Short-term trajectories of workplace bullying and its impact on strain: A latent class growth modeling approach

The aim of this weekly diary study was (a) to identify trajectories of workplace bullying over time and (b) to examine the association of each cluster with strain indicators (i.e., insomnia and anxiety/depression). A sample of 286 employees during 4 weeks of data was used (N occasions = 1,144). Results of latent class growth modeling showed that 3 trajectories could be identified: a nonbullying trajectory, which comprised 90.9% of the sample; an inverted U trajectory; and a delayed increase bullying trajectory; the latter two each had 4.2% of the participants. We found a significant interaction between time and trajectories when predicting insomnia and anxiety/depression, with each strain showing a differential pattern with each trajectory. It seems that the negative effects on insomnia are long-lasting and remain after bullying has already decreased. In the case of anxiety and depression, when bullying decreases strain indicators also decrease. In this study, by examining trajectories of bullying at work over time and their associations with strain, we provide new insights into the temporal dynamics of workplace bullying

Photospheric structure of an extended penumbra

The photospheric structure of an extended penumbra belonging to a complex spot observed near disk center is investigated by means of the inversion of the full Stokes vector of two Fe I lines at 1.56 μm. An attempt is made to classify the observed Stokes V profiles in terms of their shapes. It turns out that about 28% of the profiles have abnormal shapes indicative of two different magnetic-field components within the resolution element. The spatial distribution of abnormal Stokes V profiles is studied. It is found that such profiles are evenly distributed in the penumbra, without any particular tendency to concentrate near the so-called neutral line. Anomalous profiles are not only seen in the outer penumbra and beyond, but also in the middle part of it. A Milne-Eddington–like inversion is carried out first, revealing a smooth picture of the spatial distribution of magneticfield vector and velocities along the line of sight. In particular, dark spines with stronger and more vertical magnetic fields are seen to coexist with nearly horizontal magnetic fields throughout the penumbra. A full inversion allowing for gradients of the atmospheric parameters along the line of sight indicates the existence of cool magnetic tubes returning back to the solar surface (inclination angles greater than 90◦) and carrying the largest material flows

Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

Proliferation of smooth muscle cells (SMCs) during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT), indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT

The Metabolic Core and Catalytic Switches Are Fundamental Elements in the Self-Regulation of the Systemic Metabolic Structure of Cells

[Background] Experimental observations and numerical studies with dissipative metabolic networks have shown that cellular enzymatic activity self-organizes spontaneously leading to the emergence of a metabolic core formed by a set of enzymatic reactions which are always active under all environmental conditions, while the rest of catalytic processes are only intermittently active. The reactions of the metabolic core are essential for biomass formation and to assure optimal metabolic performance. The on-off catalytic reactions and the metabolic core are essential elements of a Systemic Metabolic Structure which seems to be a key feature common to all cellular organisms. [Methodology/Principal Findings] In order to investigate the functional importance of the metabolic core we have studied different catalytic patterns of a dissipative metabolic network under different external conditions. The emerging biochemical data have been analysed using information-based dynamic tools, such as Pearson's correlation and Transfer Entropy (which measures effective functionality). Our results show that a functional structure of effective connectivity emerges which is dynamical and characterized by significant variations of bio-molecular information flows. [Conclusions/Significance] We have quantified essential aspects of the metabolic core functionality. The always active enzymatic reactions form a hub –with a high degree of effective connectivity- exhibiting a wide range of functional information values being able to act either as a source or as a sink of bio-molecular causal interactions. Likewise, we have found that the metabolic core is an essential part of an emergent functional structure characterized by catalytic modules and metabolic switches which allow critical transitions in enzymatic activity. Both, the metabolic core and the catalytic switches in which also intermittently-active enzymes are involved seem to be fundamental elements in the self-regulation of the Systemic Metabolic Structure.Consejo Superior de Investigaciones Cientificas (CSIC),grant 201020I026. Ministerio de Ciencia e Innovacion (MICINN). Programa Ramon y Cajal. Campus de Excelencia Internacional CEI BioTIC GENIL, grant PYR-2010-14. Junta de Andalucia, grant P09-FQM-4682

Use of aequorin-based indicators for monitoring Ca2+ in acidic organelles

Over the last years, there is accumulating evidence that acidic organelles can accumulate and release Ca2+ upon cell activation. Hence, reliable recording of Ca2+ dynamics in these compartments is essential for understanding the physiopathological aspects of acidic organelles. Genetically encoded Ca2+ indicators (GECIs) are valuable tools to monitor Ca2+ in specific locations, although their use in acidic compartments is challenging due to the pH sensitivity of most available fluorescent GECIs. By contrast, bioluminescent GECIs have a combination of features (marginal pH sensitivity, low background, no phototoxicity, no photobleaching, high dynamic range and tunable affinity) that render them advantageous to achieve an enhanced signal-to-noise ratio in acidic compartments. This article reviews the use of bioluminescent aequorin-based GECIs targeted to acidic compartments. A need for more measurements in highly acidic compartments is identified

How stable are visions for protected area management? Stakeholder perspectives before and during a pandemic

Envisioning processes enable protected area managers to chart a course for future management to reach desired goals, but unexpected changes that could affect future visions are not usually considered. The global COVID-19 pandemic provided an opportunity to explore changes in stakeholder visions, the values that underpin the visions, and their perceptions of landscape changes and the underlying drivers (e.g. climate change, mass tourism and demographic trends). Through a mixed-methods approach in this post-evaluation study, we gathered comparative data on these issues from stakeholders in the Sierra de Guadarrama National Park, Spain, between July 2019 (pre-pandemic) and October 2020 (mid-pandemic). Our qualitative analysis demonstrates that pre-pandemic, differences in visions for protected area management were largely spurred by different perceptions of drivers of change, rather than differences in values or perceived landscape changes, which were similar across different vision themes. One year later, in the midst of the COVID-19 pandemic, the majority of stakeholders reported that their values, visions and perceptions of drivers did not change despite this large-scale disturbance. Of the 20%-30% of stakeholders that did report changes, visions generally shifted towards greater prioritization of biodiversity and nature conservation as a result of heightened perceptions of the impacts of drivers of change associated with an increase in the numbers of park visitors. These drivers included mass tourism, mountain recreation, lack of environmental awareness, and change in values and traditions. Our findings reinforce the importance of adaptive and inclusive management of protected areas, including enhancing transparency and communications regarding factors driving change in the landscape, and integration of local and traditional knowledge and stakeholder perceptions of changes and drivers. Furthermore, management plans integrating stakeholder values have the potential to stay relevant even in the face of wildcard events such as a pandemic. To enhance the relevancy of visions and scenarios in conservation and land-use planning, scenario planning methodologies should more strongly consider different potential disturbances and how drivers of change in the near and far future can be affected by wildcard events such as a pandemic. A free Plain Language Summary can be found within the Supporting Information of this article.Peer reviewe

Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNgamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNgamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found. Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFNgamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNgamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFNgamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer