The Effect of Heavy Metals on Conjugation Efficiency of an F-Plasmid in .

Conjugation, the process by which conjugative plasmids are transferred between bacteria, is regarded as a major contributor to the spread of antibiotic resistance, in both environmental and clinical settings. Heavy metals are known to co-select for antibiotic resistance, but the impact of the presence of these metals on conjugation itself is not clear. Here, we systematically investigate the impact that five heavy metals (arsenic, cadmium, copper, manganese, and zinc) have on the transfer of an IncF conjugative plasmid in .

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia.

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination.

Low-cost and versatile electrodes for extracellular chronic recordings in rodents.

Electrophysiological data are used to investigate fundamental properties of brain function, its relation to cognition, and its dysfunction in diseases. The development of reliable and open-source systems for electrophysiological data acquisition is decreasing the total cost of constructing and operating an electrophysiology laboratory, and facilitates low-cost methods to extract and analyze the data (Siegle et al., 2017).

Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia.

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC.

Perturbed Developmental Serotonin Signaling Affects Prefrontal Catecholaminergic Innervation and Cortical Integrity.

Proper development of the medial prefrontal cortex (mPFC), crucial for correct cognitive functioning, requires projections from, among others, the serotonergic (5-HT) and catecholaminergic systems, but it is unclear how these systems influence each other during development. Here, we describe the parallel development of the 5-HT and catecholaminergic prefrontal projection systems in rat and demonstrate a close engagement of both systems in the proximity of Cajal-Retzius cells. We further show that in the absence of the 5-HT transporter (5-HTT), not only the developing 5-HT but also the catecholaminergic system, including their projections towards the mPFC, are affected.

Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake.

Background: Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes.

Methods: We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout.

Increased GABA receptor signaling in a rat model for schizophrenia.

Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20-22.

Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature.

Maternal care affects the phenotype of a rat model for schizophrenia.

Schizophrenia is a complex mental disorder caused by an interplay between genetic and environmental factors, including early postnatal stressors. To explore this issue, we use two rat lines, apomorphine-susceptible (APO-SUS) rats that display schizophrenia-relevant features and their phenotypic counterpart, apomorphine-unsusceptible (APO-UNSUS) rats. These rat lines differ not only in their gnawing response to apomorphine, but also in their behavioral response to novelty (APO-SUS: high, APO-UNSUS: low).

Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation.

Besides its "classical" neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders.

Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity.

The hemoglobin-degrading aspartic proteases plasmepsin I (Plm I) and plasmepsin II (Plm II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C(2)-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy.

C2-symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions.

A series of C(2)-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography.

Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes.

A series of protease inhibitors targeted at the malarial enzymes plasmepsin I and II, and encompassing a basic hydroxyethylamine transition state isostere scaffold, was prepared. The substituents in the P1' position were varied and the biological activities expressed in K(i)-values ranged from 60 to >2000 nM. A more than 4-fold selectivity for either of the plasmepsins could be achieved.

Resistance profiles of cyclic and linear inhibitors of HIV-1 protease.

Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used.

How to master absorption during transurethral resection of the prostate: basic measures guided by the ethanol method.

Objective: To evaluate the effect of basic measures to minimize the absorption of irrigating fluid during transurethral resection of the prostate (TURP) to the planned end-point, using the ethanol method to guide the surgeon.

Patients And Methods: Forty-six patients underwent TURP with intermittent irrigation using sterile water and 2% ethanol. The ethanol content in the expired breath of the patients was assessed every 5 min using a breath-alcohol monitor.

P1/P1' modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays.

The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods.

Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors.

We have previously reported on the unexpected flipped conformation in the cyclic sulfamide class of inhibitors. An attempt to induce a symmetric binding conformation by introducing P2/P2' substituents foreseen to bind preferentially in the S2/S2' subsite was unsuccessful. On the basis of the flipped conformation we anticipated that nonsymmetric sulfamide inhibitors, with P2/P2' side chains modified individually for the S1' and S2 subsites, should be more potent than the corresponding symmetric analogues.

The control of haemolysis during transurethral resection of the prostate when water is used for irrigation: monitoring absorption by the ethanol method.

Objective: To determine whether the addition of ethanol to water for irrigation during transurethral resection of the prostate (TURP) and monitoring breath ethanol could be used to detect irrigant absorption and to limit free plasma haemoglobin in cases of absorption.

Patients And Methods: One hundred patients (46 in Piteå, Sweden and 54 in Uong bi, Vietnam) underwent surgery for benign prostatic hyperplasia (BPH) under an intermittent irrigation technique using water containing 2% ethanol. An expired breath alcohol meter was used to monitor ethanol in the patients' breath every 5 min.

Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains.

Symmetric cyclic sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.

Human immunodeficiency virus type 1 proteinase resistance to symmetric cyclic urea inhibitor analogs.

Resistant virus was isolated from virus propagated in cell culture in the presence of the human immunodeficiency virus type 1 (HIV-1) proteinase inhibitor DMP 323, Ro 31-8959, or A-75925. The proteinase gene of resistant virus was sequenced, and key mutations (G48V, V82A, I84V, L90M, and G48V/L90M) were introduced into clones used for the expression, purification, and further characterization of the enzyme. The mutant enzymes were all less active than the wild-type enzyme, as judged by k(cat) and k(cat)/Km values.

Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor.

Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1' positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 A resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al.

Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities.

Ten C2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (1a and 2-5).

On clinical loading of osseointegrated implants. A methodological and clinical study.

Strain gauges were used to record in vivo and in vitro functional deformations in a fixed prosthetic appliance supported and retained by osseointegrated titanium implants. Four linear gauges were attached to each of totally 5 implant abutment cylinders and gauge signals were transferred into a computer via a digital converter. A computer program (ASYST) was used for collection, calibration and analysis of data obtained.

Long term clinical evaluation of conical crown retained dentures.

The conical crown was introduced by K.H. Körber more than twenty years ago, as a development of the well known telescopic crown.

Influence of low-viscosity liners on the retention of three luting materials.

A number of materials are available to protect the pulp from postoperative sensitivity. The effect of a calcium hydroxide liner and a dentinal desensitizing agent (potassium oxalate) on crown retention was investigated. Gold crowns were cemented on standardized crown preparations with zinc phosphate cement, glass-ionomer cement, or one of two resin cements.