50 research outputs found
Towards a Runtime Comparison of Natural and Artificial Evolution
Evolutionary algorithms (EAs) form a popular optimisation paradigm inspired by natural evolution. In recent years the field of evolutionary computation has developed a rigorous analytical theory to analyse the runtimes of EAs on many illustrative problems. Here we apply this theory to a simple model of natural evolution. In the Strong Selection Weak Mutation (SSWM) evolutionary regime the time between occurrences of new mutations is much longer than the time it takes for a mutated genotype to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a stochastic process evolving one genotype by means of mutation and selection between the resident and the mutated genotype. The probability of accepting the mutated genotype then depends on the change in fitness. We study this process, SSWM, from an algorithmic perspective, quantifying its expected optimisation time for various parameters and investigating differences to a similar evolutionary algorithm, the well-known (1+1) EA. We show that SSWM can have a moderate advantage over the (1+1) EA at crossing fitness valleys and study an example where SSWM outperforms the (1+1) EA by taking advantage of information on the fitness gradient
Frequent mechanical stress suppresses proliferation of mesenchymal stem cells from human bone marrow without loss of multipotency
Mounting evidence indicated that human mesenchymal stem cells (hMSCs) are responsive not only
to biochemical but also to physical cues, such as substrate topography and stiffness. To simulate the
dynamic structures of extracellular environments of the marrow in vivo, we designed a novel surrogate
substrate for marrow derived hMSCs based on physically cross-linked hydrogels whose elasticity can
be adopted dynamically by chemical stimuli. Under frequent mechanical stress, hMSCs grown on
our hydrogel substrates maintain the expression of STRO-1 over 20 d, irrespective of the substrate
elasticity. On exposure to the corresponding induction media, these cultured hMSCs can undergo
adipogenesis and osteogenesis without requiring cell transfer onto other substrates. Moreover,
we demonstrated that our surrogate substrate suppresses the proliferation of hMSCs by up to 90%
without any loss of multiple lineage potential by changing the substrate elasticity every 2nd days.
Such “dynamic in vitro niche” can be used not only for a better understanding of the role of dynamic
mechanical stresses on the fate of hMSCs but also for the synchronized differentiation of adult stem
cells to a specific lineage
Simulating Intravitreal Injections in Anatomically Accurate Models for Rabbit, Monkey, and Human Eyes
Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial
Purpose: To develop a population pharmacokinetic (PK) model for intravitreal
ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free
vascular endothelial growth factor (VEGF) pharmacodynamics (PD).
Methods: The RAnibizumab compared with laser therapy for the treatment of INfants
BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants
to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg,
or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD
analysis. An adult PK model using infant body weight as a fixed allometric covariate was
re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based
individual predicted concentrations of ranibizumab were plotted against observed free
VEGF concentrations.
Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and
0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach
maximum concentration was rapid (median: 1.3 days). Maximum concentration (median
24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over
time. Plotted individual predicted concentrations of ranibizumab against observed free
VEGF concentrations showed no relationship.
Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was
the rate-limiting step and was faster compared with adults. No reduction in plasma free
VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing.
Translational Relevance: Our population PK and VEGF PD findings suggest a favorable
ocular efficacy: systemic safety profile for ranibizumab in preterm infants