An Integrated Computational/Experimental Model of Lymphoma Growth

Non-Hodgkin''s lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We investigate the tissue-scale physiologic effects of this loss by integrating in vivo and immunohistological data with computational modeling to study the spatiotemporal physical dynamics of lymphoma growth. We compare between drug-sensitive Eμ-myc Arf-/- and drug-resistant Eμ-myc p53-/- lymphoma cell tumors grown in live mice. Initial values for the model parameters are obtained in part by extracting values from the cellular-scale from whole-tumor histological staining of the tumor-infiltrated inguinal lymph node in vivo. We compare model-predicted tumor growth with that observed from intravital microscopy and macroscopic imaging in vivo, finding that the model is able to accurately predict lymphoma growth. A critical physical mechanism underlying drug-resistant phenotypes may be that the Eμ-myc p53-/- cells seem to pack more closely within the tumor than the Eμ-myc Arf-/- cells, thus possibly exacerbating diffusion gradients of oxygen, leading to cell quiescence and hence resistance to cell-cycle specific drugs. Tighter cell packing could also maintain steeper gradients of drug and lead to insufficient toxicity. The transport phenomena within the lymphoma may thus contribute in nontrivial, complex ways to the difference in drug sensitivity between Eμ-myc Arf-/- and Eμ-myc p53-/- tumors, beyond what might be solely expected from loss of functionality at the molecular scale. We conclude that computational modeling tightly integrated with experimental data gives insight into the dynamics of Non-Hodgkin''s lymphoma and provides a platform to generate confirmable predictions of tumor growth.     

An In Vivo Experimental Validation of a Computational Model of Human Foot

Reliable computational foot models offer an alternative means to enhance knowledge on the biomechanics of human foot.Model validation is one of the most critical aspects of the entire foot modeling and analysis process.This paper presents an invivo experiment combining motion capture system and plantar pressure measure platform to validate a three-dimensional finiteelement model of human foot.The Magnetic Resonance Imaging(MRI)slices for the foot modeling and the experimental datafor validation were both collected from the same volunteer subject.The validated components included the comparison of staticmodel predictions of plantar force,plantar pressure and foot surface deformation during six loading conditions,to equivalentmeasured data.During the whole experiment,foot surface deformation,plantar force and plantar pressure were recorded simultaneouslyduring six different loaded standing conditions.The predictions of the current FE model were in good agreementwith these experimental results.     

Treating Cutis Verticis Gyrata Using Skin Expansion Method

The objective of this study was to evaluate the feasibility and clinical effect of repairing scalp defect after the excision of cutis verticis gyrata using expanded scalp skin flaps. For this purpose, 8 patients with cutis verticis gyrata were subjected to scalp skin expander implantation under the skin. After saline injection and scalp expansion for 2–3 months, the cutis verticis gyrata was excised and the expanded scalp flaps were applied to recover the skin defect. As a result, the flaps and hair grew well without contractures and significant scarring, suggesting that this method is useful for surgical correction of cutis verticis gyrata.     

An Off-Lattice Hybrid Discrete-Continuum Model of Tumor Growth and Invasion

We have developed an off-lattice hybrid discrete-continuum (OLHDC) model of tumor growth and invasion. The continuum part of the OLHDC model describes microenvironmental components such as matrix-degrading enzymes, nutrients or oxygen, and extracellular matrix (ECM) concentrations, whereas the discrete portion represents individual cell behavior such as cell cycle, cell-cell, and cell-ECM interactions and cell motility by the often-used persistent random walk, which can be depicted by the Langevin equation. Using this framework of the OLHDC model, we develop a phenomenologically realistic and bio/physically relevant model that encompasses the experimentally observed superdiffusive behavior (at short times) of mammalian cells. When systemic simulations based on the OLHDC model are performed, tumor growth and its morphology are found to be strongly affected by cell-cell adhesion and haptotaxis. There is a combination of the strength of cell-cell adhesion and haptotaxis in which fingerlike shapes, characteristic of invasive tumor, are observed.     

Scabies Mites Alter the Skin Microbiome and Promote Growth of Opportunistic Pathogens in a Porcine Model

Background

The resident skin microbiota plays an important role in restricting pathogenic bacteria, thereby protecting the host. Scabies mites (Sarcoptes scabiei) are thought to promote bacterial infections by breaching the skin barrier and excreting molecules that inhibit host innate immune responses. Epidemiological studies in humans confirm increased incidence of impetigo, generally caused by Staphylococcus aureus and Streptococcus pyogenes, secondary to the epidermal infestation with the parasitic mite. It is therefore possible that mite infestation could alter the healthy skin microbiota making way for the opportunistic pathogens. A longitudinal study to test this hypothesis in humans is near impossible due to ethical reasons. In a porcine model we generated scabies infestations closely resembling the disease manifestation in humans and investigated the scabies associated changes in the skin microbiota over the course of a mite infestation.

