Virus Infections--What of the Future?

The rate of progress in virus research today is so rapid that for many the present is the future. Consequently, in order to discuss the future in comprehensible fashion, I must talk about the present state of affairs--to discuss current knowledge which furnishes the basis for contemporary enormous interest in viruses. It is precisely those considerations which will furnish the springboard for future progress in understanding and controlling the effects of virus infections

Casidoro De Reina Translator of the Spanish Bible

Casiodoro de Reina printed the first complete Spanish Bible in 1569. The main purpose of this study is to present the biography of Casiodoro de Reina. It was considered of interest to observe what, if any, Lutheran influence could be traced in Reina\u27s Bible translation

FURTHER IMPLICATION OF MURINE LEUKEMIA-LIKE VIRUS IN THE DISORDERS OF NZB MICE

Further evidence implicating murine leukemia-like virus in the disorders of NZB mice was afforded by a study of antigens associated with murine leukemia virus (MuLV). MuLV group antigens were prevalent in extracts of spleen, kidney, and, to a lesser extent, thymus throughout a substantial portion of the life span of NZB mice as well as in extracts of lymphomas and sarcomas indigenous to the strain. G (Gross) soluble antigen, type-specific antigen, was first detected in plasma of untreated NZB mice at 3 months of age. G soluble antigen production increased thereafter in line with age, with 50% of reactions becoming positive at 5.3 months and 100% at 7 to 9 months. From months 3 to 9, the time-response curve for positive conversion of direct antiglobulin (Coombs) tests in untreated NZB mice corresponded closely to that for G soluble antigen production. Beyond the 9th month, G soluble antigen underwent elimination from the plasma of NZB mice, with positive reactions reduced to 50% at 13.3 months and to 0% at 18 months. G natural antibody was first detected in the serum of NZB mice at about 10 months of age and increased thereafter in line with age. The curves for G antibody production and G soluble antigen elimination bore a reciprocal relation to each other with crossover at 50% response occurring at 13.3 months. Significant proteinuria, a functional manifestation of membranous glomerulonephritis, became increasingly prevalent in female NZB mice as G soluble antigen was eliminated from plasma. Cumulative mortality of female NZB mice, mainly attributable to renal glomerular disease, increased in phase with G antibody production. MuLV group antigens were identified in the glomerular lesions by the immunofluorescence method. Positive conversion of direct antiglobulin tests was significantly delayed by vaccinating baby NZB mice with formaldehyde-inactivated cell-free filtrates of older NZB mouse spleens. The plasmas of vaccinated NZB mice with negative direct antiglobulin reactions at 4 to 7 months were likewise negative when tested for G soluble antigen. The 50% response time for G antibody production in the vaccinated NZB mice occurred at 7.3 months, that is, 6 months earlier than in untreated NZB mice. The collective findings implicate murine leukemia-like virus in the etiology of autoimmune hemolytic disease and membranous glomerulonephritis, as well as malignant lymphoma, of NZB mice and suggest that virus-specified cell-surface and soluble antigen is a factor in the immunopathogenesis of the renal disease and possibly also the autoimmune hemolytic disease

Cellular and Molecular Foundations of Mammary Branching Morphogenesis

Epithelial tubes provide the compartmentalization required for processes such as fluid and gas exchange, nutrient absorption, secretion, and waste elimination. Decades of study have provided insight into the genetic and molecular regulators of mammalian tube formation, but internal development left us with an incomplete understanding of how cells respond to these signals to build epithelial organs. Using organotypic culture of primary mouse mammary epithelium and time-lapse microscopy, we were able to study mammalian epithelial morphogenesis in real-time at subcellular resolution. This allowed us to identify the cellular and molecular mechanisms that underlie epithelial stratification and elongation. Mammary ducts transition from a simple polarized state to low-polarity stratified architecture at the onset of development. The low-polarity stratified epithelium then functions as the elongation front during mammary branch elongation. We determined that stratification was initiated by a novel vertical cell division of apically localized epithelial cells in culture and in vivo. The vertical divisions also directly resulted in the polarity-loss that is associated with the stratified epithelium. We then showed that this developmental mechanism of stratification could be hijacked in response to acute oncogene activation during the initial steps of tumor formation. To determine the cellular mechanism of mammary duct elongation we tracked the migration of individual cells within the epithelium. We found that cells at the elongation front displayed a significant increase in cell motility. When we decreased cell motility by inhibition of Rac we found that branches stopped elongating. The high motility cells were specifically enriched for high levels of mitogen-activated protein kinase (MAPK) signaling and MAPK signaling was required for branching. Mosaic expression of an activated mitogen-activated protein kinase kinase (MEK), a member of the MAPK cascade, was sufficient to induce branch elongation in the absence of external stimulation. We concluded that mammary branches are elongated by a subset of actively migrating epithelial cells and that the increase in cell motility is driven by MAPK signaling. Finally it is worth noting that collective cell migration through aberrant MAPK signaling is a key feature of tumor progression and here we show that MAPK signaling also drives collective cell migration in normal epithelium

Prediction of Effective Permittivity of Diphasic Dielectrics Using an Equivalent Capacitance Model

An analytical model based on an equivalent capacitance circuit for expressing a static effective permittivity of a composite dielectric with complex-shaped inclusions is presented. The dielectric constant of 0-3 composites is investigated using this model. The geometry of the capacitor containing a composite dielectric is discretized into partial parallel-plate capacitor elements, and the effective permittivity of the composite is obtained from the equivalent capacitance of the structure. First, an individual cell diphasic dielectric (a high-permittivity spherical inclusion enclosed in a lower permittivity parallelepiped) is considered. The capacitance of this cell is modeled as a function of an inclusion radius/volume fraction. The proposed approach is extended over a periodic three-dimensional structure comprised of multiple individual cells. The results of modeling are compared with results obtained using different effective medium theories, including Maxwell Garnett, logarithmic, Bruggeman, series, and parallel mixing rules. It is found that the model predictions are in good agreement with the experimental data. The equivalent capacitance model may be applied to composites containing inclusions of any geometry and size. Although the method presented is at static electric field, it can be easily generalized for prediction of frequency-dependent effective permittivity

Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure