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Background: Boolean networks capture switching behavior of many naturally occurring regulatory networks. For semi-quantitative modeling, interpolation between ON and OFF states is necessary. The high degree polynomial interpolation of Boolean genetic regulatory networks (GRNs) in cellular processes such as apoptosis or proliferation allows for the modeling of a wider range of node interactions than continuous activator-inhibitor models, but suffers from scaling problems for networks which contain nodes with more than ~10 inputs. Many GRNs from literature or new gene expression experiments exceed those limitations and a new approach was developed.
Results: (i) As a part of our new GRN simulation framework Jimena we introduce and setup Boolean-tree-based data structures; (ii) corresponding algorithms greatly expedite the calculation of the polynomial interpolation in almost all cases, thereby expanding the range of networks which can be simulated by this model in reasonable time. (iii) Stable states for discrete models are efficiently counted and identified using binary decision diagrams. As application example, we show how system states can now be sampled efficiently in small up to large scale hormone disease networks (Arabidopsis thaliana development and immunity, pathogen Pseudomonas syringae and modulation by cytokinins and plant hormones).
Conclusions: Jimena simulates currently available GRNs about 10-100 times faster than the previous implementation of the polynomial interpolation model and even greater gains are achieved for large scale-free networks. This speed-up also facilitates a much more thorough sampling of continuous state spaces which may lead to the identification of new stable states. Mutants of large networks can be constructed and analyzed very quickly enabling new insights into network robustness and behavior.
Control of genetic regulatory networks is challenging to define and quantify. Previous control centrality metrics, which aim to capture the ability of individual nodes to control the system, have been found to suffer from plausibility and applicability problems. Here we present a new approach to control centrality based on network convergence behaviour, implemented as an extension of our genetic regulatory network simulation framework Jimena (http://stefan-karl.de/jimena). We distinguish three types of network control, and show how these mathematical concepts correspond to experimentally verified node functions and signalling pathways in immunity and cell differentiation: Total control centrality quantifies the impact of node mutations and identifies potential pharmacological targets such as genes involved in oncogenesis (e.g. zinc finger protein GLI2 or bone morphogenetic proteins in chondrocytes). Dynamic control centrality describes relaying functions as observed in signalling cascades (e.g. src kinase or Jak/Stat pathways). Value control centrality measures the direct influence of the value of the node on the network (e.g. Indian hedgehog as an essential regulator of proliferation in chondrocytes). Surveying random scale-free networks and biological networks, we find that control of the network resides in few high degree driver nodes and networks can be controlled best if they are sparsely connected.
Background:
Evidence that home telemonitoring for patients with chronic heart failure (CHF) offers clinical benefit over usual care is controversial as is evidence of a health economic advantage.
Methods:
Between January 2010 and June 2013, patients with a confirmed diagnosis of CHF were enrolled and randomly assigned to 2 study groups comprising usual care with and without an interactive bi-directional remote monitoring system (Motiva\(^{®}\)). The primary endpoint in CardioBBEAT is the Incremental Cost-Effectiveness Ratio (ICER) established by the groups' difference in total cost and in the combined clinical endpoint "days alive and not in hospital nor inpatient care per potential days in study" within the follow-up of 12 months.
Results:
A total of 621 predominantly male patients were enrolled, whereof 302 patients were assigned to the intervention group and 319 to the control group. Ischemic cardiomyopathy was the leading cause of heart failure. Despite randomization, subjects of the control group were more often in NYHA functional class III-IV, and exhibited peripheral edema and renal dysfunction more often. Additionally, the control and intervention groups differed in heart rhythm disorders. No differences existed regarding risk factor profile, comorbidities, echocardiographic parameters, especially left ventricular and diastolic diameter and ejection fraction, as well as functional test results, medication and quality of life. While the observed baseline differences may well be a play of chance, they are of clinical relevance. Therefore, the statistical analysis plan was extended to include adjusted analyses with respect to the baseline imbalances.
Conclusions:
CardioBBEAT provides prospective outcome data on both, clinical and health economic impact of home telemonitoring in CHF. The study differs by the use of a high evidence level randomized controlled trial (RCT) design along with actual cost data obtained from health insurance companies. Its results are conducive to informed political and economic decision-making with regard to home telemonitoring solutions as an option for health care. Overall, it contributes to developing advanced health economic evaluation instruments to be deployed within the specific context of the German Health Care System.
Biological systems such as cells or whole organisms are governed by complex regulatory networks of transcription factors, hormones and other regulators which determine the behavior of the system depending on internal and external stimuli. In mathematical models of these networks, genes are represented by interacting “nodes” whose “value” represents the activity of the gene.
Control processes in these regulatory networks are challenging to elucidate and quantify. Previous control centrality metrics, which aim to mathematically capture the ability of individual nodes to control biological systems, have been found to suffer from problems regarding biological plausibility.
