Global crop improvement networks to bridge technology gaps.

To ensure future food security, there is an urgent need for improved co-ordination of agricultural research. While advances in biotechnology hold considerable promise, significant technology gaps exist that may reduce their impact. Examples include an incomplete knowledge of target breeding environments, a limited understanding and/or application of optimal crop management practices, and underfunded extension services. A better co-ordinated and more globalized approach to agricultural research through the implementation of Global Crop Improvement Networks (GCIN) is proposed. Such networks could underpin agricultural research and development by providing the following types of services: (i) increased resolution and precision of environmental information, including meteorological data, soil characteristics, hydrological data, and the identification of environmental 'hotspots' for a range of biotic, abiotic, and socio-economic constraints; (ii) augmented research capacity, including network-based variety and crop management trials, faster and more comprehensive diagnosis of emerging constraints, timely sharing of new technologies, opportunities to focus research efforts better by linking groups with similar productivity constraints and complementary skills, and greater control of experimental variables in field-based phenotyping; and (iii) increased communication and impacts via more effective dissemination of new ideas and products, the integration of information globally to elicit well-timed local responses to productivity threats, an increased profile, and the publicity of threats to food security. Such outputs would help target the translation of research from the laboratory into the field while bringing the constraints of rural communities closer to the scientific community. The GCIN could provide a lens which academia, science councils, and development agencies could use to focus in on themes of common interest, and working platforms to integrate novel research approaches on crop adaptation and rural development.

SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo.

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -ß (ER-ß) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 µg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 µM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.

A novel steroidal inhibitor of estrogen-related receptor alpha (ERR alpha).

The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) has been implicated in the development of various human malignancies, including breast, prostate, ovary, and colon cancer. ERRalpha, bound to a co-activator protein (e.g., peroxisome proliferator receptor gamma co-activator-1alpha, PGC-1alpha), regulates cellular energy metabolism by activating transcription of genes involved in various metabolic processes, such as mitochondrial genesis, oxidative phosphorylation, and fatty acid oxidation. Accumulating evidence suggests that ERRalpha is a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor microenvironments. This report describes a novel steroidal antiestrogen (SR16388) that binds selectively to ERRalpha, but not to ERRbeta or ERRgamma, as determined using a time-resolved fluorescence resonance energy transfer assay. SR16388 potently inhibits ERRalpha's transcriptional activity in reporter gene assays, and prevents endogenous PGC-1alpha and ERRalpha from being recruited to the promoters or enhancers of target genes. Representative in vivo results show that SR16388 inhibited the growth of human prostate tumor xenografts in nude mice as a single agent at 30mg/kg given once daily and 100mg/kg given once weekly. In a combination study, SR16388 (10mg/kg, once daily) and paclitaxel (7.5mg/kg, twice weekly) inhibited the growth of prostate tumor xenografts in nude mice by 61% compared to untreated xenograft tumors. SR16388 also inhibited the proliferation of diverse human tumor cell lines after a 24-h exposure to the compound. SR16388 thus has utility both as an experimental antitumor agent and as a chemical probe of ERRalpha biology.

Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity.

(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.

The role of conservation agriculture in sustainable agriculture.

The paper focuses on conservation agriculture (CA), defined as minimal soil disturbance (no-till, NT) and permanent soil cover (mulch) combined with rotations, as a more sustainable cultivation system for the future. Cultivation and tillage play an important role in agriculture. The benefits of tillage in agriculture are explored before introducing conservation tillage (CT), a practice that was borne out of the American dust bowl of the 1930s. The paper then describes the benefits of CA, a suggested improvement on CT, where NT, mulch and rotations significantly improve soil properties and other biotic factors. The paper concludes that CA is a more sustainable and environmentally friendly management system for cultivating crops. Case studies from the rice-wheat areas of the Indo-Gangetic Plains of South Asia and the irrigated maize-wheat systems of Northwest Mexico are used to describe how CA practices have been used in these two environments to raise production sustainably and profitably. Benefits in terms of greenhouse gas emissions and their effect on global warming are also discussed. The paper concludes that agriculture in the next decade will have to sustainably produce more food from less land through more efficient use of natural resources and with minimal impact on the environment in order to meet growing population demands. Promoting and adopting CA management systems can help meet this goal.

An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity.

Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.

Determinants of retinoid X receptor transcriptional antagonism.

The synthesis and bioactivity of the retinoid X receptor (RXR) antagonist 4-[(3'-n-butyl-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2'-naphthalenyl)(cyclopropylidene)methyl]benzoic acid and several heteroatom-substituted analogues are described. Ligand design was based on the scaffold of the 3'-methyl RXR-selective agonist analogue and reports that 3'-n-propyl and longer n-alkyl groups conferred RXR antagonism. The transcriptional antagonism of the 3'-n-butyl analogue was demonstrated by its blockade of retinoic acid receptor (RAR) beta expression induced by the RXRalpha/peroxisome proliferator-activated receptor (PPAR) gamma heterodimer complexed with an RXRalpha agonist plus the PPARgamma agonist ciglitazone and the inhibition of 9-cis-RA-induced coactivator SRC-1a recruitment to RXRalpha. Receptor-ligand docking studies using full-atom flexible ligand and flexible receptor suggested that binding of the antagonist to the RXRalpha antagonist conformation was favored because the salt bridge that formed between the retinoid carboxylate and the RXRalpha helix H5 arginine-321 was far stronger than that formed on its binding to the agonist conformation. The antagonist also blocked activation of RAR subtypes alpha and beta by 9-cis-RA but not that of RARgamma.

Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest.

The retinoid 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) and its active analogues induce cell-cycle arrest and programmed cell death (apoptosis) in cancer cells independently of retinoic acid receptor (RAR) interaction. Its analogue, (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-(3'-acetamidopropyloxy)cinnamic acid (3-A-AHPC) selectively antagonized cell apoptotic events (TR3/nur77/NGFI-B expression and nuclear-to-mitochondrial translocation) but not the proliferative events (cell-cycle arrest and p21(WAF1/CIP1) expression) induced by proapoptotic AHPN and its analogues. The syntheses of 3-A-AHPC and proapoptotic (E)-6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-5-chloronaphthalenecarboxylic acid (5-Cl-AHPN) are described. Computational studies on AHPN, AHPC, and three substituted analogues (5-Cl-AHPN, 3-Cl-AHPC, and 3-A-AHPC) suggested reasons for their diametric effects on RAR activation. Density functional theory studies indicated that the 1-adamantyl (1-Ad) groups of the AHPN and AHPC configurations assumed positions that were nearly planar with the aromatic rings of their polar termini. In contrast, in the configurations of the substituted analogues having chloro and 3-acetamidopropyloxy groups, rather than a hydrogen, ortho to the diaryl bonds, the diaryl bond torsion angles increased so that the 1-Ad groups were oriented out of this plane. Docking and molecular dynamics of AHPN, AHPC, and these substituted analogues in the RARgamma ligand-binding domain illustrated how specific substituents on the AHPN and AHPC scaffolds modulated the positions and dynamics of the 1-Ad groups. As a result, the position of RARgamma helix H12 in forming the coactivator-binding site was impacted in a manner consistent with the experimental effect of each analogue on RARgamma transcriptional activation.

Airborne Lidar Measurements of a Smoke Plume Produced by a Controlled Burn of Crude Oil on the Ocean.

An airborne lidar was used to study the smoke plume from the burning of a controlled oil spill on the ocean. The ratio of the amount of light (at a wavelength, λ, of 0.532 u.m) backscattered by the smoke to the amount of light extinguished by the smoke was determined by measuring the strength of a laser beam after it had passed through the smoke plume, been reflected from the ocean, and passed through the smoke plume again, and comparing this to the strength of the laser beam reflected directly from the ocean. The optical depth of the smoke (at λ = 0.532 µm) was typically between 0.2 and 0.5. The mass fluxes of smoke particles that passed through four vertical cross sections of the (nonsteady state) smoke plume were estimated from lidar measurements to be 142, 175, 423, and 414 g s-1, compared to an average smoke mass production rate of ~770 g s-1. The spatial distribution of smoke mass along the long axis of the plume was also estimated from the lidar measurements; derived smoke mass concentrations were generally <300 µg m-3, with a few isolated values up to ~800 µg m-3.