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This study aimed to assess the relationship between surgeons' leadership style and team behavior in the hybrid operating room through video coding. Secondly, possible fluctuations in leadership styles and team behavior during operative phases were studied.Leadership is recognized as a key component to successful team functioning in high-risk industries. The 'full range of leadership' theory is commonly used to evaluate leadership, marking transformational, transactional and passive. Few studies have examined the effects of these leadership styles on team behavior in surgery and/or their fluctuations during surgery.A single-center study included patients planned for routine endovascular procedures. A medical data capture system was used to allow post-hoc video coding through Behavior Anchored Rating Scales. Multilevel statistical analysis was performed to assess possible correlations between leadership style and three team behavior indicators (speaking up, knowledge sharing, collaboration) on an operative phase level.Twenty-two cases were analyzed (47 hours recording). Transformational leadership is positively related to the extent to which team members work together (γ=0.20, P0.001), share knowledge (γ=0.45, P0.001) and speak up (γ=0.64, P0.001). Passive leadership is significantly positively correlated with speaking up (γ=0.29, P=0.004). Leadership style and team behavior clearly fluctuate during a procedure, with similar patterns across different types of endovascular procedures.Consistent with other professional fields, surgeons' transformational leadership enhances team behavior, especially during the most complex operative phases. This suggests that encouraging surgeons to learn and actively implement a transformational leadership style is meaningful to enhance patient safety and team performance.

We explore the parameter space for the contribution to Callisto's H corona observed by the Hubble Space Telescope (Roth et al. 2017a) from sublimated H2O and radiolytically produced H2 using the Direct Simulation Monte Carlo (DSMC) method. The spatial morphology of this corona produced via photo- and magnetospheric electron impact-induced dissociation is described by tracking the motion of and simulating collisions between the hot H atoms and thermal molecules including a near-surface O2 component. Our results indicate that sublimated H2O produced from the surface ice, whether assumed to be intimately mixed with or distinctly segregated from the dark non-ice or ice-poor regolith, cannot explain the observed structure of the H corona. On the other hand, a global H2 component can reproduced the observation, and is also capable of producing the enhanced electron densities observed at high altitudes by Galileo's plasma-wave instrument (Gurnett et al., 1997, 2000), providing the first evidence of H2 in Callisto's atmosphere. The range of H2 surface densities explored, under a variety of conditions, that are consistent with these observations is ~(0.4-1)x10^8 cm^-3. The simulated H2 escape rates and estimated lifetimes suggest that Callisto has a neutral H2 torus. We also place a rough upper limit on the peak H2O number density (

More than 30 types of amyloids are linked to close to 50 diseases in humans, the most prominent being Alzheimer’s disease (AD). AD is brain-related local amyloidosis, while another amyloidosis, such as AA amyloidosis, tends to be more systemic. Therefore, we need to know more about the biological entities’ influencing these amyloidosis processes. However, there is currently no support system developed specifically to handle this extraordinarily complex and demanding task. To acquire a systematic view of amyloidosis and how this may be relevant to the brain and other organs, we needed a means to explore "amyloid network systems" that may underly processes that leads to an amyloid-related disease. In this regard, we developed the DES-Amyloidoses knowledgebase (KB) to obtain fast and relevant information regarding the biological network related to amyloid proteins/peptides and amyloid-related diseases. This KB contains information obtained through text and data mining of available scientific literature and other public repositories. The information compiled into the DES-Amyloidoses system based on 19 topic-specific dictionaries resulted in 796,409 associations between terms from these dictionaries. Users can explore this information through various options, including enriched concepts, enriched pairs, and semantic similarity. We show the usefulness of the KB using an example focused on inflammasome-amyloid associations. To our knowledge, this is the only KB dedicated to human amyloid-related diseases derived primarily through literature text mining and complemented by data mining that provides a novel way of exploring information relevant to amyloidoses.

A simulation tool which utilizes parallel processing is developed to describe molecular kinetics in 2D, single- and multi-component atmospheres on Callisto. This expands on our previous study on the role of collisions in 1D atmospheres on Callisto composed of radiolytic products (Carberry Mogan et al., 2020) by implementing a temperature gradient from noon to midnight across Callisto’s surface and introducing sublimated water vapor. We compare single-species, ballistic and collisional O 2 , H 2 and H 2 O atmospheres, as well as an O 2 +H 2 O atmosphere to 3-species atmospheres which contain H 2 in varying amounts. Because the H 2 O vapor pressure is extremely sensitive to the surface temperatures, the density drops several orders of magnitude with increasing distance from the subsolar point, and the flow transitions from collisional to ballistic accordingly. In an O 2 +H 2 O atmosphere the local temperatures are determined by H 2 O near the subsolar point and transition with increasing distance from the subsolar point to being determined by O 2 . When radiolytically produced H 2 is not negligible in O 2 +H 2 O+H 2 atmospheres, this much lighter molecule, with a scale height roughly an order of magnitude larger than that for the heavier species, can cool the local temperatures via collisions. In addition, if the H 2 component is dense enough, particles originating on the day-side and precipitating into the night-side atmosphere deposit energy via collisions, which in turn heats the local atmosphere relative to the surface temperature. Moreover, the difference between H 2 atmospheric escape rates in single-species and multi-species atmospheres is small: the H 2 only has to diffuse through a few hundred km of the heavier gases before it is the lone species in the atmosphere out to the Hill sphere. Finally, we discuss the potential implications of this study on the presence of H 2 in Callisto’s atmosphere and how the simulated densities correlate with expected detection thresholds at flyby altitudes of the proposed JUpiter ICy moons Explorer (JUICE) spacecraft.

The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are conformationally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S447N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S447N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.

Tomato is the most economically important horticultural crop used as a model to study plant biology and particularly fruit development. Knowledge obtained from tomato research initiated improvements in tomato and, being transferrable to other such economically important crops, has led to a surge of tomato-related research and published literature. We developed DES-TOMATO knowledgebase (KB) for exploration of information related to tomato. Information exploration is enabled through terms from 26 dictionaries and combination of these terms. To illustrate the utility of DES-TOMATO, we provide several examples how one can efficiently use this KB to retrieve known or potentially novel information. DES-TOMATO is free for academic and nonprofit users and can be accessed at http://cbrc.kaust.edu.sa/des_tomato/, using any of the mainstream web browsers, including Firefox, Safari and Chrome.

Microorganisms produce an enormous variety of chemical compounds. It is of general interest for microbiology and biotechnology researchers to have means to explore information about molecular and genetic basis of functioning of different microorganisms and their ability for bioproduction. To enable such exploration, we compiled 45 topic-specific knowledgebases (KBs) accessible through DESM portal (www.cbrc.kaust.edu.sa/desm). The KBs contain information derived through text-mining of PubMed information and complemented by information data-mined from various other resources (e.g. ChEBI, Entrez Gene, GO, KOBAS, KEGG, UniPathways, BioGrid). All PubMed records were indexed using 4,538,278 concepts from 29 dictionaries, with 1 638 986 records utilized in KBs. Concepts used are normalized whenever possible. Most of the KBs focus on a particular type of microbial activity, such as production of biocatalysts or nutraceuticals. Others are focused on specific categories of microorganisms, e.g. streptomyces or cyanobacteria. KBs are all structured in a uniform manner and have a standardized user interface. Information exploration is enabled through various searches. Users can explore statistically most significant concepts or pairs of concepts, generate hypotheses, create interactive networks of associated concepts and export results. We believe DESM will be a useful complement to the existing resources to benefit microbiology and biotechnology research.

Glycogen synthase kinase-3 (GSK3) are ubiquitously expressed serine-threonine kinases involved in a plethora of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK3 inhibition triggers JNK-cJUN-dependent apoptosis in human pancreatic cancer cells. However, the comprehensive picture of downstream GSK3-regulated pathways/functions remains elusive. Herein, counterbalancing the death signals, we show that GSK3 inhibition induces prosurvival signals through increased activity of the autophagy/lysosomal network. Our data also reveal a contribution of GSK3 in the regulation of the master transcriptional regulator of autophagy and lysosomal biogenesis, transcription factor EB (TFEB) in pancreatic cancer cells. Similarly to mammalian target of rapamycin (mTOR) inhibition, GSK3 inhibitors promote TFEB nuclear localization and leads to TFEB dephosphorylation through endogenous serine/threonine phosphatase action. However, GSK3 and mTOR inhibition impinge differently and independently on TFEB phosphorylation suggesting that TFEB is regulated by a panel of kinases and/or phosphatases. Despite their differential impact on TFEB phosphorylation, both GSK3 and mTOR inhibitors promote 14-3-3 dissociation and TFEB nuclear localization. Quantitative mass spectrometry analyses further reveal an increased association of TFEB with nuclear proteins upon GSK3 and mTOR inhibition suggesting a positive impact on TFEB transcriptional function. Finally, a predominant nuclear localization of TFEB is unveiled in fully fed pancreatic cancer cells, whereas a reduction in TFEB expression significantly impairs their capacity for growth in an anchorage-independent manner. In addition, TFEB-restricted cells are more sensitive to apoptosis upon GSK3 inhibition. Altogether, our data uncover new functions under the control of GSK3 in pancreatic cancer cells in addition to providing key insight into TFEB regulation.

Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long ncRNAs (lncRNAs), are important players in diseases and emerge as novel drug targets. Thus, unraveling the relationships between ncRNAs and other biomedical entities in cells are critical for better understanding ncRNA roles that may eventually help develop their use in medicine. To support ncRNA research and facilitate retrieval of relevant information regarding miRNAs and lncRNAs from the plethora of published ncRNA-related research, we developed DES-ncRNA (www.cbrc.kaust.edu.sa/des_ncrna). DES-ncRNA is a knowledgebase containing text- and data-mined information from public scientific literature and other public resources. Exploration of mined information is enabled through terms and pairs of terms from 19 topic-specific dictionaries including, for example, antibiotics, toxins, drugs, enzymes, mutations, pathways, human genes and proteins, drug indications and side effects, mutations, diseases, etc. DES-ncRNA contains approximately 878,000 associations of terms from these dictionaries of which 36,222 (5,373) are with regards to miRNAs (lncRNAs). We provide several ways to explore information regarding ncRNAs to users including controlled generation of association networks as well as hypotheses generation. We show an example how DES-ncRNA can aid research on Alzheimer disease and suggest potential therapeutic role for Fasudil. DES-ncRNA is a powerful tool that can be used on its own or as a complement to the existing resources, to support research in human ncRNA. To our knowledge, this is the only knowledgebase dedicated to human miRNAs and lncRNAs derived primarily through literature-mining enabling exploration of a broad spectrum of associated biomedical entities, not paralleled by any other resource.

The transcription factor EB (TFEB) was identified as a master regulator of autophagy and lysosomal biogenesis. We recently demonstrated that TFEB is aberrantly regulated in pancreatic cancer (PDAC) cells. Interference with TFEB impairs PDAC cell growth supporting an important role for TFEB in maintaining PDAC cell phenotype. Given the limited impact of chemotherapeutic drugs in the context of PDAC, we aimed at testing whether the aberrantly regulated TFEB in PDAC cells could confer resistance to DNA damage agents, commonly used in PDAC therapeutic regimens. Methods: Experiments were performed in PDAC cells (MIA PaCa2, PANC1). The DNA damage agents gemcitabine, 5-FU, cisplatin and doxorubicin were used. Autophagic flux was measured upon 4-hours treatment with bafilomycin A1. Results: Treatment with DNA damage agents 1) increased the autophagic flux in PDAC cells. This autophagic signal was associated with 2) the dephosphorylation and nuclear accumulation of TFEB. The mTORC1 pathway is well-known to regulate TFEB phosphorylation and nuclear localization of TFEB. 3) However, the impact of the DNA damage agents on TFEB appeared independent of the mTORC1 pathway since no modulation in the phosphorylation of the mTORC1 target S6K1 was observed. To delineate whether TFEB influenced the response to DNA damage agents, we generated stable populations of PDAC cells expressing a non-targeting or shRNA targeting TFEB. Interfering with TFEB function 4) prevented the autophagic response upon treatment with DNA damage agents. This correlated with 5) increased accumulation of DNA damage and 6) increased sensitivity to the DNA damage agents. Conclusion: Our results suggest that DNA damage agents can induce a pro-survival autophagic response involving TFEB. Interfering with TFEB function limits the autophagic response and leads to increased sensitivity to DNA damage agents. Altogether, our results suggest that the aberrantly expressed TFEB in PDAC cells could confer resistance to DNA damage agents by, among others, promoting autophagy and limiting DNA damage accumulation. Citation Format: Benoit Marchand, Marie-Josée Boucher. DNA damage agents promote TFEB function and induce pro-survival autophagy signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2619.

We recently demonstrated that prolonged inhibition of GSK3 activity induces JNK-dependent cell death in human pancreatic cancer cells. Surprisingly, we observed that, concomitant to apoptosis, GSK3 inhibition also induces autophagy. Preventing this autophagic response sensitizes pancreatic cancer cells to the GSK3 inhibition-induced apoptosis suggesting a protective role for autophagy against cell death caused by prolonged inhibition of GSK3. Nevertheless, the mechanisms underlying the control of autophagy by GSK3 remain unknown. The aim of this study was to determine the molecular mechanism involved in the regulation of autophagy by GSK3 in pancreatic cancer cells. Methods: Experiments were performed in pancreatic cancer cells (PANC1, MIA PaCa2 and BxPC3), and HEK293T cells. GSK3 activity was inhibited using shRNA directed against GSK3beta and/or GSK3alpha or by using the GSK3 specific inhibitors CHIR99021 and SB216763. The JNK inhibitor SP600125 and the mTOR specific inhibitor Torin1 were also used. Results: 1) Inhibition of the JNK-cJun pathway prevented the apoptotic response but not the autophagic response upon GSK3 inhibition excluding a contribution of the JNK-cJUN pathway in the autophagy induced by GSK3 inhibition. We therefore analyzed the activity of the mTOR pathway since this pathway is well known to modulate autophagy. 2) Inhibition of GSK3 activity reduced the activity of S6K1, a direct substrate of the mTOR complex suggesting an inhibition of the mTOR pathway upon GSK3 inhibition. The mTOR pathway was recently shown to regulate autophagy through its impact on the transcription factor TFEB, a master regulator of an autophagic/lysosomal gene network. 3) Interestingly, treatment of cells with GSK3 inhibitors or a mTOR inhibitor both led to the nuclear translocation of TFEB, 4) and correlated with the expression of a lower molecular weight TFEB protein. 5) Pre-treatment of cells with the serine/threonine phosphatase inhibitor calyculin A prevented the molecular weight shift of TFEB induced upon GSK3 inhibition suggesting that GSK3 impacts on TFEB phosphorylation. 6) Furthermore, either GSK3 or mTOR inhibition correlated with increased activity of a TFEB-luciferase reporter gene, 7) and with an increased staining of lysosomes (lysotracker). 8) Interestingly, shRNA-mediated reduction of TFEB expression sensitized pancreatic cancer cells to the apoptosis induced upon GSK3 inhibition. Conclusion: Our results demonstrate that GSK3 inhibition promotes the dephosphorylation of TFEB that correlates with increased transcriptional activity of this master regulator of autophagy and lysosomal biogenesis. Furthermore, our results support a protective role against cell death assumed by TFEB upon GSK3 inhibition. Citation Format: Benoît Marchand, Alexandre Raymond-Fleury, Marie-Josée Boucher. Regulation of the transcription factor TFEB and the autophagic/lysosomal network by GSK3 in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 315. doi:10.1158/1538-7445.AM2014-315