Antimicrobial Activity Classification of Imidazolium Derivatives Predicted by Artificial Neural Networks.

Purpose: This study assesses the Multilayer Perceptron (MLP) neural network, complemented by other Machine Learning techniques (CART, PCA), in predicting the antimicrobial activity of 140 newly designed imidazolium chlorides against Klebsiella pneumoniae before synthesis. Emphasis is on leveraging molecular properties for predictive analysis.

Methods: Classification and regression decision trees (CART) identified the top 200 predictive molecular descriptors.

Toward the General Mechanistic Model of Liquid Chromatographic Retention.

Large datasets of chromatographic retention times are relatively easy to collect. This statement is particularly true when mixtures of compounds are analyzed under a series of gradient conditions using chromatographic techniques coupled with mass spectrometry detection. Such datasets carry much information about chromatographic retention that, if extracted, can provide useful predictive information.

Statistical analysis of isocratic chromatographic data using Bayesian modeling.

Chromatographic retention times are usually modeled considering only one analyte at a time. However, it has certain limitations as no information is shared between the analytes, and consequently the model predictions poorly generalize to out-of-sample analytes. In this work, a publicly available dataset was used to illustrate the benefits of pooling the individual data and analyzing them simultaneously utilizing Bayesian hierarchical approach.

Frequency Spectra Analysis of Drawbar Pulls Generated by Special Driving Wheels Improving Tractive Performance.

Driving wheel operation is characterized by force interactions with the ground, manifested in the form of vibrations. Signals generated by driving wheels can be analyzed in the frequency spectrum of tractor drawbar pull. The paper presents the analysis of a drawbar pull signal generated by a tractor equipped with two types of special driving wheels and standard tires.

Application of Bayesian Multilevel Modeling in the Quantitative Structure-Retention Relationship Studies of Heterogeneous Compounds.

Quantitative structure-retention relationships (QSRRs) are used in the field of chromatography to model the relationship between an analyte structure and chromatographic retention. Such models are typically difficult to build and validate for heterogeneous compounds because of their many descriptors and relatively limited analyte-specific data. In this study, a Bayesian multilevel model is proposed to characterize the isocratic retention time data collected for 1026 heterogeneous analytes.

Analysis of Isocratic-Chromatographic-Retention Data using Bayesian Multilevel Modeling.

The objective of this work was to develop a multilevel (hierarchical) model based on isocratic-reversed-phase-high-performance-chromatographic data collected in methanol and acetonitrile for 58 chemical compounds. Such a multilevel model is a regression model of the analyte-specific chromatographic measurements, in which all the regression parameters are given a probability model. It is a fundamentally different approach from the most common approach, where parameters are separately estimated for each analyte (without sharing information across analytes and different organic modifiers).

Regulation of Drug Metabolism by the Interplay of Inflammatory Signaling, Steatosis, and Xeno-Sensing Receptors in HepaRG Cells.

Nonalcoholic fatty liver disease (NAFLD), which is characterized by triglyceride deposition in hepatocytes resulting from imbalanced lipid homeostasis, is of increasing concern in Western countries, along with progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH.

pH-Gradient Liquid Chromatography: Fundamentals and Examples.

In this paper, we acquaint the readers with the fundamentals of gradient separation, followed by the latest innovations in this field. We describe the principles of organic modifier- and pH-gradient elution emphasizing the differences and similarities with isocratic separation. The double organic modifier-/pH-gradient is also thoroughly reviewed as a useful method for the simultaneous determination of logkw (substitute of logP) and the pka of analytes present in complex mixtures.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects.

Correction: Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

[This corrects the article DOI: 10.1371/journal.pone.

Quantitative structure-(chromatographic) retention relationship models for dissociating compounds.

The aim of this work was to develop mathematical models relating the hydrophobicity and dissociation constant of an analyte with its structure, which would be useful in predicting analyte retention times in reversed-phase liquid chromatography. For that purpose a large and diverse group of 115 drugs was used to build three QSRR models combining retention-related parameters (logkw-chromatographic measure of hydrophobicity, S-slope factor from Snyder-Soczewinski equation, and pKa) with structural descriptors calculated by means of molecular modeling for both dissociated and nondissociated forms of analytes. Lasso, Stepwise and PLS regressions were used to build statistical models.

Simultaneous determination of hydrophobicity and dissociation constant for a large set of compounds by gradient reverse phase high performance liquid chromatography-mass spectrometry technique.

Fast and reliable methods for the determination of hydrophobicity and acidity are desired in pre-clinical drug development phases to eliminate compounds with poor pharmacokinetic properties. Reversed-phase high-performance liquid chromatography (RP HPLC) coupled with time-of-flight mass spectrometry (RP HPLC-ESI-TOF-MS) is a convenient technique for that purpose. In this work we determined the chromatographic measure of hydrophobicity (logkw) and dissociation constant (pKa) simultaneously for a large and diverse group of 161 drugs.

Activation of Human Toll-like Receptor 4 (TLR4)·Myeloid Differentiation Factor 2 (MD-2) by Hypoacylated Lipopolysaccharide from a Clinical Isolate of Burkholderia cenocepacia.

Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Host-microbe interplay largely depends on interactions between pathogen-specific molecules and innate immune receptors such as Toll-like receptor 4 (TLR4), which recognizes the lipid A moiety of the bacterial lipopolysaccharide (LPS). The human TLR4·myeloid differentiation factor 2 (MD-2) LPS receptor complex is strongly activated by hexa-acylated lipid A and poorly activated by underacylated lipid A.

Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C.

Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales.

Maximum A Posteriori Bayesian Estimation of Chromatographic Parameters by Limited Number of Experiments.

The aim of this work was to develop a nonlinear mixed-effect chromatographic model able to describe the retention times of weak acids and bases in all possible combinations of organic modifier content and mobile-phase pH. Further, we aimed to identify the influence of basic covariates, like lipophilicity (log P), dissociation constant (pK(a)), and polar surface area (PSA), on the intercompound variability of chromatographic parameters. Lastly, we aimed to propose the optimal limited experimental design to the estimation process of parameters through a maximum a posteriori (MAP) Bayesian method to facilitate the method development process.

Least absolute shrinkage and selection operator and dimensionality reduction techniques in quantitative structure retention relationship modeling of retention in hydrophilic interaction liquid chromatography.

The objective of this study was to model the retention of nucleosides and pterins in hydrophilic interaction liquid chromatography (HILIC) via QSRR-based approach. Two home-made (Amino-P-C18, Amino-P-C10) and one commercial (IAM.PC.

The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration.

In recent decades, there has been a significant expansion in our understanding of the role of astrocytes in neuroprotection, including spatial buffering of extracellular ions, secretion of metabolic coenzymes, and synaptic regulation. Astrocytic neuroprotective functions require energy, and therefore require a network of functional mitochondria. Disturbances to astrocytic mitochondrial homeostasis and their ability to produce ATP can negatively impact neural function.

1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria-related proteins in brain.

Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve.

The simultaneous determination of hydrophobicity and dissociation constant by liquid chromatography-mass spectrometry.

Convenient methods for testing drug candidates' lipophilicity and acidity are highly requested in modern pharmaceutical research and drug development strategies. Reversed-phase high-performance liquid chromatography (RP HPLC) might be particularly useful for the determination of both dissociation constant and the (pH-dependent) partition coefficient related parameters, applicable in high-throughput analysis of multi-component mixtures. The general theory of combined pH/organic modifier gradient has recently provided equations relating gradient retention time and pH of the mobile phase.

Modulation of CD14 and TLR4·MD-2 activities by a synthetic lipid A mimetic.

Monosaccharide lipid A mimetics based on a glucosamine core linked to two fatty acid chains and bearing one or two phosphate groups have been synthesized. Compounds 1 and 2, each with one phosphate group, were practically inactive in inhibiting LPS-induced TLR4 signaling and cytokine production in HEK-blue cells and murine macrophages, but compound 3, with two phosphate groups, was found to be active in efficiently inhibiting TLR4 signal in both cell types. The direct interaction between compound 3 and the MD-2 coreceptor was investigated by NMR spectroscopy and molecular modeling/docking analysis.

A new pH/organic modifier gradient RP HPLC method for convenient determination of lipophilicity and acidity of drugs as applied to established imidazoline agents.

Convenient drug candidates testing methods for lipophilicity and acidity are highly requested in modern pharmaceutical research and development strategy. Reversed-phase high-performance liquid chromatography (RP HPLC) might be particularly useful for the determination of both pK(a) and the apparent (pH-dependent) octanol-water partition coefficient, applicable in high-throughput analysis of multi-component mixtures. In this report the pH/organic modifier gradient RP HPLC is presented as a means of simultaneous determination of acidity and lipophilicity of a series of 26 imidazoline-like drugs.

[Thrombus or tumour of the mitral valve--a case of 75-year-old woman with acute coronary syndrome and aortic insufficiency].

Papillary fibroelastomas are rare, primary, benign cardiac tumors most frequently located in the heart valves. They are a potential cause of systemic embolization and may be associated with myocardial ischaemia, transient ischaemic attacks, strokes, or sudden death. We describe the case of 75-year-old woman with diagnosed aortic insufficiency who was admitted to hospital with acute coronary syndrome.

[Cardiovascular diseases risk factors knowledge among soldiers of the Polish army].

Unlabelled: Cardiovascular diseases (CVDs) are the main cause of death and disability in Poland. There are many risk factors of CVD which are modifiable due to preventive strategies. Knowledge about these factors among population at risk of CVD is the most important condition for success of them.

[Inappropriate therapy of an implantable cardioverter-defibrillator--is it always an undesired event? A case report].

Inappropriate implantable cardioverter defibrillator (ICD) therapy is the commonest adverse event in patients with ICD. We present a case of sinus rhythm restoration after an inappropriate shock in a man with permanent atrial fibrillation and dilated cardiomyopathy. During follow-up, clinical improvement has been observed.