Ultrasensitivity in (supra)molecularly organized and crowded environments

The ultrasensitive response of biological systems is a more sensitive one than that expected from the classical hyperbola of Michaelis-Menten kinetics, and whose physiological relevance depends upon the range of variation of substrate or effector for which ultrasensitivity is observed. Triggering and modulation of the ultrasensitive response in enzymatic and cellular systems are reviewed. Several demonstrations of ultrasensitive behavior in cellular systems and its impact on the amplification properties in signalling cascades and metabolic pathways are also highlighted. It is shown that ubiquitous cytoskeletal proteins may up- or downmodulate ultrasensitivity under physico-chemical conditions resembling those predominant in cells.     

Sensitivity analysis of metabolic cascades catalyzed by bifunctional enzymes

Covalent modification/demodification cycles are common in metabolism. When the modification and demodification steps are carried out by two independent enzymes, the degree of modification can be ultrasensitive to the total concentration of either catalyst. We recently showed that the degree of modification of a target molecule cannot exhibit ultrasensitivity to the free concentrations of effectors that decide whether a bifunctional enzyme acts as modifier or demodifier. However, here we can now demonstrate that the degree of modification of a target molecule can display ultrasensitivity to the total, rather than free, concentrations of such effectors. Our results clarify some general aspects of ultrasensitive responses to effectors, including competitive inhibitors, in mono-cyclic cascades.     

Switching On Depression and Potentiation in the Cerebellum

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Ultrasensitive response motifs: basic amplifiers in molecular signalling networks

Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm.     

降钙素原和超敏C-反应蛋白在病毒和细菌感染早期鉴别中的临床应用

为探讨降钙素原(PCT)和超敏C-反应蛋白(hs-CRP)在病毒感染和细菌感染患者鉴别诊断中的价值,对我院276例患者,包括病毒感染组(64例)、细菌感染组(164例)和非感染组(48例)进行降钙素原和超敏C-反应蛋白水平的检测,并对三组间的差异进行分析。结果显示,细菌感染组和病毒感染组PCT、hs-CRP水平显著性高于非感染组(p<0.05);细菌感染组PCT、hs-CRP水平显著性高于病毒感染组(p<0.05)。工作特征曲线及Logistic回归分析结果显示,PCT在鉴别诊断细菌感染和病毒感染的效果高于hs-CRP。研究结果表明,降钙素原、超敏C-反应蛋白可对病毒感染和细菌感染进行早期的鉴别诊断,而降钙素原的效果较好。     

Structural basis of the ultrasensitive calcium indicator GCaMP6

GCaMP is one of the most widely used calcium indicators in neuronal imaging and calcium cell biology.The newly developed GCaMP6 shows superior brightness and ultrasensitivity to calcium concentration change.In this study,we determined crystal structures of Ca2+-bound GCaMP6 monomer and dimer and presented detailed structural analyses in comparison with its parent version GCaMP5G.Our analyses reveal the structural basis for the outperformance of this newly developed Ca2+indicator.Three substitution mutations and the resulting changes of local structure and interaction explain the ultrasensitivity and increased fluorescence intensity common to all three versions of GCaMP6.Each particular substitution in the three GCaMP6 is also structurally consistent with their differential sensitivity and intensity,maximizing the potential of using GCaMP6 in solving diverse problems in neuronal research and calcium signaling.Our studies shall also be beneficial to further structure-guided optimization of GCaMP and facilitate the design of novel calcium indicators.