This thesis presents a new approach to control centrality in biological networks. Three types of network control are distinguished: Total control centrality quantifies the impact of gene mutations and identifies potential pharmacological targets such as genes involved in oncogenesis (e.g. zinc finger protein GLI2 or bone morphogenetic proteins in chondrocytes). Dynamic control centrality describes relaying functions as observed in signaling cascades (e.g control in mouse colon stem cells). Value control centrality measures the direct influence of the value of the node on the network (e.g. Indian hedgehog as an essential regulator of proliferation in chondrocytes). Well-defined network manipulations define all three centralities not only for nodes, but also for the interactions between them, enabling detailed insights into network pathways.
The calculation of the new metrics is made possible by substantial computational improvements in the simulation algorithms for several widely used mathematical modeling paradigms for genetic regulatory networks, which are implemented in the regulatory network simulation framework Jimena created for this thesis.
Applying the new metrics to biological networks and artificial random networks shows how these mathematical concepts correspond to experimentally verified gene functions and signaling pathways in immunity and cell differentiation. In contrast to controversial previous results even from the Barabási group, all results indicate that the ability to control biological networks resides in only few driver nodes characterized by a high number of connections to the rest of the network. Autoregulatory loops strongly increase the controllability of the network, i.e. its ability to control itself, and biological networks are characterized by high controllability in conjunction with high robustness against mutations, a combination that can be achieved best in sparsely connected networks with densities (i.e. connections to nodes ratios) around 2.0 - 3.0.
The new concepts are thus considerably narrowing the gap between network science and biology and can be used in various areas such as system modeling, plausibility trials and system analyses.
Medical applications discussed in this thesis include the search for oncogenes and pharmacological targets, as well their functional characterization.
West African savannas are severely threatened with intensified land use and increasing degradation. Bees are important for terrestrial biodiversity as they provide native plant species with pollination services. However, little information is available regarding their mutualistic interactions with woody plant species. In the first network study from sub-Saharan West Africa, we investigated the effects of land-use intensity and climatic seasonality on plant–bee communities and their interaction networks. In total, we recorded 5686 interactions between 53 flowering woody plant species and 100 bee species. Bee-species richness and the number of interactions were higher in the low compared to medium and high land-use intensity sites. Bee- and plant-species richness and the number of interactions were higher in the dry compared to the rainy season. Plant–bee visitation networks were not strongly affected by land-use intensity; however, climatic seasonality had a strong effect on network architecture. Null-model corrected connectance and nestedness were higher in the dry compared to the rainy season. In addition, network specialization and null-model corrected modularity were lower in the dry compared to the rainy season. Our results suggest that in our study region, seasonal effects on mutualistic network architecture are more pronounced compared to land-use change effects. Nonetheless, the decrease in bee-species richness and the number of plant–bee interactions with an increase in land-use intensity highlights the importance of savanna conservation for maintaining bee diversity and the concomitant provision of ecosystem services.
Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
Since the discovery of the quantum anomalous Hall (QAH) effect in the magnetically doped topological insulators (MTI) Cr:(Bi,Sb)\(_2\)Te\(_3\) and V:(Bi,Sb)\(_2\)Te\(_3\), the search for the magnetic coupling mechanisms underlying the onset of ferromagnetism has been a central issue, and a variety of different scenarios have been put forward. By combining resonant photoemission, X-ray magnetic circular dichroism and density functional theory, we determine the local electronic and magnetic configurations of V and Cr impurities in (Bi,Sb)\(_2\)Te\(_3\). State-of-the-art first-principles calculations find pronounced differences in their 3d densities of states, and show how these impurity states mediate characteristic short-range pd exchange interactions, whose strength sensitively varies with the position of the 3d states relative to the Fermi level. Measurements on films with varying host stoichiometry support this trend. Our results explain, in an unified picture, the origins of the observed magnetic properties, and establish the essential role of impurity-state-mediated exchange interactions in the magnetism of MTI.
Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.
Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases. Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the “Association of the Scientific Medical Societies in Germany” (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation. Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction <40%) especially benefit in terms of exercise capacity and health-related quality of life. Patients with other cardiovascular diseases also benefit from CR-participation, but the scientific evidence is less clear. There is increasing evidence that the beneficial effect of CR strongly depends on “treatment intensity” including medical supervision, treatment of cardiovascular risk factors, information and education, and a minimum of individually adapted exercise volume. Additional psychologic interventions should be performed on the basis of individual needs. Conclusions: These guidelines reinforce the substantial benefit of CR in specific clinical indications, but also describe remaining deficits in CR-delivery in clinical practice as well as in CR-science with respect to methodology and presentation.
Prospective longitudinal follow‐up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6‐months' follow‐up in patients with a predischarge LVEF ≤40%, and determined predictors and prognostic implications of LVEF changes through 18‐months' follow‐up.
Methods and Results
Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6‐months' follow‐up: normalized LVEF (>50%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41%–50%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40%; heart failure with persistently reduced LVEF , n=291). All received guideline‐directed medical therapies. At 6‐months' follow‐up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end‐diastolic/end‐systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end‐diastolic wall‐thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event‐free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18‐months' follow‐up (P<0.001), while LV end‐diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end‐diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6‐months' follow‐up and 18‐months' follow‐up.
Conclusions
Six‐month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18‐months' follow‐up. Repeat hospitalizations were associated with attenuation of reverse remodeling."