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VIII
Kinds of VIII Terms modified by VIII Selected AbstractsFocal nodular hyperplasia: what are the indications for resection?HPB, Issue 4 2005Li Chun Hsee Focal nodular hyperplasia (FNH) is a benign condition of the liver that is often discovered incidentally on radiological investigation. FNH has no malignant potential, is rarely symptomatic and surgical intervention is almost never required. However, eight patients with a diagnosis of FNH associated with upper abdominal pain or rapid growth were referred for surgery. All patients had been extensively investigated for other causes of pain and had been observed for between 1 and 7 years prior to surgical referral. The FNH lesions were between 1 cm and 8 cm in diameter. One FNH lesion 7.5 cm in diameter lay in segment VII/VIII and was related to the right and middle hepatic veins. All patients were resected with immediate and lasting control of their symptoms. Based on this experience FNH should be managed in a manner similar to haemangiomas with most lesions being safe to observe. However, it should be recognized that symptomatic FNH does occur, as well as FNH behaving in an unusual fashion such as rapid growth. Both of these findings are indications for resection. [source] The Arabidopsis class VIII myosin ATM2 is involved in endocytosisCYTOSKELETON, Issue 6 2008Amirali Sattarzadeh Abstract Members of the class XI of the myosin superfamily comprising higher plant, actin-based molecular motors have been shown to be involved in peroxisome and Golgi vesicle trafficking comparable to yeast and animal class V myosins. The tasks of the second class of myosins of higher plants, class VIII, are unclear. In this study the class VIII myosin ATM2 from the model plant Arabidopsis thaliana was selected for the examination of cargo specificity in vivo. Fluorescent protein-fusion plasmid constructs with fragments of the ATM2 cDNA were generated and used for Agrobacterium tumefaciens -based transient transformation of Nicotiana benthamiana leaves. The resulting subcellular localization patterns were recorded by live imaging with confocal laser scanning microscopy (CLSM) in epidermal leaf cells. Expression of a nearly full-length construct displayed labeling of filaments and vesicles, a head + neck fragment led to decoration of filaments only. However, expression of fluorescent protein-tagged C-terminal tail domain constructs labeled vesicular structures of different appearance. Most importantly, coexpression of different RFP/YFP-ATM2 tail fusion proteins showed colocalization and, hence, binding to the same type of vesicular target. Further coexpression experiments of RFP/YFP-ATM2 tail fusion proteins with the endosomal marker FYVE and the endosomal tracer FM4-64 demonstrated colocalization with endosomes. Colocalization was also detected by expression of the CFP-tagged membrane receptor BRI1 as marker, which is constantly recycled via endosomes. Occasionally the ATM2 tail targeted to sites at the plasma membrane closely resembling the pattern obtained upon expression of the YFP-ATM1 C-terminal tail. ATM1 is known for its localization at the plasma membrane at sites of plasmodesmata. Cell Motil. Cytoskeleton 2008. © 2008 Wiley-Liss, Inc. [source] Cover Picture: Electrophoresis 16'2010ELECTROPHORESIS, Issue 16 2010Article first published online: 19 AUG 2010 Issue no. 16 is a regular issue with an Emphasis on "Proteins and Proteomics" comprising 20 manuscripts distributed over 4 separate parts. Part I has 7 research articles on various aspects of proteins and proteomics including combinatorial peptide ligand library for accessing low abundance proteins, analysis of membrane proteins, proteomic profiling of human colon cancer cells, quantitative determinations of biomarkers in clinical diagnostics, recombinant factor VIII, analysis of E. coli soluble proteins, and a weakly basic amino-reactive fluorescent label for IEF of proteins and chip electrophoresis. Part II has 2 research articles dealing with the CE analysis of magnetic nanoparticles and a microfluidic magnetic bead impact for cell stimulation. Part III consists of 2 research articles dealing with on-line preconcentration in CE. Instrumentation, devices and various methodologies are described in 9 research articles, which make the content of Part IV. Featured articles include: Combinatorial peptide ligand library plasma treatment: Advantages for accessing low-abundance proteins ((doi: 10.1002/elps.201000188)) Precautions to improve the accuracy of quantitative determinations of biomarkers in clinical diagnostics ((doi: 10.1002/elps.201000243)) Rapid identification of Candida albicans in blood by combined capillary electrophoresis and fluorescence in situ hybridization ((doi: 10.1002/elps.201000138)) [source] Recombinant clotting factor VIII concentrates: Heterogeneity and high-purity evaluationELECTROPHORESIS, Issue 16 2010Gian Maria D'Amici Abstract Factor VIII is an important glycoprotein involved in hemostasis. Insertion of expression vectors containing either the full-length cDNA sequence of human factor VIII (FLrFVIII) or B-domain deleted (BDDrFVIII) into mammalian cell lines results in the production of recombinant factor VIII (rFVIII) for therapeutic usage. Three commercially available rFVIII concentrates (Advate®, Helixate NexGen® and Refacto®), either FLrFVIII or BDDrFVIII, were investigated by 1- and 2-DE and MS. The objective of this study was to compare the heterogeneity and the high purity of both rFVIII preparations before and after thrombin digestion. In particular, the 2-D gel was optimized to better highlight the presence of contaminants and many unexpected proteins. Recombinant strategies consisting of insertion of expression vectors containing BDDrFVIII and FLrFVIII resulted in homogeneous and heterogeneous protein products, respectively, the latter consisting in a heterogeneous mixture of various B-domain-truncated forms of the molecule. Thrombin digestion of all the three rFVIII gave similar final products, plus one unexpected fragment of A2 domain missing 11 amino acids. Regarding the contaminants, Helixate NexGen® showed the presence of impurities, such as Hsp70,kDa, haptoglobin and proapolipoprotein; Refacto® showed glutathione S -transferase and ,-lactamase, whereas Advate® apparently did not contain any contaminants. The proteomic approach will contribute to improving the quality assurance and manufacturing processes of rFVIII