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Direct association of Bazooka/PAR 3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling

Direct association of Bazooka/PAR 3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling

Surprisingly, PTEN does not appear to be required for the control of apicobasal polarity of neuroblasts and epithelia, despite its apical colocalization with Baz in these two cell types. The asymmetric localization of cell fate determinants to the basal cortex of mitotic neuroblasts requires both an intact actin cytoskeleton and the activity of the PAR/aPKC complex (Broadus and Doe, 1997; Knoblich et al., 1997) (reviewed by Wodarz and Huttner, 2003). Thus, the PAR/aPKC complex must be communicating with the actin cytoskeleton, but how this occurs is unknown. Our finding that mutations in Pten lead to severe defects in several actin dependent processes during oogenesis and early embryonic development support the hypothesis that PTEN may provide a link between the PAR/aPKC complex and the actin cytoskeleton in neuroblasts and epithelia. However, this link may not be essential in these cell types because of functional redundancy in the system that controls the levels of PtdIns(4,5)P 2 and PtdIns(3,4,5)P 3 at the

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Par Pal Golf

Par Pal Golf

Because there is no competition and hopefully a lot of demand we can expect that about 1/5 of our total target market will purchase a Par Pal within the first 5 years. If this happens and there are no major set-backs in our target market, we would consider mass-producing our product and selling it across North America. The production costs of the Par Pal will be very high, when all the other costs are included in the selling price there will be little mark-up room left to make a profit (that people are willing to pay).

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Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma Par-4 levels and apoptosis in diverse tumors

Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma Par-4 levels and apoptosis in diverse tumors

Our previous studies have indicated that HCQ induces secretion of Par-4 and that plasma samples collected following HCQ treatment of mice and patients exhibit ex vivo apoptotic activity that is neutralized by the Par-4 antibody. However, the relationship between elevated Par-4 secretion and apoptosis in patients’ tumors was not known, providing a strong rationale for conducting this phase I trial. A total of 9 patients with early stage solid malignancies were enrolled in this trial and allocated to 200 mg twice daily or 400 mg twice daily cohorts. Our clinical results demonstrate significant induction of plasma Par-4 levels with both dose levels in cancer patients. No HCQ related toxicities were observed in these dose levels. After 14-day administration of HCQ, four out of six patients (67%) from dose level 1 and two out of three patients (67%) from dose level 2 showed a 2-fold or more elevation of plasma levels of Par-4 relative to pre-treatment baseline levels. Given these toxicity and Par-4 results, the optimal biological dose, defined as the lowest safe dose with a biological response was identified as 200 mg twice daily (dose level 1).

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Elaborating polarity: PAR proteins and the cytoskeleton

Elaborating polarity: PAR proteins and the cytoskeleton

AP axis specification in the Drosophila oocyte occurs before fertilization, in contrast to postfertilization in C. elegans. Although there is currently no evidence that asymmetric actomyosin contraction influences AP polarity in Drosophila, as it does in C. elegans, AP polarity is generated by subdividing the cortex and cytoplasm of a single cell and involves an analogous distribution of PAR proteins (Fig. 3A,B). Drosophila Baz, Par-6 and aPKC localize to the anterior and lateral cortex of the oocyte, and Par-1 and Lgl [also known as L(2)gl; a homolog of worm LGL-1] localize to the posterior cortex. These two domains are established by antagonistic interactions between anterior and posterior proteins mediated in part by phosphorylation. Anterior aPKC phosphorylates and excludes Par-1 and Lgl, restricting their localization to the posterior (Hurov et al., 2004; Tian and Deng, 2008; Doerflinger et al., 2010), and Par-1 phosphorylates and excludes Baz from the posterior domain (Vaccari and Ephrussi, 2002; Benton and St Johnson, 2003). Localized kinase activity also regulates asymmetric cell division in Drosophila neural stem cells (neuroblasts) (Fig. 3C,D). Apical aPKC phosphorylates Lgl, the Notch inhibitor Numb and the adaptor protein Miranda, displacing them to the opposite domain. This molecular asymmetry causes Numb and the Miranda cargo proteins Prospero and Brain tumor to segregate into one of the two daughter cells, where they specify cell fate (Petronczki and Knoblich, 2001; Betschinger et al., 2003; Smith et al., 2007; Wirtz-Peitz et al., 2008; Atwood and Prehoda, 2009). In addition, Lgl can stably associate with the Par-6- aPKC complex and inhibit its activity. Activation of aPKC by

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PAR 3 mediates the initial clustering and apical localization of junction and polarity proteins during C  elegans intestinal epithelial cell polarization

PAR 3 mediates the initial clustering and apical localization of junction and polarity proteins during C elegans intestinal epithelial cell polarization

that PAR-3 performs a similar function in polarizing pharyngeal epithelial cells (Fig. 4; see Fig. S5 in the supplementary material). In contrast to intestinal and pharyngeal epithelial cells, epidermal epithelial cells form on the embryo surface from a single layer of superficial precursor cells. In epidermal cells of par-3(MZ) embryos, PAR-6 and PKC-3 were distributed uniformly within the cytoplasm, rather than concentrated apically as in wild type (Fig. 6A-D). EAT-20 apical localization was variably disrupted in the epidermis, with cells in dorsal regions of the embryo showing the most severe mislocalization (see Fig. 4J). Surprisingly, however, the junction proteins HMR-1, HMP-1, DLG-1 and AJM-1 were properly positioned in par-3(MZ) embryos (Fig. 6E,F; data not shown) and formed mature belt-like structures as in wild-type epidermal epithelial cells (see Fig. S6C,D in the supplementary material). A similar phenotype was observed when par-3(MZ) embryos were constructed using the par-3(tm2010) deletion allele (see Fig. S7 in the supplementary material). Altogether, these observations indicate that internal epithelial cells of the intestine and pharynx require PAR-3 to polarize, but external epidermal cells can utilize PAR-3-independent mechanisms to form apical junctions. Functional apical junctions within the epidermis of par- 3(MZ) embryos are likely to explain why these cells do not rupture in random positions, as occurs in par-6(MZ) embryos in which junctions fail to mature (Totong et al., 2007).

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CDC 42 and RHO 1 coordinate acto myosin contractility and PAR protein
localization during polarity establishment in C  elegans
embryos

CDC 42 and RHO 1 coordinate acto myosin contractility and PAR protein localization during polarity establishment in C elegans embryos

In ect-2(RNAi) (n=6) and rho-1(RNAi) (n=5) embryos, YFP- CDC-42 remained localized over the whole cortex and did not segregate into an anterior domain (Fig. 4; data not shown; see Movie 7 in the supplementary material). From this, we conclude that RHO-1 activity is essential for CDC-42 segregation to the anterior, but not its localization to the cortex. To test whether PAR- 6 localization also requires RHO-1 activity, we made time-lapse movies of GFP-PAR-6 in rho-1(RNAi) and ect-2(RNAi) embryos. In all rho-1(RNAi) (n=6) and ect-2(RNAi) (n=11) one-cell embryos studied, GFP-PAR-6 remained localized throughout the cortex during the whole cell cycle and failed to segregate into an anterior domain (Fig. 3B; see Movies 8 and 9 in the supplementary material; data not shown). Thus, RHO-1 activity is also essential for the establishment of an anterior PAR-6 domain. Because CDC-42 distribution appears to dictate cortical PAR-6 localization, it is possible that the symmetric distribution of PAR-6 in rho- 1(RNAi)/ect-2(RNAi) embryos reflects the defect in CDC-42 segregation. Interestingly, embryos depleted of RHO-1 (n=9/10, data not shown) or ECT-2 (Fig. 6A, n=17/21) sometimes segregated myosin to the anterior, whereas in all embryos studied under the same RNAi conditions, PAR-6 localization remained uniform [ect- 2(RNAi), n=63/63; rho-1(RNAi), n=6/6]. RHO-1 activity may therefore couple the anterior movement of myosin II with the anterior segregation of CDC-42 and PAR-6. In support of this idea, co-depletion of RHO-1 and CDC-42 resulted into an additive phenotype (see Fig. S1 in the supplementary material), from which we conclude that RHO-1 and CDC-42 function in separate pathways to localize the PAR proteins.

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PAR 2, LGL 1 and the CDC 42 GAP CHIN 1 act in distinct pathways to maintain polarity in the C  elegans embryo

PAR 2, LGL 1 and the CDC 42 GAP CHIN 1 act in distinct pathways to maintain polarity in the C elegans embryo

A key finding is that CDC-42 has a dual role: a major role in regulating the size of the anterior cortical domain via its binding to PAR-6 and a minor role in regulating cortical myosin during maintenance. The basis for this conclusion is that cgef-1 can suppress par-2 mutation or depletion but lowering the level of MRCK-1, a downstream effector of CDC-42, fails to suppress par-2 depletion; indeed, it appears to enhance it. It is well established that lowering the steady state level of PAR-6 can suppress par-2 mutations (Hyenne et al., 2008; Watts et al., 1996). Lowering active CDC-42 levels by mutation of cgef-1 will affect both cortical PAR-6 accumulation (Aceto et al., 2006) and MRCK-1 activity (Kumfer et al., 2010). We propose that the two effects exert unequal influence on polarity maintenance and that suppression of PAR-2 by CGEF-1 occurs because reduced active CDC-42 will restore the balance between the antagonistic forces of the anterior and posterior domains. Lowering MRCK-1 levels lowers the levels of cortical myosin in the anterior (Kumfer et al., 2010) but appears to have no effect on the size of the PAR-6 domain, consistent with the observation that the actomyosin cytoskeleton is not required for the maintenance of distinct cortical domains (Dawes and Munro, 2011; Goehring et al., 2011a; Goehring et al., 2011b). As mentioned above, however, the ability of mrck-1(RNAi) to partially block LGL-1 overexpression rescue of par-2 argues that MRCK-1 normally contributes to maintaining the anterior cortical domain, although this contribution is non- essential in a normal genetic background.

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A Genomewide Screen for Suppressors of par-2 Uncovers Potential Regulators of PAR Protein-Dependent Cell Polarity in Caenorhabditis elegans

A Genomewide Screen for Suppressors of par-2 Uncovers Potential Regulators of PAR Protein-Dependent Cell Polarity in Caenorhabditis elegans

anterior PARs) proteins are localized at the anterior cortex of the embryo (E temad -M oghadam et al. 1995; T abuse et al. 1998; H ung and K emphues 1999), while PAR-1 and PAR-2 are restricted to the posterior cortex (G uo and K emphues 1995; B oyd et al. 1996). This localization along the antero-posterior axis is mutually exclusive, as members of the anterior and posterior groups show little overlap in their respective localization and the PAR-2 and PAR-3 proteins exclude each other from their respective cortices (E temad -M oghadam et al. 1995; B oyd et al. 1996; C uenca et al. 2003). Therefore, PAR proteins define anterior and posterior cortical domains in the zygote and specify cell polarity and asymmetric cell divisions in the early C. elegans embryo. While PAR proteins are conserved across species, little is known about the precise molecular mechanisms by which they contribute to the establishment and main- tenance of cell polarity. This lack of understanding is partly due to the fact that only a limited number of PAR protein activators and effectors that function during these processes have been identified thus far (M acara 2004). Interestingly, previous work demonstrated that while removing both copies of par-2 leads to the mis- localization of the anterior PARs to the posterior of the embryo, and thus to defects in polarity and embry- onic lethality, reducing by half the amounts of PAR-6 in a par-2 mutant background is sufficient to restore viability (W atts et al. 1996) (supplemental Figure 1 at http://www.genetics.org/supplemental/). Similarly, dis- ruption by RNA interference (RNAi) (F ire et al. 1998) of cdc-42, a regulator of the anterior PAR activity, in a par-2 mutant also restores viability (G otta et al. 2001). These results indicate that genes that are required to regulate the levels, the localization, and/or the activity of anterior PAR components can be identified on the basis of their ability to restore viability in a par-2 mutant background

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Designing Tone Reservation PAR Reduction

Designing Tone Reservation PAR Reduction

The solid lines in Figure 6 show the allowed and required magnitude based on derivations only assuming one peak. Here Figure 4 comes to our aid. There we can see that the one-peak-only assumption almost always holds above 12 dB. To evaluate the derivations, simulation results are shown in Figure 7 with thin dashed lines next to the bounds. Looking at the thick curves for allowed tone magnitude, we see that for a low number of tones, the simulations closely follow the bound. For a higher number of tones, we cannot allow our- selves as high magnitude as the bound suggests. The reason is that with a high number of tones, we can work at low PAR levels, which means that we may have several peaks (cf. the leftmost grey area in Figure 4). Then the reduction algorithm has to spend power on reducing many peaks, and not one single peak, which is the situation the bound describes. Also, for the thin bound lines we see that the bounds are tighter at higher PAR levels. Reduction to low levels will generate sig- nals with many peaks, again deviating from the basic case the bound is based on. Considering the simulations, the intersec- tion points move upwards, to a higher magnitude per tone, rather than rightwards, to a higher PAR. The bound gives a good indication about the PAR, while it may show a too low required tone magnitude. The bounds will be further evalu- ated with simulations in Section 5.

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PSD Constrained PAR Reduction for DMT/OFDM

PSD Constrained PAR Reduction for DMT/OFDM

Common to all DMT/OFDM systems is a large peak-to-average ratio (PAR), which can lead to low power efficiency and nonlinear distortion. Tone reservation uses unused or reserved tones to design a peak-canceling signal to lower the PAR of a transmit block. In DMT ADSL systems, the power allocated to these tones may be limited due to crosstalk issues with many users in one twisted pair bundle. This PSD limitation not only limits PAR reduction ability, but also makes the optimization problem more challenging to solve. Extending the recently proposed active set tone reservation method, we develop an efficient algorithm with performance close to the optimal solution.

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PAR 6 is required for junction formation but not apicobasal polarization
in C  elegans embryonic epithelial cells

PAR 6 is required for junction formation but not apicobasal polarization in C elegans embryonic epithelial cells

We used PAR-6 antibodies (Hung and Kemphues, 1999) and GFP- tagged PAR-6 (hereafter PAR-6 GFP ) to examine the localization of PAR-6 in embryonic epithelial cells. Early embryos contain maternally supplied PAR-6, which diminishes in level after the onset of gastrulation (26-cell stage) (Hung and Kemphues, 1999; Nance and Priess, 2002). Levels of PAR-6 immunostaining increase in epithelial cells that form during the middle stages of embryogenesis (~300- to 400-cell stage) (Bossinger et al., 2001; Leung et al., 1999; McMahon et al., 2001). Epidermal epithelial cells are superficial and have contact-free apical surfaces that face the eggshell, whereas pharyngeal and intestinal epithelial cells are internal and have apical surfaces that contact other epithelial cells and the digestive tract lumen (Fig. 1A,B). We noted a previously undescribed PAR-6 immunostaining at the apical surfaces of epidermal cells (arrow, Fig. 1A); staining was most intense when epidermal cells first formed and diminished as embryos aged (compare Fig. 1A,B). PAR-6 antibodies also labeled the apical surfaces of pharyngeal and intestinal epithelial cells, as has been described by others (Bossinger et al., 2001; Leung et al., 1999; McMahon et al., 2001), as well as the excretory cell (Fig. 1B). Because specificity of PAR-6 immunostaining in epithelial cells has not been established, we analyzed the localization of a functional PAR-6 GFP fusion protein expressed from the par-6 promoter (Nance et al., 2003) (see Materials and methods). PAR-6 GFP was expressed in epidermal, pharyngeal, intestinal, and excretory epithelial cells, colocalized with PAR-6 at apical surfaces, and was present even when we introduced the transgene at fertilization (Fig. 1C,F and data not shown). In summary, PAR-6 localizes to the apical cortex of most or all embryonic epithelial cells and at least some PAR-6 in epithelial cells arises from zygotic par-6 expression.

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Magnetic activity and radial velocity filtering of young Suns : the weak line T Tauri stars Par 1379 and Par 2244

Magnetic activity and radial velocity filtering of young Suns : the weak line T Tauri stars Par 1379 and Par 2244

As well as placing the stars at younger ages, with lower masses, the internal structure is also somewhat different between these two evolutionary models, as can be seen in Fig. 1. Here, the size of the convective envelope (by radius) for the Siess et al. (2000) models is around 70 per cent for both stars, whereas the Baraffe et al. (2015) models suggest both stars are fully convective. The most critical change in large-scale magnetic field topology is expected to occur when the star evolves from one that is largely convective, to one that is largely radiative (>50 per cent by radius, depending on the stellar evolution model; e.g. Gregory et al. 2012). Given that the observed field topologies for both stars show non-axisymmetric, mid-to-weak strength poloidal fields (see Section 4.2), the mod- els of Siess et al. (2000) place the stars in better agreement with expectations. Furthermore, the weaker field strength and higher dif- ferential shear (see Section 4.3) of Par 1379 suggest that it is likely more structurally evolved than Par 2244, possibly to the point of being mostly radiative (despite the model predictions), whereas Par 2244 is still in a largely convective state.

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Mast cell tryptase regulates rat colonic myocytes through proteinase activated receptor 2

Mast cell tryptase regulates rat colonic myocytes through proteinase activated receptor 2

Johnson Pharmaceutical Research Institute, Spring House PA). Detection of PAR-2 in myocytes by RT-PCR and Southern blot- ting. Total RNA was reverse-transcribed and amplified using the Gene- Amp RNA PCR kit (Perkin Elmer Cetus Instruments, Emeryville, CA). Oligonucleotide primers to rat PAR-2 (sense, 5 9 -AAGTCT- CAGCCTGGCGTGGC-3 9 , 1 6 to 1 25; antisense, 5 9 -ACGACGAG- CAGCACGTTGCT-3 9 , 1 926 to 1 907) were chosen to bridge the in- tron of PAR-2, and to amplify a 921-bp fragment. The PCR amplification used 1.5 m g RNA according to the manufacturer’s di- rections. PCR products were separated on a 1% agarose gel, trans- ferred to a nylon membrane, cross-linked, and analyzed by Southern blotting using a probe labeled with digoxigenin-11-dUTP according to the manufacturer’s directions (Boehringer Mannheim, Mannheim, Germany). A 162-bp digoxigenin-labeled probe was generated by PCR using a vector containing a rat PAR-2 fragment as a template (from Dr. Morley Hollenberg) and oligonucleotide primers to rat PAR-2 (sense, 5 9 -TGCTGGGAGGTATCACCCTT-3 9 , 1 26 to 1 45; antisense, 5 9 -CATCAACGGAAAAGCCTGGT-3 9 , 1 187 to 1 168). The probe was purified using Chroma Spin X-100 columns (Clontech, Palo Alto, CA). Membranes were prehybridized in 5 3 SSPE, 10 3 Denhardt’s, 50% deionized formamide, 100 mg/ml salmon sperm DNA, and 2% SDS for 3 h at 42 8 C, and hybridized with probe over- night at 42 8 C. They were washed 40 min at room temperature in 2 3 SSC with 0.05% SDS, and 20 min at 55 8 C in 0.1 3 SSC with 0.1% SDS. Membranes were incubated with anti-digoxigenin antibody cou- pled to alkaline phosphatase (Boehringer Mannheim) and developed with BCIP/NBT substrate.

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NATURAL VARIATION IN UV-B PROTECTION AMONGST ARABIDOPSIS THALIANAACCESSIONS

NATURAL VARIATION IN UV-B PROTECTION AMONGST ARABIDOPSIS THALIANAACCESSIONS

Notwithstanding the UV-A induced induction of phenolics in several Arabidopsis accessions, it appeared that there is no simple statistical association between levels of phenolics and UV-B protection of photosynthesis among the accessions raised under PAR + UV-A (Table 2). Rather, UV-B tolerance in PAR + UV-A-raised plants was significantly correlated with the levels of carotenoids, suggesting a role for these antioxidants in UV-B protection. This is consistent with work by Gö tz et al. (1999) who showed that the photosynthetic activities of genetically modified Synechococcus with higher levels of β-carotene and zeaxanthin are UV-B protected (Gö tz et al., 1999). It has also been shown that accumulated β-carotene in Dunaliella bardawil prevents UV-related photosynthetic damage through absorption of blue- light/ultraviolet-A radiation (White and Jahnke, 2002). The observed accumulation of carotenoids in plants exposed to UV-A, but not UV-B (Figure 3b), is consistent with literature reports (Jahnke, 1999; Mogedas et al., 2009). The decrease in carotenoid level in plants raised under PAR + UV-A + UV-B is less easily explained. However, Jansen et al. (2008) previously reported that UV-B mediated changes in carotenoid levels depend in a complex manner on plant species, developmental stage and UV-B dose.

