Carbogen-Induced Respiratory Acidosis Blocks Experimental Seizures by a Direct and Specific Inhibition of Na1.2 Channels in the Axon Initial Segment of Pyramidal Neurons.

Brain pH is a critical factor for determining neuronal activity, with alkalosis increasing and acidosis reducing excitability. Acid shifts in brain pH through the breathing of carbogen (5% CO/95% O) reduces seizure susceptibility in animal models and patients. The molecular mechanisms underlying this seizure protection remain to be fully elucidated.

Electric fields control water-gated proton transfer in cytochrome oxidase.

Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome oxidase (CO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O reduction into proton pumping. Here we show that CO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways.

Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors.

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory "danger" signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors.

Structural basis for isoform-specific inhibition of human CTPS1.

Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin ], [] [510], [288-292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E.

Health Care Resource Utilization and Exacerbation Rates in Patients with COPD Stratified by Disease Severity in a Commercially Insured Population.

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is associated with substantial economic burden. There is a lack of data regarding COPD outcomes and costs in a real-world setting, particularly by Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity.

Objectives: To (a) characterize a commercially insured U.

Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A receptor antagonists: SAR and molecular modeling studies.

A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives () showed weak to moderate affinity towards the human adenosine receptors.

K-Cl Cotransporter 2-mediated Cl- Extrusion Determines Developmental Stage-dependent Impact of Propofol Anesthesia on Dendritic Spines.

Background: General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2).

Methods: In utero electroporation of KCC2 was used to prematurely increase the efficacy of (GABAA)-mediated inhibition in layer 2/3 pyramidal neurons in the immature rat somatosensory cortex.

Hsp90 dependence of a kinase is determined by its conformational landscape.

Heat shock protein 90 (Hsp90) is an abundant molecular chaperone, involved in the folding and activation of 60% of the human kinome. The oncogenic tyrosine kinase v-Src is one of the most stringent client proteins of Hsp90, whereas its almost identical homolog c-Src is only weakly affected by the chaperone. Here, we perform atomistic molecular simulations and in vitro kinase assays to explore the mechanistic differences in the activation of v-Src and c-Src.

Exploring the Light-Capturing Properties of Photosynthetic Chlorophyll Clusters Using Large-Scale Correlated Calculations.

Chlorophylls are light-capturing units found in photosynthetic proteins. We study here the ground and excited state properties of monomeric, dimeric, and tetrameric models of the special chlorophyll/bacteriochlorophyll (Chl/BChl) pigment (P) centers P700 and P680/P870 of type I and type II photosystems, respectively. In the excited state calculations, we study the performance of the algebraic diagrammatic construction through second-order (ADC(2)) method in combination with the reduced virtual space (RVS) approach and the recently developed Laplace-transformed scaled-opposite-spin (LT-SOS) algorithm, which allows us, for the first time, to address multimeric effects at correlated ab initio levels using large basis sets.

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90.

Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency.

Factors associated with student learning processes in primary health care units: a questionnaire study.

Background: Clinical placement plays a key role in education intended to develop nursing and caregiving skills. Studies of nursing students' clinical learning experiences show that these dimensions affect learning processes: (i) supervisory relationship, (ii) pedagogical atmosphere, (iii) management leadership style, (iv) premises of nursing care on the ward, and (v) nursing teachers' roles. Few empirical studies address the probability of an association between these dimensions and factors such as student (a) motivation, (b) satisfaction with clinical placement, and (c) experiences with professional role models.

Development and validation of a reversed-phase ultra-performance liquid chromatographic method for the simultaneous determination of six drugs used for combined hypertension therapy.

A simple, rapid, and reliable ultra-performance LC assay method has been developed for the simultaneous estimation of orally administered hypertension drugs (atenolol, hydrochlorothiazide, amlodipine besylate, indapamide, nifedipine, and lercanidipine hydrochloride), any of which may be administered with atenolol in combined hypertension therapy. Chromatography was carried out at 25 degrees C on a 2.1 x 50 mm id, 1.

General anaesthetics do not impair developmental expression of the KCC2 potassium-chloride cotransporter in neonatal rats during the brain growth spurt.

Background: The developmental transition from depolarizing to hyperpolarizing γ-aminobutyric acid-mediated neurotransmission is primarily mediated by an increase in the amount of the potassium-chloride cotransporter KCC2 during early postnatal life. However, it is not known whether early neuronal activity plays a modulatory role in the expression of total KCC2 mRNA and protein in the immature brain. As general anaesthetics are powerful modulators of neuronal activity, the purpose of this study was to explore how these drugs affect KCC2 expression during the brain growth spurt.

A Chromatographic Determination of Aripiprazole using HPLC and UPLC: A Comparative Validation Study.

A simple, precise, and accurate isocratic reversed-phase (RP) stability-indicating HPLC assay method was developed and validated for determination of Aripiprazole in bulk and solid pharmaceutical dosage form. A reversed-phase C8 (250×4.0 mm, 5 μm particle size) column for HPLC and C8 (50×2.

A Stability-indicating High Performance Liquid Chromatographic Assay for the Simultaneous Determination of Atenolol and Lercanidipine Hydrochloride in Tablets.

A simple, rapid, precise and accurate isocratic reversed phase stability indicating HPLC method was developed and validated for the simultaneous determination of atenolol and lercanidipine hydrochloride in commercial tablets. The chromatographic separation was achieved on phenomenex Gemini C18 (250×4.6 mm, 5 μm) column using a mobile phase consisting of acetonitrile and buffer (20 mM potassium dihydrogen phosphate pH 3.

A New Improved RP-HPLC Method for Assay of Rosuvastatin Calcium in Tablets.

A reliable and sensitive isocratic stability indicating RP-HPLC method has been developed and validated for assay of rosuvastatin calcium in tablets and for determination of content uniformity. An isocratic separation of rosuvastatin calcium was achieved on YMC C8, 150×4.6 mm i.

A Stability-indicating HPLC Method for Assay of Lercanidipine Hydrochloride in Tablets and for Determining Content Uniformity.

A simple, precise and accurate HPLC method has been developed and validated for assay of lercanidipine hydrochloride in tablets and for determination of content uniformity. An isocratic separation was achieved using a Chromasil YMC Pack C(8), 150 × 4.6 mm i.

Redox-coupled proton transfer in the active site of cytochrome cbb3.

Cytochrome cbb3 is a distinct member of the superfamily of respiratory heme-copper oxidases, and is responsible for driving the respiratory chain in many pathogenic bacteria. Like the canonical heme-copper oxidases, cytochrome cbb3 reduces oxygen to water and couples the released energy to pump protons across the bacterial membrane. Homology modeling and recent electron paramagnetic resonance (EPR) studies on wild type and a mutant cbb3 enzyme [V.

Mechanism and energetics by which glutamic acid 242 prevents leaks in cytochrome c oxidase.

Cytochrome c oxidase (CcO) is the terminal enzyme of aerobic respiration. The energy released from the reduction of molecular oxygen to water is used to pump protons across the mitochondrial or bacterial membrane. The pump function introduces a mechanistic requirement of a valve that prevents protons from flowing backwards during the process.

A double blind, randomized trial on augmentation of labour with a combination of intravenous propranolol and oxytocin versus oxytocin only.

Objective: To compare the combination of intravenous propranolol and oxytocin with oxytocin only in augmentation of labour.

Study Design: A prospective randomized double-blind study in an obstetric department of a large university hospital in Finland. A total of 107 parturients with arrested first stage of labour owing to inadequate uterine contractility were randomized to receive intravenously once or twice a 2 mg dose of propranolol or placebo combined with oxytocin infusion.

Very slow EEG responses lateralize temporal lobe seizures: an evaluation of non-invasive DC-EEG.

Background: This study tested the idea that very slow EEG responses (direct current [DC] potential shifts) could be detected noninvasively during temporal lobe (TL) seizures, and that these shifts give lateralizing information consistent with that obtained by other methods.

Methods: Seven patients with TL epilepsy (TLE) were recorded with scalp DC-EEG technique at bedside. All recordings were performed simultaneously with conventional EEG (scalp in five, and intracranially in two; two patients with scalp recordings were recorded intracranially later).

Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect.

1. In this study, the analysis of spontaneous baroreflex sensitivity (BRS) was applied to the dynamic assessment of cardiac anticholinergic drug effect in healthy male volunteers. 2.

Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect--integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs.

The time course and concentration-effect relationship of parasympatholytic effects of three anticholinergic drugs were investigated using spectral analysis of heart rate (HR) variability. Single intravenous (i.v.

Long-lasting GABA-mediated depolarization evoked by high-frequency stimulation in pyramidal neurons of rat hippocampal slice is attributable to a network-driven, bicarbonate-dependent K+ transient.

Biphasic GABAA-mediated postsynaptic responses can be readily evoked in CA1 pyramidal neurons of rat hippocampal slices by high-frequency stimulus (HFS) trains in the presence of ionotropic glutamate receptor antagonists. In the present experiments with sharp microelectrodes, whole-cell techniques, and K+-selective microelectrodes, an HFS train (40 pulses at 100 Hz) applied in stratum radiatum close to the recording site evoked a brief hyperpolarizing IPSP (hIPSP), which turned into a prolonged (2-3 sec) depolarization (GABA-mediated depolarizing postsynaptic potential; GDPSP). The I-V relationships of the postsynaptic currents (hIPSC and GDPSC) had distinct characteristics: the hIPSC and the early GDPSC showed outward rectification, whereas the late GDPSC was reduced with positive voltage steps to zero or beyond (inward rectification), but often no clear reversal was seen.