Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Differential Detection of Genetic Loci Underlying Stem and Root Lignin Content in Populus

In this study, we established a comprehensive genetic map with a large number of progeny from a three-generation hybrid Populus intercross, and phenotyped the lignin content, S/G ratio and 28 cell wall subcomponents both in stems and roots for the mapping individuals. Phenotypic analysis revealed that lignin content and syringyl-to-guaiacyl (S/G) ratio using pyrolysis molecular beam mass spectroscopy (pyMBMS) varied among mapping individuals. Phenotypic analysis revealed that stem lignin content is significantly higher than that in root and the quantified traits can be classified into four distinct groups, with strong correlations observed among components within organs. Altogether, 179 coordinating QTLs were detected, and they were co-localized into 49 genetic loci, 27 of which appear to be pleiotropic. Many of the detected genetic loci were detected differentially in stem and root. This is the first report of separate genetic loci controlling cell wall phenotypes above and below ground. These results suggest that it may be possible to modify lignin content and composition via breed and/or engineer as a means of simultaneously improving Populus for cellulosic ethanol production and carbon sequestration

The Timing of the Cognitive Cycle

We propose that human cognition consists of cascading cycles of recurring brain events. Each cognitive cycle senses the current situation, interprets it with reference to ongoing goals, and then selects an internal or external action in response. While most aspects of the cognitive cycle are unconscious, each cycle also yields a momentary “ignition” of conscious broadcasting. Neuroscientists have independently proposed ideas similar to the cognitive cycle, the fundamental hypothesis of the LIDA model of cognition. High-level cognition, such as deliberation, planning, etc., is typically enabled by multiple cognitive cycles. In this paper we describe a timing model LIDA's cognitive cycle. Based on empirical and simulation data we propose that an initial phase of perception (stimulus recognition) occurs 80–100 ms from stimulus onset under optimal conditions. It is followed by a conscious episode (broadcast) 200–280 ms after stimulus onset, and an action selection phase 60–110 ms from the start of the conscious phase. One cognitive cycle would therefore take 260–390 ms. The LIDA timing model is consistent with brain evidence indicating a fundamental role for a theta-gamma wave, spreading forward from sensory cortices to rostral corticothalamic regions. This posteriofrontal theta-gamma wave may be experienced as a conscious perceptual event starting at 200–280 ms post stimulus. The action selection component of the cycle is proposed to involve frontal, striatal and cerebellar regions. Thus the cycle is inherently recurrent, as the anatomy of the thalamocortical system suggests. The LIDA model fits a large body of cognitive and neuroscientific evidence. Finally, we describe two LIDA-based software agents: the LIDA Reaction Time agent that simulates human performance in a simple reaction time task, and the LIDA Allport agent which models phenomenal simultaneity within timeframes comparable to human subjects. While there are many models of reaction time performance, these results fall naturally out of a biologically and computationally plausible cognitive architecture

Burden of obesity in the Eastern Mediterranean Region: findings from the Global Burden of Disease 2015 study

Mokdad AH, El Bcheraoui C, Afshin A, et al. Burden of obesity in the Eastern Mediterranean Region: findings from the Global Burden of Disease 2015 study. INTERNATIONAL JOURNAL OF PUBLIC HEALTH. 2018;63(Suppl. 1):165-176.We used the Global Burden of Disease (GBD) 2015 study results to explore the burden of high body mass index (BMI) in the Eastern Mediterranean Region (EMR). We estimated the prevalence of overweight and obesity among children (2-19 years) and adults (20 years) in 1980 and 2015. The burden of disease related to high BMI was calculated using the GBD comparative risk assessment approach. The prevalence of obesity increased for adults from 15.1% (95% UI 13.4-16.9) in 1980 to 20.7% (95% UI 18.8-22.8) in 2015. It increased from 4.1% (95% UI 2.9-5.5) to 4.9% (95% UI 3.6-6.4) for the same period among children. In 2015, there were 417,115 deaths and 14,448,548 disability-adjusted life years (DALYs) attributable to high BMI in EMR, which constitute about 10 and 6.3% of total deaths and DALYs, respectively, for all ages. This is the first study to estimate trends in obesity burden for the EMR from 1980 to 2015. We call for EMR countries to invest more resources in prevention and health promotion efforts to reduce this burden

First measurement of the |t|-dependence of coherent J/ψ photonuclear production

The first measurement of the cross section for coherent J/ψ photoproduction as a function of |t|, the square of the momentum transferred between the incoming and outgoing target nucleus, is presented. The data were measured with the ALICE detector in ultra-peripheral Pb–Pb collisions at a centre-of-mass energy per nucleon pair sNN=5.02TeV with the J/ψ produced in the central rapidity region |y|<0.8, which corresponds to the small Bjorken-x range (0.3−1.4)×10−3. The measured |t|-dependence is not described by computations based only on the Pb nuclear form factor, while the photonuclear cross section is better reproduced by models including shadowing according to the leading-twist approximation, or gluon-saturation effects from the impact-parameter dependent Balitsky–Kovchegov equation. These new results are therefore a valid tool to constrain the relevant model parameters and to investigate the transverse gluonic structure at very low Bjorken-x.publishedVersio

First measurement of coherent ρ0 photoproduction in ultra-peripheral Xe–Xe collisions at √sNN = 5.44 TeV

The first measurement of the coherent photoproduction of ρ0 vector mesons in ultra-peripheral Xe–Xe collisions at sNN=5.44 TeV is presented. This result, together with previous HERA γp data and γ–Pb measurements from ALICE, describes the atomic number (A) dependence of this process, which is particularly sensitive to nuclear shadowing effects and to the approach to the black-disc limit of QCD at a semi-hard scale. The cross section of the Xe+Xe→ρ0+Xe+Xe process, measured at midrapidity through the decay channel ρ0→π+π−, is found to be dσ/dy=131.5±5.6(stat.)−16.9+17.5(syst.) mb. The ratio of the continuum to resonant contributions for the production of pion pairs is also measured. In addition, the fraction of events accompanied by electromagnetic dissociation of either one or both colliding nuclei is reported. The dependence on A of cross section for the coherent ρ0 photoproduction at a centre-of-mass energy per nucleon of the γA system of WγA,n=65 GeV is found to be consistent with a power-law behaviour σ(γA→ρ0A)∝Aα with a slope α=0.96±0.02(syst.). This slope signals important shadowing effects, but it is still far from the behaviour expected in the black-disc limit.publishedVersio

Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents

Background: Osteoporosis is the most prevalent skeletal disorder, characterized by a low bone mineral density (BMD) and bone structural deterioration, leading to bone fragility fractures. Accelerated bone resorption by osteoclasts has been established as a principal mechanism in osteoporosis. However, recent experimental evidences suggest that inappropriate apoptosis of osteoblasts/osteocytes accounts for, at least in part, the imbalance in bone remodeling as occurs in osteoporosis. The aim of this study is to examine whether aspirin, which has been reported as an effective drug improving bone mineral density in human epidemiology studies, regulates the balance between bone resorption and bone formation at stem cell levels. Methods and Findings: We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studies revealed that T cell-mediated BMMSC impairment was mainly attributed to the apoptosis of BMMSCs via the Fas/Fas ligand pathway. To explore potential of using pharmacologic stem cell based intervention as an approach for osteoporosis treatment, we selected ovariectomy (OVX)- induced ostoeporosis mouse model to examine feasibility and mechanism of aspirin-mediated therapy for osteoporosis. We found that aspirin can inhibit T cell activation and Fas ligand induced BMMSC apoptosis in vitro. Further, we revealed that aspirin increases osteogenesis of BMMSCs by aiming at telomerase activity and inhibits osteoclast activity in OVX mice, leading to ameliorating bone density. Conclusion: Our findings have revealed a novel osteoporosis mechanism in which activated T cells induce BMMSC apoptosis via Fas/Fas ligand pathway and suggested that pharmacologic stem cell based intervention by aspirin may be a new alternative in osteoporosis treatment including activated osteoblasts and inhibited osteoclasts.Takayoshi Yamaza, Yasuo Miura, Yanming Bi, Yongzhong Liu, Kentaro Akiyama, Wataru Sonoyama, Voymesh Patel, Silvio Gutkind, Marian Young, Stan Gronthos, Anh Le, Cun-Yu Wang, WanJun Chen and Songtao Sh

Differential profiling of lacrimal cytokines in patients suffering from thyroid-associated orbitopathy.

The aim was to investigate the levels of cytokines and soluble IL-6R in the tears of patients with thyroid-associated orbitopathy (TAO) disease. Schirmer's test was adopted to collect tears from TAO patients (N = 20, 17 women, mean age (±SD): 46.0 years (±13.4)) and healthy subjects (N = 18, 10 women, 45.4 years (±18.7)). Lacrimal cytokines and soluble IL-6R (sIL-6R) were measured using a 10-plex panel (Meso Scale Discovery Company) and Invitrogen Human sIL-6R Elisa kit, respectively. Tear levels of IL-10, IL-12p70, IL-13, IL-6 and TNF-α appeared significantly higher in TAO patients than in healthy subjects. Interestingly, IL-10, IL-12p70 and IL-8 levels increased in tears whatever the form of TAO whereas IL-13, IL-6 and TNF-α levels were significantly elevated in inflammatory TAO patients, meaning with a clinical score activity (CAS) ≥ 3, compared to controls. Furthermore, only 3 cytokines were strongly positively correlated with CAS (IL-13 Spearman coeff. r: 0.703, p = 0.0005; IL-6 r: 0.553, p = 0.011; IL-8 r: 0.618, p = 0.004, respectively). Finally, tobacco use disturbed the levels of several cytokines, especially in patient suffering of TAO. The differential profile of lacrimal cytokines could be useful for the diagnosis of TAO patients. Nevertheless, the tobacco use of these patients should be taken into account in the interpretation of the cytokine levels