Methodology/Principal Findings

In a 21 week trial, skin scrapings were collected from pigs infected with S. scabies var. suis and scabies-free control animals. A total of 96 skin scrapings were collected before, during infection and after acaricide treatment, and analyzed by bacterial 16S rDNA tag-encoded FLX-titanium amplicon pyrosequencing. We found significant changes in the epidermal microbiota, in particular a dramatic increase in Staphylococcus correlating with the onset of mite infestation in animals challenged with scabies mites. This increase persisted beyond treatment from mite infection and healing of skin. Furthermore, the staphylococci population shifted from the commensal S. hominis on the healthy skin prior to scabies mite challenge to S. chromogenes, which is increasingly recognized as being pathogenic, coinciding with scabies infection in pigs. In contrast, all animals in the scabies-free cohort remained relatively free of Staphylococcus throughout the trial.

Conclusions/Significance

This is the first experimental in vivo evidence supporting previous assumptions that establishment of pathogens follow scabies infection. Our findings provide an explanation for a biologically important aspect of the disease pathogenesis. The methods developed from this pig trial will serve as a guide to analyze human clinical samples. Studies building on this will offer implications for development of novel intervention strategies against the mites and the secondary infections.     

A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.     

Nitrogen Uptake and Plant Growth II. An Empirical Model of Vegetative Growth and Partitioning

An empirical model of vegetative plant growth is presented.The model is based on experimental data on Polygonum cuspidatum,which showed (1) that the partitioning of dry matter and nitrogenamong organs was linearly related to the nitrogen concentrationof the whole plant and (2) that leaf thickness was negativelycorrelated with leaf nitrogen concentration. The model properlydescribes the behaviour of plants. Steady-state solutions ofthe model give the relative growth rate, specific leaf weight,and partitioning of dry matter and nitrogen among organs withthe net assimilation rate and the specific absorption rate asenvironmental variables. The effect of nitrogen removal on drymatter and nitrogen partitioning was examined as non-steady-statedynamic solutions of the model. The model predicted not onlyreduced leaf growth and enhanced root growth but also a fluxof nitrogen from the leaf to the root, which agreed with theexperimental results. Mathematical model, partitioning of dry matter and nitrogen, plant nitrogen, relative growth rate, shoot: root ratio, specific leaf weight     

An Extension of the Logistic Model of Plant Growth

The kinetics of growth of Dactylis glomerata L. were studiedunder controlled temperature and nutritional conditions at threelevels of irradiance (35·55 and 85 W m^–s). Thedry weights of the root and shoot parts of the plants were measuredeach week between the fourth and eleventh weeks after sowing. The growth kinetics were found to be dependent on the levelof irradiance, but no significant differences in the root: totaldry weight ratio were observed. To characterize the effect of illuminance, the experimentalgrowth curves were analysed initially using the logistic model,the adequacy of which is discussed. An extension of the logisticmodel is proposed, represented by the kinetic equation dM/dt= kM, with < 1 and where M is the dry weight of the plant.It is shown that this relationship allows a distinction to bemade between two kinds of plant material according to theirfunctions in the growth process. Dactylis glomerata L., illuminance, growth curves, kinetic analyses, logistic model, shoot:root ratio, partition of assimilates     

Growth Type and Functional Trajectories: An Empirical Study of Urban Expansion in Nanjing,China

Drawing upon the Landsat satellite images of Nanjing from 1985, 1995, 2001, 2007, and 2013, this paper integrates the convex hull analysis and common edge analysis at double scales, and develops a comprehensive matrix analysis to distinguish the different types of urban land expansion. The results show that Nanjing experienced rapid urban expansion, dominated by a mix of residential and manufacturing land from 1985 to 2013, which in turn has promoted Nanjing’s shift from a compact mononuclear city to a polycentric one. Spatial patterns of three specific types of growth, namely infilling, extension, and enclave were quite different in four consecutive periods. These patterns result primarily from the existing topographic constraints, as well as government-oriented urban planning and policies. By intersecting the function maps, we also reveal the functional evolution of newly-developed urban land. Moreover, both self-enhancing and mutual promotion of the newly developed functions are surveyed over the last decade. Our study confirms that the integration of a multi-scale method and multi-perspective analysis, such as the spatiotemporal patterns and functional evolution, helps us to better understand the rapid urban growth in China.     

