Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy

<p>Abstract</p> <p>Background</p> <p>Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (<it>SMN1</it>) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil.</p> <p>Methods</p> <p>Fasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at <it>P </it>< 0.05. For the remaining analyses, the Student's two-tail <it>t </it>test for paired variables and one-way analysis of variance (ANOVA) were used to test for differences between samples and data were considered significantly different at <it>P </it>< 0.05.</p> <p>Results</p> <p>Fasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific.</p> <p>Conclusions</p> <p>Our work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA and for other degenerative diseases characterized by muscular atrophy and postsynaptic immaturity.</p

The importance of language for language development: Linguistic determinism in the 1980s

The semantic and syntactic functions of verbs are the major aspects of linguistic complexity that contribute to the cognitive requirements for learning language between two and three years of age. Several contrastive categories of verbs emerged from our studies with action/state as the largest and most general. Contrastive subcategories of action verbs were locative/nonlocative action, durative/nondurative action, and completive/noncompletive action. The subcategories of state verbs were volitional/epistemic/notice/communication states. The psychological and linguistic validity of these semantic categories rests on their being coextensive with major grammatical developments and/or their sequential development

Association of proximal elements of social disadvantage with children's language development at 2 years: An analysis of data from the Children in Focus (CiF) sample from the ALSPAC birth cohort

This is the peer reviewed version of the following article: Law, J., Clegg, J., Rush, R., Roulstone, S. & Peters, T. J. (2018) Association of proximal elements of social disadvantage with children's language development at 2 years: An analysis of data from the Children in Focus (CiF) sample from the ALSPAC birth cohort. International Journal of Language & Communication Disorders, which has been published in final form at https://doi.org/10.1111/1460-6984.12442. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Background: An association between social disadvantage and early language development is commonly reported in the literature, but less attention has been paid to the way that different aspects of social disadvantage affect both expressive and receptive language in the first 2 years of life. Aims: To examine the contributions of gender, parental report of early language skills and proximal social variables (the amount of stimulation in the home, the resources available to the child and the attitudes/emotional status of the primary carer and the support available to him/her) controlling for distal social variables (family income and maternal education) to children's expressive and receptive language development at 2 years in a community ascertained population cohort. Methods & Procedures: Data from 1314 children in the Children in Focus (CiF) sample from the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. Multivariable regression models identified the contribution of proximal (what parents do with their children) measures of social disadvantage adjusting for more distal (e.g., family income and material wealth) measures as well as early language development at 15 months to the development of verbal comprehension, expressive vocabulary and expressive grammar (word combinations) at 2 years of age. Outcome & Results: In the final multivariable models gender, earlier language and proximal social factors, co‐varying for distal factors predicted 36% of the variance for expressive vocabulary, 22% for receptive language and 27% for word combinations at 2 years. Language development at 15 months remained a significant predictor of outcomes at 24 months. Environmental factors were associated with both expressive scales but the picture was rather more mixed for receptive language suggesting that there may be different mechanisms underlying the different processes. Conclusions & Implications: This study supports the argument that social advantage makes a strong contribution to children's language development in the early years. The results suggest that what parents/carers do with their children is critical even when structural aspects of social disadvantage such as family income and housing have been taken into consideration although this relationship varies for different aspects of language. This has the potential to inform the targeting of public health interventions focusing on early language and pre‐literacy skills on the one hand and home learning environments on the other and, potentially, the two in combination.54pubpub

HIF-1 and SKN-1 Coordinate the Transcriptional Response to Hydrogen Sulfide in Caenorhabditis elegans

Hydrogen sulfide (H2S) has dramatic physiological effects on animals that are associated with improved survival. C. elegans grown in H2S are long-lived and thermotolerant. To identify mechanisms by which adaptation to H2S effects physiological functions, we have measured transcriptional responses to H2S exposure. Using microarray analysis we observe rapid changes in the abundance of specific mRNAs. The number and magnitude of transcriptional changes increased with the duration of H2S exposure. Functional annotation suggests that genes associated with protein homeostasis are upregulated upon prolonged exposure to H2S. Previous work has shown that the hypoxia-inducible transcription factor, HIF-1, is required for survival in H2S. In fact, we show that hif-1 is required for most, if not all, early transcriptional changes in H2S. Moreover, our data demonstrate that SKN-1, the C. elegans homologue of NRF2, also contributes to H2S-dependent changes in transcription. We show that these results are functionally important, as skn-1 is essential to survive exposure to H2S. Our results suggest a model in which HIF-1 and SKN-1 coordinate a broad transcriptional response to H2S that culminates in a global reorganization of protein homeostasis networks

Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer

Novel treatment strategies, including nanomedicine, are needed for improving management of triple-negative breast cancer. Patients with triple-negative breast cancer, when considered as a group, have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, a finding that reflects the intrinsically adverse prognosis associated with the disease. The aim of this study was to improve the efficacy of docetaxel by incorporation into a novel nanoparticle platform for the treatment of taxane-resistant triple-negative breast cancer. Rod-shaped nanoparticles encapsulating docetaxel were fabricated using an imprint lithography based technique referred to as Particle Replication in Nonwetting Templates (PRINT). These rod-shaped PLGA-docetaxel nanoparticles were tested in the C3(1)-T-antigen (C3Tag) genetically engineered mouse model (GEMM) of breast cancer that represents the basal-like subtype of triple-negative breast cancer and is resistant to therapeutics from the taxane family. Thi..

