Maize mutants and variants altering developmental time and their heterochronic interactions.

It is useful to envision two fundamentally different ways by which the timing of plant development is regulated: developmental stage-transition mechanisms and time-to-flowering mechanisms. The existence of both mechanisms is indicated by the behavior of various mutants. Shoot stage transitions are defined by dominant mutants representing at least four different genes; each mutant retards transitions from juvenile shoot stages to more adult shoot stages. In addition, dominant leaf stage-transition mutants in at least seven different genes have similar phenotypes, but the leaf rather than the shoot is the focus (and at least two of these genes encode homeodomain proteins.) One mutant, Hairy sheath frayed 1-O (Hsf1-O) simultaneously affects shoot and leaf; this mutant's behavior initiated our interest in plant heterochronism. The second type of timekeeping involves time-to-flowering. As with most plant but not animal species, cultivars of the maize species vary greatly for the time-to-flowering quantitative trait: between 6 and 14 weeks is common. It is via the 'slipping time frames' interaction that takes place between stage-transition mutants and time-to-flowering genetic backgrounds that unexpected and radical phenotypes occur. We see a reservoir of previously unsuspected morphological possibilities among the few heterochronic genotypes we have constructed, possibilities that may mimic the sort of variation needed to fuel macroevolution without having to posit (as done by Goldschmidt) any special macromutational mechanisms.     

Geographic variation in timekeeping systems among three populations of garter snakes (Thamnophis sirtalis) in a common garden

Transduction of environmental cues into endocrine signals that synchronize physiology and behavior with optimal environmental conditions is central to an animal's timekeeping system. Using a common garden approach, we investigated possible geographic variation in timekeeping systems by comparing 24-h melatonin and corticosterone rhythms and reproductive behavior among three populations of garter snakes with very different life histories: red-sided garter snakes (Thamnophis sirtalis parietalis) from Manitoba, Canada; red-spotted garter snakes (Thamnophis sirtalis concinnus) from western Oregon; and eastern garter snakes (Thamnophis sirtalis sirtalis) from southern Florida. Melatonin and corticosterone cycles differed significantly among the three snake populations in a majority of the sampling periods. Population differences were observed across a wide range of acclimatization conditions and were themselves plastic (i.e., one snake population was not consistently different from the others). Changes in courtship behavior during emergence also varied significantly among populations. Our data support the hypothesis that endogenous timekeeping systems have evolved in the presence of unique environmental conditions. Further research is necessary to determine whether this geographic variation results from inherent genetic differences or whether it is a product of development. These studies provide insight into the evolution of timekeeping systems and may aid in understanding the potential effects of environmental perturbations on seasonal physiology and behavior.     

Seasonal molecular timekeeping within the rat circadian clock

In temperate zones duration of daylight, i.e. photoperiod, changes with the seasons. The changing photoperiod affects animal as well as human physiology. All mammals exhibit circadian rhythms and a circadian clock controlling the rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of two parts differing morphologically and functionally, namely of the ventrolateral (VL) and the dorsomedial (DM). Many aspects of SCN-driven rhythmicity are affected by the photoperiod. The aim of the present overview is to summarize data about the effect of the photoperiod on the molecular timekeeping mechanism in the rat SCN, especially the effect on core clock genes, clock-controlled genes and clock-related genes expression. The summarized data indicate that the photoperiod affects i) clock-driven rhythm in photoinduction of c-fos gene and its protein product within the VL SCN, ii) clock-driven spontaneous rhythms in clock-controlled, i.e. arginine-vasopressin, and in clock-related, i.e. c-fos, gene expression within the DM SCN, and iii) the core clockwork mechanism within the rat SCN. Hence, the whole central timekeeping mechanism within the rat circadian clock measures not only the daytime but also the time of the year, i.e. the actual season.     

Integrative top-down system metabolic modeling in experimental disease states via data-driven Bayesian methods

Multivariate metabolic profiles from biofluids such as urine and plasma are highly indicative of the biological fitness of complex organisms and can be captured analytically in order to derive top-down systems biology models. The application of currently available modeling approaches to human and animal metabolic pathway modeling is problematic because of multicompartmental cellular and tissue exchange of metabolites operating on many time scales. Hence, novel approaches are needed to analyze metabolic data obtained using minimally invasive sampling methods in order to reconstruct the patho-physiological modulations of metabolic interactions that are representative of whole system dynamics. Here, we show that spectroscopically derived metabolic data in experimental liver injury studies (induced by hydrazine and alpha-napthylisothiocyanate treatment) can be used to derive insightful probabilistic graphical models of metabolite dependencies, which we refer to as metabolic interactome maps. Using these, system level mechanistic information on homeostasis can be inferred, and the degree of reversibility of induced lesions can be related to variations in the metabolic network patterns. This approach has wider application in assessment of system level dysfunction in animal or human studies from noninvasive measurements.     

Encoding le quattro stagioni within the mammalian brain: photoperiodic orchestration through the suprachiasmatic nucleus

Within the suprachiasmatic nucleus (SCN) is a pacemaker that not only drives circadian rhythmicity but also directs the circadian organization of photoperiodic (seasonal) timekeeping. Recent evidence using electrophysiological, molecular, and genetic tools now strongly supports this conclusion. Important questions remain regarding the SCN's precise role(s) in the brain's photoperiodic circuits, especially among different species, and the cellular and molecular mechanisms for its photoperiodic "memory." New data suggesting that SCN "clock" genes may also function as "calendar" genes are a first step toward understanding how a photoperiodic clock is built from cycling molecules.     

A behavioral study of healthy and cancer genes by modeling electrical network

In recent years, gene network modeling is gaining popularity in genomics to monitor the activity profile of genes. More specifically, the objective of the network modeling concept is to study the genetic behavior associated with disease. Previous researchers have designed network model at nucleotide level which produces more complexity for designing circuits mostly in case of gene expression studies. Whereas the authors have designed the present network model, based on amino acid level which is simpler as well as more appropriate for prediction of the genetic abnormality. In the present concept, SISO continuous and discrete system models of genes are realized using Foster network. The model is designed based on hydropathy index value of amino acids to study the biological system behavior. The time and phase response in continuous (s) domain and pole-zero distribution in discrete (z) domain are used as measurement metric in the present study. The simulated responses of the system show genetic instability for cancer genes which truly reflects the medical reports. The proposed modeling concept can be used, to accurately identify or separate out the diseased genes from healthy genes.     

Dynamical properties of model gene networks and implications for the inverse problem

We study the inverse problem, or the "reverse-engineering" problem, for two abstract models of gene expression dynamics, discrete-time Boolean networks and continuous-time switching networks. Formally, the inverse problem is similar for both types of networks. For each gene, its regulators and its Boolean dynamics function must be identified. However, differences in the dynamical properties of these two types of networks affect the amount of data that is necessary for solving the inverse problem. We derive estimates for the average amounts of time series data required to solve the inverse problem for randomly generated Boolean and continuous-time switching networks. We also derive a lower bound on the amount of data needed that holds for both types of networks. We find that the amount of data required is logarithmic in the number of genes for Boolean networks, matching the general lower bound and previous theory, but are superlinear in the number of genes for continuous-time switching networks. We also find that the amount of data needed scales as 2(K), where K is the number of regulators per gene, rather than 2(2K), as previous theory suggests.     

Intracellular and intercellular processes determine robustness of the circadian clock

Circadian clocks are present in most organisms and provide an adaptive mechanism to coordinate physiology and behavior with predictable changes in the environment. Genetic, biochemical, and cellular experiments have identified more than a dozen component genes and a signal transduction pathway that support cell-autonomous, circadian clock function. One of the hallmarks of biological clocks is their ability to reset to relevant stimuli while ignoring most others. We review recent results showing intracellular and intercellular mechanisms that convey this robust timekeeping to a variety of circadian cell types.     

The central circadian clock proteins CCA_1 and LHY regulate iron homeostasis in Arabidopsis

Circadian clock is the endogenous timekeeping machinery that synchronizes an organism's metabolism, behavior, and physiology to the daily lightdark circles, thereby contributing to organismal fitness.Iron(Fe) is an essential micronutrient for all organisms and it plays important roles in diverse processes of plant growth and development. Here, we show that, in Arabidopsis thaliana, loss of the central clock genes,CIRCADIAN CLOCK ASSOCIATED 1(CCA_1) and LATE ELONGATED HYPOCOTYL(LHY), results in both reduced Fe uptake and photosynthetic efficiency, whereas CCA_1 overexpression confers the opposite effects. We show that root Fe(III) reduction activity, and expression of FERRIC REDUCTION OXIDASE 2(FRO_2) and IRON-REGULATED TRANSPORTER 1(IRT_1) exhibit circadian oscillations, which are disrupted in the cca_1 lhy double mutant. Furthermore,CCA_1 directly binds to the specific regulatory regions of multiple Fe homeostasis genes and activates their expression. Thus, this study established that, in plants,CCA_1 and LHY function as master regulators that maintain cyclic Fe homeostasis.     

Maternal control of pattern formation in Xenopus laevis

We review the essential role of maternal factors in pattern formation for Xenopus laevis, focusing on VegT, Vg1, and Wnt11. Results from loss of function experiments demonstrate a clear requirement for these genes in germ layer specification, dorsal-ventral axis formation, and convergence extension. We also discuss these genes in the broader context of metazoan development, exploring whether and how their functions in the X. laevis model organism may or may not be conserved in other species. Wnt11 signaling in particular provides a classic example where understanding context in development is crucial to understanding function. Genomic sequencing, gene expression, and functional screening data that are becoming available in more species are providing invaluable aid to decoding and modeling signaling pathways. More work is needed to develop a comprehensive catalog of the Wnt signaling, T-box, and TGF-beta genes in metazoans both near and far in evolutionary distance. We finally discuss some specific experimental and modeling efforts that will be needed to understand the behavior of these signaling networks in vivo so that we can interpret these critical pathways in an evolutionary framework.     

Mammalian circadian signaling networks and therapeutic targets

Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is a key feature of the circadian clock system. In particular, intercellular coupling in the SCN synchronizes neuron oscillators and confers robustness against perturbations. Recent advances in our knowledge of and ability to manipulate circadian rhythms make available cell-based clock models, which lack strong coupling and are ideal for target discovery and chemical biology.     

Synchronization of the mammalian circadian timing system: Light can control peripheral clocks independently of the SCN clock

A vast network of cellular circadian clocks regulates 24‐hour rhythms of behavior and physiology in mammals. Complex environments are characterized by multiple, and often conflicting time signals demanding flexible mechanisms of adaptation of endogenous rhythms to external time. Traditionally this process of circadian entrainment has been conceptualized in a hierarchical scheme with a light‐reset master pacemaker residing in the hypothalamus that subsequently aligns subordinate peripheral clocks with each other and with external time. Here we review new experiments using conditional mouse genetics suggesting that resetting of the circadian system occurs in a more “federated” and tissue‐specific fashion, which allows for increased noise resistance and plasticity of circadian timekeeping under natural conditions.     

Emergent cell and tissue dynamics from subcellular modeling of active biomechanical processes

Cells and the tissues they form are not passive material bodies. Cells change their behavior in response to external biochemical and biomechanical cues. Behavioral changes, such as morphological deformation, proliferation and migration, are striking in many multicellular processes such as morphogenesis, wound healing and cancer progression. Cell-based modeling of these phenomena requires algorithms that can capture active cell behavior and their emergent tissue-level phenotypes. In this paper, we report on extensions of the subcellular element model to model active biomechanical subcellular processes. These processes lead to emergent cell and tissue level phenotypes at larger scales, including (i) adaptive shape deformations in cells responding to slow stretching, (ii) viscous flow of embryonic tissues, and (iii) streaming patterns of chemotactic cells in epithelial-like sheets. In each case, we connect our simulation results to recent experiments.     

Multiscale simulations of heterogeneous model membranes

This review will focus on computer modeling aimed at providing insights into the existence, structure, size, and thermodynamic stability of localized domains in membranes of heterogeneous composition. Modeling the lateral organization within a membrane is problematic due to the relatively slow lateral diffusion rate for lipid molecules so that microsecond or longer time scales are needed to fully model the formation and stability of a raft in a membrane. Although atomistic simulations currently are not able to reach this scale, they can provide data on the intermolecular forces and correlations that are involved in lateral organization. These data can be used to define coarse grained models that are capable of predictions of lateral organization in membranes. In this paper, we review modeling efforts that use interaction data from MD simulations to construct coarse grained models for heterogeneous bilayers. In this review we will discuss MD simulations done with the aim of gaining the information needed to build accurate coarse-grained models. We will then review some of the coarse-graining work, emphasizing modeling that has resulted from or has a basis in atomistic simulations.     

Multiscale simulations of heterogeneous model membranes

This review will focus on computer modeling aimed at providing insights into the existence, structure, size, and thermodynamic stability of localized domains in membranes of heterogeneous composition. Modeling the lateral organization within a membrane is problematic due to the relatively slow lateral diffusion rate for lipid molecules so that microsecond or longer time scales are needed to fully model the formation and stability of a raft in a membrane. Although atomistic simulations currently are not able to reach this scale, they can provide data on the intermolecular forces and correlations that are involved in lateral organization. These data can be used to define coarse grained models that are capable of predictions of lateral organization in membranes. In this paper, we review modeling efforts that use interaction data from MD simulations to construct coarse grained models for heterogeneous bilayers. In this review we will discuss MD simulations done with the aim of gaining the information needed to build accurate coarse-grained models. We will then review some of the coarse-graining work, emphasizing modeling that has resulted from or has a basis in atomistic simulations.