concentrates. In this view, the 2-DE is mandatory for revealing the presence of contaminants. [source] Cover Picture: Electrophoresis 20'2009ELECTROPHORESIS, Issue 20 2009Article first published online: 27 OCT 200 Issue no. 20 is a regular issue with an Emphasis on "Fundamentals and Methodologies". The bulk of this issue (13 articles) is on fundamentals and methodologies covering various topics, e.g. EOF, affinity CE, structural analysis of glycosphingolipids by CE-ESI-MS, on-line concentration, monolithic columns, etc. The other 6 articles are on protein separation and proteomics. Selected articles are: Micropump based on electroosmosis of the second kind ((10.1002/elps.200900271)) A splicing model-based DNA computing approach on microfluidic chip ((10.1002/elps.200900323)) Proteomic Characterization of Plasma-derived Clotting Factor VIII , von Willebrand Factor Concentrates ((10.1002/elps.200900270)) [source] The Politics of Revision in Samuel Daniel's The Civil WarsENGLISH LITERARY RENAISSANCE, Issue 3 2008Gillian Wright Samuel Daniel's historical poem The Civil Wars has traditionally been regarded as a conservative text, committed in presentation and in practice to upholding the principle of hereditary right in monarchy. Such a view overlooks Daniel's many complex revisions to the poem between its first appearance in print in 1595 and the final,though still unfinished,version published in 1609. Comparative analysis of the different printed editions of the poem shows that between 1595 and 1609 Daniel's political priorities changed significantly, especially on the question of the role and legitimacy of kingship. Whereas the 1595 Civil Wars does indeed adopt a broadly conservative attitude to the rights of hereditary monarchs, the 1609 text of the poem no longer automatically endorses kingly authority but instead consistently privileges the monarch's commitment to the "publique good" and the just execution of the laws. This subtle but radical pattern of change culminates in Daniel's vignette of Elizabeth Grey and Edward IV (1609, Book VIII), which departs from the poet's sources in representing Grey's resistance to Edward's attempted seduction in explicitly politicized terms. This observable shift in Daniel's political values also foreshadows later aspects of his historiography in the prose Collection of the Historie of England (1618). (G.W.) [source] A new stem-borer of the genus Bucculatrix (Lepidoptera: Bucculatricidae) from Japan, with description of the life historyENTOMOLOGICAL SCIENCE, Issue 1 2009Shigeki KOBAYASHI Abstract A new species of bucculaticid moth, Bucculatrix hamaboella sp. nov. (Host plant: Hibiscus hamabo, Malvaceae) is described from Wakayama Prefecture, Japan. The feeding habit of the new species is unique in that: (i) the young larva is a leaf miner forming a long red linear mine but in the later instars the larva becomes a stem borer; (ii) later instar larvae undergo double molts within a cocoonet (molting cocoon); and (iii) penultimate and final instars appear on the surface of the leaf as non-feeding stages. The external non-feeding larvae of B. hamaboella undergoing double molts within one cocoonet are considered to be an abbreviated form of the external feeding instars of other bucculatricids typically making first and second cocoonets, undergoing a single molt within each cocoonet. On the basis of morphological characters, this species is related to the species of Sections I and II (Host: Asteraceae) of Braun (1963), rather than to the species of Section VIII (Host: Malvaceae). [source] Collagen type VIII expression in human diabetic nephropathyEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2007J. Gerth Abstract Background, Collagen type VIII is a non-fibrillar short-chain collagen that may modulate migration, proliferation and adherence of various cells. Only very sparse information exists on collagen type VIII expression in human diabetic nephropathy. Material and methods, We retrospectively studied mRNA expression for the two collagen type VIII chains (COL8A1 and COL8A2) in 20 biopsies with histologically confirmed diabetic nephropathy by real-time PCR, and compared glomerular and tubular expression with normal kidney [pre-transplant biopsies (n = 10)]. Expression of collagen type VIII was also studied in biopsies from patients with benign nephrosclerosis (BNS; n = 16) and focal-segmental glomerulosclerosis (FSGS; n = 9). Results, A strong specific induction of COL8A1 mRNA was found in diabetic nephropathy in both glomerular and tubular compartments. There was also a robust induction of COL8A2 in diabetic nephropathy, but overall expression was lower than that of COL8A1 transcripts. No significant increase in COL8A1 and COL8A2 mRNAs expression was found in biopsies from patients with BNS and FSGS compared with normal kidneys. The cross-reactivity of the used anti-,1(VIII) antibody with human tissue was confirmed by Western blots. Immunohistological analysis revealed only little staining for collagen type VIII in the normal kidney, localized to vessels. There was an up-regulation of collagen type VIII protein expression as shown by immunohistochemistry in the diabetic nephropathy biopsies mainly localized to mesangial cells, tubules and the interstitium. Proteinuria and serum creatinine did not correlate with glomerular or tubular COL8A1 and COL8A2 mRNA expression in diabetic patients. Conclusion, Our study systemically investigates collagen type VIII expression in human biopsies. Induction of collagen type VIII was specific for diabetic nephropathy and did not occur in the other renal diseases studied. More specific factors of the diabetic environment are likely involved in the stimulated expression because there was no correlation of collagen type VIII mRNA expression with proteinuria. Since collagen type VIII may influence proliferation and migration of cells, it is possible that an increase in renal expression of collagen type VIII initiates other pathophysiological processes (e.g. proliferation of renal fibroblasts) involved in diabetic nephropathy. [source] Procoagulant factors and the risk of myocardial infarction in young womenEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006Bea Tanis Abstract:,Objectives:,We investigated whether elevated levels of factor VIII, IX and XI is associated with myocardial infarction (MI) in young women. In addition, we studied ABO blood group, von Willebrand factor (VWF) and C-reactive protein (CRP). Methods and results:,We compared 200 women with MI before age 49 years with 626 controls from a population-based case,control study. Mean levels of factor VIII activity (VIII), von Willebrand factor antigen (VWF), factor IX activity (IX) were higher in patients (133, 134 and 132 IU/dL) than in controls (111, 107 and 120 IU/dL, respectively). Mean levels of factor XI (XI) were equal in patients (114 IU/dL) and controls (113 IU/dL). The odds ratio (OR) for MI for blood group non-O vs. O was 1.6 [95% confidence interval (CI) 1.1,2.3]. The OR adjusted for age, index year and area of residence for the highest quartile >150 IU/dL of factor VIII was 2.7 (95% CI 1.6,4.6), of VWF 4.7 (95% CI 2.3,9.7), of factor IX 2.6 (95% CI 1.3,5.4) and of factor XI 0.9 (95% CI 0.5,1.4), all compared with the lowest quartile <100 IU/dL. Conclusions:,Non-O blood group, high VWF, factor VIII and factor IX levels are associated with an increased risk of MI in young women, while high factor XI levels are not. [source] Dehydration and Dehydrogenation of Alcohols with Mononuclear Cationic Vanadium Oxides in the Gas Phase and Energetics of VOnH0/+ (n = 2, 3),EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 17 2007Marianne Engeser Abstract The ion/molecule reactions of selected alcohols with the vanadium oxide cations VO+ and VO2+ are studied by Fourier-transform ion-cyclotron resonance (FT-ICR) mass spectrometry. Dehydrogenation is the dominating reaction pathway for methanol and allyl alcohols. With larger or less unsaturated alcohols, dehydration and carbocation formations prevail. While the valence in VO+ remains unchanged during alcohol dehydrogenation, VO2+ is reduced to VIII. Thermochemical data for VO2H0/+, VO3H and VO3H2+ are derived by means of ICR bracketing. The experimental results are further complemented by ab initio calculations using density functional theory. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Differential modulation by monoamine membrane receptor agonists of reticulospinal input to lamina VIII feline spinal commissural interneuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007Ingela Hammar Abstract Noradrenaline and serotonin have previously been demonstrated to facilitate the transmission between descending reticulospinal tracts fibres and commissural interneurons coordinating left,right hindlimb muscle activity. The aim of the present study was to investigate the contribution of subclasses of monoaminergic membrane receptors to this facilitation. The neurons were located in Rexed lamina VIII in midlumbar segments and identified by their projections to the contralateral gastrocnemius,soleus motor nuclei and by lack of projections rostral to the lumbosacral enlargement. The effects of ionophoretically applied membrane receptor agonists [phenylephrine (noradrenergic ,1), clonidine (noradrenergic ,2), 8-OH-DPAT (5-HT1A, 5-HT7), 2-me-5-HT (5-HT3), 5-me-5-HT (5-HT2) and ,-me-5-HT (5-HT2)] were examined on extracellularly recorded spikes evoked monosynaptically by electric stimulation of descending reticulospinal fibres in the medial longitudinal fascicle. Application of ,1 and 5-HT2 agonists resulted in a facilitation of responses in all investigated neurons while application of ,2, 5-HT1A/7 and 5-HT3 agonists resulted in a depression. These opposite modulatory effects of different agonists suggest that the facilitatory actions of noradrenaline and serotonin on responses of commissural interneurons reported previously following ionophoretic application are the net outcome of the activation of different subclasses of monoaminergic membrane receptors. As these receptors may be distributed predominantly, or even selectively, at either pre- or postsynaptic sites their differential modulatory actions could be compatible with a presynaptically induced depression and a postsynaptically evoked enhancement of synaptic transmission between reticulospinal neurons and commissural interneurons. [source] Characterization of the mouse adenylyl cyclase type VIII gene promoter: regulation by cAMP and CREBEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2002Jennifer R. Chao Abstract Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated specifically via the canonical CRE site. Gel shift assays confirmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity. [source] CuI -Catalyzed Azide,Alkyne Intramolecular i -to-(i+4) Side-Chain-to-Side-Chain Cyclization Promotes the Formation of Helix-Like Secondary StructuresEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 3 2010Mario Scrima Abstract A solid-phase assembly of model peptides derived from human parathyroid hormone-related protein (11,19) containing ,-azido- and ,-yl-,-amino acid residues in positions i and i+4 was cyclised in solution by an intramolecular CuI -catalyzed azide,alkyne 1,3-dipolar Huisgen cycloaddition. These series of heterodetic cyclo-nonapeptides varied in the size of the disubstituted 1,2,3-triazolyl-containing bridge, the location and the orientation of the 1,2,3-triazolyl moiety within the bridge. The 1,2,3-triazolyl moiety, presented at either 1,4- or 4,1-orientation, is flanked by side chains containing 1,4 CH2 groups that result in bridges comprised from 4,7 CH2 groups connecting residues 13 and 17. Comprehensive conformational analysis employing CD, NMR and molecular dynamics reveals the conformational propensities of these heterodetic cyclo-nonapeptides. Cyclo-nonapeptides containing either the 7 methylene bridge (VII and VIII) or the 4 methylene bridge (II) are unstructured in structure-promoting solvent. Cyclo-nonapeptide I in which the 1,4-disubstituted 1,2,3-triazolyl is flanked by 3 and 1 CH2 groups in proximity to the respective residues 13 and 17, is stabilized in a non-canonical structure. All the other heterodetic cyclo-nonapeptides (III,VI) in which the 1,2,3-triazolyl is flanked by a total of 5 or 6 CH2 groups nicely accommodate ,-helical structures and reproduce very closely the helical structure stabilized by the analogous cyclo-nonapeptide in which Lys13 and Asp17 are bridged by the isosteric lactam. These studies suggest that the bioorthogonal i -to-(i+4) side-chain-to-side-chain cyclization via the prototypic "click reaction" offers a new and powerful approach for generating stable helix mimetic structures. [source] Identification of yeast aspartyl aminopeptidase gene by purifying and characterizing its product from yeast cellsFEBS JOURNAL, Issue 1 2006Ryo Yokoyama Aspartyl aminopeptidase (EC 3.4.11.21) cleaves only unblocked N-terminal acidic amino-acid residues. To date, it has been found only in mammals. We report here that aspartyl aminopeptidase activity is present in yeast. Yeast aminopeptidase is encoded by an uncharacterized gene in chromosome VIII (YHR113W, Saccharomyces Genome Database). Yeast aspartyl aminopeptidase preferentially cleaved the unblocked N-terminal acidic amino-acid residue of peptides; the optimum pH for this activity was within the neutral range. The metalloproteases inhibitors EDTA and 1.10-phenanthroline both inhibited the activity of the enzyme, whereas bestatin, an inhibitor of most aminopeptidases, did not affect enzyme activity. Gel filtration chromatography revealed that the molecular mass of the native form of yeast aspartyl aminopeptidase is ,,680 000. SDS/PAGE of purified yeast aspartyl aminopeptidase produced a single 56-kDa band, indicating that this enzyme comprises 12 identical subunits. [source] Effect of two oral doses of 17,-estradiol associated with dydrogesterone on thrombin generation in healthy menopausal women: a randomized double-blind placebo-controlled studyFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2010Alexandra Rousseau Abstract Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17,-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17,-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 ± 50.23 nm, E2: 31.08 ± 85.86 nm vs. 10.52 ± 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 ± 0.69 min vs. E1: ,0.26 ± 0.80 min, E2: ,0.55 ± 0.79 min, P <10,3 for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17,-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity. [source] Teaching and Learning Guide for: The Geopolitics of Climate ChangeGEOGRAPHY COMPASS (ELECTRONIC), Issue 5 2008Jon Barnett Author's Introduction Climate change is a security problem in as much as the kinds of environmental changes that may result pose risks to peace and development. However, responsibilities for the causes of climate change, vulnerability to its effects, and capacity to solve the problem, are not equally distributed between countries, classes and cultures. There is no uniformity in the geopolitics of climate change, and this impedes solutions. Author Recommends 1.,Adger, W. N., et al. (eds) (2006). Fairness in adaptation to climate change. Cambridge, MA: MIT Press. A comprehensive collection of articles on the justice dimensions of adaptation to climate change. Chapters discuss potential points at which climate change becomes ,dangerous', the issue of adaptation under the United Nations Framework Convention on Climate Change (UNFCCC), the unequal outcomes of adaptation within a society, the effects of violent conflict on adaptation, the costs of adaptation, and examples from Bangladesh, Tanzania, Botswana, and Hungary. 2.,Leichenko, R., and O'Brien, K. (2008). Environmental change and globalization: double exposures. New York: Oxford University Press. This book uses examples from around the world to show the way global economic and political processes interact with environmental changes to create unequal outcomes within and across societies. A very clear demonstration of the way vulnerability to environmental change is as much driven by social processes as environmental ones, and how solutions lie within the realm of decisions about ,development' and ,environment'. 3.,Nordås, R., and Gleditsch, N. (2007). Climate conflict: common sense or nonsense? Political Geography 26 (6), pp. 627,638. doi:10.1016/j.polgeo.2007.06.003 An up-to-date, systematic and balanced review of research on the links between climate change and violent conflict. See also the other papers in this special issue of Political Geography. 4.,Parry, M., et al. (eds) (2007). Climate change 2007: impacts adaptation and vulnerability. Contribution of Working Group II to the fourth assessment report of the intergovernmental panel on climate change. Cambridge, UK: Cambridge University Press. The definitive review of all the peer-reviewed research on the way climate change may impact on places and sectors across the world. Includes chapters on ecosystems, health, human settlements, primary industries, water resources, and the major regions of the world. All chapters are available online at http://www.ipcc.ch/ipccreports/ar4-wg2.htm 5.,Salehyan, I. (2008). From climate change to conflict? No consensus yet. Journal of Peace Research 45 (3), pp. 315,326. doi:10.1177/0022343308088812 A balanced review of research on the links between climate change and conflict, with attention to existing evidence. 6.,Schwartz, P., and Randall, D. (2003). An abrupt climate change scenario and its implications for United States national security. San Francisco, CA: Global Business Network. Gives insight into how the US security policy community is framing the problem of climate change. This needs to be read critically. Available at http://www.gbn.com/ArticleDisplayServlet.srv?aid=26231 7.,German Advisory Council on Global Change. (2007). World in transition: climate change as a security risk. Berlin, Germany: WBGU. A major report from the German Advisory Council on Global Change on the risks climate changes poses to peace and stability. Needs to be read with caution. Summary and background studies are available online at http://www.wbgu.de/wbgu_jg2007_engl.html 8.,Yamin, F., and Depedge, J. (2004). The International climate change regime: a guide to rules, institutions and procedures. Cambridge, UK: Cambridge University Press. A clear and very detailed explanation of the UNFCCC's objectives, actors, history, and challenges. A must read for anyone seeking to understand the UNFCCC process, written by two scholars with practical experience in negotiations. Online Materials 1.,Environmental Change and Security Program at the Woodrow Wilson International Center for Scholars http://www.wilsoncenter.org/ecsp The major website for information about environmental security. From here, you can download many reports and studies, including the Environmental Change and Security Project Report. 2.,Global Environmental Change and Human Security Project http://www.gechs.org This website is a clearing house for work and events on environmental change and human security. 3.,Intergovernmental Panel on Climate Change (IPCC) http://www.ipcc.ch/ From this website, you can download all the chapters of all the IPCC's reports, including its comprehensive and highly influential assessment reports, the most recent of which was published in 2007. The IPCC were awarded of the Nobel Peace Prize ,for their efforts to build up and disseminate greater knowledge about man-made (sic) climate change, and to lay the foundations for the measures that are needed to counteract such change'. 4.,Tyndall Centre for Climate Change Research http://www.tyndall.ac.uk The website of a major centre for research on climate change, and probably the world's leading centre for social science based analysis of climate change. From this site, you can download many publications about mitigation of and adaptation to climate change, and about various issues in the UNFCCC. 5.,United Nations Framework Convention on Climate Change http://unfccc.int/ The website contains every major document relation to the UNFCCC and its Kyoto Protocol, including the text of the agreements, national communications, country submissions, negotiated outcomes, and background documents about most key issues. Sample Syllabus: The Geopolitics of Climate Change topics for lecture and discussion Week I: Introduction Barnett, J. (2007). The geopolitics of climate change. Geography Compass 1 (6), pp. 1361,1375. United Nations Secretary General, Kofi Annan, address to the 12th Conference of Parties to the United Nations Framework Convention on Climate Change, Nairobi, 15 November 2006. Available online at http://www.unep.org/Documents.Multilingual/Default.asp?DocumentID=495&ArticleID=5424&l=en Week II: The History and Geography of Greenhouse Gas Emissions Topic: The drivers of climate change in space and time Reading Baer, P. (2006). Adaptation: who pays whom? In: Adger, N., et al. (eds) Fairness in adaptation to climate change. Cambridge, MA: MIT Press, pp. 131,154. Boyden, S., and Dovers, S. (1992). Natural-resource consumption and its environmental impacts in the Western World: impacts of increasing per capita consumption. Ambio 21 (1), pp. 63,69. Week III: The Environmental Consequences of climate change Topic: The risks climate change poses to environmental systems Reading Intergovernmental Panel on Climate Change. (2007). Climate change 2007: climate change impacts, adaptation and vulnerability: summary for policymakers. Geneva, Switzerland: IPCC Secretariat. Watch: Al Gore. The Inconvenient Truth. Weeks IV and V: The Social Consequences of Climate Change Topic: The risks climate change poses to social systems Reading Adger, W. N. (1999). Social vulnerability to climate change and extremes in coastal Vietnam. World Development 27, pp. 249,269. Comrie, A. (2007). Climate change and human health. Geography Compass 1 (3), pp. 325,339. Leary, N., et al. (2006). For whom the bell tolls: vulnerability in a changing climate. A Synthesis from the AIACC project, AIACC Working Paper No. 21, International START Secretariat, Florida. Stern, N. (2007). Economics of climate change: the Stern review. Cambridge, UK: Cambridge University Press (Chapters 3,5). Week VI: Mitigation of Climate Change: The UNFCCC Topic: The UNFCCC and the Kyoto Protocol Reading Najam, A., Huq, S., and Sokona, Y. (2003). Climate negotiations beyond Kyoto: developing countries concerns and interests. Climate Policy 3 (3), pp. 221,231. UNFCCC Secretariat. (2005). Caring for climate: a guide to the climate change convention and the Kyoto Protocol. Bonn, Germany: UN Framework Convention on Climate Change Secretariat. Weeks VII and VIII: Adaptation to Climate Change Topic: What can be done to allow societies to adapt to avoid climate impacts? Reading Adger, N., et al. (2007). Assessment of adaptation practices, options, constraints and capacity. In: Parry, M., et al. (eds) Climate change 2007: impacts, adaptation and vulnerability. Contribution of Working Group II to the fourth assessment report of the intergovernmental panel on climate change. Cambridge, UK: Cambridge University Press, pp. 717,744. Burton, I., et al. (2002). From impacts assessment to adaptation priorities: the shaping of adaptation policy. Climate Policy 2 (2,3), pp. 145,159. Eakin, H., and Lemos, M. C. (2006). Adaptation and the state: Latin America and the challenge of capacity-building under globalization. Global Environmental Change: Human and Policy Dimensions 16 (1), pp. 7,18. Ziervogel, G., Bharwani, S., and Downing, T. (2006). Adapting to climate variability: pumpkins, people and policy. Natural Resources Forum 30, pp. 294,305. Weeks IX and X: Climate Change and Migration Topic: Will climate change force migration? Readings Gaim, K. (1997). Environmental causes and impact of refugee movements: a critique of the current debate. Disasters 21 (1), pp. 20,38. McLeman, R., and Smit, B. (2006). Migration as adaptation to climate change. Climatic Change 76 (1), pp. 31,53. Myers, N. (2002). Environmental refugees: a growing phenomenon of the 21st century. Philosophical Transactions of the Royal Society 357 (1420), pp. 609,613. Perch-Nielsen, S., Bättig, M., and Imboden, D. (2008). Exploring the link between climate change and migration. Climatic Change (online first, forthcoming); doi:10.1007/s10584-008-9416-y Weeks XI and XII: Climate Change and Violent Conflict Topic: Will Climate change cause violent conflict? Readings Barnett, J., and Adger, N. (2007). Climate change, human security and violent conflict. Political Geography 26 (6), pp. 639,655. Centre for Strategic and International Studies. (2007). The age of consequences: the foreign policy and national security implications of global climate change. Washington, DC: CSIS. Nordås, R., and Gleditsch, N. (2007). Climate conflict: common sense or nonsense? Political Geography 26 (6), pp. 627,638. Schwartz, P., and Randall, D. (2003). An abrupt climate change scenario and its implications for United States national security. San Francisco, CA: Global Business Network. [online]. Retrieved on 8 April 2007 from http://www.gbn.com/ArticleDisplayServlet.srv?aid=26231 Focus Questions 1Who is most responsible for climate change? 2Who is most vulnerable to climate change? 3Does everyone have equal power in the UNFCCC process? 4Will climate change force people to migrate? Who? 5What is the relationship between adaptation to climate change and violent conflict? [source] Multiple Refractions, or Winning Movement out of Myth: Barbara Köhler's Poem Cycle ,Elektra.GERMAN LIFE AND LETTERS, Issue 1 2004Spiegelungen' Barbara Köhler's poem cycle ,Elektra. Spiegelungen' (written 1984,5, first published 1991) is the response of the female poet to Heiner Müller's Die Hamletmaschine (1977). The paper examines the relation between Müller's Ophelia/Elektra, who swears revenge while being bound into a wheelchair in the course of the final scene, and Köhler's multiple figure (,die gestalt nähert sich wird körper verdoppelt verviel-/facht eins in allen bildern neigt sie sich zu und fordert', I), focusing in particular on the strategies with which the woman writer seeks to elicit movement from the potential entrapment in immobility of the female figure in the mirror-images of male-created myth. If iconoclasm is rejected as an option ,,und schlag ich dann treffe ich/dein gesicht und mein gesicht//zerfällt', III , the multiple refractions created by the eight-poem cycle nevertheless win a liberating movement from reductive mythical images of Woman (in contrast to Christa Wolf's re-entrapment of her Kassandra figure in an alternative heroic narrative in her 1983 Erzählung), opening out into a utopian space ,,traum hinter dem irrgarten beginnt eine landschaft', VIII , in the final poem in the cycle. [source] ORIGINAL ARTICLE Laboratory science: Molecular analysis in two Tunisian families with combined factor V and factor VIII deficiencyHAEMOPHILIA, Issue 5 2010H. E. ABDALLAH Summary., Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2,LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state. [source] Laboratory identification of factor VIII inhibitors in the real world: the experience from AustralasiaHAEMOPHILIA, Issue 4 2010E. J. FAVALORO Summary., The laboratory has a key role in the initial detection of factor inhibitors and an ongoing role in the measurement of inhibitor titres during the course of inhibitor eradication therapy. The most commonly seen factor inhibitors are those directed against factor VIII (FVIII), usually detected either using the original or Nijmegen-modified Bethesda assay. In view of previously demonstrated high variability in laboratory results for inhibitor assays, we have more extensively examined laboratory performance in the identification of FVIII inhibitors. Over the past 3 years, we conducted two questionnaire-based surveys and two wet-challenge surveys utilizing eight samples comprising no FVIII inhibitor (n = 1), or low-titre (n = 2), medium-titre (n = 3) or high-titre (n = 2) FVIII inhibitor. Four samples were tested by 42 laboratories in 2007, and four by 52 laboratories in 2009. High inter-laboratory variation was evident, with CVs around 50% not uncommon, and some 10% of all laboratories (or around 15% of laboratories using Bethesda method) failed to detect low-level inhibitors of around 1 BU mL,1. Laboratories using the Nijmegen method appeared to perform better than those using a standard Bethesda assay, with lower evident assay variation and no false negatives. There was a wide variety of laboratory practice, with no two laboratories using exactly the same process for testing and interpretation of factor inhibitor findings. In conclusion, our study indicates that there is still much need for standardization and improvement in factor inhibitor detection, and we hope that our findings provide a basis for future improvements in this area. [source] Thrombin generation in haemophilia A patients with mutations causing factor VIII assay discrepancyHAEMOPHILIA, Issue 4 2010R. GILMORE Summary., Up to 40% of patients with mild haemophilia A have a discrepancy whereby factor VIII (FVIII) measurements by a two-stage chromogenic assay (FVIII:CCH) are disproportionately reduced compared with the FVIII one-stage clotting value (FVIII:C). Which assay best reflects the coagulation potential and clinical phenotype in this patient group is of clinical significance, yet remains unclear. We have assessed the global coagulant ability of haemophilia patients with FVIII assay discrepancy using calibrated automated thrombography (CAT). A total of 18 patients with mutations Arg531His/Cys or Arg698Trp causing FVIII discrepancy were investigated, together with 12 haemophilia patients with concordant FVIII values and 15 normal controls. Factor VIII levels in all patients and controls were measured using both one-stage clotting assay and two-stage chromogenic assay. Thrombin generation was assessed in platelet-poor plasma by CAT using a low tissue factor concentration (1 pm). FVIII:CCH values were below normal in all patients, and in the discrepant group were between 1.5- and 8-fold lower than FVIII:C values. CAT parameters were affected in all haemophilia patients. The endogenous thrombin potential (ETP) was reduced to 58,67% of the mean normal value (1301 nm min,1), whereas peak thrombin was further reduced to 27,30% of the mean normal value (178 nm) in both discrepant and concordant patient groups. Analysis of the discrepant patient group showed the most significant correlation between the one-stage FVIII:C assay and ETP (r2 = 0.44) and peak thrombin parameters (r2 = 0.27). [source] Mild haemophilia: a disease with many faces and many unexpected pitfallsHAEMOPHILIA, Issue 2010K. PEERLINCK Summary., Despite major advances in diagnosis and treatment, the management of patients with mild haemophilia (MH) remains a major challenge. Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU mL,1. The bleeding associated with mild haemophilia is most frequently episodic, occurring during surgery or following trauma. Spontaneous bleeding is rare. Diagnosis is sometimes delayed because of insensitivity of screening clotting assays or discrepancies in factor VIII activity as measured by different assays. The treatment of choice in mild haemophilia A is desmopressin, which typically induces a 2,6-fold increase of factor VIII over baseline. However, desmopressin has its limitations in this setting such as the occurrence of tachyphylaxis and failure to respond in an undetermined proportion of patients. Factors underlying poor biological response or magnitude of response to desmopressin are incompletely understood. Inhibitor development in mild haemophilia is particularly distressing. This complication arises at an older age in this patient group because of infrequent need for factor VIII replacement. Inhibitors in mild haemophilia patients often cross-react with endogenous factor VIII resulting in severe spontaneous bleeding frequently in a postoperative setting. Intensive perioperative use of factor VIII and some specific mutations induce a particularly high risk for inhibitor development, but risk factors are incompletely understood. For reasons of the older age of the patients, treatment of bleeding with bypassing agents may cause major thrombotic complications. Data on therapeutic options for inhibitor eradication in patients with mild haemophilia are particularly scarce. With increased life-expectancy for all haemophilia patients, the group of elderly patients with mild haemophilia requiring major surgery will further increase. Prevention of inhibitors, particularly in this patient group, should be a major topic of interest in both clinic and research. [source] HLA-DR-restricted T-cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201PHAEMOPHILIA, Issue 102 2010R. A. ETTINGER Summary., An HLA-DRA-DRB1*0101-restricted T-cell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII-A2201P. His T cells responded to synthetic peptides FVIII2186,2205 and FVIII2194,2213 (J Thromb Haemost 2007; 5: 2399). T cells from family members with genotype FVIII-A2201P were analysed to determine if FVIII-specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjects'HLA-DRB1 types were loaded with 20-mer peptides and utilized to label antigen-specific CD4+ T cells. T-cell responses to peptides spanning the FVIII-C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T-cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII2194,2213. A haemophilic cousin's HLA-DRA-DRB1*1104-restricted response to FVIII2202,2221 was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII-C2-specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low-titre FVIII inhibitor. FVIII-specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub-clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non-infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA-DRA-DRB1*1104-restricted T-cell response to FVIII. Specific T-cell responses to FVIII can occur without clinically significant inhibitors. [source] The relevance of the bleeding severity in the treatment of acquired haemophilia , an update of a single-centre experience with 67 patientsHAEMOPHILIA, Issue 102 2010H. ZEITLER Summary., Acquired haemophilia (AH), an autoimmune disorder with clinical features ranging from harmless haematomas to life-threatening bleedings, still has a mortality rate of up to 25%. Owing to its low frequency (1,4 × 106), standardized treatment protocols for its variable manifestations are not available. In case of prominent severe bleedings, the treatment should aim at rapid elimination of the antibody to protect patients from bleedings and on reinduction of long-term immune tolerance. Clinical data, short- and long-term treatment results of 67 patients diagnosed by our centre are presented. Patients were treated depending on their bleeding severity either by an immunosuppressive treatment alone, or in case of life-threatening bleedings, by a combined protocol (modified Bonn,Malmö protocol, MBMP) consisting of antibody depletion through immunoadsorption, intravenous immunoglobulin treatment, immunosuppression and high-dose factor VIII (FVIII) substitution. Mild bleedings occurred in two patients who were treated successfully alone by immunosuppression. Complete remission (CR) was achieved in 90% of the patients treated with MBMP (60). Of the six patients (10%) who achieved a partial remission (PR), four suffered from cancer. Mortality under MBMP was not seen. In contrast, five patients, in whom diagnosis of AH was delayed, experienced fatal outcome during surgical interventions before initiation of MBMP treatment. Prognosis in AH depends mainly on its prompt diagnosis. Treatment procedures should be adapted to bleeding severity and inhibitor titres. Under these conditions, AH is a potentially curable autoimmune disorder with an excellent prognosis. [source] Ten novel factor VIII (F8C) mutations in eighteen haemophilia A families detected in SingaporeHAEMOPHILIA, Issue 3 2010A. ABDUL-GHAFAR No abstract is available for this article. [source] Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importanceHAEMOPHILIA, Issue 1 2010V. TERRAUBE Summary., The interaction of factor VIII (FVIII) with von Willebrand Factor (VWF) is of direct clinical significance in the diagnosis and treatment of patients with haemophilia A and von Willebrand disease (VWD). A normal haemostatic response to vascular injury requires both FVIII and VWF. It is well-established that in addition to its role in mediating platelet to platelet and platelet to matrix binding, VWF has a direct role in thrombin and fibrin generation by acting as a carrier molecule for the cofactor FVIII. Recent studies show that the interaction affects not only the biology of both FVIII and VWF, and the pathology of haemophilia and VWD, but also presents opportunities in the treatment of haemophilia. This review details the mechanisms and the molecular determinants of FVIII interaction with VWF, and the role of FVIII,VWF interaction in modulating FVIII interactions with other proteases, cell types and cellular receptors. The effect of defective interaction of FVIII with VWF as a result of mutations in either protein is discussed. [source] Study of mutations in Jordanian patients with haemophilia A: identification of five novel mutationsHAEMOPHILIA, Issue 1 2010A. AWIDI Summary., Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by mutations in the factor VIII gene (F8), which encodes factor VIII (FVIII) protein, a plasma glycoprotein, that plays an important role in the blood coagulation cascade. In the present study, our aim was to identify F8 gene mutations in HA patients from Jordan. One hundred and seventy-five HA patients from 42 unrelated families were included in this study. Among these patients, 117 (67%) had severe HA, 13 (7%) had moderate HA and 45 (26%) had mild HA. Severe patients were first tested for intron-22 inversion using long range polymerase chain reaction (PCR), then negative patients were tested for intron-1 inversion using PCR. Sequencing for the entire F8 gene was performed for all severe HA patients who were found negative for intron-22 and -1 inversions and it was also performed for moderate and mild HA patients. HA causative mutations were identified in all patients. Intron-22 and -1 inversions were detected in 52% and 2% of families respectively. Beside these two mutations, 19 different mutations were identified, which include 15 missense and four frameshift mutations. Five novel mutations were identified including one frameshift and four missense mutations. No large deletions or nonsense mutations were detected in patients who participated in this study. Only 17 patients with severe HA were found positive for FVIII inhibitors. The data presented will play an important role for genetic counselling and health care of HA patients in Jordan. [source] Functional roles of the factor VIII B domainHAEMOPHILIA, Issue 6 2009S. W. PIPE Summary., Unravelling the structure, function and molecular interactions of factor VIII (FVIII) throughout its life cycle from biosynthesis to clearance has advanced our understanding of the molecular mechanisms of haemophilia and the development of effective treatment strategies including recombinant replacement therapy. These insights are now influencing bioengineering strategies toward novel therapeutics. Whereas available molecular models and crystal structures have helped elucidate the structure and function of the A and C domains of FVIII, these models have not included detailed structural information of the B domain. Therefore, insights into the role of the FVIII B domain have come primarily from expression studies in heterologous systems, biochemical studies on bioengineered FVIII variants and clinical studies with B domain-deleted FVIII. This manuscript reviews the available data on the potential functional roles of the FVIII B domain. A detailed literature search was performed, and the data extracted were qualitatively summarized. Intriguing emerging evidence suggests that the FVIII B domain is involved in intracellular interactions that regulate quality control and secretion, as well as potential regulatory roles within plasma during activation, platelet binding, inactivation and clearance. [source] Enhancement of haemostatic efficacy of plasma-derived FVIII by formulation with PEGylated liposomesHAEMOPHILIA, Issue 5 2009I. DAYAN Summary., We have shown previously that PEGylated liposomes (PEGLip) bind recombinant FVIII (rFVIII) with high affinity and specificity. This binding resulted in a significant extension of the biological activity of rFVIII as demonstrated in animal models and in clinical trials. In the present study we found that PEGLip bind plasma-derived factor VIII (pdFVIII). PEGLip binding did not affect potency or stability in vitro and did not alter levels of FVIII activity in vivo immediately after injection. However, formulation of pdFVIII with PEGLip led to several important improvements. Twenty-four and 30 hours after injection, FVIII activity levels were significantly higher in haemophilic mice injected with PEGLip-pdFVIII than in mice injected with standard pdFVIII. Half life, area under the curve and mean residence time were increased while clearance was decreased. In vivo efficacy was evaluated in a tail vein transection assay performed in haemophilic mice. Prophylactic treatment with PEGLip-pdFVIII was much more effective in prolonging survival in this assay than similar treatment with standard pdFVIII. These results suggest that formulation of pdFVIII with PEGLip has the potential to improve patient care by prolonging the biological efficacy of pdFVIII and reducing the frequency of FVIII infusions. [source] Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancyHAEMOPHILIA, Issue 4 2009E. P. MAUSER-BUNSCHOTEN Summary., Because of an increased life expectancy, (age-related) co-morbidity is becoming a common occurrence in haemophilia patients. In this review, haemophilia-related and non-haemophilia-related medical problems, treatment recommendations and psychosocial consequences in ageing haemophilia patients are discussed. Haemophilic arthropathy is an important cause of pain and disability, and a frequent indication for surgery in haemophilia patients. In addition, many adult patients are infected with hepatitis C or HIV, the consequences and treatment of which can add to physical and mental discomfort. Moreover, inhibitors against factor VIII can also develop in adulthood, especially in patients with mild haemophilia. Hypertension is reported to occur more often in haemophilia patients than in the general population. Other internal problems, like renal abnormalities, overweight, diabetes mellitus and hypercholesterolemia are discussed. Haemophilia seems to protect against cardiovascular disease, although the incidence is increasing. Recommendations are given on dealing with tooth extractions, surgical interventions and sexuality problems in patients with haemophilia. In addition to haemophilia in itself, co-morbidity has a major psychological impact, and an important effect on quality of life. It can also result in complex treatment regimens, in which coordination between health care workers is essential. [source] Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and functionHAEMOPHILIA, Issue 4 2009A. MARKOFF Summary., Most small lesions in the factor VIII (FVIII) gene that cause haemophilia A (HA) are single nucleotide substitutions resulting in amino acid replacing (missense) mutations and leading to various phenotypes, ranging from mild to severe. We took a combined approach of homology modelling and quantitative evaluation of evolutionary significance of amino acid replacing alterations using the Grantham Matrix Score (GMS) to assess their structural effects and significance of pathological expression. Comparative homology models of all amino acid substitutions summarized in the FVIII mutations database plus these identified and reported lately by us or by our collaborators were evaluated. Altogether 640 amino acid replacing mutations were scored for potential distant or local conformation changes, influence on the molecular stability and predicted contact residues, using available FVIII domain models. The average propensity to substitute amino acid residues by mutation was found comparable to the overall probability of de novo mutations. Missense changes reported with various HA phenotypes were all confirmed significant using GMS. The fraction of these, comprising residues apparently involved in intermolecular interactions, exceeds the average proportion of such residues for FVIII. Predicted contact residues changed through mutation were visualized on the surface of FVIII domains and their possible functional implications were verified from the literature and are discussed considering available structural information. Our predictive modelling adds on the current view of domain interface molecular contacts. This structural insight could aid in part to the design of engineered FVIII constructs for therapy, to possibly enhance their stability and prolong circulating lifetime. [source] | ||||||||||||||||||||||