MHC-Linked Syngeneic Developmental Preference in Thymic Lobes Colonized with Bone Marrow Cells: A Mathematical model

Reconstitution of the T-cell compartment after bone marrow transplantation depends on successful colonization of the thymus by bone-marrow-derived progenitor cells. Recent studies compared the development of syngeneic and allogeneic bone-marrow-derived cells in cocultures with lymphoid-depleted fetal thymus explants, leading to the discovery of MHC-linked syngeneic developmental preference (SDP) in the thymus. To determine the nature of cell interactions among the bone marrow and thymic elements that might underlie SDP, we analyzed this phenomenon by mathematical modeling. The results indicate that syngeneic mature T cells, responsible for inducing this preference, probably interfere both with the seeding of allogeneic bone-marrow-derived thymocyte progenitors in the thymic stroma and with their subsequent proliferation. In addition, the possibility of augmented death among the developing allogeneic thymocytes cannot be ruled out

Nonlinear competition between asters and stripes in filament-motor-systems

A model for polar filaments interacting via molecular motor complexes is investigated which exhibits bifurcations to spatial patterns. It is shown that the homogeneous distribution of filaments, such as actin or microtubules, may become either unstable with respect to an orientational instability of a finite wave number or with respect to modulations of the filament density, where long wavelength modes are amplified as well. Above threshold nonlinear interactions select either stripe patterns or periodic asters. The existence and stability ranges of each pattern close to threshold are predicted in terms of a weakly nonlinear perturbation analysis, which is confirmed by numerical simulations of the basic model equations. The two relevant parameters determining the bifurcation scenario of the model can be related to the concentrations of the active molecular motors and of the filaments respectively, which both could be easily regulated by the cell.Comment: 13 pages, 7 figure

The influence of gene expression time delays on Gierer-Meinhardt pattern formation systems

There are numerous examples of morphogen gradients controlling long range signalling in developmental and cellular systems. The prospect of two such interacting morphogens instigating long range self-organisation in biological systems via a Turing bifurcation has been explored, postulated, or implicated in the context of numerous developmental processes. However, modelling investigations of cellular systems typically neglect the influence of gene expression on such dynamics, even though transcription and translation are observed to be important in morphogenetic systems. In particular, the influence of gene expression on a large class of Turing bifurcation models, namely those with pure kinetics such as the Gierer–Meinhardt system, is unexplored. Our investigations demonstrate that the behaviour of the Gierer–Meinhardt model profoundly changes on the inclusion of gene expression dynamics and is sensitive to the sub-cellular details of gene expression. Features such as concentration blow up, morphogen oscillations and radical sensitivities to the duration of gene expression are observed and, at best, severely restrict the possible parameter spaces for feasible biological behaviour. These results also indicate that the behaviour of Turing pattern formation systems on the inclusion of gene expression time delays may provide a means of distinguishing between possible forms of interaction kinetics. Finally, this study also emphasises that sub-cellular and gene expression dynamics should not be simply neglected in models of long range biological pattern formation via morphogens

Making nonlinear manifold learning models interpretable: The manifold grand tour

Dimensionality reduction is required to produce visualisations of high dimensional data. In this framework, one of the most straightforward approaches to visualising high dimensional data is based on reducing complexity and applying linear projections while tumbling the projection axes in a defined sequence which generates a Grand Tour of the data. We propose using smooth nonlinear topographic maps of the data distribution to guide the Grand Tour, increasing the effectiveness of this approach by prioritising the linear views of the data that are most consistent with global data structure in these maps. A further consequence of this approach is to enable direct visualisation of the topographic map onto projective spaces that discern structure in the data. The experimental results on standard databases reported in this paper, using self-organising maps and generative topographic mapping, illustrate the practical value of the proposed approach. The main novelty of our proposal is the definition of a systematic way to guide the search of data views in the grand tour, selecting and prioritizing some of them, based on nonlinear manifold models

Narratives for drug design

We explore the role of narratives of complex systems in anti-cancer drug design. We set out the value of narratives relating to cancer in promoting awareness of risky behaviour and in supporting decision-making regarding treatment options. We present cancer as a dysregulated, complex system that has emergent behaviours at multiple scales, and is governed by dynamical spatio-temporal processes. We show that this system changes structure and function in response to anti-cancer drugs, and explain that these changes are sufficiently complex to impede effective drug design. We pose what narrative might offer to support the process of drug design, providing an example of work done to date that might serve as a foundation for narrating complexity. We suggest ways of using this work combined with that of others to begin to consider narrating drug design

Effect of Antenatal Corticosteroid and Antibiotics in Pregnancies Complicated by Premature Rupture of Membranes between 24 and 28 weeks of Gestation

The aim of this study was to assess the effectiveness of active intervention with antenatal maternal corticosteroid and antibiotics therapy in infants delivered between 24 and 28 weeks of gestation after premature rupture of membrane. This retrospective study included pregnant women complicated by preterm delivery at the Dong-A University Hospital from 1998 to 2002. Patients were divided into labor induction group 1 (n=20), observation group 2 (n=19), and medication group 3 (n=20). We evaluated the effects of prolongation of pregnancy and intervention with maternal corticosteroids and antibiotics therapy on perinatal and neonatal outcomes. Each group did not have a significant difference (p<0.05) in neonatal outcomes, such as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, pneumonia, bronchopulmonary dysplasia, and sepsis. The mean latency period was 4.7 days and 7.6 days in groups 2 and 3, respectively. Therefore, this study was unable to demonstrate any beneficial effects of corticosteroids in improving neonatal outcomes and prolongation of the latency period with antibiotics

Protein Pattern Formation

Protein pattern formation is essential for the spatial organization of many intracellular processes like cell division, flagellum positioning, and chemotaxis. A prominent example of intracellular patterns are the oscillatory pole-to-pole oscillations of Min proteins in \textit{E. coli} whose biological function is to ensure precise cell division. Cell polarization, a prerequisite for processes such as stem cell differentiation and cell polarity in yeast, is also mediated by a diffusion-reaction process. More generally, these functional modules of cells serve as model systems for self-organization, one of the core principles of life. Under which conditions spatio-temporal patterns emerge, and how these patterns are regulated by biochemical and geometrical factors are major aspects of current research. Here we review recent theoretical and experimental advances in the field of intracellular pattern formation, focusing on general design principles and fundamental physical mechanisms.Comment: 17 pages, 14 figures, review articl

Simulation of Drosophila Circadian Oscillations, Mutations, and Light Responses by a Model with VRI, PDP-1, and CLK

A model of Drosophila circadian rhythm generation was developed to represent feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1, and vri (vrille). The model postulates that histone acetylation kinetics make transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity is essential to simulate robust circadian oscillations of transcription in our model and in previous models. Simulations suggest two positive feedback loops involving Clk are not essential for oscillations, because oscillations of [PER] were preserved when Clk, vri, or Pdp-1 expression was fixed. Eliminating the negative feedback loop in which PER represses per expression abolished oscillations. Simulations of per or Clk null mutations and of vri, Clk, or Pdp-1 heterozygous null mutations altered model behavior in ways similar to experimental data. The model simulated a photic phase-response curve resembling experimental curves, and oscillations entrained to simulated light-dark cycles. The model makes experimental predictions, some of which could be tested in transgenic Drosophila.Comment: Accepted to Biophysical Journal, 1/16/04. Single PDF file, 7 figures at en

Measurements of Deuteron Photodisintegration up to 4.0 GeV

The first measurements of the differential cross section for the d(gamma,p)n reaction up to 4.0 GeV were performed at Continuous Electron Beam Accelerator Facility (CEBAF) at Jefferson Lab. We report the cross sections at the proton center-of-mass angles of 36, 52, 69 and 89 degrees. These results are in reasonable agreement with previous measurements at lower energy. The 89 and 69 degree data show constituent-counting-rule behavior up to 4.0 GeV photon energy. The 36 and 52 degree data disagree with the counting rule behavior. The quantum chromodynamics (QCD) model of nuclear reactions involving reduced amplitudes disagrees with the present data.Comment: 5 pages (REVTeX), 1 figure (postscript