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A three‐dimensional ensemble‐variational global aerosol data assimilation system based on the Joint Effort for Data assimilation Integration (JEDI) was developed for the Global Ensemble Forecast System‐Aerosols (GEFS‐Aerosols) coupled with the Goddard Chemistry Aerosol Radiation and Transport (GOCART) model at the National Centers for Environmental Prediction. Aerosol mass mixing ratios in GEFS‐Aerosols were selected as control or analysis variables and were adjusted by assimilating 550 nm Aerosol Optical Depth (AOD) retrievals from the Visible Infrared Imaging Radiometer Suite (VIIRS) instruments onboard the Suomi National Polar‐orbiting Partnership (S‐NPP) satellite produced by the National Environmental Satellite, Data, and Information Service (NESDIS) at National Oceanic and Atmospheric Administration (NOAA). The original NOAA/NESDIS S‐NPP VIIRS Level 2.0 550 nm AOD retrievals were converted to JEDI Interface for Observation Data Access format. AOD forward operator and its tangent‐linear and adjoint models were implemented based on GOCART in JEDI Unified Forward Operator. A stochastically perturbed emission (SPE) approach was developed in the Common Community Physics Package‐based GEFS‐Aerosols to account for aerosol emission uncertainty. One‐month retrospective and three‐month near‐real‐time experiments consistently showed improved GEFS‐Aerosols analyses and forecasts from assimilating VIIRS 550 nm AOD retrievals against independent NASA Aqua and Terra Moderate Resolution Imaging Spectroradiometer AOD retrievals, Aerosol Robotic Network AOD, and independent AOD and aerosol analyses from NASA and European Centre for Medium‐Range Weather Forecasts. Through scaling and perturbing aerosol emissions, SPE enhanced ensemble error‐spread consistency and further improved AOD assimilation. The valid‐time‐shifting ensemble approach in a cost‐effective manner of populating background ensembles showed positive impacts on AOD assimilation. Plain Language Summary Accurate representation of atmospheric aerosols is becoming increasingly important for weather, climate, and air quality. Data assimilation (DA) that “optimally” combines information from various sources has been widely applied to generate initial conditions or analyses for atmospheric numerical models. In this study, an ensemble‐based global aerosol DA capability was developed within the Joint Effort for Data assimilation Integration to synthesize information from aerosol model forecasts and aerosol observations to improve initial conditions and subsequent forecasts in the global aerosol model at National Centers for Environmental Prediction. In an ensemble‐based DA system where model uncertainty needs to be accurately estimated, two approaches were explored to better account for aerosol model uncertainty by scaling and stochastically perturbing aerosol emissions and leveraging background ensembles valid at different times to inexpensively populate background ensembles at the analysis time. Robustness of this newly developed global aerosol DA system and positive impacts of these two approaches were demonstrated in the retrospective and near‐real‐time experiments against independent aerosol observations and analyses. Key Points A Joint Effort for Data assimilation Integration‐based three‐dimensional ensemble‐variational global aerosol data assimilation system was developed for Global Ensemble Forecast System‐Aerosols (GEFS‐Aerosols) at NCEP A stochastically perturbed emission approach was developed in GEFS‐Aerosols to account for aerosol emission uncertainty Assimilation of Visible Infrared Imaging Radiometer Suite aerosol optical depth (AOD) retrievals improves GEFS‐Aerosols analyses and forecasts against independent AOD and aerosol analyses

This review addresses the issue of the numerous roles played by Rap1 GTPase (guanosine triphosphatase) in different cell types, in terms of both physiology and pathology. It is one among a myriad of small G proteins with endogenous GTP-hydrolyzing activity that is considerably stimulated by posttranslational modifications (geranylgeranylation) or guanine nucleotide exchange factors (GEFs), and inhibited by GTPase-activating proteins (GAPs). Rap1 is a ubiquitous protein that plays an essential role in the control of metabolic processes, such as signal transduction from plasma membrane receptors, cytoskeleton rearrangements necessary for cell division, intracellular and substratum adhesion, as well as cell motility, which is needed for extravasation or fusion. We present several examples of how Rap1 affects cells and organs, pointing to possible molecular manipulations that could have application in the therapy of several diseases.

The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS–PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target.

Plakophilin 4 (PKP4) is a component of cell–cell junctions that regulates intercellular adhesion and Rho-signaling during cytokinesis with an unknown function during epidermal differentiation. Here we show that keratinocytes lacking PKP4 fail to develop a cortical actin ring, preventing adherens junction maturation and generation of tissue tension. Instead, PKP4-depleted cells display increased stress fibers. PKP4-dependent RhoA localization at AJs was required to activate a RhoA-ROCK2-MLCK-MLC2 axis and organize actin into a cortical ring. AJ-associated PKP4 provided a scaffold for the Rho activator ARHGEF2 and the RhoA effectors MLCK and MLC2, facilitating the spatio-temporal activation of RhoA signaling at cell junctions to allow cortical ring formation and actomyosin contraction. In contrast, association of PKP4 with the Rho suppressor ARHGAP23 reduced ARHGAP23 binding to RhoA which prevented RhoA activation in the cytoplasm and stress fiber formation. These data identify PKP4 as an AJ component that transduces mechanical signals into cytoskeletal organization.

One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders.

The small GTPase Rac1 (Ras‐related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial‐mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1‐SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1‐SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO‐GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co‐localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer‐related deaths, POTEE could represent a potential therapeutic target for these types of cancer. SUMOylation of the small GTPase Rac1 is essential for tumor cell dissemination. POTEE is identified as a novel Rac1‐SUMO1 effector, promoting breast cancer malignancy through invadopodium formation. POTEE activates Rac1 by recruiting TRIO‐GEF, increasing tumor cell metastasis in vitro and in vivo. Colocalization of POTEE and Rac1 correlates with aggressive breast cancer subtypes, suggesting POTEE as a potential therapeutic target.

The study assesses the predictability of rainfall patterns in India through 3-day precipitation forecasts from a regional climate model ensemble framework operating at convection-permitting (CP) scales. Initially, 149 experiments are conducted across four events representing different rainfall mechanisms. The performance of a larger set of 55 ensemble members within the multi-physics ensemble framework is evaluated using quantitative metrics such as composite scaled scores and cross-correlation analyses. This evaluation led to the development of an optimally designed smaller member ensemble framework, WRF-CP7, which reduces turnaround time while maintaining the spatial and temporal performance of simulated precipitation fields. The study further assesses the reliability of this framework over an extended period, utilizing insights from 5544 simulations (792 days × 7 ensemble members running for a 90-h lead time) conducted between September 2015 and December 2017. Comparisons between WRF-CP7 and a global climate model forecasts available at coarser resolution highlight the need of parameterization and ensemble framework at convection-permitting scale. WRF-CP7 demonstrates skill in capturing spatiotemporal variability of rainfall occurrences, evidenced by a higher spread–error correlation (0.9 vs. 0.6 in the global model) among ensemble members. The correlation remains consistent even at higher lead-times, in contrast to the reducing skill of the global model with increasing lead-time. WRF-CP7 also shows reduction in spatial and temporal errors within simulated diurnal precipitation patterns, notably during Indian Summer Monsoon, Pre-Monsoon Thunderstorm activities and North-East Monsoon. A notable 30% increase in predictability for moderate to heavy rain intensities is observed across all seasons, accompanied by a 10% decrease in false alarms compared to global model ensemble forecasts. The spatial skill of WRF-CP7 for moderate-heavy intensity events remains high (50–80%) even with a longer lead time of 72-h on an intra-seasonal timescale. With a substantial sample size, the results underscore the effectiveness of using the multi-physics ensemble framework at convective scales for operational forecasting and dynamic downscaling of climatology across the Indian subcontinent.

This research proposes a method based on the greatest and shortest eigen fuzzy sets of fuzzy relations to evaluate the effectiveness of policies and strategies implemented in urban settlements aimed at increasing the livability and well-being of citizens. This assessment is performed by extracting population census data collected at the beginning and end of the analyzed period and grouping them by subzone, that is, for each of the urban areas into which the urban settlement is divided. The greatest eigen fuzzy set (GEFS) and the smallest eigen fuzzy set (SEFS) are determined symmetrically as min-max and max-min solutions of fuzzy relations; they are calculated to estimate the average impact of urban strategies on generating symptoms of growth in citizen well-being during the investigated period. The method is implemented on a GIS (Geographic Information System) platform and was tested to assess the effectiveness of local policies applied between 2011 and 2021 on the growth of employment rates and educational attainment in the city of Naples (Italy), partitioned by neighborhood. Our model, unlike other fuzzy-based models for evaluating the effectiveness of actions and strategies to improve the quality of life in urban settlements, does not allow for subjective interpretations based on the knowledge or experience of different stakeholders, but relies solely on measurements over time of characteristics collected during census activities. Furthermore, it is integrated into a GIS-based platform, providing additional capabilities for identifying the urban areas where the impact of local strategies and policies has been most significant and those most critical. The test results show that the proposed framework can be a valuable tool for supporting decision makers in evaluating the effectiveness of local actions and policies aimed at improving the livability and well-being of citizens.

Rac-GTPases and their Rac-GEF activators play important roles in neutrophil-mediated host defence. These proteins control the adhesion molecules and cytoskeletal dynamics required for neutrophil recruitment to inflamed and infected organs, and the neutrophil effector responses that kill pathogens. Here, we used live cell TIRF-FRET imaging in neutrophils from Rac-FRET reporter mice with deficiencies in the Rac-GEFs Dock2, Tiam1 or Prex1/Vav1 to evaluate if these proteins activate spatiotemporally distinct pools of Rac, and to correlate patterns of Rac activity with the neutrophil responses they control. All the GEFs were required for neutrophil adhesion, and Prex1/Vav1 were important during spreading and for the velocity of migration during chemotaxis. However, Dock2 emerged as the prominent regulator of neutrophil responses, as this GEF was required for neutrophil polarisation and random migration, for migration velocity during chemokinesis, for the likelihood to migrate and for the speed of migration and of turning during chemotaxis, as well as for rapid particle engulfment during phagocytosis. We identified characteristic spatiotemporal patterns of Rac activity generated by Dock2 which correlate with the importance of the Rac-GEF in these neutrophil responses. We also demonstrate a requirement for Dock2 in neutrophil recruitment during aseptic peritonitis. Collectively, our data provide a first direct comparison of the pools of Rac activity generated by different types of Rac-GEFs, and identify Dock2 as a key regulator of polarisation, migration and phagocytosis in primary neutrophils.

Segregation Distorter (SD) is an autosomal meiotic drive system found worldwide in natural populations of Drosophila melanogaster. This gene complex induces the preferential and nearly exclusive transmission of the SD chromosome in SD/SD+ males. This selfish propagation occurs through the interplay of the Sd locus, its enhancers and the Rsps locus during spermatid development. The key distorter locus, Sd, encodes a truncated but enzymatically active RanGAP (RanGTPase-activating protein), a key nuclear transport factor in the Ran signaling pathway. When encoded by Sd, RanGAP is mislocalized to the nucleus interior, which then traps Ran inside the nucleus and disrupts nuclear import. As a result of this aberrant nuclear transport, a process known as the histone-to-protamine transition that is required for proper spermatid condensation fails to occur in SD/SD+ males. In this process, sperm-specific protamine proteins enter the spermatid nucleus and replace the formerly chromatin-complexed histones. Previously, we have shown that mutations affecting nuclear import and export can enhance distortion in an SD background, thus verifying that a defect in nuclear transport is responsible for the unequal transmission of chromosomes. Herein, we show that specifically reducing protamines induces distortion in an SD background, verifying that protamines are transported via the RanGAP/GEF pathway and indicating that E(SD) plays a significant and unique role in the process of distortion.