Querying XML data streams from wireless sensor networks: an evaluation of query engines

As the deployment of wireless sensor networks increase and their application domain widens, the opportunity for effective use of XML filtering and streaming query engines is ever more present. XML filtering engines aim to provide efficient real-time querying of streaming XML encoded data. This paper provides a detailed analysis of several such engines, focusing on the technology involved, their capabilities, their support for XPath and their performance. Our experimental evaluation identifies which filtering engine is best suited to process a given query based on its properties. Such metrics are important in establishing the best approach to filtering XML streams on-the-fly

Mechanisms of RNA polymerase III transcriptional activation by c-Myc

The Myc family of proto-oncogenes encodes transcription factors that play a pivotal role in regulating cellular proliferation, cellular growth, differentiation and apoptosis. To regulate cellular growth, it can activate a number of RNA polymerase II- transcribed genes which encode ribosomal proteins, translation factors and other components of the biosynthetic apparatus. c-Myc can also directly activate transcription by RNA polymerases I and III, thereby stimulating the production of ribosomal (r)RNA and transfer (t)RNA. As such, c-Myc may possess the capacity to induce the expression of all the ribosomal components. The work in this project aimed to investigate the mechanisms behind the c-Myc-dependent activation of RNA polymerase III transcription. One mechanism by which activators of pol III transcription can stimulate the expression of class III genes is by promoting transcription complex formation. It had been previously demonstrated that c-Myc can interact with the pol Ill-specific transcription factor TFIIIB. Work in this thesis has further defined this interaction and demonstrated that activation of transcription by c-Myc can recruit this complex along with pol III to 5S rRNA and tRNA genes in vivo. Furthermore, the recruitment of TFIIIB and polymerase by c-Myc are distinct events, with a significant delay between TFIIIB and pol III binding, arguing against a pol III holoenzyme being recruited to the genes. Most recent work on the mechanisms of transcriptional activation by c-Myc has focussed on its ability to influence chromatin structure. Transcriptional activation of target genes by c-Myc may involve the remodelling of nucleosomes, since c-Myc has been shown to bind to the Snf5 subunit of the SWI/SNF complex, as well as the ATPase/helicases TIP48 and TIP49. In the present study, Snf5 and Brg1, both components of SWI/SNF, have been found at the promoters of pol Ill-transcribed genes. These may have a role in the regulation of pol III transcriptional activity. c-Myc can also recruit a variety of histone modifying enzymes to the promoters of its target genes. It can bind to the co-factor TRRAP, a 440 kDa protein that forms the scaffold of a variety of histone acetyltransferase complexes. It has been demonstrated that c-Myc can recruit these complexes to certain target genes, and the increase in histone acetylation correlates with gene expression. The TRRAP co-factor along with an associated HAT was found to be present in a c-Myc-sensitive manner on pol Ill- transcribed genes, and their presence correlated with histone acetylation and gene expression. In addition to these findings, depletion of endogenous TRRAP by RNAi in cultured cells resulted in a specific down-regulation of pol III transcription in vivo. In summary, this thesis has identified previously undescribed mechanisms by which c-Myc can activate transcription by pol III, and has identified novel co-activator proteins involved in the regulation of class III gene expression. This work has important implications in understanding the molecular basis of how activators can stimulate the expression of pol Ill-transcribed genes

Demixing of Speech Mixtures and Enhancement of Noisy Speech Using ADRess Algorithm

This paper describes the ability of the Azimuth Discrimination and Resynthesis algorithm (ADRess) to separate multiple speech signals from two mixtures in a simulation environment. ADRess exploits the spatial signature of each of the contributing speech sources to demix the mixtures. Speech sentences taken from the TIMIT database and noise signals from the NOISEX database were mixed synthetically to create pairs of mixtures. ADRess can exploit the spatial signature of noise and speech sources to remove or isolate them from a mixture. To simulate the spatial location of different sources the relative attenuation and phase difference of each source between the two mixtures were manipulated. This was performed for numerous different angles of arrival so as to robustly test the algorithm. Objective measures and promising informal listening test results show the suitability of ADRess for cleaning noisy speech mixtures and document the performance of ADRess for speech mixtures with different numbers of sources

Demixing of Speech Mixtures and Enhancement of Noisy Speech Using ADRess Algorithm

This paper describes the ability of the Azimuth Discrimination and Resynthesis algorithm (ADRess) to separate multiple speech signals from two mixtures in a simulation environment. ADRess exploits the spatial signature of each of the contributing speech sources to demix the mixtures. Speech sentences taken from the TIMIT database and noise signals from the NOISEX database were mixed synthetically to create pairs of mixtures. ADRess can exploit the spatial signature of noise and speech sources to remove or isolate them from a mixture. To simulate the spatial location of different sources the relative attenuation and phase difference of each source between the two mixtures were manipulated. This was performed for numerous different angles of arrival so as to robustly test the algorithm. Objective measures and promising informal listening test results show the suitability of ADRess for cleaning noisy speech mixtures and document the performance of ADRess for speech mixtures with different numbers of sources

XIAP upregulates expression of HIF target genes by targeting HIF1 alpha for Lys(63)-linked polyubiquitination

The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1α subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X-linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys63-linked polyubiquitination of HIF1α. Lys63-linked ubiquitination of HIF1α by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys63-linked polyubiquitination promotes HIF1α nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys63-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1α, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease

PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here we investigated how PBRM1 controls HIF-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathway

PERK/eIF2 alpha signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1 alpha translation

HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation. Activation of PERK inhibits de novo HIF1α protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1α mRNA 5′UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells

Hypoxic stress suppresses RNA polymerase III recruitment and tRNA gene transcription in cardiomyocytes

RNA polymerase (pol) III transcription decreases when primary cultures of rat neonatal cardiomyocytes are exposed to low oxygen tension. Previous studies in fibroblasts have shown that the pol III-specific transcription factor IIIB (TFIIIB) is bound and regulated by the proto-oncogene product c-Myc, the mitogen-activated protein kinase ERK and the retinoblastoma tumour suppressor protein, RB. The principal function of TFIIIB is to recruit pol III to its cognate gene template, an activity that is known to be inhibited by RB and stimulated by ERK. We demonstrate by chromatin immunoprecipitation (ChIP) that c-Myc also stimulates pol III recruitment by TFIIIB. However, hypoxic conditions cause TFIIIB dissociation from c-Myc and ERK, at the same time as increasing its interaction with RB. Consistent with this, ChIP assays indicate that the occupancy of tRNA genes by pol III is significantly reduced, whereas promoter binding by TFIIIB is undiminished. The data suggest that hypoxia can inhibit pol III transcription by altering the interactions between TFIIIB and its regulators and thus compromising its ability to recruit the polymerase. These effects are independent of cell cycle changes

Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial

BACKGROUND Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers