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  • 1
    ISSN: 0948-5023
    Keywords: HIV-1 reverse transcriptase ; Minor groove binding track ; Particle-mesh Ewald
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have built a molecular dynamics model for human immunodeficiency virus (HIV-1) reverse transcriptase (RT) complexed with a 19/18-mer template/primer by combining the structural information of a low resolution crystal structure of a HIV-1 RT/DNA complex (1hmi) with that of a high resolution crystal structure of unliganded HIV-1 RT (1rtj). The process involved slow forcing of the α-carbons of 1rtj onto those of 1hmi using constrained MD simulations, while immersing the protein in aqueous solution. A similar technique was used to build the bent all-atom DNA duplex, which was then docked into the modeled protein. The resulting model complex was refined using molecular dynamics simulation with the Particle-mesh Ewald method employed to accommodate long-range electrostatic interactions. New parameters of the Amber force field that affect DNA twist are tested and largely validated. The model has been used successfully to explain the results of vertical scanning mutagenesis of residue 266 (Trp266). Recently, the low resolution crystal structure of the HIV-1 RT/DNA complex has been refined to a 2.8 Å resolution (2hmi) and a crystal structure of a HIV-1/RT/dTTP ternary complex has been determined at 3.2 Å resolution (1rtd). A detailed structural comparison of the prior model structure and the two experimental structures becomes possible. Overall, the three structures share many similarities. The root mean square deviations of the α-carbons for the individual subdomains among the three structures are within the same ranges. The secondary structure assignments in the three structures are nearly identical. Key protein-DNA contacts such as those in the region of the primer grip are also similar in the three structures.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 89 (2001), S. 586-589 
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The temperature and dielectric stability of magnetic tunnel junctions are important requirements for magnetic memory devices and their integration in the semiconductor process technology. We have investigated the changes of the tunneling magnetoresistance (TMR), the barrier properties (height, thickness, and asymmetry) and the dielectric stability upon isochronal annealing up to 410 °C in Co/Al2O3/Co junctions with an artificial antiferromagnet as a pinning layer. Besides a small decrease of the TMR signal after annealing up to 230 °C, a strong decrease between 300 and 350 °C is found. According to Auger and transmission electron microscopy investigations, this decrease is mainly due to interdiffusion of the metallic layers. The dielectric breakdown is characterized by voltage ramp experiments. The size-averaged breakdown voltage improves from 1.35 V for the as prepared junctions to 1.55 V by annealing at 300 °C. At higher temperatures the breakdown voltage decreases strongly to 0.8 V (at 380 °C). Simultaneously, the typical breakdown process changes from few sudden current jumps to a large number of small steps. The breakdown properties are discussed within a statistical model and related to structural changes of the barrier. © 2001 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Effective blockade of the pluripotent cytokine TGF-beta as a means of cutaneous scar reduction is a strategy with great potential. This desired effect may be achieved through the overexpression of mutant TGF beta receptors within the wound milieu. Our goal was to examine the effects of dominant negative mutant TGF-beta receptor II (dnTGFRII) protein expression in a well-established rabbit ear model of hypertrophic scarring. Serial injections of a retroviral construct encoding a truncated TGFβRII and the marker green fusion protein (pMSCV-rIIdn-GFP) were performed in 7mm punch wounds at day 10 and day 14 (two-day injection group) or day 8, 10, 12 (three-day injection group) post wounding. Delivery of a null vector (pMSCV-GFP) at the same time points served as a negative control. Histomorphometric analysis of wounds harvested at day 28 revealed a statistically significant reduction (33%) in the scar elevation index in 2-day treated and a more modest reduction in SEI (17.5%) in the 3-day treated arm compared to null-treated controls. Confocal microscopy confirmed stable transfection of the construct in both peri-wound tissue as well as rabbit dermal fibroblasts transfected in vitro. Optimization of this novel application in retroviral gene therapy could lead to effective anti-scarring strategies.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd/Inc.
    Wound repair and regeneration 12 (2004), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Introduction: Ischemia-reperfusion (IR) injury is commonly associated with numerous pathologies including pressure sores, venous stasis ulcers, and lower extremity diabetic ulcers. The purpose of this study is to further investigate the relationship between age and ischemia-reperfusion skin injury in a rat model utilizing magnets for the purpose of injury creation.
Methods: Magnets were designed for subcutaneous placement and calibrated such that a second magnet placed externally over them would cause compression that exceeds capillary perfusion pressure (ischemia). Removing the external magnet results in reperfusion of the skin. After placing subcutaneous magnets in aged and young Fisher 344 rats, repeated cycles of external magnet placement and removal were performed. 
Results: Visual analysis of the skin revealed statistically significant greater areas of injury in the aged rats relative to their younger counterparts (37.4 ± 13.3% vs. 24.1 ± 14.8%, P 〈 .02)
Conclusions: Aged rats demonstrate an increased degree of injury relative to their younger counterparts in response to ischemia-reperfusion injury. Future studies will attempt to delineate differences in the markers of IR injury (such as myeloperoxidase and vitamin E levels) in aged versus young rats, giving insight to the mechanisms responsible for the impaired wound healing seen in the elderly.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd/Inc.
    Wound repair and regeneration 12 (2004), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Introduction: Telomeres are nucleoprotein structures at the ends of each chromosome. Due to the inability of DNA polymerase to replicate the full length of the chromosome, up to 50–200 base pairs of the telomere are lost during each successive round of cell division. In adult human somatic cells, telomerase is not active resulting in progressive loss of telomere length and entry into replicative senescence as observed in cell culture. hTERT is the catalytic subunit of telomerase, an enzyme which maintains telomere length. Transfection of human dermal fibroblasts (HDFs) by hTERT has been shown to reverse the senescent phenotype seen in aging HDFs in vitro. ERK (p44/42) is a MAP kinase which functions as a critical intermediary in the determination of cell growth and differentiation. Activation of ERK occurs through phosphorylation of threonine and tyrosine residues. 
Methods: In order to delineate some of the cellular mechanisms by which hTERT functions, we treated adenoviral hTERT (Ad-hTERT) transfected HDFs with TGFB1, and assayed phosphorylated ERK activity by Western blotting.
Results: Ad-hTERT treated HDFs demonstrated a 2–3 fold increase in phospho-ERK activity. In addition, our preliminary findings show that Ad-hTERT transfected HDFs have increased TGFB1, TGFB1-Receptor I and II, and COL1A1 gene expression by real-time rtPCR. 
Conclusions: Increased phosphor-ERK activity as well as increased TGFB1, TGFB1-Receptor I and II, and COL1A1 gene expression is seen in hTERT transfected HDF’s. Further studies will focus on defining other intermediary changes resulting from Ad-hTERT tranfection.Funding source: Geron Corporation
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd/Inc.
    Wound repair and regeneration 12 (2004), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A critical limitation of using retroviral vectors for gene therapy is their inability to infect non-dividing cells. Although, the adenoviral vectors have the advantage of being able to infect both dividing and non-dividing cells, they elicit inflammatory response, thus making the interpretation of in vivo experiments harder. Adeno-associated virus (AAV) and Lentiviral vectors do not have those limitations, however, scant information is available about their transfection efficiency under low-oxygen tension. To determine if low-oxygen microenvironment affects viral vector-mediated gene transfection, we have used two other viral vectors, Adeno-associated virus (AAV) and Lentiviral constructs in vitro and in vivo to express foreign genes in hypoxic cultured human dermal fibroblasts and ischemic rat wounds. Both cultured normoxic and hypoxic (1% O2) human dermal fibroblasts were identically transfected by the AAV vector. A lenti6-LacZ construct was injected onto the periphery of rat ischemic and non-ischemic wound (106 pfu/wound) at the time of wounding. Wounds were harvested at post-operative day 7. Frozen sections of the wounds were fixed in cold acetone and stained with a in situ β-gal staining kit. Intense expression of β-gal was observed without any inflammatory response. No significant difference of transfection efficiency was observed between the ischemic and non-ischemic wounds. Thus our data indicates that both AAV and Lentiviral vectors are suitable to use in gene-therapy experiments in both ischemic and non-ischemic cells and tissues in vitro and in vivo.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Science Ltd/Inc.
    Wound repair and regeneration 12 (2004), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Accumulating data strongly suggests that under hypoxic conditions the adaptive physiological response of the cells involves co-operation between oxygen sensing and growth factor signals that cause HIF-1 mediated gene expression. The HIF-1 has been identified as a central and critical molecule in oxygen sensing and possibly a master switch. Of the many cytokines that have been shown to modulate collagen production, TGFβ1 appears to be crucial as it can sustain stimulation of collagen production as well as autoinduction of its own synthesis. Several genes that are known to be hypoxia inducible are also up-regulated by TGFβs, and the promoter of TGFβ3, a member of the family, has a hypoxia-response element (HRE). Recent reports indicate that HIF-1α physically interacts with Smad3 and that the TGFβ and hypoxia signaling pathways synergize at the transcriptional level to regulate gene expression. To determine if this interaction upregulates gene expression through the HRE element, we have co-transfected cultured human dermal fibroblasts with the mammalian expression plasmid for HIF-1α(pCEP1-HIF-1α) with a reporter construct 5HRE-luc, containing a concatemer of five copies of HRE derived from human vascular endothelial growth factor (VEGF), a minimal cytomegalovirus (CMV) promoter and a reporter gene,luciferase.). When treated with 2 ng/ml of TGFβ1 protein, co- transfected hypoxic aged and young human dermal fibroblasts showed significant synergistic upregulation of the reporter gene expression. To further confirm the TGFβ-HIF-1α interaction we have created a TGFβ1 -RNAi construct by subcloning a 19-nucleotide sequence derived from rabbit in a mammalian expression vector (p-SUPER) that directs the synthesis of small interfering RNAs (siRNAs). Hypoxic rabbit cultured dermal fibroblasts co-transfected with TGFβ1-RNAi and 5HRE-luc showed down-regulation of reporter gene expression.As a prerequisite to understanding the biology of physiological and pathological ischemic tissue repair process it is important to delineate the molecular basis of regulation of collagen gene expression in fibroblasts. Each step in the TGFβ signaling cascade is a potential target for highly specific therapy and information about how hypoxic low-oxygen microenvironments affect the TGFβ cascade could be useful to develop novel therapeutic strategies that will involve agonist and antagonist agents that directly interfere with these steps.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Malden, USA : Blackwell Science Inc
    Wound repair and regeneration 11 (2003), S. 0 
    ISSN: 1524-475X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Tissue PO2 levels are known to directly modulate numerous processes involved in the reparative response to cutaneous tissue injury, including cell differentiation and migration, extracellular matrix synthesis and maturation, and effectiveness of endogenous and exogenous growth factors. Oxygen is therefore likely the critical variable determining the healing capabilities of any tissue. Significant advances in the understanding of cutaneous wound healing progressed with advances in the measurement of tissue PO2, which has advanced over the past several decades from implantable probes to now include molecular tools such as the transcription factor hypoxia inducible factor-1 (HIF-1). HIF-1 modulates the expression of genes that drive the cellular adaptive response to hypoxia and possess the HIF-1 binding sequence named hypoxia response element within their promoter sequence. Molecular biology techniques are now allowing exploitation of the HIF-1/hypoxia response element pathway to drive the expression of potential vulnerary ectopic genes. Here we show the utility of the hypoxia response element for hypoxia-driven expression of the transforming growth factor-β–signaling component Smad3 in vitro and the in vivo detection of ischemic hypoxia using luciferase. Smad3 is a positive effector of transforming growth factor-β superfamily signal transduction. Such approaches are the latest evolution of work championed by Hunt and colleagues over the past 4 decades. (WOUND REP REG 2003;11:496–503)
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Boston, USA and Oxford, UK : Blackwell Publishers Inc.
    Risk analysis 21 (2001), S. 0 
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: The state of Washington operates the largest passenger vessel ferry system in the United States. In part due to the introduction of high-speed ferries, the state of Washington established an independent blue-ribbon panel to assess the adequacy of requirements for passenger and crew safety aboard the Washington state ferries. On July 9, 1998, the Blue Ribbon Panel on Washington State Ferry Safety engaged a consultant team from The George Washington University and Rensselaer Polytechnic Institute/Le Moyne College to assess the adequacy of passenger and crew safety in the Washington state ferry (WSF) system, to evaluate the level of risk present in the WSF system, and to develop recommendations for prioritized risk reduction measures, which, once implemented, can improve the level of safety in the WSF system. The probability of ferry collisions in the WSF system was assessed using a dynamic simulation methodology that extends the scope of available data with expert judgment. The potential consequences of collisions were modeled in order to determine the requirements for onboard and external emergency response procedures and equipment. The methodology was used to evaluate potential risk reduction measures and to make detailed risk management recommendations to the blue-ribbon panel and the Washington State Transportation Commission.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Inc
    The @breast journal 9 (2003), S. 0 
    ISSN: 1524-4741
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract:  Breast sarcomas account for about 1% of all malignant breast cancers. Leiomyosarcoma (LMS), one of the rarest, was first described 20 years ago, and yet few published reports exist. A case of primary LMS in a 25-year-old woman is presented and is only the 18th well-documented case in the literature. The clinical presentation, diagnosis, therapy, and pathologic features are reviewed.
    Type of Medium: Electronic Resource
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