Spinoza

"Spinoza", second edition. Encyclopedia entry for the Springer Encyclopedia of EM Phil and the Sciences, ed. D. Jalobeanu and C. T. Wolfe

Field Deployment of an Ambient Vibration-Based Scour Monitoring System at Baildon Bridge, UK

Scour, the loss of material around bridge foundations due to hydraulic action, is the main cause of bridge failures in the United Kingdom and in many other parts of the world. Various techniques have been used to monitor bridge scour, ranging from scuba divers using crude depth measuring instrumentation to high-tech sonar and radar-based systems. In contrast to most other techniques, vibration-based scour monitoring uses accelerometers to provide real-time monitoring whilst also being robust and relatively simple to install. This is an indirect technique that aims to measure changes in the dynamic response of the structure due to the effects of scour, rather than attempting to measure scour directly. To date, research on vibration-based scour monitoring has been limited to laboratory-based experiments and numerical simulations, both of which have indicated that the natural frequencies of bridges should indeed be sensitive to scour. Due to pre-existing scouring, and planned repair work, Baildon Bridge in Shipley, Yorkshire provided a rare opportunity to validate vibration-based scour monitoring in both a scoured and a repaired state. A sensor system was deployed with 10 Epson low-noise, high-sensitivity accelerometers to measure the ambient vibration of the bridge before, during, and after the repair. This paper describes the installation of the accelerometer-based system, the numerical modelling of the bridge and the model updating carried out with the initial findings. Initial operational modal analysis has found two consistent vibration modes of the bridge that were scour sensitive according to the updated numerical model. But the variability of the measured frequencies, compared to the expected scour induced change in frequency, indicates a potential challenge for monitoring scour of small span bridges with vibration-based methods

Avoidable readmission in Hong Kong - system, clinician, patient or social factor?

<p>Abstract</p> <p>Background</p> <p>Studies that identify reasons for readmissions are gaining importance in the light of the changing demographics worldwide which has led to greater demand for hospital beds. It is essential to profile the prevalence of avoidable readmissions and understand its drivers so as to develop possible interventions for reducing readmissions that are preventable. The aim of this study is to identify the magnitude of avoidable readmissions, its contributing factors and costs in Hong Kong.</p> <p>Methods</p> <p>This was a retrospective analysis of 332,453 inpatient admissions in the Medical specialty in public hospital system in Hong Kong in year 2007. A stratified random sample of patients with unplanned readmission within 30 days after discharge was selected for medical record reviews. Eight physicians reviewed patients' medical records and classified whether a readmission was avoidable according to an assessment checklist. The results were correlated with hospital inpatient data.</p> <p>Results</p> <p>It was found that 40.8% of the 603 unplanned readmissions were judged avoidable by the reviewers. Avoidable readmissions were due to: clinician factor (42.3%) including low threshold for admission and premature discharge etc.; patient factor (including medical and health factor) (41.9%) such as relapse or progress of previous complaint, and compliance problems etc., followed by system factor (14.6%) including inadequate discharge planning, inadequate palliative care/terminal care, etc., and social factor (1.2%) such as carer system, lack of support and community services. After adjusting for patients' age, gender, principal diagnosis at previous discharge and readmission hospitals, the risk factors for avoidable readmissions in the total population i.e. all acute care admissions irrespective of whether there was a readmission or not, included patients with a longer length of stay, and with higher number of hospitalizations and attendance in public outpatient clinics and Accident and Emergency departments in the past 12 months. In the analysis of only unplanned readmissions, it was found that the concordance of the principal diagnosis for admission and readmission, and shorter time period between discharge and readmission were associated with avoidable readmissions.</p> <p>Conclusions</p> <p>Our study found that almost half of the readmissions could have been prevented. They had been mainly due to clinician and patient factors, in particular, both of which were intimately related to clinical management and patient care. These readmissions could be prevented by a system of ongoing clinical review to examine the clinical practice/decision for discharge, and improving clinical care and enhancing patient knowledge of the early warning signs for relapse. The importance of adequate and appropriate ambulatory care to support the patients in the community was also a key finding to reduce avoidable readmissions. Education on patient self-management should also be enhanced to minimize the patient factors with regard to avoidable readmission. Our findings thus provide important insights into the development of an effective discharge planning system which should place patients and carers as the primacy focus of care by engaging them along with the healthcare professionals in the whole discharge planning process.</p

Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world

Genetic analysis of D-xylose metabolism by endophytic yeast strains of Rhodotorula graminis and Rhodotorula mucilaginosa

Two novel endophytic yeast strains, WP1 and PTD3, isolated from within the stems of poplar (Populus) trees, were genetically characterized with respect to their xylose metabolism genes. These two strains, belonging to the species Rhodotorula graminis and R. mucilaginosa, respectively, utilize both hexose and pentose sugars, including the common plant pentose sugar, D-xylose. The xylose reductase (XYL1) and xylitol dehydrogenase (XYL2) genes were cloned and characterized. The derived amino acid sequences of xylose reductase (XR) and xylose dehydrogenase (XDH) were 32%∼41% homologous to those of Pichia stipitis and Candida. spp., two species known to utilize xylose. The derived XR and XDH sequences of WP1 and PTD3 had higher homology (73% and 69% identity) with each other. WP1 and PTD3 were grown in single sugar and mixed sugar media to analyze the XYL1 and XYL2 gene regulation mechanisms. Our results revealed that for both strains, the gene expression is induced by D-xylose, and that in PTD3 the expression was not repressed by glucose in the presence of xylose

Cleavage of ST6Gal I by Radiation-Induced BACE1 Inhibits Golgi-Anchored ST6Gal I-Mediated Sialylation of Integrin β1 and Migration in Colon Cancer Cells

<p>Abstract</p> <p>Background</p> <p>Previously, we found that β-galactoside α2,6-sialyltransferase (ST6Gal I), an enzyme that adds sialic acids to N-linked oligosaccharides of glycoproteins and is frequently overexpressed in cancer cells, is up-regulated by ionizing radiation (IR) and cleaved to a form possessing catalytic activity comparable to that of the Golgi-localized enzyme. Moreover, this soluble form is secreted into the culture media. Induction of ST6Gal I significantly increased the migration of colon cancer cells via sialylation of integrin β1. Here, we further investigated the mechanisms underlying ST6Gal I cleavage, solubilization and release from cells, and addressed its functions, focusing primarily on cancer cell migration.</p> <p>Methods</p> <p>We performed immunoblotting and lectin affinity assay to analyze the expression of ST6 Gal I and level of sialylated integrin β1. After ionizing radiation, migration of cells was measured by in vitro migration assay. α2, 6 sialylation level of cell surface was analyzed by flow cytometry. Cell culture media were concentrated and then analyzed for soluble ST6Gal I levels using an α2, 6 sialyltransferase sandwich ELISA.</p> <p>Result</p> <p>We found that ST6Gal I was cleaved by BACE1 (β-site amyloid precursor protein-cleaving enzyme), which was specifically overexpressed in response to IR. The soluble form of ST6Gal I, which also has sialyltransferase enzymatic activity, was cleaved from the Golgi membrane and then released into the culture media. Both non-cleaved and cleaved forms of ST6Gal I significantly increased colon cancer cell migration in a sialylation-dependent manner. The pro-migratory effect of the non-cleaved form of ST6Gal I was dependent on integrin β1 sialylation, whereas that of the cleaved form of ST6Gal I was not, suggesting that other intracellular sialylated molecules apart from cell surface molecules such as integrin β1 might be involved in mediating the pro-migratory effects of the soluble form of ST6Gal I. Moreover, production of soluble form ST6Gal I by BACE 1 inhibited integrin β1 sialylation and migration by Golgi-anchored form of ST6Gal I.</p> <p>Conclusions</p> <p>Our results suggest that soluble ST6Gal I, possibly in cooperation with the Golgi-bound form, may participate in cancer progression and metastasis prior to being secreted from cancer cells.</p

NMDA and Dopamine Converge on the NMDA-Receptor to Induce ERK Activation and Synaptic Depression in Mature Hippocampus

