Genetic mapping of the rice ionome in leaves and grain:Identification of QTLs for 17 elements including arsenic, cadmium, iron and selenium

Research into the composition of cereal grains is motivated by increased interest in food quality. Here multi-element analysis is conducted on leaves and grain of the Bala x Azucena rice mapping population grown in the field. Quantitative trait loci (QTLs) for the concentration of 17 elements were detected, revealing 36 QTLs for leaves and 41 for grains. Epistasis was detected for most elements. There was very little correlation between leaf and grain element concentrations. For selenium, lead, phosphorus and magnesium QTLs were detected in the same location for both tissues. In general, there were no major QTL clusters, suggesting separate regulation of each element. QTLs for grain iron, zinc, molybdenum and selenium are potential targets for marker assisted selection to improve seed nutritional quality. An epistatic interaction for grain arsenic also looks promising to decrease the concentration of this carcinogenic element. © Springer Science+Business Media B.V. 2009.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment

The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.

Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

BACKGROUND: While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease.

RESULTS: We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations.

Comparison of optimal designs of steel portal frames including topological asymmetry considering rolled, fabricated and tapered sections

A structural design optimisation has been carried out to allow for asymmetry and fully tapered portal frames. The additional weight of an asymmetric structural shape was found to be on average 5–13% with additional photovoltaic (PV) loading having a negligible effect on the optimum design. It was also shown that fabricated and tapered frames achieved an average percentage weight reduction of 9% and 11%, respectively, as compared to comparable hot-rolled steel frames. When the deflection limits recommended by the Steel Construction Institute were used, frames were shown to be deflection controlled with industrial limits yielding up to 40% saving.

A Constrained Optimization Approach to Dynamic State Estimation for Power Systems Including PMU and Missing Measurements.

In this brief, a hybrid filter algorithm is developed to deal with the state estimation (SE) problem for power systems by taking into account the impact from the phasor measurement units (PMUs). Our aim is to include PMU measurements when designing the dynamic state estimators for power systems with traditional measurements. Also, as data dropouts inevitably occur in the transmission channels of traditional measurements from the meters to the control center, the missing measurement phenomenon is also tackled in the state estimator design. In the framework of extended Kalman filter (EKF) algorithm, the PMU measurements are treated as inequality constraints on the states with the aid of the statistical criterion, and then the addressed SE problem becomes a constrained optimization one based on the probability-maximization method. The resulting constrained optimization problem is then solved using the particle swarm optimization algorithm together with the penalty function approach. The proposed algorithm is applied to estimate the states of the power systems with both traditional and PMU measurements in the presence of probabilistic data missing phenomenon. Extensive simulations are carried out on the IEEE 14-bus test system and it is shown that the proposed algorithm gives much improved estimation performances over the traditional EKF method.