculations suggested that the Asp dyad in β-secretase bound to hydroxylethylene containing inhibitors adopts a neutral charged state. In this work, we show that the Asp dyad diprotonated state reproduced the binding ranking of a set of these inhibitors better than alternative protonation states.

Effect of the protonation state of the titratable residues on the inhibitor affinity to BACE-1.

BACE-1 is one of the aspartic proteases involved in the cleavage of beta amyloid peptide, an initial step in the formation of amyloid plaques whose toxicity induces neuron death in Alzheimer's disease patients. One of the central issues in the search of novel BACE-1 inhibitors is the optimum pH for the binding of inhibitors to the enzyme. It is known that the enzyme has optimal catalytic activity at acidic pH, while cell active inhibitors may bind optimally at higher pH.

Cardioverter defibrillator implantation in a pregnant woman guided with transesophageal echocardiography.

This report describes a 28-year-old pregnant woman with mitral valve prolapse and sudden cardiac death due to a ventricular fibrillation who underwent an ICD implantation guided by tranesophageal echocardiography.