Investigation of \u3cem\u3ede novo\u3c/em\u3e cholesterol synthetic capacity in the gonads of goldfish (\u3cem\u3eCarassius auratus\u3c/em\u3e) exposed to the phytosterol beta-sitosterol

Total and intra-mitochondrial gonadal cholesterol concentrations are decreased in fish exposed to the phytoestrogen beta-sitosterol (beta-sit). The present study examined the potential for beta-sit to disrupt de novo cholesterol synthesis in the gonads of goldfish exposed to 200 microgram/g beta-sit and 10 microgram/g 17beta-estradiol (E2; estrogenic control) by intra-peritoneal Silastic® implants for 21 days. The de novo cholesterol synthetic capacity was estimated by incubating gonadal tissue with 14C-acetate for a period of 18 hours, followed by chloroform/methanol lipid extraction and thin layer chromatography (TLC) lipid separation. Lipid classes were confirmed using infrared spectroscopy. Plasma testosterone (T) and total cholesterol concentration were measured and gonadosomatic index (GSI) was calculated. Plasma T was significantly reduced in male beta-sit-treated fish compared to control and E2-treated fish (p \u3c 0.001). 14C-Acetate incorporation into cholesterol and cholesterol esters was not significantly different among treatment groups for male and female fish, however, 14C-enrichment was higher than expected in both triglycerides (TG) and free fatty acids (FFA). FFA incorporation was significantly higher in male control fish than either beta-sit or E2 treatments (p = 0.005). Plasma cholesterol concentration was significantly increased in the male beta-sit treatment group compared to controls (p = 0.027). These results indicate gonadal de novo cholesterol biosynthetic capacity is not disrupted by betasit or E2 treatment in early recrudescing male or female goldfish, while plasma cholesterol and steroid concentrations are sensitive to beta-sit exposure

Electrodynamics of a Magnet Moving through a Conducting Pipe

The popular demonstration involving a permanent magnet falling through a conducting pipe is treated as an axially symmetric boundary value problem. Specifically, Maxwell's equations are solved for an axially symmetric magnet moving coaxially inside an infinitely long, conducting cylindrical shell of arbitrary thickness at nonrelativistic speeds. Analytic solutions for the fields are developed and used to derive the resulting drag force acting on the magnet in integral form. This treatment represents a significant improvement over existing models which idealize the problem as a point dipole moving slowly inside a pipe of negligible thickness. It also provides a rigorous study of eddy currents under a broad range of conditions, and can be used for precision magnetic braking applications. The case of a uniformly magnetized cylindrical magnet is considered in detail, and a comprehensive analytical and numerical study of the properties of the drag force is presented for this geometry. Various limiting cases of interest involving the shape and speed of the magnet and the full range of conductivity and magnetic behavior of the pipe material are investigated and corresponding asymptotic formulas are developed.Comment: 20 pages, 3 figures; computer program posted to http://www.csus.edu/indiv/p/partovimh/magpipedrag.nb Submitted to the Canadian Journal of Physic

Bolaamphiphiles as a novel drug delivery system in the treatment of diseases of the brain

The incidence of central nervous system (CNS) diseases, such as glioblastoma, Alzheimer’s disease and Parkinson’s disease, will increase substantially in the next few decades. However, treatment for diseases of the brain is limited due to the restrictive physical and functional blood-brain barrier (BBB) dividing the brain and the vascular system. Bolaamphiphilic (BA) vesicles, produced from vernonia oil, encapsulate a wide range of therapeutic molecules, and offer an alternative drug delivery system to penetrate the brain to treat diseases of the CNS. We present novel anionic BA vesicles that cross biological barriers including the blood-brain barrier. BA vesicles were characterised by dynamic light scattering, transmission electron microscopy, zeta potential analysis and size exclusion column chromatography. In vitro studies were performed on numerous CNS-representative and other cell lines - BV2 microglia, SH-SY5Y neurones, LN229 glioblastoma, HEK-293T epithelia, hCMEC/D3 endothelia and HASTR/ci35 astrocytes. In vivo studies were performed using C57BL/6 male mice. A novel methodology was developed to permit synthesis of the novel BAs first described here, directly from vernonia oil, the starting material. This study has shown that a novel preparation of anionic BA form vesicles that encapsulate a range of different cargoes including tracer dyes and antibody fragments albeit with a low encapsulation efficiency. They do not influence cell viability or cause an acute immune response. They have been shown to penetrate the BBB in vivo. Analysis of the original BA material has shown to consist of two compounds, both of which have been synthesised and characterised. The original material synthesised from vernonia oil and used to produce BA vesicles was thought to be cationic. However, after profiling the vesicles synthesised were found to have a negative zeta potential demonstrating that they are novel. They were further tested and found to cross biological barriers in vitro. Newly synthesised vesicles require further characterisation and optimisation to improve stability and encapsulation efficiency. The original anionic BA material has been shown to cross the BBB within 30 minutes of intravenous injection. These results demonstrate that whilst further studies are required this is a candidate drug delivery system to treat diseases of the brain

