How to survive a nerve-wracking journey

When the axons that carry signals to muscles are growing, they rely on help from Frizzled3—a protein that is known to perform a number of other important functions in cells—to reach their final destination

Early Language and Literacy Skills of Spanish-Speaking Dual Language Learners

The purpose of this study is to examine the early language measures that are the best predictors of English reading achievement and to determine whether assessing DLLs’ Spanish language skills contributes to the prediction of English reading achievement. Preschool and kindergarten often represent DLLs’ first significant exposure to English, and development of English language proficiency is strongly linked to English reading achievement (Storch & Whitehurst, 2002). Because DLLs may not be exposed to English consistently prior to preschool or kindergarten, they often enter kindergarten with lower levels of English proficiency than their monolingual peers. This makes it difficult to identify DLLs who may be at risk for reading difficulties based on their language proficiency. Currently, many measures exist to assess the early language skills of dual language learners early in school, but little research has been conducted to compare which assessments are the best predictors of students’ future English reading achievement. The fact that many DLLs enter elementary school with low English proficiency complicates identification of students at risk for later difficulties. For example, is the limited English proficiency of DLLs simply a result of lack of exposure? Or do DLLs also have low proficiency in their first language (Spanish)? Therefore, an additional purpose to this study is to examine whether assessing children’s language skills in Spanish further contributes to prediction of English reading achievement

Expression and functionality of beta-chemokines in endothelial cells of the rheumatoid synovium

RA is a destructive and chronic autoimmune inflammatory disease. The inflammation of the synovium is associated with the local invasion of inflammatory cells across blood vessel endothelial cells (ECs), increases in synovial fluid volume and local pannus invasion of the connective tissues and bone. Synovial ECs in RA are involved in a wide range of processes, and chemokines are known mediators of inflammatory cell invasion into the tissue. Chemokines at the ECs of lymph vessels play a further role in attracting the infiltrates out of the tissue. This study used immunofluorescence to investigate the presentation of a number chemokines in RA tissue ECs, and also the presentation of CCL7, CCL14, CCL16 and CCL22 in lymphatic ECs. A number of chemokines were newly identified in synovial ECs, and continued investigation showed a marked dysregulation in blood vessel and lymphatic vessel chemokine presentation, including CCL7. In vitro studies showed that the chemokines also preferentially generated microvilli which may facilitate transendothelial migration in vivo. Mononuclear cells expressed the receptors for the chemokines and transmigration analysis showed CCL7 (among others) to significantly chemoattract monocytes. This suggests that dysregulation of chemokines may have a functional role in RA pathology. Furthermore, the analysis of these chemokines in matched synovial fluid (DF) and serum indicates that EC chemokines may be inflammatory markers in arthritic diseases. Overall, this study has shown that the EC interface between the influx and efflux of inflammatory cells in the RA synovium may offer currently unexplored therapeutic opportunities

Vertebrate Lrig3-ErbB Interactions Occur In Vitro but Are Unlikely to Play a Role in Lrig3-Dependent Inner Ear Morphogenesis

Background: The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes. Methodology/Principal Findings: Here, we report that Lrig3, like Lrig1, is able to interact with ErbB receptors in vitro. We examined the in vivo significance of these interactions in the inner ear, where Lrig3 controls semicircular canal formation by determining the timing and extent of Netrin1 expression in the otic vesicle epithelium. We find that ErbB2 and ErbB3 are present in the early otic epithelium, and that Lrig3 acts cell-autonomously here, as would be predicted if Lrig3 regulates ErbB2/B3 activity. However, inhibition of ErbB activation in the chick otic vesicle has no detectable effect on Netrin gene expression or canal morphogenesis. Conclusions/Significance: Our results suggest that although both Lrig1 and Lrig3 can interact with ErbB receptors in vitro, modulation of Neuregulin signaling is unlikely to contribute to Lrig3-dependent processes of inner ear morphogenesis. These results highlight the similar binding properties of Lrig1 and Lrig3 and underscore the need to determine how these two family members bind to and regulate different receptors to affect diverse aspects of cell behavior in vivo

Comparison of Phenotypes between Different vangl2vangl2 Mutants Demonstrates Dominant Effects of the LooptailLooptail Mutation during Hair Cell Development

Experiments utilizing the $Looptail$ mutant mouse, which harbors a missense mutation in the $vangl2$ gene, have been essential for studies of planar polarity and linking the function of the core planar cell polarity proteins to other developmental signals. Originally described as having dominant phenotypic traits, the molecular interactions underlying the $Looptail$ mutant phenotype are unclear because Vangl2 protein levels are significantly reduced or absent from mutant tissues. Here we introduce a $vangl2$ knockout mouse and directly compare the severity of the knockout and $Looptail$ mutant phenotypes by intercrossing the two lines and assaying the planar polarity of inner ear hair cells. Overall the $vangl2$ knockout phenotype is milder than the phenotype of compound mutants carrying both the $Looptail$ and $vangl2$ knockout alleles. In compound mutants a greater number of hair cells are affected and changes in the orientation of individual hair cells are greater when quantified. We further demonstrate in a heterologous cell system that the protein encoded by the Looptail mutation $(Vangl2^{S464N})$ disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface as a result of oligomer formation between Vangl1 and $Vangl2^{S464N}$, or Vangl2 and $Vangl2^{S464N}$, coupled to the intracellular retention of $Vangl2^{S464N}$. As a result, Vangl1 protein is missing from the apical cell surface of vestibular hair cells in $Looptail$ mutants, but is retained at the apical cell surface of hair cells in $vangl2$ knockouts. Similarly the distribution of Prickle-like2, a putative Vangl2 interacting protein, is differentially affected in the two mutant lines. In summary, we provide evidence for a direct physical interaction between Vangl1 and Vangl2 through a combination of in vitro and in vivo approaches and propose that this interaction underlies the dominant phenotypic traits associated with the $Looptail$ mutation

Vertebrate Lrig3-ErbB Interactions Occur In Vitro but Are Unlikely to Play a Role in Lrig3-Dependent Inner Ear Morphogenesis.

The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes

A Spatial and Temporal Gradient of Fgf Differentially Regulates Distinct Stages of Neural Development in the Zebrafish Inner Ear

Neuroblasts of the statoacoustic ganglion (SAG) initially form in the floor of the otic vesicle during a relatively brief developmental window. They soon delaminate and undergo a protracted phase of proliferation and migration (transit-amplification). Neuroblasts eventually differentiate and extend processes bi-directionally to synapse with hair cells in the inner ear and various targets in the hindbrain. Our studies in zebrafish have shown that Fgf signaling controls multiple phases of this complex developmental process. Moderate levels of Fgf in a gradient emanating from the nascent utricular macula specify SAG neuroblasts in laterally adjacent otic epithelium. At a later stage, differentiating SAG neurons express Fgf5, which serves two functions: First, as SAG neurons accumulate, increasing levels of Fgf exceed an upper threshold that terminates the initial phase of neuroblast specification. Second, elevated Fgf delays differentiation of transit-amplifying cells, balancing the rate of progenitor renewal with neuronal differentiation. Laser-ablation of mature SAG neurons abolishes feedback-inhibition and causes precocious neuronal differentiation. Similar effects are obtained by Fgf5-knockdown or global impairment of Fgf signaling, whereas Fgf misexpression has the opposite effect. Thus Fgf signaling renders SAG development self-regulating, ensuring steady production of an appropriate number of neurons as the larva grows

Treatment intensity and characteristics of MRSA infection in CF

Background: Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and interchange of hospital-associated strains carrying the staphylococcal chromosomal cassette mec-II (SCCmec-II) with those in the community (SCCmec-IV) has increased. This study assesses the impact of MRSA and different MRSA types on clinical outcomes, medication use, and antibiotic sensitivities. Methods: MRSA isolates from CF patients at our center were typed by SCCmec- and pvl status. Patient characteristics, lung function and nutrition are compared between MRSA types and to age, gender and Pseudomonas aeruginosa matched patients with chronic methicillin sensitive S. aureus (MSSA) infection. Results: Seventy-two percent of patients carry pvl negative SCCmec-II isolates. Seventeen percent of all MRSA were SCCmec-IV pvl positive (USA300). These patients were younger and fewer had chronic P. aeruginosa infection, whereas pvl-negative SCCmec-IV isolates show highest antibiotic resistance. Nutritional outcomes and FEV1 percent predicted (75.1±2.7 versus 77.9±2.7) did not differ in patients with MRSA compared to those with MSSA but MRSA patients received more pulmonary maintenance but not oral antibiotic medications. Conclusion: Patients with chronic MRSA are treated more intensely than age, gender and Pseudomonas aeruginosa matched MSSA-positive patients but clinical characteristics within MRSA patients vary depending on MRSA types