Structural and Functional Analyses of the Human PDH Complex Suggest a "Division-of-Labor" Mechanism by Local E1 and E3 Clusters.

The pseudo-atomic structural model of human pyruvate dehydrogenase complex (PDHc) core composed of full-length E2 and E3BP components, calculated from our cryoelectron microscopy-derived density maps at 6-Å resolution, is similar to those of prokaryotic E2 structures. The spatial organization of human PDHc components as evidenced by negative-staining electron microscopy and native mass spectrometry is not homogeneous, and entails the unanticipated formation of local clusters of E1:E2 and E3BP:E3 complexes. Such uneven, clustered organization translates into specific duties for E1-E2 clusters (oxidative decarboxylation and acetyl transfer) and E3BP-E3 clusters (regeneration of reduced lipoamide) corresponding to half-reactions of the PDHc catalytic cycle.

Histamine H receptor antagonists/inverse agonists: Where do they go?

Since the discovery of the histamine H receptor in 1983, tremendous advances in the pharmacological aspects of H receptor antagonists/inverse agonists have been accomplished in preclinical studies. At present, there are several drug candidates that reached clinical trial studies for various indications. However, entrance of these candidates to the pharmaceutical market is not free from challenges, and a variety of difficulties is engaged with their developmental process.

Cognitive Improvements in Children with Prader-Willi Syndrome Following Pitolisant Treatment-Patient Reports.

While children with Prader-Willi Syndrome (PWS), a rare genetic disease with an incidence of 1:15,000, typically present with hypotonia and hyperphagia, their lives are made more difficult by an ever-present sleepiness as well as multiple neuro-cognitive dysfunctions, including cognitive defects. We describe a case series of 3 children who were treated with the histamine 3 receptor inverse agonist pitolisant. While this first-in-class inverse agonist is approved for another orphan disease (i.

Time-Resolved Measurements of Indoor Chemical Emissions, Deposition, and Reactions in a University Art Museum.

A 6-week study was conducted at the University of Colorado Art Museum, during which volatile organic compounds (VOCs), carbon dioxide (CO), ozone (O), nitric oxide (NO), nitrogen dioxide (NO), other trace gases, and submicron aerosol were measured continuously. These measurements were then analyzed using a box model to quantify the rates of major processes that transformed the composition of the air. VOC emission factors were quantified for museum occupants and their activities.

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus.

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown.

Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition.

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (HR - HR), are present in the heart.

Investigation of the retention forces of secondary telescopic crowns made from Pekkton® ivory in combination with primary crowns made from four different dental alloys: an in vitro study.

The aim of this study was to investigate the retention forces of secondary telescopic crowns made of polyetherketoneketone (PEKK) in combination with primary crowns made of four different dental alloys and to determine whether the retention forces change in the course of up to 5000 simulated wear cycles. A total of four groups of telescopic crowns were investigated: group 1: 10 primary crowns made of a gold alloy (NEOCAST®3), group 2: 10 primary crowns made of a non-precious metal alloy (Girobond NB), group 3: 10 primary crowns made of zirconium (Cercon®base) and group 4: 10 primary crowns made from PEKK (Pekkton®ivory). The corresponding secondary crowns were made from PEKK in all the four groups.

Role of Histamine H₃ Receptor Antagonists on Intraocular Pressure Reduction in Rabbit Models of Transient Ocular Hypertension and Glaucoma.

Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations.

Alkyl derivatives of 1,3,5-triazine as histamine H receptor ligands.

This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H receptor (hHR) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hHR affinity with a K of 160 nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC = 32 nM) and [S]GTPγS binding assay (pK = 6.

A flowing pair of particles in inertial microfluidics.

A flowing pair of particles in inertial microfluidics gives important insights into understanding and controlling the collective dynamics of particles like cells or droplets in microfluidic devices. They are applied in medical cell analysis and engineering. We study the dynamics of a pair of solid particles flowing through a rectangular microchannel using lattice Boltzmann simulations.

Ligand binding kinetics at histamine H receptors by fluorescence-polarization with real-time monitoring.

Growing evidence recommends incorporating the concept of drug-target residence times within drug development and screening programs. For many targets, systematic research for binding kinetics is emerging and reported, as in case of the histamine H receptor. Alternatively, fluorescent methods based on Foerster resonance energy transfer have been reported recently but application of fluorescence polarization to kinetics of unlabeled ligands is not known to us.

