Non-linear regression of biological temperature-dependent rate models based on absolute reaction-rate theory

Biological temperature-dependent rate models based on Arrhenius' and Eyring's equations have been formulated by Johnson & Lewin (1946), Hultin (1955), and Sharpe & DeMichele (1977). The original formulation of Sharpe and DeMichele is poorly suited for non-linear regression. Very high correlations of parameter estimators occassionally make regression with their equation impossible using Marquardt's algorithm (1963).This analysis describes a new formulation of Sharpe and DeMichele's model that greatly alleviates the non-linear regression problem. It is partly based on Hultin's formulation (1955). Biological and graphical interpretation of the model parameters is discussed. Regression suitability is illustrated with a typical data set. Similar modifications to the equations of Hultin (1955) and Johnson & Lewin (1946) are described.     

The development of experimental allergic encephalomyelitis with immunizing doses of myelin basic protein.

Rabbits immunized with low (11.25 mg) and high (57.50 mg) doses of myelin basic protein from several species develop antibasic protein antibodies, delayed type hypersensitivity, and clinical and pathological signs of experimental allergic encephalomyelitis. More than 55% of rabbits immunized with relatively high doses of basic protein develop disease. The absence of circulating antibasic protein antibodies in immunorespondent animals is associated with the appearance of clinical or histological signs of experimental allergic encephalomyelitis; however, the presence of humoral antibodies did not prevent completely the development of disease. Delayed-type hypersensitivity, specific for the basic protein, appears as early as 5 days after immunization and is maintained in nondiseased and surviving animals. Neither excess encephalitogen nor encephalitogen-induced antibody is sufficient to suppress completely the eventual development of clinical or histological manifestations of disease.     

Studies on closure of the ductus arteriosus. XII. effect of indomethacin and sodium salicylate in rats and rabbits

Administration of prostaglandin synthetase inhibitors to pregnant does and dams in late gestation was followed by contraction of the fetal ductus arteriosus when studied by the whole-body freezing method. In the rat this contraction was well established within 6 h and persisted up to 36 h following 15 mg/kg indomethacin p.o. No effect was observed in the 18 d rat fetus but fetuses at 20 d and 22 d of gestation responded significantly to indomethacin. Doses of indomethacin approaching clinical usage (2.5 mg/kg) also caused a positive response . The rat was found to be sensitive also to sodium salicylate and in the rabbit both indomethacin and sodium salicylate were effective. Exposure to prostaglandin synthetase inhibitors with resulting contraction of the ductus may seriously disturb cardiac function in the fetus.     

Intratumor heterogeneity of biomarker expression in breast carcinomas

Small biopsy samples are used increasingly to assess the biomarker expression for prognostic information and for monitoring therapeutic responses prior to and during neoadjuvant therapy. The issue of intratumor heterogeneity of expression of biomarkers, however, has raised questions about the validity of the assessment of biomarker expression based on limited tissue samples. We examined immunohistochemically the expression of HER-2neu (p185^erbB-2), epidermal growth factor receptor (EGFR), Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) in 30 breast carcinomas using archived, paraffin embedded tissue and determined the extent of intratumor heterogeneity. Each section was divided into four randomly oriented discrete regions, each containing a portion of the infiltrating carcinoma. For each tumor, the entire lesion and four regions were analyzed for the expression of these markers. Scores of both membrane and cytoplasmic staining of HER-2neu and EGFR, scores of cytoplasmic staining of Bcl-2, and scores of nuclear staining of both p53 and PCNA were recorded. The intensity of staining and the proportion of immunostained cells were determined. A semiquantitative immunoscore was calculated by determining the sum of the products of the intensity and corresponding proportion of stained tumor cells. We analyzed both invasive (IDC) and in situ (DCIS) carcinomas. The Wilcoxon signed-rank test was used for paired comparisons between overall and regional immunoscores and between overall and regional percentages of stained cells. Spearman's correlation coefficients were used to assess the level of agreement of overall biomarker expression with each of the regions. Generalized linear models were used to assess overall and pair-wise differences in the absolute values of percent changes between overall and regional expression of biomarkers. For IDCs, there were no statistically significant differences in the expression of the biomarkers in terms of either the percentage of cells staining or the immunoscores when comparing the entire tumor with each region except for the lower EGFR expression of arbitrarily selected region 1 and lower p53 expression of region 1 compared to that of the entire tumor section. For DCIS, there were no statistically significant differences in the expression of the biomarkers between the entire tumor and each region except in PCNA of region 2 compared to that of entire tumor section. Positive correlation of immunoscores was observed between the entire tumor and each region as well as across all four regions for IDC. Similar observations were noted with DCIS except for HER-2neu and PCNA. No statistically significant differences were observed in the absolute values of percent changes of biomarker expression between overall and the four regions for both DCIS and IDC. Therefore, no significant intratumor heterogeneity in the expression of HER-2neu, Bcl-2, and PCNA was observed in IDC. Minor regional variations were observed for EGFR and p53 in IDC. Similarly, no significant regional variation in the expression of markers was observed in DCIS except for PCNA.     

Near Infrared Optical Projection Tomography for Assessments of β-cell Mass Distribution in Diabetes Research

By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen''s (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)²; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction² and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations³. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.     

Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control.     

On the Mechanical Interplay Between Intra- and Inter-Synchronization During Collective Cell Migration: A Numerical Investigation

Collective cell migration is a fundamental process that takes place during several biological phenomena such as embryogenesis, immunity response, and tumorogenesis, but the mechanisms that regulate it are still unclear. Similarly to collective animal behavior, cells receive feedbacks in space and time, which control the direction of the migration and the synergy between the cells of the population, respectively. While in single cell migration intra-synchronization (i.e. the synchronization between the protrusion-contraction movement of the cell and the adhesion forces exerted by the cell to move forward) is a sufficient condition for an efficient migration, in collective cell migration the cells must communicate and coordinate their movement between each other in order to be as efficient as possible (i.e. inter-synchronization). Here, we propose a 2D mechanical model of a cell population, which is described as a continuum with embedded discrete cells with or without motility phenotype. The decomposition of the deformation gradient is employed to reproduce the cyclic active strains of each single cell (i.e. protrusion and contraction). We explore different modes of collective migration to investigate the mechanical interplay between intra- and inter-synchronization. The main objective of the paper is to evaluate the efficiency of the cell population in terms of covered distance and how the stress distribution inside the cohort and the single cells may in turn provide insights regarding such efficiency.     

Caspase‐7 participates in differentiation of cells forming dental hard tissues

Apoptosis during tooth development appears dependent on the apoptotic executioner caspase‐3, but not caspase‐7. Instead, activated caspase‐7 has been found in differentiated odontoblasts and ameloblasts, where it does not correlate with apoptosis. To further investigate these findings, the mouse incisor was used as a model. Analysis of caspase‐7‐deficient mice revealed a significant thinner layer of hard tissue in the adult incisor. Micro computed tomography scan confirmed this decrease in mineralized tissues. These data strongly suggest that caspase‐7 might be directly involved in functional cell differentiation and regulation of the mineralization of dental matrices.