Reduced Model and Simulation of Neuron with Passive Dendritic Cable: An Eigenfunction Expansion Approach

The neuron models with passive dendritic cables are often used for detailed cortical network simulations (Protopapas et al., 1998; Suarez et al., 1995). For this, the compartment model based on finite volume or finite difference discretization was used. In this paper, we propose an eigenfunction expansion approach combined with singular perturbation and demonstrate that the proposed scheme can achieve an order of magnitude accuracy improvement with the same number of equations. Moreover, it is also shown that the proposed scheme converges much faster to attain a given accuracy. Hence, for a network simulation of the neurons with passive dendritic cables, the proposed scheme can be an attractive alternative to the compartment model, that leads to a low order model with much higher accuracy or that converges faster for a given accuracy.     

Auxin-Induced Expansion Growth of Cells and Protoplasts of Yeast

Using an auxin-responsive mutant of Sacchairomyces ellipsodeus, expansion growth of cells caused by auxin was studied especially in comparison with that of protoplasts.

• 1 Indole-3-acetic acid induced detectable cell expansion growth in 3 hours in a buffered simple solution where no cell division occurred.
• 2 The auxin-induced expansion growth was inhibited by an antiauxin, trans-cinnamic acid.
• 3 Actinomycin D, chloramphenicol and cycloheximide inhibited the auxin-induced cell expansion growth.
• 4 Protoplasts did not expand in response to auxin under the condition where intact cells did.
• 5 The stability of protoplasts was not changed by the low auxin concentration (20 mg/1) which induced cell expansion.
• 6 High concentrations (100–1000 mg/1) of auxin caused protoplasts to burst even under an osmotically stable condition.

     

Cell Guidance on Nanogratings: A Computational Model of the Interplay between PC12 Growth Cones and Nanostructures

Background

Recently, the effects of nanogratings have been investigated on PC12 with respect to cell polarity, neuronal differentiation, migration, maturation of focal adhesions and alignment of neurites.

Methodology/Principal Findings

A synergistic procedure was used to study the mechanism of alignment of PC12 neurites with respect to the main direction of nanogratings. Finite Element simulations were used to qualitatively assess the distribution of stresses at the interface between non-spread growth cones and filopodia, and to study their dependence on filopodial length and orientation. After modelling all adhesions under non-spread growth cone and filopodial protrusions, the values of local stress maxima resulted from the length of filopodia. Since the stress was assumed to be the main triggering cause leading to the increase and stabilization of filopodia, the position of the local maxima was directly related to the orientation of neurites. An analytic closed form equation was then written to quantitatively assess the average ridge width needed to achieve a given neuritic alignment (R² = 0.96), and the alignment course, when the ridge depth varied (R² = 0.97). A computational framework was implemented within an improved free Java environment (CX3D) and in silico simulations were carried out to reproduce and predict biological experiments. No significant differences were found between biological experiments and in silico simulations (alignment, p = 0.3571; tortuosity, p = 0.2236) with a standard level of confidence (95%).

Conclusions/Significance

A mechanism involved in filopodial sensing of nanogratings is proposed and modelled through a synergistic use of FE models, theoretical equations and in silico simulations. This approach shows the importance of the neuritic terminal geometry, and the key role of the distribution of the adhesion constraints for the cell/substrate coupling process. Finally, the effects of the geometry of nanogratings were explicitly considered in cell/surface interactions thanks to the analytic framework presented in this work.     

Ongoing Growth Challenges Fruit Skin Integrity

As a result of continuing volume and hence surface-area growth, the skins of most fruit species suffer ongoing strain throughout development. Maintenance of surface integrity is essential to protect the underlying tissues from desiccation and pathogen attack. Fruit skins are commonly “primary” in structure. They comprise a polymeric cuticle overlying an epidermis and a hypodermis. The cuticle is responsible for the skin's barrier function and the cellular layers for the skin's load-bearing functions. Skin failure can be just of the cuticle layer (microcracking) resulting in barrier impairment or it can involve cuticle and cellular layers (macrocracking) resulting in both barrier and structural impairment. Fruit skin failure is associated with a number of disorders including shriveling, cracking, russeting, and skin spots. All result in reduced market value. Our objective is to review the literature on the strategies adopted by fruit to cope with the challenge of continuing skin expansion. We uncover a multistep strategy to prevent or minimize the risk of fruit skin failure. This comprises: (1) area expansion of the load-bearing skin-cell layer(s) by ongoing cell division and (2) the avoidance of skin stress or strain concentrations by matching patterns of skin-cell division to those of area expansion. Also involved, (3) are the partitioning of cuticle strain into plastic and viscoelastic components at the expense of the elastic one. For this, wax and cutin are deposited in the cuticle during growth. Wax and cutin deposition “fix” the strain in the cuticle. Cutin is preferentially deposited on the inner surface of the cuticle, which fixes the strain, but it leaves the outer cuticle surface more strained. Last, (4) if the primary skin is damaged, the barrier functions are restored by the formation of a “secondary” fruit surface (periderm). Lignin can also be used to strengthen the underlying cells following structural failure.     

Human Growth and Body Weight Dynamics: An Integrative Systems Model

Quantifying human weight and height dynamics due to growth, aging, and energy balance can inform clinical practice and policy analysis. This paper presents the first mechanism-based model spanning full individual life and capturing changes in body weight, composition and height. Integrating previous empirical and modeling findings and validated against several additional empirical studies, the model replicates key trends in human growth including A) Changes in energy requirements from birth to old ages. B) Short and long-term dynamics of body weight and composition. C) Stunted growth with chronic malnutrition and potential for catch up growth. From obesity policy analysis to treating malnutrition and tracking growth trajectories, the model can address diverse policy questions. For example I find that even without further rise in obesity, the gap between healthy and actual Body Mass Indexes (BMIs) has embedded, for different population groups, a surplus of 14%–24% in energy intake which will be a source of significant inertia in obesity trends. In another analysis, energy deficit percentage needed to reduce BMI by one unit is found to be relatively constant across ages. Accompanying documented and freely available simulation model facilitates diverse applications customized to different sub-populations.     

皮肤的光学模型

基于人体皮肤的组织结构,光在皮肤组织中的传输特性以及皮肤各层的组织光学参数,建立了正常皮肤的光学模型,介绍了该模型中的组织光学参数的确定方法。本文建立的皮肤组织光学模型及其方法,可应用于皮肤光学基础与临床的其它研究中。     

Placental Underperfusion in a Rat Model of Intrauterine Growth Restriction Induced by a Reduced Plasma Volume Expansion

Lower maternal plasma volume expansion was found in idiopathic intrauterine growth restriction (IUGR) but the link remains to be elucidated. An animal model of IUGR was developed by giving a low-sodium diet to rats over the last week of gestation. This treatment prevents full expansion of maternal circulating volume and the increase in uterine artery diameter, leading to reduced placental weight compared to normal gestation. We aimed to verify whether this is associated with reduced remodeling of uteroplacental circulation and placental hypoxia. Dams were divided into two groups: IUGR group and normal-fed controls. Blood velocity waveforms in the main uterine artery were obtained by Doppler sonography on days 14, 18 and 21 of pregnancy. On day 22 (term = 23 days), rats were sacrificed and placentas and uterine radial arteries were collected. Diameter and myogenic response of uterine arteries supplying placentas were determined while expression of hypoxia-modulated genes (HIF-1α, VEGFA and VEGFR2), apoptotic enzyme (Caspase -3 and -9) and glycogen cells clusters were measured in control and IUGR term-placentas. In the IUGR group, impaired blood velocity in the main uterine artery along with increased resistance index was observed without alteration in umbilical artery blood velocity. Radial uterine artery diameter was reduced while myogenic response was increased. IUGR placentas displayed increased expression of hypoxia markers without change in the caspases and increased glycogen cells in the junctional zone. The present data suggest that reduced placental and fetal growth in our IUGR model may be mediated, in part, through reduced maternal uteroplacental blood flow and increased placental hypoxia.     

An Association Between Acid Invertase Activity and Cell Growth during Leaf Expansion in Phaseolus vulgaris L.

Changes in lamina area, dimensions of epidermal and palisadecells, acid invertase activity and content of sucrose and hexosein the primary leaves of Phaseolus vulgaris L. were determinedbetween emergence of the hypocotyl hook and the completion ofleaf expansion. Growth in area and thickness of the primaryleaf after emergence was attributable to the expansion of cellsalready present in the lamina at emergence. The major invertasein the expanding leaf was a readily soluble acid invertase;little insoluble invertase activity was detected. Soluble andinsoluble fractions of leaf homogenates contained little neutralinvertase activity. The specific activity of the soluble acidinvertase increased rapidly during the early stages of leafexpansion, reaching a peak at the time of most rapid cell enlargement(5 d after emergence) and then declining as the leaf matured.Highly significant positive correlations were found betweenenzyme specific activity and the rates of cell and leaf enlargement. The early, rapid phase of lamina expansion was characterizedby high concentrations of hexose sugar and low concentrationsof sucrose. As the rates of leaf cell enlargement declined theconcentration of hexose fell and that of sucrose increased.Between 5 d and 11 d after hypocotyl emergence, the hexose/sucroseratio in the primary leaf decreased approximately 10-fold asthe specific activity of acid invertase decreased. The results are discussed with reference to sources of carbonsubstrates for cell growth and to the sink/source transitionduring leaf development. Key words: Leaf expansion, Acid invertase, Hexose, Sucrose, Phaseolus