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The zebrafish is a powerful model organism to study the mechanisms governing transition metal ions within whole brain tissue. Zinc is one of the most abundant metal ions in the brain, playing a critical pathophysiological role in neurodegenerative diseases. The homeostasis of free, ionic zinc (Zn2+) is a key intersection point in many of these diseases, including Alzheimer’s disease and Parkinson’s disease. A Zn2+ imbalance can eventuate several disturbances that may lead to the development of neurodegenerative changes. Therefore, compact, reliable approaches that allow the optical detection of Zn2+ across the whole brain would contribute to our current understanding of the mechanisms that underlie neurological disease pathology. We developed an engineered fluorescence protein-based nanoprobe that can spatially and temporally resolve Zn2+ in living zebrafish brain tissue. The self-assembled engineered fluorescence protein on gold nanoparticles was shown to be confined to defined locations within the brain tissue, enabling site specific studies, compared to fluorescent protein-based molecular tools, which diffuse throughout the brain tissue. Two-photon excitation microscopy confirmed the physical and photometrical stability of these nanoprobes in living zebrafish (Danio rerio) brain tissue, while the addition of Zn2+ quenched the nanoprobe fluorescence. Combining orthogonal sensing methods with our engineered nanoprobes will enable the study of imbalances in homeostatic Zn2+ regulation. The proposed bionanoprobe system offers a versatile platform to couple metal ion specific linkers and contribute to the understanding of neurological diseases.

Abstract Aim Due to their longevity and structure, forest ecosystems are particularly affected by climate change with consequences for their biodiversity, functioning, and services to mankind. In the European Union (EU), natural and seminatural forests are protected by the Habitats Directive and the Natura 2000 network. This study aimed to assess the exposure of three legally defined forest habitat types to climate change, namely (a) Tilio‐Acerion forests of slopes, screes, and ravines (9180*), (b) bog woodlands (91D0*), and (c) alluvial forests with Alnus glutinosa and Fraxinus excelsior (91E0*). We analyzed possible changes in their Bavarian distribution, including their potential future coverage by Natura 2000 sites. We hypothesized that protected areas (PAs) with larger elevational ranges will remain suitable for the forests as they allow for altitudinal distribution shifts. Methods To estimate changes in range size and coverage by PAs, we combined correlative species distribution models (SDMs) with spatial analyses. Ensembles of SDM‐algorithms were applied to two climate change scenarios (RCP4.5 and RCP8.5) of the HadGEM2‐ES model for the period 2061–2080. Results Our results revealed that bog woodlands experience the highest range losses (>2/3) and lowest PA coverage (max. 15% of sites with suitable conditions). Tilio‐Acerion forests exhibit opposing trends depending on the scenario, while alluvial forests are less exposed to climatic changes. As expected, the impacts of climate change are more pronounced under the “business as usual” scenario (RCP8.5). Additionally, PAs in flat landscapes are more likely to lose environmental suitability for currently established forest habitat types. Main conclusions Based on these findings, we advocate the expansion of the Natura 2000 network particularly in consideration of elevational gradients, connectivity, and projected climatic suitability. Nonclimatic stressors on forest ecosystems, especially bog woodlands, should be decreased and climate change mitigation efforts enhanced. We recommend transferring the approach to other habitat types and regions.

Liver injury and acute liver failure caused by acetaminophen (APAP) overdose is the clinically most important drug toxicity in Western countries. Mechanistic investigations have revealed a central role of mitochondria in the pathophysiology. Excess formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) after an overdose leads to hepatic glutathione depletion, mitochondrial protein adducts formation and an initial oxidant stress, which triggers the activation of mitogen activated protein (MAP) kinase cascade ultimately leading to c-jun N-terminal kinase (JNK) phosphorylation. Phospho-JNK translocates to the mitochondria and amplifies the oxidative and nitrosative stress eventually causing the mitochondrial membrane permeability transition pore opening and cessation of adenosine triphosphate (ATP) synthesis. In addition, mitochondrial matrix swelling ruptures the outer membrane and releases endonucleases, which cause nuclear deoxyribonucleic acid (DNA) fragmentation. Together, the nuclear DNA damage and the extensive mitochondrial dysfunction result in necrotic cell death. However, the pro-cell death signaling events are counteracted by adaptive responses such as autophagy and mitochondrial biogenesis. The improved mechanistic insight into the pathophysiology leads to better understanding of the mechanisms of action of the existing antidote N-acetylcysteine and justifies the clinical testing of novel therapeutics such as 4-methylpyrazole and calmangafodipir. Keywords: Acetaminophen (APAP) hepatotoxicity, Mitochondrial dysfunction, Biogenesis, Oxidant stress, Peroxynitrite, c-Jun N-terminal kinase (JNK)

