Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.     

Effects of scopolamine infusions into the anterior and posterior cingulate on passive avoidance and water maze navigation

We examined the role of anterior and posterior cingulate cortical muscarinic receptors in water maze spatial learning and passive avoidance. Pretraining and posttraining trial scopolamine (a mixed a muscarinic acetylcholine antagonist) infusions into the anterior cingulate cortex dose dependently (3 no effect; 10 and 30 micrograms impaired) impaired passive avoidance performance. Pretesting infusion into the anterior cingulate had no effect on passive avoidance. Scopolamine infusion into the anterior cingulate did not impair spatial navigation. On the contrary, scopolamine (3 micrograms no effect, 10 and 30 micrograms impaired) infusions into the posterior cingulate before daily training trials impaired water maze navigation to a hidden platform, but did not affect navigation to a visible escape platform or passive avoidance. Posttraining and pretesting infusion into the posterior cingulate did not impair WM spatial navigation. The present results indicate that muscarinic acetylcholine receptor antagonist may modulate passive avoidance performance via cholinergic receptors located in anterior cingulate cortex and the ability to develop a spatial navigation strategy via muscarinic receptors located in posterior cingulate.     

A Web‐based Open‐source Geoinformation Tool for Regional Water Resources Assessment

Water Resources Management - To reduce the impact of droughts and increase the resilience of regional water systems, various competing demands, such as hydropower, supply, irrigation and river...     

A biomarker of n−3 compliance in patients taking fish oil for rheumatoid arthritis

Dietary fish oil supplements have been shown to have benefits in rheumatoid arthritis (RA), other inflammatory diseases, and in cardiovascular disease. As with any medical advice, variability will exist with regard to adherence and consequent biochemical or pharmacophysiologic effects. The aim was to explore the utility of plasma phospholipid EPA as a measure of n−3 PUFA intake and response to standardized therapeutic advice given in an outpatient or office practice setting, to increase dietary n−3 PUFA, including a fish oil supplement. Patients with early RA were given verbal and written advice to alter their dietary n−3 PUFA intake, including ingestion of 20 mL of bottled fish oil on juice daily. The advice included instructions to increase n−3 PUFA and to avoid foods rich in n−6 PUFA. Every 3 mon, blood samples were obtained for analysis of plasma phospholipid FA. Plasma phospholipid EPA was used as the primary index of n−3 PUFA intake. A diverse response was seen, with about one-third of patients achieving a substantial elevation of plasma phospholipid EPA over the 12-mon study period. A third had little change, with the remainder achieving intermediate levels. Data obtained longitudinally from individual patients indicated that substantial elevations of EPA (>5% total plasma phospholipid FA) could be maintained for more than 3 yr. Plasma phospholipid EPA is a convenient measure of adherence to advice to take a dietary n−3 PUFA-rich fish oil supplement. This measure may prove a useful adjunct to intention to treat analyses in determining the effect of dietary fish oil supplements on long-term outcomes in arthritis and other chronic inflammatory diseases. It may also provide a guide to the effectiveness of therapeutic and preventive messages designed to increase n−3 PUFA intake.     

Dynamics and self-assembly of bio-functionalized gold nanoparticles in solution: Reactive molecular dynamics simulations

The self-assembling properties, stability, and dynamics of hybrid nanocarriers (gold nanoparticles (AuNPs) functionalized with cysteine-based peptides) in solution are studied through a series of classical molecular dynamics simulations based on a recently parametrized reactive force field. The results reveal, at the atomic level, all the details regarding the peptide adsorption mechanisms, nanoparticle stabilization, aggregation, and sintering. The data confirm and explain the experimental findings and disclose aspects that cannot be scrutinized by experiments. The biomolecules are both chemisorbed and physisorbed; self-interactions of the adsorbates and formation of stable networks of interconnected molecules on the AuNP surfaces limit substrate reconstructions, protect the AuNPs from the action of the solvent, and prevent direct interactions of the gold surfaces. The possibility of agglomeration of the functionalized nanoparticles, compared with the sintering of the bare supports in a water solution, is demonstrated through relatively long simulations and fast steered dynamics. The analysis of the trajectories reveals that the AuNPs were well stabilized by the peptides. This prevented particle sintering and kept the particles far apart; however, part of their chains could form interconnections (crosslinks) between neighboring gold vehicles. The excellent agreement of these results with the literature confirm the reliability of the method and its potential application to the modeling of more complex materials relevant to the biomedical sector.

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Metabolomic Profiling of Plasma from Melioidosis Patients Using UHPLC-QTOF MS Reveals Novel Biomarkers for Diagnosis

To identify potential biomarkers for improving diagnosis of melioidosis, we compared plasma metabolome profiles of melioidosis patients compared to patients with other bacteremia and controls without active infection, using ultra-high-performance liquid chromatography-electrospray ionization-quadruple time-of-flight mass spectrometry. Principal component analysis (PCA) showed that the metabolomic profiles of melioidosis patients are distinguishable from bacteremia patients and controls. Using multivariate and univariate analysis, 12 significant metabolites from four lipid classes, acylcarnitine (n = 6), lysophosphatidylethanolamine (LysoPE) (n = 3), sphingomyelins (SM) (n = 2) and phosphatidylcholine (PC) (n = 1), with significantly higher levels in melioidosis patients than bacteremia patients and controls, were identified. Ten of the 12 metabolites showed area-under-receiver operating characteristic curve (AUC) >0.80 when compared both between melioidosis and bacteremia patients, and between melioidosis patients and controls. SM(d18:2/16:0) possessed the largest AUC when compared, both between melioidosis and bacteremia patients (AUC 0.998, sensitivity 100% and specificity 91.7%), and between melioidosis patients and controls (AUC 1.000, sensitivity 96.7% and specificity 100%). Our results indicate that metabolome profiling might serve as a promising approach for diagnosis of melioidosis using patient plasma, with SM(d18:2/16:0) representing a potential biomarker. Since the 12 metabolites were related to various pathways for energy and lipid metabolism, further studies may reveal their possible role in the pathogenesis and host response in melioidosis.