Plasmodium falciparum infections in southern China displayed markedly delayed clearance following artemisinin treatment. F446I was the predominant K13 mutation and was associated with delayed parasite clearance.
Metabolic engineering to divert carbon flux from sucrose to oil in high biomass crop like sugarcane is an emerging strategy to boost lipid yields per hectare for biodiesel production. Sugarcane stems comprise more than 70% of the crops' biomass and can accumulate sucrose in excess of 20% of their extracted juice. The energy content of oils in the form of triacylglycerol (TAG) is more than twofold that of carbohydrates. Here, we report a step change in TAG accumulation in sugarcane stem tissues achieving an average of 4.3% of their dry weight (DW) in replicated greenhouse experiments by multigene engineering. The metabolic engineering included constitutive co‐expression of wrinkled1; diacylglycerol acyltransferase1‐2; cysteine‐oleosin; and ribonucleic acid interference‐suppression of sugar‐dependent1. The TAG content in leaf tissue was also elevated by more than 400‐fold compared to non‐engineered sugarcane to an average of 8.0% of the DW and the amount of total fatty acids reached about 13% of the DW. With increasing TAG accumulation an increase of 18:1 unsaturated fatty acids was observed at the expense of 16:0 and 18:0 saturated fatty acids. Total biomass accumulation, soluble lignin, Brix and juice content were significantly reduced in the TAG hyperaccumulating sugarcane lines. Overcoming this yield drag by engineering lipid accumulation into late stem development will be critical to exceed lipid yields of current oilseed crops.
Endothelial CD39 metabolizes ADP released from activated platelets. Recombinant soluble human CD39 (solCD39) potently inhibited ex vivo platelet aggregation in response to ADP and reduced cerebral infarct volumes in mice following transient middle cerebral artery occlusion, even when given 3 hours after stroke. Postischemic platelet and fibrin deposition were decreased and perfusion increased without increasing intracerebral hemorrhage. In contrast, aspirin did not increase postischemic blood flow or reduce infarction volume, but did increase intracerebral hemorrhage. Mice lacking the enzymatically active extracellular portion of the CD39 molecule were generated by replacement of exons 4-6 (apyrase-conserved regions 2-4) with a PGKneo cassette. Although CD39 mRNA 3′ of the neomycin cassette insertion site was detected, brains from these mice lacked both apyrase activity and CD39 immunoreactivity. Although their baseline phenotype, hematological profiles, and bleeding times were normal, cd39 -/-mice exhibited increased cerebral infarct volumes and reduced postischemic perfusion. solCD39 reconstituted these mice, restoring postischemic cerebral perfusion and rescuing them from cerebral injury. These data demonstrate that CD39 exerts a protective thromboregulatory function in stroke.J. Clin. Invest. 109:1031-1040 (2002. DOI:10.1172/JCI200210649. maintain blood fluidity. These include local generation of nitric oxide, release of eicosanoids, and ectoapyrase activity. CD39, a transmembrane protein originally identified on lymphoid cells, whose extracellular portion exhibits apyrase activity (9), is a highly conserved, constitutively expressed enzyme that strongly inhibits platelet aggregation (10,11). Following transfection of CD39 into COS cells, the cells acquire the ability to inhibit ADP-induced platelet aggregation, establishing CD39 as a prime thromboregulator (10,12). Recently, a recombinant, soluble form of human CD39 (including a secretion leader but lacking transmembrane domains) was isolated from stably transfected CHO cells (11). This soluble CD39 (solCD39) preparation blocked aggregation induced by ADP and several other agonists in vitro, and circulated in mice with a half-life of approximately 2 days (11).The present studies test the hypothesis that augmentation of endogenous CD39 would inhibit ADP-mediated autoamplification of platelet recruitment in distal microvessels and thereby reduce thrombosis following stroke. Since solCD39 does not interfere with primary GPIb-mediated platelet adhesion at the site of vessel damage, solCD39 administration should not, in theory, prevent a layer of platelets from forming at the site of injury or interfere with hemostatic mechanisms that prevent intracerebral hemorrhage. Our studies examine the thromboregulatory role of endogenous CD39 in stroke and the ability of solCD39 to inhibit microvascular thrombosis and confer cerebroprotection in stroke without inducing intracerebral hemorrhage. MethodsMurine platelet aggregation. C57BL/6 mice (6-8 weeks old) were obtained...
By using two structurally unrelated hydrogen sulfide (H 2 S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H 2 S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H 2 S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H 2 S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H 2 S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of proinflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1b while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-jB) in the ischemic brain. In conclusion, H 2 S donors protected BBB integrity following experimental stroke possibly by acting through NF-jB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals. Keywords: Blood-brain barrier, cerebral ischemia, hydrogen sulfide, vasoprotection. J. Neurochem. (2014) 129, 827-838.Disruption of blood-brain barrier (BBB) is a hallmark of stroke pathogenesis, which contributes significantly to ischemic brain damage (Hacke et al. 1996). Clinically, BBB disruption occurs in more than one third of stroke patients and is associated with poor outcomes and lower survival rates following stroke (Warach and Latour 2004). Although experimental stroke has revealed several molecular cascades that contribute to post-stroke BBB disruption, BBB disruption is still inaccessible to therapeutic interventions so far (Rosenberg 2012).Hydrogen sulfide (H 2 S), classically viewed as a poisonous gas and environmental hazard, is emerging as the third gaseous signaling molecule alongside with nitric oxide and Abbreviations used: ADT, 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione; BBB, blood-brain barrier; EB, Evans blue; H 2 S, hydrogen sulfide; MCAO, middle cerebral artery occlusion; NaHS, sodium hydrosulfide; NOX, NADPH oxidase.
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