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Fonction argumentative et fonction figurative de l’analogie : quelle relation entre l’argument par analogie et l’argument par métaphore ?

Fonction argumentative et fonction figurative de l’analogie : quelle relation entre l’argument par analogie et l’argument par métaphore ?

Commençons par Perelman et Olbrechts-Tyteca (1958) qui structurent l’ensemble des schèmes argumentatifs à partir d’une opposition entre procédés de liaison et procédés de dissociation. Les premiers, sur lesquels l’analyse est concentrée en raison de leur importance, sont définis de la façon suivante : « Nous entendons par procédés de liaison des schèmes qui rapprochent des éléments distincts et permettent d’établir entre ces derniers une solidarité visant soit à les structurer, soit à les valoriser positivement ou négativement l’un par l’autre » (Perelman et Olbrechts-Tyteca, 1958, 255). Parmi les procédés de liaison, trois types d’arguments sont distingués : les arguments quasi-logiques (incluant notamment l’argument par la définition et l’argument par comparaison), les arguments basés sur la structure du réel et les arguments qui fondent la structure du réel. C’est dans cette dernière rubrique qu’apparaît l’argument par analogie. A la différence des arguments basés sur la structure du réel, qui « se servent de celle-ci pour établir une solidarité entre des jugements admis et d’autres que l’on cherche à promouvoir » (Perelman et Olbrechts-Tyteca, 1958, 351), les arguments qui fondent la structure du réel visent à établir des rapports non préétablis, ou bien en se fondant sur un cas particulier (argumentation par l’exemple ou par l’illustration notamment) ou bien en mobilisant un raisonnement par analogie, qui peut prendre deux formes distinctes : l’analogie ou la métaphore. Le « raisonnement par analogie » est défini traditionnellement à partir de sa structure proportionnelle : « Il nous semble que sa valeur argumentative sera le plus clairement mise en évidence si on envisage l’analogie comme une similitude de structures, dont la formule la plus générale serait : A est à B ce que C est à D. Cette conception de l’analogie se rattache à une tradition très ancienne. » (Perelman et Olbrechts-Tyteca, 1958, 500). Quant à la métaphore, elle est présentée comme une sorte de cas limite de l’analogie : « Nous ne pourrions mieux, en ce

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La préposition par comme marqueur polyphonique ?

La préposition par comme marqueur polyphonique ?

À ces différentes considérations théoriques s’ajoutent, d’un côté, la linguistique harrissienne, avec les distributions lexicales et paradigmatiques sélectionnées par les unités linguistiques mises en jeu et la construction du sens à partir des formes linguistiques (voir Leeman,1999 et 2001), de l’autre, la pensée de Ducrot (1972 et 1984) et Anscombre & Ducrot (1983), dans le cadre de l’argumentation dans la langue, avec la loi des enchaînements possibles et dans le recours aux stéréotypes (Anscombre, 2001). La pragmatique telle que considérée ici est fondamentalement adossée au cotexte et aux distributions permises ou interdites dans le discours ; la signification explicite ou implicite des énoncés est, de ce fait, issue des formes linguistiques elles-mêmes. C’était, d’ailleurs, le dessein initial de Bakhtine, lui-même, qui défend l’idée que le contenu sémantique est nécessairement véhiculé par les formes linguistiques : « Il (le contenu sémantique) se manifeste ainsi, dans les formes de transmission du discours d’autrui, un rapport actif d’une énonciation à une autre, et cela non pas sur le plan thématique, mais par l’intermédiaire de constructions stables relevant de la langue » (1977 : 162). De même, Bres (2005 : 15- 16), en parlant de la « double énonciation », fait remarquer que cette « dualité énonciative » s’accompagne par une « dualité syntaxique » et un certain nombre de marqueurs textuels qui en rendent compte. Considérons l’exemple (1) cité par l’auteur :

