R-modes in the ocean of a magnetic neutron star

We study the dynamics of r-modes in the ocean of a magnetic neutron star. We modeled the star's ocean with a spherical rotating thin shell and assumed that the magnetic field symmetry axis is not aligned to the shell's spin axis. In the magnetohydrodynamic approximation, we calculate the frequency of $\ell=m$ r-modes in the shell of an incompressible fluid. Different r-modes with $\ell$ and $\ell\pm2$ are coupled by the {\it inclined} magnetic field. Kinematical secular effects for the motion of a fluid element in the shell undergoing $\ell=m=2$ r-mode are studied. The magnetic corrected drift velocity of a given fluid element undergoing the $\ell=m$ r-mode oscillations is obtained. The magnetic field increases the magnitude of the fluid drift produced by the r-mode drift velocity, the high-$\ell$ modes in the ocean fluid will damp faster than the low-$\ell$ ones.Comment: 24 pages, 5 figures, to appear in ApJ, v574 n2 August 1, 2002 issu

Model of ionic currents through microtubule nanopores and the lumen

It has been suggested that microtubules and other cytoskeletal filaments may act as electrical transmission lines. An electrical circuit model of the microtubule is constructed incorporating features of its cylindrical structure with nanopores in its walls. This model is used to study how ionic conductance along the lumen is affected by flux through the nanopores when an external potential is applied across its two ends. Based on the results of Brownian dynamics simulations, the nanopores were found to have asymmetric inner and outer conductances, manifested as nonlinear IV curves. Our simulations indicate that a combination of this asymmetry and an internal voltage source arising from the motion of the C-terminal tails causes a net current to be pumped across the microtubule wall and propagate down the microtubule through the lumen. This effect is demonstrated to enhance and add directly to the longitudinal current through the lumen resulting from an external voltage source, and could be significant in amplifying low-intensity endogenous currents within the cellular environment or as a nano-bioelectronic device.Comment: 43 pages, 6 figures, revised versio

Analyzing utilization of biomass in combined heat and power and combined cooling, heating, and power systems

Nowadays, ever-increasing energy demands and the depletion of fossil fuels require efficient and environmentally friendly technologies for energy generation. In this context, energy systems integration makes for a very strong proposition since it results in energy saving, fuel diversification, and the supply of cleaner energy. To this end, it is of the utmost importance to realize the current developments in this field and portray the state of the art of renewable generation in integrated energy systems. This review evaluates the utilization of bioenergy in cogeneration and trigeneration systems. The statistical reports of bioenergy and combined heat and power deployments in 28 countries of the European Union are discussed. Then, the most common research objectives of biomass-fueled combined heat and power systems are classified into three primary performance analyses, namely, energy and exergy analysis, thermo-economic optimization, and environment assessment. The influencing parameters of biomass utilization on each type of assessment are discussed, and the basic principles for carrying out such analyses in energy systems are explained. It is illustrated that the properties of feedstock, selection of appropriate conversion technology, associated costs with the biomass-to-bioenergy process, and sustainability of biomass are the primary influencing factors that could significantly affect the results of each assessment

MARIS: Method for Analyzing RNA following Intracellular Sorting

Transcriptional profiling is a key technique in the study of cell biology that is limited by the availability of reagents to uniquely identify specific cell types and isolate high quality RNA from them. We report a Method for Analyzing RNA following Intracellular Sorting (MARIS) that generates high quality RNA for transcriptome profiling following cellular fixation, intracellular immunofluorescent staining and FACS. MARIS can therefore be used to isolate high quality RNA from many otherwise inaccessible cell types simply based on immunofluorescent tagging of unique intracellular proteins. As proof of principle, we isolate RNA from sorted human embryonic stem cell-derived insulin-expressing cells as well as adult human β cells. MARIS is a basic molecular biology technique that could be used across several biological disciplines.Howard Hughes Medical InstituteHarvard Stem Cell InstituteNational Institutes of Health (U.S.) (grant 2U01DK07247307)National Institutes of Health (U.S.) (grant RL1DK081184)National Institutes of Health (U.S.) (grant 1U01HL10040804

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors.

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage

Potential Pathways to Restore β-Cell Mass: Pluripotent Stem Cells, Reprogramming, and Endogenous Regeneration

Currently available β-cell replacement therapies for patients with diabetes, including islet and pancreas transplantation, are largely successful in restoring normal glucose metabolism, but the scarcity of organ donors restricts their more widespread use. To solve this supply problem, several different strategies for achieving β-cell mass restoration are being pursued. These include the generation of β cells from stem cells and their subsequent transplantation, or regeneration-type approaches, such as stimulating endogenous regenerative mechanisms or inducing reprogramming of non-β cells into β cells. Because these strategies would ultimately generate allogeneic or syngeneic β cells in humans, the control of alloimmunity and/or autoimmunity in addition to replacing lost β cells will be of utmost importance. We briefly review the recent literature on these three promising strategies toward β-cell replacement or restoration and point out the major issues impacting their translation to treating human diabetes

A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry