Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Hybrid stochastic simulations of intracellular reaction-diffusion systems.

With the observation that stochasticity is important in biological systems, chemical kinetics have begun to receive wider interest. While the use of Monte Carlo discrete event simulations most accurately capture the variability of molecular species, they become computationally costly for complex reaction-diffusion systems with large populations of molecules. On the other hand, continuous time models are computationally efficient but they fail to capture any variability in the molecular species. In this study a hybrid stochastic approach is introduced for simulating reaction-diffusion systems. We developed an adaptive partitioning strategy in which processes with high frequency are simulated with deterministic rate-based equations, and those with low frequency using the exact stochastic algorithm of Gillespie. Therefore the stochastic behavior of cellular pathways is preserved while being able to apply it to large populations of molecules. We describe our method and demonstrate its accuracy and efficiency compared with the Gillespie algorithm for two different systems. First, a model of intracellular viral kinetics with two steady states and second, a compartmental model of the postsynaptic spine head for studying the dynamics of Ca+2 and NMDA receptors.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Neutral biodiversity theory can explain the imbalance of phylogenetic trees but not the tempo of their diversification

Numerous evolutionary studies have sought to explain the distribution of diversity across the limbs of the tree of life. At the same time, ecological studies have sought to explain differences in diversity and relative abundance within and among ecological communities. Traditionally, these patterns have been considered separately, but models that consider processes operating at the level of individuals, such as neutral biodiversity theory (NBT), can provide a link between them. Here, we compare evolutionary dynamics across a suite of NBT models. We show that NBT can yield phylogenetic tree topologies with imbalance closely resembling empirical observations. In general, metacommunities that exhibit greater disparity in abundance are characterized by more imbalanced phylogenetic trees. However, NBT fails to capture the tempo of diversification as represented by the distribution of branching events through time. We suggest that population-level processes might therefore help explain the asymmetry of phylogenetic trees, but that tree shape might mislead estimates of evolutionary rates unless the diversification process is modeled explicitly.

Eco-evolutionary Dynamics of Individual-Based Food Webs

The past decade has seen the rise of high resolution datasets. One of the main surprises of analysing such data has been the discovery of a large genetic, phenotypic and behavioural variation and heterogeneous metabolic rates among individuals within natural populations. A parallel discovery from theory and experiments has shown a strong temporal convergence between evolutionary and ecological dynamics, but a general framework to analyse from individual-level processes the convergence between ecological and evolutionary dynamics and its implications for patterns of biodiversity in food webs has been particularly lacking. Here, as a first approximation to take into account intraspecific variability and the convergence between the ecological and evolutionary dynamics in large food webs, we develop a model from population genomics and microevolutionary processes that uses sexual reproduction, genetic-distance-based speciation and trophic interactions. We confront the model with the prey consumption per individual predator, species-level connectance and prey–predator diversity in several environmental situations using a large food web with approximately 25,000 sampled prey and predator individuals. We show higher than expected diversity of abundant species in heterogeneous environmental conditions and strong deviations from the observed distribution of individual prey consumption (i.e. individual connectivity per predator) in all the environmental conditions. The observed large variance in individual prey consumption regardless of the environmental variability collapsed species-level connectance after small increases in sampling effort. These results suggest (1) intraspecific variance in prey–predator interactions has a strong effect on the macroscopic properties of food webs and (2) intraspecific variance is a potential driver regulating the speed of the convergence between ecological and evolutionary dynamics in species-rich food webs. These results also suggest that genetic–ecological drift driven by sexual reproduction, equal feeding rate among predator individuals, mutations and genetic-distance-based speciation can be used as a neutral food web dynamics test to detect the ecological and microevolutionary processes underlying the observed patterns of individual and species-based food webs at local and macroecological scales.

Ice Dynamics Preceding Catastrophic Disintegration of the Floating Part of Jakobshavn Isbrie, Greenland

The floating terminal of Jakobshavn Isbr ae, the fastest Greenland ice stream, has disintegrated since 2002, resulting in a doubling of ice velocity and rapidly lowering inland ice elevations. Conditions prior to disintegration were modeled using control theory in a plane-stress solution, and the Missoula model of ice-shelf flow. Both approaches pointed to a mechanism that inhibits ice flow and that is not captured by either approach. Jamming of flow, an inherent property of granular materials passing through a constriction (Jakobshavn Isfjord), is postulated as the mechanism. Rapid disintegration of heavily crevassed floating ice accompanies break-up of the ice jam.

