Hyperdoctrines and the Ontology of Stratified Semantics

I present a version of Kit Fine's stratified semantics for the logic RWQ and define a natural family of related structures called RW hyperdoctrines. After proving that RWQ is sound with respect to RW hyperdoctrines, we show how to construct, for each stratified model, a hyperdoctrine that verifies precisely the same sentences. Completeness of RWQ for hyperdoctrinal semantics then follows from completeness for stratified semantics, which is proved in an appendix. By examining the base category of RW hyperdoctrines, we find reason to be worried about the ontology of stratified models

Pulse pressure and age at menopause

BACKGROUND: The objective of this study was to study the association of early age at menopause with pulse pressure (PP), a marker of arterial stiffness, and PP change. METHODS: The effect of natural menopause was studied in 2484 women from the Atherosclerosis Risk in Communities (ARIC) Study who had not used hormone replacement therapy and who had not had a hysterectomy. The cross-sectional association of age with PP was evaluated in the entire cohort. The cross-sectional association of recalled age at menopause was evaluated in the 1688 women who were postmenopausal at baseline. PP change over 6 years was assessed in relation to menopausal age separately in women who were postmenopausal at baseline and in those whose menopause occurred during the 6-year interval. RESULTS: Chronological age was strongly and positively associated with PP in cross-sectional analyses, but not independently associated with PP change. While menopausal age was not associated cross-sectionally with PP, early age at menopause (age<45) was significantly and independently associated with a slightly larger increase in PP (8.4, 95% CI 7.0–9.8) than later menopause (6.5, 95% CI 5.8;7.2). However, among normotensive women the difference was not statistically significant (p = 0.07, 6.1 vs 4.7). CONCLUSIONS: Early age at menopause may be related to a greater increase in arterial stiffness, but the effect appears to be small and further evidence is needed

MiR-137 Targets Estrogen-Related Receptor Alpha and Impairs the Proliferative and Migratory Capacity of Breast Cancer Cells

ERRα is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERRα in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERRα is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERRα 3′UTR at nt 480–486 and nt 596–602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERRα expression at both protein level and mRNA level, and the miR-137 induced ERRα-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137mimics suppressed at least two downstream target genes of ERRα–CCNE1 and WNT11, which are important effectors of ERRα implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERRα expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERRα by microRNAs has the potential to influence breast cancer progression

Transient integral boundary layer method to calculate the translesional pressure drop and the fractional flow reserve in myocardial bridges

BACKGROUND: The pressure drop – flow relations in myocardial bridges and the assessment of vascular heart disease via fractional flow reserve (FFR) have motivated many researchers the last decades. The aim of this study is to simulate several clinical conditions present in myocardial bridges to determine the flow reserve and consequently the clinical relevance of the disease. From a fluid mechanical point of view the pathophysiological situation in myocardial bridges involves fluid flow in a time dependent flow geometry, caused by contracting cardiac muscles overlying an intramural segment of the coronary artery. These flows mostly involve flow separation and secondary motions, which are difficult to calculate and analyse. METHODS: Because a three dimensional simulation of the haemodynamic conditions in myocardial bridges in a network of coronary arteries is time-consuming, we present a boundary layer model for the calculation of the pressure drop and flow separation. The approach is based on the assumption that the flow can be sufficiently well described by the interaction of an inviscid core and a viscous boundary layer. Under the assumption that the idealised flow through a constriction is given by near-equilibrium velocity profiles of the Falkner-Skan-Cooke (FSC) family, the evolution of the boundary layer is obtained by the simultaneous solution of the Falkner-Skan equation and the transient von-Kármán integral momentum equation. RESULTS: The model was used to investigate the relative importance of several physical parameters present in myocardial bridges. Results have been obtained for steady and unsteady flow through vessels with 0 – 85% diameter stenosis. We compare two clinical relevant cases of a myocardial bridge in the middle segment of the left anterior descending coronary artery (LAD). The pressure derived FFR of fixed and dynamic lesions has shown that the flow is less affected in the dynamic case, because the distal pressure partially recovers during re-opening of the vessel in diastole. We have further calculated the wall shear stress (WSS) distributions in addition to the location and length of the flow reversal zones in dependence on the severity of the disease. CONCLUSION: The described boundary layer method can be used to simulate frictional forces and wall shear stresses in the entrance region of vessels. Earlier models are supplemented by the viscous effects in a quasi three-dimensional vessel geometry with a prescribed wall motion. The results indicate that the translesional pressure drop and the mean FFR compares favourably to clinical findings in the literature. We have further shown that the mean FFR under the assumption of Hagen-Poiseuille flow is overestimated in developing flow conditions

Skeletal Muscle Phenotypically Converts and Selectively Inhibits Metastatic Cells in Mice

Skeletal muscle is rarely a site of malignant metastasis; the molecular and cellular basis for this rarity is not understood. We report that myogenic cells exert pronounced effects upon co-culture with metastatic melanoma (B16-F10) or carcinoma (LLC1) cells including conversion to the myogenic lineage in vitro and in vivo, as well as inhibition of melanin production in melanoma cells coupled with cytotoxic and cytostatic effects. No effect is seen with non-tumorigenic cells. Tumor suppression assays reveal that the muscle-mediated tumor suppressor effects do not generate resistant clones but function through the down-regulation of the transcription factor MiTF, a master regulator of melanocyte development and a melanoma oncogene. Our findings point to skeletal muscle as a source of therapeutic agents in the treatment of metastatic cancers