The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxia induced apoptosis occurs. These resistant tumours probably have a more aggressive phenotype and may have decreased responsiveness to treatment. The key regulator of this process, hypoxia inducible factor 1 (HIF-1), can initiate apoptosis by inducing high concentrations of proapoptotic proteins, such as BNIP3, and can cause stabilisation of p53. However, during hypoxia, antiapoptotic proteins, such as IAP-2, can be induced, whereas the proapoptotic protein Bax can be downregulated. During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation. Understanding the regulation of apoptosis during hypoxia and the mechanisms of resistance to apoptosis might lead to more specific treatments for solid tumours

The trees in urban cities : A study of four municipal tree policies

Allt eftersom städer växer blir de urbana miljöerna mer hårdgjorda. De hårdgjorda ytorna skapar ett varmare lokalklimat och skapar en ökad ytavrinning. Det tuffa förhållandet i städerna med hårdgjorda ytor kan göra det svårt för stadsträd att bli gamla och vidare exploatering i städer riskerar att skada träden. För att skapa ett hållbart trädbestånd med vitala träd som kan bidra till att minska den lokala temperaturökningen och ta hand om dagvatten krävs styrdokument som prioriterar träden. Inom kommuner arbetar man med olika styrdokument som ska bidra till att värna om stadsträden, ett av de övergripande styrdokumenten är en trädpolicy. Arbetets syfte är att undersöka om olika kommuners trädpolicyer är likvärdiga och om de är aktuella samt användbara dokument. För att svara på syftet genomfördes en dokumentanalys och en intervjustudie. Dokumentanalysen berör fyra svenska kommuner och i intervjustudien tre personer som arbetar inom kommunerna. Av resultatet kan man se skillnader på vad policyerna innehåller och hur dem används. Innehållet i trädpolicyerna är i några fall bristfällig i jämförelse med den forskning som finns kring stadsträd och viktiga värden att arbeta för. Likheter som vi kan dra slutsatser om är att alla kommuner värnar om biologisk mångfald. Genom studien har vi märkt en skillnad på att två av de granskade trädpolicyer är mer omfattade kring antal av trädens värden och målsättningar som tas upp. Användandet av policyn skiljer sig då de granskade kommunerna använder dokumentet olika, några använder det i stor utsträckning från planering till utförandeärenden och andra har dokumentet som grund för andra mer användbara dokument. Även om dokumentet används på olika sätt fyller policyn en viktig funktion eftersom dokumentet är politiskt beslutad vilket stödjer personalens arbetssätt kring vilka riktlinjer och mål man ska förhålla sig till.Our cities are growing which leads to an increase in impervious urban surfaces. The impervious urban surfaces create a warmer local climate and increased surface runoff. The harsh urban climate can make it difficult for urban trees to grow old, and further exploitation in cities risks damaging the trees. In order to create a sustainable tree population with vital trees that can contribute to reducing the local temperature and take care of stormwater runoff, municipal documents are required that prioritize the urban trees. Within municipalities, they work with various municipal documents that contribute to protecting the city's trees, one of the overarching municipal documents is tree policy. The purpose of the work is to investigate whether different municipalities tree policies are equivalent and whether they are relevant and useful documents. To answer the purpose, a document analysis and an interview study are implemented. The document analysis concerns four Swedish municipalities and in the interview study included three people who work within the municipality. The results show differences in what the policies contain and how they are used. The content of the tree policies is in some cases deficient in comparison with research that exists around urban trees and important values to work for. Similarities that we can draw conclusions about are that all municipalities contain biodiversity. Through the studies, we have noticed a difference in that the two of the reviewed tree policies are more comprehensive in terms of tree values and objectives that are addressed. The use of the policy differs as some use it extensively from planning to execution matters and others use the document as a basis for other more useful documents. Even if the document is used in different ways, the policy fulfils an important function because the document is politically decided, which supports the staff's way of working through the guidelines and goals that are stated in the policy

Factors influencing stoichiometry and stability of polyoxometalate - peptide complexes

In the pursuit of understanding the factors guiding interactions between polyoxometalates (POMs) and biomolecules, several complexes between Keggin phosphomolybdate and diglycine have been produced at different acidity and salinity conditions, leading to difference in stoichiometry and in crystal structure. Principal factors determining how the POM and dipeptide interact appear to be pH, ionic strength of the medium, and the molar ratio of POM to peptide. An important effect turned out to be even the structure-directing role of the sodium cations coordinating carbonyl functions of the peptide bond. Given the interest in applying POMs in biological systems, these factors are highly relevant to consider. In the view of recent interest in using POMs as nano catalysts in peptide hydrolysis also the potential Keggin POM transformation in phosphate buffered saline medium was investigated leading to insight that nanoparticles of zirconium phosphate (ZrP) can be actual catalysts for breakdown of the peptide bond

Tuneable conductivity at extreme electric fields in ZnO tetrapod-silicone composites for high-voltage power cable insulation

Resistive Field Grading Materials (RFGM) are used in critical regions in the electrical insulation system of high-voltage direct-current cable systems. Here, we describe a novel type of RFGM, based on a percolated network of zinc oxide (ZnO) tetrapods in a rubber matrix. The electrical conductivity of the composite increases by a factor of 108 for electric fields > 1\ua0kV\ua0mm-1, as a result of the highly anisotropic shape of the tetrapods and their significant bandgap (3.37\ua0eV). We demonstrate that charge transport at fields < 1\ua0kV\ua0mm-1 is dominated by thermally activated hopping of charge carriers across spatially, as well as energetically, localized states at the ZnO-polymer interface. At higher electric fields (> 1\ua0kV\ua0mm-1) band transport in the semiconductive tetrapods triggers a large increase in conductivity. These geometrically enhanced ZnO semiconductors outperform standard additives such as SiC particles and ZnO micro varistors, providing a new class of additives to achieve variable conductivity in high-voltage cable system applications

Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population

<p>Abstract</p> <p>Background</p> <p>Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection.</p> <p>Methods</p> <p>Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied.</p> <p>Results</p> <p>NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%.</p> <p>Conclusion</p> <p>Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.</p

Variable EBV DNA load distributions and heterogeneous EBV mRNA expression patterns in the circulation of solid organ versus stem cell transplant recipients

Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially life-threatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell-associated EBV DNA showed BARTs an

Epstein-Barr Virus-Encoded BARF1 Protein is a Decoy Receptor for Macrophage Colony Stimulating Factor and Interferes with Macrophage Differentiation and Activation

Epstein-Barr virus (EBV), like many other persistent herpes viruses, has acquired numerous mechanisms for subverting or evading immune surveillance. This study investigates the role of secreted EBV-encoded BARF1 protein (sBARF1) in creating an immune evasive microenvironment. Wild-type consensus BARF1 was expressed in the human 293 cell line and purified. This native hexameric sBARF1 had inhibitory capacity on macrophage colony stimulating factor (M-CSF)-stimulated, and not on granulocyte macrophage-colony stimulating factor (GM-CSF)-stimulated growth and differentiation of myeloid cells. Antibodies specific to hexameric sBARF1 were able to block this effect. M-CSF was shown to interact with sBARF1 via the protruding N-terminal loops involving Val38 and Ala84. Each BARF1 hexamer was capable of binding three M-CSF dimers. Mutations in the BARF1 loops greatly affected M-CSF interaction, and showed loss of growth inhibition. Analysis of the activation state of the M-CSF receptor c-fms and its downstream kinase pathways showed that sBARF1 prevented M-CSF-induced downstream phosphorylation. Since M-CSF is an important factor in macrophage differentiation, the effect of sBARF1 on the function of monocyte-derived macrophages was evaluated. sBARF1 affected overall survival and morphology and significantly reduced expression of macrophage differentiation surface markers such as CD14, CD11b, CD16, and CD169. Macrophages differentiating in the presence of sBARF1 showed impaired responses to lipopolysaccharide and decreased oxygen radical formation as well as reduced phagocytosis of apoptotic cells. In conclusion, EBV sBARF1 protein is a potent decoy receptor for M-CSF, hampering the function and differentiation of macrophages. These results suggest that sBARF1 contributes to the modulation of immune responses in the microenvironment of EBV-positive carcinoma

Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer

&lt;p&gt;Aims: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.&lt;/p&gt; &lt;p&gt;Methods and Results: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.&lt;/p&gt; &lt;p&gt;Conclusions: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.&lt;/p&gt