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A single E-box in the <i>Cel-lin-3</i> CRM is not sufficient for <i>lin-3</i> expression in the anchor cell of <i>C</i>. <i>elegans</i>.
No full text(A) New cis-regulatory lin-3 alleles with deleted E-boxL and NHR or NHR and E-boxR. (B) Quantification of vulval induction in these new mutants. Note the complete absence of any induction in the recovered lin-3 alleles (n>30). Scorings of lin-3(1417) animals are the same as those reported in Fig 5 and are used here to indicate that this mutation leads to vulval hypo-induction rather than no induction at all. (C-D) smFISH in lin-3(mf72) (C) and N2 (D) animals. Green spots correspond to lin-3 transcripts and red spots to lag-2 that is used as an anchor cell marker. Blue is DAPI staining of nuclei. Note the absence of lin-3 expression in the anchor cell in the lin-3(mf72) mutant animal. Absence of lin-3 signal in the anchor cell was also confirmed for the other lin-3 alleles.</p
The stem cell E3-ligase Lin-41 promotes liver cancer progression through inhibition of microRNA-mediated gene silencing
No full textLin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is over-expressed in hepatocellular carcinoma (HCC). Lin-41 over-expression correlates with high a-fetoprotein level, high tumour grade and high tumour stage and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knock-down by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, over-expression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Over-expression and knock-down of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Over-expression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 over-expression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor (IGF1R). Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of c-Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
On the sheaf-theoretic SL(2, C) Casson–Lin invariant
No full textWe prove that the (τ-weighted, sheaf-theoretic) SL(2, C) Casson–Lin invariant introduced by Manolescu and the first author is generically independent of the parameter τ and additive under connected sums of knots in integral homology 3-spheres. This addresses two questions asked by Manolescu and the first author. Our arguments involve a mix of topology and algebraic geometry, and rely crucially on the fact that the SL(2, C) Casson–Lin invariant admits an alternative interpretation via the theory of Behrend functions.</p
Spatial Chow-Lin Methods for Data Completion in Econometric Flow Models
Get PDFFlow data across regions can be modeled by spatial econometric models, see LeSage and Pace (2009). Recently, regional studies became interested in the aggregation and disaggregation of flow models, because trade data cannot be obtained at a disaggregated level but data are published on an aggregate level. Furthermore, missing data in disaggregated flow models occur quite often since detailed measurements are often not possible at all observation points in time and space. In this paper we develop classical and Bayesian methods to complete flow data. The Chow and Lin (1971) method was developed for completing disaggregated incomplete time series data. We will extend this method in a general framework to spatially correlated flow data using the cross-sectional Chow-Lin method of Polasek et al. (2009). The missing disaggregated data can be obtained either by feasible GLS prediction or by a Bayesian (posterior) predictive density.Missing values in spatial econometrics, MCMC, non-spatial Chow-Lin (CL) and spatial Chow-Lin (SCL) methods, spatial internal flow (SIF) models, origin and destination (OD) data
LIN-39 promotes neuronal fate specification in the Q and V5 lineage.
No full text(A) The expression of lin-39 in AVM, SDQL/R, PDEL/R, and PVDL/R, indicated by the overlapping with neurotransmitter identity markers and specific fate markers (uIs115[mec-17p::TagRFP] for AVM, otIs181[dat-1p::mCh] for PDE, uIs117[lad-2p::mCh] for SDQ). (B) The expression of mab-5 in SDQL. (C) Summary of lin-39 (green) and mab-5 (cyan) expression in the descendants of Q and V5 lineages. (D) The loss of gcy-37 expression in AQR and AVM neurons in lin-39(n1760) mutants and the mispositioning of PQR in mab-5(gk670) mutants; the loss of lad-2 expression in SDQR in lin-39(n1760) mutants, the displacement of SDQL in mab-5(gk670) mutants, and the loss of lad-2 expression in both SDQs in lin-39(n1760) mab-5(e1239) mutants. The right panels show the penetrance for the loss of marker expression and cell body mispositioning. Mean ± SD for the percentage of cells showing corresponding phenotypes from three biological replicates are shown. Double asterisks indicate statistically significant difference (p Chi-square test. (E) The loss of ser-2 expression in PVD and PDE neurons and the loss of F49H12.4 expression in PVD in lin-39(n1760) and ceh-20(u843) mutants. (F) Dopaminergic marker dat-1 is normally expressed in PDE neurons in lin-39 mutants, but PDE shows axonal growth defects. The arrows indicate the termini of PDE axons. The expression of glutamatergic identity marker eat-4 and the PVD terminal selector gene mec-3 in PVD neurons in lin-39 mutants.</p
LIN-2 and FRM-3 are required to maintain locomotory behaviour.
No full text(A) Genomic structure of lin-2 and frm-3 locus, mutant allele characterization, and protein architecture for LIN-2 and FRM-3. The whole promoter region of lin-2a and part of the kinase domain of LIN-2A is deleted in the e1309 mutants. The FERM domain in both frm-3a and frm-3b is deleted in the gk585 mutants. Syb1019 and syb1036 are stop codons in lin-2 and frm-3 that inactivate the expression of lin-2a and lin-2b, and frm-3a and frm-3b. (E, F) Locomotion speed is reduced by the loss of LIN-2 and FRM-3. Representative trajectories of locomotion in wild type (E) and mean locomotion speed in wild type, lin-2(e1309), frm-3(gk585), lin-2(syb1019), frm-3(syb1036), and lin-2(e1309);frm-3(gk585) mutants. To measure locomotion speed, young adult animals were washed with a drop of PBS and then transferred to fresh NGM plates with no bacterial lawn (30 worms per plate). Worm movement recordings (under room temperature 22°C) were started 10 min after the worms were transferred. A 2 min digital video of each plate was captured at 3.75 Hz frame rate by WormLab System (MBF Bioscience). Average speed and tracks were generated for each animal using WormLab software. To confirm the repeatability of the data, the locomotion speed was measured in two independent experiments in two days. For each mutant, around 10–40 animals were analyzed in one experiment. Significance was tested for each experiment. Data are mean ± SEM (**, p p < 0.001 when compared to wild type; n.s., non-significant; one-way ANOVA). The number of worms analyzed for each genotype is indicated in the bar.</p
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<it>lin-12 </it>Notch functions in the adult nervous system of <it>C. elegans</it>
Get PDFAbstract Background Notch signaling pathways are conserved across species and traditionally have been implicated in cell fate determination during embryonic development. Notch signaling components are also expressed postdevelopmentally in the brains of adult mice and Drosophila. Recent studies suggest that Notch signaling may play a role in the physiological, rather than developmental, regulation of neurons. Here, we investigate a new non-developmental role for Caenorhabditis elegans lin-12 Notch signaling in neurons regulating the spontaneous reversal rate during locomotion. Results The spontaneous reversal rate of C. elegans during normal locomotion is constant. Both lin-12 gain and loss of function mutant animals had significantly increased reversal rates compared to wild type controls. These defects were caused by lin-12 activity, because the loss of function defect could be rescued by a wild type lin-12 transgene. Furthermore, overexpression of lin-12 recapitulated the gain-of-function defect. Increasing or decreasing lin-12 activity in the postdevelopmental adult animal was sufficient to rapidly and reversibly increase reversals, thereby excluding a developmental role for lin-12. Although lin-12 is expressed in the vulval and somatic gonad lineages, we find that these tissues play no role in regulating reversal rates. In contrast, altering lin-12 activity specifically in the nervous system was sufficient to increase reversals. These behavioral changes require components of the canonical lin-12 signaling cascade, including the ligand lag-2 and the transcriptional effector lag-1. Finally, the C. elegans AMPA/kainate glutamate receptor homolog glr-1 shows strong genetic interactions with lin-12, suggesting that glr-1 and/or other glutamate gated channels may be targets of lin-12 regulation. Conclusion Our results demonstrate a neuronal role for lin-12 Notch in C. elegans and suggest that lin-12 acutely regulates neuronal physiology to modulate animal behavior, without altering neuronal cell fate specification or neurite outgrowth. This is consistent with a role for Notch signaling in neurological disease with late onset symptoms.</p
Mammalian LIN-7 PDZ proteins associate with beta-catenin at the cell junctions of epithelia and neurons
No full textThe heterotrimeric PDZ complex containing LIN-2, LIN-7 and LIN-10 is known to be involved in the organization of epithelial and neuronal junctions in Caenorhabditis elegans and mammals. We report here that mammalian LIN-7 PDZ proteins form a complex with cadherin and β-catenin in epithelia and neurons. The association of LIN-7 with cadherin and β-catenin is Ca2+ dependent and is mediated by the direct binding of LIN-7 to the C-terminal PDZ target sequence of β-catenin, as demonstrated by means of co-immunoprecipitation experiments and in vitro binding assays with the recombinant glutathione S-transferase:LIN-7A. The presence of β-catenin at the junction is required in order to relocate LIN-7 from the cytosol to cadherin-mediated adhesions, thus indicating that LIN-7 junctional recruitment is β-catenin dependent and that one functional role of the binding is to localize LIN-7. Moreover, when LIN-7 is present at the β-catenin-containing junctions, it determines the accumulation of binding partners, thus suggesting the mechanism by which β-catenin mediates the organization of the junctional domai
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