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Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations
(2012)
Background: Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states.
Results: Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states.
Conclusions: Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.
Using the eye-movement monitoring technique in two reading comprehension experiments, this study investigated the timing of constraints on wh-dependencies (so-called island constraints) in first- and second-language (L1 and L2) sentence processing. The results show that both L1 and L2 speakers of English are sensitive to extraction islands during processing, suggesting that memory storage limitations affect L1 and L2 comprehenders in essentially the same way. Furthermore, these results show that the timing of island effects in L1 compared to L2 sentence comprehension is affected differently by the type of cue (semantic fit versus filled gaps) signaling whether dependency formation is possible at a potential gap site. Even though L1 English speakers showed immediate sensitivity to filled gaps but not to lack of semantic fit, proficient German-speaking learners of English as a L2 showed the opposite sensitivity pattern. This indicates that initial wh-dependency formation in L2 processing is based on semantic feature matching rather than being structurally mediated as in L1 comprehension.
This article investigates the nature of preposition copying and preposition pruning structures in present-day English. We begin by illustrating the two phenomena and consider how they might be accounted for in syntactic terms, and go on to explore the possibility that preposition copying and pruning arise for processing reasons. We then report on two acceptability judgement experiments examining the extent to which native speakers of English are sensitive to these types of 'error' in language comprehension. Our results indicate that preposition copying creates redundancy rather than ungrammaticality, whereas preposition pruning creates processing problems for comprehenders that may render it unacceptable in timed (but not necessarily in untimed) judgement tasks. Our findings furthermore illustrate the usefulness of combining corpus studies and experimentally elicited data for gaining a clearer picture of usage and acceptability, and the potential benefits of examining syntactic phenomena from both a theoretical and a processing perspective.
Background
To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method′s potential value in the prediction of LN metastases.
Methods
Axillary LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups.
Results
In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex >3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex >3mm in B-mode and blue cortex in the elastogram, SP=99.3%).
Conclusions
Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.
Background/Purpose
Muscular reflex responses of the lower extremities to sudden gait disturbances are related to postural stability and injury risk. Chronic ankle instability (CAI) has shown to affect activities related to the distal leg muscles while walking. Its effects on proximal muscle activities of the leg, both for the injured- (IN) and uninjured-side (NON), remain unclear. Therefore, the aim was to compare the difference of the motor control strategy in ipsilateral and contralateral proximal joints while unperturbed walking and perturbed walking between individuals with CAI and matched controls.
Materials and methods
In a cross-sectional study, 13 participants with unilateral CAI and 13 controls (CON) walked on a split-belt treadmill with and without random left- and right-sided perturbations. EMG amplitudes of muscles at lower extremities were analyzed 200 ms after perturbations, 200 ms before, and 100 ms after (Post100) heel contact while walking. Onset latencies were analyzed at heel contacts and after perturbations. Statistical significance was set at alpha≤0.05 and 95% confidence intervals were applied to determine group differences. Cohen’s d effect sizes were calculated to evaluate the extent of differences.
Results
Participants with CAI showed increased EMG amplitudes for NON-rectus abdominus at Post100 and shorter latencies for IN-gluteus maximus after heel contact compared to CON (p<0.05). Overall, leg muscles (rectus femoris, biceps femoris, and gluteus medius) activated earlier and less bilaterally (d = 0.30–0.88) and trunk muscles (bilateral rectus abdominus and NON-erector spinae) activated earlier and more for the CAI group than CON group (d = 0.33–1.09).
Conclusion
Unilateral CAI alters the pattern of the motor control strategy around proximal joints bilaterally. Neuromuscular training for the muscles, which alters motor control strategy because of CAI, could be taken into consideration when planning rehabilitation for CAI.
This study provides a detailed analysis of the mid-Holocene to present-day precipitation change in the Asian monsoon region. We compare for the first time results of high resolution climate model simulations with a standardised set of mid-Holocene moisture reconstructions. Changes in the simulated summer monsoon characteristics (onset, withdrawal, length and associated rainfall) and the mechanisms causing the Holocene precipitation changes are investigated. According to the model, most parts of the Indian subcontinent received more precipitation (up to 5 mm/day) at mid-Holocene than at present-day. This is related to a stronger Indian summer monsoon accompanied by an intensified vertically integrated moisture flux convergence. The East Asian monsoon region exhibits local inhomogeneities in the simulated annual precipitation signal. The sign of this signal depends on the balance of decreased pre-monsoon and increased monsoon precipitation at mid-Holocene compared to present-day. Hence, rainfall changes in the East Asian monsoon domain are not solely associated with modifications in the summer monsoon circulation but also depend on changes in the mid-latitudinal westerly wind system that dominates the circulation during the pre-monsoon season. The proxy-based climate reconstructions confirm the regional dissimilarities in the annual precipitation signal and agree well with the model results. Our results highlight the importance of including the pre-monsoon season in climate studies of the Asian monsoon system and point out the complex response of this system to the Holocene insolation forcing. The comparison with a coarse climate model simulation reveals that this complex response can only be resolved in high resolution simulations.
Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.
The size of plant organs, such as leaves and flowers, is determined by an interaction of genotype and environmental influences. Organ growth occurs through the two successive processes of cell proliferation followed by cell expansion. A number of genes influencing either or both of these processes and thus contributing to the control of final organ size have been identified in the last decade. Although the overall picture of the genetic regulation of organ size remains fragmentary, two transcription factor/microRNA-based genetic pathways are emerging in the control of cell proliferation. However, despite this progress, fundamental questions remain unanswered, such as the problem of how the size of a growing organ could be monitored to determine the appropriate time for terminating growth. While genetic analysis will undoubtedly continue to advance our knowledge about size control in plants, a deeper understanding of this and other basic questions will require including advanced live-imaging and mathematical modeling, as impressively demonstrated by some recent examples. This should ultimately allow the comparison of the mechanisms underlying size control in plants and in animals to extract common principles and lineage-specific solutions.
All's well that ends well
(2012)
The transition from cell proliferation to cell expansion is critical for determining leaf size. Andriankaja et al. (2012) demonstrate that in leaves of dicotyledonous plants, a basal proliferation zone is maintained for several days before abruptly disappearing, and that chloroplast differentiation is required to trigger the onset of cell expansion.