3,365 research outputs found
Chronic exposure to neonicotinoids increases neuronal vulnerability to mitochondrial dysfunction in the bumblebee (Bombus terrestris)
This work was funded jointly by the Biotechnology and Biological Sciences Research Council, the Department for Environment, Food and Rural Affairs, the Natural Environment Research Council, the Scottish Government, and The Wellcome Trust, under the Insect Pollinators Initiative (United Kingdom) Grant BB/ 1000313/1 (to C.N.C.).The global decline in the abundance and diversity of insect pollinators could result from habitat loss, disease, and pesticide exposure. The contribution of the neonicotinoid insecticides (e.g., clothianidin and imidacloprid) to this decline is controversial, and key to understanding their risk is whether the astonishingly low levels found in the nectar and pollen of plants is sufficient to deliver neuroactive levels to their site of action: the bee brain. Here we show that bumblebees (Bombusterrestris audax) fed field levels [10 nM, 2.1 ppb (w/w)] of neonicotinoid accumulate between 4 and 10 nM in their brains within 3 days. Acute (minutes) exposure of cultured neurons to 10 nM clothianidin, but not imidacloprid, causes a nicotinic acetylcholine receptor-dependent rapid mitochondrial depolarization. However, a chronic (2 days) exposure to 1 nM imidacloprid leads to a receptor-dependent increased sensitivity to a normally innocuous level of acetylcholine, which now also causes rapid mitochondrial depolarization in neurons. Finally, colonies exposed to this level of imidacloprid show deficits in colony growth and nest condition compared with untreated colonies. These findings provide a mechanistic explanation for the poor navigation and foraging observed in neonicotinoid treated bumblebee colonies.Publisher PDFPeer reviewe
Evaluation for computational platforms of LC-MS based label-free quantitative proteomics:A global view
High intensity exercise as a dishabituating stimulus restores counterregulatory responses in recurrently hypoglycemic rodents
Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (high-intensity exercise) to demonstrate two classic features of a habituated response, namely dishabituation and response recovery. We demonstrate that after recurrent hypoglycemia the introduction of a novel dishabituating stimulus (a single burst of high-intensity exercise) in male Sprague-Dawley rats restores the defective hypoglycemia counterregulatory response. In addition, the rats showed an enhanced response to the novel stimulus (response recovery). We make the further observation using proteomic analysis of hypothalamic extracts that high-intensity exercise in recurrently hypoglycemic rats increases levels of a number of proteins linked with brain-derived neurotrophic factor signaling. These findings may lead to novel therapeutic approaches for individuals with T1D and IAH.</jats:p
Origin and tuning of the magnetocaloric effect for the magnetic refrigerant MnFe(P1-xGex)
Neutron diffraction and magnetization measurements of the magneto refrigerant
Mn1+yFe1-yP1-xGex reveal that the ferromagnetic and paramagnetic phases
correspond to two very distinct crystal structures, with the magnetic entropy
change as a function of magnetic field or temperature being directly controlled
by the phase fraction of this first-order transition. By tuning the physical
properties of this system we have achieved a maximum magnetic entropy change
exceeding 74 J/Kg K for both increasing and decreasing field, more than twice
the value of the previous record.Comment: 6 Figures. One tabl
A Targeted<em> in Vivo</em> SILAC Approach for Quantification of Drug Metabolism Enzymes:Regulation by the Constitutive Androstane Receptor
The modulation of drug metabolism enzyme (DME) expression by therapeutic agents is a central mechanism of drug-drug interaction and should be assessed as early as possible in preclinical drug development. Direct measurement of DME levels is typically achieved by Western blotting, qPCR, or microarray, but these techniques have their limitations; antibody cross-reactivity among highly homologous subfamilies creates ambiguity, while discordance between mRNA and protein expression undermines observations. The aim of this study was to design a simple targeted workflow by combining in vivo SILAC and label-free proteomics approaches for quantification of DMEs in mouse liver, facilitating a rapid and comprehensive evaluation of metabolic potential at the protein level. A total of 197 peptides, representing 51 Phase I and Phase II DMEs, were quantified by LC-MS/MS using targeted high resolution single ion monitoring (tHR/SIM) with a defined mass-to-charge and retention time window for each peptide. In a constitutive androstane receptor (Car) activated mouse model, comparison of tHR/SIM-in vivo SILAC with Western blotting for analysis of the expression of cytochromes P450 was favorable, with agreement in fold-change values between methods. The tHR/SIM-in vivo SILAC approach therefore permits the robust analysis of multiple DME in a single protein sample, with clear utility for the assessment of the drug-drug interaction potential of candidate therapeutic compounds. </p
Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy
Collagen 24 Ξ±1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue
Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes
Novel Pathways Of Ponatinib Disposition Catalysed By CYP1A1 Involving Generation Of Potentially Toxic Metabolites
The sputum microbiome and clinical outcomes in patients with bronchiectasis:a prospective observational study
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Confirmatory Spirometry for Adults Hospitalized with a Diagnosis of Asthma or Chronic Obstructive Pulmonary Disease Exacerbation
Background: Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry and to determine its utility to confirm the diagnosis in patients hospitalized with a physician diagnosis of asthma or COPD exacerbation. Methods: Multi-center study of four academic healthcare institutions. Spirometry was performed in 113 adults admitted to general medicine wards with a physician diagnosis of asthma or COPD exacerbation. Two board-certified pulmonologists evaluated the spirometry tracings to determine the proportion of patients able to produce adequate quality spirometry data. Findings were interpreted to evaluate the utility of spirometry to confirm the presence of obstructive lung disease, according to the 2005 European Respiratory Society/American Thoracic Society recommendations. Results: There was an almost perfect agreement for acceptability (ΞΊ = 0.92) and reproducibility (ΞΊ =0.93) of spirometry tracings. Three-quarters (73%) of the tests were interpreted by both pulmonologists as being of adequate quality. Of these adequate quality tests, 22% did not present objective evidence of obstructive lung disease. Obese patients (BMI β₯30 kg/m2) were more likely to produce spirometry tracings with no evidence of obstructive lung disease, compared to non-obese patients (33% vs. 8%, p = 0.007). Conclusions: Adequate quality spirometry can be obtained in most hospitalized adults with a physician diagnosis of asthma or COPD exacerbation. Confirmatory spirometry could be a useful tool to help reduce overdiagnosis of obstructive lung disease, especially among obese patients
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