Bacteriophage-resistance systems in dairy starter strains: molecular analysis to application

Starter inhibition by bacteriophage infection in dairy fermentations can limit the usage of specific bacterial strains used in the manufacture of Cheddar, Mozzarella and other cheeses and can result in substantial economic losses. A variety of practical measures to alleviate the problem of phage infection have been adopted over the years but has invariably resulted in a very limited number of strains which can withstand intensive usage in industry. The application of genetic techniques to improve the phage-resistance of starter cultures for dairy fermentations has been intensively studied for the last 20 years to a point where this approach now has significant potential to alleviate the problem. This paper highlights the recent findings and developments that have been described in the literature that will have an impact on improvement of the phage-resistance of starter cultures.     

Use of factor analysis to characterize arterial geometry and predict hemodynamic risk: application to the human carotid bifurcation

The detailed geometry of atherosclerosis-prone vascular segments may influence their susceptibility by mediating local hemodynamics. An appreciation of the role of specific geometric variables is complicated by the considerable correlation among the many parameters that can be used to describe arterial shape and size. Factor analysis is a useful tool for identifying the essential features of such an inter-related data set, as well as for predicting hemodynamic risk in terms of these features and for interpreting the role of specific geometric variables. Here, factor analysis is applied to a set of 14 geometric variables obtained from magnetic resonance images of 50 human carotid bifurcations. Two factors alone were capable of predicting 12 hemodynamic metrics related to shear and near-wall residence time with adjusted squared Pearson's correlation coefficient as high as 0.54 and P-values less than 0.0001. One factor measures cross-sectional expansion at the bifurcation; the other measures the colinearity of the common and internal carotid artery axes at the bifurcation. The factors explain the apparent lack of an effect of branch angle on hemodynamic risk. The relative risk among the 50 bifurcations, based on time-average wall shear stress, could be predicted with a sensitivity and specificity as high as 0.84. The predictability of the hemodynamic metrics and relative risk is only modestly sensitive to assumptions about flow rates and flow partitions in the bifurcation.     

A simple local sensitivity analysis tool for nonignorable coarsening: application to dependent censoring

Right- and interval-censored data are common special cases of coarsened data (Heitjan and Rubin, 1991, Annals of Statistics19, 2244-2253). As with missing data, standard statistical methods that ignore the random nature of the coarsening mechanism may lead to incorrect inferences. We extend a simple sensitivity analysis tool, the index of local sensitivity to nonignorability (Troxel, Ma, and Heitjan, 2004, Statistica Sinica14, 1221-1237), to the evaluation of nonignorability of the coarsening process in the general coarse-data model. By converting this index into a simple graphical display one can easily assess the sensitivity of key inferences to nonignorable coarsening. We illustrate the validity of the method with a simulated example, and apply it to right-censored data from an observational study of cardiac transplantation and to interval-censored data on time to detectable viral load from a clinical trial in HIV disease.     

A simple method to approximate gene content in large pedigree populations: application to the myostatin gene in dual-purpose Belgian Blue cattle

Gene content is the number of copies of a particular allele in a genotype of an animal. Gene content can be used to study additive gene action of candidate gene. Usually genotype data are available only for a part of population and for the rest gene contents have to be calculated based on typed relatives. Methods to calculate expected gene content for animals on large complex pedigrees are relatively complex. In this paper we proposed a practical method to calculate gene content using a linear regression. The method does not estimate genotype probabilities but these can be approximated from gene content assuming Hardy-Weinberg proportions. The approach was compared with other methods on multiple simulated data sets for real bovine pedigrees of 1 082 and 907 903 animals. Different allelic frequencies (0.4 and 0.2) and proportions of the missing genotypes (90, 70, and 50%) were considered in simulation. The simulation showed that the proposed method has similar capability to predict gene content as the iterative peeling method, however it requires less time and can be more practical for large pedigrees. The method was also applied to real data on the bovine myostatin locus on a large dual-purpose Belgian Blue pedigree of 235 133 animals. It was demonstrated that the proposed method can be easily adapted for particular pedigrees.     

Inverse analysis and robustness evaluation for biological structure behaviour in FE simulation: application to the liver

To prevent traumas to abdominal organs, the selection of efficient safety devices should be based on a detailed knowledge of injury mechanisms and related injury criteria. In this sense, finite element (FE) simulation coupled with experiment could be a valuable tool to provide a better understanding of the behaviour of internal organs under crash conditions. This work proposes a methodology based on inverse analysis which combines exploration process optimisation and robustness study to obtain mechanical behaviour of the complex structure of the liver through FE simulation. The liver characterisation was based on Mooney-Rivlin hyperelastic behaviour law considering whole liver structure under uniform quasi-static compression. With the global method used, the model fits experimental data. The variability induced by modelling parameters is quantified within a reasonable time.     

Inverse analysis and robustness evaluation for biological structure behaviour in FE simulation: application to the liver

To prevent traumas to abdominal organs, the selection of efficient safety devices should be based on a detailed knowledge of injury mechanisms and related injury criteria. In this sense, finite element (FE) simulation coupled with experiment could be a valuable tool to provide a better understanding of the behaviour of internal organs under crash conditions. This work proposes a methodology based on inverse analysis which combines exploration process optimisation and robustness study to obtain mechanical behaviour of the complex structure of the liver through FE simulation. The liver characterisation was based on Mooney–Rivlin hyperelastic behaviour law considering whole liver structure under uniform quasi-static compression. With the global method used, the model fits experimental data. The variability induced by modelling parameters is quantified within a reasonable time.     

Manipulating redox systems: application to nanotechnology

Redox proteins and enzymes are attractive targets for nanobiotechnology. The theoretical framework of biological electron transfer is increasingly well-understood, and several properties make redox centres good systems for exploitation: many can be detected both electrochemically and optically; they can perform specific reactions; they are capable of self-assembly; and their dimensions are in the nanoscale. Great progress has been made with the two main approaches of protein engineering: rational design and combinatorial synthesis. Rational design has put our understanding of the structure-function relationship to the test, whereas combinatorial synthesis has generated new molecules of interest. This article provides selected examples of novel approaches where redox proteins are "wired up" in efficient electron-transfer chains, are "assembled" in artificial multidomain structures (molecular Lego), are "linked" to surfaces in nanodevices for biosensing and nanobiotechnological applications.     

Functional genomics via multiscale analysis: application to gene expression and ChIP-on-chip data

We present a fast, versatile and adaptive-multiscale algorithm for analyzing a wide-variety of DNA microarray data. Its primary application is in normalization of array data as well as subsequent identification of 'enriched targets', e.g. differentially expressed genes in expression profiling arrays and enriched sites in ChIP-on-chip experimental data. We show how to accommodate the unique characteristics of ChIP-on-chip data, where the set of 'enriched targets' is large, asymmetric and whose proportion to the whole data varies locally. SUPPLEMENTARY INFORMATION: Supplementary figures, related preprint, free software as well as our raw DNA microarray data with PCR validations are available at http://www.math.umn.edu/~lerman/supp/bioinfo06 as well as Bioinformatics online.     

A simple SIS epidemic model with a backward bifurcation

It is shown that an SIS epidemic model with a non-constant contact rate may have multiple stable equilibria, a backward bifurcation and hysteresis. The consequences for disease control are discussed. The model is based on a Volterra integral equation and allows for a distributed infective period. The analysis includes both local and global stability of equilibria.     

Absolute enrichment: gene set enrichment analysis for homeostatic systems

The Gene Set Enrichment Analysis (GSEA) identifies sets of genes that are differentially regulated in one direction. Many homeostatic systems will include one limb that is upregulated in response to a downregulation of another limb and vice versa. Such patterns are poorly captured by the standard formulation of GSEA. We describe a technique to identify groups of genes (which sometimes can be pathways) that include both up- and down-regulated components. This approach lends insights into the feedback mechanisms that may operate, especially when integrated with protein interaction databases.     

Temporal analysis of metabolic systems and its application to metabolite channelling

When a metabolic system undergoes a transition between steady states, the lag or transition time of the system is determined by the aggregated lifetimes of the metabolite pools. This allows the transition time, and hence the temporal responsiveness of the system, to be estimated from a knowledge of the starting and finishing steady states and obviates the need for dynamic measurements. The analysis of temporal response in metabolic systems may be integrated with the general field of metabolic control analysis by the definition of a temporal control coefficient (C) in terms of flux and concentration control coefficients. The temporal control coefficient exhibits summation and other properties analogous to the flux and concentration control coefficients. For systems in which static metabolite channels exits, the major kinetic advantage of channelling is a reduction in pool sizes and, as a result, a more rapid system response reflected in a reduced transition time. The extent of the channelling advantage may therefore be assessed from a knowledge of the system transition time. This reveals that no channelling advantage is achieved at high enzyme concentration (i.e., comparable to K_m) or, in the case of ‘leaky’ channels, where rapid equilibrium kinetic mechanisms obtain. In the case of a perfect channel with no leakage and direct transfer of metabolite between adjacent enzyme active sites, the transition time is minimized and equal to the lifetime of the enzyme–substrate complex.     

Inverse and forward dynamics: models of multi-body systems

Connected multi-body systems exhibit notoriously complex behaviour when driven by external and internal forces and torques. The problem of reconstructing the internal forces and/or torques from the movements and known external forces is called the 'inverse dynamics problem', whereas calculating motion from known internal forces and/or torques and resulting reaction forces is called the 'forward dynamics problem'. When stepping forward to cross the street, people use muscle forces that generate angular accelerations of their body segments and, by virtue of reaction forces from the street, a forward acceleration of the centre of mass of their body. Inverse dynamics calculations applied to a set of motion data from such an event can teach us how temporal patterns of joint torques were responsible for the observed motion. In forward dynamics calculations we may attempt to create motion from such temporal patterns, which is extremely difficult, because of the complex mechanical linkage along the chains forming the multi-body system. To understand, predict and sometimes control multi-body systems, we may want to have mathematical expressions for them. The Newton-Euler, Lagrangian and Featherstone approaches have their advantages and disadvantages. The simulation of collisions and the inclusion of muscle forces or other internal forces are discussed. Also, the possibility to perform a mixed inverse and forward dynamics calculation are dealt with. The use and limitations of these approaches form the conclusion.     

An application of the non-linear bifurcation theory to tumor growth modeling

The purpose of the work reported in this paper was to understand how a few cancerous cells (either from the primary growth, or as result of breaking away from a tumor and lodging in a different part of the body — metastasis) can grow to form a sizable mass and what decides whether such growth will indeed take place. The intermediate region, lying between the molecular (or micro) level to the fully developed (or macro) level, is not readily accessible to experimental observations. A mathematical model with a firm physiological basis has been proposed to develop a unified field theory that bridges the two regimes. The techniques of non-linear global analysis have been used. The global behavior, (which determines the long-term prognosis), is found to be significantly influenced by the presence or absence of two critical bifurcations. Both of these have practical consequences regarding the inception and the cure of the disease. Several conclusions have been drawn which lead to practical suggestions for experimentation. It is predicted that reducing the food intake immediately after an exposure to carcinogens, would lead to a reduced chance of cancer. A preliminary case has been made to lend support to the idea that an absence of snacking (and even periodic fasting) might work as a preventive measure against cancer.