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The taccalonolides are a class of microtubule stabilizing agents isolated from plants of the genus Tacca. In efforts to define their structure activity relationships, we isolated 5 new taccalonolides, AC-AF, and H2, from one fraction of an ethanol extract of Tacca plantaginea. The structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HRESIMS. Taccalonolide AJ, an epoxidation product of taccalonolide B, was generated by semi-synthesis. Five of these taccalonolides demonstrated cellular microtubule stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ exhibiting the highest potency with an IC50 value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to greater than 50 µM, for the first time provides the opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays taccalonolide AF and AJ stimulated the polymerization of purified tubulin, an activity that had not previously been observed for the taccalonolides A and B, providing the first evidence that this class of microtubule stabilizers can interact directly with tubulin/microtubules. Taccalonolides AF and AJ were able to enhance tubulin polymerization to the same extent as paclitaxel, but with a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site. The potencies of taccalonolides AF and AJ, their direct interaction with tubulin, together with the previous excellent in vivo antitumor activity of this class reveal the potential of the taccalonolides as new anticancer agents.

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BackgroundIt is very difficult to prevent pulmonary tuberculosis (TB) due to the lack of specific and diagnostic markers, which could lead to a high incidence of pulmonary TB. We screened the differentially expressed serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of pulmonary TB.MethodsIn this study, serum miRNAs were screened using the Solexa sequencing method as the potential biomarkers for the diagnosis of pulmonary TB. The stem-loop quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was used to verify differentially expressed serum miRNAs. The receiver operating characteristic (ROC) curve and logistic regression model were used to analyze the sensitivity and specificity of the single miRNA and a combination of miRNAs for diagnosis, respectively. Using the predicted target genes, we constructed the regulatory networks of miRNAs and genes that were related to pulmonary TB.ResultsThe Solexa sequencing data showed that 91 serum miRNAs were differentially expressed in pulmonary TB patients, compared to healthy controls. Following qRT-PCR confirmation, six serum miRNAs (hsa-miR-378, hsa-miR-483-5p, hsa-miR-22, hsa-miR-29c, hsa-miR-101 and hsa-miR-320b) showed significant difference among pulmonary TB patients, healthy controls (P<0.001) and differential diagnosis groups (including patients with pneumonia, lung cancer and chronic obstructive pulmonary disease) (P<0.05). The logistic regression analysis of a combination of six serum miRNAs revealed that the sensitivity and the specificity of TB diagnosis were 95.0% and 91.8% respectively. The miRNAs-gene regulatory networks revealed that several miRNAs may regulate some target genes involved in immune pathways and participate in the pathogenesis of pulmonary TB.ConclusionOur study suggests that a combination of six serum miRNAs have great potential to serve as non-invasive biomarkers of pulmonary TB.

Complications after de novo defibrillator implantation were strongly associated with device type. Major complications were associated with increased risk of mortality.

Age- and sex-specific estimates of the rate of cardiac morbidity among Hodgkin lymphoma (HL) patients treated with doxorubicin-based chemotherapy and radiation therapy (RT) are scarce. We evaluated the risk of hospital admission for cardiac disease in 615 HL patients, adjusting for age, sex, treatment, cardiac risk factors and competing causes of death. Compared with the general population, the risk of cardiac morbidity was highest among patients treated with both doxorubicin and mediastinal RT (HR = 2.77, p < 0.0001). Mediastinal RT without chemotherapy also significantly increased the risk (HR = 1.82, p = 0.038). For females and males treated with doxorubicin plus mediastinal RT at age 40, the estimated 15-year incidence rate of cardiac hospitalisation were 7.3% and 16.5%, respectively, rates 5-15% higher than expected. These results suggest that the risk of clinically important cardiac toxicity following HL treatment that includes both doxorubicin and mediastinal RT may be greater than that reported in prior studies of patients treated with RT alone.

Nitrogen is the main limiting nutrient after carbon, hydrogen and oxygen for photosynthetic process, phyto-hormonal, proteomic changes and growth-development of plants to complete its lifecycle. Excessive and inefficient use of N fertilizer results in enhanced crop production costs and atmospheric pollution. Atmospheric nitrogen (71%) in the molecular form is not available for the plants. For world’s sustainable food production and atmospheric benefits, there is an urgent need to up-grade nitrogen use efficiency in agricultural farming system. The nitrogen use efficiency is the product of nitrogen uptake efficiency and nitrogen utilization efficiency, it varies from 30.2 to 53.2%. Nitrogen losses are too high, due to excess amount, low plant population, poor application methods etc., which can go up to 70% of total available nitrogen. These losses can be minimized up to 15–30% by adopting improved agronomic approaches such as optimal dosage of nitrogen, application of N by using canopy sensors, maintaining plant population, drip fertigation and legume based intercropping. A few transgenic studies have shown improvement in nitrogen uptake and even increase in biomass. Nitrate reductase, nitrite reductase, glutamine synthetase, glutamine oxoglutarate aminotransferase and asparagine synthetase enzyme have a great role in nitrogen metabolism. However, further studies on carbon–nitrogen metabolism and molecular changes at omic levels are required by using “whole genome sequencing technology” to improve nitrogen use efficiency. This review focus on nitrogen use efficiency that is the major concern of modern days to save economic resources without sacrificing farm yield as well as safety of global environment, i.e. greenhouse gas emissions, ammonium volatilization and nitrate leaching.

Background— Complications after implantable cardioverter-defibrillator (ICD) replacement are often clinically devastating, particularly when infection or reoperation occurs. Identifying factors contributing to complications may permit identification of high-risk individuals that warrant incremental monitoring and therapy to attenuate risk. In addition, replacement may be a discretionary decision in the context of an advisory or borderline device performance and patient, device, and implanter factors that predict adverse outcome may assist in clinical decision-making. Methods and Results— In a prospective, multicenter, population-based registry of all ICD patients at 18 centers in Ontario, Canada, we examined 45-day complication and all-cause mortality rates from February 2007 to August 2009 in patients undergoing ICD generator replacement. Complications were determined longitudinally and were categorized as major or minor. ICD replacement was performed in 1081 of 5176 patients (20.8%) undergoing ICD implantation (age, 64.3±12.7 years; 78.5% men). In patients undergoing ICD replacement, 47 patients (4.3%) had a complication within 45 days, with 47 major complications in 28 patients (2.6%), most commonly infection (n=23), lead revision (n=35), electrical storm (n=14), and pulmonary edema (n=13). Minor complications occurred in 2.3% of patients, most commonly incisional infection (n=10) and pocket hematoma (n=10). On multivariable analysis, risk factors associated with major complications were Canadian Cardiovascular Society angina class (adjusted hazard ratio [HR], 3.70 for class 2 to 4 versus 0 to 1; P =0.027) and multiple previous procedures on the pocket (adjusted HR, 3.35 for >1 versus 1; P =0.058). Risk factors associated with any complication were the use of antiarrhythmic therapy (adjusted HR, 6.29; P =0.001), implanter volume (adjusted HR 10.4 for <60/y versus >120/y, P =0.026), and Canadian Cardiovascular Society angina class (adjusted HR, 3.00 for class 2 to 4 versus 0 to 1; P =0.031). In a Cox model with a time-dependent variable of major complication within 45 days after replacement, major complications after ICD replacement were associated with an increased risk of mortality at 45, 90, and 180 days (adjusted HR, 9.61, 12.69, and 6.41, respectively; P =0.002 to 0.039). Conclusions— Risk factors associated with complications after ICD replacement include the presence of angina, antiarrhythmic therapy, increased number of previous procedures, and low implanter volume. Major complications may be associated with increased risk of subsequent mortality.