Avoiding dative overgeneralisation errors: semantics, statistics or both?

Item does not contain fulltextHow do children eventually come to avoid the production of overgeneralisation errors, in particular, those involving the dative (e.g., *I said her "no")? The present study addressed this question by obtaining from adults and children (5-6, 9-10 years) judgements of well-formed and over-general datives with 301 different verbs (44 for children). A significant effect of pre-emption - whereby the use of a verb in the prepositional-object (PO)-dative construction constitutes evidence that double-object (DO)-dative uses are not permitted - was observed for every age group. A significant effect of entrenchment - whereby the use of a verb in any construction constitutes evidence that unattested dative uses are not permitted - was also observed for every age group, with both predictors also accounting for developmental change between ages 5-6 and 9-10 years. Adults demonstrated knowledge of a morphophonological constraint that prohibits Latinate verbs from appearing in the DO-dative construction (e.g., *I suggested her the trip). Verbs' semantic properties (supplied by independent adult raters) explained additional variance for all groups and developmentally, with the relative influence of narrow- vs broad-range semantic properties increasing with age. We conclude by outlining an account of the formation and restriction of argument-structure generalisations designed to accommodate these findings.26 p

A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)

We present a measurement of time-dependent CP-violating asymmetries in neutral B meson decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data sample consists of 29.7 ${\rm fb}^{-1}$ recorded at the $\Upsilon(4S)$ resonance and 3.9 ${\rm fb}^{-1}$ off-resonance. One of the neutral B mesons, which are produced in pairs at the $\Upsilon(4S)$, is fully reconstructed in the CP decay modes $J/\psi K^0_S$, $\psi(2S) K^0_S$, $\chi_{c1} K^0_S$, $J/\psi K^{*0}$ ($K^{*0}\to K^0_S\pi^0$) and $J/\psi K^0_L$, or in flavor-eigenstate modes involving $D^{(*)}\pi/\rho/a_1$ and $J/\psi K^{*0}$ ($K^{*0}\to K^+\pi^-$). The flavor of the other neutral B meson is tagged at the time of its decay, mainly with the charge of identified leptons and kaons. The proper time elapsed between the decays is determined by measuring the distance between the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample finds $\Delta m_d = 0.516\pm 0.016 {\rm (stat)} \pm 0.010 {\rm (syst)} {\rm ps}^{-1}$. The value of the asymmetry amplitude $\sin2\beta$ is determined from a simultaneous maximum-likelihood fit to the time-difference distribution of the flavor-eigenstate sample and about 642 tagged $B^0$ decays in the CP-eigenstate modes. We find $\sin2\beta=0.59\pm 0.14 {\rm (stat)} \pm 0.05 {\rm (syst)}$, demonstrating that CP violation exists in the neutral B meson system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review

Measurement of the quasi-elastic axial vector mass in neutrino-oxygen interactions

The weak nucleon axial-vector form factor for quasi-elastic interactions is determined using neutrino interaction data from the K2K Scintillating Fiber detector in the neutrino beam at KEK. More than 12,000 events are analyzed, of which half are charged-current quasi-elastic interactions nu-mu n to mu- p occurring primarily in oxygen nuclei. We use a relativistic Fermi gas model for oxygen and assume the form factor is approximately a dipole with one parameter, the axial vector mass M_A, and fit to the shape of the distribution of the square of the momentum transfer from the nucleon to the nucleus. Our best fit result for M_A = 1.20 \pm 0.12 GeV. Furthermore, this analysis includes updated vector form factors from recent electron scattering experiments and a discussion of the effects of the nucleon momentum on the shape of the fitted distributions.Comment: 14 pages, 10 figures, 6 table

Study of e+e- --> pi+ pi- pi0 process using initial state radiation with BABAR

The process e+e- --> pi+ pi- pi0 gamma has been studied at a center-of-mass energy near the Y(4S) resonance using a 89.3 fb-1 data sample collected with the BaBar detector at the PEP-II collider. From the measured 3pi mass spectrum we have obtained the products of branching fractions for the omega and phi mesons, B(omega --> e+e-)B(omega --> 3pi)=(6.70 +/- 0.06 +/- 0.27)10-5 and B(phi --> e+e-)B(phi --> 3pi)=(4.30 +/- 0.08 +/- 0.21)10-5, and evaluated the e+e- --> pi+ pi- pi0 cross section for the e+e- center-of-mass energy range 1.05 to 3.00 GeV. About 900 e+e- --> J/psi gamma --> pi+ pi- pi0 gamma events have been selected and the branching fraction B(J/psi --> pi+ pi- pi0)=(2.18 +/- 0.19)% has been measured.Comment: 21 pages, 37 postscript figues, submitted to Phys. Rev.