DYNAMICS OF Cercospora zeina POPULATIONS IN MAIZE-BASED AGRO-ECOLOGIES OF UGANDA

Stability of pathogen populations characterised by slow temporal variation is important for durability of disease management systems in any agroecology. Temporal variation in population structure is attributed to factors related to ecology, biology and life history, and varies among organisms and ecosystems. The objective of this study was to investigate genetic variability of Cercospora zeina (previously called Cercospora zeae-maydis Type II) populations in maize ( Zea mays ) producing areas under Uganda conditions. Populations of the fungus were analysed for genetic variability using a fluorescent amplified fragment length polymorphism (AFLP) technique. Little or no genetic differentiation (\u3a6FST 0.05) was detected for populations sampled within the same year, within an agroecology. However, a weak to moderate population structure was detected between populations from different locations, within the same (\u3a6FST = 0.08) or different agroecologies (\u3a6FST = 0.09). Pair-wise comparisons using \u3a6FST gene diversity and genetic distance, showed a reduction in genetic diversity in younger populations, suggestive of minor effects of selection and genetic drift. Overall, the data suggest that during the 3 years of study the impact of selection and genetic drift on C. zeina populations in the two Ugandan agroecologies is slow, but progressive leading to homogenetity with agroecologies and differences between agroecologies.La stabilit\ue9 des populations d\u2019agents pathog\ue8nes caract\ue9ris\ue9e par une faible variation dans le temps, est importante pour la durabilit\ue9 dans les syst\ue8mes de gestion des pathologies des plantes dans n\u2019importe quelle zone agro-\ue9cologique. La variation dans le temps au sein d\u2019une population, est fonction de facteurs relatifs \ue0 l\u2019\ue9cologie, la biologie et l\u2019histoire de vie des pathog\ue8nes. Elle varie d\u2019un \ueatre vivant \ue0 un autre et d\u2019un \ue9cosyst\ue8me \ue0 un autre. L\u2019objectif de cette \ue9tude \ue9tait d\u2019\ue9valuer la variabilit\ue9 g\ue9n\ue9tique au sein des populations de Cercospora zeina (pr\ue9cedemment appel\ue9 Cercospora zeae-maydis Type II) dans les zones productrice de ma\uefs ( Zea mays ) en Ouganda. Les populations de ce champignon microscopique ont \ue9t\ue9 soumises \ue0 une \ue9tude de variabilit\ue9 g\ue9n\ue9tique gr\ue2ce \ue0 la technique du polymorphisme de longueur de fragments amplifi\ue9s (AFLP). Tr\ue8s peu ou aucune variation g\ue9n\ue9tique (\u3a6FST 0.05) n\u2019a \ue9t\ue9 observ\ue9e pour les populations \ue9chantillonn\ue9es au cours de la m\ueame ann\ue9e, dans une zone agro-\ue9cologique donn\ue9e. N\ue9anmoins, une structure populationnelle d\u2019envergure faible \ue0 mod\ue9r\ue9e a \ue9t\ue9 observ\ue9e entre les populations de diff\ue9rentes origines, (\u3a6FST = 0.08) \ue0 l\u2019int\ue9rieur d\u2019une m\ueame population ou (\u3a6FST = 0.09) entre les populations de diff\ue9rente zones agro \ue9cologique. La comparaison par paires utilisant \u3a6FST diversit\ue9 des g\ue8nes et distance g\ue9n\ue9tique, a montr\ue9 une r\ue9duction de diversit\ue9 g\ue9n\ue9tique dans les populations les plus jeunes, sugg\ue9rant ainsi un effet mineur de s\ue9lection et de d\ue9rive g\ue9n\ue9tique. Au total, les donn\ue9es collect\ue9es indiquent un faible impact de s\ue9lection et de d\ue9rive g\ue9n\ue9tique sur les populations de C. zeina dans les deux zones agro-\ue9cologiques Ougandaise durant les 3 ann\ue9es de l\u2019\ue9tude, mais cet impact est progressif et responsable de l\u2019homog\ue9n\ue9it\ue9 au sein des zones agro-\ue9cologiques et des diff\ue9rences entre les zones agro-\ue9cologiques

Stop worrying; start growing: Risk research on GM crops is a dead parrot: it is time to start reaping the benefits of GM

Opponents of genetically modified crops continue to raise concerns about risk, despite 20 years of research disproving their claims. Science should close the book on risk research and turn to studying the economic and environmental benefits of agricultural biotechnolog

A 3′ UTR SNP in COL18A1 Is Associated with Susceptibility to HBV Related Hepatocellular Carcinoma in Chinese: Three Independent Case-Control Studies

BACKGROUND: Accumulated evidences indicate that single nucleotide polymorphisms (SNP) in angiogenesis and tumorigenesis related genes are associated with risk of Hepatocellular carcinoma (HCC). COL18A1 encodes the precursor of endostatin, which is a broad-spectrum angiogenesis inhibitor, and we speculate that SNPs in COL18A1 may be associated with susceptibility to HCC. METHODS AND FINDINGS: We carried out a 2-stage association study in 3 independent case-control groups in a total of 1067 chronic hepatitis B (CHB) patients and 808 hepatitis B virus (HBV) related HCC patients in Han Chinese. Four SNPs which can represent all potential functional SNPs with MAF>0.1 recorded in HapMap database were genotyped using TaqMan methods. Levels of total COL18A1 mRNA were also examined using quantitative real-time RT-PCR. We found that rs7499 located in 3'-UTR to be strongly associated with HBV related HCC (P(combined) = 0.0000005, OR = 0.72, 95%CI = 0.63-0.82). COL18A1 mRNA expression was significantly decreased as the disease progressed (P = 0.000026). CONCLUSION: These findings indicate that COL18A1 rs7499 may contribute to the risk of HCC in Han Chinese

Early endostatin treatment inhibits metastatic seeding of murine colorectal cancer cells in the liver and their adhesion to endothelial cells

Endostatin, a carboxy-terminal fragment of collagen XVIII, potently inhibits angiogenesis and tumour growth, presumably through induction of apoptosis in endothelial cells and/or inhibition of their migration. Here we have tested how the timing of recombinant human endostatin (rh-E) administration affects its antitumour activity in a liver metastasis model of mouse C26 colorectal carcinoma cells. The effects of rh-E treatment on hepatic tumour load and on early tumour cell seeding were evaluated. Recombinant human endostatin was most effective in reducing intrahepatic tumour growth when administered prior to tumour cell inoculation. Analysis of early tumour cell seeding by using [125I]iododeoxyuridine-labelled C26 cells or by in vivo microscopy showed that rh-E reduced tumour cell seeding in the liver sinusoids. Recombinant human endostatin did not inhibit tumour growth when administered later than 4 days after tumour injection. Pretreatment of human umbilical vein endothelial cells with rh-E in vitro reduced C26 tumour cell adhesion under flow conditions two-fold as assessed by video microscopy and multiphoton laser scanning microscopy. Our results show that rh-E, in addition to antiangiogenic effects, reduces tumour cell adhesion in the liver sinusoids during the very early phases of metastasis formation. These data point towards a previously unknown mode of action of endostatin, that is, its ability to interfere with tumour cell seeding. Such insights may be helpful in the design of trials to improve (surgical) treatment of colorectal carcinoma and liver metastases

Targeting lymphangiogenesis to prevent tumour metastasis

Recent studies involving animal models of cancer and clinicopathological analyses of human tumours suggest that the growth of lymphatic vessels (lymphangiogenesis) in or nearby tumours is associated with the metastatic spread of cancer. The best validated molecular signalling system for tumour lymphangiogenesis involves the secreted proteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D that induce growth of lymphatic vessels via activation of VEGF receptor-3 (VEGFR-3) localised on the surface of lymphatic endothelial cells. In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis

Histidine-Rich Glycoprotein Can Prevent Development of Mouse Experimental Glioblastoma

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma)

The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis

VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis

Vicrostatin – An Anti-Invasive Multi-Integrin Targeting Chimeric Disintegrin with Tumor Anti-Angiogenic and Pro-Apoptotic Activities

Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN