Influence of inlet boundary conditions on the local haemodynamics of intracranial aneurysms

Haemodynamics is believed to play an important role in the initiation, growth and rupture of intracranial aneurysms. In this context, computational haemodynamics has been extensively used in an effort to establish correlations between flow variables and clinical outcome. It is common practice in the application of Dirichlet boundary conditions at domain inlets to specify transient velocities as either a flat (plug) profile or a spatially developed profile based on Womersley's analytical solution. This paper provides comparative haemodynamics measures for three typical cerebral aneurysms.

Three dimentional rotational angiography images of aneurysms at three common locations, viz. basilar artery tip, internal carotid artery and middle cerebral artery were obtained. The computational tools being developed in the European project @neurIST were used to reconstruct the fluid domains and solve the unsteady Navier–Stokes equations, using in turn Womersley and plug-flow inlet velocity profiles. The effects of these assumptions were analysed and compared in terms of relevant haemodynamic variables within the aneurismal sac. For the aneurysm at the basilar tip geometries with different extensions of the afferent vasculature were considered to study the plausibility of a fully-developed axial flow at the inlet boundaries.

The study shows that assumptions made on the velocity profile while specifying inlet boundary conditions have little influence on the local haemodynamics in the aneurysm, provided that a sufficient extension of the afferent vasculature is considered and that geometry is the primary determinant of the flow field within the aneurismal sac. For real geometries the Womersley profile is at best an unnecessary over-complication, and may even be worse than the plug profile in some anatomical locations (e.g. basilar confluence).     

Late‐life rapamycin treatment reverses age‐related heart dysfunction

Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity‐enhancing paradigm in mammalian tissues. We treated 24‐month‐old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late‐life cardiovascular function with a reversal or attenuation of age‐related changes in the heart. RNA‐seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late‐life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age‐related inflammation.     

Identification and characterization of Cryptococcus neoformans protein fractions that induce protective immune responses

Cryptococcus neoformans, the main causative agent of cryptococcosis, is a fungal pathogen that causes life‐threatening meningoencephalitis in immunocompromised patients. To date, there is no vaccine or immunotherapy approved to treat cryptococcosis. Cell‐ and antibody‐mediated immune responses collaborate to mediate optimal protection against C. neoformans infections. Accordingly, we identified cryptococcal protein fractions capable of stimulating cell‐ and antibody‐mediated immune responses and determined their efficacy to elicit protection against cryptococcosis. Proteins were extracted from C. neoformans and fractionated based on molecular mass. The fractions were then evaluated by immunoblot analysis for reactivity to serum extracted from protectively immunized mice and in cytokine recall assays for their efficacy to induce pro‐inflammatory and Th1‐type cytokine responses associated with protection. MS analysis revealed a number of proteins with roles in stress response, signal transduction, carbohydrate metabolism, amino acid synthesis, and protein synthesis. Immunization with select protein fractions containing immunodominant antigens induced significantly prolonged survival against experimental pulmonary cryptococcosis. Our studies support using the combination of immunological and proteomic approaches to identify proteins that elicit antigen‐specific antibody and Th1‐type cytokine responses. The immunodominant antigens that were discovered represent attractive candidates for the development of novel subunit vaccines for treatment and/or prevention of cryptococcosis.     

Plasmon-Enhanced Light Trapping to Improve Efficiency of TiO2 Nanorod-Based Dye-Sensitized Solar Cell

Localized surface plasmon resonance incurred by silver nanoparticles is used to enhance the photoelectric conversion efficiency of a TiO₂ nanorod-based dye-sensitized solar cell (DSSC). Improved light transmission is observed experimentally in silver nanoparticle-coated FTO glass. The transmission data are used to explore the effect on electrical parameters of DSSC using theoretical model. Current density increased from 11.7 to 12.34 mA/cm² and open-circuit voltage increased from 704 to 709.5 mV. Overall efficiency enhancement of 6.67 % is observed in TiO₂ nanorod-based DSSC due to plasmon-induced light trapping.     

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α₁ subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α₁–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α₁ and β₁ subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.     

Role of CTLA4 in the Proliferation and Survival of Chronic Lymphocytic Leukemia

Earlier, we reported that CTLA4 expression is inversely correlated with CD38 expression in chronic lymphocytic leukemia (CLL) cells. However, the specific role of CTLA4 in CLL pathogenesis remains unknown. Therefore, to elucidate the possible role of CTLA4 in CLL pathogenesis, CTLA4 was down-regulated in primary CLL cells. We then evaluated proliferation/survival in these cells using MTT, ³H-thymidine uptake and Annexin-V apoptosis assays. We also measured expression levels of downstream molecules involved in B-cell proliferation/survival signaling including STAT1, NFATC2, c-Fos, c-Myc, and Bcl-2 using microarray, PCR, western blotting analyses, and a stromal cell culture system. CLL cells with CTLA4 down-regulation demonstrated a significant increase in proliferation and survival along with an increased expression of STAT1, STAT1 phosphorylation, NFATC2, c-Fos phosphorylation, c-Myc, Ki-67 and Bcl-2 molecules. In addition, compared to controls, the CTLA4-downregulated CLL cells showed a decreased frequency of apoptosis, which also correlated with increased expression of Bcl-2. Interestingly, CLL cells from lymph node and CLL cells co-cultured on stroma expressed lower levels of CTLA4 and higher levels of c-Fos, c-Myc, and Bcl-2 compared to CLL control cells. These results indicate that microenvironment-controlled-CTLA4 expression mediates proliferation/survival of CLL cells by regulating the expression/activation of STAT1, NFATC2, c-Fos, c-Myc, and/or Bcl-2.