The formation of enduring internal representation of sensory information demands, in many cases, convergence in time and space of two different stimuli. The first conveys the sensory input, mediated via fast neurotransmission. The second conveys the meaning of the input, hypothesized to be mediated via slow neurotransmission. We tested the biochemical conditions and feasibility for fast (NMDA) and slow (dopamine) neurotransmission to converge on the Mitogen Activated Protein Kinase signaling pathways, crucial in several forms of synaptic plasticity, and recorded its effects upon synaptic transmission. We detected differing kinetics of ERK2 activation and synaptic strength changes in the CA1 for low and high doses of neurotransmitters in hippocampal slices. Moreover, when weak fast and slow inputs are given together, they converge on ERK2, but not on p38 or JNK, and induce strong short-term synaptic depression. Surprisingly, pharmacological analysis revealed that a probable site of such convergence is the NMDA receptor itself, suggesting it serves as a detector and integrator of fast and slow neurotransmission in the mature mammalian brain, as revealed by ERK2 activation and synaptic function

Adaptation of cortical activity to sustained pressure stimulation on the fingertip

Background Tactile adaptation is a phenomenon of the sensory system that results in temporal desensitization after an exposure to sustained or repetitive tactile stimuli. Previous studies reported psychophysical and physiological adaptation where perceived intensity and mechanoreceptive afferent signals exponentially decreased during tactile adaptation. Along with these studies, we hypothesized that somatosensory cortical activity in the human brain also exponentially decreased during tactile adaptation. The present neuroimaging study specifically investigated temporal changes in the human cortical responses to sustained pressure stimuli mediated by slow-adapting type I afferents. Methods We applied pressure stimulation for up to 15 s to the right index fingertip in 21 healthy participants and acquired functional magnetic resonance imaging (fMRI) data using a 3T MRI system. We analyzed cortical responses in terms of the degrees of cortical activation and inter-regional connectivity during sustained pressure stimulation. Results Our results revealed that the degrees of activation in the contralateral primary and secondary somatosensory cortices exponentially decreased over time and that intra- and inter-hemispheric inter-regional functional connectivity over the regions associated with tactile perception also linearly decreased or increased over time, during pressure stimulation. Conclusion These results indicate that cortical activity dynamically adapts to sustained pressure stimulation mediated by SA-I afferents, involving changes in the degrees of activation on the cortical regions for tactile perception as well as in inter-regional functional connectivity among them. We speculate that these adaptive cortical activity may represent an efficient cortical processing of tactile information.open

De-Novo Identification of PPARγ/RXR Binding Sites and Direct Targets during Adipogenesis

BACKGROUND: The pathophysiology of obesity and type 2 diabetes mellitus is associated with abnormalities in endocrine signaling in adipose tissue and one of the key signaling affectors operative in these disorders is the nuclear hormone transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma has pleiotropic functions affecting a wide range of fundamental biological processes including the regulation of genes that modulate insulin sensitivity, adipocyte differentiation, inflammation and atherosclerosis. To date, only a limited number of direct targets for PPARgamma have been identified through research using the well established pre-adipogenic cell line, 3T3-L1. In order to obtain a genome-wide view of PPARgamma binding sites, we applied the pair end-tagging technology (ChIP-PET) to map PPARgamma binding sites in 3T3-L1 preadipocyte cells. METHODOLOGY/PRINCIPAL FINDINGS: Coupling gene expression profile analysis with ChIP-PET, we identified in a genome-wide manner over 7700 DNA binding sites of the transcription factor PPARgamma and its heterodimeric partner RXR during the course of adipocyte differentiation. Our validation studies prove that the identified sites are bona fide binding sites for both PPARgamma and RXR and that they are functionally capable of driving PPARgamma specific transcription. Our results strongly indicate that PPARgamma is the predominant heterodimerization partner for RXR during late stages of adipocyte differentiation. Additionally, we find that PPARgamma/RXR association is enriched within the proximity of the 5' region of the transcription start site and this association is significantly associated with transcriptional up-regulation of genes involved in fatty acid and lipid metabolism confirming the role of PPARgamma as the master transcriptional regulator of adipogenesis. Evolutionary conservation analysis of these binding sites is greater when adjacent to up-regulated genes than down-regulated genes, suggesting the primordial function of PPARgamma/RXR is in the induction of genes. Our functional validations resulted in identifying novel PPARgamma direct targets that have not been previously reported to promote adipogenic differentiation. CONCLUSIONS/SIGNIFICANCE: We have identified in a genome-wide manner the binding sites of PPARgamma and RXR during the course of adipogenic differentiation in 3T3L1 cells, and provide an important resource for the study of PPARgamma function in the context of adipocyte differentiation