Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients

Epitope specificity and clonality of EBV-specific CTLs used to treat posttransplant lymphoproliferative disease

In a recent phase II clinical trial using banked allogeneic CTL lines to treat EBV-associated posttransplant lymphoproliferative disease, a response rate of 52% was recorded 6 mo posttreatment. Tumor response was associated with an increase in both CTL/recipient HLA matches and CD4<sup>+</sup> T cells within the infused CTL lines. The present study was undertaken to correlate tumor response with CTL specificity. The majority of CTL lines infused recognized EBV-encoded nuclear Ag-3 proteins, but CTL protein specificity itself did not correlate with tumor response. Specificity in conjunction with donor/recipient functional HLA matching as opposed to HLA matching alone, however, was important for tumor response. CTL receptor TCR β-chain variable gene subfamilies were polyclonal, with no preferential use of a particular family. However, tumor response was improved in those receiving CTL lines with polyclonal vs clonal distribution for subfamilies 2, 3, and 9. Interestingly, in five of six tumors (five Hodgkin’s-like and one Burkitt’s-like posttransplant lymphoproliferative disease) with restricted viral gene expression a complete response was recorded, although in some cases the tumor cells did not express the proteins recognized by the infused CTL. Thus CTL were advantageous when functionally HLA matched but for certain tumor types complete responses occurred in the absence of detectable specific CTL/tumor recognition. We suggest that either the allogenic CTL contained small, undetectable, EBV-specific, HLA-matched T cell populations or perhaps they stimulated nonspecific inflammatory responses in vivo, which were beneficial for tumor regression. These observations should be considered when designing and implementing CTL therapies

Influence of a native strain of Staphylococcus xylosus on the microbiological, physicochemical and sensorial characteristics on milano salami type

In this work, the influence of native starter cultures on the microbiological, physicochemical and sensorial characteristics of Milano salami type was studied. Two batches of Milano salami type were produced: Batch A, with the addition of Staphylococcus xylosus U5 and Batch B (control) without the starter culture. The Milano salami type was characterized by an important microbial activity of coagulase-negative staphylococci (CNS) that resulted in substantial growth in Batch A during the ripening with an initial count of 7.60 log cfu.g-1 and reached 9.84 log CFU.g-1 after 14 days. Bacterial enzymes that showed efficient activity under the conditions found in Milano salami type were catalase, nitrite and nitrate reductase, contributing for sensory and physicochemical properties of the product. There were no significant differences in general free fatty acids composition among the batches, while the color parameters (L *, a * and b *) in the Batch A presented significantly higher values in relation to Batch B. Moreover, batch A had the higher preference in sensorial analysis.<br>A análise da influência de culturas iniciadoras nativas nas características microbiológicas, físicoquímicas e sensoriais de salame tipo Milano foi o objeto deste estudo. Foram produzidos dois grupos de salame tipo Milano: Grupo A - com aplicação de linhagem Staphylococcus xylosus U5 enquanto o controle, Grupo B, foi produzido sem culturas iniciadoras. O salame tipo Milano foi caracterizado pela importante atividade microbiana de estafilococos coagulase negativo (SCN), que resultou significativo crescimento no Grupo A durante a maturação, com contagem inicial de 7,60 ufc.g-1 e alcançando um crescimento de 9,84 cfu.g-1 depois de 14 dias. As enzimas bacterianas que mostraram eficiente atividade sob as condições encontradas no salame tipo Milano foram catalase, nitrito e nitrato redutase, contribuindo para as propriedades físicoquímicas e sensoriais do produto. Não houve diferenças significativas na composição geral dos ácidos graxos livres entre as amostras, enquanto os parâmetros de cor (L*, a* e b*) obtidos no salame inoculado (Grupo A) diferiram significativamente em relação ao controle (Grupo B) e foi o grupo preferido pelos degustadores