Synchrotron Radiation X-Ray Microfluorescence Reveals Polarized Distribution of Atomic Elements during Differentiation of Pluripotent Stem Cells

The mechanisms underlying pluripotency and differentiation in embryonic and reprogrammed stem cells are unclear. In this work, we characterized the pluripotent state towards neural differentiated state through analysis of trace elements distribution using the Synchrotron Radiation X-ray Fluorescence Spectroscopy. Naive and neural-stimulated embryoid bodies (EB) derived from embryonic and induced pluripotent stem (ES and iPS) cells were irradiated with a spatial resolution of 20 µm to make elemental maps and qualitative chemical analyses. Results show that these embryo-like aggregates exhibit self-organization at the atomic level. Metallic elements content rises and consistent elemental polarization pattern of P and S in both mouse and human pluripotent stem cells were observed, indicating that neural differentiation and elemental polarization are strongly correlated

Relative deprivation and inequalities in social and political activism

In this paper we analyse whether relative deprivation has divergent effects on different types of social and political action. We expect that it will depress volunteering with parties as well as different types of conventional political participation more generally while stimulating volunteering with anti-cuts organisations and engagement in various kinds of protest activism. There is little research into how relative deprivation impacts on different types of social and political action from the wide range of activities available to citizens in contemporary democracies as well as into how this relationship might vary based on the wider economic context. While many studies construct scales, we examine participation in specific activities and associations, such as parties or anti-cuts organisations, voting, contacting, demonstrating and striking to show that deprivation has divergent effects that depart from what is traditionally argued. We apply random effects models with cross-level interactions utilizing an original cross-national European dataset collected in 2015 (N = 17,667) within a collaborative funded-project. We show that a negative economic context has a mobilizing effect by both increasing the stimulating effect of relative deprivation on protest activism as well as by closing or reversing the gap between resource-poor and resource-rich groups for volunteering with parties and voting

Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition

Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death.In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited.Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition

Daily precipitation statistics in a EURO-CORDEX RCM ensemble: added value of raw and bias-corrected high-resolution simulations

Daily precipitation statistics as simulated by the ERA-Interim-driven EURO-CORDEX regional climate model (RCM) ensemble are evaluated over two distinct regions of the European continent, namely the European Alps and Spain. The potential added value of the high-resolution 12 km experiments with respect to their 50 km resolution counterparts is investigated. The statistics considered consist of wet-day intensity and precipitation frequency as a measure of mean precipitation, and three precipitation-derived indicators (90th percentile on wet days?90pWET, contribution of the very wet days to total precipitation?R95pTOT and number of consecutive dry days?CDD). As reference for model evaluation high resolution gridded observational data over continental Spain (Spain011/044) and the Alpine region (EURO4M-APGD) are used. The assessment and comparison of the two resolutions is accomplished not only on their original horizontal grids (approximately 12 and 50 km), but the high-resolution RCMs are additionally regridded onto the coarse 50 km grid by grid cell aggregation for the direct comparison with the low resolution simulations. The direct application of RCMs e.g. in many impact modelling studies is hampered by model biases. Therefore bias correction (BC) techniques are needed at both resolutions to ensure a better agreement between models and observations. In this work, the added value of the high resolution (before and after the bias correction) is assessed and the suitability of these BC methods is also discussed. Three basic BC methods are applied to isolate the effect of biases in mean precipitation, wet-day intensity and wet-day frequency on the derived indicators. Daily precipitation percentiles are strongly affected by biases in the wet-day intensity, whereas the dry spells are better represented when the simulated precipitation frequency is adjusted to the observed one. This confirms that there is no single optimal way to correct for RCM biases, since correcting some distributional features typically leads to an improvement of some aspects but to a deterioration of others. Regarding mean seasonal biases before the BC, we find only limited evidence for an added value of the higher resolution in the precipitation intensity and frequency or in the derived indicators. Thereby, evaluation results considerably depend on the RCM, season and indicator considered. High resolution simulations better reproduce the indicators? spatial patterns, especially in terms of spatial correlation. However, this improvement is not statistically significant after applying specific BC methods.The authors are grateful to Prof. C. Schär for his helpful comments and E. van Meijgaard for making available the RACMO model data. We acknowledge the observational data providers. Calculations for WRF311F were made using the TGCC super computers under the GENCI time allocation GEN6877. The WRF331A from CRP-GL (now LIST) was funded by the Luxembourg National Research Fund (FNR) through grant FNR C09/SR/16 (CLIMPACT). The KNMI-RACMO2 simulations were supported by the Dutch Ministry of Infrastructure and the Environment. The CCLM and REMO simulations were supported by the Federal Ministry of Education and Research (BMBF) and performed under the Konsortial share at the German Climate Computing Centre (DKRZ). The CCLM simulations were furthermore supported by the Swiss National Supercomputing Centre (CSCS) under project ID s78. Part of the SMHI contribution was carried out in the Swedish Mistra-SWECIA programme founded by Mistra (the Foundation for Strategic Environmental Research). This work is supported by CORWES (CGL2010-22158-C02) and EXTREMBLES (CGL2010-21869) projects funded by the Spanish R&D programme and the European COST ACTION VALUE (ES1102). A. C. thanks the Spanish Ministry of Economy and Competitiveness for the funding provided within the FPI programme (BES-2011-047612 and EEBB-I-13-06354). We also thank two anonymous referees for their useful comments that helped to improve the original manuscript

Guideline for diagnosis and treatment of subacromial pain syndrome

Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears

Multidimensional Signals and Analytic Flexibility: Estimating Degrees of Freedom in Human-Speech Analyses

Recent empirical studies have highlighted the large degree of analytic flexibility in data analysis that can lead to substantially different conclusions based on the same data set. Thus, researchers have expressed their concerns that these researcher degrees of freedom might facilitate bias and can lead to claims that do not stand the test of time. Even greater flexibility is to be expected in fields in which the primary data lend themselves to a variety of possible operationalizations. The multidimensional, temporally extended nature of speech constitutes an ideal testing ground for assessing the variability in analytic approaches, which derives not only from aspects of statistical modeling but also from decisions regarding the quantification of the measured behavior. In this study, we gave the same speech-production data set to 46 teams of researchers and asked them to answer the same research question, resulting in substantial variability in reported effect sizes and their interpretation. Using Bayesian meta-analytic tools, we further found little to no evidence that the observed variability can be explained by analysts’ prior beliefs, expertise, or the perceived quality of their analyses. In light of this idiosyncratic variability, we recommend that researchers more transparently share details of their analysis, strengthen the link between theoretical construct and quantitative system, and calibrate their (un)certainty in their conclusions

The effects of mutant Ras proteins on the cell signalome

The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells. © 2020, The Author(s)

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease