The Effect of Social Determinants of Health on Psychological Health Among Older Adults in Ghana.

This study examines the effects of various factors, including socioeconomic status, built environment, access to healthcare, educational level, social participation, and economic stability, on older adults' psychological health. The current study analyzed a nationally representative sub-sample of 2,577 respondents aged 50 and above from the World Health Organization's Study on Global AGEing and Adult Health (WHO SAGE) Wave 2. WHO SAGE Wave 2 is cross-sectional data collected via in-person structured interviews. Ordinal least square (OLS) was used to measure the average effect of social determinants of health (SDoH), and quantile regression analysis was used to determine the effects of SDoH on older adults' psychological health at different quantiles, specifically 10th, 50th, and 90th percentiles. Significant determinants of psychological health across all quantiles included age, healthcare access, marital status, economic stability, and neighborhood and built environment. However, the degrees of significance for residence, gender, educational level, chronic diseases, and social participation varied between quantiles, showing differing effects on older adults with high or low psychological health. Religion was insignificant across all quantiles. This study highlights the need for governments and public health agencies to develop targeted interventions and strategies that support the psychological well-being of older adults in the country.

LRRK2 and WAVE2 regulate microglial-transition through distinct morphological phenotypes to induce neurotoxicity in a novel two-hit in vitro model of neurodegeneration.

We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live-cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Transwell cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre-stressed or healthy neurons. This two-hit paradigm was developed to model the vast evidence that neurodegenerative conditions, like Parkinson's disease (PD), may stem from the collective impact of multiple environmental stressors. We found that healthy neurons were resistant to microglial-mediated inflammation, whereas glutamate pre-stressed neurons were highly susceptible and in fact, appeared to recruit microglia. The LPS treated microglia progressed through distinct morphological states and expressed high levels of ROS and formed large cellular aggregates. Recent evidence implicates leucine-rich repeat kinase 2 (LRRK2) as an important player in the microglial inflammatory state, as well as in the genesis of PD. We found that inhibition of the LRRK2 signaling pathway using the kinase inhibitor cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi2) or inhibition of the actin regulatory protein, Wiskott-Aldrich syndrome family Verprolin-homologous Protein-2 (WAVE2), stunted microglial activation and prevented neurotoxicity. Furthermore, inhibition of LRRK2 kinase activity reduced pro-inflammatory chemokines including MIP-2, CRG-2, and RANTES. These data together support the notion that LRRK2 and WAVE2 are important mediators of cytokine production and cytoskeletal rearrangement necessary for microglial-induced neurotoxicity. Furthermore, our model demonstrated unique microglial phenotypic changes that might be mechanistically important for better understanding neuron-microglial crosstalk.

Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2-G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2-G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2-WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.

SARS-CoV-2 Wave Two Surveillance in East Asia and the Pacific: Longitudinal Trend Analysis.

BACKGROUND: The COVID-19 pandemic has had a profound global impact on governments, health care systems, economies, and populations around the world. Within the East Asia and Pacific region, some countries have mitigated the spread of the novel coronavirus effectively and largely avoided severe negative consequences, while others still struggle with containment. As the second wave reaches East Asia and the Pacific, it becomes more evident that additional SARS-CoV-2 surveillance is needed to track recent shifts, rates of increase, and persistence associated with the pandemic. OBJECTIVE: The goal of this study is to provide advanced surveillance metrics for COVID-19 transmission that account for speed, acceleration, jerk, persistence, and weekly shifts, to better understand country risk for explosive growth and those countries who are managing the pandemic successfully. Existing surveillance coupled with our dynamic metrics of transmission will inform health policy to control the COVID-19 pandemic until an effective vaccine is developed. We provide novel indicators to measure disease transmission. METHODS: Using a longitudinal trend analysis study design, we extracted 330 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in East Asia and the Pacific as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. RESULTS: The standard surveillance metrics for Indonesia, the Philippines, and Myanmar were concerning as they had the largest new caseloads at 4301, 2588, and 1387, respectively. When looking at the acceleration of new COVID-19 infections, we found that French Polynesia, Malaysia, and the Philippines had rates at 3.17, 0.22, and 0.06 per 100,000. These three countries also ranked highest in terms of jerk at 15.45, 0.10, and 0.04, respectively. CONCLUSIONS: Two of the most populous countries in East Asia and the Pacific, Indonesia and the Philippines, have alarming surveillance metrics. These two countries rank highest in new infections in the region. The highest rates of speed, acceleration, and positive upwards jerk belong to French Polynesia, Malaysia, and the Philippines, and may result in explosive growth. While all countries in East Asia and the Pacific need to be cautious about reopening their countries since outbreaks are likely to occur in the second wave of COVID-19, the country of greatest concern is the Philippines. Based on standard and enhanced surveillance, the Philippines has not gained control of the COVID-19 epidemic, which is particularly troubling because the country ranks 4th in population in the region. Without extreme and rigid social distancing, quarantines, hygiene, and masking to reverse trends, the Philippines will remain on the global top 5 list of worst COVID-19 outbreaks resulting in high morbidity and mortality. The second wave will only exacerbate existing conditions and increase COVID-19 transmissions.

Dynamic Panel Data Modeling and Surveillance of COVID-19 in Metropolitan Areas in the United States: Longitudinal Trend Analysis.

BACKGROUND: The COVID-19 pandemic has had profound and differential impacts on metropolitan areas across the United States and around the world. Within the United States, metropolitan areas that were hit earliest with the pandemic and reacted with scientifically based health policy were able to contain the virus by late spring. For other areas that kept businesses open, the first wave in the United States hit in mid-summer. As the weather turns colder, universities resume classes, and people tire of lockdowns, a second wave is ascending in both metropolitan and rural areas. It becomes more obvious that additional SARS-CoV-2 surveillance is needed at the local level to track recent shifts in the pandemic, rates of increase, and persistence. OBJECTIVE: The goal of this study is to provide advanced surveillance metrics for COVID-19 transmission that account for speed, acceleration, jerk and persistence, and weekly shifts, to better understand and manage risk in metropolitan areas. Existing surveillance measures coupled with our dynamic metrics of transmission will inform health policy to control the COVID-19 pandemic until, and after, an effective vaccine is developed. Here, we provide values for novel indicators to measure COVID-19 transmission at the metropolitan area level. METHODS: Using a longitudinal trend analysis study design, we extracted 260 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in the 25 largest US metropolitan areas as a function of the prior number of cases and weekly shift variables based on a dynamic panel data model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. RESULTS: Minneapolis and Chicago have the greatest average number of daily new positive results per standardized 100,000 population (which we refer to as speed). Extreme behavior in Minneapolis showed an increase in speed from 17 to 30 (67%) in 1 week. The jerk and acceleration calculated for these areas also showed extreme behavior. The dynamic panel data model shows that Minneapolis, Chicago, and Detroit have the largest persistence effects, meaning that new cases pertaining to a specific week are statistically attributable to new cases from the prior week. CONCLUSIONS: Three of the metropolitan areas with historically early and harsh winters have the highest persistence effects out of the top 25 most populous metropolitan areas in the United States at the beginning of their cold weather season. With these persistence effects, and with indoor activities becoming more popular as the weather gets colder, stringent COVID-19 regulations will be more important than ever to flatten the second wave of the pandemic. As colder weather grips more of the nation, southern metropolitan areas may also see large spikes in the number of cases.

Rac1/Wave2/Arp3 Pathway Mediates Rat Blood-Brain Barrier Dysfunction under Simulated Microgravity Based on Proteomics Strategy.

The blood-brain barrier (BBB) is critical to maintaining central nervous system (CNS) homeostasis. However, the effects of microgravity (MG) on the BBB remain unclear. This study aimed to investigate the influence of simulated MG (SMG) on the BBB and explore its potential mechanism using a proteomic approach. Rats were tail-suspended to simulate MG for 21 days. SMG could disrupt the BBB, including increased oxidative stress levels, proinflammatory cytokine levels, and permeability, damaged BBB ultrastructure, and downregulated tight junctions (TJs) and adherens junctions (AJs) protein expression in the rat brain. A total of 554 differentially expressed proteins (DEPs) induced by SMG were determined based on the label-free quantitative proteomic strategy. The bioinformatics analysis suggested that DEPs were mainly enriched in regulating the cell-cell junction and cell-extracellular matrix biological pathways. The inhibited Ras-related C3 botulinum toxin substrate 1 (Rac1)/Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 (Wave2)/actin-related protein 3 (Arp3) pathway and the decreased ratio of filamentous actin (F-actin) to globular actin contributed to BBB dysfunction induced by SMG. In the human brain microvascular endothelial cell (HBMECs), SMG increased the oxidative stress levels and proinflammatory cytokine levels, promoted apoptosis, and arrested the cell cycle phase. Expression of TJs and AJs proteins were downregulated and the distribution of F-actin was altered in SMG-treated HBMECs. The key role of the Rac1/Wave2/Arp3 pathway in BBB dysfunction was confirmed in HBMECs with a specific Rac1 agonist. This study demonstrated that SMG induced BBB dysfunction and revealed that Rac1/Wave2/Arp3 could be a potential signaling pathway responsible for BBB disruption under SMG. These results might shed a novel light on maintaining astronaut CNS homeostasis during space travel.

Dragon's Blood Regulates Rac1-WAVE2-Arp2/3 Signaling Pathway to Protect Rat Intestinal Epithelial Barrier Dysfunction Induced by Simulated Microgravity.

Dragon's Blood is a red resin from Dracaena cochinchinensis (Lour.) S.C. Chen (Yunnan, China). As a traditional Chinese medicinal herb, it has shown protective effects on intestinal disorders. Microgravity could alter intestinal homeostasis. However, the potential herbal drugs for preventing intestine epithelial barrier (IEB) dysfunction under microgravity are not available. This study aimed to investigate the effects of Dragon's Blood (DB) on microgravity-induced IEB injury and explore its underlying mechanism. A rat tail-suspension model was used to simulate microgravity (SMG). Histomorphology, ultrastructure, permeability, and expression of junction proteins in jejunum, ileum, and colon of SMG rats were determined. Proteomic analysis was used to identify differentially expressed proteins (DEPs) in rat ileum mucosa altered by DB. The potential mechanism of DB to protect IEB dysfunction was validated by western blotting. The effects of several components in DB were evaluated in SMG-treated Caco-2 cells. DB protected against IEB disruption by repairing microvilli and crypts, inhibiting inflammatory factors, lowering the permeability and upregulating the expression of tight and adherens junction proteins in the ileum of SMG rats. Proteomic analysis showed that DB regulated 1080 DEPs in rat ileum mucosa. DEPs were significantly annotated in cell-cell adhesion, focal adhesion, and cytoskeleton regulation. DB increased the expression of Rac1-WAVE2-Arp2/3 pathway proteins and F-actin to G-actin ratio, which promoted the formation of focal adhesions. Loureirin C in DB showed a protective effect on epithelial barrier injury in SMG-treated Caco-2 cells. DB could protect against IEB dysfunction induced by SMG, and its mechanism is associated with the formation of focal adhesions mediated by the Rac1-WAVE2-Arp2/3 pathway, which benefits intestinal epithelial cell migration and barrier repair.

Evaluation of the Association Between Health State Utilities and Obesity in Sub-Saharan Africa: Evidence From World Health Organization Study on Global AGEing and Adult Health Wave 2.

BACKGROUND: Obesity is a major public health challenge and its prevalence has increased across the age spectrum from 1980 to date in most parts of the world including sub-Saharan Africa. Studies that derive health state utilities (HSUs) stratified by weight status to support the conduct of economic evaluations and prioritization of cost-effective weight management interventions are lacking in sub-Saharan Africa. OBJECTIVES: To estimate age- and sex-specific HSUs for Ghana, along with HSUs by weight status. Associations between HSUs and overweight and obesity will be examined. STUDY DESIGN: Cross-sectional survey of the Ghanaian population. METHODS: Data were sourced from the World Health Organization Study of Global AGEing and Adult Health (WHO SAGE), 2014 to 2015. Using a "judgment-based mapping" method, responses to items from the World Health Organization Quality-of-Life (WHOQOL-100) used in the WHO SAGE were mapped to EQ-5D-5L profiles, and the Zimbabwe value set was applied to calculate HSUs. Poststratified sampling weights were applied to estimate mean HSUs, and a multivariable linear regression model was used to examine associations between HSUs and overweight or obesity. RESULTS: Responses from 3966 adults aged 18 to 110 years were analyzed. The mean (95% confidence interval) HSU was 0.856 (95% CI: 0.850, 0.863) for the population, 0.866 (95% CI: 0.857, 0.875) for men, and 0.849 (95% CI: 0.841, 0.856) for women. Lower mean HSUs were observed for obese individuals and with older ages. Multivariable regression analysis showed that HSUs were negatively associated with obesity (-0.024; 95% CI: -0.037, -0.011), female sex (-0.011; 95% CI: -0.020, -0.003), and older age groups in the population. CONCLUSIONS: The study provides HSUs by sex, age, and body mass index (BMI) categories for the Ghanaian population and examines associations between HSU and high BMI. Obesity was negatively associated with health state utility in the population. These data can be used in future economic evaluations for Ghana and sub-Saharan African populations.

SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin.

Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target Wave2 is required for cell motility, thus regarded as an essential regulator of cancer cell metastasis. However, the exact effects and molecular mechanisms of SH3BP1 in cervical cancer progression are still unknown. The present study is aimed to investigate the mechanism of SH3BP1 in regulation of cervical cancer cell metastasis and chemoresistance. In the present study, we demonstrated a high SH3BP1 expression in cervical cancer tissues; a higher SH3BP1 expression is also correlated with a shorter overall survival of patients with cervical cancer. Further, we revealed that SH3BP1 overexpression promoted the invasion, migration, and chemoresistance of cervical cancer cell through increasing Rac1 activity and Wave2 protein level. The promotive effect of SH3BP1 could be partially reversed by a Rac1 inhibitor, NSC 23766. In cisplatin-resistant cervical cancer tissues, SH3BP1, Rac1, and Wave2 mRNA expression was significantly up-regulated compared to that of the cisplatin-sensitive cervical cancer tissues. Taken together, SH3BP1/Rac1/Wave2 pathway may potentially act as an effective therapeutic target combined with traditional cisplatin-based chemotherapy for cervical cancer.

The Rho GTPase Rif signals through IRTKS, Eps8 and WAVE2 to generate dorsal membrane ruffles and filopodia.

Rif induces dorsal filopodia but the signaling pathway responsible for this has not been identified. We show here that Rif interacts with the I-BAR family protein IRTKS (also known as BAIAP2L1) through its I-BAR domain. Rif also interacts with Pinkbar (also known as BAIAP2L2) in N1E-115 mouse neuroblastoma cells. IRTKS and Rif induce dorsal membrane ruffles and filopodia. Dominant-negative Rif inhibits the formation of IRTKS-induced morphological structures, and Rif activity is blocked in IRTKS-knockout (KO) cells. To further define the Rif-IRTKS signaling pathway, we identify Eps8 and WAVE2 (also known as WASF2) as IRTKS interactors. We find that Eps8 regulates the size and number of dorsal filopodia and membrane ruffles downstream of Rif-IRTKS signaling, whereas WAVE2 modulates dorsal membrane ruffling. Furthermore, our data suggests that Tir, a protein essential for enterohemorrhagic Escherichia coli infection, might compete for Rif for interaction with the I-BAR domain of IRTKS. Based on this evidence, we propose a model in which Rho family GTPases use the I-BAR proteins, IRSp53 (also known as BAIAP2), IRTKS and Pinkbar, as a central mechanism to modulate cell morphology.

[Breastfeeding behaviour in Germany-News from KiGGS Wave 2]. / Stillverhalten in Deutschland ­ Neues aus KiGGS Welle 2.

Breast milk is the optimal nutrition for babies in their first six months of life and provides health benefits for both children and mothers. As part of the Robert Koch Institute's health monitoring, the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) regularly collects population-based data on the health situation of children and adolescents living in Germany, including information on breastfeeding. This article describes breastfeeding behaviour based on the results of KiGGS Wave 2 (2014-2017). The prevalence of breastfeeding and the duration of breastfeeding in the birth cohorts 2009-2016 as well as information on intention to breastfeed and reasons for weaning are described. The results from KiGGS Wave 2 show that breastfeeding proportions for any type of breastfeeding tended to increase between the birth cohorts 2009/2010 and 2013/2014, while the prevalence for full and exclusive breastfeeding show no change. The average duration of breastfeeding has remained constant. Almost 90% of mothers intended to breastfeed their baby after birth and 97% of these mothers actually started breastfeeding. Having insufficient breast milk has often been mentioned as a problem, both by mothers who intended to breastfeed but did not start breastfeeding and by mothers who have been breastfeeding their infants for less than six months. Despite some limitations, the KiGGS study is an important part of breastfeeding monitoring. Regular data collection and the largely consistent study design make it possible to map trends in time and to measure the impact of breastfeeding promotion on the population. KiGGS Wave 2 shows that breastfeeding promotion measures are still necessary.

WASp family verprolin-homologous protein-2 (WAVE2) and Wiskott-Aldrich syndrome protein (WASp) engage in distinct downstream signaling interactions at the T cell antigen receptor site.

T cell antigen receptor (TCR) engagement has been shown to activate pathways leading to actin cytoskeletal polymerization and reorganization, which are essential for lymphocyte activation and function. Several actin regulatory proteins were implicated in regulating the actin machinery, such as members of the Wiskott-Aldrich syndrome protein (WASp) family. These include WASp and the WASp family verprolin-homologous protein-2 (WAVE2). Although WASp and WAVE2 share several structural features, the precise regulatory mechanisms and potential redundancy between them have not been fully characterized. Specifically, unlike WASp, the dynamic molecular interactions that regulate WAVE2 recruitment to the cell membrane and specifically to the TCR signaling complex are largely unknown. Here, we identify the molecular mechanism that controls the recruitment of WAVE2 in comparison with WASp. Using fluorescence resonance energy transfer (FRET) and novel triple-color FRET (3FRET) technology, we demonstrate how WAVE2 signaling complexes are dynamically regulated during lymphocyte activation in vivo. We show that, similar to WASp, WAVE2 recruitment to the TCR site depends on protein-tyrosine kinase, ZAP-70, and the adaptors LAT, SLP-76, and Nck. However, in contrast to WASp, WAVE2 leaves this signaling complex and migrates peripherally together with vinculin to the membrane leading edge. Our experiments demonstrate that WASp and WAVE2 differ in their dynamics and their associated proteins. Thus, this study reveals the differential mechanisms regulating the function of these cytoskeletal proteins.

Cortactin scaffolds Arp2/3 and WAVE2 at the epithelial zonula adherens.

Cadherin junctions arise from the integrated action of cell adhesion, signaling, and the cytoskeleton. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. But how this is coordinated with cadherin adhesion is not known. We now identify cortactin as a key scaffold for actin regulation at the ZA, which localizes to the ZA through influences from both E-cadherin and N-WASP. Using cell-free protein expression and fluorescent single molecule coincidence assays, we demonstrate that cortactin binds directly to the cadherin cytoplasmic tail. However, its concentration with cadherin at the apical ZA also requires N-WASP. Cortactin is known to bind Arp2/3 directly (Weed, S. A., Karginov, A. V., Schafer, D. A., Weaver, A. M., Kinley, A. W., Cooper, J. A., and Parsons, J. T. (2000) J. Cell Biol. 151, 29-40). We further show that cortactin can directly bind WAVE2, as well as Arp2/3, and both these interactions are necessary for actin assembly at the ZA. We propose that cortactin serves as a platform that integrates regulators of junctional actin assembly at the ZA.

Inhibition of invasion by glycogen synthase kinase-3 beta inhibitors through dysregulation of actin re-organisation via down-regulation of WAVE2.

Cancer cell invasion is a critical phenomenon in cancer pathogenesis. Glycogen synthase kinase-3ß (GSK-3ß) has been reported to regulate cancer cell invasion both negatively and positively. Thus, the net effect of GSK-3ß on invasion is unclear. In this report, we showed that GSK-3ß inhibitors induced dysregulation of the actin cytoskeleton and functional insufficiency of focal adhesion, which resulted in suppressed invasion. In addition, WAVE2, an essential molecule for actin fibre branching, was down-regulated after GSK-3ß inhibition. Collectively, we propose that the WAVE2-actin cytoskeleton axis is an important target of GSK-3ß inhibitors in cancer cell invasion.

Decreased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 may be involved in the development of pre-eclampsia.

Wiskott­Aldrich syndrome protein family verprolin-homologous protein 2 (WAVE2) is a protein that mediates actin cytoskeletal reorganization and lamellipodia protrusion formation, which are required for cell migration and invasion. The primary purpose of this study was to determine whether there is an association between reactive oxygen species (ROS) and WAVE2 in pre-eclampsia, and whether WAVE2 expression in trophoblast cells is vulnerable to oxidative stress. This study observed excessive generation of ROS and decreased expression of WAVE2 in pre-eclamptic placentas compared with normotensive controls. Moreover, there was a significant negative correlation between ROS and WAVE2 protein in pre-eclamptic placenta (P < 0.001). An in-vitro model of hypoxia­reoxygenation (H/R) was used to imitate oxidative stress in placental trophoblasts, and it was found that the expression of WAVE2 protein in trophoblasts was decreased after H/R treatment. Additionally, compared with normoxia, decreased cell proliferation, higher cell apoptosis and attenuated cell migration and invasion were detected in trophoblasts exposed to H/R. In conclusion, the findings strongly suggest that excessive oxidative stress can decrease WAVE2 expression in trophoblasts and that the decreased expression of WAVE2 in trophoblast cells may be involved in the development of pre-eclampsia.

Integration of the DIAMONDS and CAPTION situation taxonomies based on the South Korean culture.

Introduction: In this study, we developed an integrated situational taxonomy by merging the second-generation situational taxonomies of the DIAMONDS and CAPTION models. Method: The study participants included 363 adults aged 25-39 years, residing in South Korea, with at least a college degree, and currently employed. To integrate the factors of both models, we conducted an exploratory factor analysis and further examined the hierarchical structure of these factors using bass-ackwards analysis. Results: Our analysis revealed that the integrated situational taxonomy comprises seven domains with a confirmed hierarchical structure. Building on these findings, we further conducted a comparative analysis of the results with prior situational taxonomy research. Discussion: It was found that the factors constituting integrated domains derived from previous studies that employed correlation analysis or factor analysis differed from those of our study. However, the taxonomy of the three domains in the third level (negativity, positivity, and tasks) aligned with that of previous relevant research, suggesting that these domains are universally applicable to situational taxonomy. Hence, although the taxonomy of the three domains does not encapsulate specific situational characteristics, like the seven domains, if one seeks a culturally universal, statistically clear, and concise structure of situational taxonomy, the three-domain one is a promising alternative to the seven domains. Moreover, this study is the first situational taxonomic research outside the United States and European cultural spheres that confirms that an integrated situational taxonomy is similarly applicable in East Asian cultures.

HIV-1 Mediated Cortical Actin Disruption Mirrors ARP2/3 Defects Found in Primary T Cell Immunodeficiencies.

During cell movement, cortical actin balances mechanical and osmotic forces to maintain cell function while providing the scaffold for cell shape. Migrating CD4+ T cells have a polarized structure with a leading edge containing dynamic branched and linear F-actin structures that bridge intracellular components to surface adhesion molecules. These actin structures are complemented with a microtubular network beaded with membrane bound organelles in the trailing uropod. Disruption of actin structures leads to dysregulated migration and changes in morphology of affected cells. In HIV-1 infection, CD4+ T cells have dysregulated movement. However, the precise mechanisms by which HIV-1 affects CD4+ T cell movement are unknown. Here, we show that HIV-1 infection of primary CD4+ T cells causes at least four progressive morphological differences as a result of virally induced cortical cytoskeleton disruption, shown by ultrastructural and time lapse imaging. Infection with a ΔNef virus partially abrogated the dysfunctional phenotype in infected cells and partially restored a wild-type shape. The pathological morphologies after HIV-1 infection phenocopy leukocytes which contain genetic determinants of specific T cell Inborn Errors of Immunity (IEI) or Primary Immunodeficiencies (PID) that affect the actin cytoskeleton. To identify potential actin regulatory pathways that may be linked to the morphological deformities, uninfected CD4+ T cell morphology was characterized following addition of small molecule chemical inhibitors. The ARP2/3 inhibitor CK-666 recapitulated three of the four abnormal morphologies we observed in HIV-1 infected cells. Restoring ARP2/3 function and cortical actin integrity in people living with HIV-1 infection is a new avenue of investigation to eradicate HIV-1 infected cells from the body.

Dragon's blood attenuates LPS-induced intestinal epithelial barrier dysfunction via upregulation of FAK-DOCK180-Rac1-WAVE2-Arp3 and downregulation of TLR4/NF-κB signaling pathways.

