Differential splicing of COL4A5 mRNA in kidney and white blood cells: A complex mutation in the COL4A5 gene of an Alport patient deletes the NC1 domain

Differential splicing of COL4A5 mRNA in kidney and white blood cells: A complex mutation in the COL4A5 gene of an Alport patient deletes the NC1 domain. PCR conditions were optimized to amplify the COL4A5 cDNA from lymphoblasts and kidney tissue. Sequencing of the COL4A5 mRNA isolated from the kidney of an Alport syndrome patient revealed two differences with the published sequence. One divergence, the insertion of an 18 bp sequence between exon 11 and 10 of the COL4A5 mRNA added two Gly-X-Y triplets to the COL4A5 sequence and was subsequently found in the mRNA of four normal kidney mRNA samples. This sequence was absent in all white blood cell RNA samples sequenced by us, indicating tissue specific splicing with the presence of an additional exon in kidney COL4A5 mRNA. This finding of differential splicing of COL4A5 mRNA in kidney and white blood cells might affect the use of white blood cell mRNA for the analysis of Alport mutations. Second, a complex mutation was detected in the mRNA from the AS patient introducing a premature stop codon in the message, deleting part of the triple helical domain and the complete NC domain. The mother of the patient was shown to be heterozygous for this mutation

Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn's disease

Background: Sacroiliitis is a common extraintestinal manifestation of Crohn's disease but its association with the HLA-B27 phenotype is less evident. Polymorphisms in the CARD15 gene have been linked to higher susceptibility for Crohn's disease. In particular, associations have been found with ileal and fibrostenosing disease, young age at onset of disease, and familial cases. Objectives: To investigate whether the presence of sacroiliitis in patients with Crohn's disease is linked to the carriage of CARD15 polymorphisms. Methods: 102 consecutive patients with Crohn's disease were clinically evaluated by a rheumatologist. Radiographs of the sacroiliac joints were taken and assessed blindly by two investigators. The RFLP-PCR technique was used to genotype all patients for three single nucleotide polymorphisms (SNP) in the CARD15 gene. Every SNP was verified by direct sequencing. The HLA-B27 phenotype was determined. Results: Radiological evidence of sacroiliitis with or without ankylosing spondylitis was found in 23 patients (23%), of whom only three were HLA-B27 positive. In contrast, 78% of patients with sacroiliitis carried a CARD15 variant v 48% of those without sacroiliitis (p = 0.01; odds ratio 3.8 (95% confidence interval, 1.3 to 11.5)). Multivariate analysis (logistic regression) showed that the association between sacroiliitis and CARD15 polymorphisms was independent of other CARD15 related phenotypes (ileal and fibrostenosing disease, young age at onset of disease, familial Crohn's disease) (p = 0.039). Conclusions: CARD15 variants were identified as genetic predictors of Crohn's disease related sacroiliitis. An association was demonstrated between these polymorphisms and an extraintestinal manifestation of Crohn's disease

Internal representation and factional faultlines as antecedents for board performance in social enterprises

There is an increasing scholarly interest in how social enterprises manage their hybrid nature. As hybrid organizational forms, social enterprises combine mission-driven social goals and revenue generating activities in a variety of organizational constellations and in diverse institutional contexts. Acknowledging the potentially conflicting demands that institutional environments impose on social enterprises there is an increasing research interest in the existence and proliferation of these conflicting demands at the organizational level. Some researchers have pointed to the importance of particular management practices and governance characteristics – such as authority relations and internal representation – as mechanisms to deal with the conflicting demands at the organizational level. This paper adds to this stream of literature by taking into account the organizational level dynamics of internal representation and the proliferation of factional groups in the boards of directors of hybrid organizational forms and their impact on board performance, ultimately influencing the organizational performance

Análisis de ADN Mitocondrial en restos de hijo putativo de Luis XVI, Rey de Francia y María Antonieta

Carl Wilhelm Naundorff fue sepultado en 1845 en Delft como Luis Charles, Duque de Normandía, “Luis XVII”. Sin embargo, el hijo de Luis XVI y María Antonieta-Luis XVII- falleció oficialmente en el templo de París en 1795. Con el fin de determinar la identidad de Naundorff, se comparó las secuencias de las ondas del ADNmitocondrial (ADNmt) de sus restos con las secuencias obtenidas a partir del cabello de dos hermanas de María Antonieta, de la misma María Antonieta, y con las secuencias obtenidas de las muestras del ADN de dos parientes maternos vivos. La secuencia del ADNmt de una muestra de hueso de Naundorff mostró dos diferencias en los nucleótidos en cuanto a la secuencia del de las tres hermanas y cuatro diferencias en las secuencias de los parientes maternos vivos basado en esta evidencia resulta muy remoto que Naundorff sea el hijo de María Antonieta

Epigenetic Inactivation of the miR-124-1 in Haematological Malignancies

miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2′-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study

The dominant ethnic moment: towards the abolition of 'whiteness'?

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