339 research outputs found
Integration of Notch1 and calcineurin/NFAT signaling pathway in keratinocyte growth and differentiation control.
No full textNoThe Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J¿ protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control
Delta Np63 Knockdown Mice: A Mouse Model for AEC Syndrome
No full textDominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia. and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since Delta Np63 alpha is the predominantly expressed TP63 isoform, in postnatal skin, we hypothesized that mutant Delta Np63 alpha proteins are primarily responsible for skin fragility in AEC patients. We found that mutant Delta Np63 alpha proteins expressed in AEC patients function as dominant-negative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating Delta Np63 alpha. Indeed, downregulating Delta Np63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by Delta Np63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions. (C) 2009 Wiley-Liss, Inc
Brucella MucR acts as an H-NS-like protein to silence virulence genes and structure the nucleoid
No full textHistone-like nucleoid structuring (H-NS) and H-NS-like proteins serve as global gene silencers and work with antagonistic transcriptional activators (counter-silencers) to properly coordinate the expression of virulence genes in pathogenic bacteria. In Brucella, MucR has been proposed as a novel H-NS-like gene silencer, but direct experimental evidence is lacking. Here, we show that MucR serves as an H-NS-like silencer of the Brucella abortus genes encoding the polar autotransporter adhesins BtaE and BmaC, the c-di-GMP-specific phosphodiesterase BpdB, and the quorum-sensing regulator BabR. We also demonstrate that the MarR-type transcriptional activator MdrA can displace MucR from the btaE promoter, supporting the existence of MucR counter-silencers in Brucella. Moreover, our chromatin immunoprecipitation (ChIP)-seq analysis identified 546 MucR enrichment peaks along the genome, including in the promoters of the genes encoding the Type IV secretion machinery and effectors and the quorum-sensing regulator VjbR. Importantly, MucR ChIP-seq peaks overlap with the previously described binding sites for the transcriptional activators VjbR, BvrR, and CtrA suggesting that these regulators serve as MucR counter-silencers and work in concert with MucR to coordinate virulence gene expression in Brucella. In addition, using chromosome conformation capture (Hi-C), we show that like H-NS in Escherichia coli, MucR alters the global structure of the Brucella nucleoid. Finally, a copy of the E. coli hns rescues the distinctive growth defect and elevated btaE expression of a B. abortus mucR mutant. Together, these findings solidify the role of MucR as a novel type of H-NS-like protein and suggest that MucR’s gene-silencing properties play a key role in virulence in Brucella. IMPORTANCE Histone-like nucleoid structuring (H-NS) and H-NS-like proteins coordinate host-associated behaviors in many pathogenic bacteria, often through forming silencer/counter-silencer pairs with signal-responsive transcriptional activators to tightly control gene expression. Brucella and related bacteria do not encode H-NS or homologs of known H-NS-like proteins, and it is unclear if they have other proteins that perform analogous functions during pathogenesis. In this work, we provide compelling evidence for the role of MucR as a novel H-NS-like protein in Brucella. We show that MucR possesses many of the known functions attributed to H-NS and H-NS-like proteins, including the formation of silencer/counter-silencer pairs to control virulence gene expression and global structuring of the nucleoid. These results uncover a new role for MucR as a nucleoid structuring protein and support the importance of temporal control of gene expression in Brucella and related bacteria
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SEADS 3.0 Sectoral Energy/Employment Analysis and Data System
No full textSEADS 3.0, the Sectoral Energy/Employment Analysis and Data System, is a revision and upgrading of SEADS–PC, a software package designed for the analysis of policy that could be described by modifying final demands of consumer, businesses, or governments (Roop, et al., 1995). If a question can be formulated so that implications can be translated into changes in final demands for goods and services, then SEADS 3.0 provides a quick and easy tool to assess preliminary impacts. And SEADS 3.0 should be considered just that: a quick and easy way to get preliminary results. Often a thorough answer, even to such a simple question as, “What would be the effect on U. S. energy use and employment if the Federal Government doubled R&D expenditures?” requires a more sophisticated analytical framework than the input-output structure embedded in SEADS 3.0. This tool uses a static, input-output model to assess the impacts of changes in final demands on first industry output, then employment and energy use. The employment and energy impacts are derived by multiplying the industry outputs (derived from the changed final demands) by industry-specific energy and employment coefficients. The tool also allows for the specification of regional or state employment impacts, though this option is not available for energy impacts
Minor salivary gland sialolithiasis: a clinical diagnostic challenge
No full textSialolithiasis is a non-neoplastic salivary gland disease that rarely affects the minor salivary glands. There are no guidelines in the literature which can suggest which is the best surgical approach to treat Minor Salivary Glands Sialolithiasis (MSGL). The present case was of a 48-year-old male patient complaining of painful swelling localized in the left back-commissural zone which was 0.5 mm in diameter, for which surgical enucleation approach was done and in that some small calcific masses ranging from 0.2 to 4 mm in diameter were found. They were surrounded by granulation tissue and associated with small pus oozing. Histopathological examination was carried out leading to a final diagnosis of MSGL
Isolation and Characterization of Squamous Cell Carcinoma-Derived Stem-like Cells: Role in Tumor Formation
No full textIn human epidermis, keratinocyte stem cells (KSC) are characterized by high levels of β1-integrin, resulting in the rapid adhesion to type IV collagen. Since epithelial tumors originate from KSC, we evaluated the features of rapidly adhering (RAD) keratinocytes derived from primary human squamous cell carcinoma of the skin (cSCC).
RAD cells expressed higher levels of survivin, a KSC marker, as compared to non-rapidly adhering (NRAD) cells. Moreover, RAD cells proliferated to a greater extent and were more efficient in forming colonies than NRAD cells. RAD cells also migrated significantly
better than NRAD cells. When seeded in a silicone chamber and grafted onto the back skin of NOD SCID mice, RAD cells formed tumors 2–4 fold bigger than those derived from NRAD cells. In tumors derived from RAD cells, the mitotic index was significantly higher
than in those derived from NRAD cells, while Ki-67 and survivin expression were more pronounced in RAD tumors. This study suggests that SCC RAD stem cells play a critical role in the formation and development of epithelial tumors
Evaluation of speed and accident reduction through increased traffic law enforcement
No full textIncludes bibliographical references (leaves 58-59)Increased traffic law enforcement activities were implemented in six Texas counties in an effort to reduce traffic speed and accidents on selected rural roadways. Patrol activities, in addition to normal enforcement efforts, were continued for a 5 month period from August 13, 1979 until December 15, 1979. Speed and accident data were collected and analyzed throughout the study in order to assess the degree of reduction achieved. Data were also collected on several patrol measures in order to evaluate the effort necessary to bring about specified reductions in the traffic parameters of interest. The results indicate that increased patrol activity had the effect of decreasing mean vehicle speed and the percentage of motorists exceeding 55 mph over time. Mean speed was reduced 2.4%, and percent exceeding 55 mph was reduced 19%. Increased patrol activity, in reducing speeds, seems to have the effect of reducing the frequency and severity of accidents. Injury accidents were reduced 9.5%, and property damage accidents were reduced 11.3% on treatment roadways. Regression analyses indicated that a three variable model of speeding tickets per mile of roadway, total number of speeding tickets, and total number of warnings predicted the reduction in mean speed and percent exceeding 55 mph better than a single factor or other multi-factor models. A systematic relationship between patrol activity and accident reduction was not discovered. A set of administrative guidelines were developed based on a regression analysis on the variable speeding tickets per mile. These guidelines provide information regarding the expenditures required to bring about specified degrees of change in speed parameters and are applicable to programs employing increased patrol activity in rural areas over a 5 month period
Evaluation of speed and accident reduction through increased traffic law enforcement
No full textIncludes bibliographical references (leaves 58-59)Increased traffic law enforcement activities were implemented in six Texas counties in an effort to reduce traffic speed and accidents on selected rural roadways. Patrol activities, in addition to normal enforcement efforts, were continued for a 5 month period from August 13, 1979 until December 15, 1979. Speed and accident data were collected and analyzed throughout the study in order to assess the degree of reduction achieved. Data were also collected on several patrol measures in order to evaluate the effort necessary to bring about specified reductions in the traffic parameters of interest. The results indicate that increased patrol activity had the effect of decreasing mean vehicle speed and the percentage of motorists exceeding 55 mph over time. Mean speed was reduced 2.4%, and percent exceeding 55 mph was reduced 19%. Increased patrol activity, in reducing speeds, seems to have the effect of reducing the frequency and severity of accidents. Injury accidents were reduced 9.5%, and property damage accidents were reduced 11.3% on treatment roadways. Regression analyses indicated that a three variable model of speeding tickets per mile of roadway, total number of speeding tickets, and total number of warnings predicted the reduction in mean speed and percent exceeding 55 mph better than a single factor or other multi-factor models. A systematic relationship between patrol activity and accident reduction was not discovered. A set of administrative guidelines were developed based on a regression analysis on the variable speeding tickets per mile. These guidelines provide information regarding the expenditures required to bring about specified degrees of change in speed parameters and are applicable to programs employing increased patrol activity in rural areas over a 5 month period
International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome
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