Inflammation-induced intestinal epithelial barrier (IEB) dysfunction is one of the important reasons for the occurrence and development of intestinal inflammatory-related diseases, including ulcerative colitis (UC), Crohn's disease and necrotizing enterocolitis (NEC). Dragon's blood (DB) is a traditional Chinese medicine and has been clinically used to treat UC. However, the protective mechanism of DB on intestinal inflammatory-related diseases has still not been elucidated. The present study aimed to explore the protection mechanism of DB on IEB dysfunction in rat ileum and human colorectal adenocarcinoma cells (Caco-2)/human umbilical vein endothelial cells (HUVECs) coculture system induced by lipopolysaccharide (LPS). DB could ameliorate rat ileum mucosa morphological injury, reduce the accumulation of lipid-peroxidation products and increase the expression of junction proteins. DB also alleviated LPS-induced Caco-2 cells barrier integrity destruction in Caco-2/ HUVECs coculture system, leading to increased trans-endothelial electrical resistance (TEER), reduced cell permeability, and upregulation of expressions of F-actin and junction proteins. DB contributed to the assembly of actin cytoskeleton by upregulating the FAK-DOCK180-Rac1-WAVE2-Arp3 pathway and contributed to the formation of intercellular junctions by downregulating TLR4-MyD88-NF-κB pathway, thus reversing LPS-induced IEB dysfunction. These novel findings illustrated the potential protective mechanism of DB on intestinal inflammatory-related diseases and might be useful for further clinical application of DB.

WAVE2 Is a Vital Regulator in Myogenic Differentiation of Progenitor Cells through the Mechanosensitive MRTFA-SRF Axis.

Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and myogenic transcription factors. Although recent studies have demonstrated the pivotal roles of actin-binding proteins (ABPs) as mechanosensors and signal transducers, the biological significance of WAVE2 (Wiskott-Aldrich syndrome protein family member 2), an ABP essential for actin polymerization, in myogenic differentiation of progenitor cells has not been investigated. Our study provides important insights into the regulatory roles played by WAVE2 in the myocardin-related transcription factor A (MRTFA)-serum response factor (SRF) signaling axis and differentiation of myoblasts. We demonstrate that WAVE2 expression is induced during myogenic differentiation and plays a pivotal role in actin cytoskeletal remodeling in C2C12 myoblasts. Knockdown of WAVE2 in C2C12 cells reduced filamentous actin levels, increased globular actin accumulation, and impaired the nuclear translocation of MRTFA. Furthermore, WAVE2 depletion in myoblasts inhibited the expression and transcriptional activity of SRF and suppressed cell proliferation in myoblasts. Consequently, WAVE2 knockdown suppressed myogenic regulatory factors (i.e., MyoD, MyoG, and SMYD1) expressions, thereby hindering the differentiation of myoblasts. Thus, this study suggests that WAVE2 is essential for myogenic differentiation of progenitor cells by modulating the mechanosensitive MRTFA-SRF axis.

WAVE2 Regulates Actin-Dependent Processes Induced by the B Cell Antigen Receptor and Integrins.

B cell antigen receptor (BCR) signaling induces actin cytoskeleton remodeling by stimulating actin severing, actin polymerization, and the nucleation of branched actin networks via the Arp2/3 complex. This enables B cells to spread on antigen-bearing surfaces in order to increase antigen encounters and to form an immune synapse (IS) when interacting with antigen-presenting cells (APCs). Although the WASp, N-WASp, and WAVE nucleation-promoting factors activate the Arp2/3 complex, the role of WAVE2 in B cells has not been directly assessed. We now show that both WAVE2 and the Arp2/3 complex localize to the peripheral ring of branched F-actin when B cells spread on immobilized anti-Ig antibodies. The siRNA-mediated depletion of WAVE2 reduced and delayed B cell spreading on immobilized anti-Ig, and this was associated with a thinner peripheral F-actin ring and reduced actin retrograde flow compared to control cells. Depleting WAVE2 also impaired integrin-mediated B cell spreading on fibronectin and the LFA-1-induced formation of actomyosin arcs. Actin retrograde flow amplifies BCR signaling at the IS, and we found that depleting WAVE2 reduced microcluster-based BCR signaling and signal amplification at the IS, as well as B cell activation in response to antigen-bearing cells. Hence, WAVE2 contributes to multiple actin-dependent processes in B lymphocytes.