Cancellous bone and theropod dinosaur locomotion. Part II—a new approach to inferring posture and locomotor biomechanics in extinct tetrapod vertebrates

This paper is the second of a three-part series that investigates the architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and therefore has the potential to provide insight into locomotor biomechanics in extinct tetrapod vertebrates such as dinosaurs. Here in Part II, a new biomechanical modelling approach is outlined, one which mechanistically links cancellous bone architectural patterns with three-dimensional musculoskeletal and finite element modelling of the hindlimb. In particular, the architecture of cancellous bone is used to derive a single ‘characteristic posture’ for a given species—one in which bone continuum-level principal stresses best align with cancellous bone fabric—and thereby clarify hindlimb locomotor biomechanics. The quasi-static approach was validated for an extant theropod, the chicken, and is shown to provide a good estimate of limb posture at around mid-stance. It also provides reasonable predictions of bone loading mechanics, especially for the proximal hindlimb, and also provides a broadly accurate assessment of muscle recruitment insofar as limb stabilization is concerned. In addition to being useful for better understanding locomotor biomechanics in extant species, the approach hence provides a new avenue by which to analyse, test and refine palaeobiomechanical hypotheses, not just for extinct theropods, but potentially many other extinct tetrapod groups as well

Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson’s Disease Rat Model

The detection of early molecular mechanisms and potential biomarkers in Parkinson’s disease (PD) remains a challenge. Recent research has pointed to novel roles for post-translational citrullination/deimination caused by peptidylarginine deiminases (PADs), a family of calcium-activated enzymes, in the early stages of the disease. The current study assessed brain-region-specific citrullinated protein targets and their associated protein–protein interaction networks alongside PAD isozymes in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb) were compared between controls/shams and the pre-motor PD model. For all brain regions, there was a significant difference in citrullinated protein IDs between the PD model and the controls. Citrullinated protein hits were most abundant in cortex and hippocampus, followed by cerebellum, midbrain, olfactory bulb and striatum. Citrullinome-associated pathway enrichment analysis showed correspondingly considerable differences between the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in PD brains only were associated with neurological, metabolic, immune and hormonal functions and included the following: “Axon guidance”; “Spinocerebellar ataxia”; “Hippo signalling pathway”; “NOD-like receptor signalling pathway”; “Phosphatidylinositol signalling system”; “Rap1 signalling pathway”; “Platelet activation”; “Yersinia infection”; “Fc gamma R-mediated phagocytosis”; “Human cytomegalovirus infection”; “Inositol phosphate metabolism”; “Thyroid hormone signalling pathway”; “Progesterone-mediated oocyte maturation”; “Oocyte meiosis”; and “Choline metabolism in cancer”. Some brain-region-specific differences were furthermore observed for the five PAD isozymes (PADs 1, 2, 3, 4 and 6), with most changes in PAD 2, 3 and 4 when comparing control and PD brain regions. Our findings indicate that PAD-mediated protein citrullination plays roles in metabolic, immune, cell signalling and neurodegenerative disease-related pathways across brain regions in early pre-motor stages of PD, highlighting PADs as targets for future therapeutic avenues

Investigation of de novo cholesterol synthetic capacity in the gonads of goldfish (Carassius auratus) exposed to the phytosterol beta-sitosterol

Total and intra-mitochondrial gonadal cholesterol concentrations are decreased in fish exposed to the phytoestrogen beta-sitosterol (beta-sit). The present study examined the potential for beta-sit to disrupt de novo cholesterol synthesis in the gonads of goldfish exposed to 200 microgram/g beta-sit and 10 microgram/g 17beta-estradiol (E2; estrogenic control) by intra-peritoneal Silastic(® )implants for 21 days. The de novo cholesterol synthetic capacity was estimated by incubating gonadal tissue with 14C-acetate for a period of 18 hours, followed by chloroform/methanol lipid extraction and thin layer chromatography (TLC) lipid separation. Lipid classes were confirmed using infrared spectroscopy. Plasma testosterone (T) and total cholesterol concentration were measured and gonadosomatic index (GSI) was calculated. Plasma T was significantly reduced in male beta-sit-treated fish compared to control and E2-treated fish (p < 0.001). 14C-Acetate incorporation into cholesterol and cholesterol esters was not significantly different among treatment groups for male and female fish, however, 14C-enrichment was higher than expected in both triglycerides (TG) and free fatty acids (FFA). FFA incorporation was significantly higher in male control fish than either beta-sit or E2 treatments (p = 0.005). Plasma cholesterol concentration was significantly increased in the male beta-sit treatment group compared to controls (p = 0.027). These results indicate gonadal de novo cholesterol biosynthetic capacity is not disrupted by beta-sit or E2 treatment in early recrudescing male or female goldfish, while plasma cholesterol and steroid concentrations are sensitive to beta-sit exposure