Brain factor 1 (BF-1) is a winged-helix transcriptional repressor that plays important roles in both progenitor cell differentiation and regional patterning in the mammalian telencephalon. The aim of this study was to elucidate the molecular mechanisms underlying BF-1 functions. It is shown here that BF-1 interacts in vivo with global transcriptional corepressors of the Groucho family and also associates with the histone deacetylase 1 protein. The ability of BF-1 to mediate transcriptional repression is promoted by Groucho and inhibited by the histone deacetylase inhibitor trichostatin A, suggesting that BF-1 recruits Groucho and histone deacetylase activities to repress transcription. Our studies also provide the first demonstration that Groucho mediates a specific interaction between BF-1 and the basic helix-loop-helix protein Hes1 and that BF-1 potentiates transcriptional repression by Hes1 in a Groucho-dependent manner. These findings suggest that Groucho participates in the transcriptional functions of BF-1 by acting as both a corepressor and an adapter between BF-1 and Hes1. Taken together with the demonstration that these proteins are coexpressed in telencephalic neural progenitor cells, these results also suggest that complexes of BF-1, Groucho, and Hes factors may be involved in the regulation of progenitor cell differentiation in the telencephalon.

The proline-rich homeodomain protein (PRH/Hex) is important in the control of cell proliferation and differentiation and in the regulation of multiple processes in embryonic development. We have shown previously that PRH contains two domains that can independently bring about transcriptional repression. The PRH homeodomain represses transcription by binding to TATA box sequences, whereas the proline-rich N-terminal domain of PRH can repress transcription when attached to a heterologous DNA-binding domain. The Groucho/ transducin-like enhancer of split (TLE) family of proteins are transcriptional co-repressors that interact with a number of DNA-bound transcription factors and play multiple roles in development. Here we demonstrate that the proline-rich N-terminal domain of PRH binds to TLE1 in vitro and in yeast two-hybrid assays. We show that PRH and TLE proteins are co-expressed in hematopoietic cells and interact in co-immunoprecipitation assays. We demonstrate that TLE1 increases repression by PRH in transient transfection assays and that titration of endogenous TLE proteins by co-expression of Grg5, a natural trans-dominant negative protein, alleviates transcriptional repression by PRH. Finally, we show that a mutation in the PRH N-terminal domain that blocks the PRH-TLE1 interaction in vitro eliminates co-repression. We discuss these results in terms of the roles of PRH and TLE in cell differentiation and development.

Objective. Because the magnetic resonance imaging (MRI) transverse relaxation time (T2) of cartilage is sensitive to organization of collagen fibers in the cartilage, it may be a noninvasive image marker for senescent changes in cartilage collagen and early cartilage degeneration. The purpose of this study was to determine age-dependent differences in cartilage T2 values in healthy asymptomatic women.Methods. Quantitative T2 maps of patellar cartilage from 30 asymptomatic women ages 22-86 years were obtained using a 3.0T MRI scanner. The study population was stratified by age into 4 cohorts: 18-30, 31-45, 46-65, and 66-86 years. Spatial differences in cartilage T2 were determined as a function of normalized distance from bone. Older groups were compared with the 18-30-year-old group to determine the effects of age on cartilage T2 values. Regions were considered statistically significantly different if the mean T2 values between groups differed at P < 0.05.Results. Mean cartilage T2 profiles were nearly identical for the 2 youngest cohorts. Compared with the 18-30-year-old group, T2 values were statistically significantly longer in the superficial 40% of cartilage in the 46-65-year-old group and over the entire cartilage thickness in the 66-86-year-old group.Conclusion. The location of T2 elevations in women over the age of 45 years is consistent with the theory that senescent changes of cartilage collagen begin near the articular surface and progress to the deeper cartilage with advancing age.Age is a recognized risk factor in the development of osteoarthritis (OA) (1). Epidemiology studies demonstrate a linear increase in OA in individuals younger than 45 years of age, with an exponential increase in those of older ages (1). Understanding of both OA and the basic aging of connective tissue would be of benefit if specific parameters in cartilage could be identified that reflect senescent modification of tissue. Because magnetic resonance imaging (MRI) can directly visualize articular cartilage, it is likely to be a useful modality in the study of cartilage aging and OA. Current clinical MRI techniques demonstrate joint anatomy and can be used to determine morphologic parameters such as cartilage volume, thickness, and presence of focal, superficial cartilage lesions (2). More recently, techniques for generating spatially localized quantitative maps of the MRI relaxation times of cartilage have been described (3). These MRI parametric mapping techniques have the potential to identify and localize specific biochemical and structural changes within the extracellular matrix of cartilage.The transverse relation time (T2) is a measurable MRI time constant that is sensitive to the slow molecular motion of mobile protons. In articular cartilage, the T2 relaxation time has a linear correlation with the water content of tissue (4) and is sensitive to loss of collagen content (5) and to the orientation of collagen fibers (6) in the extracellular matrix. There is a strong inverse correlation between spatially localized cart...

Human T cell lymphotropic/leukemia virus type I (HTLV‐I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV‐I‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV‐I, and whether an HTLV‐I‐infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4+ T cells represent an important target for HTLV‐I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV‐I can infect several additional cellular compartments in vivo, including CD8+ T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV‐I+ CD34+ hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV‐I‐infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax‐specific CD8+ T cell population, anti‐HTLV‐I antibodies, and neurotoxic cytokines involved in disruption of myelin‐producing cells and neuronal degradation characteristic of HAM/TSP. J. Cell. Physiol. 190: 133–159, 2002. © 2002 Wiley‐Liss, Inc.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) tops the list of threats to human health. Studies exploring predictors of mortality in patients with CRAB infection produced conflicting results. Methods: A systematic search of the PubMed, Embase, and the Cochrane Library databases was performed from inception to June 2018 to identify studies reporting mortality predictors in patients infected with CRAB. Two authors independently assessed trials for inclusion and data extraction. Results: A total of 19 observational studies were enrolled in this study. Factors associated with mortality of patients infected with CRAB were inappropriate empirical antimicrobial treatment (odds ratio [OR]

Highlights d FiNad responds to subtle changes of NAD + metabolism in live cells and animals d The role of NAD + precursors in boosting NAD + levels is mapped in various organisms d Increased NAD + synthesis controls morphofunctional changes of activated macrophages d FiNad enables live-cell and in vivo imaging of NAD + decline during aging

The Drosophila protein Groucho is involved in the regulation of cell-determination events during insect neurogenesis and segmentation. A group of mammalian proteins, referred to as transducin-like Enhancer of split (TLE) 1 through 4, share with Groucho identical structures and molecular properties. The aim was to determine whether individual TLE proteins participate in the regulation of cell determination in mammals like their Drosophila counterpart. It is here reported that TLE family members are expressed in combinatorial ways during the in vitro differentiation of mouse P19 embryonic carcinoma cells (a model for neural determination) and rat CFK2 cells (a model for chondrocytic determination). TLE1 is up-regulated and TLE2 and TLE4 are down-regulated to different extents during early stages of differentiation. In contrast, later stages correlate with up-regulation of TLE2 and TLE4, and decreased expression of TLE1. Individual TLE proteins are also expressed in combinatorial as well as complementary patterns during the development of the cerebral cortex and spinal cord of mouse embryos. In particular, TLE1 is robustly expressed in both neural progenitor cells and postmitotic neurons of the outer layers of the cortical plate, whereas TLE4 expression marks preferentially postmitotic neurons of the inner layers. Taken together, these results strongly suggest non-redundant roles for individual TLE proteins during both cell-determination and cell-differentiation events.

Light-regulated modules offer unprecedented new ways to control cellular behaviour with precise spatial and temporal resolution. Among a variety of bacterial light-switchable gene expression systems, single-component systems consisting of single transcription factors would be more useful due to the advantages of speed, simplicity, and versatility. In the present study, we developed a single-component light-activated bacterial gene expression system (eLightOn) based on a novel LOV domain from Rhodobacter sphaeroides (RsLOV). The eLightOn system showed significant improvements over the existing single-component bacterial light-activated expression systems, with benefits including a high ON/OFF ratio of &gt;500-fold, a high activation level, fast activation kinetics, and/or good adaptability. Additionally, the induction characteristics, including regulatory windows, activation kinetics and light sensitivities, were highly tunable by altering the expression level of LexRO. We demonstrated the usefulness of the eLightOn system in regulating cell division and swimming by controlling the expression of the FtsZ and CheZ genes, respectively, as well as constructing synthetic Boolean logic gates using light and arabinose as the two inputs. Taken together, our data indicate that the eLightOn system is a robust and highly tunable tool for quantitative and spatiotemporal control of bacterial gene expression.