Three-Dimensional Stochastic Off-Lattice Model of Binding Chemistry in Crowded Environments

Molecular crowding is one of the characteristic features of the intracellular environment, defined by a dense mixture of varying kinds of proteins and other molecules. Interaction with these molecules significantly alters the rates and equilibria of chemical reactions in the crowded environment. Numerous fundamental activities of a living cell are strongly influenced by the crowding effect, such as protein folding, protein assembly and disassembly, enzyme activity, and signal transduction. Quantitatively predicting how crowding will affect any particular process is, however, a very challenging problem because many physical and chemical parameters act synergistically in ways that defy easy analysis. To build a more realistic model for this problem, we extend a prior stochastic off-lattice model from two-dimensional (2D) to three-dimensional (3D) space and examine how the 3D results compare to those found in 2D. We show that both models exhibit qualitatively similar crowding effects and similar parameter dependence, particularly with respect to a set of parameters previously shown to act linearly on total reaction equilibrium. There are quantitative differences between 2D and 3D models, although with a generally gradual nonlinear interpolation as a system is extended from 2D to 3D. However, the additional freedom of movement allowed to particles as thickness of the simulation box increases can produce significant quantitative change as a system moves from 2D to 3D. Simulation results over broader parameter ranges further show that the impact of molecular crowding is highly dependent on the specific reaction system examined

Phosphatase and tensin homologue: a therapeutic target for SMA

Spinal muscular atrophy (SMA) is one of the most common juvenile neurodegenerative diseases, which can be associated with child mortality. SMA is caused by a mutation of ubiquitously expressed gene, Survival Motor Neuron1 (SMN1), leading to reduced SMN protein and the motor neuron death. The disease is incurable and the only therapeutic strategy to follow is to improve the expression of SMN protein levels in motor neurons. Significant numbers of motor neurons in SMA mice and SMA cultures are caspase positive with condensed nuclei, suggesting that these cells are prone to a process of cell death called apoptosis. Searching for other potential molecules or signaling pathways that are neuroprotective for central nervous system (CNS) insults is essential for widening the scope of developmental medicine. PTEN, a Phosphatase and Tensin homologue, is a tumor suppressor, which is widely expressed in CNS. PTEN depletion activates anti-apoptotic factors and it is evident that the pathway plays an important protective role in many neurodegenerative disorders. It functions as a negative regulator of PIP3/AKT pathway and thereby modulates its downstream cellular functions through lipid phosphatase activity. Moreover, previous reports from our group demonstrated that, PTEN depletion using viral vector delivery system in SMN delta7 mice reduces disease pathology, with significant rescue on survival rate and the body weight of the SMA mice. Thus knockdown/depletion/mutation of PTEN and manipulation of PTEN medicated Akt/PKB signaling pathway may represent an important therapeutic strategy to promote motor neuron survival in SMA

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis

Date of Acceptance: 27/08/2015 Funding was provided by the Wellcome Trust grant WT081633MA-NCE and Biological Sciences Research Council Grant BB/K001043/1. Prof Fragoso is the recipient of a Post Doctoral Science without Borders grant from the Brazilian National Council for Scientific and Technological Development (CNPq, 237450/2012-7).Peer reviewedPublisher PD

Rapid photochemical production of ozone at high concentrations in a rural site during winter

Ozone is an air pollutant that can cause severe respiratory health effects. Photochemical ozone production near the Earth’s surface is considered a summertime, urban phenomenon1,2,3, where hourly average ozone concentrations can exceed 150 p.p.b., compared with background values of about 50  p.p.b., and wintertime ozone concentrations in the US are usually in the range of 35–50 p.p.b. (refs 1, 2, 3). Here we report rapid, diurnal photochemical production of ozone during air temperatures as low as −17 ∘C, in the rural Upper Green River Basin, Wyoming, in the vicinity of the Jonah–Pinedale Anticline natural gas field. We find that hourly average ozone concentrations rise from 10–30 p.p.b. at night to more than 140 p.p.b. shortly after solar noon, under the influence of a stagnant, high-pressure system that promotes cold temperatures, low wind speeds and limited cloudiness. Under these conditions, an intense, shallow temperature inversion develops in the lowest 100 m of the atmosphere, which traps high concentrations of ozone precursors at night. During daytime, photolytic ozone production then leads to the observed high concentrations. We suggest that similar ozone production during wintertime is probably occurring around the world under comparable industrial and meteorological conditions