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Aglaia duperreana , a species with a long cultivation history, is of high ornamental value. To understand the growth and photosynthetic changes of A. duperreana seedlings under variable environmental conditions, we conducted an experiment with light intensities adjusted at 70%, 50% and 30%, crossed with three moisture treatments at 70%, 50% and 30% of field capacity, and a control group which maintained 90% light intensity and 90% field capacity. The results showed that both drought stress and shading propensity significantly inhibited the growth of A. duperreana seedlings, with stronger impacts from drought stress. The increments in stem height and ground diameter, net photosynthetic rate, transpiration rate, stomatal conductance, and chlorophyll content were decreased with the maximum declines by 71.4%, 81.2%, 93.2%, 71.5%, 70.6% and 30.4%, respectively. Under severe drought stress (30% of field capacity), partial shading (50% of translucency) appeared to lessen the detrimental effects of drought. The combination of 70% translucency and 70% field capacity was optimal, resulting in higher increments in stem height, leaf area, net photosynthetic rate, transpiration rate, and stomatal conductance. The maximum fluorescence, variable fluorescence, PSⅡ potential activity, and PSⅡ maximum light energy conversion efficiency increased and then decreased with decreasing moisture. These findings suggested that A. duperreana could adapt to drought and shading stress by modulating growth, enhancing chlorophyll content, and adjusting photosynthetic system. Maintaining translucency at 70% and field moisture capacity at 70% could promote photosynthesis, with positive consequences on growth of A. duperreana .

DNA methylation (DNAm) is an epigenetic modification that acts to regulate gene transcription, is essential for cellular processes and plays an important role in complex traits and disease. Variation in DNAm levels is influenced by both genetic and environmental factors. Several studies have examined the extent to which common genetic variation influences DNAm (i.e. mQTLs), however, an improved understanding of mQTLs across diverse human populations is needed to increase their utility in integrative genomic studies in order to further our understanding of complex trait and disease biology. Here, we systematically examine cis-mQTLs in three Southeast Asian populations in the Singapore Integrative Omics (iOmics) Study, comprised of Chinese (n = 93), Indians (n = 83) and Malays (n = 78). A total of 24 851 cis-mQTL probes were associated with at least one SNP in meta- and ethnicity-specific analyses at a stringent significance level. These cis-mQTL probes show significant differences in local SNP heritability between the ethnicities, enrichment in functionally relevant regions using data from the Roadmap Epigenomics Mapping Consortium and are associated with nearby genes and complex traits due to pleiotropy. Importantly, DNAm prediction performance and the replication of cis-mQTLs both within iOmics and between two independent mQTL studies in European and Bangladeshi individuals is best when the genetic distance between the ethnicities is small, with differences in cis-mQTLs likely due to differences in allele frequency and linkage disequilibrium. This study highlights the importance of, and opportunities from, extending investigation of the genetic control of DNAm to Southeast Asian populations., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In recent years, quality control charts have been increasingly applied in the healthcare environment, for example, to monitor surgical performance. Risk-adjusted cumulative (CUSUM) charts that utilize risk scores like the Parsonnet score to estimate the probability of death of a patient from an operation turn out to be susceptible to misfitted risk models causing deterioration of the charts' properties, in particular, the false alarm behavior. Our approach considers the application of power transformations in the logistic regression model to improve the fit to the binary outcome data. We propose two different approaches of estimating the power exponent δ. The average run length (ARL) to false alarm is calculated with the popular Markov chain approximation in a more efficient way by utilizing the Toeplitz structure of the transition matrix. A sensitivity analysis of the in-control ARL against the true value δ shows potential effects of incorrect choice of δ. Depending on the underlying patient mix, the results vary from robustness to severe impact (doubling of false alarm rate)., (© 2019 John Wiley & Sons, Ltd.)

The variable life-adjusted display (VLAD) is the first risk-adjusted graphical procedure proposed in the literature for monitoring the performance of a surgeon. It displays the cumulative sum of expected minus observed deaths. It has since become highly popular because the statistic plotted is easy to understand. But it is also easy to misinterpret a surgeon's performance by utilizing the VLAD, potentially leading to grave consequences. The problem of misinterpretation is essentially caused by the variance of the VLAD's statistic that increases with sample size. In order for the VLAD to be truly useful, a simple signaling rule is desperately needed. Various forms of signaling rules have been developed, but they are usually quite complicated. Without signaling rules, making inferences using the VLAD alone is difficult if not misleading. In this paper, we establish an equivalence between a VLAD with V-mask and a risk-adjusted cumulative sum (RA-CUSUM) chart based on the difference between the estimated probability of death and surgical outcome. Average run length analysis based on simulation shows that this particular RA-CUSUM chart has similar performance as compared to the established RA-CUSUM chart based on the log-likelihood ratio statistic obtained by testing the odds ratio of death. We provide a simple design procedure for determining the V-mask parameters based on a resampling approach. Resampling from a real data set ensures that these parameters can be estimated appropriately. Finally, we illustrate the monitoring of a real surgeon's performance using VLAD with V-mask., (Copyright © 2018 John Wiley & Sons, Ltd.)

Chalcones present in edible plants possess anti-cancer and anti-inflammatory properties, with the Michael acceptor moiety reported to be responsible for their biological activities. In this study, two novel dihydrotriazine-chalcone compounds previously identified to exert anti-proliferative effects through dual-targeting of dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR), were evaluated for their anti-invasive and anti-inflammatory abilities. At non-lethal concentrations, the compounds suppressed in vitro migration of MDA-MB-231 breast carcinoma cells, which was correlated with a dose-dependent downregulation of phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) expression and secretion. At similar concentrations, these chalcone-based compounds suppressed expression of inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated murine macrophage-like RAW 264.7 cells, as well as tumor necrosis factor alpha (TNF-α) in LPS-stimulated human monocytes isolated from healthy donors. Mechanistically, inhibition of cancer cell invasion and inflammation by the compounds were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway, which corroborated with the reported mechanism of action of chalcones. Their abilities to target multiple biological mediators relevant to multi-step carcinogenesis and with bioactivities stronger than those of the parent chalcone scaffold have warranted dihydrotriazine-chalcone compounds as promising candidates for use in pharmacological intervention of aggressive cancers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is naive and incorrect to use the proportions of successful operations to compare the performance of surgeons because the patients' risk profiles are different. In this paper, we explore the use of risk-adjusted procedures to compare the performance of surgeons. One such risk-adjusted statistic is the standardized mortality ratio (SMR), which measures the performance of a surgeon adjusted for the risks of patients assuming the average performance of a group of surgeons. Unlike the traditional SMR which is defined based on a population, this SMR is a random variable. Thus, all existing results for the traditional SMR are not valid unless the sample is large enough to be considered a population. In this paper, we develop two risk-adjusted procedures for comparing the performance of surgeons. The asymptotic distributions of the test statistics are derived. We also use the bootstrap procedure to estimate finite-sample distributions. Both probability of type I error and power of these procedures are investigated. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Quality Problem or Issue: The traditional variable life-adjusted display (VLAD) is a graphical display of the difference between expected and actual cumulative deaths. The VLAD assumes binary outcomes: death within 30 days of an operation or survival beyond 30 days. Full recovery and bedridden for life, for example, are considered the same outcome. This binary classification results in a great loss of information., Initial Assessment: Although there are many grades of survival, the binary outcomes are commonly used to classify surgical outcomes. Consequently, quality monitoring procedures are developed based on binary outcomes. With a more refined set of outcomes, the sensitivities of these procedures can be expected to improve., Choice of Solution: A likelihood ratio method is used to define a penalty-reward scoring system based on three or more surgical outcomes for the new VLAD. The likelihood ratio statistic W is based on testing the odds ratio of cumulative probabilities of recovery R. Two methods of implementing the new VLAD are proposed., Implementation: We accumulate the statistic W-W¯R to estimate the performance of a surgeon where W¯R is the average of the W's of a historical data set. The accumulated sum will be zero based on the historical data set. This ensures that if a new VLAD is plotted for a future surgeon of performance similar to this average performance, the plot will exhibit a horizontal trend., Evaluation: For illustration of the new VLAD, we consider 3-outcome surgical results: death within 30 days, partial and full recoveries. In our first illustration, we show the effect of partial recoveries on surgical results of a surgeon. In our second and third illustrations, the surgical results of two surgeons are compared using both the traditional VLAD based on binary-outcome data and the new VLAD based on 3-outcome data. A reversal in relative performance of surgeons is observed when the new VLAD is used. In our final illustration, we display the surgical results of four surgeons using the new VLAD based completely on 3-outcome data., Lessons Learned: Full recovery and bedridden for life are two completely different outcomes. There is a great loss of information when different grades of 'successful' operations are naively classified as survival. When surgical outcomes are classified more accurately into more than two categories, the resulting new VLAD will reveal more accurately and fairly the surgical results., (© The Author 2017. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E2 (PGE2) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies., (© 2013.)

Aims: The role of thioredoxin reductase (TrxR) in tumorigenesis has made it an attractive anticancer target. A systematic approach for development of novel compounds as TrxR inhibitors is currently lacking. Structurally diversified TrxR inhibitors share in common electrophilic propensities for the sulfhydryl groups, among which include the Michael reaction acceptors containing an α,β-unsaturated carbonyl moiety. We aimed to identify features among structurally diversified Michael acceptor-based compounds that would yield a strong TrxR inhibitory character., Results: Structurally dissimilar Michael acceptor-based natural compounds such as isobutylamides, zerumbone, and shogaols (SGs) were found to possess a poor TrxR inhibitory activity, indicating that a sole Michael acceptor moiety was insufficient to produce TrxR inhibition. The 1,7-diphenyl-hept-3-en-5-one pharmacophore in 3-phenyl-3-SG, a novel SG analog that possessed comparable TrxR inhibitory and antiproliferative potencies as 6-SG, was modified to yield 1,5-diphenyl-pent-1-en-3-one (DPPen) and 1,3-diphenyl-pro-1-en-3-one (DPPro, also known as chalcone) pharmacophores. These Michael acceptor-centric pharmacophores, when substituted with the hydroxyl and fluorine groups, gave rise to analogs displaying a TrxR inhibitory character positively correlated to their antiproliferative potencies. Lead analogs 2,2'-diOH-5,5'-diF-DPPen and 2-OH-5-F-DPPro yielded a half-maximal TrxR inhibitory concentration of 9.1 and 10.5 μM, respectively, after 1-h incubation with recombinant rat TrxR, with the C-terminal selenocysteine residue found to be targeted., Innovation: Identification of Michael acceptor-centric pharmacophores among diversified compounds demonstrates that a systematic approach to discover and develop Michael acceptor-based TrxR inhibitors is feasible., Conclusion: A strong TrxR inhibitory character correlated to the antiproliferative potency is attributed to structural features that include an α,β-unsaturated carbonyl moiety centered in a DPPen or DPPro pharmacophore bearing hydroxyl and fluorine substitutions.

Ixeris sonchifolia Hance is an herb distributed in northeastern part of China and has been used by natives to invigorate circulation. In the present study, bioactivity-guided fractionation of I. sonchifolia Hance extract was performed with the aim to isolate and identify the compounds underlying the potential protective effects against ischemia brain injury. Among the four fractions isolated from the herb extract, the ethyl acetate fraction was found to scavenge DPPH radicals, induce ARE-dependent transcriptional activity and upregulate Nrf2 protein levels. The isolation work focused on this fraction revealed the presence of two categories of compounds: flavonoids and sesquiterpene lactones. Among the five isolated flavonoids, luteolin was evaluated to possess direct and indirect antioxidant activities by scavenging free radicals and inducing the upregulation of ARE-dependent phase II enzymes. Concomitant with the findings from the cell-based assays, in the middle cerebral artery occlusion-induced ischemia rat model, administration of luteolin at 4 mg/kg displayed neuroprotective effects by reducing infarct area and inhibiting neuronal cell death. In summary, the obtained results suggest that flavonoids in I. sonchifolia Hance, in particular luteolin, contribute at least partly to the neuroprotective effects against ischemia-induced cellular injury and can be potentially developed for treatment of ischemia-reperfusion induced diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.

Shogaols have been previously reported to induce cancer cell death via multiple mechanisms, among which one analog 6-shogaol has been reported to cause microtubule damage through specific reaction with sulfhydryl groups in tubulin. In this study, a series of shogaols with different side chain lengths (4-, 6-, 8- and 10-shogaol) was synthesized and evaluated for antiproliferative activity in HCT 116 colon carcinoma and SH-SY5Y neuroblastoma cells. 4- and 6-shogaol were identified as lead compounds possessing the strongest antiproliferative activity. In the soft agar assay, the lead shogaols displayed dose-dependent inhibition on cancer cell colony formation under anchorage-independent conditions. Using HCT 116 as the selected cancer cell line, the molecular events linking shogaols-induced G(2)/M cell cycle arrest to apoptosis characterized by caspase 3 and PARP cleavage were investigated. At sublethal concentrations, the halt at G(2)/M phase was alleviated along time and cells survived. Conversely, proapoptotic concentrations of 4- and 6-shogaol induced irreversible G(2)/M arrest that was at least in part associated with down-regulation of cell cycle checkpoint proteins cdk1, cyclin B and cdc25C, as well as spindle assembly checkpoint proteins mad2, cdc20 and survivin. A dose- and time-dependent accumulation of insoluble tubulin in the insoluble fractions of cell lysates provided evidence that G(2) checkpoint failure led to disruption of microtubule turnover. In summary, our results conclude that shogaols cause apoptosis by inducing aberrant mitosis at least through the attenuation of cell cycle and spindle assembly checkpoint proteins.

Risk-adjusted charts for monitoring a surgical or patient care process have recently gained prominence in the literature. To monitor a patient care process, especially to detect deterioration is crucial in saving patients' lives. In this paper, a new charting procedure is developed for monitoring a patient care process for patients admitted to a hospital with acute myocardial infarctions. This procedure is based on the number-between failures by taking the patients' risks into account. When there is a change in the risk distribution of incoming patients, it is demonstrated that this procedure will behave properly while the non-risk-adjusted counterpart will signal incorrectly that the patient care process has changed. The setting up of this chart to monitor a patient care process for patients with acute myocardial infarctions is described in detail.

A new, efficient synthesis of sphingofungin F has been accomplished with 10.4% overall yield in 15 steps. The salient features of the synthesis are the utilization of methyl tricyclic iminolactone 3 for the asymmetric aldol reaction as a key step to introduce two desired stereogenic centers, one-pot reaction for the synthesis of omega-hydroxyketone from epsilon-caprolactone, and an effective one-step deprotection strategy to remove all protecting groups using 0.2 N HCl.

The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.