Double Field Theory Formulation of Heterotic Strings

We extend the recently constructed double field theory formulation of the low-energy theory of the closed bosonic string to the heterotic string. The action can be written in terms of a generalized metric that is a covariant tensor under O(D,D+n), where n denotes the number of gauge vectors, and n additional coordinates are introduced together with a covariant constraint that locally removes these new coordinates. For the abelian subsector, the action takes the same structural form as for the bosonic string, but based on the enlarged generalized metric, thereby featuring a global O(D,D+n) symmetry. After turning on non-abelian gauge couplings, this global symmetry is broken, but the action can still be written in a fully O(D,D+n) covariant fashion, in analogy to similar constructions in gauged supergravities.Comment: 28 pages, v2: minor changes, version published in JHE

Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance

Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.published_or_final_versio

Hybrid Fuzzy Logic Scheme for Efficient Channel Utilization in Cognitive Radio Networks

© 2013 IEEE. The proliferation of mobile devices and the heterogeneous environment of wireless communications have increased the need for additional spectrum for data transmission. It is not possible to altogether allocate a new band to all networks, which is why fully efficient use of the already available spectrum is the demand of the day. Cognitive radio (CR) technology is a promising solution for efficient spectrum utilization, where CR devices, or secondary users (SUs), can opportunistically exploit white spaces available in the licensed channels. SUs have to immediately vacate the licensed channel and switch to another available channel when they detect the arrival of the incumbent primary user. However, performance for the SU severely degrades if successive channel switching happens. Moreover, taking the channel-switching decisions based on crisp logic is not a suitable approach in the brain-empowered CR networks (CRNs) where sensing information is not only imprecise and inaccurate but also involves a major uncertainty factor. In this paper, we propose a fuzzy logic-based decision support system (FLB-DSS) that jointly deals with channel selection and channel switching to enhance the overall throughput of CRNs. The proposed scheme reduces the SU channel switching rate and makes channel selection more adaptable. The performance of the proposed scheme is evaluated using a Matlab simulator, and a comprehensive comparison study with a baseline scheme is presented. The simulation results are promising in terms of the throughput and the number of handoffs and making our proposed FLB-DSS a good candidate mechanism for SUs while making judicious decisions in the CR environment

Search for CP violation in D0 and D+ decays

A high statistics sample of photoproduced charm particles from the FOCUS (E831) experiment at Fermilab has been used to search for CP violation in the Cabibbo suppressed decay modes D+ to K-K+pi+, D0 to K-K+ and D0 to pi-pi+. We have measured the following CP asymmetry parameters: A_CP(K-K+pi+) = +0.006 +/- 0.011 +/- 0.005, A_CP(K-K+) = -0.001 +/- 0.022 +/- 0.015 and A_CP(pi-pi+) = +0.048 +/- 0.039 +/- 0.025 where the first error is statistical and the second error is systematic. These asymmetries are consistent with zero with smaller errors than previous measurements.Comment: 12 pages, 4 figure

A new pathway of glucocorticoid action for asthma treatment through the regulation of PTEN expression

<p>Abstract</p> <p>Background</p> <p>"Phosphatase and tensin homolog deleted on chromosome 10" (PTEN) is mostly considered to be a cancer-related gene, and has been suggested to be a new pathway of pathogenesis of asthma. The purpose of this study was to investigate the effects of the glucocorticoid, dexamethasone, on PTEN regulation.</p> <p>Methods</p> <p>OVA-challenged mice were used as an asthma model to investigate the effect of dexamethasone on PTEN regulation. Immunohistochemistry was used to detect expression levels of PTEN protein in lung tissues. The human A549 cell line was used to explore the possible mechanism of action of dexamethasone on human PTEN regulation <it>in vitro</it>. A luciferase reporter construct under the control of PTEN promoter was used to confirm transcriptional regulation in response to dexamethasone.</p> <p>Results</p> <p>PTEN protein was found to be expressed at low levels in lung tissues in asthmatic mice; but the expression was restored after treatment with dexamethasone. In A549 cells, human PTEN was up-regulated by dexamethasone treatment. The promoter-reporter construct confirmed that dexamethasone could regulate human PTEN transcription. Treatment with the histone deacetylase inhibitor, TSA, could increase PTEN expression in A549 cells, while inhibition of histone acetylase (HAT) by anacardic acid attenuated dexamethasone-induced PTEN expression.</p> <p>Conclusions</p> <p>Based on the data a new mechanism is proposed where glucocorticoids treat asthma partly through up-regulation of PTEN expression. The <it>in vitro </it>studies also suggest that the PTEN pathway may be involved in human asthma.</p

Gene Expression Pattern in Transmitochondrial Cytoplasmic Hybrid Cells Harboring Type 2 Diabetes-Associated Mitochondrial DNA Haplogroups

Decreased mitochondrial function plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Recently, it was reported that mitochondrial DNA (mtDNA) haplogroups confer genetic susceptibility to T2DM in Koreans and Japanese. Particularly, mtDNA haplogroup N9a is associated with a decreased risk of T2DM, whereas haplogroups D5 and F are associated with an increased risk. To examine functional consequences of these haplogroups without being confounded by the heterogeneous nuclear genomic backgrounds of different subjects, we constructed transmitochondrial cytoplasmic hybrid (cybrid) cells harboring each of the three haplogroups (N9a, D5, and F) in a background of a shared nuclear genome. We compared the functional consequences of the three haplogroups using cell-based assays and gene expression microarrays. Cell-based assays did not detect differences in mitochondrial functions among the haplogroups in terms of ATP generation, reactive oxygen species production, mitochondrial membrane potential, and cellular dehydrogenase activity. However, differential expression and clustering analyses of microarray data revealed that the three haplogroups exhibit a distinctive nuclear gene expression pattern that correlates with their susceptibility to T2DM. Pathway analysis of microarray data identified several differentially regulated metabolic pathways. Notably, compared to the T2DM-resistant haplogroup N9a, the T2DM-susceptible haplogroup F showed down-regulation of oxidative phosphorylation and up-regulation of glycolysis. These results suggest that variations in mtDNA can affect the expression of nuclear genes regulating mitochondrial functions or cellular energetics. Given that impaired mitochondrial function caused by T2DM-associated mtDNA haplogroups is compensated by the nuclear genome, we speculate that defective nuclear compensation, under certain circumstances, might lead to the development of T2DM

Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80–90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.American Society for Radiation Oncology (Junior Faculty Career Research Training Award)Harvard University. Joint Center for Radiation Therapy (Foundation Grant)Dana-Farber/Harvard Cancer Center (SPORE Developmental Research Project Award in Lung Cancer Research)National Cancer Institute (U.S.) (Award K08CA172354

Identification of Spt5 Target Genes in Zebrafish Development Reveals Its Dual Activity In Vivo

Spt5 is a conserved essential protein that represses or stimulates transcription elongation in vitro. Immunolocalization studies on Drosophila polytene chromosomes suggest that Spt5 is associated with many loci throughout the genome. However, little is known about the prevalence and identity of Spt5 target genes in vivo during development. Here, we identify direct target genes of Spt5 using fogsk8 zebrafish mutant, which disrupts the foggy/spt5 gene. We identified that fogsk8 and their wildtype siblings differentially express less than 5% of genes examined. These genes participate in diverse biological processes from stress response to cell fate specification. Up-regulated genes exhibit shorter overall gene length compared to all genes examined. Through chromatin immunoprecipitation in zebrafish embryos, we identified a subset of developmentally critical genes that are bound by both Spt5 and RNA polymerase II. The protein occupancy patterns on these genes are characteristic of both repressive and stimulatory elongation regulation. Together our findings establish Spt5 as a dual regulator of transcription elongation in vivo and identify a small but diverse set of target genes critically dependent on Spt5 during development