Linguistic constraints on statistical word segmentation: The role of consonants in Arabic and English

Statistical learning is often taken to lie at the heart of many cognitive tasks, including the acquisition of language. One particular task in which probabilistic models have achieved considerable success is the segmentation of speech into words. However, these models have mostly been tested against English data, and as a result little is known about how a statistical learning mechanism copes with input regularities that arise from the structural properties of different languages. This study focuses on statistical word segmentation in Arabic, a Semitic language in which words are built around consonantal roots. We hypothesize that segmentation in such languages is facilitated by tracking consonant distributions independently from intervening vowels. Previous studies have shown that human learners can track consonant probabilities across intervening vowels in artificial languages, but it is unknown to what extent this ability would be beneficial in the segmentation of natural language. We assessed the performance of a Bayesian segmentation model on English and Arabic, comparing consonant-only representations with full representations. In addition, we examined to what extent structurally different proto-lexicons reflect adult language. The results suggest that for a child learning a Semitic language, separating consonants from vowels is beneficial for segmentation. These findings indicate that probabilistic models require appropriate linguistic representations in order to effectively meet the challenges of language acquisition

Conditional Wwox Deletion in Mouse Mammary Gland by Means of Two Cre Recombinase Approaches

Loss of WWOX expression has been reported in many different cancers including breast cancer. Elucidating the function of this gene in adult tissues has not been possible with full Wwox knockout models. Here we characterize the first conditional models of Wwox ablation in mouse mammary epithelium utilizing two transgenic lines expressing Cre recombinase, keratin 5-Cre (BK5-Cre) and MMTV-Cre. In the BK5-Cre model we observed very efficient Wwox ablation in KO mammary glands. However, BK5-Cre Wwox KO animals die prematurely for unknown reasons. In the MMTV-Cre model we observed significant ablation of Wwox in mammary epithelium with no effect on survival. In both of these models we found that Wwox deletion resulted in impaired mammary branching morphogenesis. We demonstrate that loss of Wwox is not carcinogenic in our KO models. Furthermore, no evidence of increase proliferation or development of premalignant lesions was observed. In none of the models did loss of a single Wwox allele (i.e. haploinsufficiency) have any observable phenotypic effect in mammary gland. To better understand the function of Wwox in the mammary gland, transcriptome profiling was performed. We observed that Wwox ablation results in the deregulation of genes involved in various cellular processes. We found that expression of the non-canonical Wnt ligand, Wnt5a, was significantly upregulated in Wwox KO mammary epithelium. Interestingly, we also determined that components of the Jak/Stat3 signaling pathway were upregulated in KO mice and this correlated with a very robust increase in phospho-Stat3 signaling, which warrants further testing. Even though the loss of Wwox expression in breast and other cancers is very well documented, our findings suggest that Wwox does not act as a classical tumor suppressor as previously thought

NADPH Oxidase 4 (Nox4) suppresses mitochondrial biogenesis and bioenergetics in lung fibroblasts via a nuclear factor erythroid-derived 2-like 2 (Nrf2)-dependent pathway

Mitochondrial bioenergetics are critical for cellular homeostasis and stress responses. The reactive oxygen speciesgenerating enzyme, NADPH oxidase 4 (Nox4), regulates a number of physiological and pathological processes, including cellular differentiation, host defense, and tissue fibrosis. In this study we explored the role of constitutive Nox4 activity in regulating mitochondrial function. An increase in mitochondrial oxygen consumption and reserve capacity was observed in murine and human lung fibroblasts with genetic deficiency (or silencing) of Nox4. Inhibition of Nox4 expression/activity by genetic or pharmacological approaches resulted in stimulation of mitochondrial biogenesis, as evidenced by elevated mitochondrial-to-nuclear DNA ratio and increased expression of the mitochondrial markers transcription factor A (TFAM), citrate synthase, voltage-dependent anion channel (VDAC), and cytochrome c oxidase subunit 4 (COX IV). Induction of mitochondrial biogenesis was dependent on TFAM up-regulation but was independent of the activation of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). The enhancement of mitochondrial bioenergetics as well as the increase in mitochondrial proteins in Nox4-deficient lung fibroblasts is inhibited by silencing of nuclear factor erythroid-derived 2-like 2 (Nrf2), supporting a key role for Nrf2 in control of mitochondrial biogenesis. Together, these results indicate a critical role for both Nox4 and Nrf2 in counter-regulation of mitochondrial biogenesis and metabolism.National Institutes of Health Grant P30AG050886)Peer Reviewe

Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma

<div><p>A small molecule which specifically blocks the interaction of Rictor and mTOR was identified utilizing a high-throughput yeast two-hybrid screen and evaluated as a potential inhibitor of mTORC2 activity in glioblastoma multiforme (GBM). <i>In vitro</i>, CID613034 inhibited mTORC2 kinase activity at submicromolar concentrations and in cellular assays specifically inhibited phosphorylation of mTORC2 substrates, including AKT (Ser-473), NDRG1 (Thr-346) and PKC<b>α</b> (Ser-657), while having no appreciable effects on the phosphorylation status of the mTORC1 substrate S6K (Thr-389) or mTORC1-dependent negative feedback loops. CID613034 demonstrated significant inhibitory effects on cell growth, motility and invasiveness in GBM cell lines and sensitivity correlated with relative Rictor or SIN1 expression. Structure-activity relationship analyses afforded an inhibitor, JR-AB2-011, with improved anti-GBM properties and blocked mTORC2 signaling and Rictor association with mTOR at lower effective concentrations. In GBM xenograft studies, JR-AB2-011 demonstrated significant anti-tumor properties. These data support mTORC2 as a viable therapeutic target in GBM and suggest that targeting protein-protein interactions critical for mTORC2 function is an effective strategy to achieve therapeutic responses.</p></div

<i>Wnt5a</i> expression increases in <i>BK5 Wwox KO</i> mammary epithelium.

<p>Semi-quantitative RT-PCR was performed on cDNA synthesized from RNA obtained from mammary epithelial organoids (3 different animals per group) as discussed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036618#s4" target="_blank">Materials and Methods</a>. Lanes from left to right are: (lanes 1–3) 8 week virgin <i>Wwox WT</i>, (lanes 4–6) P18.5 <i>Wwox WT</i>, (lanes 7–9) 8 week virgin <i>Wwox KO</i>, and (lanes 10–12) P18.5 <i>Wwox KO</i>. <i>Wwox</i> expression is shown in the middle panel as further verification of <i>Wwox</i> ablation. <i>Gapdh</i> expression is shown as a normalization control. Each PCR reaction was performed at 24, 26, 28 and 32 cycles to ensure that reaction was in linear range. Results shown at 24 cycles.</p

<i>Wwox-KO BK5-Cre</i> transgenic mice model gene expression profile study.

<p>(A) Heatmap of the differentially expressed genes between <i>Wwox WT vs. Wwox KO</i> mammary gland epithelial organoid samples (p<0.01; 2 Fold changes). Color scale at bottom of picture is used to represent expression level: low expression is represented by green, and high expression is represented by red. (B) Expression graph of the 913 deregulated probes (136 probes down-modulated and 777 up-modulated) among <i>Wwox WT</i> and <i>Wwox KO</i> mammary epithelial organoid samples. (C) Scatterplot graph showing the representative clusters, after redundancy reduction of the statistical significant GO terms (p<0.025) enriched in the deregulated gene list, in a two dimensional space related to GO terms' semantic similarities. Bubble color indicates the p-value of GO terms (expressed as Log10 p-value) and bubble size indicates the frequency of the GO term in the underlying GOA database (bubbles of more general terms are larger).</p

<i>Wwox</i> deletion correlates with increased phospho-Stat3 protein in mammary epithelium.

<p>(A–B) Immunostaining for phospho-Stat3 (pStat3) protein in histological sections from 12 week virgin <i>BK5 Wwox WT</i> (A) and <i>Wwox KO</i> (B) mammary glands. Strong nuclear staining can be seen in the majority of cells in <i>Wwox KO</i> sections. (C) Quantification of percentage of cells positive for pStat3 staining in <i>Wwox WT</i> (n = 3) and <i>Wwox KO</i> (n = 3) histological sections. A total of 1000 cells were counted from random fields within each sample. (D) Whole cell lysates from mammary epithelial organoids from P18.5 <i>BK5 Wwox WT</i> (n = 3; WT4, WT5, WT6) and <i>Wwox KO</i> (n = 3; KO4, KO5, KO6) mice, were probed pStat3 levels. Wwox protein levels are shown to verify Wwox knockdown. Total Stat3 levels are shown as a control and Actin protein levels are shown as a loading control.</p

Conditional <i>KO</i> of <i>Wwox via BK5-Cre</i> and <i>MMTV-Cre</i>.

<p>(A–F) Immunostaining of formalin-fixed histological sections of mammary glands from each model of deletion reveals strong cytoplasmic Wwox staining in <i>WT</i> samples and significant loss of Wwox protein expression in <i>KO</i> animals. (A) 8 week virgin <i>BK5 Wwox WT</i>, (B) 8 week virgin <i>BK5 Wwox KO</i>, (C) P18.5 days <i>BK5 Wwox WT</i>, (D) P18.5 days <i>BK5 Wwox KO</i>, (E) 24 week virgin <i>MMTV Wwox WT</i>, (F) 24 week <i>MMTV Wwox KO</i>. Rabbit anti-Wwox <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036618#pone.0036618-Bednarek2" target="_blank">[14]</a> antibody was used at a 1∶50 dilution and counterstained with hematoxylin. All images were obtained at the same 10× magnification.</p