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Background Cellular memory is a ubiquitous function of biological systems. By generating a sustained response to a transient inductive stimulus, often due to bistability, memory is central to the robust control of many important biological processes. However, our understanding of the origins of cellular memory remains incomplete. Stochastic fluctuations that are inherent to most biological systems have been shown to hamper memory function. Yet, how stochasticity changes the behavior of genetic circuits is generally not clear from a deterministic analysis of the network alone. Here, we apply deterministic rate equations, stochastic simulations, and theoretical analyses of Fokker-Planck equations to investigate how intrinsic noise affects the memory function in a mutual repression network. Results We find that the addition of negative autoregulation improves the persistence of memory in a small gene regulatory network by reducing stochastic fluctuations. Our theoretical analyses reveal that this improved memory function stems from an increased stability of the steady states of the system. Moreover, we show how the tuning of critical network parameters can further enhance memory. Conclusions Our work illuminates the power of stochastic and theoretical approaches to understanding biological circuits, and the importance of considering stochasticity when designing synthetic circuits with memory function.

Background Exposure to toxins/chemicals is considered to be a significant risk factor in the pathogenesis of Parkinson's disease (PD); one putative chemical is the naturally occurring herbicide rotenone that is now used widely in establishing PD models. We, and others, have shown that chronic low dose rotenone treatment induces excessive accumulation of Reactive Oxygen Species (ROS), inclusion body formation and apoptosis in dopaminergic neurons of animal and human origin. Some studies have also suggested that microglia enhance the rotenone induced neurotoxicity. While the effects of rotenone on neurons are well established, there is little or no information available on the effect of rotenone on microglial cells, and especially cells of human origin. The aim of the present study was to investigate the effects of chronic low dose rotenone treatment on human microglial CHME-5 cells. Methods We have shown previously that rotenone induced inclusion body formation in human dopaminergic SH-SY5Y cells and therefore used these cells as a control for inclusion body formation in this study. SH-SY5Y and CHME-5 cells were treated with 5 nM rotenone for four weeks. At the end of week 4, both cell types were analysed for the presence of inclusion bodies, superoxide dismutases and cell activation (only in CHME-5 cells) using Haematoxylin and Eosin staining, immunocytochemical and western blotting methods. Levels of active caspases and ROS (both extra and intra cellular) were measured using biochemical methods. Conclusion The results suggest that chronic low dose rotenone treatment activates human microglia (cell line) in a manner similar to microglia of animal origin as shown by others. However human microglia release excessive amounts of ROS extracellularly, do not show excessive amounts of intracellular ROS and active caspases and most importantly do not show any protein aggregation or inclusion body formation. Human microglia appear to be resistant to rotenone (chronic, low dose) induced damage.

Background We implemented a high-protein diet (2 g·kg −1 ·d −1 ) throughout 12 weeks of concurrent exercise training to determine whether interferences to adaptation in muscle hypertrophy, strength and power could be attenuated compared to resistance training alone. Methods Thirty-two recreationally active males (age: 25 ± 5 years, body mass index: 24 ± 3 kg·m −2 ; mean ± SD) performed 12 weeks of either isolated resistance (RES; n  = 10) or endurance (END; n  = 10) training (three sessions·w −1 ), or concurrent resistance and endurance (CET; n  = 12) training (six sessions·w −1 ). Maximal strength (1RM), body composition and power were assessed pre- and post-intervention. Results Leg press 1RM increased ~ 24 ± 13% and ~ 33 ± 16% in CET and RES from PRE-to-POST ( P  < 0.001), with no difference between groups. Total lean mass increased ~ 4% in both CET and RES from PRE-to-POST ( P  < 0.001). Ultrasound estimated vastus lateralis volume increased ~ 15% in CET and ~ 11% in RES from PRE-to-POST ( P  < 0.001), with no difference between groups. Wingate peak power relative to body mass displayed a trend ( P  = 0.053) to be greater in RES (12.5 ± 1.6 W·kg BM −1 ) than both CET (10.8 ± 1.7 W·kg BM −1 ) and END (10.9 ± 1.8 W·kg BM −1 ) at POST. Absolute VO 2peak increased 6.9% in CET and 12% in END from PRE-to-POST ( P  < 0.05), with no difference between groups. Conclusion Despite high protein availability, select measures of anaerobic power-based adaptations, but not muscle strength or hypertrophy, appear susceptible to ‘interference effects’ with CET and should be closely monitored throughout training macro-cycles. T rials Registry : This trial was registered with the Australian-New Zealand Clinical Trials Registry (ACTRN12617001229369).

Inside living cells, proteins or mRNA can show oscillations even without a periodic driving force. Such genetic oscillations are precise timekeepers for cell-cycle regulations, pattern formation during embryonic development in higher animals, and daily cycle maintenance in most organisms. The synchronization between oscillations in adjacent cells happens via intercellular coupling, which is essential for periodic segmentation formation in vertebrates and other biological processes. While molecular mechanisms of generating sustained oscillations are quite well understood, how do simple intercellular coupling produces robust synchronizations are still poorly understood? To address this question, we investigate two models of coupled gene oscillators - activator-based coupled oscillators (ACO) and repressor-based coupled oscillators (RCO) models. In our study, a single autonomous oscillator (that operates in a single cell) is based on a negative feedback, which is delayed by intracellular dynamics of an intermediate species. For the ACO model (RCO), the repressor protein of one cell activates (represses) the production of another protein in the neighbouring cell after a intercellular time delay. We investigate the coupled models in the presence of intrinsic noise due to the inherent stochasticity of the biochemical reactions. We analyze the collective oscillations from stochastic trajectories in the presence and absence of explicit coupling delay and make careful comparison between two models. Our results show no clear synchronizations in the ACO model when the coupling time delay is zero. However, a non-zero coupling delay can lead to anti-phase synchronizations in ACO. Interestingly, the RCO model shows robust in-phase synchronizations in the presence and absence of the coupling time delay. Our results suggest that the naturally occurring intercellular couplings might be based on repression rather than activation where in-phase synchronization is crucial. Competing Interest Statement The authors have declared no competing interest.

Cellular memory is a ubiquitous function of biological systems. By generating a sustained response to a transient inductive stimulus, often due to bistability, memory is central to the robust control of many important biological functions. However, our understanding of the mechanistic basis of cellular memory remains incomplete. Specifically, stochastic fluctuations that are inherent to most biological systems have been shown to hamper memory function. Yet, how stochasticity changes the behavior of genetic circuits is generally not clear from a deterministic analysis of the network alone. Here, we apply deterministic, stochastic, and theoretical analyses to investigate how intrinsic noise affects the memory function in a mutual repression network. We find that the addition of negative autoregulation improves the persistence of memory by reducing stochastic fluctuations. Our theoretical analyses reveal that this improved memory function stems from an increased stability of the steady states of the system. Moreover, we show how the tuning of critical network parameters can further enhance memory. Our work highlights the power of stochastic and theoretical approaches to understanding biological circuits, and the importance of considering stochasticity to designing synthetic circuits with memory function. Footnotes * Revised introduction; reduction and consolidation of figures and results sections to better differentiate what is new and what was recalculated for comparison to a previously published paper.

THERE will be more pmgrammes of regional and local interest with a bias for rural and semi- urban audience on Doordarshan.

It's a Dog's life Attempts to clone dogs using the method that made Dolly have failed due to the difficulty of maturing canine oocytes in vitro . This obstacle was by-passed in an experiment that produced two Afghan hounds by nuclear transfer from adult fibroblasts into oocytes matured in vivo . Several mammals — including sheep, mice, cows, goats, pigs, rabbits, cats 1 , a mule 2 , a horse 3 and a litter of three rats 4 — have been cloned by transfer of a nucleus from a somatic cell into an egg cell (oocyte) that has had its nucleus removed. This technology has not so far been successful in dogs because of the difficulty of maturing canine oocytes in vitro . Here we describe the cloning of two Afghan hounds by nuclear transfer from adult skin cells into oocytes that had matured in vivo . Together with detailed sequence information generated by the canine-genome project 5 , 6 , the ability to clone dogs by somatic-cell nuclear transfer should help to determine genetic and environmental contributions to the diverse biological and behavioural traits associated with the many different canine breeds 7 , 8 .