EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells

Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants and found to have potential anticancer activities. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. In this study, we observed that EM23, a natural SL, exhibited anti-cancer activity in human cervical cancer cell lines by inducing apoptosis as indicated by caspase 3 activation, XIAP downregulation and mitochondrial dysfunction. Mechanistic studies indicated that EM23-induced apoptosis was mediated by reactive oxygen species (ROS) and the knockdown of thioredoxin (Trx) or thioredoxin reductase (TrxR) resulted in a reduction in apoptosis. EM23 attenuated TrxR activity by alkylation of C-terminal redox-active site Sec498 of TrxR and inhibited the expression levels of Trx/TrxR to facilitate ROS accumulation. Furthermore, inhibition of Trx/TrxR system resulted in the dissociation of ASK1 from Trx and the downstream activation of JNK. Pretreatment with ASK1/JNK inhibitors partially rescued cells from EM23-induced apoptosis. Additionally, EM23 inhibited Akt/mTOR pathway and induced autophagy, which was observed to be proapoptotic and mediated by ROS. Together, these results reveal a potential molecular mechanism for the apoptotic induction observed with SL compound EM23, and emphasize its putative role as a therapeutic agent for human cervical cancer.published_or_final_versio

Long-term organic carbon preservation enhanced by iron and manganese.

The balance between degradation and preservation of sedimentary organic carbon (OC) is important for global carbon and oxygen cycles1. The relative importance of different mechanisms and environmental conditions contributing to marine sedimentary OC preservation, however, remains unclear2-8. Simple organic molecules can be geopolymerized into recalcitrant forms by means of the Maillard reaction5, although reaction kinetics at marine sedimentary temperatures are thought to be slow9,10. More recent work in terrestrial systems suggests that the reaction can be catalysed by manganese minerals11-13, but the potential for the promotion of geopolymerized OC formation at marine sedimentary temperatures is uncertain. Here we present incubation experiments and find that iron and manganese ions and minerals abiotically catalyse the Maillard reaction by up to two orders of magnitude at temperatures relevant to continental margins where most preservation occurs4. Furthermore, the chemical signature of the reaction products closely resembles dissolved and total OC found in continental margin sediments globally. With the aid of a pore-water model14, we estimate that iron- and manganese-catalysed transformation of simple organic molecules into complex macromolecules might generate on the order of approximately 4.1 Tg C yr-1 for preservation in marine sediments. In the context of perhaps only about 63 Tg C yr-1 variation in sedimentary organic preservation over the past 300 million years6, we propose that variable iron and manganese inputs to the ocean could exert a substantial but hitherto unexplored impact on global OC preservation over geological time

Entanglement of single-photons and chiral phonons in atomically thin WSe2_2

Quantum entanglement is a fundamental phenomenon which, on the one hand, reveals deep connections between quantum mechanics, gravity and the space-time; on the other hand, has practical applications as a key resource in quantum information processing. While it is routinely achieved in photon-atom ensembles, entanglement involving the solid-state or macroscopic objects remains challenging albeit promising for both fundamental physics and technological applications. Here, we report entanglement between collective, chiral vibrations in two-dimensional (2D) WSe$_2$ host --- chiral phonons (CPs) --- and single-photons emitted from quantum dots (QDs) present in it. CPs which carry angular momentum were recently observed in WSe$_2$ and are a distinguishing feature of the underlying honeycomb lattice. The entanglement results from a "which-way" scattering process, involving an optical excitation in a QD and doubly-degenerate CPs, which takes place via two indistinguishable paths. Our unveiling of entanglement involving a macroscopic, collective excitation together with strong interaction between CPs and QDs in 2D materials opens up ways for phonon-driven entanglement of QDs and engineering chiral or non-reciprocal interactions at the single-photon level

Distance-Based and Low Energy Adaptive Clustering Protocol for Wireless Sensor Networks

A wireless sensor network (WSN) comprises small sensor nodes with limited energy capabilities. The power constraints of WSNs necessitate efficient energy utilization to extend the overall network lifetime of these networks. We propose a distance-based and low-energy adaptive clustering (DISCPLN) protocol to streamline the green issue of efficient energy utilization in WSNs. We also enhance our proposed protocol into the multi-hop-DISCPLN protocol to increase the lifetime of the network in terms of high throughput with minimum delay time and packet loss. We also propose the mobile-DISCPLN protocol to maintain the stability of the network. The modelling and comparison of these protocols with their corresponding benchmarks exhibit promising results

Female sex pheromone of the cone moth, dioryctria mendacella: Investigation of synergism between Type I and Type II pheromone components

Polyunsaturated hydrocarbons (Type II pheromone components) have been reported to be synergists for unsaturated acetates, alcohols or aldehydes (Type I components) in the sex pheromones of several species of Lepidoptera. However, there is some debate over whether the active components are the hydrocarbons themselves or more volatile degradation products. Extracts of pheromone glands of adult females of the cone moth, Dioryctria mendacella (Lepidoptera: Pyralidae), contain (Z,E)-9,11-tetradecadienyl acetate (ZE9,11-14:Ac) and at least ten times as much (Z,Z,Z,Z,Z)-3,6,9,12,15-pentacosapentaene (ZZZZZ3,6,9,12,15-25:H). The former elicits a strong electroantennogram response from males while no response could be recorded to the latter. In field trapping tests, both compounds were individually unattractive to male D. mendacella moths, but blends of the two compounds containing at least a 10:1 ratio of ZZZZZ3,6,9,12,15-25:H : ZE9,11-14:Ac were highly attractive. The relatively involatile hydrocarbon was shown to be released from the dispensers used and no significant degradation could be detected. Furthermore, blends of ZE9,11-14:Ac and analogs of ZZZZZ3,6,9,12,15-25:H with fewer carbons and/or double bonds that might be expected to produce similar degradation products to ZZZZZ3,6,9,12,15-25:H were unattractive. This indicated a specific response to the hydrocarbon itself, further substantiated by the observation that related hydrocarbons did not interfere with the activity of ZZZZZ3,6,9,12,15-25:H. Thus a three-step conversion of fish oil was used to produce a blend of unsaturated hydrocarbons containing ZZZZZ3,6,9,12,15-25:H as the major component, albeit only 30% of the total, and a blend of this material with ZE9,11-14:Ac was as attractive to male D. mendacella moths as blends with an equivalent amount of the purified material. This mixture of unsaturated hydrocarbons is much cheaper to produce than the pure pentaene, and may be useful in lures for other species using these compounds. Dioryctria mendacella is a major constraint to production of edible pine kernels throughout the Mediterranean region. Pheromone traps will provide a means to improve monitoring of seasonal flight patterns and changes in population abundance of this pest

High Diversity of Cryptosporidium Subgenotypes Identified in Malaysian HIV/AIDS Individuals Targeting gp60 Gene

BACKGROUND: Currently, there is a lack of vital information in the genetic makeup of Cryptosporidium especially in developing countries. The present study aimed at determining the genotypes and subgenotypes of Cryptosporidium in hospitalized Malaysian human immunodeficiency virus (HIV) positive patients. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 346 faecal samples collected from Malaysian HIV positive patients were genetically analysed via PCR targeting the 60 kDa glycoprotein (gp60) gene. Eighteen (5.2% of 346) isolates were determined as Cryptosporidium positive with 72.2% (of 18) identified as Cryptosporidium parvum whilst 27.7% as Cryptosporidium hominis. Further gp60 analysis revealed C. parvum belonging to subgenotypes IIaA13G1R1 (2 isolates), IIaA13G2R1 (2 isolates), IIaA14G2R1 (3 isolates), IIaA15G2R1 (5 isolates) and IIdA15G1R1 (1 isolate). C. hominis was represented by subgenotypes IaA14R1 (2 isolates), IaA18R1 (1 isolate) and IbA10G2R2 (2 isolates). CONCLUSIONS/SIGNIFICANCE: These findings highlighted the presence of high diversity of Cryptosporidium subgenotypes among Malaysian HIV infected individuals. The predominance of the C. parvum subgenotypes signified the possibility of zoonotic as well as anthroponotic transmissions of cryptosporidiosis in HIV infected individuals

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

Associations of education with 30 year life course blood pressure trajectories: Framingham Offspring Study

Background: Education is inversely associated with cardiovascular disease incidence in developed countries. Blood pressure may be an explanatory biological mechanism. However few studies have investigated educational gradients in longitudinal blood pressure trajectories, particularly over substantial proportions of the life course. Study objectives were to determine whether low education was associated with increased blood pressure from multiple longitudinal assessments over 30 years. Furthermore, we aimed to separate antecedent effects of education, and other related factors, that might have caused baseline differences in blood pressure, from potential long-term effects of education on post-baseline blood pressure changes. Methods: The study examined 3890 participants of the Framingham Offspring Study (mean age 36.7 years, 52.0% females at baseline) from 1971 through 2001 at up to 7 separate examinations using multivariable mixed linear models. Results: Mixed linear models demonstrated that mean systolic blood pressure (SBP) over 30 years was higher for participants with ≤12 vs. ≥17 years education after adjusting for age (3.26 mmHg, 95% CI: 1.46, 5.05 in females, 2.26 mmHg, 95% CI: 0.87, 3.66 in males). Further adjustment for conventional covariates (antihypertensive medication, smoking, body mass index and alcohol) reduced differences in females and males (2.86, 95% CI: 1.13, 4.59, and 1.25, 95% CI: -0.16, 2.66 mmHg, respectively). Additional analyses adjusted for baseline SBP, to evaluate if there may be educational contributions to post-baseline SBP. In analyses adjusted for age and baseline SBP, females with ≤12 years education had 2.69 (95% CI: 1.09, 4.30) mmHg higher SBP over follow-up compared with ≥17 years education. Further adjustment for aforementioned covariates slightly reduced effect strength (2.53 mmHg, 95% CI: 0.93, 4.14). Associations were weaker in males, where those with ≤12 years education had 1.20 (95% CI: -0.07, 2.46) mmHg higher SBP over follow-up compared to males with ≥17 years of education, after adjustment for age and baseline blood pressure; effects were substantially reduced after adjusting for aforementioned covariates (0.34 mmHg, 95% CI: -0.90, 1.68). Sex-by-education interaction was marginally significant (p = 0.046). Conclusion: Education was inversely associated with higher systolic blood pressure throughout a 30-year life course span, and associations may be stronger in females than males.Eric B Loucks, Michal Abrahamowicz, Yongling Xiao, John W Lync