533 research outputs found
Activin-A and Bmp4 Levels Modulate Cell Type Specification during CHIR-Induced Cardiomyogenesis
The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin-A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To further enhance the reproducibility of CHIR-induced cardiomyogenesis, and to ultimately promote myocyte maturation, we are using exogenous growth factors to optimize cardiomyogenic signaling downstream of CHIR induction. As indicated by RNA-seq, induction with CHIR during Day 1 (Days 0–1) was followed by immediate expression of Nodal ligands and receptors, followed later by Bmp ligands and receptors. Co-induction with CHIR and high levels of the Nodal mimetic Activin-A (50–100 ng/ml) during Day 0–1 efficiently induced definitive endoderm, whereas CHIR supplemented with Activin-A at low levels (10 ng/ml) consistently improved cardiomyogenic efficiency, even when CHIR alone was ineffective. Moreover, co-induction using CHIR and low levels of Activin-A apparently increased the rate of cardiomyogenesis, as indicated by the initial appearance of rhythmically beating cells by Day 6 instead of Day 8. By contrast, co-induction with CHIR plus low levels (3–10 ng/ml) of Bmp4 during Day 0–1 consistently and strongly inhibited cardiomyogenesis. These findings, which demonstrate that cardiomyogenic efficacy is improved by optimizing levels of CHIR-induced growth factors when applied in accord with their sequence of endogenous expression, are consistent with the idea that Nodal (Activin-A) levels toggle the entry of cells into the endodermal or mesodermal lineages, while Bmp levels regulate subsequent allocation into mesodermal cell types
Spring-block model for a single-lane highway traffic
A simple one-dimensional spring-block chain with asymmetric interactions is
considered to model an idealized single-lane highway traffic. The main elements
of the system are blocks (modeling cars), springs with unidirectional
interactions (modeling distance keeping interactions between neighbors), static
and kinetic friction (modeling inertia of drivers and cars) and spatiotemporal
disorder in the values of these friction forces (modeling differences in the
driving attitudes). The traveling chain of cars correspond to the dragged
spring-block system. Our statistical analysis for the spring-block chain
predicts a non-trivial and rich complex behavior. As a function of the disorder
level in the system a dynamic phase-transition is observed. For low disorder
levels uncorrelated slidings of blocks are revealed while for high disorder
levels correlated avalanches dominates.Comment: 6 pages, 7 figure
Human gene copy number spectra analysis in congenital heart malformations
The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways
Relationship between a Non-Markovian Process and Fokker-Planck Equation
We demonstrate the equivalence of a non-Markovian evolution equation with a linear memory-coupling and a Fokker-Planck equation (FPE). In case the feedback term offers a direct and permanent coupling of the current probability density to an initial distribution, the corresponding FPE offers a non-trivial drift term depending itself on the diffusion parameter. As the consequence the deterministic part of the underlying Langevin equation is likewise determined by the noise strength of the stochastic part. This memory induced stochastic behavior is discussed for different, but representative initial distributions. The analytical calculations are supported by numerical results. © 2006 Elsevier B.V. All rights reserved.The authors (S.T. and K.Z.) acknowledge support by the DFG (SFB 418) as well as by DAAD (S. Tatur)
Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome
Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications
Cluster formation and anomalous fundamental diagram in an ant trail model
A recently proposed stochastic cellular automaton model ({\it J. Phys. A 35,
L573 (2002)}), motivated by the motions of ants in a trail, is investigated in
detail in this paper. The flux of ants in this model is sensitive to the
probability of evaporation of pheromone, and the average speed of the ants
varies non-monotonically with their density. This remarkable property is
analyzed here using phenomenological and microscopic approximations thereby
elucidating the nature of the spatio-temporal organization of the ants. We find
that the observations can be understood by the formation of loose clusters,
i.e. space regions of enhanced, but not maximal, density.Comment: 11 pages, REVTEX, with 11 embedded EPS file
Towards a variational principle for motivated vehicle motion
We deal with the problem of deriving the microscopic equations governing the
individual car motion based on the assumptions about the strategy of driver
behavior. We suppose the driver behavior to be a result of a certain compromise
between the will to move at a speed that is comfortable for him under the
surrounding external conditions, comprising the physical state of the road, the
weather conditions, etc., and the necessity to keep a safe headway distance
between the cars in front of him. Such a strategy implies that a driver can
compare the possible ways of his further motion and so choose the best one. To
describe the driver preferences we introduce the priority functional whose
extremals specify the driver choice. For simplicity we consider a single-lane
road. In this case solving the corresponding equations for the extremals we
find the relationship between the current acceleration, velocity and position
of the car. As a special case we get a certain generalization of the optimal
velocity model similar to the "intelligent driver model" proposed by Treiber
and Helbing.Comment: 6 pages, RevTeX
Long-lived states in synchronized traffic flow. Empirical prompt and dynamical trap model
The present paper proposes a novel interpretation of the widely scattered
states (called synchronized traffic) stimulated by Kerner's hypotheses about
the existence of a multitude of metastable states in the fundamental diagram.
Using single vehicle data collected at the German highway A1, temporal velocity
patterns have been analyzed to show a collection of certain fragments with
approximately constant velocities and sharp jumps between them. The particular
velocity values in these fragments vary in a wide range. In contrast, the flow
rate is more or less constant because its fluctuations are mainly due to the
discreteness of traffic flow.
Subsequently, we develop a model for synchronized traffic that can explain
these characteristics. Following previous work (I.A.Lubashevsky, R.Mahnke,
Phys. Rev. E v. 62, p. 6082, 2000) the vehicle flow is specified by car
density, mean velocity, and additional order parameters and that are
due to the many-particle effects of the vehicle interaction. The parameter
describes the multilane correlations in the vehicle motion. Together with the
car density it determines directly the mean velocity. The parameter , in
contrast, controls the evolution of only. The model assumes that
fluctuates randomly around the value corresponding to the car configuration
optimal for lane changing. When it deviates from this value the lane change is
depressed for all cars forming a local cluster. Since exactly the overtaking
manoeuvres of these cars cause the order parameter to vary, the evolution
of the car arrangement becomes frozen for a certain time. In other words, the
evolution equations form certain dynamical traps responsible for the long-time
correlations in the synchronized mode.Comment: 16 pages, 10 figures, RevTeX
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