Nuclear Punctate Distribution of ALL-1 is Conferred by Distinct Elements at the N-terminus of the Protein

The ALL-1 gene positioned at 11q23 is directly involved in human acute leukemia either through a variety of chromosome translocations or by partial tandem duplications. ALL-1 is the human homologue of Drosophila trithorax which plays a critical role in maintaining proper spatial and temporal expression of the Antennapedia-bithorax homeotic genes determining the fruit fly's body pattern. Utilizing specific antibodies, we found that the ALL-1 protein distributes in cultured cells in a nuclear punctate pattern. Several chimeric ALL-1 proteins encoded by products of the chromosome translocations and expressed in transfected cells showed similar speckles. Dissection of the ALL-1 protein identified within its -1,100 N-terminal residues three polypeptides directing nuclear localization and at least two main domains conferring distribution in dots. The latter spanned two short sequences conserved with TRITHORAX. Enforced nuclear expression of other domains of ALL-1, such as the PHD (zinc) fingers and the SET motif, resulted in uniform nonpunctate patterns. This indicates that positioning of the ALL-1 protein in subnuclear structures is mediated via interactions of ALL-1 N-terminal elements. We suggest that the speckles represent protein complexes which contain multiple copies of the ALL-1 protein and are positioned at ALL-1 target sites on the chromatin. Therefore, the role of the N-terminal portion of ALL-1 is to direct the protein to its target genes

PENGARUH ATOPI TERHADAP TIMBULNYA DERMATITIS KONTAK PADA MAHASISWIRNPENDIDIKAN DOKTER FAKULTAS KEDOKTERAN UNIVERSITAS SYIAH KUALA RNBANDA ACEH

Dermatitis kontak adalah inflamasi non infeksi pada kulit yang disebabkan karena pemaparan dengan suatu zat tertentu yang dapat mengiritasi kulit atau menyebabkan reaksi alergi. Perempuan lebih sering mengalami dermatitis kontak dibandingkan laki-laki. Atopi merupakan salah satu faktor predisposisi timbulnya dermatitis kontak. Penelitian ini bertujuan untuk mengetahui pengaruh atopi terhadap timbulnya dermatitis kontak pada mahasiswi Pendidikan Dokter Fakultas Kedokteran Universitas Syiah Kuala Banda Aceh. Penelitian ini bersifat analitik dengan pendekatan cross sectional. Data yang digunakan adalah data primer yang diperoleh dengan wawancara langsung pada responden. Uji statistik dengan menggunakan Chi Square diperoleh nilai p yang signifikan sebesar 0,00, ini berarti p < 0,05 maka secara statistik didapatkan hubungan antara atopi dengan dermatitis kontak dengan rasio prevalensi 2,17, artinya seseorang yang menderita atopi memiliki peluang sebesar 2,17 kali untuk mengalami dermatitis kontak dibandingkan dengan orang yang tidak menderita atopi. Bahan yang paling sering menyebabkan dermatitis kontak pada mahasiswi adalah deterjen dan kosmetik. Hasil penelitian yang diperoleh ada pengaruh atopi terhadap timbulnya dermatitis kontak pada mahasiswi Pendidikan Dokter FK Unsyiah Banda Aceh, dimana mahasiswi yang menderita atopi cenderung mengalami dermatitis kontak.Kata kunci: Atopi, Dermatitis kontak Alergi, Dermatitis kontak iritanBanda Ace

Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia

Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.Peer reviewe

2′-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase

RNA modification plays an important role in modulating host-pathogen interaction. Flavivirus NS5 protein encodes N-7 and 2′-O methyltransferase activities that are required for the formation of 5′ type I cap (m7GpppAm) of viral RNA genome. Here we reported, for the first time, that flavivirus NS5 has a novel internal RNA methylation activity. Recombinant NS5 proteins of West Nile virus and Dengue virus (serotype 4; DENV-4) specifically methylates polyA, but not polyG, polyC, or polyU, indicating that the methylation occurs at adenosine residue. RNAs with internal adenosines substituted with 2′-O-methyladenosines are not active substrates for internal methylation, whereas RNAs with adenosines substituted with N6-methyladenosines can be efficiently methylated, suggesting that the internal methylation occurs at the 2′-OH position of adenosine. Mass spectroscopic analysis further demonstrated that the internal methylation product is 2′-O-methyladenosine. Importantly, genomic RNA purified from DENV virion contains 2′-O-methyladenosine. The 2′-O methylation of internal adenosine does not require specific RNA sequence since recombinant methyltransferase of DENV-4 can efficiently methylate RNAs spanning different regions of viral genome, host ribosomal RNAs, and polyA. Structure-based mutagenesis results indicate that K61-D146-K181-E217 tetrad of DENV-4 methyltransferase forms the active site of internal methylation activity; in addition, distinct residues within the methyl donor (S-adenosyl-L-methionine) pocket, GTP pocket, and RNA-binding site are critical for the internal methylation activity. Functional analysis using flavivirus replicon and genome-length RNAs showed that internal methylation attenuated viral RNA translation and replication. Polymerase assay revealed that internal 2′-O-methyladenosine reduces the efficiency of RNA elongation. Collectively, our results demonstrate that flavivirus NS5 performs 2′-O methylation of internal adenosine of viral RNA in vivo and host ribosomal RNAs in vitro

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis

A new member of the CAB gene family: structure, expression and chromosomal location of Cab -8, the tomato gene encoding the Type III chlorophyll a/b-binding polypeptide of photosystem I

We have previously reported the isolation and characterization of tomato nuclear genes encoding two types of chlorophyll a/b-binding (CAB) polypeptides localized in photosystem (PS) I and two types of CAB polypeptides localized in PSII. Sequence comparisons shows that all these genes are related to each other and thus belong to a single gene family. Here we report the isolation and characterization of an additional member of the tomato CAB gene family, the single tomato nuclear gene, designated Cab -8, which encodes a third type of CAB polypeptide localized in PSI. The protein encoded by Cab -8 is 65% and 60% divergent from the PSI Type I and Type II CAB polypeptides, respectively. The latter two are 65% divergent from each other. Only some short regions of the polypeptides are strongly conserved. The Cab -8 locus maps to chromosome 10, 9 map units from Cab -7, the gene encoding the Type II PSI CAB polypeptide. The Cab -8 gene contains two introns; the first intron matches in position the single intron in the Type II PSII CAB genes and the second intron matches in position the second intron in the Type II PSI CAB gene. Like other CAB genes, Cab -8 is light-regulated and is highly expressed in the leaf and to a lesser extent in other green organs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43422/1/11103_2004_Article_BF00043203.pd

Early bilirubinemia after allogeneic stem cell transplantation - an endothelial complication

Hyperbilirubinemia occurs frequently after allogeneic stem cell transplantation. Causes include primary liver damage and endothelial complications as major contributors. Here, we have investigated the impact of early bilirubinemia (EB) on posttransplant outcomes. Maximum total bilirubin levels (days 0-28) were categorized using maximally selected log rank statistics to identify a cut off for the endpoint non-relapse mortality (NRM) in a training cohort of 873 patients. EB above this cut off was correlated with NRM and overall survival (OS) and with pre- and posttransplant Angiopoietin-2, interleukin (IL)18, CXCL8 and suppressor of tumorigenicity-2 (ST2) serum levels, and the endothelial activation and stress index (EASIX). Clinical correlations were validated in a sample of 388 patients transplanted in an independent institution. The EB cut off was determined at 3.6 mg/dL (61.6 mu M). EB predicted OS (HR 1.60, 95% CI 1.21-2.12, p < 0.001), and NRM (CSHR 2.14; 1.28-3.56, p = 0.004), also independent of typical endothelial complications such as veno-occlusive disease, refractory acute graft-versus-host disease, or transplant-associated microangiopathy. However, EB correlated with high Angiopoietin-2, EASIX-pre and EASIX-day 0, as well as increased levels of posttransplant CXCL8, IL18, and ST2. In summary, EB indicates a poor prognosis. The association of EB with endothelial biomarkers suggests an endothelial pathomechanism also for this posttransplant complication