A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain

Alterations in sodium channel expression and function have been suggested as a key molecular event underlying the abnormal processing of pain after peripheral nerve or tissue injury. Although the relative contribution of individual sodium channel subtypes to this process is unclear, the biophysical properties of the tetrodotoxin-resistant current, mediated, at least in part, by the sodium channel PN3 (SNS), suggests that it may play a specialized, pathophysiological role in the sustained, repetitive firing of the peripheral neuron after injury. Moreover, this hypothesis is supported by evidence demonstrating that selective “knock-down” of PN3 protein in the dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury. In contrast, knock-down of NaN/SNS2 protein, a sodium channel that may be a second possible candidate for the tetrodotoxin-resistant current, appears to have no effect on nerve injury-induced behavioral responses. These data suggest that relief from chronic inflammatory or neuropathic pain might be achieved by selective blockade or inhibition of PN3 expression. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.

Estimation of evolutionary distances under stationary and nonstationary models of nucleotide substitution

Estimation of evolutionary distances has always been a major issue in the study of molecular evolution because evolutionary distances are required for estimating the rate of evolution in a gene, the divergence dates between genes or organisms, and the relationships among genes or organisms. Other closely related issues are the estimation of the pattern of nucleotide substitution, the estimation of the degree of rate variation among sites in a DNA sequence, and statistical testing of the molecular clock hypothesis. Mathematical treatments of these problems are considerably simplified by the assumption of a stationary process in which the nucleotide compositions of the sequences under study have remained approximately constant over time, and there now exist fairly extensive studies of stationary models of nucleotide substitution, although some problems remain to be solved. Nonstationary models are much more complex, but significant progress has been recently made by the development of the paralinear and LogDet distances. This paper reviews recent studies on the above issues and reports results on correcting the estimation bias of evolutionary distances, the estimation of the pattern of nucleotide substitution, and the estimation of rate variation among the sites in a sequence.

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of inherited blinding diseases caused by mutations in multiple genes including RDS. RDS encodes rds/peripherin (rds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) discs. Rom1 is related to rds with similar membrane topology and the identical distribution in OS. In contrast to RDS, no mutations in ROM1 alone have been associated with retinal disease. However, an unusual digenic form of RP has been described. Affected individuals in several families were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substitution in rds (L185P) and a null mutation in ROM1. Neither mutation alone caused clinical abnormalities. Here, we generated transgenic/knockout mice that duplicate the amino acid substitutions and predicted levels of rds and rom1 in patients with RDS-mediated digenic and dominant RP. Photoreceptor degeneration in the mouse model of digenic RP was faster than in the wild-type and monogenic controls by histological, electroretinographic, and biochemical analysis. We observed a positive correlation between the rate of photoreceptor loss and the extent of OS disorganization in mice of several genotypes. Photoreceptor degeneration in RDS-mediated RP appears to be caused by a simple deficiency of rds and rom1. The critical threshold for the combined abundance of rds and rom1 is ≈60% of wild type. Below this value, the extent of OS disorganization results in clinically significant photoreceptor degeneration.

Normal development and function of natural killer cells in CD3 epsilon delta 5/delta 5 mutant mice.

The CD3 epsilon polypeptide contributes to the cell surface display as well as to the signal transduction properties of the T-cell antigen receptor complex. Intriguingly, the distribution of CD3 epsilon is not restricted to T cells, since activated mouse, human, and avian natural killer (NK) cells do express intracytoplasmic CD3 epsilon polypeptides. CD3 epsilon is also present in the cytoplasm of fetal thymic T/NK bipotential progenitor cells, suggesting that it constitutes a component of the NK differentiation program. We report here that the genetic disruption of CD3 epsilon exon 5 alters neither NK cell development nor in vitro and in vivo NK functions, although it profoundly blocked T-cell development. These results support the notion that CD3 epsilon is dispensable for mouse NK cell ontogeny and function and further suggest that the common NK/T-cell progenitor cell utilizes CD3 epsilon as a mandatory component only when differentiating toward the T-cell lineage.

Dynamics of maize endosperm development and DNA endoreduplication.

Endosperm development in Zea mays is characterized by a period of intense mitotic activity followed by a period in which mitosis is essentially eliminated and the cell cycle becomes one of alternating S and G phases, leading to endoreduplication of the nuclear DNA. The endosperm represents a significant contribution to the grain yield of maize; thus, methods that facilitate the study of cellular kinetics may be useful in discerning cellular and molecular components of grain yield. Two mathematical models have been developed to describe the kinetics of endosperm growth. The first describes the kinetics of mitosis during endosperm development; the second describes the kinetics of DNA endoreduplication during endosperm development. The mitotic model is a modification of standard growth curves. The endoreduplication model is composed of six differential equations that represent the progression of nuclei from one DNA content to another during the endoreduplication process. Total nuclei number per endosperm and the number of 3C, 6C, 12C, 24C, 48C, and 96C nuclei per endosperm (C is the haploid DNA content per nucleus) for inbred W64A from 8 to 18 days after pollination were determined by flow cytometry. The results indicate that the change in number of nuclei expressed as a function of the number of days after pollination is the same from one yearly crop to another. These data were used in the model to determine the endosperm growth rate, the maximum nuclei number per endosperm, and transition rates from one C value to the next higher C value. The kinetics of endosperm development are reasonably well represented by the models. Thus, the models provide a means to quantify the complex pattern of endosperm development.

Exact and analytic-numerical solutions of lagging models of heat transfer in a semi-infinite medium

Different non-Fourier models of heat conduction have been considered in recent years, in a growing area of applications, to model microscale and ultrafast, transient, nonequilibrium responses in heat and mass transfer. In this work, using Fourier transforms, we obtain exact solutions for different lagging models of heat conduction in a semi-infinite domain, which allow the construction of analytic-numerical solutions with prescribed accuracy. Examples of numerical computations, comparing the properties of the models considered, are presented.

Development and psychometric testing of the clinical learning environment, supervision and nurse teacher evaluation scale (CLES+T): The Spanish version

Background: The Clinical Learning Environment, Supervision and Nurse Teacher scale is a reliable and valid instrument to evaluate the quality of the clinical learning process in international nursing education contexts. Objectives: This paper reports the development and psychometric testing of the Spanish version of the Clinical Learning Environment, Supervision and Nurse Teacher scale. Design: Cross-sectional validation study of the scale. Setting: 10 public and private hospitals in the Alicante area, and the Faculty of Health Sciences (University of Alicante, Spain). Participants: 370 student nurses on clinical placement (January 2011–March 2012). Methods: The Clinical Learning Environment, Supervision and Nurse Teacher scale was translated using the modified direct translation method. Statistical analyses were performed using PASW Statistics 18 and AMOS 18.0.0 software. A multivariate analysis was conducted in order to assess construct validity. Cronbach’s alpha coefficient was used to evaluate instrument reliability. Results: An exploratory factorial analysis identified the five dimensions from the original version, and explained 66.4% of the variance. Confirmatory factor analysis supported the factor structure of the Spanish version of the instrument. Cronbach’s alpha coefficient for the scale was .95, ranging from .80 to .97 for the subscales. Conclusion: This version of the Clinical Learning Environment, Supervision and Nurse Teacher scale instrument showed acceptable psychometric properties for use as an assessment scale in Spanish-speaking countries.

Syntactic and Semantic Relationships in Models of Complex Systems: An Ecological Case

In this paper, the authors extend and generalize the methodology based on the dynamics of systems with the use of differential equations as equations of state, allowing that first order transformed functions not only apply to the primitive or original variables, but also doing so to more complex expressions derived from them, and extending the rules that determine the generation of transformed superior to zero order (variable or primitive). Also, it is demonstrated that for all models of complex reality, there exists a complex model from the syntactic and semantic point of view. The theory is exemplified with a concrete model: MARIOLA model.

Development and experimental evaluation of a steel tube vehicle impact attenuation system. Final report.

Connecticut Department of Transportation, Bureau of Planning and Research, Wethersfield

Development and testing of INTRAS, a microscopic freeway simulation model. Volume 4: program documentation. Final report.

Federal Highway Administration, Office of Research and Development, Washington, D.C.

Development and verification of a three-dimensional numerical hydrodynamic, salinity, and temperature model of Chesapeake Bay.

Authors: B.H. Johnson, R.E. Heath, B.B. Hsieh, K.W. Kim, H.L. Butler.

Development and testing of INTRAS, a microscopic freeway simulation model. Volume 1: program design, parameter calibration and freeway dynamics component development. Final report.

Federal Highway Administration, Office of Research and Development, Washington, D.C.

Rear end structural crashworthiness of perimeter frame vehicles, design development and verification. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Development and testing of INTRAS, a microscopic freeway simulation model. Volume 2: user's manual. Final report.

Federal Highway Administration, Office of Research and Development, Washington, D.C.

Development and use of a computer simulation model for the evaluation of design and control alternatives for intersections of minor roads with multi-lane rural highways: field studies and model validation. Interim report.

Federal Highway Administration, Washington, D.C.