Heritability of brachydactyly type A3 in children, adolescents, and young adults from an endogamous population in eastern Nepal

Brachymesophalangia-V (BMP-V), a short and broad middle phalanx of the fifth digit, is the most common of all skeletal anomalies of the hand. When this feature appears alone, it is clinically known as brachydactyly type A3 (BDA3). A high prevalence of BDA3 has been observed among the children of the Jirel ethnic group in eastern Nepal. As part of the Jiri Growth Study, a hand-wrist radiograph is taken annually of each child to assess skeletal development. For this study the most recent radiographs of 1,357 Jirel children, adolescents, and young adults (676 boys, 681 girls), age 3-20 years, were examined for the presence or absence of BDA3, to report the prevalence and estimate the heritability of BDA3 in the Jirel population. The overall prevalence of BDA3 in this sample was 10.5% (12.9% of the males and 8.9% of the females were classified as BDA3 affected). The additive genetic heritability of BDA3 was statistically significant in this sample (h2 +/- SE = 0.87 +/- 0.16, p < 0.0001). This study is the first to estimate the prevalence and heritability of BDA3 in a large South Asian family-based sample.     

Design, synthesis, and cytostatic activity of novel cyclic curcumin analogues

A series of novel cyclic analogues of curcumin were synthesized and analyzed for in vitro cytostatic activity. Condensation of 2-acetylcycloalkanones with a variety of aromatic aldehydes resulted in the formation of 2-arylidene-6-(3-arylacryoyl)-cycloalkanone derivatives. A number of these analogues were found to have significant anticancer activity against representative murine and human cancer cell lines during in vitro bioassays. This corroborated with in vitro cytostatic activity against a panel of 60 cell lines studied at the National Cancer Institute (USA).     

Reduced C(beta) statistical potentials can outperform all-atom potentials in decoy identification

We developed a series of statistical potentials to recognize the native protein from decoys, particularly when using only a reduced representation in which each side chain is treated as a single C(beta) atom. Beginning with a highly successful all-atom statistical potential, the Discrete Optimized Protein Energy function (DOPE), we considered the implications of including additional information in the all-atom statistical potential and subsequently reducing to the C(beta) representation. One of the potentials includes interaction energies conditional on backbone geometries. A second potential separates sequence local from sequence nonlocal interactions and introduces a novel reference state for the sequence local interactions. The resultant potentials perform better than the original DOPE statistical potential in decoy identification. Moreover, even upon passing to a reduced C(beta) representation, these statistical potentials outscore the original (all-atom) DOPE potential in identifying native states for sets of decoys. Interestingly, the backbone-dependent statistical potential is shown to retain nearly all of the information content of the all-atom representation in the C(beta) representation. In addition, these new statistical potentials are combined with existing potentials to model hydrogen bonding, torsion energies, and solvation energies to produce even better performing potentials. The ability of the C(beta) statistical potentials to accurately represent protein interactions bodes well for computational efficiency in protein folding calculations using reduced backbone representations, while the extensions to DOPE illustrate general principles for improving knowledge-based potentials.     

E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: a topographical study of some novel potent cytotoxins

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 microM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.     

Isosteric probes provide structural requirements essential for detoxification of the phytoalexin brassinin by the fungal pathogen Leptosphaeria maculans

Brassinin is a plant defense metabolite with antimicrobial activity produced de novo by a variety of Brassica species in response to stress, that is, a phytoalexin. The inhibition of brassinin oxidase (BO), a brassinin-detoxifying enzyme produced by the phytopathogenic fungus Leptosphaeria maculans, is a target in our continuing search for novel crop protection agents. To probe the substrate specificity of BO, in particular the mechanism of the detoxification step, several analogues of brassinin, including functional group isosteres ((mono/dithio)carbamate, urea, and thiourea) and homologue methyl tryptaminedithiocarbamate, were investigated using fungal cultures and purified BO. It was concluded that the essential structural features of substrates of BO were: (i) an -NH at the (mono/dithio)carbamate, urea or thiourea group; (ii) a methylene bridge between indole and the functional group; (iii) a methyl or ethyl group attached to the thiol moiety of the (mono/di)thiocarbamate group. A general stepwise pathway for the oxidation of brassinin was proposed that accounts for the structural requirements of detoxification of brassinin analogues in L. maculans. All compounds that were BO substrates appeared to be oxidized in mycelial cultures to aldehydes, except for the two most polar compounds N'-(3-indolylmethyl)-N'-methylurea and methyl N'-(3-indolylmethyl)carbamate. The substrate specificity of BO suggests that selective inhibitors can be designed for the potential control of L. maculans.     

Ethylene influences green plant regeneration from barley callus

The plant hormone ethylene is involved in numerous plant processes including in vitro growth and regeneration. Manipulating ethylene in vitro may be useful for increasing plant regeneration from cultured cells. As part of ongoing efforts to improve plant regeneration from barley (Hordeum vulgare L.), we investigated ethylene emanation using our improved system and investigated methods of manipulating ethylene to increase regeneration. In vitro assays of regeneration from six cultivars, involving 10 weeks of callus initiation and proliferation followed by 8 weeks of plant regeneration, showed a correlation between regeneration and ethylene production: ethylene production was highest from ‘Golden Promise’, the best regenerator, and lowest from ‘Morex’ and ‘DH-20’, the poorest regenerators. Increasing ethylene production by addition of 1-aminocyclopropane 1-carboxylic acid (ACC) during weeks 8–10 increased regeneration from Morex. In contrast, adding ACC to Golden Promise cultures during any of the tissue culture steps reduced regeneration, suggesting that Golden Promise may produce more ethylene than needed for maximum regeneration rates. Blocking ethylene action with silver nitrate during weeks 5–10 almost doubled the regeneration from Morex and increased the Golden Promise regeneration 1.5-fold. Silver nitrate treatment of Golden Promise cultures during weeks 8–14 more than doubled the green plant regeneration. These results indicate that differential ethylene production is related to regeneration in the improved barley tissue culture system. Specific manipulations of ethylene were identified that can be used to increase the green plant regeneration from barley cultivars. The timing of ethylene action appears to be critical for maximum regeneration.     

NEKTAR,SPICE and Vortonics: using federated grids for large scale scientific applications

In response to a joint call from US’s NSF and UK’s EPSRC for applications that aim to utilize the combined computational resources of the US and UK, three computational science groups from UCL, Tufts and Brown Universities teamed up with a middleware team from NIU/Argonne to meet the challenge. Although the groups had three distinct codes and aims, the projects had the underlying common feature that they were comprised of large-scale distributed applications which required high-end networking and advanced middleware in order to be effectively deployed. For example, cross-site runs were found to be a very effective strategy to overcome the limitations of a single resource. The seamless federation of a grid-of-grids remains difficult. Even if interoperability at the middleware and software stack levels were to exist, it would not guarantee that the federated grids can be utilized for large scale distributed applications. There are important additional requirements for example, compatible and consistent usage policy, automated advanced reservations and most important of all co-scheduling. This paper outlines the scientific motivation and describes why distributed resources are critical for all three projects. It documents the challenges encountered in using a grid-of-grids and some of the solutions devised in response.     

Interactive Effects of Abiotic Stress and Elevated CO2 on Physio-Chemical and Photosynthetic Responses in Suaeda Species

Suaeda fruticosa and S. monoica are important halophytes for ecological rehabilitation of saline lands. We report differential physio-chemical, photosynthetic, and chlorophyll fluorescence responses in these halophytes under 100 mM sodium chloride (NaCl), 50% strength (16.25 ppt) of seawater (SW)-imposed salinity, and 10% polyethylene glycol 6000 imposed osmotic stress at 380 (ambient) and 1200 (elevated) µmol mol^–1 CO₂ concentrations. SW salinity enhanced the growth in both species; however, compared with S. fruticosa, the S. monoica exhibited comparatively better growth and biomass accumulation under saline conditions at elevated CO₂. Results demonstrated better photosynthetic performances of S. monoica under stress conditions at both levels of CO₂, and this resulted in higher accumulation of carbon, nitrogen, sugar, and starch contents. S. monoica exhibited improved antenna size, electron transfer at PSII donor side, and efficient working of photosynthetic machinery at elevated CO₂, which might be due to efficient upstream utilization of reducing power to fix the CO₂. The δ¹³C results supported the operation of C₄ CO₂ fixation in S. monoica and C₃ or intermediate pathway of CO₂ fixation in S. fruticosa. Lower accumulation of reactive oxygen species, reduced membrane damage, lowered solute potential, and higher accumulation of proline and polyphenol contents indicated elevated CO₂-induced abiotic stress tolerance in Suaeda. Higher activity of antioxidant enzymes in both species at both levels of CO₂ help plants to combat the oxidative stress. Upregulation of NADP-dependent malic enzyme and NADP-dependent malate dehydrogenase genes indicated their role in abiotic stress tolerance as well as photosynthetic carbon (C) sequestration. Operation of C₄ type CO₂ fixation in S. monoica and an intermediate CO₂ fixation in S. fruticosa could be the possible reason for the superior photosynthetic efficiency of S. monoica under stress conditions at elevated CO₂.

     

The DNA Replication,Repair, and Recombination Pathway Genes Modulating Yield and Stress Tolerance Traits in Chickpea

DNA replication, repair, and recombination (DRRR) are the fundamental processes required for faithful transmission of genetic information within and between generations. The DRRR genes protect the cells from potential mutations and damage during the developmental phases and stress conditions. Thus, these genes indirectly regulate diverse important agronomic traits in a crop plant. A genome-wide survey of six DRRR pathway genes, namely, DNA replication, Base Excision Repair, Nucleotide Excision Repair, Homologous Recombination, Mismatch Excision Repair, and Non-Homologous End-Joining, identified 157 DRRR genes in chickpea. Phylogenetic analysis of these genes within the legume clades and model plant Arabidopsis identified 42 conserved DRRR genes exhibiting clade-specific evolutionary patterns. Integrating the gene-based association mapping with differential expression profiling identified the natural alleles of the potential DRRR genes, primarily regulating flowering and maturation time and involved in drought tolerance of chickpea. Identifying and understanding DRRR genes’ roles in regulating yield and stress tolerance traits in a vital grain legume like chickpea is requisite for its future crop improvement endeavors. Manipulation of promising functionally relevant DRRR genes will pave the way for simultaneous improvement in multiple beneficial agronomic traits in chickpea.