A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels

The Interaction of Calcium and Metabolic Oscillations in Pancreatic β-cells

Diabetes is a disease characterized by an excessive level of glucose in the bloodstream, which may be a result of improper insulin secretion. Insulin is secreted in a bursting behavior of pancreatic $\beta$-cells in islets, which is affected by oscillations of cytosolic calcium concentration. We used the Dual Oscillator Model to explore the role of calcium in calcium oscillation independent and calcium oscillation dependent modes and the synchronization of metabolic oscillations in electrically coupled $\beta$-cells. We implemented a synchronization index in order to better measure the synchronization of the $\beta$-cells within an islet and we studied heterogeneous modes of coupled $\beta$-cells. We saw that increasing calcium coupling or voltage coupling in heterogeneous cases increases synchronization; however, in certain cases increasing both voltage and calcium coupling causes desynchronization. To better represent an islet, we altered previous code to allow for a greater number of cells to be simulated

SynGAP regulates spine formation

SynGAP is a brain-specific ras GTPase-activating protein that is an abundant component of the signaling complex associated with the NMDA-type glutamate receptor. We generated mutant mice lacking synGAP to study its physiological role. Homozygous mutant mice die in the first few days after birth; however, neurons from mutant embryos can be maintained in culture. Here, we report that spine and synapse formation are accelerated in cultured mutant neurons, and the spines of mature mutant neurons are significantly larger than those of wild type. Clusters of PSD-95 and subunits of AMPA-type and NMDA-type glutamate receptors accumulate in spines of mutant neurons by day 10 in vitro, whereas in wild-type neurons they are still mostly located in dendritic shafts. The frequency and amplitude of miniature EPSCs are larger in mutant neurons at day 10 in vitro, confirming that they have more functional synapses. At day 21 in vitro, the spines of mutant neurons remain significantly larger than those of wild type. The mutant phenotype at day 10 in vitro can be rescued by introduction of recombinant wild-type synGAP on day 9. In contrast, introduction of mutant synGAP with a mutated GAP domain or lacking the terminal domain that binds to PSD-95 does not rescue the mutant phenotype, indicating that both domains play a role in control of spine formation. Thus, the GAP activity of synGAP and its association with PSD-95 are important for normal regulation of spine and synapse formation in hippocampal neurons

Interleukin-1 polymorphisms associated with increased risk of gastric cancer

Helicobacter pylori infection is associated with a variety of clinical outcomes including gastric cancer and duodenal ulcer disease. The reasons for this variation are not clear, but the gastric physiological response is influenced by the severity and anatomical distribution of gastritis induced by H. pylori. Thus, individuals with gastritis predominantly localized to the antrum retain normal (or even high) acid secretion, whereas individuals with extensive corpus gastritis develop hypochlorhydria and gastric atrophy, which are presumptive precursors of gastric cancer. Here we report that interleukin-1 gene cluster polymorphisms suspected of enhancing production of interleukin-1-beta are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Two of these polymorphism are in near-complete linkage disequilibrium and one is a TATA-box polymorphism that markedly affects DNA-protein interactions in vitro. The association with disease may be explained by the biological properties of interleukin-1-beta, which is an important pro-inflammatory cytokine and a powerful inhibitor of gastric acid secretion. Host genetic factors that affect interleukin-1-beta may determine why some individuals infected with H. pylori develop gastric cancer while others do no

A bacterial effector counteracts host autophagy by promoting degradation of an autophagy component

Beyond its role in cellular homeostasis, autophagy plays anti- and promicrobial roles in host-microbe interactions, both in animals and plants. One prominent role of antimicrobial autophagy is to degrade intracellular pathogens or microbial molecules, in a process termed xenophagy. Consequently, microbes evolved mechanisms to hijack or modulate autophagy to escape elimination. Although well-described in animals, the extent to which xenophagy contributes to plant-bacteria interactions remains unknown. Here, we provide evidence that Xanthomonas campestris pv. vesicatoria (Xcv) suppresses host autophagy by utilizing type-III effector XopL. XopL interacts with and degrades the autophagy component SH3P2 via its E3 ligase activity to promote infection. Intriguingly, XopL is targeted for degradation by defense-related selective autophagy mediated by NBR1/Joka2, revealing a complex antagonistic interplay between XopL and the host autophagy machinery. Our results implicate plant antimicrobial autophagy in the depletion of a bacterial virulence factor and unravel an unprecedented pathogen strategy to counteract defense-related autophagy in plant-bacteria interactions

Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1

Histone H2B monoubiquitination by Rad6/Bre1 is required for the trimethylation of both histone H3K4 and H3K79 by COMPASS and Dot1 methyltransferases, respectively. The dependency of methylation at H3K4 and H3K79 on the monoubiquitination of H2BK123 was recently challenged, and extragenic mutations in the strain background used for previous studies or epitope-tagged proteins were suggested to be the sources of this discrepancy. In this study, we show that H3K4 and H3K79 methylation is solely dependent on H2B monoubiquitination regardless of any additional alteration to the H2B sequence or genome. Furthermore, we report that Y131, one of the yeast histone H2A/H2B shuffle strains widely used for the last decade in the field of chromatin and transcription biology, carries a wild-type copy of each of the HTA2 and HTB2 genes under the GAL1/10 promoter on chromosome II. Therefore, we generated the entire histone H2A and H2B alanine-scanning mutant strains in another background, which does not express wild-type histones

The effectiveness of strategies to change organisational culture to improve healthcare performance: a systematic review

<p>Abstract</p> <p>Background</p> <p>Organisational culture is an anthropological metaphor used to inform research and consultancy and to explain organisational environments. In recent years, increasing emphasis has been placed on the need to change organisational culture in order to improve healthcare performance. However, the precise function of organisational culture in healthcare policy often remains underspecified and the desirability and feasibility of strategies to be adopted have been called into question. The objective of this review was to determine the effectiveness of strategies to change organisational culture in order to improve healthcare performance.</p> <p>Methods</p> <p>We searched the following electronic databases: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Sociological Abstracts, Web of Knowledge, PsycINFO, Business and Management, EThOS, Index to Theses, Intute, HMIC, SIGLE, and Scopus until October 2009. The Database of Abstracts of Reviews of Effectiveness (DARE) was searched for related reviews. We also searched the reference lists of all papers and relevant reviews identified, and we contacted experts in the field for advice on further potential studies. We considered randomised controlled trials (RCTs) or well designed quasi-experimental studies (controlled clinical trials (CCTs), controlled before and after studies (CBAs), and interrupted time series (ITS) analyses). Studies could be set in any type of healthcare organisation in which strategies to change organisational culture in order to improve healthcare performance were applied. Our main outcomes were objective measures of professional performance and patient outcome.</p> <p>Results</p> <p>The search strategy yielded 4,239 records. After the full text assessment, two CBA studies were included in the review. They both assessed the impact of interventions aimed at changing organisational culture, but one evaluated the impact on work-related and personal outcomes while the other measured clinical outcomes. Both were at high risk of bias. Both reported positive results.</p> <p>Conclusions</p> <p>Current available evidence does not identify any effective, generalisable strategies to change organisational culture. Healthcare organisations considering implementing interventions aimed at changing culture should seriously consider conducting an evaluation (using a robust design, <it>e.g.</it>, ITS) to strengthen the evidence about this topic.</p