Comprehensive three-dimensional morphology of neoangiogenesis in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

Pulmonary veno-occlusive disease (PVOD) is a rare lung disease characterized by fibrotic narrowing of pulmonary veins leading to pulmonary hypertension (PH) and finally to death by right heart failure. PVOD is often accompanied by pulmonary capillary hemangiomatosis (PCH), a marked abnormal proliferation of pulmonary capillaries. Both morphological patterns often occur together and are thought to be distinct manifestations of the same disease process and accordingly are classified together in group 1' of the Nice classification of PH.

One-megadalton metalloenzyme complex in involved in benzene ring reduction beyond the biological redox window.

Reversible biological electron transfer usually occurs between redox couples at standard redox potentials ranging from +0.8 to -0.5 V.

Determining phoretic mobilities with Onsager's reciprocal relations: Electro- and thermophoresis revisited.

We use a hydrodynamic reciprocal approach to phoretic motion to derive general expressions for the electrophoretic and thermophoretic mobility of weakly charged colloids in aqueous electrolyte solutions. Our approach shows that phoretic motion can be understood in terms of the interfacial transport of thermodynamic excess quantities that arises when a colloid is kept stationary inside a bulk fluid flow. The obtained expressions for the mobilities are extensions of previously known results as they can account for different hydrodynamic boundary conditions at the colloidal surface, irrespective of how the colloid-fluid interaction range compares to the colloidal radius.

Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia.

Atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) represent two histologically and clinically overlapping myelodysplastic/myeloproliferative neoplasms. Also the mutational landscapes of both entities show congruencies. We analyzed and compared an aCML cohort (n = 26) and a CMML cohort (n = 59) by next-generation sequencing of 25 genes and by an nCounter approach for differential expression in 107 genes.

Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications.

Histamine H receptor ligands by hybrid virtual screening, docking, molecular dynamics simulations, and investigation of their biological effects.

Histamine H receptors (H R), belonging to G-protein coupled receptors (GPCR) class A superfamily, are responsible for modulating the release of histamine as well as of other neurotransmitters by a negative feedback mechanism mainly in the central nervous system (CNS). These receptors have gained increased attention as therapeutic target for several CNS related neurological diseases. In the current study, we aimed to identify novel H R ligands using in silico virtual screening methods.

3.5 kW coherently combined ultrafast fiber laser.

An ultrafast laser based on the coherent beam combination of four ytterbium-doped step-index fiber amplifiers is presented. The system delivers an average power of 3.5 kW and a pulse duration of 430 fs at an 80 MHz repetition rate.

Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.

Purpose: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders.

Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division.

The anaphase promoting complex/cyclosome (APC/C) E3 ligase controls mitosis and nonmitotic pathways through interactions with proteins that coordinate ubiquitylation. Since the discovery that the catalytic subunits of APC/C are conformationally dynamic cullin and RING proteins, many unexpected and intricate regulatory mechanisms have emerged. Here, we review structural knowledge of this regulation, focusing on: (i) coactivators, E2 ubiquitin (Ub)-conjugating enzymes, and inhibitors engage or influence multiple sites on APC/C including the cullin-RING catalytic core; and (ii) the outcomes of these interactions rely on mobility of coactivators and cullin-RING domains, which permits distinct conformations specifying different functions.

Optimization and preclinical evaluation of novel histamine Hreceptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives.

As a continuation of our search for novel histamine H receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H receptors (hHR). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hHR affinity (hHR K = 5.

[Injury patterns in interstitial lung diseases].

Interstitial lung diseases (ILD) consist of a complex group of hundreds of non-neoplastic pulmonary diseases with divergent clinical presentation, morphology and progression tendency. This great number of clinical entities contrasts with a limited number of injury patterns. By definition, an adequate classification requires a synopsis of the clinical, radiological and morphological findings.

Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats.

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (⁻) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.

Impact of shortened dental arch on oral health-related quality of life over a period of 10 years - A randomized controlled trial.

Objectives: To compare oral health-related quality of life (OHRQoL) in patients with either molar replacement by partial removable dental prostheses (PRDP) or with restored shortened dental arches (SDA) over a period of 10 years.

Methods: In this multi-center RCT, a consecutive sample of 215 patients with bilateral molar loss in at least one jaw was initially recruited in 14 prosthodontic departments. Of those patients, 150 could be randomly allocated to the treatment groups (SDA: n = 71; PRDP: n = 79), received the allocated treatment, and were available for follow-up assessments.