General Messenger Gauge Mediation

We discuss theories of gauge mediation in which the hidden sector consists of two subsectors which are weakly coupled to each other. One sector is made up of messengers and the other breaks supersymmetry. Each sector by itself may be strongly coupled. We provide a unifying framework for such theories and discuss their predictions in different settings. We show how this framework incorporates all known models of messengers. In the case of weakly-coupled messengers interacting with spurions through the superpotential, we prove that the sfermion mass-squared is positive, and furthermore, that there is a lower bound on the ratio of the sfermion mass to the gaugino mass.Comment: 37 pages; minor change

Oral health-related quality of life of paediatric patients with AIDS

<p>Abstract</p> <p>Background</p> <p>Children with Acquired Immune Deficiency Syndrome (AIDS) exhibit impaired dental status, which can affect their quality of life. This study assessed the oral health-related quality of life of these patients and associated factors.</p> <p>Methods</p> <p>The "Child Perceptions Questionnaire 11-14", rating overall and domain-specific (oral symptoms, functional limitations, emotional well being, and social well being) oral health-related quality of life (OHR-QoL) was completed by 88 children with AIDS assisted in the Child Institute, Sao Paulo, Brazil. Parents or guardians provided behavioural and socio-demographic information. The clinical status was provided by hospital records. OHR-QoL covariates were assessed by Poisson regression analysis.</p> <p>Results</p> <p>The most affected OHR-QoL subscale concerned oral symptoms, whose rate was 23.9%. The direct answer for oral health and well being made up a rate of 47.7%. Brushing the teeth less than two times a day and viral load exceeding 10,000 HIV-RNA copies per millilitre of plasma were directly associated (p < 0.05) with a poorer oral health-related quality of life.</p> <p>Conclusions</p> <p>Children with more severe AIDS manifestations complained of poorer status of oral symptoms, functional limitations, emotional and social well being related to their oral health. Recognizing the factors that are associated with poorer OHR-QoL in children with AIDS may contribute to the planning of dental services for this population.</p

Effects of Anesthetic Agents on Brain Blood Oxygenation Level Revealed with Ultra-High Field MRI

During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine). We showed that the brain/vessels contrast in T2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation

Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi

Short hairpin RNAs can provide stable gene silencing via RNA interference. Recent studies have shown toxicity in vivo that appears to be related to saturation of the endogenous microRNA pathway. Will these findings limit the therapeutic use of such hairpins

NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation

N-terminal acetylation (N-Ac) is a highly abundant eukaryotic protein modification. Proteomics revealed a significant increase in the occurrence of N-Ac from lower to higher eukaryotes, but evidence explaining the underlying molecular mechanism(s) is currently lacking. We first analysed protein N-termini and their acetylation degrees, suggesting that evolution of substrates is not a major cause for the evolutionary shift in N-Ac. Further, we investigated the presence of putative N-terminal acetyltransferases (NATs) in higher eukaryotes. The purified recombinant human and Drosophila homologues of a novel NAT candidate was subjected to in vitro peptide library acetylation assays. This provided evidence for its NAT activity targeting Met-Lys- and other Met-starting protein N-termini, and the enzyme was termed Naa60p and its activity NatF. Its in vivo activity was investigated by ectopically expressing human Naa60p in yeast followed by N-terminal COFRADIC analyses. hNaa60p acetylated distinct Met-starting yeast protein N-termini and increased general acetylation levels, thereby altering yeast in vivo acetylation patterns towards those of higher eukaryotes. Further, its activity in human cells was verified by overexpression and knockdown of hNAA60 followed by N-terminal COFRADIC. NatF's cellular impact was demonstrated in Drosophila cells where NAA60 knockdown induced chromosomal segregation defects. In summary, our study revealed a novel major protein modifier contributing to the evolution of N-Ac, redundancy among NATs, and an essential regulator of normal chromosome segregation. With the characterization of NatF, the co-translational N-Ac machinery appears complete since all the major substrate groups in eukaryotes are accounted for

Resveratrol, by Modulating RNA Processing Factor Levels, Can Influence the Alternative Splicing of Pre-mRNAs

Alternative pre-mRNA splicing defects can contribute to, or result from, various diseases, including cancer. Aberrant mRNAs, splicing factors and other RNA processing factors have therefore become targets for new therapeutic interventions. Here we report that the natural polyphenol resveratrol can modulate alternative splicing in a target-specific manner. We transfected minigenes of several alternatively spliceable primary mRNAs into HEK293 cells in the presence or absence of 1, 5, 20 and 50 µM resveratrol and measured exon levels by semi-quantitative PCR after separation by agarose gel electrophoresis. We found that 20 µg/ml and 50 µg/ml of resveratrol affected exon inclusion of SRp20 and SMN2 pre-mRNAs, but not CD44v5 or tau pre-mRNAs. By Western blotting and immunofluorescence we showed that this effect may be due to the ability of resveratrol to change the protein level but not the localization of several RNA processing factors. The processing factors that increased significantly were ASF/SF2, hnRNPA1 and HuR, but resveratrol did not change the levels of RBM4, PTBP1 and U2AF35. By means of siRNA-mediated knockdown we depleted cells of SIRT1, regarded as a major target of resveratrol, and showed that the effect on splicing was not dependent on SIRT1. Our results suggest that resveratrol might be an attractive small molecule to treat diseases in which aberrant splicing has been implicated, and justify more extensive research on the effects of resveratrol on the splicing machinery

Resveratrol Inhibits Inflammatory Responses via the Mammalian Target of Rapamycin Signaling Pathway in Cultured LPS-Stimulated Microglial Cells

Resveratrol have been known to possess many pharmacological properties including antioxidant, cardioprotective and anticancer effects. Although current studies indicate that resveratrol produces neuroprotection against neurological disorders, the precise mechanisms for its beneficial effects are still not fully understood. We investigate the effect of anti-inflammatory and mechamisms of resveratrol by using lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells.BV-2 cells were treated with resveratrol (25, 50, and 100 µM) and/or LPS (1 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of PTEN (phosphatase and tensin homolog deleted on chromosome 10), Akt, mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) cascades, inhibitor κB-α (IκB-α) and cyclic AMP-responsive element-binding protein (CREB) were measured by western blot. Resveratrol significantly attenuated the LPS-induced expression of NO, PGE2, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB) in BV-2 cells. Resveratrol increased PTEN, Akt and mTOR phosphorylation in a dose-dependent manner or a time-dependent manner. Rapamycin (10 nM), a specific mTOR inhibitor, blocked the effects of resveratrol on LPS-induced microglial activation. In addition, mTOR inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of IκB-α, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK).This study indicates that resveratrol inhibited LPS-induced proinflammatory enzymes and proinflammatory cytokines via down-regulation phosphorylation of NF-κB, CREB and MAPKs family in a mTOR-dependent manner. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of resveratrol