Time delays in quasi-periodic pulsations observed during the X2.2 solar flare on 2011 February 15

We report observations of quasi-periodic pulsations (QPPs) during the X2.2 flare of 2011 February 15, observed simultaneously in several wavebands. We focus on fluctuations on time scale 1-30 s and find different time lags between different wavebands. During the impulsive phase, the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) channels in the range 25-100 keV lead all the other channels. They are followed by the Nobeyama RadioPolarimeters at 9 and 17 GHz and the Extreme Ultra-Violet (EUV) channels of the Euv SpectroPhotometer (ESP) onboard the Solar Dynamic Observatory (SDO). The Zirconium and Aluminum filter channels of the Large Yield Radiometer (LYRA) onboard the Project for On-Board Autonomy (PROBA2) satellite and the SXR channel of ESP follow. The largest lags occur in observations from the Geostationary Operational Environmental Satellite (GOES), where the channel at 1-8 {\AA} leads the 0.5-4 {\AA} channel by several seconds. The time lags between the first and last channels is up to 9 s. We identified at least two distinct time intervals during the flare impulsive phase, during which the QPPs were associated with two different sources in the Nobeyama RadioHeliograph at 17 GHz. The radio as well as the hard X-ray channels showed different lags during these two intervals. To our knowledge, this is the first time that time lags are reported between EUV and SXR fluctuations on these time scales. We discuss possible emission mechanisms and interpretations, including flare electron trapping

Changes in compliance with school-based physical activity recommendations in Spanish youth: The UP&DOWN longitudinal study

The study aimed (a) to examine changes in physical activity (PA) during the whole day, school hours, recess, and physical education classes (PEC) during a 2-year period in primary and secondary students; (b) to identify changes in the proportion of compliance with specific PA recommendations for these periods; and (c) to examine whether PA levels at baseline are associated with PA levels 2 years later. Eight hundred and fourteen (51.8% boys) children and 658 (50.1% boys) adolescents from 41 Spanish schools participated in the study. Hip-worn accelerometers were used to assess PA during different time periods. Light PA (LPA) declined during the whole day, school hours, recess (all P < 0.001, except child girls for recess), and PEC (all, P < 0.05) in children and adolescents. Moderate-to-vigorous PA (MVPA) during the whole day and recess declined in child boys (P < 0.01 and P < 0.001, respectively) and adolescent boys (P < 0.001 and P < 0.05, respectively). MVPA during PEC declined in adolescent boys (P < 0.001) and adolescent girls (all P < 0.05). The proportion of compliance with the specific PA recommendations for these periods declined (P < 0.05), except for PEC in adolescent girls. PA during the whole day at baseline was moderately associated with PA during the whole day years later (ICCs = 0.210-0.544, with one exception), but this association was lower for the school-based PA. In conclusion, time spent in MVPA and LPA during the whole day and recess declined over time in child and adolescent boys and during PEC in adolescents. These findings highlight the need to promote PA interventions in these settings

Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors

Colorectal cancer; Lung cancer; Monoclonal antibodyCáncer colorrectal; Cáncer de pulmón; Anticuerpo monoclonalCàncer colorectal; Càncer de pulmó; Anticòs monoclonalBackground The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors. Patients and methods Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab. Results A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival. Conclusions Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.This work was supported by Glycotope GmbH (no grant number)

A Surface Reconstruction with a Fractional Hole: (5×5)R26.6∘(\sqrt{5}\times\sqrt{5}) R26.6^\circ LaAlO3_3 (001)

The structure of the $(\sqrt{5}\times\sqrt{5})R26.6^\circ$ reconstruction of LaAlO$_3$ (001) has been determined using transmission electron diffraction combined with direct methods. The structure is relatively simple, consisting of a lanthanum oxide termination with one lanthanum cation vacancy per surface unit cell. The electronic structure is unusual since a fractional number of holes or atomic occupancies per surface unit cell are required to achieve charge neutrality. Density functional calculations indicate that the charge compensation mechanism occurs by means of highly delocalized holes. The surface contains no oxygen vacancies and with a better than 99% confidence level, the holes are not filled with hydrogen. The reconstruction can be understood in terms of expulsion of the more electropositive cation from the surface followed by an increased covalency between the remaining surface lanthanum atoms and adjacent oxygen atoms.Comment: 4 Pages, 3 Figure

Depression at Work, Authenticity in Question: Experiencing, Concealing and Revealing

Australia and the UK have both introduced policies to protect employees who experience mental illness, including depression. However, a better understanding of the issues workers face (e.g. sense of moral failure) is needed for the provision of appropriate and beneficial support. We analysed 73 interviews from the UK and Australia where narratives of depression and work intersected. Participants encountered difficulties in being (and performing as if) ‘authentic’ at work, with depression contributing to confusions about the self. The diffuse post-1960s imperative to ‘be yourself’ is experienced in conflicting ways: While some participants sought support from managers and colleagues (e.g. sick leave, back to work plans), many others put on a façade in an attempt to perform the ‘well’ and ‘authentic’ employee. We outline the contradictory forces at play for participants when authenticity and visibility are expected, yet moral imperatives to be good (healthy) employees are normative

Extracellular Vesicles Enriched in Connexin 43 Promote a Senescent Phenotype in Bone and Synovial Cells Contributing to Osteoarthritis Progression

[Abstract] The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.This work was supported in part through funding from Health Institute ‘Carlos III’ (ISCIII, Spain), the European Regional Development Fund, ‘A way of making Europe’ from the European Union (to MDM): grant PI19/00145; a grant from the Joint Transnational Call for Proposals for “European Innovative Research & Technological Development Projects in Nanomedicine” EURONANOMED III (AC21_2/00026) (to MDM); a grant from Xunta de Galicia (IN607B2020/12) (to MDM) and from H2020, Future and Emerging Technologies (grant 858014 “PANACHE”) to MDM. MV-E was funded with a predoctoral (ED481A-2015/188) and post-doctoral fellowship (IN606B-2019/004) from Xunta de Galicia. AG-C was funded with a predoctoral fellowship (FIS20/00310) from ISCIII. PC-F was funded with a post-doctoral fellowship and a grant from Xunta de Galicia (INB606B 2017/014 and IN606C 2021/006). We thank members of the CellCOM group for helpful technical suggestion, María Dolores Álvarez Alvariño (CHUS) for generously collecting tissue samples in the operating room after surgery and Arantxa Tabernero (INCYL, University of Salamanca) for kindly providing the human Cx43 plasmid used in this studyXunta de Galicia; IN607B2020/12Xunta de Galicia; ED481A-2015/188Xunta de Galicia; IN606B-2019/004Xunta de Galicia; INB606B 2017/014Xunta de Galicia; IN606C 2021/00