Immediate response of myocardium to pressure overload includes transient regulation of genes associated with mitochondrial bioenergetics and calcium availability

Ventricular hypertrophy is one of the major myocardial responses to pressure overload (PO). Most studies on early myocardial response focus on the days or even weeks after induction of hypertrophic stimuli. Since mechanotransduction pathways are immediately activated in hearts undergoing increased work load, it is reasonable to infer that the myocardial gene program may be regulated in the first few hours. In the present study, we monitored the expression of some genes previously described in the context of myocardial hypertrophic growth by using the Northern blot technique, to estimate the mRNA content of selected genes in rat myocardium for the periods 1, 3, 6, 12 and 48 h after PO stimuli. Results revealed an immediate switch in the expression of genes encoding alpha and beta isoforms of myosin heavy chain, and up-regulation of the cardiac isoform of alpha actin. We also detected transitory gene regulation as the increase in mitochondrial cytochrome c oxidase 1 gene expression, parallel to down-regulation of genes encoding sarco(endo)plasmic reticulum Ca+2 ATPase and sodium-calcium exchanger. Taken together, these results indicate that initial myocardial responses to increased work load include alterations in the contractile properties of sarcomeres and transitory adjustment of mitochondrial bioenergetics and calcium availability

Hypothetical biomolecular probe based on a genetic switch with tunable symmetry and stability

Background: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable, or even to multistable, based on the experimental fine-tuning of readily accessible parameters. In order to successfully design robust, bistable synthetic circuits to be used as biomolecular probes, or understand modes of operation of such naturally occurring circuits, we must identify parameters that are key in determining their characteristics. Results: Here, we analyze the bistability properties of a general, asymmetric genetic toggle switch based on a chemical-reaction kinetic description. By making appropriate approximations, we are able to reduce the system to two coupled differential equations. Their deterministic stability analysis and stochastic numerical simulations are in excellent agreement. Drawing upon this general framework, we develop a model of an experimentally realized asymmetric bistable genetic switch based on the LacI and TetR repressors. By varying the concentrations of two synthetic inducers, doxycycline and isopropyl ??-D-1-thiogalactopyranoside, we predict that it will be possible to repeatedly fine-tune the mode of operation of this genetic switch from monostable to bistable, as well as the switching rates over many orders of magnitude, in an experimental setting. Furthermore, we find that the shape and size of the bistability region is closely connected with plasmid copy number. Conclusions: Based on our numerical calculations of the LacI-TetR asymmetric bistable switch phase diagram, we propose a generic work-flow for developing and applying biomolecular probes: Their initial state of operation should be specified by controlling inducer concentrations, and dilution due to cellular division would turn the probes into memory devices in which information could be preserved over multiple generations. Additionally, insights from our analysis of the LacI-TetR system suggest that this particular system is readily available to be employed in this kind of probe.clos

Assessing seasonal variations and aquifer vulnerability in coastal aquifers of semi-arid regions using a multi-tracer isotopic approach: the case of Grombalia (Tunisia)

The Grombalia aquifer (NE Tunisia) is an example of an important source of water supply for regional and national development, where the weak controls over abstraction, fertilizer application and waste disposal, coupled with limited knowledge of aquifer dynamics, is causing aquifer over-exploitation and water quality degradation. Assessing the key role of groundwater in water-resources security is therefore of paramount importance to support new actions to preserve water quality and quantity in the long-run. This study presents one of the first investigations targeted at a complete assessment of aquifer dynamics in the Grombalia aquifer. A multi-tracer hydrogeochemical and isotopic (δ2H, δ18O and 3H) approach was used to study the influence of seasonal variation on piezometric levels, chemical and isotopic compositions, and groundwater recharge. A total of 116 samples were collected from private wells and boreholes during three periods in a 1 year monitoring campaign (February–March 2014, September 2014 and February 2015). Results revealed the overall unsuitability of groundwater for drinking and irrigation purposes (NO3 > 50 mg/L in 51% of the wells; EC >1,000 μS/cm in 99% of the wells). Isotopic balance coupled to piezometric investigation indicated the contribution of the shallow aquifer to deep groundwater recharge. The study also revealed the weakness of ‘business as usual’ management practices, highlighting possible solutions to tackle water-related challenges in the Grombalia region, where climate change, population growth and intensive agricultural activities have generated a large gap between demand and available water reserves, hence becoming a possible driver for social insecurity

Interpreting different measures of glomerular filtration rate in obesity and weight loss: pitfalls for the clinician

To combat the increasing incidence of obesity, much research has been devoted to devising successful strategies for weight loss, including manipulation of diet and gastric surgery. Obesity itself can be associated with renal dysfunction, and the degree of reversibility of this with weight loss has being studied. However, there are significant limitations and flaws in the methods we have available to measure glomerular filtration rate (GFR) in overweight and obese subjects. Obesity is associated with changes in body composition including lean and fat mass. This has implications for assumptions that underpin creatinine-based measures such as creatinine clearance, estimated GFR and other equations devised for obesity including the Salazar–Corcoran equation. These changes in body composition also affect measures of glomerular filtration such as cystatin C and nuclear medicine isotope scans. This article will review the accuracy of these current measures of renal function in the obese and consider the evidence for adjusting for body surface area or adjusting for lean body mass. Finally, the effect of weight loss itself on serial measurements of renal function in a given individual, independent of a true change in renal function, will be reviewed. Ultimately using the Cockcroft–Gault equation with an adjustment for lean body mass seems to be the best measure for renal function in obesity. No method for measuring renal function in situations of weight loss has been shown to be unequivocally superior.D.R. Jesudason and P. Clifto