一种非线性多阶段动力系统的最优控制及数值优化

针对间歇发酵过程的非线性多阶段动力系统,建立了以初始浓度为控制变量、以生产强度为性能指标的最优控制模型.证明了非线性多阶段动力系统的主要性质、最优控制的存在性及达到最优解的必要条件.构造了优化算法并应用于实际数据计算,其数值结果表明了本文模型与算法的有效性.     

Clinical trial outcome of anti-tumour necrosis factor alpha therapy in rheumatic arthritis

Rheumatoid arthritis is a common debilitating disease. Chronic joint inflammation leads to irreversible joint damage. Disability is a common sequel, therefore it is a major healthcare burden. Treatment by convention disease modifying anti-rheumatic drugs improves symptoms and signs but does not improve long-term prognosis. Tumour necrosis factor alpha is a powerful pro-inflammatory cytokine. Blocking this cytokine by either monoclonal antibody or soluble receptor reduces inflammation, improves symptoms and significantly reduces joint damage. Tumour necrosis factor alpha antagonists are major breakthroughs in the treatment of rheumatoid arthritis. In the UK, they are approved for the treatment of rheumatoid arthritis in patients with active disease who have failed at least two disease modifying anti-rheumatic drugs.     

The evolution of dominance: a direct approach through the theory of linkage and selection

The mathematical model of evolution of dominance proposed by Fisher and Wright, and expanded upon by Ewens and others is subjected to a more thorough examination. The model is treated as a bonafide two locus system of a major and modifying locus involving mutation, selection and recombination. In the usual case we confirm Ewens' conclusion to the effect that in the final stages the rate of evolution is essentially algebraic. Further, we establish the role of linkage in determining the rate of evolution. Specifically we show that in both the initial and final stages of the process the looser the linkage the faster the progress towards complete dominance.     

Analysis of the effect of swimmer's head position on swimming performance using computational fluid dynamics

The aim of this numerical work is to analyze the effect of the position of the swimmer's head on the hydrodynamic performances in swimming. In this initial study, the problem was modeled as 2D and in steady hydrodynamic state. The geometry is generated by the CAD software CATIA and the numerical simulation is carried out by the use of the CFD Fluent code. The standard k-epsilon turbulence model is used with a specific wall law. Three positions of the head were studied, for a range of Reynolds numbers about 10(6). The obtained numerical results revealed that the position of the head had a noticeable effect on the hydrodynamic performances, strongly modifying the wake around the swimmer. The analysis of these results made it possible to propose an optimal position of the head of a swimmer in underwater swimming.     

Heparan sulfate in chronic kidney diseases: Exploring the role of 3-O-sulfation

One of the main feature of chronic kidney disease is the development of renal fibrosis. Heparan Sulfate (HS) is involved in disease development by modifying the function of growth factors and cytokines and creating chemokine gradients. In this context, we aimed to understand the function of HS sulfation in renal fibrosis. Using a mouse model of renal fibrosis, we found that total HS 2-O-sulfation was increased in damaged kidneys, whilst, tubular staining of HS 3-O-sulfation was decreased. The expression of HS modifying enzymes significantly correlated with the development of fibrosis with HS3ST1 demonstrating the strongest correlation. The pro-fibrotic factors TGFβ1 and TGFβ2/IL1β significantly downregulated HS3ST1 expression in both renal epithelial cells and renal fibroblasts. To determine the implication of HS3ST1 in growth factor binding and signalling, we generated an in vitro model of renal epithelial cells overexpressing HS3ST1 (HKC8-HS3ST1). Heparin Binding EGF like growth factor (HB-EGF) induced rapid, transient STAT3 phosphorylation in control HKC8 cells. In contrast, a prolonged response was demonstrated in HKC8-HS3ST1 cells. Finally, we showed that both HS 3-O-sulfation and HB-EGF tubular staining were decreased with the development of fibrosis. Taken together, these data suggest that HS 3-O-sulfation is modified in fibrosis and highlight HS3ST1 as an attractive biomarker of fibrosis progression with a potential role in HB-EGF signalling.     

The limit of the modifiability of cellular radiosensitivity in sequential exposure to ionizing radiation and physical factors of a nonionizing nature

The application of a mathematical model of synergism in describing the consecutive combined actions of ionizing radiation and other physical agents has been considered. Using various cell systems it has been shown that the model permits to predict the highest dose modifying factor and conditions in which it can be achieved.     

Sphingolipids and glycerophospholipids – The “ying and yang” of lipotoxicity in metabolic diseases

Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of “ying/yang” interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.     

