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Berlin Brandenburg

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  • 1
    Language: English
    In: PloS one, 2015, Vol.10(4), pp.e0124373
    Description: Haemophilus ducreyi resists the cytotoxic effects of human antimicrobial peptides (APs), including α-defensins, β-defensins, and the cathelicidin LL-37. Resistance to LL-37, mediated by the sensitive to antimicrobial peptide (Sap) transporter, is required for H. ducreyi virulence in humans. Cationic APs are attracted to the negatively charged bacterial cell surface. In other gram-negative bacteria, modification of lipopolysaccharide or lipooligosaccharide (LOS) by the addition of positively charged moieties, such as phosphoethanolamine (PEA), confers AP resistance by means of electrostatic repulsion. H. ducreyi LOS has PEA modifications at two sites, and we identified three genes (lptA, ptdA, and ptdB) in H. ducreyi with homology to a family of bacterial PEA transferases. We generated non-polar, unmarked mutants with deletions in one, two, or all three putative PEA transferase genes. The triple mutant was significantly more susceptible to both α- and β-defensins; complementation of all three genes restored parental levels of AP resistance. Deletion of all three PEA transferase genes also resulted in a significant increase in the negativity of the mutant cell surface. Mass spectrometric analysis revealed that LptA was required for PEA modification of lipid A; PtdA and PtdB did not affect PEA modification of LOS. In human inoculation experiments, the triple mutant was as virulent as its parent strain. While this is the first identified mechanism of resistance to α-defensins in H. ducreyi, our in vivo data suggest that resistance to cathelicidin LL-37 may be more important than defensin resistance to H. ducreyi pathogenesis.
    Keywords: Bacterial Proteins -- Genetics ; Drug Resistance, Bacterial -- Genetics ; Ethanolaminephosphotransferase -- Genetics ; Haemophilus Ducreyi -- Genetics ; Lipid A -- Metabolism
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(5), p.e35584
    Description: Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC 50 values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1 , MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.
    Keywords: Research Article ; Biology ; Medicine ; Computational Biology ; Oncology ; Biochemistry
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: 2015, Vol.10(9), p.e0137935
    Keywords: Correction
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, March 18, 2015, Vol.10(3), p.e0120016
    Description: Marijuana (Cannabis sativa L.) cultivation has proliferated in northwestern California since at least the mid-1990s. The environmental impacts associated with marijuana cultivation appear substantial, yet have been difficult to quantify, in part because cultivation is clandestine and often occurs on private property. To evaluate the impacts of water diversions at a watershed scale, we interpreted high-resolution aerial imagery to estimate the number of marijuana plants being cultivated in four watersheds in northwestern California, USA. Low-altitude aircraft flights and search warrants executed with law enforcement at cultivation sites in the region helped to validate assumptions used in aerial imagery interpretation. We estimated the water demand of marijuana irrigation and the potential effects water diversions could have on stream flow in the study watersheds. Our results indicate that water demand for marijuana cultivation has the potential to divert substantial portions of streamflow in the study watersheds, with an estimated flow reduction of up to 23% of the annual seven-day low flow in the least impacted of the study watersheds. Estimates from the other study watersheds indicate that water demand for marijuana cultivation exceeds streamflow during the low-flow period. In the most impacted study watersheds, diminished streamflow is likely to have lethal or sub-lethal effects on state-and federally-listed salmon and steelhead trout and to cause further decline of sensitive amphibian species.
    Keywords: Trout – Laws, Regulations and Rules ; Marijuana Trade – Laws, Regulations and Rules ; Water Resources – Laws, Regulations and Rules ; Streamflow – Laws, Regulations and Rules ; Marijuana – Laws, Regulations and Rules
    ISSN: 1932-6203
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(8), p.e101604
    Description: Research has shown that bisexuals have poorer health outcomes than heterosexuals, gays, or lesbians, particularly with regard to mental health and substance use. However, research on bisexuals is often hampered by issues in defining bisexuality, small sample sizes, and by the failure to address age differences between bisexuals and other groups or age gradients in mental health. The Risk & Resilience Survey of Bisexual Mental Health collected data on 405 bisexuals from Ontario, Canada, using respondent-driven sampling, a network-based sampling method for hidden populations. The weighted prevalence of severe depression (PHQ-9 ≥ 20) was 4.7%, possible anxiety disorder (OASIS ≥ 8) was 30.9%, possible post-traumatic stress disorder (PCL-C ≥ 50) was 10.8%, and past year suicide attempt was 1.9%. With respect to substance use, the weighted prevalence of problem drinking (AUDIT ≥ 5) was 31.2%, and the weighted prevalence of illicit polydrug use was 30.5%. Daily smoking was low in this sample, with a weighted prevalence of 7.9%. Youth (aged 16-24) reported significantly higher weighted mean scores on depression and post-traumatic stress disorder, and higher rates of past year suicidal ideation (29.7% vs. 15.2%) compared with those aged 25 and older. The burden of mental health and substance use among bisexuals in Ontario is high relative to population-based studies of other sexual orientation groups. Bisexual youth appear to be at risk for poor mental health. Additional research is needed to understand if and how minority stress explains this burden.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: PLoS ONE, 2009, Vol.4(4), p.e5342
    Description: HER2-targeted therapy with the monoclonal antibody trastuzumab (Herceptin®) has improved disease-free survival for women diagnosed with HER2-positive breast cancers; however, treatment resistance and disease progression are not uncommon. Current data suggest that resistance to treatment in HER2 cancers may be a consequence of NF-κB overexpression and increased COX2-derived prostaglandin E2 (PGE 2 ). Conjugated linoleic acid (CLA) has been shown to have anti-tumor properties and to inhibit NF-κB activity and COX2. ; In this study, HER2-overexpressing SKBr3 breast cancer cells were treated with CLA. Protein expression of the HER2 receptor, nuclear NF-κB p65, and total and phosphorylated IκB were examined by western blot and immunofluorescence. PGE levels were determined by ELISA. Proliferation was measured by metabolism of 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), and apoptosis was measured by FITC-conjugated Annexin V staining and flow cytometry. ; We observed a significant decrease in HER2 protein expression on western blot following treatment with 40 and 80 µM CLA (p〈0.01 and 0.001, respectively) and loss of HER2 protein in cells using immunoflourescence that was most pronounced at 80 µM. Protein levels of nuclear NF-κB p65 were also significantly reduced at the 80 µM dose. This was accompanied by a significant decrease in PGE levels (p = 0.05). Pretreatment with CLA significantly enhanced TNFα-induced apoptosis and the anti-proliferative action of trastuzumab (p = 0.05 and 0.001, respectively). These data add to previous reports of an anti-tumor effect of CLA and suggest an effect on the HER2 oncogene that may be through CLA mediated downregulation of COX2-derived PGE.
    Keywords: Research Article ; Nutrition ; Cell Biology -- Cell Signaling ; Oncology -- Breast Cancer ; Women's Health -- Breast Cancer
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, 2009, Vol.4(5), p.e5578
    Description: Avicins, a class of electrophilic triterpenoids with pro-apoptotic, anti-inflammatory and antioxidant properties, have been shown to induce redox-dependant post-translational modification of cysteine residues to regulate protein function. Based on (a) the cross-talk that occurs between redox and phosphorylation processes, and (b) the role of Stat3 in the process of apoptosis and carcinogenesis, we chose to study the effects of avicins on the processes of phosphorylation/dephosphorylation in Stat3. Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3. The expression of Stat3-regulated proteins such as c-myc, cyclin D1, Bcl2, survivin and VEGF were reduced in response to avicin treatment. Underlying avicin-induced dephosphorylation of Stat3 was dephosphorylation of JAKs, as well as activation of protein phosphatase-1. Downregulation of both Stat3 activity and expression of Stat 3-controlled pro-survival proteins, contributes to the induction of apoptosis in avicin treated tumor cells. Based on the role of Stat3 in inflammation and wounding, and the in vivo inhibition of VEGF by avicins in a mouse skin carcinogenesis model, it is likely that avicin-induced inhibition of Stat3 activity results in the suppression of the pro-inflammatory and pro-oxidant stromal environment of tumors. Activation of PP-1, which also acts as a cellular economizer, combined with the redox regulation by avicins, can aid in redirecting metabolism from growth promoting anabolic to energy sparing pathways.
    Keywords: Research Article ; Cell Biology ; Oncology ; Cell Biology -- Cell Signaling
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: PLoS ONE, 2009, Vol.4(12), p.e8115
    Description: There has been much interest in targeting intracellular redox pathways as a therapeutic approach for cancer. Given recent data to suggest that the redox status of extracellular protein thiol groups (i.e. exofacial thiols) effects cell behavior, we hypothesized that redox active anti-cancer agents would modulate exofacial protein thiols. ; To test this hypothesis, we used the sesquiterpene lactone parthenolide, a known anti-cancer agent. Using flow cytometry, and western blotting to label free thiols with Alexa Fluor 633 C maleimide dye and N-(biotinoyl)-N-(iodoacetyl) ethylendiamine (BIAM), respectively, we show that parthenolide decreases the level of free exofacial thiols on Granta mantle lymphoma cells. In addition, we used immuno-precipitation techniques to identify the central redox regulator thioredoxin, as one of the surface protein thiol targets modified by parthenolide. To examine the functional role of parthenolide induced surface protein thiol modification, we pretreated Granta cells with cell impermeable glutathione (GSH), prior to exposure to parthenolide, and showed that GSH pretreatment; (a) inhibited the interaction of parthenolide with exofacial thiols; (b) inhibited parthenolide mediated activation of JNK and inhibition of NFκB, two well established mechanisms of parthenolide activity and; (c) blocked the cytotoxic activity of parthenolide. That GSH had no effect on the parthenolide induced generation of intracellular reactive oxygen species supports the fact that GSH had no effect on intracellular redox. Together these data support the likelihood that GSH inhibits the effect of parthenolide on JNK, NFκB and cell death through its direct inhibition of parthenolide's modulation of exofacial thiols. ; Based on these data, we postulate that one component of parthenolide's anti-lymphoma activity derives from its ability to modify the redox state of critical exofacial thiols. Further, we propose that cancer cell exofacial thiols may be important and novel targets for therapy.
    Keywords: Research Article ; Biochemistry ; Hematology ; Hematology -- Acute Lymphoblastic Leukemia ; Hematology -- Acute Myeloid Leukemia ; Oncology -- Myelomas And Lymphoproliferative Diseases ; Oncology -- Myeloproliferative Disorders, Including Chronic Myeloid Leukemia
    E-ISSN: 1932-6203
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