Hedgehog Signaling Pathway Database: a repository of current annotation efforts and resources for the Hh research community

The Hedgehog Signaling Pathway Database is a curated repository of information pertaining to the Hedgehog developmental pathway. It was designed to provide centralized access to a wide range of relevant information in an organism-agnostic manner. Data are provided for all genes and gene targets known to be involved in the Hh pathway across various organisms. The data provided include DNA and protein sequences as well as domain structure motifs. All known human diseases associated with the Hh pathway are indexed including experimental data on therapeutic agents and their molecular targets. Hh researchers will find useful information on relevant protocols, tissue cell lines and reagents used in current Hh research projects. Curated content is also provided for publications, grants and patents relating to the Hh pathway. The database can be accessed at

Effects of Backpacks on Ground Reaction Forces in Children of Different Ages When Walking, Running, and Jumping

Backpacks for transporting school loads are heavily utilized by children, and their mechanical advantages have been allowing children to transport heavy loads. These heavy loads may increase ground reaction forces (GRFs), which can have a negative effect on joints and bone health. The aim of this study was to investigate the effect of backpacks on the GRFs generated by children during walking, running, and jumping. Twenty-one children from the fifth (G-5, n = 9) and ninth (G-9, n = 12) grades walked, ran, and jumped over a force plate. When walking, the G-5 had GRF increments in the first (17.3%; p 0.05), unlike the G-5 (p = 0.001). When running, total stance time increased 15% (p < 0.001) and 8.5% (p < 0.001) proportionally to the relative load carried, in the G-5 and G-9, respectively. Peak GRF did not increase in any group when running or landing from a jump over an obstacle. It was found that GRF was affected by the backpack load when walking and running. However, when landing from a jump with the backpack, schoolchildren smoothed the landing by prolonging the reception time and thus avoiding GRF peak magnitudes.info:eu-repo/semantics/publishedVersio

Protective Effects of Memantine on Hydroquinone-Treated Human Retinal Pigment Epithelium Cells and Human Retinal Muller Cells

Purpose: Memantine (MEM) acts on the glutamatergic system by blocking N-methyl-d-aspartate (NMDA) glutamate receptors. The role that MEM plays in protecting retinal cells is unknown. Hydroquinone (HQ) is one of the cytotoxic components in cigarette smoke. In the present study, we tested whether pretreatment with MEM could protect against the cytotoxic effects of HQ on human retinal pigment epithelium cells (ARPE-19) and human retinal Müller cells (MIO-M1) in vitro. Methods: Cells were plated, pretreated for 6 h with 30 μM of MEM, and then exposed for 24 h to 200, 100, 50, and 25 μM of HQ while MEM was still present. Cell viability (CV), reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and lactate dehydrogenase (LDH) release assays were performed. Results: HQ-treated cells showed a dose-dependent decrease in CV and ΔΨm, but an increase in ROS production and LDH levels in both cell lines. MEM pretreatment reversed the CV in 50, 100, and 200 μM doses in ARPE-19 cells and at all HQ concentrations in MIO-M1 cells compared to HQ-treated cultures. ROS production was reversed in all HQ concentrations in both cell lines. ΔΨm was significantly increased after MEM pretreatment only in 50 μM HQ concentration for both cell lines. LDH levels were decreased at 50 and 25 μM HQ in ARPE-19 and MIO-M1 cells, respectively. Conclusion: HQ-induced toxicity is concentration dependent in ARPE-19 and MIO-M1 cultures. MEM exerts protective effects against HQ-induced toxicity on human retinal pigment epithelial and Müller cells in vitro

A framework to evaluate the viability of robotic process automation for business process activities

Robotic process automation (RPA) is a technology for centralized automation of business processes. RPA automates user interaction with graphical user interfaces, whereby it promises efficiency gains and a reduction of human negligence during process execution. To harness these benefits, organizations face the challenge of classifying process activities as viable automation candidates for RPA. Therefore, this work aims to support practitioners in evaluating RPA automation candidates. We design a framework that consists of thirteen criteria grouped into five perspectives which offer different evaluation aspects. These criteria leverage a profound understanding of the process step. We demonstrate and evaluate the framework by applying it to a real-life data set.Comment: This is an accepted manuscript for the "RPA Forum" at the "Int. Conference on Business Process Management (BPM 2020)". The final authenticated version is available online at https://doi.org/10.1007/978-3-030-58779-6_1

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Fail-safe optimization of viscous dampers for seismic retrofitting

This paper presents a new optimization approach for designing minimum-cost fail-safe distributions of fluid viscous dampers for seismic retrofitting. Failure is modeled as either complete damage of the dampers or partial degradation of the dampers' properties. In general, this leads to optimization problems with large number of constraints. Thus, the use of a working-set optimization algorithm is proposed. The main idea is to solve a sequence of relaxed optimization sub-problems with a small sub-set of all constraints. The algorithm terminates once a solution of a sub-problem is found that satisfies all the constraints of the problem. The retrofitting cost is minimized with constraints on the inter-story drifts at the peripheries of frame structures. The structures considered are subjected to a realistic ensemble of ground motions, and their response is evaluated with time-history analyses. The transient optimization problem is efficiently solved with a gradient-based sequential linear programming algorithm. The gradients of the response functions are calculated with a consistent adjoint sensitivity analysis procedure. Promising results attained for 3-D irregular frames are presented and discussed. The numerical results highlight the fact that the optimized layout and size of the dampers can change significantly even for moderate levels of damage

CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes

CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ~2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3′UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene

A population-based controlled experiment assessing the epidemiological impact of digital contact tracing

While Digital contact tracing (DCT) has been argued to be a valuable complement to manual tracing in the containment of COVID-19, no empirical evidence of its effectiveness is available to date. Here, we report the results of a 4-week population-based controlled experiment that took place in La Gomera (Canary Islands, Spain) between June and July 2020, where we assessed the epidemiological impact of the Spanish DCT app Radar Covid. After a substantial communication campaign, we estimate that at least 33% of the population adopted the technology and further showed relatively high adherence and compliance as well as a quick turnaround time. The app detects about 6.3 close-contacts per primary simulated infection, a significant percentage being contacts with strangers, although the spontaneous follow-up rate of these notified cases is low. Overall, these results provide experimental evidence of the potential usefulness of DCT during an epidemic outbreak in a real population