SARS-CoV-2 Transmission in Alberta, British Columbia, and Ontario, Canada, January 2020-January 2022.

We estimated COVID-19 transmission potential and case burden by variant type in Alberta, British Columbia, and Ontario, Canada, during January 23, 2020-January 27, 2022; we also estimated the effectiveness of public health interventions to reduce transmission. We estimated time-varying reproduction number (Rt) over 7-day sliding windows and nonoverlapping time-windows determined by timing of policy changes. We calculated incidence rate ratios (IRRs) for each variant and compared rates to determine differences in burden among provinces. Rt corresponding with emergence of the Delta variant increased in all 3 provinces; British Columbia had the largest increase, 43.85% (95% credible interval [CrI] 40.71%-46.84%). Across the study period, IRR was highest for Omicron (8.74 [95% CrI 8.71-8.77]) and burden highest in Alberta (IRR 1.80 [95% CrI 1.79-1.81]). Initiating public health interventions was associated with lower Rt and relaxing restrictions and emergence of new variants associated with increases in Rt.

High-pressure studies of size dependent yield strength in rhenium diboride nanocrystals.

The superhard ReB2 system is the hardest pure phase diboride synthesized to date. Previously, we have demonstrated the synthesis of nano-ReB2 and the use of this nanostructured material for texture analysis using high-pressure radial diffraction. Here, we investigate the size dependence of hardness in the nano-ReB2 system using nanocrystalline ReB2 with a range of grain sizes (20-60 nm). Using high-pressure X-ray diffraction, we characterize the mechanical properties of these materials, including bulk modulus, lattice strain, yield strength, and texture. In agreement with the Hall-Petch effect, the yield strength increases with decreasing size, with the 20 nm ReB2 exhibiting a significantly higher yield strength than any of the larger grained materials or bulk ReB2. Texture analysis on the high pressure diffraction data shows a maximum along the [0001] direction, which indicates that plastic deformation is primarily controlled by the basal slip system. At the highest pressure (55 GPa), the 20 nm ReB2 shows suppression of other slip systems observed in larger ReB2 samples, in agreement with its high yield strength. This behavior, likely arises from an increased grain boundary concentration in the smaller nanoparticles. Overall, these results highlight that even superhard materials can be made more mechanically robust using nanoscale grain size effects.

Perception of affordable diet is associated with pre-school children's diet diversity in Addis Ababa, Ethiopia: the EAT Addis survey.

BACKGROUND: Despite improvements in food access and nutrition security over the last few decades, malnutrition remains a major public health problem. One of the significant contributors to these problems is affordability of nutritious food. This study aimed to examine the association between perceived food affordability and pre-school children's diet diversity in Addis Ababa, Ethiopia. METHODS: Cross-sectional data from 2017 to 18 were used for the analysis. A 24-hour dietary recall assessment was done to assess children's dietary diversity (DD). We used a modified operational definition of affordability indicator called perceived affordability of dietary diversity (afford-DD) to evaluate the impact of the food environment in terms of affordability at the household level. A sample (n 4,898) of children aged 6-59 months representative of households in Addis Ababa was randomly selected using a multistage sampling procedure including all districts in the city. Mixed-effects linear regression models were used to assess the association between children's DD and afford-DD. RESULTS: The survey revealed that the mean (standard deviation [SD]) of children's DD was 3.9 [± 1.4] while the mean [SD] of afford-DD was 4.6 [± 2.1]. Overall, 59.8% of children met the minimum dietary diversity (≥ 4 food groups). White roots and tubers were the most commonly consumed food groups regardless of their affordability. Considerable variations were observed between households that reported the food item affordable and not affordable in consumption of Vitamin A rich vegetables and fruits, meat and fish, egg, and dairy. The children's DD was positively associated with afford-DD after adjusting for maternal education, household wealth status and other relevant confounding. Higher maternal education modified the association between affordability and children's diet diversity. CONCLUSIONS: This study suggests higher perceived food affordability was associated with better diet diversity in children. A higher level of maternal education had the potential to mitigate affordability challenges in meeting the children's dietary diversity needs. Our study emphasizes the need for inclusive food programs and nutrition interventions addressing social differences, intensifying efforts to make nutrient-rich diets affordable for the less privileged, and highlights the potential benefits of targeting maternal education in addressing child dietary diversity.

Hic-5 regulates extracellular matrix-associated gene expression and cytokine secretion in cancer associated fibroblasts.

