Toward a classification of isodynamic feed-forward motifs

A preceding study analysed how the topology of network motifs affects the overall rate of the underlying biochemical processes. Surprisingly, it was shown that topologically non-isomorphic motifs can still be isodynamic in the sense that they exhibit the exact same performance rate. Because of the high prevalence of feed-forward functional modules in biological networks, one may hypothesize that evolution tends to favour motifs with faster dynamics. As a step towards ranking the efficiency of feed-forward network motifs, we use a linear flow model to prove theorems establishing that certain classes of motifs are isodynamic. In partitioning the class of all motifs on n nodes into equivalence classes based upon their dynamics, we establish a basis for comparing the efficiency/performance rates of different motifs. The potential biological importance of the theorems is briefly discussed and is the subject of an ongoing large-scale project.     

Toward a classification of isodynamic feed-forward motifs

A preceding study analysed how the topology of network motifs affects the overall rate of the underlying biochemical processes. Surprisingly, it was shown that topologically non-isomorphic motifs can still be isodynamic in the sense that they exhibit the exact same performance rate. Because of the high prevalence of feed-forward functional modules in biological networks, one may hypothesize that evolution tends to favour motifs with faster dynamics. As a step towards ranking the efficiency of feed-forward network motifs, we use a linear flow model to prove theorems establishing that certain classes of motifs are isodynamic. In partitioning the class of all motifs on n nodes into equivalence classes based upon their dynamics, we establish a basis for comparing the efficiency/performance rates of different motifs. The potential biological importance of the theorems is briefly discussed and is the subject of an ongoing large-scale project.     

Regulation of apoptotic c-Jun N-terminal kinase signaling by a stabilization-based feed-forward loop

A sequential kinase cascade culminating in activation of c-Jun N-terminal kinases (JNKs) plays a fundamental role in promoting apoptotic death in many cellular contexts. The mechanisms by which this pathway is engaged in response to apoptotic stimuli and suppressed in viable cells are largely unknown. Here, we show that apoptotic stimuli increase endogenous cellular levels of pathway components, including POSH, mixed lineage kinases (MLKs), and JNK interacting protein 1, and that this effect occurs through protein stabilization and requires the presence of POSH as well as activation of MLKs and JNKs. Our findings suggest a self-amplifying, feed-forward loop mechanism by which apoptotic stimuli promote the stabilization of JNK pathway components, thereby contributing to cell death.     

Environmental selection of the feed-forward loop circuit in gene-regulation networks

Gene-regulation networks contain recurring elementary circuits termed network motifs. It is of interest to understand under which environmental conditions each motif might be selected. To address this, we study one of the most significant network motifs, a three-gene circuit called the coherent feed-forward loop (FFL). The FFL has been demonstrated theoretically and experimentally to perform a basic information-processing function: it shows a delay following ON steps of an input inducer, but not after OFF steps. Here, we ask under what environmental conditions might the FFL be selected over simpler gene circuits, based on this function. We employ a theoretical cost-benefit analysis for the selection of gene circuits in a given environment. We find conditions that the environment must satisfy in order for the FFL to be selected over simpler circuits: the FFL is selected in environments where the distribution of the input pulse duration is sufficiently broad and contains both long and short pulses. Optimal values of the biochemical parameters of the FFL circuit are determined as a function of the environment such that the delay in the FFL blocks deleterious short pulses of induction. This approach can be generally used to study the evolutionary selection of other network motifs.     

Transcriptional regulation of post-aggregation genes in Dictyostelium by a feed-forward loop involving GBF and LagC

Expression profiles of developmental genes in Dictyostelium were determined on microarrays during development of wild type cells and mutant cells lacking either the DNA binding protein GBF or the signaling protein LagC. We found that the mutant strains developed in suspension with added cAMP expressed the pulse-induced and early adenylyl cyclase (ACA)-dependent genes, but not the later ACA-dependent, post-aggregation genes. Since expression of lagC itself is dependent on GBF, expression of the post-aggregation genes might be controlled only by signaling from LagC. However, expression of lagC in a GBF-independent manner in a gbfA- null strain did not result in expression of the post-aggregation genes. Since GBF is necessary for accumulation of LagC and both the DNA binding protein and the LagC signal transduction pathway are necessary for expression of post-aggregation genes, GBF and LagC form a feed-forward loop. Such network architecture is a common motif in diverse organisms and can act as a filter for noisy inputs. Breaking the feed-forward loop by expressing lagC in a GBF-independent manner in a gbfA+ strain does not significantly affect the patterns of gene expression for cells developed in suspension with added cAMP, but results in a significant delay at the mound stage and asynchronous development on solid supports. This feed-forward loop can integrate temporal information with morphological signals to ensure that post-aggregation genes are only expressed after cell contacts have been made.     

Coordination of gene expression with growth rate: A feedback or a feed-forward strategy?

In the budding yeast, a large fraction of genes is coordinately regulated with growth rate. We argue that this correlation does not reflect a direct feedback from growth rate to gene expression. Rather, what appears to be a response to growth rate is dominated by environmental sensing. External parameters, such as nutrition or temperature, feed-forward to define gene expression pattern that is tuned to the evolutionary-predicted growth rate. While such a feed-forward strategy requires fine-tuning of signaling mechanisms, and is limited in the range of environments that can be monitored, it enables advanced preparation to physiological changes that predictably occur following environmental switching. The capacity to anticipate and prepare for changing conditions was probably a major selection force during yeast evolution.     

抑制还是转导:信号分子调节机体健康与疾病

细胞内的信号转导网络是由多条功能特异且彼此关联的信号通路所构成,它们赋予了细胞功能的多样性和可塑性,同时也必须受到精细严谨的调控。一些功能广泛的信号调节因子,如β-抑制蛋白(β-arrestin),在细胞信号转导网络完整性的维持中扮演着重要的角色。β-arrestin分子的经典功能是终止G-蛋白偶联受体(G-protein-coupled receptors)下游信号转导,即受体脱敏,但最近许多研究证据表明,这种脱敏功能(负调控)还可以针对其他的信号转导途径。例如,β-arrestin能够通过不同的机制负调控三条重要的NF-κB激活通路,该功能异常则导致NF-κB持续激活以及下游炎性因子的过度分泌。此外,近年来发现β-arrestin还能作为支架蛋白介导功能性信号复合物的形成。例如,在特定外界信号刺激下,β-arrestin1能够转移至细胞核内并与组蛋白乙酰化酶p300相互作用而调控基因表达。该机制的生理意义之一反映在多发性硬化症的小鼠模型中,β-arrestin1在发病小鼠中较正常小鼠表达上调并能够显著加重病情。与之相反,在细胞质中富集的β-arrestin2参与了胰岛素激活时InsR/Akt/β-arrestin2/Src信号复合体的形成,它的缺失能够导致胰岛素耐受和2型糖尿病的发生。因此,在特定的条件下,β-arrestin对于胞内信号的传递究竟是抑制还是激活,已成为细胞信号转导中的关键问题,并在机体健康和疾病状态的相互转化中的起着重要作用。     

The learning process in biofeedback: is it feed-forward or feedback?

Twenty participants responded to inquiries about strategies used, and thoughts during, each of three electromyograph biofeedback sessions. The purpose of the study was to learn more about what individuals report doing during biofeedback and, specifically, to determine if individuals construct a response using feedback to sense subtle differences in muscle tension (feedback processes), or select a response from an existing repertoire using feedback primarily for confirmation (feed-forward processes). Protocol analyses found considerable support for feed-forward processes and little support for feedback processes. Such results are important because early reliance on feed-forward processes may result in limited control and limited transfer.     

The learning process in biofeedback: Is it feed-forward or feedback?

Twenty participants responded to inquiries about strategies used, and thoughts during, each of three electromyograph biofeedback sessions. The purpose of the study was to learn more about what individuals report doing during biofeedback and, specifically, to determine if individuals construct a response using feedback to sense subtle differences in muscle tension (feedback processes), or select a response from an existing repertoire using feedback primarily for confirmation (feed-forward processes). Protocol analyses found considerable support for feed-forward processes and little support for feedback processes. Such results are important because early reliance on feedforward processes may result in limited control and limited transfer.