A Normative Theory of Forgetting: Lessons from the Fruit Fly

Recent experiments revealed that the fruit fly Drosophila melanogaster has a dedicated mechanism for forgetting: blocking the G-protein Rac leads to slower and activating Rac to faster forgetting. This active form of forgetting lacks a satisfactory functional explanation. We investigated optimal decision making for an agent adapting to a stochastic environment where a stimulus may switch between being indicative of reward or punishment. Like Drosophila, an optimal agent shows forgetting with a rate that is linked to the time scale of changes in the environment. Moreover, to reduce the odds of missing future reward, an optimal agent may trade the risk of immediate pain for information gain and thus forget faster after aversive conditioning. A simple neuronal network reproduces these features. Our theory shows that forgetting in Drosophila appears as an optimal adaptive behavior in a changing environment. This is in line with the view that forgetting is adaptive rather than a consequence of limitations of the memory system.

Dynamics of governance and control in inter-organizational software development

In recent years, development of information systems (IS) has rapidly changed towards increasing division of labor between firms. Two trends are emerging. First, client companies increasingly outsource software development to external service providers. Second, the formerly oligopolistic enterprise application software industry has started to disintegrate into focal partnership networks – so called platform ecosystems. Despite the increasing prominence of IS outsourcing and platform ecosystems, many of these inter-organizational partnerships fail to achieve expected benefits. Ineffective governance and control frequently plays a pivotal role in producing these failures. While designing effective governance and control mechanisms is always challenging, inter-organizational software development projects are often business-critical and exhibit additional dynamics and uncertainty. As a consequence governance and control have to be adapted over time. The three research projects included in this book provide a better understanding of how and why governance and control can be effectively adapted over time. The implications for successful management of inter-organizational software development projects are highly relevant for theory and practice.

Atmospheric Dynamics of Hot Exoplanets

The characterization of exoplanetary atmospheres has come of age in the last decade, as astronomical techniques now allow for albedos, chemical abundances, temperature profiles and maps, rotation periods and even wind speeds to be measured. Atmospheric dynamics sets the background state of density, temperature and velocity that determines or influences the spectral and temporal appearance of an exoplanetary atmosphere. Hot exoplanets are most amenable to these characterization techniques; in the present review, we focus on highly-irradiated, large exoplanets (the "hot Jupiters"), as astronomical data begin to confront theoretical questions. We summarize the basic atmospheric quantities inferred from the astronomical observations. We review the state of the art by addressing a series of current questions and look towards the future by considering a separate set of exploratory questions. Attaining the next level of understanding will require a concerted effort of constructing multi-faceted, multi-wavelength datasets for benchmark objects. Understanding clouds presents a formidable obstacle, as they introduce degeneracies into the interpretation of spectra, yet their properties and existence are directly influenced by atmospheric dynamics. Confronting general circulation models with these multi-faceted, multi-wavelength datasets will help us understand these and other degeneracies. The coming decade will witness a decisive confrontation of theory and simulation by the next generation of astronomical data.

Constraints on the effective fluid theory of stationary branes

We develop further the effective fluid theory of stationary branes. This formalism applies to stationary blackfolds as well as to other equilibrium brane systems at finite temperature. The effective theory is described by a Lagrangian containing the information about the elastic dynamics of the brane embedding as well as the hydrodynamics of the effective fluid living on the brane. The Lagrangian is corrected order-by-order in a derivative expansion, where we take into account the dipole moment of the brane which encompasses finite-thickness corrections, including transverse spin. We describe how to extract the thermodynamics from the Lagrangian and we obtain constraints on the higher-derivative terms with one and two derivatives. These constraints follow by comparing the brane thermodynamics with the conserved currents associated with background Killing vector fields. In particular, we fix uniquely the one- and two-derivative terms describing the coupling of the transverse spin to the background space-time. Finally, we apply our formalism to two blackfold examples, the black tori and charged black rings and compare the latter to a numerically generated solution.