Importance of Initial Concentration of Factor VIII in a Mechanistic Model of In Vitro Coagulation

This computational study generates a hypothesis for the coagulation protein whose initial concentration greatly influences the course of coagulation. Many clinical malignancies of blood coagulation arise due to abnormal initial concentrations of coagulation factors. Sensitivity analysis of mechanistic models of blood coagulation is a convenient method to assess the effect of such abnormalities. Accordingly, the study presents sensitivity analysis, with respect to initial concentrations, of a recently developed mechanistic model of blood coagulation. Both the model and parameters to which model sensitivity is being analyzed provide newer insights into blood coagulation: the model incorporates distinct equations for plasma-phase and platelet membrane-bound species, and sensitivity to initial concentrations is a new dimension in sensitivity analysis. The results show that model predictions are most uncertain with respect to changes in initial concentration of factor VIII, and this hypothesis is supported by results from other models developed independently.     

The formation of photoreactivable damage by direct excitation of DNA in X-irradiated E. coli cells

The role of the direct excitation process in the formation of photoreactivable damage (pyrimidine dimers) in E. coli WP2 hcr-exr- cells has been studied. The pyrimidine dimers were detected by photoreactivation following anoxic irradiation by X-rays (220 kVp). The dose modifying factor (DMF) is 1.28 +/- 0.09. A biophysical model is used for a theoretical examination of the importance of the direct excitation process in the formation of photoreactivable damage and the experimental data are consistent with this model.     

Stromal–epithelial cell interactions and alteration of branching morphogenesis in macromastic mammary glands

True macromastia is a rare but disabling condition characterized by massive breast growth. The aetiology and pathogenic mechanisms for this disorder remain largely unexplored because of the lack of in vivo or in vitro models. Previous studies suggested that regulation of epithelial cell growth and development by oestrogen was dependent on paracrine growth factors from the stroma. In this study, a co‐culture model containing epithelial and stromal cells was used to investigate the interactions of these cells in macromastia. Epithelial cell proliferation and branching morphogenesis were measured to assess the effect of macromastic stromal cells on epithelial cells. We analysed the cytokines secreted by stromal cells and identified molecules that were critical for effects on epithelial cells. Our results indicated a significant increase in cell proliferation and branching morphogenesis of macromastic and non‐macromastic epithelial cells when co‐cultured with macromastic stromal cells or in conditioned medium from macromastic stromal cells. Hepatocyte growth factor (HGF) is a key factor in epithelial–stromal interactions of macromastia‐derived cell cultures. Blockade of HGF with neutralizing antibodies dramatically attenuated epithelial cell proliferation in conditioned medium from macromastic stromal cells. The epithelial–stromal cell co‐culture model demonstrated reliability for studying interactions of mammary stromal and epithelial cells in macromastia. In this model, HGF secreted by macromastic stromal cells was found to play an important role in modifying the behaviour of co‐cultured epithelial cells. This model allows further studies to investigate basic cellular and molecular mechanisms in tissue from patients with true breast hypertrophy.     

基于地形因素的新疆荒漠植被-气候模型应用研究

本研究在新疆荒漠植被型分类的基础上,用植被与气候Holdridge生命带模型进行荒漠植被型的模拟,并用Kappa检验系数进行结果检验,模拟结果很差(0.19),将地形作为模拟模型具体考虑的一个因素,对重新分类的气候区进行二次植被模拟。二次模拟结果Kappa检验系数平均值为0.45,二次模拟整体荒漠植被型模拟结果的Kappa检验系数为0.64,极大地提高了模型模拟的准确度。模型模拟准确度的提高在于将影响新疆水分分配的地形因素作为改进Holdridge生命带模型的参数,该参数的引入为提高Holdridge生命带模型的准确度提供了新的思路,也为较准确地模拟新疆地区的植被提供了新途径。     

Modelling and parameter estimation of the enzymatic synthesis of oligosaccharides by β‐galactosidase from Bacillus circulans

The aim of this research is to develop a model to describe oligosaccharide synthesis and simultaneously lactose hydrolysis. Model A (engineering approach) and model B (biochemical approach) were used to describe the data obtained in batch experiments with β‐galactosidase from Bacillus circulans at various initial lactose concentrations (from 0.19 to 0.59 mol·kg⁻¹). A procedure was developed to fit the model parameters and to select the most suitable model. The procedure can also be used for other kinetically controlled reactions. Each experiment was considered as an independent estimation of the model parameters, and consequently, model parameters were fitted to each experiment separately. Estimation of the parameters per experiment preserved the time dependence of the measurements and yielded independent sets of parameters. The next step was to study by ordinary regression methods whether parameters were constant under the altering conditions examined. Throughout all experiments, the parameters of model B did not show a trend upon the initial lactose concentration when inhibition was included. Therefore model B, a galactosyl‐enzyme complex‐based model, was chosen to describe the oligosaccharide synthesis, and one parameter set was determined for various initial lactose concentrations. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 64: 558–567, 1999.     

Studies on the participation of epididymal sperm protein DE/CRISP-1 in egg activation.

Protein DE (32 kDa) associates with sperm during epididymal maturation and participates in sperm-egg fusion through its binding to complementary sites on the egg surface. In the present work we investigated the participation of DE in two mechanisms probably involved in egg activation: the ability of DE to trigger activation by its interaction with the binding sites on the egg surface (receptor model) and its ability to regulate intracellular calcium channels (sperm factor model). The incubation of eggs with DE did not promote activation parameters such as calcium oscillations or meiosis resumption. Secondly, microinjection of DE into eggs was ineffective in either eliciting calcium release or modifying oscillations induced by an activating sperm extract. Together, these results argue against the participation of DE in egg activation, restricting the activity of this protein and its egg binding sites to the sperm-egg fusion process.     

Estimating of changes in the amyloid and prion content of yeast cells

An attempt was made at estimating the overall amyloid content of yeast cells by treating crude cellular lysates with thioflavin T, the agent specifically staining amyloid fibrils. We demonstrated that overproduction of the yeast chaperone Hsp104p, as well as GuHCI treatment of the [PSI+] cells led both to elimination of the [PSI+] factor and to a stable decrease of the overall amyloid content estimated by intensity of fluorescence (IF) of the thioflavin T. At the same time, overexpression of gene SUP35, coding the protein prionizable to [PSI+], led to generation of [PSI+] clones with higher IF of thioflavin T. Cytoduction in the crosses involving PSI factor leads to considerable enhancement of IF; cytoductants with the nucleus of the recipient [psi-] strain not only got [PSI+] factor from the donor strain but also increased their amyloid content. In these model experiments all treatments modifying one of the yeast prions, [PSI+] factor, led to a predictable shift of IF of thioflavin T that behaved like a cytoplasmic hereditary determinant. The data obtained show that IF of thioflavin T staining gives reliable estimates of cellular amyloid content and that mitotically stable shift of IF after a battery of treatments modifying cellular prion set provides quantitative estimate of the input of prionizable protein molecules to the amyloid pool. The combination of thioflavin staining and prionotropic treatments applied here can be possibly used for future attempts of checking yeast strains for cryptic prions.     

Numerical simulation for electrochemical cultivation of iron oxidizing bacteria

A numerical simulation model was constructed for electrochemical cultivation of iron oxidizing bacterium, Thiobacillus ferrooxidans, based on Monod's dual limitation equation. In this model, two limiting factors were examined, low supply of Fe(II) ion and dissolved oxygen, from empirical viewpoints. The simulation model was constructed taking into consideration the energy balance based on the amount of the electronic flow from the electrode to bacteria via an iron ion, and then to oxygen. The model consisted of a logarithmic bacterial growth phase during the first three days, followed by a plateau and growth limitation thereafter. The predicted results were in agreement with the actual growth under electrochemical cultivation. It was predicted the growth limiting factor would be changed from insufficient supply of Fe(II) ions to that of oxygen by decreasing the value of oxygen transfer constant K, which correlated with the aeration rate. The optimum aeration rate was determined for the ideal electrochemical cultivation. The algorithm described here can be used in any electrochemical cultivation by modifying the parameters for each system.     

Establishment of a tetraploid cytotype in a diploid population: Effect of relative fitness of the cytotypes

The conditions for the establishment of a tetraploid in a diploid population were investigated by means of a deterministic model, on the assumption that the diploid cytotype produces some 2n gametes. If the fertility and viability of both cytotypes were the same and the initial population was diploid, then a mixed population would occur if the production of 2n gametes was below 17.16%. The tetraploid excluded the diploid above this limit. By modifying the fertility and the viability of the polyploid this threshold varied, dropping to 10% when one of the two parameters was twice that of the diploid, and falling to as low as 6% if both fertility and viability were double that of the diploid. The conditions for the establishment of a polyploid are therefore quite restrictive under the assumptions of this model. In nature, such processes would probably allow the spread of the polyploid only if the immigration of polyploids considerably enhanced the frequency of tetraploids, or if genetical or environmental changes, or chance processes in small populations caused a substantial increase in the frequency of 2n gametes produced by the diploid.     

Self-eating in skeletal development: Implications for lysosomal storage disorders

Macroautophagy (a.k.a. autophagy) is a cellular process aimed at the recycling of proteins and organelles that is achieved when autophagosomes fuse with lysosomes. Accordingly, lysosomal dysfunctions are often associated with impaired autophagy. We demonstrated that inactivation of the sulfatase modifying factor 1 gene (Sumf1), a gene mutated in Multiple Sulfatase Deficiency (MSD), causes glycosaminoglycans (GAGs) to accumulate in lysosomes, which in turn disrupts autophagy. We utilized a murine model of MSD to study how impairment of this process affects chondrocyte viability and thus skeletal development.