POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA

Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression

Patient enablement requires physician empathy: a cross-sectional study of general practice consultations in areas of high and low socioeconomic deprivation in Scotland

<b>Background</b> Patient 'enablement' is a term closely aligned with 'empowerment' and its measurement in a general practice consultation has been operationalised in the widely used patient enablement instrument (PEI), a patient-rated measure of consultation outcome. However, there is limited knowledge regarding the factors that influence enablement, particularly the effect of socio-economic deprivation. The aim of the study is to assess the factors influencing patient enablement in GP consultations in areas of high and low deprivation.<p></p> <b>Methods</b> A questionnaire study was carried out on 3,044 patients attending 26 GPs (16 in areas of high socio-economic deprivation and 10 in low deprivation areas, in the west of Scotland). Patient expectation (confidence that the doctor would be able to help) was recorded prior to the consultation. PEI, GP empathy (measured by the CARE Measure), and a range of other measures and variables were recorded after the consultation. Data analysis employed multi-level modelling and multivariate analyses with the PEI as the dependant variable.<p></p> <b>Results</b> Although numerous variables showed a univariate association with patient enablement, only four factors were independently predictive after multilevel multivariate analysis; patients with multimorbidity of 3 or more long-term conditions (reflecting poor chronic general health), and those consulting about a long-standing problem had reduced enablement scores in both affluent and deprived areas. In deprived areas, emotional distress (GHQ-caseness) had an additional negative effect on enablement. Perceived GP empathy had a positive effect on enablement in both affluent and deprived areas. Maximal patient enablement was never found with low empathy.<p></p> <b>Conclusions</b> Although other factors influence patient enablement, the patients' perceptions of the doctors' empathy is of key importance in patient enablement in general practice consultations in both high and low deprivation settings

Thermoelectric spin voltage in graphene

In recent years, new spin-dependent thermal effects have been discovered in ferromagnets, stimulating a growing interest in spin caloritronics, a field that exploits the interaction between spin and heat currents. Amongst the most intriguing phenomena is the spin Seebeck effect, in which a thermal gradient gives rise to spin currents that are detected through the inverse spin Hall effect. Non-magnetic materials such as graphene are also relevant for spin caloritronics, thanks to efficient spin transport, energy-dependent carrier mobility and unique density of states. Here, we propose and demonstrate that a carrier thermal gradient in a graphene lateral spin valve can lead to a large increase of the spin voltage near to the graphene charge neutrality point. Such an increase results from a thermoelectric spin voltage, which is analogous to the voltage in a thermocouple and that can be enhanced by the presence of hot carriers generated by an applied current. These results could prove crucial to drive graphene spintronic devices and, in particular, to sustain pure spin signals with thermal gradients and to tune the remote spin accumulation by varying the spin-injection bias

On the Schoenberg Transformations in Data Analysis: Theory and Illustrations

The class of Schoenberg transformations, embedding Euclidean distances into higher dimensional Euclidean spaces, is presented, and derived from theorems on positive definite and conditionally negative definite matrices. Original results on the arc lengths, angles and curvature of the transformations are proposed, and visualized on artificial data sets by classical multidimensional scaling. A simple distance-based discriminant algorithm illustrates the theory, intimately connected to the Gaussian kernels of Machine Learning

HEE-GER: a systematic review of German economic evaluations of health care published 1990–2004

BACKGROUND: Studies published in non-English languages are systematically missing in systematic reviews of growth and quality of economic evaluations of health care. The aims of this study were: to characterize German evaluations, published in English or German-language, in terms of various key parameters; to investigate methods to derive quality-of-life weights in cost-utility studies; and to examine changes in study characteristics over the years. METHODS: We conducted a country-specific systematic review of the German and English-language literature of German economic evaluations (assessment of or application to the German health care system) published 1990–2004. Generic and specialized health economic databases were searched. Two independent reviewers verified fulfillment of inclusion criteria and extracted study characteristics. RESULTS: The fulltexts of 730 articles were reviewed of which 283 fulfilled all entry criteria. 32% of included studies were published in German-language. 51% of studies evaluated pharmaceuticals and 63% were cost-effectiveness analyses. Economic appraisals concentrate on few disease categories and important health areas are strongly underrepresented. Declaration of sponsorship was associated with article language (49% English articles vs. 29% German articles, p < 0.001). The methodology used to obtain quality-of-life weights in published cost-utility studies was very diverse, poorly reported and most studies did not use German patients' or community health state valuations. CONCLUSION: Many of the German-language evaluations included in our study are likely to be missing in international reviews and may be systematically different from English-language reviews from Germany. Lack of transparency and adherence to recommended reporting practices constitute a serious problem in German economic evaluations

Experimental evidence for splicing of intron-containing transcripts of plant LTR retrotransposon Ogre

Ogre elements are a distinct group of plant Ty3/gypsy-like retrotransposons characterized by several specific features, one of which is a separation of the gag-pol region into two non-overlapping open reading frames: ORF2 coding for Gag-Pro, and ORF3 coding for RT/RH-INT proteins. Previous characterization of Ogre elements from several plant species revealed that part of their transcripts lacks the region between ORF2 and ORF3, carrying one uninterrupted ORF instead. In this work, we investigated a hypothesis that this region represents an intron that is spliced out from part of the Ogre transcripts as a means for preferential production of ORF2-encoded proteins over those encoded by the complete ORF2–ORF3 region. The experiments involved analysis of transcription patterns of well-defined Ogre populations in a model plant Medicago truncatula and examination of transcripts carrying dissected pea Ogre intron expressed within a coding sequence of chimeric reporter gene. Both experimental approaches proved that the region between ORF2 and ORF3 is spliced from Ogre transcripts and showed that this process is only partial, probably due to weak splice signals. This is one of very few known cases of spliced LTR retrotransposons and the only one where splicing does not involve parts of the element’s coding sequences, thus resembling intron splicing found in most cellular genes

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas