Mechanical modeling of collective cell migration: An agent-based and continuum material approach

We develop a novel modeling approach that combines a discrete agent-based model and a continuum material model to simulate collective cell migration in epithelial layers. In this approach, cells are represented as particles located at their geometrical center, but also as a polygonal body derived from the Voronoi diagram. Furthermore, we model the tissue as a continuum medium with different spatial domains that represent cell and substrate materials. In fact, the mechanical behavior of each domain is affected by the presence of cells from the discrete model. Moreover, we solve this mechanical problem using the finite element method (FEM). The forces generated by cells are projected to the FE mesh, that is created dynamically during the simulation from the discrete cell representation. After the FE resolution, we use the mesh displacements to determine the new cell positions in the agent-based model. Finally, to demonstrate the potential of this approach to model epithelial tissue mechanics, we simulate two well-studied cases of collective cell migration: durotaxis and gap closure. We use the experimental data from the literature to validate our numerical results. Therefore, the modeling strategy here presented offers a new perspective for a deeper understanding of tissue mechanics that emerge from cell dynamics in epithelial layers

Towards a global model of the martian atmosphere

In an effort to continuously improve the capabilities of the Martian atmospheric predictions at LMD, the GCM has been extended into thermospheric heights thus creating the first model to self-consistently couple the lower and upper regions of the Martian atmosphere. The behaviour of the Martian thermosphere is strongly influenced by lower atmospheric processes and has complex dynamics. Such a fully coupled model will certainly aid in the preparation of future missions and on the analysis of future high altitude data, as well as serve as a base for the simulation of ionospheric processes, escape, etc

Automated detection of lupus white matter lesions in MRI

Brain magnetic resonance imaging provides detailed information which can be used to detect and segment white matter lesions (WML). In this work we propose an approach to automatically segment WML in Lupus patients by using T1w and fluid-attenuated inversion recovery (FLAIR) images. Lupus WML appear as small focal abnormal tissue observed as hyperintensities in the FLAIR images. The quantification of these WML is a key factor for the stratification of lupus patients and therefore both lesion detection and segmentation play an important role. In our approach, the T1w image is first used to classify the three main tissues of the brain, white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF), while the FLAIR image is then used to detect focal WML as outliers of its GM intensity distribution. A set of post-processing steps based on lesion size, tissue neighborhood, and location are used to refine the lesion candidates. The proposal is evaluated on 20 patients, presenting qualitative, and quantitative results in terms of precision and sensitivity of lesion detection [True Positive Rate (62%) and Positive Prediction Value (80%), respectively] as well as segmentation accuracy [Dice Similarity Coefficient (72%)]. Obtained results illustrate the validity of the approach to automatically detect and segment lupus lesions. Besides, our approach is publicly available as a SPM8/12 toolbox extension with a simple parameter configuration

Autophagy resolves early retinal inflammation in Igf1-deficient mice

Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1(-/-)), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1(-/-) mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1(-/-) mice compared to those in age-matched Igf1(+/+) controls. In 6-month-old Igf1(-/-) retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1(-/-) mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1(+/+) controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1(+/+) and Igf1(-/-) mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1(-/-) mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1(-/-) mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during agein

Efficacy of mindfulness to regulate induced emotions in the laboratory: A systematic review and meta-analysis of self-report and biobehavioral measures

A substantial part of the research on the efficacy of mindfulness-based interventions on mood regulation is conducted in the laboratory. Nevertheless, a systematic review of the results is lacking. This meta-analysis aimed to investigate the effects of mindfulness as an emotion regulation (ER) strategy when using mood induction procedures. A systematic search of databases was conducted and a total of 43 studies were included in the meta-analysis. We found a small significant overall effect size of mindfulness [g= -0.15 (95% CI [-0.30, -0.01], p = 0.04)], which became non-significant after removing outliers (g=-0.15, p = 0.06). We also found high levels of heterogeneity which was not explained by the moderating variables analyzed. Thus, there is limited meta-analytic evidence of the efficacy of mindfulness strategies in down-regulating or preventing heightened or chronic effects of induced mood states in well-controlled laboratory settings. We propose that this could be partially due to some limitations in laboratory methodologies and suggest some guidelines to overcome them in future primary research

Specific targeting of the NRF2/β-TrCP axis promotes beneficial effects in NASH

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises liver function, for which there is not a specifically approved medicine. Recent research has identified transcription factor NRF2 as a potential therapeutic target. However, current NRF2 activators, designed to inhibit its repressor KEAP1, exhibit unwanted side effects. Alternatively, we previously introduced PHAR, a protein-protein interaction inhibitor of NRF2/β-TrCP, which induces a mild NRF2 activation and selectively activates NRF2 in the liver, close to normal physiological levels. Herein, we assessed the effect of PHAR in protection against NASH and its progression to fibrosis. We conducted experiments to demonstrate that PHAR effectively activated NRF2 in hepatocytes, Kupffer cells, and stellate cells. Then, we used the STAM mouse model of NASH, based on partial damage of endocrine pancreas and insulin secretion impairment, followed by a high fat diet. Non-invasive analysis using MRI revealed that PHAR protects against liver fat accumulation. Moreover, PHAR attenuated key markers of NASH progression, including liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. Notably, transcriptomic data indicate that PHAR led to upregulation of 3 anti-fibrotic genes (Plg, Serpina1a, and Bmp7) and downregulation of 6 pro-fibrotic (including Acta2 and Col3a1), 11 extracellular matrix remodeling, and 8 inflammatory genes. Overall, our study suggests that the mild activation of NRF2 via the protein-protein interaction inhibitor PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosisThis research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grants PID2019-110061RB-I00, PID-2021-122766OB-100 and PDC2021-121421-I00, PDC2022-133765-I00, MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” by the European Union.), CIBERdem and CIBERned (ISCIII), and The Autonomous Community of Madrid (grant P2022/BMD-7230). RFG enjoyed a FPI contract of MINECO (FPI-2017). DCS is a holder of a FPI contract of MICINN (Ministry of Science and Innovation, FPI-2020, PRE2020-091886). JJV is holder of a FPU contract of MIU (Ministry of Universities, FPU2020, FPU20/03326

Vertical dust mixing and the interannual variations in the Mars thermosphere

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94815/1/jgre2303.pd

Four Martian years of nightside upper thermospheric mass densities derived from electron reflectometry: Method extension and comparison with GCM simulations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95498/1/jgre2766.pd

WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of oxidant and xenobiotic metabolism, but it is unknown how it is regulated to provide basal expression of this defense system. Here, we studied the putative connection between NRF2 and the canonical WNT pathway, which modulates hepatocyte metabolism. Results: WNT-3A increased the levels of NRF2 and its transcriptional signature in mouse hepatocytes and HEK293T cells. The use of short interfering RNAs in hepatocytes and mouse embryonic fibroblasts which are deficient in the redox sensor Kelch-like ECH-associated protein 1 (KEAP1) indicated that WNT-3A activates NRF2 in a β-Catenin- and KEAP1-independent manner. WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/β-TrCP-dependent ubiquitination and proteasomal degradation. Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2. Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. The relevance of this novel pathway was assessed in mice with a conditional deletion of Axin1 in the liver, which showed upregulation of the NRF2 signature in hepatocytes and disruption of liver zonation of antioxidant metabolism. Innovation: NRF2 takes part in a protein complex with Axin1 that is regulated by the canonical WNT pathway. This new WNT-NRF2 axis controls the antioxidant metabolism of hepatocytes. Conclusion: These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism