Synthesis and Antitumor Activity of N-Triazol-5-yl-oxazolidin-4-one Derivatives.

Fifteen novel N-triazol-5-yl-oxazolidin-4-ones were synthesized through a few of steps from the benzaldehydes. It was found that N-iodosuccinimide (NIS) can promote intramolecular amination reaction which is the key step of the syntheses, which will be used as new method for the intramolecular formation of nitrogen-containing heterocycles. Part of the compounds were evaluated for their anticancer activity. Among them, compounds 6a, 6b and 6c showed moderate antiprolifiration activity toward human breast cancer cells MDA-MB-231 cell lines, while the mild activity of 6a, 6b and 6d against human cervical cancer HeLa cell lines was confirmed in vitro assay

Copper Salt-Catalyzed Formation of a Novel Series of Triazole-Spirodienone Conjugates with Potent Anticancer Activity.

Copper salt-catalyzed oxidative amination resulted in the formation of a novel series of triazole-spirodienone conjugates, 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-3,8-diones and 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-8-ones. A single crystal of compound 1p among them was grown and analyzed by X-ray crystallography. These compounds were evaluated for their antiproliferative activities against MDA-MB-231, HeLa, A549 and MCF-7 cell lines. Most of them showed moderate to high anticancer potency in the four cancer cell lines. The discovery of the triazole-spirodienone conjugates as cytotoxic agents against cancer cells may open up a new field in which these novel small molecules could be further explored as promising anticancer agents

Novel daidzein analogs enhance osteogenic activity of bone marrow-derived mesenchymal stem cells and adipose-derived stromal/stem cells through estrogen receptor dependent and independent mechanisms

INTRODUCTION: Osteoporosis is a disease characterized by low bone mineral density (BMD) and increased risk of fractures. Studies have demonstrated the use of phytoestrogens, or plant-derived estrogens, such as genistein and daidzein, to effectively increase osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs). Herein, the effects of daidzein analogs on the osteogenic differentiation efficiency of human BMSC and adipose-derived stromal/stem cells (ASC) were explored. METHODS: BMSCs and ASCs underwent osteogenic differentiation in the presence of vehicle, 17β-estradiol (E2), phytoestrogens, or daidzein analogs. Cells were stained for alkaline phosphatase (ALP) enzymatic activity, calcium deposition by alizarin red s, and phosphate mineralization by silver nitrate. Gene expression analysis was conducted on cells treated with daidzein analogs. RESULTS: Cells treated with E2, daidzein, or genistein increased calcium deposition by 1.6-, 1.5-, and 1.4-fold, respectively, relative to vehicle-treated BMSCs and 1.6-, 1.7-, and 1.4-fold relative to vehicle-treated ASCs, respectively. BMSCs treated with daidzein analog 2c, 2g, and 2l demonstrated a 1.6-, 1.6-, and 1.9-fold increase in calcium deposition relative to vehicle-treated BMSCs, respectively, while ASCs treated with daidzein analog 2c, 2g, or 2l demonstrated a 1.7-, 2.0-, and 2.2-fold increase in calcium deposition relative to vehicle-treated ASCs, respectively. Additional analysis with BMSCs and ASCs was conducted in the more efficient compounds: 2g and 2l. ALP activity and phosphate mineralization was increased in 2g- and 2l-treated cells. The analysis of lineage specific gene expression demonstrated increased expression of key osteogenic genes (RUNX2, c-FOS, SPARC, DLX5, SPP1, COL1A1, IGF1, SOST, and DMP1) and earlier induction of these lineage specific genes, following treatment with 2g or 2l, relative to vehicle-treated cells. Estrogen receptor (ER) inhibitor studies demonstrated that ER antagonist fulvestrant inhibited the osteogenic differentiation of 2g in BMSCs and ASCs, while fulvestrant only attenuated the effects of 2l, suggesting that 2l acts by both ER dependent and independent pathways. CONCLUSIONS: These studies provide support for exploring the therapeutic efficacy of daidzein derivatives for the treatment of osteoporosis. Furthermore, the patterns of gene induction differed following treatment with each daidzein analog, suggesting that these daidzein analogs activate distinct ER and non-ER pathways to induce differentiation in BMSCs and ASCs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/scrt493) contains supplementary material, which is available to authorized users

Performance evaluation of digital pulse position modulation for wavelength division multiplexing FSO systems impaired by interchannel crosstalk

Wavelength division multiplexing (WDM) has been proposed for fibre, intersatellite, free space and indoor optical communication systems. Digital pulse position modulation (DPPM) is a more power efficient modulation format than on-off keying (OOK) and a strong contender for the modulation of free-space systems. Although DPPM obtains this advantage in exchange for a bandwidth expansion, WDM systems using it are still potentially attractive, particularly for moderate coding levels. However, WDM systems are susceptible to interchannel crosstalk and modelling this in a WDM DPPM system is necessary. Models of varying complexity, based on simplifying assumptions, are presented and evaluated for the case of a single crosstalk wavelength. For a single crosstalk, results can be straightforwardly obtained by artificially imposing the computationally convenient constraint that frames (and thus slots also) align. Multiple crosstalk effects are additionally investigated, for the most practically relevant cases of modest coding level, and using both simulation and analytical methods. In general, DPPM maintains its sensitivity advantage over OOK even in the presence of crosstalk while predicting lower power penalty at low coding level in WDM systems

Influence of Spring and Autumn Phenological Transitions on Forest Ecosystem Productivity

We use eddy covariance measurements of net ecosystem productivity (NEP) from 21 FLUXNET sites (153 site-years of data) to investigate relationships between phenology and productivity (in terms of both NEP and gross ecosystem photosynthesis, GEP) in temperate and boreal forests. Results are used to evaluate the plausibility of four different conceptual models. Phenological indicators were derived from the eddy covariance time series, and from remote sensing and models. We examine spatial patterns (across sites) and temporal patterns (across years); an important conclusion is that it is likely that neither of these accurately represents how productivity will respond to future phenological shifts resulting from ongoing climate change. In spring and autumn, increased GEP resulting from an ¿extra¿ day tends to be offset by concurrent, but smaller, increases in ecosystem respiration, and thus the effect on NEP is still positive. Spring productivity anomalies appear to have carry-over effects that translate to productivity anomalies in the following autumn, but it is not clear that these result directly from phenological anomalies. Finally, the productivity of evergreen needleleaf forests is less sensitive to phenology than is productivity of deciduous broadleaf forests. This has implications for how climate change may drive shifts in competition within mixed-species stands.JRC.H.5-Land Resources Managemen

Contrasting effects of CO₂ fertilization, land-use change and warming on seasonal amplitude of Northern Hemisphere CO₂ exchange

Continuous atmospheric CO₂ monitoring data indicate an increase in the amplitude of seasonal CO₂-cycle exchange (SCA_(NBP)) in northern high latitudes. The major drivers of enhanced SCA_(NBP) remain unclear and intensely debated, with land-use change, CO₂ fertilization and warming being identified as likely contributors. We integrated CO₂-flux data from two atmospheric inversions (consistent with atmospheric records) and from 11 state-of-the-art land-surface models (LSMs) to evaluate the relative importance of individual contributors to trends and drivers of the SCA_(NBP) of CO₂ fluxes for 1980–2015. The LSMs generally reproduce the latitudinal increase in SCA_(NBP) trends within the inversions range. Inversions and LSMs attribute SCA_(NBP) increase to boreal Asia and Europe due to enhanced vegetation productivity (in LSMs) and point to contrasting effects of CO₂ fertilization (positive) and warming (negative) on SCA_(NBP). Our results do not support land-use change as a key contributor to the increase in SCA_(NBP). The sensitivity of simulated microbial respiration to temperature in LSMs explained biases in SCA_(NBP) trends, which suggests that SCA_(NBP) could help to constrain model turnover times

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Background Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. Methods This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). Results Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). Interpretation Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. Funding National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme)

Lower land-use emissions responsible for increased net land carbon sink during the slow warming period

The terrestrial carbon sink accelerated during 1998–2012, concurrently with the slow warming period, but the mechanisms behind this acceleration are unclear. Here we analyse recent changes in the net land carbon sink (NLS) and its driving factors, using atmospheric inversions and terrestrial carbon models. We show that the linear trend of NLS during 1998–2012 is about 0.17 ± 0.05 Pg C yr−2 , which is three times larger than during 1980–1998 (0.05 ± 0.05 Pg C yr−2). According to terrestrial carbon model simulations, the intensification of the NLS cannot be explained by CO2 fertilization or climate change alone. We therefore use a bookkeeping model to explore the contribution of changes in land-use emissions and find that decreasing land-use emissions are the dominant cause of the intensification of the NLS during the slow warming period. This reduction of land-use emissions is due to both decreased tropical forest area loss and increased afforestation in northern temperate regions. The estimate based on atmospheric inversions shows consistently reduced land-use emissions, whereas another bookkeeping model did not reproduce such changes, probably owing to missing the signal of reduced tropical deforestation. These results highlight the importance of better constraining emissions from land-use change to understand recent trends in land carbon sinks