73 research outputs found

    Behavioral Characterization of GCLM-Knockout Mice, a Model for Enhanced Susceptibility to Oxidative Stress

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    Glutathione (GSH) is a major player in cellular defense against oxidative stress. Deletion of the modifier subunit of glutamate cysteine ligase (GCLM), the first and the rate-limiting enzyme in the synthesis of GSH, leads to significantly lower GSH levels in all tissues including the brain. GCLM-knockout (Gclm−/−) mice may thus represent a model for compromised response to oxidative stress amenable to in vitro and in vivo investigations. In order to determine whether the diminished GSH content would by itself cause behavioral alterations, a series of behavioral tests were carried out comparing young adult Gclm−/− with wild-type mice. Tests included the rotarod, acoustic startle reflex and prepulse inhibition of the startle reflex, open field behavior, and the platform reversal variant of the Morris Water Maze. Results showed no differences between Gclm−/− and wild-type mice in any of the neurobehavioral tests. However, more subtle alterations, or changes which may appear as animals age, cannot be excluded

    New genetic loci link adipose and insulin biology to body fat distribution.

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    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

    Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

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    Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    Elimination of zinc from synaptic visicles in the intact mouse brain by targeted disruption of ZnT3

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    Thesis (Ph. D.)--University of Washington, 2000This dissertation demonstrates that zinc is taken up into synaptic vesicles by a mechanism that requires the zinc transporter, ZnT3, at the vesicle membrane and begins to address the physiological importance of synaptic vesicle zinc. In situ hybridization and immunohistochemistry showed that ZnT3 expression is limited to zinc-containing neurons in the brain, and that ZnT3 protein resides on the membranes of zinc-rich synaptic vesicles in mouse, monkey, and human brain. A genetic approach was used to test whether ZnT3 was essential for vesicular zinc transport, by generating mice that were homozygous for a null mutation in the ZnT3 gene. Histochemically-reactive zinc (i.e., zinc accessible to Timm and TSQ staining reagents) was undetectable in synaptic vesicles in the brains of these ZnT3-deficient mice, indicating that ZnT3 is required for vesicular zinc transport. Upon neuronal activation vesicular zinc is released into the synaptic cleft, where it has been proposed to modulate excitatory and inhibitory neurotransmitter receptors. In addition, synaptically-released zinc has been widely considered to be the source of the zinc that may kill neurons following seizures or ischemic insults. To assess the physiological importance of synaptic vesicle zinc, ZnT3-deficient mice were tested for deficits in sensorimotor functions, learning and memory, sensitivity to seizure-inducing drugs, and neuronal damage. Most of these functions were remarkably normal in the absence of vesicular zinc. ZnT3-deficient mice were more susceptible than wildtype mice to kainic acid-induced seizures, demonstrating that zinc has a net inhibitory effect on seizures. Despite the lack of histochemically reactive zinc in synaptic vesicles in the ZnT3-deficient brain, zinc accumulated in the cytosol of postsynaptic neurons following seizures, and this zinc accumulation was associated with extensive neuronal death. Thus, the histochemically reactive zinc found in synaptic vesicles is not the major source of toxic zinc accumulation following seizures

    Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism

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    PURPOSE OF REVIEW: Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component.RECENT FINDINGS: Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted

    Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates

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    Paraoxonase (PON1) is an HDL-associated enzyme capable of hydrolyzing multiple substrates, including several organophosphorous insecticides and nerve agents, oxidized lipids, and a number of drugs or pro-drugs. Several polymorphisms in the paraoxonase (PON1) gene have been described, which have been shown to affect either the catalytic efficiency of hydrolysis or the expression level of PON1. This review discusses the relevance of these polymorphisms for modulating sensitivity to organophosphorous compounds. Animal studies characterizing the PON1 polymorphisms have demonstrated the relevance of PON1 in modulating OP toxicity and have indicated the importance of an individual's PON1 status (i.e., genotype and phenotype taken together) rather than genotyping alone. Nevertheless, direct confirmation in humans of the relevance of PON1 status in conferring susceptibility to OP toxicity is still elusive. Recent studies examining the involvement of PON1 status in determining OP susceptibility of Gulf War veterans, sheep dippers, and individuals poisoned with chemical warfare agents represent a step in the right direction, but more studies are needed, with better documentation of both the level of exposure and the consequences of exposure

    Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice

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    Abstract Background Escalating prevalence of autism spectrum disorders (ASD) in recent decades has triggered increasing efforts in understanding roles played by environmental risk factors as a way to address this widespread public health concern. Several epidemiological studies show associations between developmental exposure to traffic-related air pollution and increased ASD risk. In rodent models, a limited number of studies have shown that developmental exposure to ambient ultrafine particulates or diesel exhaust (DE) can result in behavioral phenotypes consistent with mild ASD. We performed a series of experiments to determine whether developmental DE exposure induces ASD-related behaviors in mice. Results C57Bl/6J mice were exposed from embryonic day 0 to postnatal day 21 to 250–300 μg/m3 DE or filtered air (FA) as control. Mice exposed developmentally to DE exhibited deficits in all three of the hallmark categories of ASD behavior: reduced social interaction in the reciprocal interaction and social preference tests, increased repetitive behavior in the T-maze and marble-burying test, and reduced or altered communication as assessed by measuring isolation-induced ultrasonic vocalizations and responses to social odors. Conclusions These findings demonstrate that exposure to traffic-related air pollution, in particular that associated with diesel-fuel combustion, can cause ASD-related behavioral changes in mice, and raise concern about air pollution as a contributor to the onset of ASD in humans
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