Clinicopathological characteristics and prognostic factors for canine multicentric non‐indolent T‐cell lymphoma: 107 cases

Canine lymphoma, as the most common haematopoietic malignancy, encompasses a group of heterogeneous diseases and even within the T-cell immunophenotype, differences in clinical presentation and responses to treatment exist. The aim of this retrospective study was to determine outcomes and prognostic factors of 107 dogs with multicentric non-indolent T-cell lymphoma (TCL) receiving lomustine-based (70%) and non-lomustine-based (30%) treatment. The majority were Labradors, Boxers, mixed-breed dogs and Dogue de Bordeaux. Eighty-six percent were substage b, 77% had mediastinal involvement, 15% had suspected bone marrow involvement and 12% had other extra-nodal sites of disease. The overall response rate to induction therapy was 80%; dogs receiving procarbazine in the induction protocol (P = .042), dogs with neutrophil concentration below 8.7 × 10e9 /L (P = .006) and mitotic rate below 10 per 5 high power field (P = .013), had greater response rates. Median progression-free survival (PFS) for the first remission was 105 days; lack of expression of CD3 on flow cytometry (P < .0001) and pretreatment with steroid (P = .012) were significantly associated with shorter PFS. Median overall survival time (OST) was 136 days; co-expression of CD79a (P = .002), lack of CD3 expression on flow cytometry, presence of anaemia (P = .007), and monocytopenia (P = .002) were predictive of shorter OST. Multicentric non-indolent TCL in dogs is an aggressive cancer with new possible prognostic factors

A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms

Abstract Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients

Conserved determinants of lentiviral genome dimerization

Abstract Background Retroviruses selectively package two copies of their unspliced genomes by what appears to be a dimerization-dependent RNA packaging mechanism. Dimerization of human immunodeficiency virus Type-1 (HIV-1) genomes is initiated by “kissing” interactions between GC-rich palindromic loop residues of a conserved hairpin (DIS), and is indirectly promoted by long-range base pairing between residues overlapping the gag start codon (AUG) and an upstream Unique 5′ element (U5). The DIS and U5:AUG structures are phylogenetically conserved among divergent retroviruses, suggesting conserved functions. However, some studies suggest that the DIS of HIV-2 does not participate in dimerization, and that U5:AUG pairing inhibits, rather than promotes, genome dimerization. We prepared RNAs corresponding to native and mutant forms of the 5′ leaders of HIV-1 (NL4-3 strain), HIV-2 (ROD strain), and two divergent strains of simian immunodeficiency virus (SIV; cpz-TAN1 and -US strains), and probed for potential roles of the DIS and U5:AUG base pairing on intrinsic and NC-dependent dimerization by mutagenesis, gel electrophoresis, and NMR spectroscopy. Results Dimeric forms of the native HIV-2 and SIV leaders were only detectable using running buffers that contained Mg2+, indicating that these dimers are more labile than that of the HIV-1 leader. Mutations designed to promote U5:AUG base pairing promoted dimerization of the HIV-2 and SIV RNAs, whereas mutations that prevented U5:AUG pairing inhibited dimerization. Chimeric HIV-2 and SIV leader RNAs containing the dimer-promoting loop of HIV-1 (DIS) exhibited HIV-1 leader-like dimerization properties, whereas an HIV-1NL4-3 mutant containing the SIVcpzTAN1 DIS loop behaved like the SIVcpzTAN1 leader. The cognate NC proteins exhibited varying abilities to promote dimerization of the retroviral leader RNAs, but none were able to convert labile dimers to non-labile dimers. Conclusions The finding that U5:AUG formation promotes dimerization of the full-length HIV-1, HIV-2, SIVcpzUS, and SIVcpzTAN1 5′ leaders suggests that these retroviruses utilize a common RNA structural switch mechanism to modulate function. Differences in native and NC-dependent dimerization propensity and lability are due to variations in the compositions of the DIS loop residues rather than other sequences within the leader RNAs. Although NC is a well-known RNA chaperone, its role in dimerization has the hallmarks of a classical riboswitch.http://deepblue.lib.umich.edu/bitstream/2027.42/113284/1/12977_2015_Article_209.pd

Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

During transcription, the nascent RNA can invade the DNA template, forming extended RNA-DNA duplexes (R-loops). Here we employ ChIP-seq in strains expressing or lacking RNase H to map targets of RNase H activity throughout the budding yeast genome. In wild-type strains, R-loops were readily detected over the 35S rDNA region, transcribed by Pol I, and over the 5S rDNA, transcribed by Pol III. In strains lacking RNase H activity, R-loops were elevated over other Pol III genes, notably tRNAs, SCR1 and U6 snRNA, and were also associated with the cDNAs of endogenous TY1 retrotransposons, which showed increased rates of mobility to the 5'-flanking regions of tRNA genes. Unexpectedly, R-loops were also associated with mitochondrial genes in the absence of RNase H1, but not of RNase H2. Finally, R-loops were detected on actively transcribed protein-coding genes in the wild-type, particularly over the second exon of spliced ribosomal protein genes

Blood dendritic cells in cattle infected with bovine leukemia virus (BLV): isolation and phenotyping

Dendritic cells (DCs) are most potent antigen presenting cells (APCs) with unique ability to prime effective immune responses. They express higher levels of MHC class II and accesory molecules on their surface, than other professional APCs. The investigations were performed on DCs generated from blood with the use of microbeads magnetically labeled with mouse anti human CD14. Flow cytometry was applied for determination of DCs immunophenotype in healthy and naturally infected with BLV cattle. For immunophenotyping mouse monoclonal antibodies anti bovine: CD11a, CD11b, CD11c, MHC-I and MHC-II were used. Our results demonstrated that dendritic cells infected with BLV expressed very high percentage of determinants: CD11a, CD11b, CD11c, MHC-I and MHC-II class. Leukaemic DCs exhibited DCs morphology and had a phenotype of mature DCs. The expression of gp51 glycoprotein of BLV on leukaemic DCs was detected in flow cytometry investigations

RESEARCH Open Access

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