Review of lattice results concerning low-energy particle physics

We review lattice results related to pion, kaon, D- and B-meson physics with the aim of making them easily accessible to the particle-physics community. More specifically, we report on the determination of the lightquark masses, the form factor f+(0), arising in semileptonic K → π transition at zero momentum transfer, as well as the decay-constant ratio fK / fπ of decay constants and its consequences for the CKM matrix elements Vus and Vud. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of SU(2)L × SU(2)R and SU(3)L×SU(3)R Chiral Perturbation Theory and review the determination of the BK parameter of neutral kaon mixing. The inclusion of heavy-quark quantities significantly expands the FLAG scope with respect to the previous review. Therefore, we focus here on D- and B-meson decay constants, form factors, and mixing parameters, since these are most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. In addition we review the status of lattice determinations of the strong coupling constant αs.

Laser ablation and induced nano-particle synthesis

Laser pulses are largely used for processing and analysis of materials and in particular for nano-particle synthesis. This paper addresses fundamentals of the generation of nano-materials following specific thermodynamic paths of the irradiated material. Computer simulations using the hydro code MULTI and the SESAME equation of state have been performed to follow the dynamics of a target initially heated by a short laser pulse over a distance comparable to the metal skin depth.

Of mice, macaques and men: scaling of virus dynamics and immune responses

In this Opinion piece, I argue that the dynamics of viruses and the cellular immune response depend on the body size of the host. I use allometric scaling theory to interpret observed quantitative differences in the infection dynamics of lymphocytic choriomeningitis virus (LCMV) in mice (Mus musculus), simian immunodeficiency virus (SIV) in rhesus macaques (Macaca mulatta) and human immunodeficiency virus (HIV) in humans.

Range-based Weighted-likelihood Particle Filter for RSS-based Indoor Tracking

Attractive business cases in various application fields contribute to the sustained long-term interest in indoor localization and tracking by the research community. Location tracking is generally treated as a dynamic state estimation problem, consisting of two steps: (i) location estimation through measurement, and (ii) location prediction. For the estimation step, one of the most efficient and low-cost solutions is Received Signal Strength (RSS)-based ranging. However, various challenges - unrealistic propagation model, non-line of sight (NLOS), and multipath propagation - are yet to be addressed. Particle filters are a popular choice for dealing with the inherent non-linearities in both location measurements and motion dynamics. While such filters have been successfully applied to accurate, time-based ranging measurements, dealing with the more error-prone RSS based ranging is still challenging. In this work, we address the above issues with a novel, weighted likelihood, bootstrap particle filter for tracking via RSS-based ranging. Our filter weights the individual likelihoods from different anchor nodes exponentially, according to the ranging estimation. We also employ an improved propagation model for more accurate RSS-based ranging, which we suggested in recent work. We implemented and tested our algorithm in a passive localization system with IEEE 802.15.4 signals, showing that our proposed solution largely outperforms a traditional bootstrap particle filter.

Details of left ventricular radial wall motion supporting the ventricular theory of the third heart sound obtained by cardiac MR.

OBJECTIVE Obtaining new details of radial motion of left ventricular (LV) segments using velocity-encoding cardiac MRI. METHODS Cardiac MR examinations were performed on 14 healthy volunteers aged between 19 and 26 years. Cine images for navigator-gated phase contrast velocity mapping were acquired using a black blood segmented κ-space spoiled gradient echo sequence with a temporal resolution of 13.8 ms. Peak systolic and diastolic radial velocities as well as radial velocity curves were obtained for 16 ventricular segments. RESULTS Significant differences among peak radial velocities of basal and mid-ventricular segments have been recorded. Particular patterns of segmental radial velocity curves were also noted. An additional wave of outward radial movement during the phase of rapid ventricular filling, corresponding to the expected timing of the third heart sound, appeared of particular interest. CONCLUSION The technique has allowed visualization of new details of LV radial wall motion. In particular, higher peak systolic radial velocities of anterior and inferior segments are suggestive of a relatively higher dynamics of anteroposterior vs lateral radial motion in systole. Specific patterns of radial motion of other LV segments may provide additional insights into LV mechanics. ADVANCES IN KNOWLEDGE The outward radial movement of LV segments impacted by the blood flow during rapid ventricular filling provides a potential substrate for the third heart sound. A biphasic radial expansion of the basal anteroseptal segment in early diastole is likely to be related to the simultaneous longitudinal LV displacement by the stretched great vessels following repolarization and their close apposition to this segment.