Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores

We propose a mathematical model for mitochondria-dependent apoptosis, in which kinetic cooperativity in formation of the apoptosome is a key element ensuring bistability. We examine the role of Bax and Bcl-2 synthesis and degradation rates, as well as the number of mitochondrial permeability transition pores (MPTPs), on the cell response to apoptotic stimuli. Our analysis suggests that cooperative apoptosome formation is a mechanism for inducing bistability, much more robust than that induced by other mechanisms, such as inhibition of caspase-3 by the inhibitor of apoptosis (IAP). Simulations predict a pathological state in which cells will exhibit a monostable cell survival if Bax degradation rate is above a threshold value, or if Bax expression rate is below a threshold value. Otherwise, cell death or survival occur depending on initial caspase-3 levels. We show that high expression rates of Bcl-2 can counteract the effects of Bax. Our simulations also demonstrate a monostable (pathological) apoptotic response if the number of MPTPs exceeds a threshold value. This study supports our contention, based on mathematical modeling, that cooperativity in apoptosome formation is critically important for determining the healthy responses to apoptotic stimuli, and helps define the roles of Bax, Bcl-2, and MPTP vis-à-vis apoptosome formation.     

Rate and irregularity of electrical activation during atrial fibrillation affect myocardial NGF expression via different signalling routes

An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD) = 5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD = 1 vs. 5 Hz 25% SD = 1.57, P < 0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD + BQ123 = 0.66, P < 0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50 Hz = 0.55, P < 0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz + CsA = 1.14, P < 0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.     

Local tissue temperature increase of a generic implant compared to the basic restrictions defined in safety guidelines

The objective of this study was to investigate if persons with implantable medical devices are intrinsically protected by the current electromagnetic safety guidelines. For inter-laboratory comparisons, the U.S. Food and Drug Administration has defined a generic implant as consisting of an insulated wire with noninsulated tips, simulating active implants composed of a metallic case, and insulated wires with electric contacts at the tip. In this study, we determined the amplitude of the uniform electric fields induced in body tissues that cause a local increase in the tissue temperature by 1 °C in the presence of this generic implant for a wide range of frequencies and wire lengths. The field amplitudes were compared to the basic restrictions of the current exposure guidelines for both occupational and uncontrolled exposure. Results showed that a 1 °C temperature increase in the tissues around the tips of the generic implant can be reached for field strengths much smaller than 1% of those in the basic restrictions. The simulated results were validated by experimental evaluations. The impact of perfusion was investigated and was found to lead to a reduction in the local temperature peak by only 1.6-3 times. Additional simulations inside an inhomogeneous anatomical model were performed to ascertain whether similar heating as in the generic model was observed. The significant temperature elevations due to the presence of a generic implant indicate that demonstrating compliance with the basic restrictions might not be sufficient for persons with implants. Special considerations may be required, especially in the case of novel, emerging technologies that feature strong near-fields at frequencies below 10 MHz (e.g., wireless power-transfer systems).     

Leukotriene D4 receptor antagonist montelukast alleviates water avoidance stress-induced degeneration of the gastrointestinal mucosa

We investigated the role of montelukast (ML), a cysteinyl leukotriene-1 receptor antagonist, on the water avoidance stress (WAS)-induced degeneration of the rat gastric, ileal and colonic mucosa. One group of Wistar albino rats were exposed to chronic WAS (WAS group) 2h daily for 5 days. Another group was administered ML (10mg/kg; i.p.; WAS+ML group) following every WAS exposure for 5 days. Control rats were injected with the vehicle solution only. The stomach, ileum and colon were dissected and investigated for histopathological changes with a light microscope as well as for topographical changes with a scanning electron microscope. The levels of malondialdehyde (MDA, a biomarker of oxidative damage) and glutathione (GSH, a biomarker of protective oxidative injury) were also determined in all dissected tissues. In the WAS group, the stomach epithelium showed ulceration in some areas, dilatations of the gastric glands, degeneration of gastric glandular cells, and prominent congestion of the capillaries. In a similar fashion, degenerated epithelium and severe vascular congestions were observed in the ileum and colon. In all the tissues dense inflammatory cell infiltration and mast cell degranulation in mucosa were observed. The levels of MDA were significantly increased whereas those of GSH were significantly decreased in all test tissues in the WAS group compared to the control group. The morphology of gastric, ileal and colonic mucosa in WAS+ML group showed a significant amelioration showing a reduction in inflammatory cell infiltration and mast cell degranulation. Increased MDA and decreased GSH levels in the WAS group were also ameliorated with ML treatment. Based on the results, ML supplement seems attenuated inflammatory effects of WAS induction in gastrointestinal mucosa.     

Modeling intracranial aneurysm stability and growth: an integrative mechanobiological framework for clinical cases

We present a novel patient-specific fluid-solid-growth framework to model the mechanobiological state of clinically detected intracranial aneurysms (IAs) and their evolution. The artery and IA sac are modeled as thick-walled, non-linear elastic fiber-reinforced composites. We represent the undulation distribution of collagen fibers: the adventitia of the healthy artery is modeled as a protective sheath whereas the aneurysm sac is modeled to bear load within physiological range of pressures. Initially, we assume the detected IA is stable and then consider two flow-related mechanisms to drive enlargement: (1) low wall shear stress; (2) dysfunctional endothelium which is associated with regions of high oscillatory flow. Localized collagen degradation and remodelling gives rise to formation of secondary blebs on the aneurysm dome. Restabilization of blebs is achieved by remodelling of the homeostatic collagen fiber stretch distribution. This integrative mechanobiological modelling workflow provides a step towards a personalized risk-assessment and treatment of clinically detected IAs.

     

Evaluation of secondary infertility in the gorilla

Reproductive failure in two female gorillas in the Los Angeles Zoo led to evaluation for secondary infertility. Male factor was excluded by noting routine conceptions in other individuals in the same group, and by behavioral observations of coital activity with the infertile females. Biochemical evidence of ovarian function was obtained by urinary sex steroid analysis. Continuity of the reproductive tract of the infertile apes was then studied by hysterosalpingography and laparoscopy while their general health was evaluated by ultrasonography and physical examination. Progressive, multiorgan involvement with Echinococcus vogeli was documented and mebendazole therapy begun. The investigation of secondary infertility in great apes by combined methods is safe and accurate, but requires special equipment and experienced personnel.     

A triple bottom line evaluation of solid waste management strategies: a case study for an arid Gulf State,Kuwait

Purpose

We extend a life cycle assessment (LCA) embracing both economic and social perspectives to develop an integrated solid waste management system for Kuwait. This study considers the domestic waste generated by households and waste generated commercially. Six municipal solid waste (MSW) scenarios (SR₁, SR₂, …, SR₆) are evaluated using a triple bottom line (TBL) approach that incorporates environmental, financial, and social bottom lines (social BLs).

Methods

Within the TBL framework, the environmental BL employs LCA in accordance with ISO 14044. The financial BL is calculated using capital and operational costs as well as the associated recycling revenues. The social BL applies macro-economic indicators that examine the effects of a given MSW scenario (SR) on the inhabitants. To integrate the TBLs, we apply an analytic hierarchy process (AHP) because of its advantage of pairwise unit-free rescaling. The relative importance of each BL is determined by considering the political, legal, socio-cultural, and economic climates of the country. The relative weights are cross-multiplied with indicators from each BL to calculate a composite sustainability index (CSI) for the proposed MSW SR.

Results and discussion

The environmental BL (LCA) indicates that global warming, acidification, and human toxicity are the most adversely affected impact categories, considering the local conditions and waste composition. Environmentally, SR₁ (landfilling) scored the worst in almost all impact categories and, thus, was labeled the worst-case scenario environmentally. SR₆ (composting, recycling, and incineration) performed the best from an environmental perspective. Financially, landfilling (SR₁) is the most economical scenario. Any SR that focused on incineration (SR₂ and SR₅) was financially unfavorable. The scenarios that involved composting were scored as financially reasonable (SR₃, SR₄, and SR₆). From a social acceptability perspective, SR₂ (incineration) scored the highest, while SR₁ (landfills) scored the lowest. Finally, across the TBL framework, SR₄ (composting and incineration) had the highest CSI based on the relative importance scheme adopted for each BL.

Conclusions

Although they are often overlooked in most LCA studies, the financial and social aspects are indispensable to proving feasibility and credibility at a strategic level. The complexity of financial and social formulations in LCA is inherited from the difficulty in quantifying emissions and other impacts. In addition, from a social perspective, the contingent risks and associated uncertainty vary widely across cultures, ideologies, and degrees of development and are further complicated because of the scarcity and uncertainty of the data.