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Note d'introduction sur l'évaluation d'impact d'un programme public par la méthode de régression par discontinuité

Note d'introduction sur l'évaluation d'impact d'un programme public par la méthode de régression par discontinuité

L'équation (5) reste toutefois incomplète afin d’identifier l'incidence d’un programme avec seuil de participation. Bien que les valeurs attendues de Y soient conditionnées sur le(s) facteur(s) de sélection connu(s), les participants et les non-participants à ce type de programme ne partagent pas le même support 9 du facteur de sélection. Autrement dit, il est impossible de constituer un groupe de non-participants qui soit comparable aux participants en regard du facteur de sélection étant donné la règle d’inéquation qui régit la participation au programme. Il est possible néanmoins de modifier le problème d'évaluation décrit plus haut de telle sorte que la comparaison souhaitée puisse être réalisée dans une région « avoisinante » au seuil de participation où les unités participantes et non participantes partagent des valeurs relativement semblables, et à la limite identiques, du facteur de sélection. C’est précisément cette idée qui sous-tend la méthode de régression par discontinuité.

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La pelade par plaques

La pelade par plaques

Le jeune homme a choisi de subir une thérapie avec de l’acétonide de triamcinolone intralésionnelle. Même s’il s’est produit une amélioration modérée dans la repousse des cheveux au début, quelques plaques ont persisté et de nouvelles ont apparu. De nombreuses plaques résistaient au traitement. La progression s’est poursuivie jusqu’à ce que plus de 50  % du cuir chevelu soient affectés. Une demande de consultation en dermatologie a été présentée. Lors de la consultation, il a été décidé qu’il était un can- didat propice à une thérapie à la DPCP. Pendant qu’il suivait son traitement, il a décidé d’utiliser une pro- thèse capillaire pour cacher l’ampleur de sa pelade par plaques. Après 6 mois, la majorité de sa cheve- lure avait repoussé grâce au traitement. On a cessé la DPCP et il reçoit actuellement chaque mois des injections intralésionnelles de triamcinolone lorsque de nouvelles plaques apparaissent. Depuis qu’il suit sa thérapie, il est devenu membre d’un groupe local d’entraide pour soutenir les patients atteints de pelade par plaques et sensibiliser sa communauté à ce problème.

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Role of PAR-4 in ovarian cancer

Role of PAR-4 in ovarian cancer

Thus, we first determined that PAR-4 and GRP78 colocalize in the ovarian cancer cell line SKOV-3 by immunofluorescence and further substantiated a possible interaction between PAR-4 and GRP78 by immunoprecipitation. It is found that neither increasing nor decreasing PAR-4 expression has an impact on total GRP78 levels indicating that GRP78 expression is independent of PAR-4. Thus, we focused on the role of PAR-4 in GRP78 relocation, and find that PAR-4 is involved in the relocation of GRP78 from ER to the cell surface in SKOV-3 cells, as indicated by the decreased amount of membranous GRP78 with the decreased PAR-4 expression. To supplement this finding, we observed a significant correlation between levels of PAR- 4 mRNA and membranous GRP78 expression in purified ovarian cells strengthening the hypothesis that PAR-4 participates in the GRP78 transport in ovarian cancer cells (Supplementary Figure S3). It has also been shown that GRP78 could be secreted into human peripheral circulation and activates pro-survival pathways [28, 29]. We analysed the secreted form of GRP78 in relation to the amount of PAR-4 expressed in the cells and saw that changes in PAR- 4 expression don’t influence the level of secreted GRP78 suggesting that the role of PAR-4 in GRP78 relocation is limited to its transport to the cell membrane.

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La pelade par plaques

La pelade par plaques

Cet homme de 25 ans présentait la forme classique de la pelade par plaques au stade des plaques multiples. Une évaluation plus approfondie a révélé des antécé- dents d’atopie et un examen a permis de constater des ongles de couturière. Les résultats d’une formule san- guine normale n’ont pas fait ressortir d’autres troubles concomitants. L’homme est troublé par cette perte de cheveux et veut comprendre ses options de traitement.

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