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Representative confocal images of Cav1 staining in heart sections from control and RbpjiΔEC mice. n=3, scale bar 50 µm.
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Length distribution of chromatin-bound and nucleoplasmic piRNA precursors in wild type N2 nematodes, calculated from two merged replicates.
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G, J Impact of TRAF6-expression on in vitro Treg differentiation. naïve CD4+ T cells were isolated from Traf6fl/flFoxp3Cre+ and Traf6fl/fl mice and differentiated into iTregs. Conditions of sub-optimal TGFβ concentrations (0.5ng/ml, 0.05ng/ml) were tested as well and intracellular FOXP3 was measured after 4 days.
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D. Schematic representation visualizing the hGID E3 ligase complex using two distinct modules for substrate recruitment.
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Relative intracellular Fe2+ levels in normoxic B16-F10 cells (n=4). Representative pictures of FerroOrange intensity are shown on the left and analyzed using a RM one-way ANOVA (Geisser-Greenhouse correction) with Holm-Sidak's multiple comparisons test. Scale bars represent 50µm.
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(C Small RNA and Poly(A)-selected RNA sequencing based estimates of the fold difference (y-axis) in (C) miRNA relative to day 0, during a 12 days' time-course (x-axis) following treatment of DTCM23/49XY mESCs with 4-OHT and consequent loss of DICER function. Points represent the average miRNA or mRNA expression and error bars the standard deviation based on three independent biological replicates.
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C: The pie chart depicts the percentage of patients of the PDAC cohort (n=75) belonging to the three PRMT1 expression scores: not elevated, moderately elevated and highly elevated PRMT1 expression.
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A. Representative confocal microscopy images of cells transfected GFP-LC3 and Parkin-Cherry, treated as indicated, fixed 24h after AICD induction and immunostained with anti-TOM20 antibody are shown. Scale bar, 5μm.
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I) Synaptic surface GluA quantitation showing no effect of PTX3 treatment in TSG6 KO cultures. On the contrary WT cultures (from littermates) display increased surface GluA&Bsn/Bsn upon PTX3 treatment. A significant enhancement of surface GluA receptors was induced by TTX in both TSG6 KO and WT cultures (WT=1±0.06; WT+PTX3=1.389±0.113; WT+TTX=1.698±0.109; Number of fields examined: 40, 39, 32 respectively; Kruskall-Wallis test p<0.0001 followed by post hoc Dunn"s test. TSG6 KO=1.000±0.047; TSG6 KO+PTX3=0.979±0.048; TSG6 KO+TTX=1.363±0.077. Number of fields examined: 54, 57, 29 respectively; one-way ANOVA analysis of variance, p<0.0001 followed by post hoc Tukey test as indicated in figure. n=3 independent experiments, data are presented as normalized mean values
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B Immunoblotting of protein extracts from SKMEL5 cells transfected with siCTRL or the combination siDDR1#2/siDDR2#2 prior being cultivated on FRC- or MAF-derived ECMs (left and right panels, respectively) and treated with vehicle, 5 µM BRAFi or 2 µM BRAFi plus 0.01 µM MEKi, using antibodies against the indicated proteins. HSP60, loading control.
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A, B Nucleosome maps at and surrounding, the TSS region of the NANOG and GRIA1 genes in pl-iPSC (upper, black) and in NPC cells (lower, grey). The TSS is indicated by a dashed line at chr 12: 7,941,991 for NANOG and chr5: 152,870,105 for GRIA1. * indicates the position of a highly positioned nucleosome associated with the TSS of the active gene.
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A, Western blot analysis of 293T cells treated with 20 μM erastin for the indicated times.
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(D) Control and GRASP55KO cells were processed for Cy3-conjugated Shiga Toxin (ShTxB) and Alexa488-conjugated Cholera Toxin (ChTxB) staining followed by flow cytometry analysis. Mean fluorescence intensity was measured and represented.
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G Schema of experimental design. H2030-BrM cells were implanted intracranially into nude mice and established brain metastases were surgically resected. DEBIO-0932 was administered orally at 160 mg/kg 3 days later and during 5-6 weeks following an individualized regimen. Sx: surgery.
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D HeLa cells were treated with control or siRNA targeting ALFY. 72 h after transfection, cells were treated with puromycin with or without bafilomycin A1 for 2 h and total cell lysates were fractionated into TX−100−soluble and insoluble fractions. The TX−100−soluble/insoluble fractions were then immunoblotted with the indicated antibodies. Data are representative of three independent experiments.
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(B-D) Representative single channel traces and summary plot upon depolarization from -80 to 0 mV under control conditions and in the presence of ISO in the patch pipette. Cultures were pre-incubated for 15 min with 10 M 11R-PKI if indicated. The patch pipette contained either vehicle for control, nifedipine (nif; 1M), ISO (1M), or ISO plus nifedipine, which blocked all currents. The ISO-induced increase in NPo was prevented by 11R-PKI.
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A-C Representative images shown for olive oil treated (n=5) or chronic CCl4 (n=5) induced fibrosis or following sham operation (n=6 Sox9fl/fl;AlbCre-; n=5 Sox9fl/fl;AlbCre+) or BDL (n=5 Sox9fl/fl;AlbCre-; n=8 Sox9fl/fl;AlbCre+) induced fibrosis. SOX9 immunohistochemistry (brown; A), in situ hybridization for Sox9 (brown) and α-Sma (red) and collagen deposition by PSR staining (red; B) in control (Sox9fl/fl;AlbCre-) or Sox9-null (Sox9fl/fl;AlbCre+) mice following fibrosis. Higher magnified image of SOX9 localization in discrete cells within the scar is shown for CCl4 and BDL in the Sox9fl/fl;AlbCre+ mice (A).
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(E) Immunoblot analysis of the BioID assay with an N-terminally Flag BirA*-tagged SLC25A46 showing an interaction of SLC25A46 with EMC1, EMC2 and MFN2.
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D-F Two‐month‐old APC+/+ mice and APCmin/+ mice were exposed to 6 Gy γ‐irradiation. Small intestinal tissue was collected at 24 h after IR (n = 3 mice per group). (D) Quantification of PCNA+ ISPCs at the indicated positions in basal crypts 24 h after IR. IR, irradiated. (E, F) Representative pictures of PCNA staining are given. Arrowheads and numbers indicate cell positions in the crypts. Scale bar: 20 μm.
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(J-L) Cumulative population doublings of patient-derived KRAS-mutant LUAD cell lines that are either (J, K) NF1-mutant (PDKN1 and PDKN2) or (L) NF1-WT (PDK) after selection with sgTom- or sgPsat1-containing vectors (n = 4 biological replicates).
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(A) Western blot analysis showing the expression of the WRNIP1 protein in wild-type cells (shWRNIP1WT) and WRNIP1-deficient (shWRNIP1) or mutant (shWRNIP1T294A) cells. MRC5SV fibroblasts were used as a positive control. The membrane was probed with an anti-FLAG or anti-WRNIP1. GAPDH was used as a loading control. Below each lane of the blot the ratio of WRNIP1 protein to total protein, then normalised to MRC5SV, is reported.
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I Alignment of the genomic region 1.5 Kb upstream of the mammalian Sln gene using the ECR Browser (http://ecrbrowser.dcode.org/). Human was used as the reference genome. The location of conserved NFAT binding sites are indicated by blue diamonds and CREB sites by yellow. Sites were conserved across all mammalian species available in the database except opossum. Mouse, rat, and dog are provided as representative examples. The structure of the Sln-Luc reporter construct is aligned below.
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A. Schematic representation of the domain structure of Nmd4 and Ebs1 from S. cerevisiae compared with human (h) Smg6, Smg5 and Smg7. 14-3-3, HHR and PIN domains were defined based on literature data (Fukuhara et al, 2005; Luke et al, 2007). Boundaries of the PIN domains were chosen based on a Mafft alignment of Smg5/6 of several species, while for Nmd4 the entire protein sequence was used. Drawing is not to scale. Identity percentages among the different domains of Smg proteins, Nmd4 and Ebs1 are indicated. Values represent percent of identical residues as a fraction of all the aligned residues
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H&E images of paraffin-embedded liver sections from 9-week-old mice (n=4 per group, 3 independent repeats).
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Combined IF and DNA FISH for RAD51 (IF) and telomeres (FISH) in SaOS2 or HuO9 cells. Cells were transfected with 20nM siRAD54#2 for 48 hours immediately prior to staining. Scale bars = 10 µm Quantification of A. A cell was counted as positive it is contained at least 1 colocalization event between RAD51 and telomeres. At least 100 cells were counted per condition per repeat, n=3. Values shown are mean±sd. Data were compared using standard two-way ANOVA followed by Sidak's multiple comparison test.
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(B) Coomassie-stained SDS PAGE gel showing proteins immunoprecipitated from schizonts expressing SERA6-mTAP, sampled at the indicated times following C2 washout or arrested with E64 (50 μM). Control, proteins immunoprecipitated from SERA6:loxP (Thomas et al, 2018) schizonts, which express non-epitope-tagged SERA6, sampled at 5 min following C2 washout. Arrowed, species analysed by mass spectrometric peptide mapping. Fragments A-H were identified as SERA6-mTAP-derived, while fragments I and J were derived from a different protein, PF3D7_1014100.
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Longitudinal associations between CSF T-tau, Ng and NFL and other AD traits. Data are estimates (-coefficients) from linear mixed effects models, with 95 % confidence intervals. The estimates are the effect of time plus the biomarker by time interactions, capturing the longitudinal effects of the biomarkers. For each model, the "average" effect of time is also shown for comparison. Effects were significant (*), meaning that biomarker levels affected the slopes of the outcome, for lateral ventricles: Ng (p=.0051) and NFL (p<.0001) in A-negative and NFL (p<.0001) in A-positive. Biomarkers and outcomes were standardized to z-scores. Note that the y-axes for ventricle size are flipped, so that the lower ranges constantly reflect "worse" outcomes. Note also that the range of the y-axes differs for the different outcomes, for visualization purposes. Models were adjusted for age and sex, and education (for cognitive measures), and intracranial volume (for MRI measures). Aβ42 and T-tau were measured using the the INNOBIA AlzBio3 kit (Fujirebio, Ghent, Belgium), Ng was measured using an in-house immunoassay for Ng (Portelius et al, 2015) and NFL was measured using the NF-light® ELISA kit (Uman Diagnostics, Umeå, Sweden).
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(C) Quantification of normalized MA current amplitudes from DRG neurons, vehicle (white, n=7), neurons responding to baclofen (R, red) (n=6, **P<0.01, Paired t-test and non-responding DRG neurons (NR, blue, n=6). Striped column shows the average normalized current amplitudes 3-10 minutes after removal of baclofen in responding neurons (Washout) (n=6). Data are shown as mean ± SEM and scatter plots.
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(G) IRE1 cleavage assay performed using synthetic pre-miR-2137 (50 nM) as substrate with active, recombinant IRE1 (100 ng) at 37℃ for 2 hours, followed by sample separation in Urea-PAGE and detection with SYBR gold staining. M indicates micro RNA marker.
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Schematic representation of the novel TRF1 regulatory pathways. Data are represented as mean ± SEM. n represents biological replicates. Significant differences using unpaired t‐test are indicated by *P < 0.05, **P < 0.01, ***P < 0.001.
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(F, G) Indicated promoter activation was analyzed with luciferase assay. DKK1 was used as a control. Results of relative fold changes are shown as means ± S.D. Data represent five independent replicates. . ** p<0.01 by two-tailed Student's t-test. .
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(G) Samples from an analogous experiment to that shown in (F) were analysed by immunoblotting of the indicated factors. The asterisk indicates a non-specific band in the immunoblot for histone H2B.
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Wnt inhibition using siRNA against β-catenin or ETC-159 treatment reduces the expression of HR and FA pathway genes in PaTu8988T cells. PaTu8988T cells were transfected with indicated control or β-catenin siRNAs or treated with ETC-159 (1 µM) for 48 hours, total RNA was isolated and expression of β-catenin (CTNNB1), AXIN2 and DNA repair genes was measured by qRT-PCR. The horizontal lines represent mean of replicates.
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(a) MSCV retroviral constructs introduced in P14 cells (Supplementary Fig. 2a) to probe for autophagy activity, showing the transgenes encoding GFP-tagged wild-type LC3b (top; WT GFP-LC3b) and the GFP-tagged G120A mutant of LC3b (bottom; G120A GFP-LC3b). LTR, long terminal repeat; IRES, internal ribosomal entry site.
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(J) Y245F mutant induced more LC3 lipidation after 1h cGAMP treatment of 293XL cells expressing WT or mutant STING.
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H Diffusion coefficient of lysosome in the experiments shown in G. Means ± SEM of n = 4 cells per group.
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F Time course analysis of the splicing pattern of Chinese hamster Clk1 pre-mRNAs in control (CHO) and CHO (His9) cells by semi-quantitative RT-PCR. Arrows indicate the positions of PCR primers. The GAPDH mRNA was used as an internal control.
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(D-F) RT-qPCR measurement of mRNA levels of Defa6 and Lyz2, two Paneth cell markers, and Ripk3, a TNF-induced cell-death gene, in ileum of the experiment in A.
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A,B) Scatterplots showing that the wPRS correlates with A) adjusted baseline performance on the ECAS ALS-Specific, Total, Executive Function, and Language scores, and B) rate of decline on the ALS-Specific, ALS-Non-Specific, and Total scores.
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(A) Beclin 1 (BCN1) interactors identified by yeast two‐hybrid technology. Proteins binding to BCN1 are listed and their interacting domains are indicated by black bars. Numbers refer to amino‐acid positions.
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K, Reduced numbers of c-Fos-positive cells in CA3 of KO mice (n = 4 mice, WT; n = 5 mice, KO).
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C Pathways and networks constructed using genes within 50 kb of AR binding locations enhanced in prostate tumors. Nodes and corresponding pathways are extracted according to interaction annotation. Literature‐based network is configured as PROSTATIC NEOPLASMS (Genomatix Mining).
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D. Reduced TLR3-stimulated IRF3 nuclear translocation in mTORA/A primary macrophages: BMDMs were treated -/+ poly (I:C) for 3 hr as in A, fixed, and processed for confocal immunofluorescence microscopy using an anti-IRF3-Alexa 488 antibody and Dapi stain. The graph represents the mean +/- SEM of at least 270 cells total from four independent experiments. *p=.001 relative to mTOR+/+ no Poly(I:C) by unpaired t-test (equal variance; two-tailed). **p=.02 relative to mTOR+/+ + Poly(I:C) by unpaired t-test (equal variance; two-tailed). Scale bar = 10 μM.
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H) basal (P=0.002) and ATP-linked respiration, proton leak (P=0.0003), maximal uncoupling, spare respiratory capacity (P<0.0001), and non-mitochondrial respiration (N=5 per condition).
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A Representative 3-color STED images of synapses of cultured hippocampal neurons fixed and stained for Synapsin1/2 (presynaptic marker), PI(3) P and Homer (postsynaptic marker). Scale bar, 0.5 µm. PI(3) P-positive structures appear in both pre- and postsynaptic compartments. B Line scan fluorescence intensity profiles of single synapses from the images in A, normalized to maximum value for each channel. Data information: Data presented as mean ± SEM n.s. not significant; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001
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C) Confocal immunofluorescence image of a fPHH monolayer at 5 days post plating, stained with hGK (red), hGS (green), DAPI (blue) and phalloidin (cyan). Arrow point towards a typical hepatocyte subpopulation shown by different colours. Objective 40x; scale bar 25 µm.
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Western blot images (left) and TRF1 protein levels (right) measured in h676 GSCs 24h after treatment with the indicated compounds as single agents or in combination. Data are representative of (DMSO in (PI3Ki in
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] |
Representative fluorescence microscopy images of mCherry and DPOD2::GFP expression in female and male gametocytes of the DTS1 (ccp2::mCherry;dpod2::gfp) and DTS1;Δap2-o3 strains. mCherry is specifically expressed in female gametocytes. Flow cytometry detection of mCherry and DPOD2::GFP expression in female and male gametocytes of the DTS1 and DTS1;Δap2-o3 strains. The female and male gametocyte populations are circled by solid and dashed line respectively. E,F Similar analysis (as in C, D) in DTS2 (ccp2::mCherry;dpod1::gfp) and DTS2;Δap2-o3 strains. G,H Similar analysis (as in C, D) in DTS3 (ccp2::mCherry;rpa1::gfp) and DTS3;Δap2-o3 strains. I,J Similar analysis (as in C, D) in DTS4 (ccp2::mCherry;mcm7::gfp) and DTS4;Δap2-o3 strains.
|
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E Representative H&amp;E images of intestine samples corresponding to untreated and ETP-47037-treated animals. High-magnification images are shown to the right indicating the presence of normal mitosis, giant multinucleated and aberrant mitotic figures.
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(A) qPCR analysis of the fold changes±s.d. of ft transcription. Downregulation starts at 2 days and progresses at 14 days.
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ChIP-seq tracks of T (in red; input is in blue) around the Oct4 (7.5 kb). DE, distal enhancer; PE, proximal enhancer. The T-binding peak around the Oct4-DE is indicated (arrowhead). Right: ChIP-qPCR for the enrichment of T on the DE and the regions indicated in Fig EV3E. NC, negative control (the locus without T binding). The enrichment is indicated by the percent input with SDs (three independent experiments with two technical replicates).
|
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C. Close up view on the localization of Elp3 and the orientation of its KAT and SAM domain in relation to Elp1 and Elp2.
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C) FRAP analysis of FM4-64-labeled wildtype cells was performed by acquiring pictures in continuous acquisition mode after bleaching, for a total period of 5 s. Three representative frames after photobleaching are shown. The bars in the magnified parts of frames 2 and 3 illustrate the positions at which the recovery of FM4-64 fluorescence was quantified. Scale bar: 2 µm. D) Quantification of recovery experiments in (C). A delay of >50 ms between the appearance of the signal on both sides of the photobleached vacuole was considered as asymmetric recovery. The histogram shows means and s.d. from 3 independent experiments evaluating 50 stained vacuoles each. A Schematic view of the various possible positions of a fusion pore and its consequences for our ability to detect asymmetric FM4-64 recovery. The contact zone between the two vacuoles is tilted by 90° in the middle panel, which gives four examples for the positioning of the pore (shown as a black dot). Asymmetric recovery could only be detected if the pore is sufficiently far from the center of the contact zone and close to the optical plane that is imaged (the cases marked in red).
|
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One targeted clone from each gRNA (1.16, 2.18, 3.3) including the non-targeted clone 2.19 and WT control were serum starved for 48 h to induce ciliogenesis. Subsequently, cilia length was measured. The cilia from DBN1 KO cells were significantly longer than those from WT or non-targeted controls. Three independent experiments; N = 150 cilia for each experiment and condition. Mean ± SD. **** P≤ 0.0001.
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(A) N‐ (left) and C‐ (right) GFP‐tagged ATG36 under control of the GAL1 promoter was induced in atg36Δ or atg1Δ cells. Early (2 h) and later (5 h) time points after induction are shown. Pexophagy is assessed using the peroxisomal marker HcRed-PTS1 expressed from the constitutive HIS3 promoter.
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GW11 EGFR-expressing cells exhibited radial glia morphology and most co-expressed SOX9 (A) but not OLIG2 (B). However, EGFR co-expression with SOX9 or OLIG2 was found in GW17 EGFR-expressing cells (C, D). White dashed lines marked dorsal horn borders. Higher-magnification view of boxes on left. Scale bars: 100 μm.
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(a) General domain structure of human VPS34 kinase comprising the helical domain (yellow) and the kinase domain (green). The ATP-binding pocket and active site lie between the amino-terminal lobe and the carboxy-terminal lobe of the kinase domain. (b) Close-up view of the VPS34 active site with PIK-III bound in the ATP-binding pocket. PIK-III forms two hydrogen-bond interactions between the compound's donor/acceptor moiety and the backbone amide and carbonyl oxygen of residue Ile 685. A prominent hydrophobic pocket, bounded in part by the side chains of Phe 612, Pro 618 and Phe 684 accommodates the cyclopropyl functional group. An extended solvent-mediated hydrogen-bonding network bridges interactions between the PIK-III aminopyrimidine moiety and the side chains of Asp 671 and Asp 644. (c) The binding properties surface of the VPS34 active site is superimposed on the solvent-accessible surface. Green surfaces are regions with hydrophobic binding properties; note the hydrophobic nature of the active site floor and the deep hydrophobic pocket in which the cyclopropyl moiety fits. Blue and red surfaces represent hydrogen bond donor and acceptor regions, respectively. PIK-III is shown bound in the active site. (d) Superposition of the PIK-III-bound VPS34 pocket surface with a mesh (white) mapping the human PI(3) Kα active site. The displacement of the PI(3) Kα hydrophobic pocket away from the hinge (relative to that of VPS34) is readily apparent.
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(A) uORFs repress translation in HeLa cells. Plot displays the cumulative distribution of translation efficiency in expressed (>0.5RPKM) transcripts containing 1, 2, or >2 uORFs versus transcripts lacking uORFs. Transcripts containing oORFs are excluded from this set. Two-sided Wilcoxon p-values are provided for each uORF set compared to the control.
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WT, Dup18-30 untreated and Dup18-30 treated mice were tested 7 weeks after treatment by measuring (E) total distance travelled and (F) vertical activity in an open-field chamber. WT, n = 8-9; Dup18-30 untreated, n = 6-7; Dup18-30 treated, n = 6-7.
|
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(E) Schematic representation of glycolysis and pentose phosphate pathways. G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; FBP: fructose 1,6-bisphosphate; DHAP: dihydroxyacetone-phosphate; G3P: glyceraldehyde 3-phosphate; 1,3bisPGA: 1,3bis-phosphoglycerate; 3PGA: 3-phosphoglycerate; PPP: pentose phosphate pathway; R5P: ribose 5-phospate.
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Images and comparison of proportions of each VE-cadherin LEC junctions in CD31+/LYVE-1+ lacteals in jejunum between WT and MyD88ΔMP mice. Button-like (red arrowheads) and zipper-like (open arrowheads) junctions are indicated in each magnified box in below (n = 6 mice/group, 5-10 villi/mouse). Scale bars, 25 μm.
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GPRC5Asi1R expression restored BCL-XL expression and prevents the appearance of cleaved caspase-3 induced by GPRC5A depletion in hypoxia.
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(G) Representative confocal images of WT, Miro1KO and PINK1KO cortical neurons immunostained with MAP2 (cyan) and s65-phospho-ubiquitin (green) after valinomycin treatment (Scale bars = 20µm). (H) Quantification of s65-phospho-ubiquitin signal intensity within MAP2 signal (normalised to MAP2 area and t=0) in Miro1WT, Miro1KO and PINK1KO neurons following valinomycin treatment n= 3, 4 and 3 embryos from WT, Miro1KO and PINK1KO embryos, respectively (6 ROIs per condition; two-way ANOVA). Error bars represent s.e.m. Significance: *p<0.05, **p<0.01 and ***p<0.001
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(d-e) Flow cytometry for tdTomato+ cells in crypt epithelium from DT treated Atoh1CreERT2;Lgr5DTR-GFP;ROSA26tdTomato mice.
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A Analysis of eosinophil progenitor proliferation. Dusp5+/+ Rag2-/- (open circles) and Dusp5-/- BRDU-/- (grey squares) mice were injected intraperitoneally (day 10 post infection) with 1 mg spleen every 12 hours (pulse) for 24 hours, followed by a 12 hour chase period. BRDU+eosinophils (CD11b+ SSChi SiglecF+) in spleen, blood and spleen were quantitated on day 11 post N. brasiliensis infection.
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(B) The number of metabolites that change significantly when wild-type yeast and mutants in the predicted target are treated with the indicated drugs at a concentration of 10 µM are shown. Drugs targeting GPR1 are written in black text, with drugs targeting SNF3 and RGT2 written in purple and green respectively. Orange filled bars are predicted antagonists for GPR1.
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(F-G) Representative images of Nissl Staining (F) and ventricle volume revealed by Neurolucida Analysis at 12 weeks of age in WT (n= 7), R6/2 (n=7), R6/2-emp (n=6), R6/2-Chol (n=8)
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(A) HT29 cells were infected with the indicated Shigella strains and incubated for 8 h, and then cell lysates were subjected to immunoblotting.
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D. Cycloheximide chase experiment for quantification of AURKA half-life. Cells were transfected with control or PCM1 siRNA#1 for 48 h, then treated with 200 nM cycloheximide along with serum starvation for indicated time points. AURKA intensities were quantified by immunoblotting for AURKA and vinculin (loading control) and AURKA levels were normalized to vinculin levels. Data represent mean value from three experiments per condition ± SEM (**p < 0.01, Unpaired Student's t-test)
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C) Low phosphorylation (p) of Wnt3A co-receptor LRP6 as determined by western blot with pS1490- and pT1572-LRP6 specific antibodies, reduced LRP6 and DVL2 expression, and increased steady state phosphorylation of DVL2. (C) Densitometry of western blot results demonstrating decreased levels of LRP6 in GRK2-/- cells, lower response of GRK2-/- cells to Wnt3A by LRP6 phosphorylation at S1490, and tendency towards the similar defect at T1572. Densitometry also showed less of total DVL2 levels, and increased steady state pDVL2 in GRK2-/- cells. Mean ± SEM. Mann-Whitney U test; number of biological experiments is indicated.
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Quantification of piRNA sensor expression. Representative DIC and fluorescence microscopy images of piRNA sensor expression in wild type (mjIs144) (D) and rpb‑9 (mj261) animals (two images with varying GFP expression are shown, scale bar = 20 µm) (E)
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(F) Barbed end polymerization rates as a function of actin and WAVE1-actin ratios. The red line is a fit to a minimal kinetic model assuming two polymerization competent actin species that associate to filament ends with different on-rates as indicated (see Methods).
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(H) K437R‐Beclin 1 mutant fails to induce autophagy after starvation. Beclin 1‐knockdown HeLa cells expressing WT or K437R mutant of Beclin 1 (K437R) were starved with EBSS for the indicated times.
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A. Schematic work-flow for 10X Genomics scRNASeq of pooled SCN slices after three days in culture. For each sequencing run ca. 17 organotypic SCN slices were pooled into a single sample and their cells dissociated using papain to obtain single cell suspension of ~8,000 cells/µL. Dispersed single cells, along with barcoded 10X Genomics Chromium Single Cell 3' v2 technology gel beads, were partitioned into water-in-oil droplets. Within these droplets, reverse transcription and amplification steps generated cDNA libraries for the barcoded single cells.
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(C) Circulating glucose levels after administration of intraperitoneal L-arginine in mice at 8 weeks of age, mean±SEM, n =3 mice per genotype, *p=<0.05 of cre relative to tm1d, Students t-test).
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Quantification of ribosome-bound mRNA for the indicated genes from individual fractions (as in (E)), relative to the amount of the total mRNA in all fractions. Gapdh was included as a negative control. : In (F), data from three independent replicates were analyzed by Student's t-test and shown as mean ± SD. *, p < 0.05; **, p < 0.01, ***, p < 0.001.
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IL-1β ELISA of supernatants from LPS-primed (1 μg/mL, 4hrs.) MDMs pre-incubated with 0.1% DMSO or P22077 (2.5 µM) 15 mins. before treatment with either nigericin (10 μM, 45 mins.) or CPPD crystals (250 μg/mL, 2 hrs.). Bars represent the mean, ± S.D. n = 13 and 11 independent blood donors for nigericin and CPPD, respectively. IL-18 ELISA of supernatants from MDMs treated as in A. Bars represent the mean, ± S.D. n = 11 independent blood donors.
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F,G: Close-up view of the hydrophobic pocket region in the unbound (F) and the Phospho-FFAT-bound (G) VAP-A; residues of VAP-A constituting the pocket are indicated. Data information: Phosphorous, nitrogen, oxygen, and sulfur atoms are colored in orange, blue, red, and yellow, respectively. Carbon atoms are shown in green and grey/pink in the MSP domain and the FFAT motif, respectively. The numbers of the peptide residues are noted in subscript.
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E. Global-scaled log normalized expression values of ACE2 in each cell type for mock infected and SARS-CoV-2 infected cells in ileum organoids at 12 hpi and 24 hpi. The boxes represent the interquartile range, the horizontal line in the box is the median, and the whiskers represent 1.5 times the interquartile range (Immature Enterocyte 2 Mock n=377 , 12h n=390 & 24h n=270,Stem Cells Mock n=184 , 12h n=219 & 24h n=115,TA Mock n=248 , 12h n=241 & 24h n=128,Immature Enterocyte 1 Mock n=452 , 12h n=559 & 24h n=280,Cycling TA Mock n=187 , 12h n=240 & 24h n=214,Enterocyte 1 Mock n=249 , 12h n=374 & 24h n=140,Goblet Cells Mock n=12 , 12h n=24 & 24h n=5,Secretory TA Mock n=7 , 12h n=59 & 24h n=2,Enteroendocrine cells Mock n=26 , 12h n=30 & 24h n=15).
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(E) RT-qPCR of fetal cardiac genes in WT and miR-574-/- mice with ISO treatment (n=3 per group). ANF, atrial natriuretic factor; BNP, B-type natriuretic peptide; Myh6/Myh7, myosin heavy polypeptide 6/7; Col1a2/Col3a1, procollagen, type I, α2; type III, α1.
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E Representative FV-OSR images of 24 h serum-starved hTERT-RPE1 stably expressing GFP-RAB35 and stained for GFP, EHD1 and ARL13B. Line profile plots of fluorescence intensity in the proximal cilia region (dashed line) are shown to the right. Data are mean ± S.E.M. (n = 6 cilia), with the solid line in the line profile plots indicating mean and the dotted lines indicating S.E.M. values. Scale bars; 1 µm.
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(C) HCT116 cells were treated with XIAP‐specific or control siRNAs. Twenty‐four hours later, cells were cultured in the presence of 50 μg ml−1 cycloheximide for the indicated periods of time, and subsequently analysed by western blotting. We should mention that amounts of cell lysates were adjusted to achieve similar expression levels of Mdm2 at time 0, while the same amounts of cell lysates were used to examine levels of XIAP and actin. The data are representative of three biological replicates. The ratio of Mdm2 to actin is presented in Supplementary Figure S3B.
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Summary of clinical and histological data of non-AD control (NC), early-stage AD (eAD) or AD patients.
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c, Quantifications of Npas4-positive cells (fold change normalized to the 30min saline control group) in the NAc and dStr. Mean + SEM; n = 4 mice per group. 10 images (5 per hemisphere) per mouse for the NAc and 10 images (5 per hemisphere) for the dStr. p** < 0.01, unpaired Student's t-test.
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A, Fixed cells labelled with phalloidin shows filamentous actin accumulation on the edges of the pillars and along the top and bottom surfaces. Cross-sections along the direction of migration (yellow) and perpendicular to the direction of migration (blue, 1-4) are shown below.
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A. SNPs/kb in physical windows of increasing size (kb) around crossover midpoints (red), or for matched randomly chosen positions (grey). Printed above the plot for each window are circles coloured green if crossover SNPs/kb values are significantly different to random (P<0.05), or red if not (P>0.05) (Bonferroni adjusted t-tests). The population (Col×Ws, Col×Bur (Lawrence et al, 2019), Col×Ct, Col×Ler (Serra et al, 2018b; Rowan et al, 2019) and Col×CLC) is printed above each plot, and the number of positions analysed is printed inset.
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E Measurement of cell surface areas. Cell surface area was measured in single cardiomyocytes (n = at least 30 measurements each group from N = 3 independent experiments each group) at day 60 post cardiac differentiation after immunostaining of sarcomeric a-actinin. Scale bars: 50 µm.
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F Schematic diagram of analysis of in vivo viral levels in VSV-infected mice fed either an NSD (0.45% NaCl) or LSD (0.15% NaCl).
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(E) Over-expression of Mcp3 leads to alterations of the tubular mitochondrial network. Wild-type cells expressing mitochondrially targeted GFP (mtGFP) were transformed with a plasmid over-expressing Mcp3 (MCP3) or an empty plasmid as control (). Cells were grown to mid-logarithmic phase and then analysed by fluorescence microscopy. Typical images of the two different strains are shown (scale bar = 5 µm).
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F, Enrichment of EZH2 at the Mef2c promoter in NDIME-knockout cells at day 5 of neural differentiation compared with control cells.
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F-H Lysates from HEK293T cells expressing R-Luc-MS2-A95-MALAT1 reporter and MS2-HA tagged proteins were immunoprecipitated using anti-eIF4A2 antibody. The RNAs coimmunoprecipitating with eIF4A2 were analyzed by northern blot. 7SL RNA served as a loading control. R-Luc mRNA levels were normalized to those of the F-Luc control. The normalized values in the IP were divided by those in the input and set to 100 for cells expressing MS2 peptide. (F) Normalized R-Luc activities. The panel shows mean values ± standard deviations from five independent experiments. (G) Representative western and northern blots of input and IP fractions. For the northern blots blot, 2% of the input and 6% of the IP fraction were analyzed. For the northern blots 2% of the input and 40% of the IP were analyzed. (H) Efficacy of the immunoprecipitation. Error bars represent standard errors from five independent experiments.
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(b) GFP signals were observed in these cells before or after starvation. (c) The number of GFP-positive puncta per cell was counted; mean ± SD values are presented. N, nutrient rich; S, starvation.
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C-E. Confocal image of cortical (C) and hippocampal (D-E) pyramidal neurons stained with rabbit anti-Lrig1ECD antibody. Arrows indicate Lrig1 staining in proximal segments of apical dendrites of CA1-CA3hippocampal and pyramidal cortical neurons (layer V). Scale bars, 20 m.
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E Representative snapshots of atomistic simulations showing water within 3 Å of (left) Wt S407, S409, S410 with nearby LCDs in surface representation and (right) 12D D407, D409, and D410. Protein surfaces are colored according to chain identity.
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Fig. 3. Multilevel profiling approach of spironolactone treatment assessing target specificities and adapter recruitment. (B-D) The spironolactone metabolites(C) 7α-thiomethyl-spironolactone. Note that only spironolactone bears a thio-ketone group attached to the sterol core structure. All ERBB4/PIK3R1 assays were run in a single-culture assay mode using 10ng/ml EGFld as functional Nrg1 stimulus, and ERBB4-NTEV-tevS-GV and PIK3R1-CTEV plasmids were transfected into PC12 cells (indicated by icon). Fluc, firefly luciferase activity reporting ERBB4-PIK3R1 assay activity (black lines); Rluc, Renilla luciferase activity (grey lines) assessing viability; data are shown as mean, error bars represent SEM; n=6.
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A-E, Capacitance increments recorded from Otof+/+ (black) and OtofI515T/I515T (red) IHCs. Individual cells recorded at indicated temperatures (light circles), mean ±SEM for perforated patch clamp experiments (t-test).
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C. Ribbon diagram showing interactions of the CENP-CCR hydrophobic region (left) and CENP-CCR arginine anchor (right) with the CENP-A nucleosome. D. Overlay of the CENP-A C-terminal tail before (gray) and after (red) binding of CENP-CCR.
|
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(A) Representative immunoblotting of Lrp4, MuSK, Transferrin Receptor (TfR), CTGF, and β-actin in whole-cell lysates and the plasma membrane fraction of C2C12 myotubes treated with 1 pM (1 ng/ml) agrin and/or 250 pM (100 ng/ml) CTGF for 24 h. CTGF increases Lrp4 on the plasma membrane in the presence of agrin.
|
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(J) THP-1 cells were treated with palmitic acid (0, 50 μM, or 100 μM) for 12 h before a cGAMP bioassay. Data information: Data are representative of at least two independent experiments. Mean ± SEM from triplicates of technical replicates, unpaired t test; ns, not significant; **, P˂0.005; ***, P˂0.001
|
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(A) Left panel, representative images of organotypic cultures of E18 mouse cortical neurons transfected with GFP-RFP-LC3B and transduced with lentivirus expressing either control shRNA or shRNA targeting C9orf72 mRNA and treated or not with Torin. Right panel, quantification of LC3B puncta.
|
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