A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.

DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.

Fragments de textes bibliques et de rituels de prières . Allemagne

Contient : Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Isaïe (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Job (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Acte notarié en allemand et notes d'un hébraïsant ; Notes en hébreu et document officiel en allemand ; Notes en hébreu ; Variantes de texte du livre d'Isaïe (chap. 49) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Bible. A.T. (hébreu) (extraits) ; Mahzor (hébreu) (extrait)

Fragments de textes bibliques et de rituels de prières . Allemagne

Contient : Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Isaïe (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Job (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Acte notarié en allemand et notes d'un hébraïsant ; Notes en hébreu et document officiel en allemand ; Notes en hébreu ; Variantes de texte du livre d'Isaïe (chap. 49) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Bible. A.T. (hébreu) (extraits) ; Mahzor (hébreu) (extrait)

Fragments de textes bibliques et de rituels de prières . Allemagne

Contient : Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Deutéronome (hébreu) (araméen) (extraits) ; Bible. A.T. Isaïe (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Job (hébreu) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Bible. A.T. Nombres (hébreu) (araméen) (extraits) ; Acte notarié en allemand et notes d'un hébraïsant ; Notes en hébreu et document officiel en allemand ; Notes en hébreu ; Variantes de texte du livre d'Isaïe (chap. 49) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Mahzor (rite ashkénaze) (extrait) ; Bible. A.T. (hébreu) (extraits) ; Mahzor (hébreu) (extrait)

Low immunoglobulin levels in patients with cystic fibrosis: reduced inflammation or sign of common variable immunodeficiency syndrome?

Introduction: In children with cystic fibrosis (CF), low immunoglobulin (IgG) levels have been reported to be associated with significantly less severe lung disease. However, decreased IgG can be a sign for common variable immunodeficiency (CVID) and affect clinical outcome. The aim of this study was to analyze clinical and serological data of patients having low IgG levels in routine blood tests at annual assessment, particularly their antibody response to polysaccharide antigens. Method: Retrospective chart review of demographic data of CF patients followed at the pediatric CF clinic throughout 2009. Clinical parameters (genotype, pancreas sufficiency, FEV1), presence of Pseudomonas aeruginosa (PA) and number of exacerbations per year were correlated with immunoglobulin and vaccination antibodies levels (antibodies to pneumococcal serotypes 14, 19, 23, 1, 5 and 7F measured by enzyme-linked immune-sorbent assay). Results: 4 out of 60 patients (6.7%) had lower IgG-levels for age. Ages ranged from 1 year 8 months to 11 years, 2 boys, 2 girls. Three patients were delF508 homozygotes, one heterozygote composite delF508/G542X. All were pancreatic insufficient. FEV1 ranged from 74 to 108%. One patient never had colonization by PA, 2 had intermittent PA colonization and one was chronically infected. After conjugated vaccination all patients had protective antibodies against serotypes 14, 19, 23F. For serotypes not included in the vaccine, only one patient had protective titers for 1 out of 3 serotypes. None of the patients had received unconjugated pneumococcal vaccine. There was no significant clinical difference in FEV1, PA colonization or number of exacerbations according to IgG and vaccination antibody levels. Conclusion: Cystic Fibrosis patients with low immunoglobulin levels have normal antibody response to protein antigens. However, despite recurrent infections, there seems to be delayed or deficient antibody response to polysaccharide antigens. Prospective studies are needed to evaluate the development of polysaccharide antibody responses in CF-patients to monitor for CVID. With early detection of CF by newborn screening program, long term follow up could be started early in childhood.

[Sicile. Musées, fragments de terre cuite]

Référence bibliographique : Weigert, 317

[Sicile. Musées, fragments des temples de Sélinonte]

Référence bibliographique : Weigert, 326

In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' down-regulation and dimers' disruption.

We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb)-trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2(low) human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras-mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab')(2) fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization.

Oligogalacturonide defense signals in plants: large fragments interact with the plasma membrane in vitro.

Oligogalacturonides are plant cell wall-derived regulatory molecules which stimulate defense gene expression during pathogenesis. In vitro, these compounds enhance the phosphorylation of an approximately 34-kDa protein (pp34) in purified plasma membranes from potato and tomato leaves. We now show that polygalacturonate-enhanced phosphorylation of pp34 occurs in plasma membranes purified from tomato roots, hypocotyls, and stems and from undifferentiated potato cells. Furthermore, a similar phosphorylation is detected in leaf plasma membranes from soybean, a plant distantly related to tomato. Purified oligogalacturonides 13 to at least 26 residues long stimulate pp34 thiophosphorylation in vitro. This stimulation pattern differs from the induction of many known defense responses in vivo, where a narrower range of smaller fragments, between approximately 10 and 15 residues long, are active. On the basis of these differences we suggest that observed effects of applied exogenous oligogalacturonides on defense responses may not necessarily reflect the situation during pathogenesis. The cell wall could act as a barrier to many exogenous oligo- and polygalacturonides as well as other large regulatory ligands.

Cocoa flavonoid-enriched diet modulates systemic and intestinal immunoglobulin synthesis in adult Lewis rats

Previous studies have reported that a diet containing 10% cocoa, a rich source of flavonoids, has immunomodulatory effects on rats and, among others effects, is able to attenuate the immunoglobulin (Ig) synthesis in both systemic and intestinal compartments. The purpose of the present study was focused on investigating whether these effects were attributed exclusively to the flavonoid content or to other compounds present in cocoa. To this end, eight-week-old Lewis rats were fed, for two weeks, either a standard diet or three isoenergetic diets containing increasing proportions of cocoa flavonoids from different sources: one with 0.2% polyphenols from conventional defatted cocoa, and two others with 0.4% and 0.8% polyphenols, respectively, from non-fermented cocoa. Diet intake and body weight were monitored and fecal samples were obtained throughout the study to determine fecal pH, IgA, bacteria proportions, and IgA-coated bacteria. Moreover, IgG and IgM concentrations in serum samples collected during the study were quantified. At the end of the dietary intervention no clear changes of serum IgG or IgM concentrations were quantified, showing few effects of cocoa polyphenol diets at the systemic level. However, in the intestine, all cocoa polyphenol-enriched diets attenuated the age-related increase of both fecal IgA and IgA-coated bacteria, as well as the proportion of bacteria in feces. As these effects were not dependent on the dose of polyphenol present in the diets, other compounds and/or the precise polyphenol composition present in cocoa raw material used for the diets could be key factors in this effect.