Depletion of Ca2+ from the sarcoplasmic reticulum of cardiac muscle prompts phosphorylation of phospholamban to stimulate store refilling

Nonmuscle cells have almost ubiquitously evolved a mechanism to detect and prevent Ca(2+) store depletionstore operated calcium entry. No such mechanism has, as yet, been reported in cardiac myocytes. However, it is conceivable that such a mechanism may play an important role in cardiac Ca(2+) homeostasis to ensure the availability of sufficient stored Ca(2+) to maintain normal excitation contraction coupling. We present data that confirms the presence of a mechanism that is able to monitor the Ca(2+) load of the SR and initiate a signaling process to accelerate Ca(2+) uptake by the SR when store depletion is detected. Depletion of SR Ca(2+) activates a protein kinase, the principal SR substrate of which is phospholamban. Phosphorylation of this SR protein promotes Ca(2+) pump activity and therefore store refilling. Furthermore, a protein kinase activity associated with the SR that is inhibited by Ca(2+) ions has been identified. We have measured lumenal [Ca(2+)] by using a fluorescent Ca(2+) indicator and found that by initiating Ca(2+) uptake and increasing Ca(2+) load, we can inhibit the protein kinase activity associated with the SR. This confirms that a protein kinase, that is regulated by lumenal [Ca(2+)], has been identified and represents part of a previously unidentified signalling cascade. This local feedback mechanism would allow the myocyte to detect and prevent SR Ca(2+) load depletio

Tonal prisms: iterated quantization in chromatic tonality and Ravel's 'Ondine'

The mathematics of second-order maximal evenness has far-reaching potential for application in music analysis. One of its assets is its foundation in an inherently continuous conception of pitch, a feature it shares with voice-leading geometries. This paper reformulates second-order maximal evenness as iterated quantization in voice-leading spaces, discusses the implications of viewing diatonic triads as second-order maximally even sets for the understanding of nineteenth-century modulatory schemes, and applies a second-order maximally even derivation of acoustic collections in an in-depth analysis of Ravel's ‘Ondine’. In the interaction between these two very different applications, the paper generalizes the concepts and analytical methods associated with iterated quantization and also pursues a broader argument about the mutual dependence of mathematical music theory and music analysis.Accepted manuscrip

The development of compartmentation of cAMP signaling in cardiomyocytes: the role of T-Tubules and caveolae microdomains

3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling

Ontology Based Query Expansion with a Probabilistic Retrieval Model

This paper examines the use of ontologies for defining query context. The information retrieval system used is based on the probabilistic retrieval model. We extend the use of relevance feedback (RFB) and pseudo-relevance feedback (PF) query expansion techniques using information from a news domain ontology. The aim is to assess the impact of the ontology on the query expansion results with respect to recall and precision. We also tested the results for varying the relevance feedback parameters (number of terms or number of documents). The factors which influence the success of ontology based query expansion are outlined. Our findings show that ontology based query expansion has had mixed success. The use of the ontology has vastly increased the number of relevant documents retrieved, however, we conclude that for both types of query expansion, the PF results are better than the RFB results

Changes in Nutrient Turnover and Supply During the Reversion of Arable Land to Acid Grassland/\u3ci\u3eCalluna\u3c/i\u3e Heathland

Lowland heath is of high conservation value because of the specialised and rare assemblages of plants and animals that it supports. Combinations of agricultural and urban development, and lack of appropriate management have resulted in large-scale loss and fragmentation of this habitat throughout the UK. Current UK conservation policies seek to re-create 6,000 ha of this habitat on land previously in agricultural and forestry production. Previous research indicated that high soil pH and fertility, together with a lack of propagules of heathland species, made it difficult to achieve this objective. The aim was to evaluate techniques to establish grass-Calluna heathland on ex-arable land in the Brecklands Environmentally Sensitive Area (ESA) in Norfolk, in particular, to assess the need for soil acidification to reduce competition and aid the establishment of Calluna

Autophagy: A cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress

The role of autophagy in the response of human hepatocytes to oxidative stress remains unknown. Understanding this process may have important implications for the understanding of basic liver epithelial cell biology and the responses of hepatocytes during liver disease. To address this we isolated primary hepatocytes from human liver tissue and exposed them ex vivo to hypoxia and hypoxia-reoxygenation (H-R). We showed that oxidative stress increased hepatocyte autophagy in a reactive oxygen species (ROS) and class III PtdIns3K-dependent manner. Specifically, mitochondrial ROS and NADPH oxidase were found to be key regulators of autophagy. Autophagy involved the upregulation of BECN1, LC3A, Atg7, Atg5 and Atg 12 during hypoxia and H-R. Autophagy was seen to occur within the mitochondria of the hepatocyte and inhibition of autophagy resulted in the lowering a mitochondrial membrane potential and onset of cell death. Autophagic responses were primarily observed in the large peri-venular (PV) hepatocyte subpopulation. Inhibition of autophagy, using 3-methyladenine, increased apoptosis during H-R. Specifically, PV human hepatocytes were more susceptible to apoptosis after inhibition of autophagy. These findings show for the first time that during oxidative stress autophagy serves as a cell survival mechanism for primary human hepatocytes

Utilising semantic technologies for intelligent indexing and retrieval of digital images

The proliferation of digital media has led to a huge interest in classifying and indexing media objects for generic search and usage. In particular, we are witnessing colossal growth in digital image repositories that are difficult to navigate using free-text search mechanisms, which often return inaccurate matches as they in principle rely on statistical analysis of query keyword recurrence in the image annotation or surrounding text. In this paper we present a semantically-enabled image annotation and retrieval engine that is designed to satisfy the requirements of the commercial image collections market in terms of both accuracy and efficiency of the retrieval process. Our search engine relies on methodically structured ontologies for image annotation, thus allowing for more intelligent reasoning about the image content and subsequently obtaining a more accurate set of results and a richer set of alternatives matchmaking the original query. We also show how our well-analysed and designed domain ontology contributes to the implicit expansion of user queries as well as the exploitation of lexical databases for explicit semantic-based query expansion

The Protective Effect of Ursodeoxycholic Acid in an in vitro model of the Human Fetal Heart occurs via Targeting Cardiac Fibroblasts

Bile acids are elevated in the blood of women with intrahepatic cholestasis of pregnancy (ICP) and this may lead to fetal arrhythmia, fetal hypoxia and potentially fetal death in utero. The bile acid taurocholic acid (TC) causes abnormal calcium dynamics and contraction in neonatal rat cardiomyocytes. Ursodeoxycholic acid (UDCA), a drug clinically used to treat ICP, prevents adverse effects of TC. During development, the fetus is in a state of relative hypoxia. Although this is essential for the development of the heart and vasculature, resident fibroblasts can transiently differentiate into myofibroblasts and form gap junctions with cardiomyocytes in vitro, resulting in cardiomyocyte depolarization. We expanded on previously published work using an in vitro hypoxia model to investigate the differentiation of human fetal fibroblasts into myofibroblasts.Recent evidence shows that potassium channels are involved in maintaining the membrane potential of ventricular fibroblasts and that ATP-dependent potassium (KATP) channel subunits are expressed in cultured fibroblasts. KATP channels are a valuable target as they are thought to have a cardioprotective role during ischaemic and hypoxic conditions. We investigated whether UDCA could modulate fibroblast membrane potential.We established the isolation and culture of human fetal cardiomyocytes and fibroblasts to investigate the effect of hypoxia, TC and UDCA on human fetal cardiac cells.UDCA hyperpolarized myofibroblasts and prevented TC-induced depolarisation, possibly through the activation of KATP channels that are expressed in cultured fibroblasts. Also, similar to the rat model, UDCA can counteract TC-induced calcium abnormalities in human fetal cultures of cardiomyocytes and myofibroblasts. Under normoxic conditions, we found a higher number of myofibroblasts in cultures derived from human fetal hearts compared to cells isolated from neonatal rat hearts, indicating a possible increased number of myofibroblasts in human fetal hearts. Hypoxia further increased the number of human fetal and rat neonatal myofibroblasts. However, chronically administered UDCA reduced the number of myofibroblasts and prevented hypoxia-induced depolarisation.In conclusion, our results show that the protective effect of UDCA involves both the reduction of fibroblast differentiation into myofibroblasts, and hyperpolarisation of myofibroblasts, most likely through the stimulation of potassium channels, i.e. KATP channels. This could be important in validating UDCA as an antifibrotic and antiarrhythmic drug for treatment of failing hearts and fetal arrhythmia

Systematic review of patient-specific predictors of pain improvement to endometriosis surgery

BACKGROUND: Up to 28% of endometriosis patients do not get pain relief from therapeutic laparoscopy but this subgroup is not defined. OBJECTIVES: To identify any prognostic patient-specific factors (such as but not limited to patients’ type or location of endometriosis, sociodemographics and lifestyle) associated with a clinically meaningful reduction in post-surgical pain response to operative laparoscopic surgery for endometriosis. SEARCH STRATEGY: PubMed, Cochrane and Embase databases were searched from inception to 19th May 2020 without language restrictions. Backward and forward citation tracking was used. SELECTION CRITERIA, DATA COLLECTION AND ANALYSIS: Cohort studies reporting prognostic factors, along with scores for domains of pain associated with endometriosis before and after surgery, were included. Studies that compared surgeries, or laboratory tests, or outcomes without stratification were excluded. Results were synthesised but variation in study designs and inconsistency of outcome reporting precluded us from doing a meta-analysis. MAIN RESULTS: Five studies were included. Quality assessment using the Newcastle Ottawa Scale graded three studies as high, one as moderate and one as having a low risk of bias. Four of five included studies separately reported that a relationship exists between more severe endometriosis and stronger pain relief from laparoscopic surgery CONCLUSION: Currently there are few studies of appropriate quality to answer the research question. We recommend future studies report core outcome sets to enable meta-analysis. FUNDING: NIHR PB-PG-0317-20018 PROSPERO: CRD4201810860