Environmental and genetic modulation of the phenotypic expression of antibiotic resistance.

Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype.

Global preamplification simplifies targeted mRNA quantification.

The need to perform gene expression profiling using next generation sequencing and quantitative real-time PCR (qPCR) on small sample sizes and single cells is rapidly expanding. However, to analyse few molecules, preamplification is required. Here, we studied global and target-specific preamplification using 96 optimised qPCR assays.

Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.

Objective: Erectile dysfunction (ED) is associated with an increased risk of cardiovascular disease in healthy men. However, the association between treatment for ED and death or cardiovascular outcomes after a first myocardial infarction (MI) is unknown.

Methods: In a Swedish nationwide cohort study all men <80 years of age without prior MI, or cardiac revascularisation, hospitalised for MI during 2007-2013 were included.

Association Between Rheumatoid Arthritis and Risk of Ischemic and Nonischemic Heart Failure.

Background: It is unknown whether the increased risk of heart failure (HF) in rheumatoid arthritis (RA) is independent of ischemic heart disease (IHD).

Objectives: This study sought to investigate the relative risk of HF overall and by subtype (ischemic and nonischemic HF) in patients with RA and to assess the impact of RA disease factors.

Methods: Two contemporary cohorts of RA subjects were identified from Swedish patient and rheumatology registries and matched 1:10 to general population comparator subjects.

Prioritizing Rare Diseases: Psychological Effects Influencing Medical Decision Making.

Background: Measuring societal preferences for rarity has been proposed to determine whether paying premium prices for orphan drugs is acceptable.

Objective: To investigate societal preferences for rarity and how psychological factors affect such preferences.

Method: A postal survey containing resource allocation dilemmas involving patients with a rare disease and patients with a common disease, equal in severity, was sent out to a randomly selected sample of the population in Sweden (return rate 42.

Omentectomy in Addition to Bariatric Surgery-a 5-Year Follow-up.

Aim: Omentectomy in addition to bariatric surgery has been suggested to improve metabolic outcome but short-term (6-24 months) studies have refuted this notion. We investigated whether there was any long-term impact of omentectomy.

Methods: Forty-nine obese women underwent gastric bypass surgery and were randomly assigned to omentectomy (n = 26) or not (n = 23).

Is the acute care of frail elderly patients in a comprehensive geriatric assessment unit superior to conventional acute medical care?

Objective: The aim of this study was to investigate whether the acute care of frail elderly patients in a comprehensive geriatric assessment (CGA) unit is superior to the care in a conventional acute medical care unit.

Design: This is a clinical, prospective, randomized, controlled, one-center intervention study.

Setting: This study was conducted in a large county hospital in western Sweden.

Variation in Mutational Robustness between Different Proteins and the Predictability of Fitness Effects.

Random mutations in genes from disparate protein classes may have different distributions of fitness effects (DFEs) depending on different structural, functional, and evolutionary constraints. We measured the fitness effects of 156 single mutations in the genes encoding AraC (transcription factor), AraD (enzyme), and AraE (transporter) used for bacterial growth on l-arabinose. Despite their different molecular functions these genes all had bimodal DFEs with most mutations either being neutral or strongly deleterious, providing a general expectation for the DFE.

Determination of Krypton Diffusion Coefficients in Uranium Dioxide Using Atomic Scale Calculations.

We present a study of the diffusion of krypton in UO using atomic scale calculations combined with diffusion models adapted to the system studied. The migration barriers of the elementary mechanisms for interstitial or vacancy assisted migration are calculated in the DFT+U framework using the nudged elastic band method. The attempt frequencies are obtained from the phonon modes of the defect at the initial and saddle points using empirical potential methods.

New Insight in Cold Pain: Role of Ion Channels, Modulation, and Clinical Perspectives.

Cold temperature detection involves the process of sensory transduction in cutaneous primary sensory nerve terminals, which converts thermal stimuli into depolarizations of the membrane. This transformation into electrical signals is followed by the subsequent propagation of action potentials in cold-sensitive afferent nerve fibers. A large array of ion channels shapes this process; however, the precise contribution of specific ion channel subtypes to cold perception and cold pain remains elusive.

The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome.

The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice).

Duplication-Insertion Recombineering: a fast and scar-free method for efficient transfer of multiple mutations in bacteria.

We have developed a new λ Red recombineering methodology for generating transient selection markers that can be used to transfer mutations between bacterial strains of both Escherichia coli and Salmonella enterica. The method is fast, simple and allows for the construction of strains with several mutations without any unwanted sequence changes (scar-free). The method uses λ Red recombineering to generate a marker-held tandem duplication, termed Duplication-Insertion (Dup-In).

Impact of childhood asthma on growth trajectories in early adolescence: Findings from the Childhood Asthma Prevention Study (CAPS).

Background And Objective: Understanding the associations between childhood asthma and growth in early adolescence by accounting for the heterogeneity of growth during puberty has been largely unexplored. The objective was to identify sex-specific classes of growth trajectories during early adolescence, using a method which takes the heterogeneity of growth into account and to evaluate the association between childhood asthma and different classes of growth trajectories in adolescence.

Methods: Our longitudinal study included participants with a family history of asthma born during 1997-1999 in Sydney, Australia.

Long-term Protective Changes in Adipose Tissue After Gastric Bypass.

Objective: Although long-term weight regain may occur after bariatric surgery, many patients are protected against relapse or development of type 2 diabetes. The study objective was to investigate whether this involves beneficial changes in adipose function.

Research Design And Methods: Forty-nine obese women were investigated before and 2 and 5 years after Roux-en-Y gastric bypass (RYGB).

Adipose and Circulating CCL18 Levels Associate With Metabolic Risk Factors in Women.

Context: Cardiometabolic complications in obesity may be linked to white adipose tissue (WAT) dysfunction. Transcriptomic studies of Sc WAT have reported that CCL18, encoding the CC chemokine ligand 18 (CCL18), is increased in obesity/insulin resistance but its functional role is unknown.

Objective: Our objectives were to determine if CCL18 is secreted from Sc WAT and if secreted and/or serum levels associate with metabolic phenotypes.

Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes.

Aims/hypothesis: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes.

Intuition and Moral Decision-Making - The Effect of Time Pressure and Cognitive Load on Moral Judgment and Altruistic Behavior.

Do individuals intuitively favor certain moral actions over others? This study explores the role of intuitive thinking-induced by time pressure and cognitive load-in moral judgment and behavior. We conduct experiments in three different countries (Sweden, Austria, and the United States) involving over 1,400 subjects. All subjects responded to four trolley type dilemmas and four dictator games involving different charitable causes.

Nonmutational compensation of the fitness cost of antibiotic resistance in mycobacteria by overexpression of tlyA rRNA methylase.

Several studies over the last few decades have shown that antibiotic resistance mechanisms frequently confer a fitness cost and that these costs can be genetically ameliorated by intra- or extragenic second-site mutations, often without loss of resistance. Another, much less studied potential mechanism by which the fitness cost of antibiotic resistance could be reduced is via a regulatory response where the deleterious effect of the resistance mechanism is lowered by a physiological alteration that buffers the mutational effect. In mycobacteria, resistance to the clinically used tuberactinomycin antibiotic capreomycin involves loss-of-function mutations in rRNA methylase TlyA or point mutations in 16S rRNA (in particular the A1408G mutation).

Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides.

Background: The clinical development of antimicrobial peptides (AMPs) is currently under evaluation to combat the rapid increase in MDR bacterial pathogens. However, many AMPs closely resemble components of the human innate immune system and the ramifications of prolonged bacterial exposure to AMPs are not fully understood.

Objectives: We show that in vitro serial passage of a clinical USA300 MRSA strain in a host-mimicking environment containing host-derived AMPs results in the selection of stable AMP resistance.

Development of Xe and Kr empirical potentials for CeO2, ThO2, UO2 and PuO2, combining DFT with high temperature MD.

The development of embedded atom method (EAM) many-body potentials for actinide oxides and associated mixed oxide (MOX) systems has motivated the development of a complementary parameter set for gas-actinide and gas-oxygen interactions. A comprehensive set of density functional theory (DFT) calculations were used to study Xe and Kr incorporation at a number of sites in CeO2, ThO2, UO2 and PuO2. These structures were used to fit a potential, which was used to generate molecular dynamics (MD) configurations incorporating Xe and Kr at 300 K, 1500 K, 3000 K and 5000 K.

The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity.

Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp.

Pipe and grain boundary diffusion of He in UO2.

Molecular dynamics simulations have been conducted to study the effects of dislocations and grain boundaries on He diffusion in [Formula: see text]. Calculations were carried out for the {1 0 0}, {1 1 0} and {1 1 1} [Formula: see text] edge dislocations, the screw [Formula: see text] dislocation and Σ5, Σ13, Σ19 and Σ25 tilt grain boundaries. He diffusivity as a function of distance from the dislocation core and grain boundaries was investigated for the temperature range 2300-3000 K.

Circulating and Adipose Levels of Adipokines Associated With Insulin Sensitivity in Nonobese Subjects With Type 2 Diabetes.

Context: The adipokines chemerin, dipeptidyl peptidase 4, and adiponectin influence insulin sensitivity. Whether their circulating levels and adipose secretion are altered in nonobese individuals with type 2 diabetes mellitus (T2DM) is unknown.

Objective: The objective of this study was to investigate SC adipose secretion and serum levels of the three adipokines in relation to T2DM features.

Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica.

Heteroresistance, a phenomenon where subpopulations of a bacterial isolate exhibit different susceptibilities to an antibiotic, is a growing clinical problem where the underlying genetic mechanisms in most cases remain unknown. We isolated colistin resistant mutants in Escherichia coli and Salmonella enterica serovar Typhimurium at different concentrations of colistin. Genetic analysis showed that genetically stable pmrAB point mutations were responsible for colistin resistance during selection at high drug concentrations for both species and at low concentrations for E.

Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy.