Teaching and learning /θ/: A non-confound

The purpose of this study was to replicate and extend the findings on the effectiveness of homonymous versus non-homonymous treatment approaches for children with phonological disorders, following Gierut (1991b). The present study was motivated by a potential confound noted in the previous report; namely, the specific sounds /θ, ð/ treated in the presumably less effective homonymous condition may have inhibited degree of phonological change. It was thus necessary to teach these more difficult, late-acquired interdental fricatives in the more effective non-homonymous treatment condition using identical methods and procedures. Results indicated that a non-homonymous teaching approach again motivated greater phonological change than a homonymous approach, regardless of sounds that were taught. These findings have implications for the independence of linguistic structures of treatment in inducing sound change, and bear upon assumptions about ease of sound learning based on normative developmental sequences.National Institutes of Health DC00433, RR7031K, DC00076, DC001694 (PI: Gierut)This is an Accepted Manuscript of an article published by Taylor & Francis in Clinical Linguistics & Phonetics on January 1992, available online: http://wwww.tandfonline.com/10.3109/02699209208985530

Strategies to Achieve Conditional Gene Mutation in Mice

The laboratory mouse is an ideal model organism for studying disease because it is physiologically similar to human and also because its genome is readily manipulated. Genetic engineering allows researchers to introduce specific loss-of-function or gain-of-function mutations into genes and then to study the resulting phenotypes in an in vivo context. One drawback of using traditional transgenic and knockout mice to study human diseases is that many mutations passed through the germline can profoundly affect development, thus impeding the study of disease phenotypes in adults. New technology has made it possible to generate conditional mutations that can be introduced in a spatially and/ or temporally restricted manner. Mouse strains carrying conditional mutations represent valuable experimental models for the study of human diseases and they can be used to develop strategies for prevention and treatment of these diseases. In this article, we will describe the most widely used DNA recombinase systems used to achieve conditional gene mutation in mouse models and discuss how these systems can be employed in vivo

Whole-Mount X-Gal Staining of Mouse Tissues

Although the development of improved mouse models, including conditional deletions, marks an exciting time in mouse genetics, it is important to characterize and validate these models. Cre reporter strains allow researchers to assess the recombinase expression profile and function in individual Cre mouse lines. These strains are engineered to express a reporter gene (usually LacZ) following the removal of a floxed STOP cassette, thus marking cell lineages that can be targeted with a given Cre line. This protocol provides a detailed method for the histochemical detection of β-galactosidase activity in Cre mouse strains

In Vivo Delivery of Lenti-Cre or Adeno-Cre into Mice Using Intranasal Instillation

Lung cancer remains the leading cause of cancer deaths among both men and women, with a lower rate of survival than both breast and prostate cancer. Development of the Cre/lox system and improved mouse models have allowed researchers to gain a better understanding of human disease, including lung cancer. Through the viral delivery of Cre, gene function in adult mice can be precisely studied at a specific developmental stage or in a specific cell/tissue type of choice. This protocol describes how to produce adenovirus-Cre precipitate. Using this adeno-Cre (or lentivirus-Cre), Cre can be expressed in mouse lungs. The virus is delivered by intranasal instillation

Producing and Concentrating Lenti-Cre for Mouse Infections

Lentiviral vectors offer versatility as vehicles for gene delivery. They can transduce a wide range of cell types and integrate into the host genome, which results in long-term expression of the transgene (Cre) both in vitro and in vivo. This protocol describes how lentiviral particles are produced, purified, and concentrated

Highly Successful Weight Control by Formerly Obese Adolescents: A Qualitative Test of the Healthy Obsession Model

Abstract Background: the Healthy Obsession Model (HOM) suggests that successful weight controllers must develop a preoccupation with the planning and execution of target behaviors to reach and maintain healthy weights (e.g., controlled eating, consistent selfmonitoring). this model further posits that committed weight controllers will feel substantial anxiety or frustration when lapses occur, which, in turn, will motivate them to reinstate target behaviors. Methods: the present study tested the HOM by examining the perceptions and attitudes of four very successful and four relatively unsuccessful adolescent weight controllers 1 year after completing immersion treatment. We expected that successful weight controllers, more so than unsuccessful weight controllers, would report more elaborate definitions of their healthy obsessions and describe more negative reactions to potential and actual lapses. in-depth interviews were conducted using a version of the scanlan Collaborative interview Method. Results and Conclusions: Reliable coding of the interviews produced results that supported the hypothesis that highly successful weight controllers seem to nurture strong healthy obsessions, including clear definitions of healthy obsessions, heightened commitment based on the emotional impact of excess weight, and negative reactions to lapses. in addition, these adolescent weight controllers seemed motivated by some of the same factors that elite athletes identified in the sport Commitment Model (e.g., emotional and experiential Consequences; social support of Parents, Friends, and Peers; institutional influences; and Valuable Opportunities)

Methods for Minimizing the Confounding Effects of Word Length in the Analysis of Phonotactic Probability and Neighborhood Density

This is the author's accepted manuscript. The original is available at http://jslhr.pubs.asha.org/article.aspx?articleid=1781521&resultClick=3Recent research suggests that phonotactic probability (the likelihood of occurrence of a sound sequence) and neighborhood density (the number of words phonologically similar to a given word) influence spoken language processing and acquisition across the lifespan in both normal and clinical populations. The majority of research in this area has tended to focus on controlled laboratory studies rather than naturalistic data such as spontaneous speech samples or elicited probes. One difficulty in applying current measures of phonotactic probability and neighborhood density to more naturalistic samples is the significant correlation between these variables and word length. This study examines several alternative transformations of phonotactic probability and neighborhood density as a means of reducing or eliminating this correlation with word length. Computational analyses of the words in a large database and reanalysis of archival data supported the use of z scores for the analysis of phonotactic probability as a continuous variable and the use of median transformation scores for the analysis of phonotactic probability as a dichotomous variable. Neighborhood density results were less clear with the conclusion that analysis of neighborhood density as a continuous variable warrants further investigation to differentiate the utility of z scores in comparison to median transformation scores. Furthermore, balanced dichotomous coding of neighborhood density was difficult to achieve, suggesting that analysis of neighborhood density as a dichotomous variable should be approached with caution. Recommendations for future application and analyses are discussed

Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif

The KRAS oncogene is mutated more frequently in human cancer than any other. The KRAS transcript is alternatively spliced to give rise to two products, K-Ras4A and K-Ras4B, both of which are oncogenic when KRAS is mutated. We detected significant amounts of each transcript in human tumor cells and colorectal carcinomas. We found that K-Ras4A is targeted to the plasma membrane by dual targeting motifs distinct from those of K-Ras4B. Because interfering with membrane association of Ras proteins remains one of the most attractive approaches to anti-Ras therapy, efforts in this direction will have to disrupt both the K-Ras4A and the K-Ras4B membrane-targeting pathways

Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression

N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in N-Ras occur in a subset of colorectal cancers, but little in known about how the mutant protein contributes to onset and progression of the disease. Using genetically engineered mice, we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation. The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function, which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3. As a result, inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients. These data demonstrate for the first time the important role that N-Ras plays in colorectal cancer.