Abstract Background Protected areas (PAs) are aimed to hold the environmental conditions that facilitate species and ecosystems to persist. PAs can become climatically unsuitable and unable to sustain their current number of species under climate change. The Natura 2000 (N2K) is the largest coordinated conservation tool assigned to maintain the long-term survival of Europe’s most significant species and habitats. In attempting to understand the effectiveness of PAs in the face of climate change scenarios, we tested two hypotheses: (1) PAs in the Alpine and the Boreal biogeographical regions will experience more newly emerged climate conditions (hotter and drier) compared to the climate representation of other biogeographical regions under future climate in Europe and (2) PAs in the Mediterranean and the Continental biogeographical regions will face more consistency in climate conditions due to less area of disappearing and novel climate in future. Methods Current climate data (1960–1990) and projections for 2050 and 2070 of PAs of N2K were extracted from WorldClim global climate data. Principal components analysis (PCA) was performed to construct climate space for the PAs across the biogeographical regions based on 19 climatic variables assessed at 5-km resolution. ArcMap 10.1 was used to map the location of the novel and disappearing climates. Results PAs in the Alpine region will experience more novel climate conditions in the future compared to other biogeographical regions. The future projections showed that 17.70% of the PAs in the Alpine region will experience novel climate by 2070. Considerable climate consistency was observed in the PAs in the Continental region compared to the other biogeographical regions. Our results showed that about 176 km2 of the selected PAs in the Continental region will face new emerging climate, while about 110 km2 will disappear under RCP 8.5 scenario. The prediction also revealed that in the Mediterranean region 08 PAs will experience novel climate and 786 km2 areas in these PAs will face disappearing climate by 2070. We found that fewer areas of PAs in the Boreal regions will experience disappearing climate in both the scenarios. Conclusions The portion of novel climate conditions can be seen as a future opportunity to assign new reserves for the species. Our study highlights the importance of conservation planning to increase the connectivity between PAs, identifying novel conservation zones to maximize representation of habitats during the emerging climatic changes as well as designing strategies, management, and monitoring of the individual PAs.

Background and aim: Overdose of acetaminophen (APAP) leads to liver injury, which is one of the most common causes of liver failure in the United States. We previously demonstrated that pharmacological activation of autophagy protects against APAP-induced liver injury in mice via removal of damaged mitochondria and APAP-adducts (APAP-ADs). Using an image-based high-throughput screening for autophagy modulators, we recently identified that chlorpromazine (CPZ), a dopamine inhibitor used for anti-schizophrenia, is a potent autophagy inducer in vitro. Therefore, the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing autophagy. Methods: Wild type C57BL/6J mice were injected with APAP to induce liver injury. CPZ was administrated either at the same time with APAP (co-treatment) or 2 h later after APAP administration (post-treatment). Hemotoxyline and eosin (H&E) staining of liver histology, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining of necrotic cell death as well as serum levels of alanine aminotransferase (ALT) were used to monitor liver injury. Results: We found that CPZ markedly protected against APAP-induced liver injury as demonstrated by decreased serum levels of ALT, liver necrotic areas as well as TUNEL-positive cells in mice that were either co-treated or post-treated with CPZ. Mechanistically, we observed that CPZ increased the number of autolysosomes and decreased APAP-induced c-Jun N-terminal kinase activation without affecting the metabolic activation of APAP. Pharmacological inhibition of autophagy by chloroquine partially weakened the protective effects of CPZ against APAP-induced liver injury. Conclusions: Our results indicate that CPZ ameliorates APAP-induced liver injury partially via activating hepatic autophagy and inhibiting JNK activation. Keywords: Chlorpromazine (CPZ), Acetaminophen (APAP), Drug-induced liver injury, Necrosis, Autolysosome, Hepatotoxicity, Glutathione (GSH), Oxidant stress

Abstract Background Despite the large number of studies and reviews available, the evidence regarding the biological determinants of physical activity (PA) is inconclusive. In this umbrella review, we summarized the current evidence on the biological determinants of PA across the life course, by pooling the results of the available systematic literature reviews (SLRs) and meta-analyses (MAs). Methods We conducted an online search on MEDLINE, ISI Web of Science, Scopus, and SPORTDiscus databases up to January 2018. SLRs and MAs of observational studies that investigated the association between biological determinants of PA and having PA as outcome were considered eligible. The extracted data were assessed based on the importance of the determinants, the strength of evidence, and the methodological quality. Results We identified 19 reviews of which most were of moderate methodological quality. Determinants that were studied most frequently among all ages and demonstrated evidence suggesting a positive association to PA were younger age, being male, higher health status, and higher physical fitness levels. Among adults, normal birth weight was found to be positively associated to PA with convincing strength of evidence, while findings among adolescents were inconsistent and with limited strength of evidence. Conclusions Different social or behavioral factors may contribute to the decrease of PA with age and among females versus males, and creating programmes targeted at diverse ages, female population, and adults with abnormal birth weight is recommended. Future studies should use prospective study designs, standardized definitions of PA, and objective measurement methods of PA assessment.

Three-dimensional (3D) cell culture models that provide a biologically relevant microenvironment are imperative to investigate cell–cell and cell–matrix interactions in vitro. Semi-synthetic star-shaped poly(ethylene glycol) (starPEG)–heparin hydrogels are widely used for 3D cell culture due to their highly tuneable biochemical and biomechanical properties. Changes in gene expression levels are commonly used as a measure of cellular responses. However, the isolation of high-quality RNA presents a challenge as contamination of the RNA with hydrogel residue, such as polymer or glycosaminoglycan fragments, can impact template quality and quantity, limiting effective gene expression analyses. Here, we compare two protocols for the extraction of high-quality RNA from starPEG–heparin hydrogels and assess three subsequent purification techniques. Removal of hydrogel residue by centrifugation was found to be essential for obtaining high-quality RNA in both isolation methods. However, purification of the RNA did not result in further improvements in RNA quality. Furthermore, we show the suitability of the extracted RNA for cDNA synthesis of three endogenous control genes confirmed via quantitative polymerase chain reaction (qPCR). The methods and techniques shown can be tailored for other hydrogel models based on natural or semi-synthetic materials to provide robust templates for all gene expression analyses.

BackgroundVisceral leishmaniasis (VL) is re-emerging in Armenia since 1999 with 167 cases recorded until 2019. The objectives of this study were (i) to determine for the first time the genetic diversity and population structure of the causative agent of VL in Armenia; (ii) to compare these genotypes with those from most endemic regions worldwide; (iii) to monitor the diversity of vectors in Armenia; (iv) to predict the distribution of the vectors and VL in time and space by ecological niche modeling.Methodology/principal findingsHuman samples from different parts of Armenia previously identified by ITS-1-RFLP as L. infantum were studied by Multilocus Microsatellite Typing (MLMT). These data were combined with previously typed L. infantum strains from the main global endemic regions for population structure analysis. Within the 23 Armenian L. infantum strains 22 different genotypes were identified. The combined analysis revealed that all strains belong to the worldwide predominating MON1-population, however most closely related to a subpopulation from Southeastern Europe, Maghreb, Middle East and Central Asia. The three observed Armenian clusters grouped within this subpopulation with strains from Greece/Turkey, and from Central Asia, respectively. Ecological niche modeling based on VL cases and collected proven vectors (P. balcanicus, P. kandelakii) identified Yerevan and districts Lori, Tavush, Syunik, Armavir, Ararat bordering Georgia, Turkey, Iran and Azerbaijan as most suitable for the vectors and with the highest risk for VL transmission. Due to climate change the suitable habitat for VL transmission will expand in future all over Armenia.ConclusionsGenetic diversity and population structure of the causative agent of VL in Armenia were addressed for the first time. Further genotyping studies should be performed with samples from infected humans, animals and sand flies from all active foci including the neighboring countries to understand transmission cycles, re-emergence, spread, and epidemiology of VL in Armenia and the entire Transcaucasus enabling epidemiological monitoring.

Secondary education around the world has been significantly disrupted by covid-19. Students have been forced into new ways of independent learning, often using remote technologies, but without the social nuances and direct teacher interactions of a normal classroom environment. Using data from the School Attitudes Survey—which surveys students regarding the perceived level of difficulty, anxiety level, self-efficacy, enjoyability, subject relevance, and opportunities for creativity with regards to each of their school subjects—this study examines students' responses to this disruption from two very different schools with two very different experiences of the pandemic. This paper reports on the composite attitudinal profiles of students in the senior secondary levels at each school (Years 10–12, n = 834). The findings challenged our expectation that the increased difficulty and anxiety caused by the disruption would reduce perceived opportunities for creativity. Indeed, our analyses showed that the students at both schools demonstrated generally positive attitudes toward their learning and strongly associated opportunities for creativity with other attitudinal constructs including enjoyability, subject relevance, and self-efficacy. These complex associations made by the students appear to have buffered the impacts of the disruption, and they may even have supported creative resilience.

Abstract Background The study estimated service coverage for severe mental disorders (psychosis, bipolar disorder and moderate-severe depression), globally and regionally, using data collected from the Mental Health Atlas 2017. Methods Service coverage was defined as the proportion of people with a disorder contacting a mental health service among those estimated to have the disorder during a 12-month period. We drew upon 12-month service utilisation data from the Mental Health Atlas 2017. Expected prevalent cases of individual disorders were estimated using the disorder-specific prevalence rate estimates of the Global Burden of Disease Study 2016 and total population sizes. Methods for assessing the validity of country-reported service utilisation data were developed and applied. Outcomes From 177 countries, 50 countries provided reliable service coverage estimates for psychosis, along with 56 countries for bipolar disorder, and 65 countries for depression. The mean service coverage for psychosis was lowest in low- [10.9% (95% confidence interval (CI) 3.3–30.4)] and lower middle-income countries [21.5% (95% CI 11.9–35.7)] and highest in high-income countries [59.5% (95% CI 42.9–74.1)]. Service coverage for bipolar disorder ranged between 3.1% (95% CI 0.8–11.5) and 10.4% (95% CI 6.7–15.8). Mean service coverage for moderate-severe depression ranged between 2.9% (95% CI 1.3–6.3) for low-income countries and 31.1% (95% CI 18.3–47.6) for high-income countries. Interpretation The reporting method utilised by the Mental Health Atlas appears to be reliable for psychosis but not for depression. This method of estimating service coverage provides progress in tracking an important indicator for mental health; however, it highlights that considerable work is needed to further develop global mental health information systems.

The impairment of LDL receptor-related protein-1 (LRP1) in numerous cell types is associated with obesity, diabetes, and fatty liver disease. Here, we compared the metabolic phenotype of C57BL/6J wild-type and LRP1 knock-in mice carrying an inactivating mutation in the distal NPxY motif after feeding a low-fat diet or high-fat (HF) diet with cholesterol supplementation (HFHC) or HF diet without cholesterol supplementation. In response to HF feeding, both groups developed hyperglycemia, hyperinsulinemia, hyperlipidemia, increased adiposity, and adipose tissue inflammation and liver steatosis. However, LRP1 NPxY mutation prevents HFHC diet-induced hypercholesterolemia, reduces adipose tissue and brain inflammation, and limits liver progression to steatohepatitis. Nevertheless, this mutation does not protect against HFHC diet-induced insulin resistance. The selective metabolic improvement observed in HFHC diet-fed LRP1 NPxY mutant mice is due to an apparent increase of hepatic LDL receptor levels, leading to an elevated rate of plasma lipoprotein clearance and lower hepatic cholesterol levels. The unique metabolic phenotypes displayed by LRP1 NPxY mutant mice indicate an LRP1-cholesterol axis in modulating tissue inflammation. The LRP1 NPxY mutant mouse phenotype differs from phenotypes observed in mice with tissue-specific LRP1 inactivation, thus highlighting the importance of an integrative approach to evaluate how global LRP1 dysfunction contributes to metabolic disease development.

Northern Africa’s past climate is characterized by a prolonged humid period known as the African Humid Period (AHP), giving origin to the “Green Sahara” and supporting human settlements into areas that are now desert. The spatial and temporal extent of climate change associated with the AHP is, however, subject to ongoing debate. Uncertainties arise from the complex nature of African climate, which is controlled by the strength and interactions of different monsoonal systems, resulting in meridional shifts in rainfall belts and zonal movements of the Congo Air Boundary. Here, we examine a ∼12,500-years record of hydroclimate variability from Lake Dendi located in the Ethiopian highlands based on a combination of plant-wax-specific hydrogen (δD) and carbon (δ13C) isotopes. In addition, pollen data from the same sediment core are used to investigate the response of the regional vegetation to changing climate. Our δD record indicates high precipitation during peak AHP (ca. 10 to 8 ka BP) followed by a gradual transition toward a drier late Holocene climate. Likewise, vegetation cover changed from predominant grassland toward an arid montane forest dominated by Juniperus and Podocarpus accompanied by a general reduction of understory grasses. This trend is corroborated by δ13C values pointing to an increased contribution of C3 plants during the mid-to late Holocene. Peak aridity occurred around 2 ka BP, followed by a return to a generally wetter climate possibly linked to enhanced Indian Ocean Monsoon strength. During the last millennium, increased anthropogenic activity, i.e., deforestation and agriculture is indicated by the pollen data, in agreement with intensified human impact recorded for the region. The magnitude of δD change (40‰) between peak wet conditions and late Holocene aridity is in line with other regional δD records of East Africa influenced by the CAB. The timing and pace of aridification parallels those of African and Indian monsoon records indicating a gradual response to local insolation change. Our new record combining plant-wax δD and δ13C values with pollen highlights the sensitive responses of the regional vegetation to precipitation changes in the Ethiopian highlands.

Summary: Optical slice microscopy is commonly used to characterize the morphometric features of 3D cellular cultures, such as in vitro vascularization. However, the quantitative analysis of those structures is often performed on a single 2D maximum intensity projection image, limiting the accuracy of data obtained from 3D cultures. Here, we present a protocol for the quantitative analysis of z stack images, utilizing Fiji, Amira, and WinFiber3D. This protocol facilitates the in-depth examination of vascular-like structures within 3D cell culture models.For complete details on the use and execution of this protocol, please refer to Koch et al. (2020).

Epidemiological models (EMs) are widely used to predict the temporal outbreak risk of vector-borne diseases (VBDs). EMs typically use the basic reproduction number (R0), a threshold quantity, to indicate risk. To provide an overall view of the risk, these model outputs can be transformed into spatial risk maps, using various aggregation methods (e.g. average R0 over time, cumulative number of days with R0 > 1). However, there is no standardized methodology available for this. Depending on the specific aggregation methods used, the yielded spatial risk maps may have considerably different interpretations. Additionally, the method used to visualize the aggregated data also affects the perceived spatial patterns. In this review, we compare commonly used aggregation and visualization methods and discuss the respective interpretation of risk maps.Research publications using epidemiological modelling methods were drawn from Web of Science. Only publications containing maps of R0 transformed from EMs were considered for the analysis. An example EM was applied to illustrate how aggregation and visualization methods affect the final presentations of risk maps.Risk maps can be generated to show duration, intensity and spatio-temporal dynamics of potential outbreak risk of VBDs. We show that 1) different temporal aggregation methods lead to different interpretations; 2) similar spatial patterns do not necessarily bear the same meaning; 3) visualization methods considerably affect how results are perceived, and thus should be applied with caution. We recommend mapping both intensity and duration of the VBD outbreak risk, using small time-steps to show spatio-temporal dynamics when possible.

Reciprocal interactions between prostate epithelial cells and their adjacent stromal microenvironment not only are essential for tissue homeostasis but also play a key role in tumor development and progression. Malignant transformation is associated with the formation of a reactive stroma where cancer-associated fibroblasts (CAFs) induce matrix remodeling and thereby provide atypical biochemical and biomechanical signals to epithelial cells. Previous work has been focused on the cellular and molecular phenotype as well as on matrix stiffness and remodeling, providing potential targets for cancer therapeutics. So far, biomechanical changes in CAFs and adjacent epithelial cells of the prostate have not been explored. Here, we compared the mechanical properties of primary prostatic CAFs and patient-matched non-malignant prostate tissue fibroblasts (NPFs) using atomic force microscopy (AFM) and real-time deformability cytometry (RT-FDC). It was found that CAFs exhibit an increased apparent Young's modulus, coinciding with an altered architecture of the cytoskeleton compared with NPFs. In contrast, co-cultures of benign prostate epithelial (BPH-1) cells with CAFs resulted in a decreased stiffness of the epithelial cells, as well as an elongated morphological phenotype, when compared with co-cultures with NPFs. Moreover, the presence of CAFs increased proliferation and invasion of epithelial cells, features typically associated with tumor progression. Altogether, this study provides novel insights into the mechanical interactions between epithelial cells with the malignant prostate microenvironment, which could potentially be explored for new diagnostic approaches.

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.

Abstract Background Usutu virus (USUV) is a mosquito-borne flavivirus, reported in many countries of Africa and Europe, with an increasing spatial distribution and host range. Recent outbreaks leading to regional declines of European common blackbird (Turdus merula) populations and a rising number of human cases emphasize the need for increased awareness and spatial risk assessment. Methods Modelling approaches in ecology and epidemiology differ substantially in their algorithms, potentially resulting in diverging model outputs. Therefore, we implemented a parallel approach incorporating two commonly applied modelling techniques: (1) Maxent, a correlation-based environmental niche model and (2) a mechanistic epidemiological susceptible-exposed-infected-removed (SEIR) model. Across Europe, surveillance data of USUV-positive birds from 2003 to 2016 was acquired to train the environmental niche model and to serve as test cases for the SEIR model. The SEIR model is mainly driven by daily mean temperature and calculates the basic reproduction number R0. The environmental niche model was run with long-term bio-climatic variables derived from the same source in order to estimate climatic suitability. Results Large areas across Europe are currently suitable for USUV transmission. Both models show patterns of high risk for USUV in parts of France, in the Pannonian Basin as well as northern Italy. The environmental niche model depicts the current situation better, but with USUV still being in an invasive stage there is a chance for under-estimation of risk. Areas where transmission occurred are mostly predicted correctly by the SEIR model, but it mostly fails to resolve the temporal dynamics of USUV events. High R0 values predicted by the SEIR model in areas without evidence for real-life transmission suggest that it may tend towards over-estimation of risk. Conclusions The results from our parallel-model approach highlight that relying on a single model for assessing vector-borne disease risk may lead to incomplete conclusions. Utilizing different modelling approaches is thus crucial for risk-assessment of under-studied emerging pathogens like USUV.

Abstract Background 24 h-accelerometry is now used to objectively assess physical activity (PA) in many observational studies like the German National Cohort; however, PA variability, observational time needed to estimate habitual PA, and reliability are unclear. Methods We assessed 24 h-PA of 50 participants using triaxial accelerometers (ActiGraph GT3X+) over 2 weeks. Variability of overall PA and different PA intensities (time in inactivity and in low intensity, moderate, vigorous, and very vigorous PA) between days of assessment or days of the week was quantified using linear mixed-effects and random effects models. We calculated the required number of days to estimate PA, and calculated PA reliability using intraclass correlation coefficients. Results Between- and within-person variance accounted for 34.4–45.5% and 54.5–65.6%, respectively, of total variance in overall PA and PA intensities over the 2 weeks. Overall PA and times in low intensity, moderate, and vigorous PA decreased slightly over the first 3 days of assessment. Overall PA (p = 0.03), time in inactivity (p = 0.003), in low intensity PA (p = 0.001), in moderate PA (p = 0.02), and in vigorous PA (p = 0.04) slightly differed between days of the week, being highest on Wednesday and Friday and lowest on Sunday and Monday, with apparent differences between Saturday and Sunday. In nested random models, the day of the week accounted for

This paper aims to understand the experience of ex-coordinators of graduation course in different institutions of higher education in Brazil. To find out the perspectives of the respondents on such questioning, a phenomenological study was developed. For this work, seven course managers were investigated. These managers are teachers trained in several areas of knowledge and who have become coordinators of some graduation course. The interviews were recorded and transcribed. The analysis of the data aimed to describe and interpret based on the reports acquired as it occurred the learning of those investigated throughout their trajectory in their institutions. That is, what contents and forms of managerial learning were acquired by them during their managerial trajectories, what challenges and overruns were present in the daily work of managerial work. As results it can be verified that the managerial learning is dynamic and that involves different factors, be they formal or informal and that the managers learn daily in the exercise of its managements. This research hopes to contribute and strengthen the study scenario on management learning in Higher Education Institutions in Brazil and to build a knowledge framework so that teachers have access to become managers of an undergraduate course.

Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI. Genetic and pharmacological activation of TFEB increases lysosomal biogenesis that promotes clearance of acetaminophen adducts resulting in protection against AILI. qHTS is a very useful platform to identify novel mTOR-dependent and independent TFEB agonists that may have translational therapeutic value for targeting drug-induced liver injury. [Display omitted] [ABSTRACT FROM AUTHOR]