Nonlinear Sigma Model for Disordered Media: Replica Trick for Non-Perturbative Results and Interactions

In these lectures, given at the NATO ASI at Windsor (2001), applications of the replicas nonlinear sigma model to disordered systems are reviewed. A particular attention is given to two sets of issues. First, obtaining non-perturbative results in the replica limit is discussed, using as examples (i) an oscillatory behaviour of the two-level correlation function and (ii) long-tail asymptotes of different mesoscopic distributions. Second, a new variant of the sigma model for interacting electrons in disordered normal and superconducting systems is presented, with demonstrating how to reduce it, under certain controlled approximations, to known ``phase-only'' actions, including that of the ``dirty bosons'' model.Comment: 25 pages, Proceedings of the NATO ASI "Field Theory of Strongly Correlated Fermions and Bosons in Low - Dimensional Disordered Systems", Windsor, August, 2001; to be published by Kluwe

Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile

BACKGROUND: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We orally infected C57BL/6 and C57BL/6.KOR-Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages. CONCLUSIONS/SIGNIFICANCE: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease

The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse

ACKNOWLEDGEMENTS We thank Professors Cheryll Tickle and Françoise Helmbacher for discussion and reagents. We thank staff at the Aberdeen Medical Research Facility for specialist technical assistance.Peer reviewedPublisher PD

Pattern Recognition Analysis of Proton Nuclear Magnetic Resonance Spectra of Brain Tissue Extracts from Rats Anesthetized with Propofol or Isoflurane

BACKGROUND: General anesthesia is routinely used as a surgical procedure and its safety has been endorsed by clinical outcomes; however, its effects at the molecular level have not been elucidated. General anesthetics influence glucose metabolism in the brain. However, the effects of anesthetics on brain metabolites other than those related to glucose have not been well characterized. We used a pattern recognition analysis of proton nuclear magnetic resonance spectra to visualize the changes in holistic brain metabolic phenotypes in response to the widely used intravenous anesthetic propofol and the volatile anesthetic isoflurane. METHODOLOGY/PRINCIPAL FINDINGS: Rats were randomized into five groups (n = 7 each group). Propofol and isoflurane were administered to two groups each, for 2 or 6 h. The control group received no anesthesia. Brains were removed directly after anesthesia. Hydrophilic compounds were extracted from excised whole brains and measured by proton nuclear magnetic resonance spectroscopy. All spectral data were processed and analyzed by principal component analysis for comparison of the metabolite profiles. Data were visualized by plotting principal component (PC) scores. In the plots, each point represents an individual sample. The propofol and isoflurane groups were clustered separately on the plots, and this separation was especially pronounced when comparing the 6-h groups. The PC scores of the propofol group were clearly distinct from those of the control group, particularly in the 6-h group, whereas the difference in PC scores was more subtle in the isoflurane group and control groups. CONCLUSIONS/SIGNIFICANCE: The results of the present study showed that propofol and isoflurane exerted differential effects on holistic brain metabolism under anesthesia

Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells

<p>Abstract</p> <p>Background</p> <p>The constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumours. In particular, MMP-2 and MMP-9 have been reported to be closely associated with invasion and angiogenesis in malignant gliomas. Our study aimed to evaluate the antitumour effects of MMI-166 (Nalpha-[4-(2-Phenyl-2H- tetrazole-5-yl) phenyl sulfonyl]-D-tryptophan), a third generation MMP inhibitor, on three human glioma cell lines (T98G, U87MG, and ONS12) in vitro and in vivo.</p> <p>Methods</p> <p>The effects of MMI-166 on the gelatinolytic activity was analysed by gelatine zymography. The anti-invasive effect of MMI-166 was analysed by an in vitro invasion assay. An in vitro angiogenesis assay was also performed. In vitro growth inhibition of glioma cells by MMI-166 was determined by the MTT assay. The effect of MMI-166 on an orthotropic implantation model using athymic mice was also evaluated.</p> <p>Results</p> <p>Gelatine zymography revealed that MMP-2 and MMP-9 activities were suppressed by MMI-166. The invasion of glioma cells was suppressed by MMI-166. The angiogenesis assay showed that MMI-166 had a suppressive effect on glioma cell-induced angiogenesis. However, MMI-166 did not suppress glioma cell proliferation in the MTT assay. In vivo, MMI-166 suppressed tumour growth in athymic mice implanted orthotropically with T98G cells and showed an inhibitory effect on tumour-induced angiogenesis and tumour growth. This is the first report of the effect of a third generation MMP inhibitor on malignant glioma cells.</p> <p>Conclusions</p> <p>These results suggest that MMI-166 may have potentially suppressive effects on the invasion and angiogenesis of malignant gliomas.</p

An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression

The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates

Relationships between anopheline mosquitoes and topography in West Timor and Java, Indonesia

<p>Abstract</p> <p>Background</p> <p>Malaria is a serious health issue in Indonesia. Mosquito control is one aspect of an integrated malaria management programme. To focus resources on priority areas, information is needed about the vectors and their habitats. This research aimed to identify the relationship between anopheline mosquitoes and topography in West Timor and Java.</p> <p>Methods</p> <p>Study areas were selected in three topographic types in West Timor and Java. These were: coastal plain, hilly (rice field) and highland. Adult mosquitoes were captured landing on humans identified to species level and counted.</p> <p>Results</p> <p>Eleven species were recorded, four of which were significant for malaria transmission: <it>Anopheles aconitus, Anopheles barbirostris, Anopheles subpictus </it>and <it>Anopheles sundaicus</it>. Each species occupied different topographies, but only five were significantly associated: <it>Anopheles annularis, Anopheles vagus </it>and <it>Anopheles subpictus </it>(Java only) with hilly rice fields; <it>Anopheles barbirostris, Anopheles maculatus </it>and <it>Anopheles subpictus </it>(West Timor only) with coastal areas.</p> <p>Conclusion</p> <p>Information on significant malaria vectors associated with specific topography is useful for planning the mosquito control aspect of malaria management.</p

Regulation of Energy Stores and Feeding by Neuronal and Peripheral CREB Activity in Drosophila

The cAMP-responsive transcription factor CREB functions in adipose tissue and liver to regulate glycogen and lipid metabolism in mammals. While Drosophila has a homolog of mammalian CREB, dCREB2, its role in energy metabolism is not fully understood. Using tissue-specific expression of a dominant-negative form of CREB (DN-CREB), we have examined the effect of blocking CREB activity in neurons and in the fat body, the primary energy storage depot with functions of adipose tissue and the liver in flies, on energy balance, stress resistance and feeding behavior. We found that disruption of CREB function in neurons reduced glycogen and lipid stores and increased sensitivity to starvation. Expression of DN-CREB in the fat body also reduced glycogen levels, while it did not affect starvation sensitivity, presumably due to increased lipid levels in these flies. Interestingly, blocking CREB activity in the fat body increased food intake. These flies did not show a significant change in overall body size, suggesting that disruption of CREB activity in the fat body caused an obese-like phenotype. Using a transgenic CRE-luciferase reporter, we further demonstrated that disruption of the adipokinetic hormone receptor, which is functionally related to mammalian glucagon and β-adrenergic signaling, in the fat body reduced CRE-mediated transcription in flies. This study demonstrates that CREB activity in either neuronal or peripheral tissues regulates energy balance in Drosophila, and that the key signaling pathway regulating CREB activity in peripheral tissue is evolutionarily conserved

Recruitment of the mitotic exit network to yeast centrosomes couples septin displacement to actomyosin constriction

The Mitotic Exit Network (MEN) promotes mitotic exit and cytokinesis but if and how MEN independently controls these two processes is unclear. Here, the authors report that MEN displaces septins from the cell division site to promote actomyosin ring constriction, independently of MEN control of mitotic exit