The focal adhesion protein, Hic-5 plays a key role in promoting extracellular matrix deposition and remodeling by cancer associated fibroblasts within the tumor stroma to promote breast tumor cell invasion. However, whether stromal matrix gene expression is regulated by Hic-5 is still unknown. Utilizing a constitutive Hic-5 knockout, Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen spontaneous breast tumor mouse model, bulk RNAseq analysis was performed on cancer associated fibroblasts isolated from Hic-5 knockout mammary tumors. Functional network analysis highlighted a key role for Hic-5 in extracellular matrix organization, with both structural matrix genes, as well as matrix remodeling genes being differentially expressed in relation to Hic-5 expression. The subcellular distribution of the MRTF-A transcription factor and expression of a subset of MRTF-A responsive genes was also impacted by Hic-5 expression. Additionally, cytokine array analysis of conditioned media from the Hic-5 and Hic-5 knockout cancer associated fibroblasts revealed that Hic-5 is important for the secretion of several key factors that are associated with matrix remodeling, angiogenesis and immune evasion. Together, these data provide further evidence of a central role for Hic-5 expression in cancer associated fibroblasts in regulating the composition and organization of the tumor stroma microenvironment to promote breast tumor progression.

Sex Differences in Dopamine Release in Nucleus Accumbens and Dorsal Striatum Determined by Chronic Fast Scan Cyclic Voltammetry: Effects of social housing and repeated stimulation.

We investigated sex differences in dopamine (DA) release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) using a chronic 16-channel carbon fiber electrode and fast-scan cyclic voltammetry (FSCV). Electrical stimulation (ES; 60Hz) induced DA release was recorded in the NAc of single or pair-housed male and female rats. When core (NAcC) and shell (NAcS) were recorded simultaneously, there was greater ES DA release in NAcC of pair-housed females compared with single females and males. Housing did not affect ES NAc DA release in males. In contrast, there was significantly more ES DA release from the DLS of female rats than male rats. This was true prior to and after treatment with methamphetamine. Furthermore, in castrated (CAST) males and ovariectomized (OVX) females, there were no sex differences in ES DA release from the DLS, demonstrating the hormone dependence of this sex difference. However, in the DLS of both intact and gonadectomized rats, DA reuptake was slower in females than in males. Finally, DA release following ES of the medial forebrain bundle at 60Hz was studied over four weeks. ES DA release increased over time for both CAST males and OVX females, demonstrating sensitization. Using this novel 16-channel chronic FSCV electrode, we found sex differences in the effects of social housing in the NAcS, sex differences in DA release from intact rats in DLS, sex differences in DA reuptake in DLS of intake and gonadectomized rats, and we report sensitization of ES-induced DA release in DLS in vivo.

Developmental changes in individual alpha frequency: Recording EEG data during public engagement events.

Statistical power in cognitive neuroimaging experiments is often very low. Low sample size can reduce the likelihood of detecting real effects (false negatives) and increase the risk of detecting non-existing effects by chance (false positives). Here, we document our experience of leveraging a relatively unexplored method of collecting a large sample size for simple electroencephalography (EEG) studies: by recording EEG in the community during public engagement and outreach events. We collected data from 346 participants (189 females, age range 6-76 years) over 6 days, totalling 29 hours, at local science festivals. Alpha activity (6-15 Hz) was filtered from 30 seconds of signal, recorded from a single electrode placed between the occipital midline (Oz) and inion (Iz) while the participants rested with their eyes closed. A total of 289 good-quality datasets were obtained. Using this community-based approach, we were able to replicate controlled, lab-based findings: individual alpha frequency (IAF) increased during childhood, reaching a peak frequency of 10.28 Hz at 28.1 years old, and slowed again in middle and older age. Total alpha power decreased linearly, but the aperiodic-adjusted alpha power did not change over the lifespan. Aperiodic slopes and intercepts were highest in the youngest participants. There were no associations between these EEG indexes and self-reported fatigue, measured by the Multidimensional Fatigue Inventory. Finally, we present a set of important considerations for researchers who wish to collect EEG data within public engagement and outreach environments.

Paxillin regulates Rab5-mediated vesicle motility through modulating microtubule acetylation.

Rab GTPase-mediated vesicle trafficking of cell surface proteins, including integrins, through endocytic and recycling pathways is important in controlling cell-extracellular matrix interactions during cell migration. The focal adhesion adaptor protein, paxillin, plays a central role in regulating adhesion dynamics and was previously shown to promote anterograde vesicle trafficking through modulation of microtubule acetylation via its inhibition of the deacetylase HDAC6. The role of paxillin in retrograde trafficking is unknown. Herein, we identified a role for paxillin in the modulation of the Rab5 GTPase, which is necessary for regulating early endosome dynamics and focal adhesion turnover. Using MDA-MB-231 breast cancer cells and paxillin (-/-) fibroblasts, paxillin was shown to impact Rab5-associated vesicle size and distribution, as well as Rab5 GTPase activity, through its modulation of HDAC6. Using a combination of real-time imaging and particle tracking analysis, paxillin was shown to promote Rab5-associated vesicle motility through inhibition of HDAC6-mediated micro-tubule deacetylation, along with the localization of active integrin to focal adhesions.

Fluid shear stress affects the metabolic and toxicological response of the rainbow trout gill cell line RTgill-W1.

The Rainbow trout gill cell-line (RTgill-W1) has been accepted by the Organisation for Economic Co-operation and Development (OECD TG249) as a replacement for fish in acute toxicity tests. In these tests cells are exposed under static conditions. In contrast, in vivo, water moves over fish gills generating fluid shear stress (FSS) that alters cell physiology and response to toxicants. The current study uses a specialised 3D printed chamber designed to house inserts and allows for the flow (0.2 dynes cm2) of water over the cells. This system was used to assess RTgill-W1 cell responses to FSS in the absence and presence of copper (Cu) over 24 h. FSS caused increased gene expression of mechanosensitive channel peizo1 and the Cu-transporter atp7a, elevated reactive oxygen species generation and increased expression of superoxidase dismutase. Cell metabolism was unaffected by Cu (0.163 µM to 2.6 µM Cu) under static conditions but significantly reduced by FSS + Cu above 1.3 µM. Differential expression of metallothionein (mt) a and b was observed with increased expression of mta under static conditions and mtb under FSS on exposure to Cu. These findings highlight toxicologically relevant mechanosensory responses by RTgill-W1 to FSS that may influence toxicological responses.

Granzyme B Contributes to Choroidal Neovascularization and Age-Related Macular Degeneration Through Proteolysis of Thrombospondin-1.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. The pathology of neovascular age-related macular degeneration (nAMD), also known as wet AMD, is associated with an abnormal blood vessel growth in the eye and involves an imbalance of proangiogenic and antiangiogenic factors. Thrombospondin (TSP)-1 and TSP-2 are endogenous matricellular proteins that inhibit angiogenesis. TSP-1 is significantly diminished in eyes with AMD, although the mechanisms involved in its reduction are unknown. Granzyme B (GzmB) is a serine protease with an increased extracellular activity in the outer retina and choroid of human eyes with nAMD-related choroidal neovascularization (CNV). This study investigated whether TSP-1 and TSP-2 are GzmB substrates using in silico and cell-free cleavage assays and explored the relationship between GzmB and TSP-1 in human eyes with nAMD-related CNV and the effect of GzmB on TSP-1 in retinal pigment epithelial culture and an explant choroid sprouting assay (CSA). In this study, TSP-1 and TSP-2 were identified as GzmB substrates. Cell-free cleavage assays substantiated the GzmB proteolysis of TSP-1 and TSP-2 by showing dose-dependent and time-dependent cleavage products. TSP-1 and TSP-2 proteolysis were hindered by the inhibition of GzmB. In the retinal pigment epithelium and choroid of human eyes with CNV, we observed a significant inverse correlation between TSP-1 and GzmB, as indicated by lower TSP-1 and higher GzmB immunoreactivity. In CSA, the vascular sprouting area increased significantly with GzmB treatment and reduced significantly with TSP-1 treatment. Western blot showed significantly reduced expression of TSP-1 in GzmB-treated retinal pigment epithelial cell culture and CSA supernatant compared with that in controls. Together, our findings suggest that the proteolysis of antiangiogenic factors such as TSP-1 by extracellular GzmB might represent a mechanism through which GzmB may contribute to nAMD-related CNV. Future studies are needed to investigate whether pharmacologic inhibition of extracellular GzmB can mitigate nAMD-related CNV by preserving intact TSP-1.

The predictive value of cortical activity during motor imagery for subacute spinal cord injury-induced neuropathic pain.

OBJECTIVE: The aim of this study is to explore whether cortical activation and its lateralization during motor imagery (MI) in subacute spinal cord injury (SCI) are indicative of existing or upcoming central neuropathic pain (CNP). METHODS: Multichannel electroencephalogram was recorded during MI of both hands in four groups of participants: able-bodied (N = 10), SCI and CNP (N = 11), SCI who developed CNP within 6 months of EEG recording (N = 10), and SCI who remained CNP-free (N = 10). Source activations and its lateralization were derived in four frequency bands in 20 regions spanning sensorimotor cortex and pain matrix. RESULTS: Statistically significant differences in lateralization were found in the theta band in premotor cortex (upcoming vs existing CNP, p = 0.036), in the alpha band at the insula (healthy vs upcoming CNP, p = 0.012), and in the higher beta band at the somatosensory association cortex (no CNP vs upcoming CNP, p = 0.042). People with upcoming CNP had stronger activation compared to those with no CNP in the higher beta band for MI of both hands. CONCLUSIONS: Activation intensity and lateralization during MI in pain-related areas might hold a predictive value for CNP. SIGNIFICANCE: The study increases understanding of the mechanisms underlying transition from asymptomatic to symptomatic early CNP in SCI.

Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation.

BACKGROUND: Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while abundant in inflamed tissues. Initially thought to play an exclusive role in immune-mediated cell death, extracellular GzmK can also promote inflammation. OBJECTIVES: To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease. METHODS: A panel of human AD and control samples was analysed to determine if GzmK is elevated. Next, to determine a pathological role for GzmK in AD-like skin inflammation, oxazolone-induced dermatitis was induced in GzmK-/- and wild-type (WT) mice. RESULTS: In human lesional AD samples, there was an increase in the number of GzmK+ cells compared with healthy controls. GzmK-/- mice exhibited reduced overall disease severity characterized by reductions in scaling, erosions and erythema. Surprisingly, the presence of GzmK did not notably increase the overall pro-inflammatory response or epidermal barrier permeability in WT mice; rather, GzmK impaired angiogenesis, increased microvascular damage and microhaemorrhage. Mechanistically, GzmK contributed to vessel damage through cleavage of syndecan-1, a key structural component of the glycocalyx, which coats the luminal surface of vascular endothelia. CONCLUSIONS: GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.

Characteristics of food environments that influence food acquisition and diets of women in low- and middle-income countries: a scoping review protocol.

OBJECTIVE: This scoping review aims to identify and map characteristics of food environments that influence food acquisition practices and dietary intake of women of reproductive age in low- and middle-income countries. INTRODUCTION: Due to the disproportionate burden of malnutrition on women of reproductive age in low- and middle-income countries, accelerated progress in improving women's nutrition is required to achieve Sustainable Development Goal 2 "Zero hunger" by 2030. Food environments are increasingly recognized as the key interface between consumers and food systems; however, little is known about the characteristics that influence women's food acquisition and diets in low- and middle-income countries, especially during physiological stages of heightened nutritional requirement, such as pre-conception, pregnancy, and breastfeeding. INCLUSION CRITERIA: This review will consider quantitative, qualitative, mixed methods, or review studies that report on the influence of food environment characteristics on food acquisition practices and dietary intake of women aged 15 to 49 years in any low- or middle-income country, as defined by the World Bank in 2021. METHODS: Twenty-one databases across EBSCO, Web of Science Core Collection, and PubMed platforms will be searched. Screening, selection, and data extraction will be performed in duplicate by 2 members of the team, with any discrepancies resolved by group discussion. The patterns of food acquisition and dietary intake in relation to food environment characteristics will be charted, mapped, and summarized in tabular and graphical formats. Findings will inform the refinement of effective food environment conceptual frameworks for this nutritionally vulnerable group.

Noncytotoxic Roles of Granzymes in Health and Disease.

Granzymes are serine proteases previously believed to play exclusive and somewhat redundant roles in lymphocyte-mediated target cell death. However, recent studies have challenged this paradigm. Distinct substrate profiles and functions have since emerged for each granzyme while their dysregulated proteolytic activities have been linked to diverse pathologies.

Sulfaphenazole reduces thermal and pressure injury severity through rapid restoration of tissue perfusion.

Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia-reperfusion (I/R) have a major causative role for tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.

Paternal nicotine taking elicits heritable sex-specific phenotypes that are mediated by hippocampal Satb2.

Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naive male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring.

Perspective: Food Environment Research Priorities for Africa-Lessons from the Africa Food Environment Research Network.

Over the last 2 decades, many African countries have undergone dietary and nutrition transitions fueled by globalization, rapid urbanization, and development. These changes have altered African food environments and, subsequently, dietary behaviors, including food acquisition and consumption. Dietary patterns associated with the nutrition transition have contributed to Africa's complex burden of malnutrition-obesity and other diet-related noncommunicable diseases (DR-NCDs)-along with persistent food insecurity and undernutrition. Available evidence links unhealthy or obesogenic food environments (including those that market and offer energy-dense, nutrient-poor foods and beverages) with suboptimal diets and associated adverse health outcomes. Elsewhere, governments have responded with policies to improve food environments. However, in Africa, the necessary research and policy action have received insufficient attention. Contextual evidence to motivate, enable, and create supportive food environments in Africa for better population health is urgently needed. In November 2020, the Measurement, Evaluation, Accountability, and Leadership Support for Noncommunicable Diseases Prevention Project (MEALS4NCDs) convened the first Africa Food Environment Research Network Meeting (FERN2020). This 3-d virtual meeting brought researchers from around the world to deliberate on future directions and research priorities related to improving food environments and nutrition across the African continent. The stakeholders shared experiences, best practices, challenges, and opportunities for improving the healthfulness of food environments and related policies in low- and middle-income countries. In this article, we summarize the proceedings and research priorities identified in the meeting to advance the food environment research agenda in Africa, and thus contribute to the promotion of healthier food environments to prevent DR-NCDs, and other forms of malnutrition.

Residential Food Environment, Household Wealth and Maternal Education Association to Preschoolers' Consumption of Plant-Based Vitamin A-Rich Foods: The EAT Addis Survey in Addis Ababa.

Vitamin A deficiency is common among preschoolers in low-income settings and a serious public health concern due to its association to increased morbidity and mortality. The limited consumption of vitamin A-rich food is contributing to the problem. Many factors may influence children's diet, including residential food environment, household wealth, and maternal education. However, very few studies in low-income settings have examined the relationship of these factors to children's diet together. This study aimed to assess the importance of residential food availability of three plant-based groups of vitamin A-rich foods, household wealth, and maternal education for preschoolers' consumption of plant-based vitamin A-rich foods in Addis Ababa. A multistage sampling procedure was used to enroll 5467 households with under-five children and 233 residential food environments with 2568 vendors. Data were analyzed using a multilevel binary logistic regression model. Overall, 36% (95% CI: 34.26, 36.95) of the study children reportedly consumed at least one plant-based vitamin A-rich food group in the 24-h dietary recall period. The odds of consuming any plant-based vitamin A-rich food were significantly higher among children whose mothers had a higher education level (AOR: 2.55; 95% CI: 2.01, 3.25), those living in the highest wealth quintile households (AOR: 2.37; 95% CI: 1.92, 2.93), and in residentials where vitamin A-rich fruits were available (AOR: 1.20; 95% CI: 1.02, 1.41). Further research in residential food environment is necessary to understand the purchasing habits, affordability, and desirability of plant-based vitamin A-rich foods to widen strategic options to improve its consumption among preschoolers in low-income and low-education communities.

Consumer experiences of food environments during the Covid-19 pandemic: Global insights from a rapid online survey of individuals from 119 countries.

This study investigates consumer experiences of food environments and food acquisition practices during the Covid-19 pandemic. Our rapid assessment online survey featured a convenience sample of 2015 individuals from 119 countries, spanning Western Europe, North America, Latin America, Asia-Pacific, and Africa. Data collection took place in April 2020 during the second month of the pandemic. Participants were recruited via existing networks of the United Nations System Standing Committee on Nutrition, through social media, and by snowballing. The majority of participants were female (71.9%), from low- and middle-income countries (51.0%), and working in nutrition or healthcare (39.3%). Qualitative thematic analysis and descriptive statistics reveal a series of common global experiences related to food availability and accessibility, food prices and affordability, food acquisition practices, and food preparation and consumption. The importance of community food participation, food sharing, and resource allocation are highlighted, along with increasing awareness of healthy diets and food waste. We identify ten synergistic policy entry points to: 1) build resilient and equitable food environments resistant to stresses and shocks; 2) harness positive dietary-related behaviors manifested during the pandemic; and, 3) mitigate the projected nutrition crisis and promote sustainable healthy diets for all.

Labeling, causal attributions, and social network ties to people with mental illness.

Evidence supports Allport's (1954) contention that social contact reduces mental illness stigma and promotes symptom recognition. However, an important limitation of existing research is that it typically relies on relatively simplistic measures of contact (e.g., any contact, number of contacts). Here, we build on prior work by examining how contact with persons with mental illness within social networks shapes labeling processes and beliefs about the causes of mental illness. Using egocentric network methods and vignette data from the 2018 General Social Survey (N = 1173), findings reveal that connections to valued ties (e.g., friends, family) that disconfirm commonly held stereotypes about people with mental illness contribute to improved recognition of mental illness and reduce the likelihood of endorsing stigmatizing beliefs about causes of mental illness. By using network theory and methods, this research extends current understanding of the role of contact by revealing not only whether contact matters, but how it matters and under what circumstances it may reduce prejudice and discrimination attached to mental illness in contemporary society.

Paxillin promotes breast tumor collective cell invasion through maintenance of adherens junction integrity.

Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro three-dimensional (3D) tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. The 2D cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell-cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases.