A review of malaria vaccine clinical projects based on the WHO rainbow table

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.     

Antigenic and catalytic disparity in the distribution of cytochrome P-450-dependent 25-hydroxyvitamin D3-1α- and 24-hydroxylases

Summary Chick 25-hydroxyvitamin D₃-1-hydroxylase, a cytochrome P-450 monooxygenase with a molecular weight of 57 kDa, can be isolated as described by Mandel et al. (1990b). Under normal physiological circumstances, it occurs exclusively in kidney mitochondria. An isozyme of the 1-hydroxylase, known as the 24-hydroxylase, which uses the same substrate to yield an isomeric product, is also a cytochrome P-450 monooxygenase, has a molecular weight of 55 kDa, and likewise occurs in kidney mitochondria. The amino-terminal sequences of the first 10 residues of the two isozymes are 100% homologous. Monoclonal antibodies of the IgM class raised against the 1-hydroxylase, which quantitatively discriminate against other P-450 cytochromes of mitochondrial or microsomal origin, recognize and interact with the 24-hydroxylase as an antigen. In the present study we show that the intestine, which is the only non-renal tissue with demonstrable 24-hydroxylase activity, gives a positive peroxidase-antiperoxidase immunohistochemical reaction using the monoclonal antibodies against the 1-hydroxylase. The reactions revealed that the antigen in the kidney is restricted to the cortical proximal tubular cells while in the intestine, the antigen is localized in the enterocytes of the villi. In kidney medullary or intestinal crypt cells, or in liver, heart and lung tissues where 1-hydroxylase or 24-hydroxylase activity could not be detected using cell or tissue homogenates, the immunohistochemical reactions were also negative. Since it has been reported that chick embryonic intestine possesses 1-hydroxylase activity that is absent in the mature intestine, our results would suggest that the mature intestinal 24-hydroxylase represents a modified 1-hydroxylase as a consequence of developmentally imposed requirements regulating calcium homeostatic activity in this tissue. The difference in the molecular weights of the two enzymes would indicate either genomic processing prior to the translation of their respective mRNAs, or a post-translational processing of the larger 1-hydroxylase to the smaller 24-hydroxylase. The abbreviations used are: 25-OH-D₃, 25-hydroxyvitamin D₃; 1,25-(OH)₂D₃, 1,25-dihydroxyvitamin D₃; 24,25-(OH)₂D₃, 24,25-dihydroxyvitamin D₃, NADP, nicotinamide adenine dinucleotide phosphate     

Glyoxylase I phenotypes in some endogamous populations of Andhra Pradesh, India

The distribution of glyoxylase (GLO) I phenotypes in six endogamous subgroups of Brahmins and in the Mala and Madiga castes of Andhra Pradesh was investigated. The GLO I gene frequencies ranged from 0.2444 to 0.3575. The frequency of 0.3565 found in the Mala is the highest recorded on the Indian subcontinent.     

Damage to living trees contributes to almost half of the biomass losses in tropical forests

Accurate estimates of forest biomass stocks and fluxes are needed to quantify global carbon budgets and assess the response of forests to climate change. However, most forest inventories consider tree mortality as the only aboveground biomass (AGB) loss without accounting for losses via damage to living trees: branchfall, trunk breakage, and wood decay. Here, we use ~151,000 annual records of tree survival and structural completeness to compare AGB loss via damage to living trees to total AGB loss (mortality + damage) in seven tropical forests widely distributed across environmental conditions. We find that 42% (3.62 Mg ha⁻¹ year⁻¹; 95% confidence interval [CI] 2.36–5.25) of total AGB loss (8.72 Mg ha⁻¹ year⁻¹; CI 5.57–12.86) is due to damage to living trees. Total AGB loss was highly variable among forests, but these differences were mainly caused by site variability in damage-related AGB losses rather than by mortality-related AGB losses. We show that conventional forest inventories overestimate stand-level AGB stocks by 4% (1%–17% range across forests) because assume structurally complete trees, underestimate total AGB loss by 29% (6%–57% range across forests) due to overlooked damage-related AGB losses, and overestimate AGB loss via mortality by 22% (7%–80% range across forests) because of the assumption that trees are undamaged before dying. Our results indicate that forest carbon fluxes are higher than previously thought. Damage on living trees is an underappreciated component of the forest carbon cycle that is likely to become even more important as the frequency and severity of forest disturbances increase.     

Neurotoxic mechanisms of triclosan: The antimicrobial agent emerging as a toxicant

Several scientific studies have suggested a link between increased exposure to pollutants and a rise in the number of neurodegenerative disorders of unknown origin. Notably, triclosan (an antimicrobial agent) is used in concentrations ranging from 0.3% to 1% in various consumer products. Recent studies have also highlighted triclosan as an emerging toxic pollutant due to its increasing global use. However, a definitive link is missing to associate the rising use of triclosan and the growing number of neurodegenerative disorders or neurotoxicity. In this article, we present systematic scientific evidence which are otherwise scattered to suggest that triclosan can indeed induce neurotoxic effects, especially in vertebrate organisms including humans. Mechanistically, triclosan affected important developmental and differentiation genes, structural genes, genes for signaling receptors and genes for neurotransmitter controlling enzymes. Triclosan-induced oxidative stress impacting cellular proteins and homeostasis which triggers apoptosis. Though the scientific evidence collated in this article unequivocally indicates that triclosan can cause neurotoxicity, further epidemiological studies may be needed to confirm the effects on humans.     

Perspectives on the nanocarriers with miRNAs for targeting melanoma stemness through epigenetic regulation

Several research reports delineated the significant role of miRNAs in cancer proliferation, and their modulatory role in cancer mitigation, and drug resistance. Melanoma cells have been acquiring stemness to several chemotherapeutic agents through drug efflux proteins, epigenetic modulation, and DNA repair. miRNAs could be applied as novel therapeutic modalities for treating several kinds of cancers to modulate these mechanisms involved in stemness. Nanocarriers to carry these tumor-targeting miRNAs to modulate stemness are a prominent strategy to overcome their low penetrability, minimal stability, and nonspecificity. We have searched several public databases such as PubMed, Medline, Google scholar, and NLM and obtained the information pertinent to the miRNA-based nanocarrier systems to target stemness through epigenetic modulation in melanomas. This review delineates that various miRNAs can modulate the stemness in melanomas by specific intricate epigenetic signaling, and other cell-based signaling mechanisms. Specific nanocarrier formulations with specific miRNAs are optimal methods to deliver these miRNAs in order to achieve significant entrapment efficiency, loading efficiency, and stability. Furthermore, the combinatorial regimen of FDA-approved chemotherapeutic molecules with tumor-targeting miRNAs and chemotherapy combined with nanocarriers can efficiently deliver the utmost therapeutic window by targeting tumor matrix, invasion, metastasis, and angiogenesis in melanomas. Substantial research should focus on the clinical application of this gene therapy in melanomas using these low immunogenic, highly degradable, and biocompatible combinatorial nanotherapeutic regimens.     

Kinetics of succinic dehydrogenase inhibition by methyl parathion and its recovery by oximes and L-cysteine in hepatopancreas of Lamellidens marginalis

Effects in vitro of methyl parathion on some kinetic constants of succinic dehydrogenase (SDH) in hepatopancreas of freshwater mussel, L. marginalis were studied. Altered pH vs. specific activity curves for SDH demonstrated significant inhibition by methyl parathion in buffered acidic, neutral and alkaline ranges. At high pH ranges IC50 (12.5 microM) of methyl parathion did not cause 50% inhibition enzyme as it did at neutral and acidic pHs. Activation energies (delta E) were found to be increased suggesting decreased efficiency of enzyme in presence of methyl parathion. Non-competitive inhibition with respect to activation by succinate was indicated by decreased maximal velocity (V) without change in Michaelis Menten constant (Km). Pyridine-2-aldoxime (25 microM), pyridine-4-aldoxime (15 microM) and L-cysteine (40 microM) neutralized the inhibition of SDH by methyl parathion (12.5 microM). The kinetic data suggests that inhibition of SDH by methyl parathion was pH and temperature independent.     

Movement and distribution pattern of the residues of granular insecticides in tropical soil and okra plants

Summary The increased downward mobility of phorate, quinalphos and carbofuran residues was detected in soil with increase in depth of soil column whereas aldicarb was found to remain localised mainly in 0–7.5 cm and 7.5–15.0 cm layers. Persistence of organophosphate insecticides was higher as compared to carbamates in all the soil layers. Residues of all the four insecticides got distributed in all parts of okra plant through uptake but accumulated in higher amounts in fruits only. Contribution No. 312/83 from I.I.H.R. Bangalore (India)     

Relationship of Cob characters with Grain Morphology in Maize (Zea mays,Poaceae)

Twenty varieties of maize (Zea mays, Poaceae) were studied through 11 attributes in three to seven randomly selected plants of each variety with a view to understanding the effect of cob characters on technologically desirable grain qualities. Canonical discriminant analysis showed thatproductivity (determined by total grain weight/cob, cob diameter and average grain weight) was the most discriminating among varieties followed by round grains fraction (represented by whole top and middle flat grains, number of rows and grain count/surface area), middle flat grains (composed of middle flat grains and grain count/surface area) and shape of the cob (determined by shape index, total grain weight/cob and cob diameter), which accounted for 35.1, 18.3, 12.2, and 9.8% of the total variance, respectively. In the light of these results, tentative norms have been suggested to evolve maize varieties of superior technological properties and yet retain high productivity. A cylindrical cob of large diameter with highest number of grains/area and smallest possible number of rows together constituted an ideal combination to achieve the objectives. Such possibilities in the light of available information are discussed.