Cellular Mechanisms of RET Receptor Dysfunction in Multiple Endocrine Neoplasia 2.

REarranged during Transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point-mutations give rise to the inherited cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of ligand. These mutations cause intrinsic biochemical changes in RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

The catalogue of Mycobacterium tuberculosis mutations associated with drug resistance to 12 drugs in China from a nationwide survey: a genomic analysis.

BACKGROUND: WHO issued the first edition catalogue of Mycobacterium tuberculosis complex (MTBC) mutations associated with drug resistance in 2021. However, country-specific issues might lead to arising complex and additional drug-resistant mutations. We aimed to fully reflect the characteristics of drug resistance mutations in China. METHODS: We analysed MTBC isolates from the nationwide drug-resistant tuberculosis surveillance with 70 counties in 31 provinces, municipalities, and autonomous regions in China. Three types of MYCOTB plates were used to perform drug susceptibility testing for 12 antibiotics (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, amikacin, kanamycin, ethionamide, clofazimine, linezolid, delamanid, and bedaquiline). Mutations were divided into five groups according to their odds ratios, positive predictive values, false discovery rate-corrected p values, and 95% CIs: (1) associated with resistance; (2) associated with resistance-interim; (3) uncertain significance; (4) not associated with resistance-interim; and (5) not associated with resistance. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to quantify the association between mutations and minimum inhibitory concentrations (MICs). Our dataset was compared with the first edition of the WHO catalogue. FINDINGS: We analysed 10 146 MTBC isolates, of which 9071 (89·4%) isolates were included in the final analysis. 744 (8·2%) isolates were resistant to rifampicin and 1339 (14·8%) to isoniazid. 208 (1·9%) of 11 065 mutations were classified as associated with resistance or associated with resistance-interim. 33 (97·1%) of 34 mutations in group 1 and 92 (52·9%) of 174 in group 2 also appeared in groups 1 or 2 of the WHO catalogue. Of 81 indel mutations in group 2, 15 (18·5%) were in the WHO catalogue. The newly discovered mutation gyrA_Ala288Asp was associated with levofloxacin resistance. MIC values for rifampicin, isoniazid, moxifloxacin, and levofloxacin corresponding to resistance mutations in group 1 were significantly different (p<0·0001), and 12 high-level resistance mutations were detected. 61 mutations in group 3 occurred as solo in at least five phenotypically susceptible isolates, but with MIC values moderately higher than other susceptible isolates. Among 945 phenotypically resistant but genotypically susceptible isolates, 433 (45·8%) were mutated for at least one efflux pump gene. INTERPRETATION: Our analysis reflects the complexity of drug resistance mutations in China and suggests that indel mutations, efflux pump genes, protein structure, and MICs should be fully considered in the WHO catalogue, especially in countries with a high tuberculosis burden. FUNDING: National Key Research and Development Program of China and the Science and Technology Major Project of Tibetan Autonomous Region of China.

The Impact of Household Dysfunction on Dating Violence Perpetration Among Adolescents in the United States: A Scoping Review.

Adverse childhood experiences, such as household dysfunction (HD), play a central role in how adolescents establish, experience, and navigate the challenges of relationship formation, maintenance, and dissolution. HD exposures have been independently associated with dating violence (DV) perpetration in both adolescents and adults. However, research examining the association between the concurrent effect of HD on DV perpetration, especially among adolescents remains scarce. Thus, we conducted a scoping review to accumulate and summarize existing research regarding the impact of HD on DV perpetration among adolescents aged 10 to 17 years in the United States. We used three electronic databases, Medline (Ovid), PsycINFO, and EMBASE, to search for studies published in English between 2013 and August 2023. A total of 14 studies were retained for this review after full-text screening. Most of the included studies (64%) were longitudinal. Concerning HD measurement, 71% of studies evaluated witnessing intimate partner violence (IPV), and the remaining 29% assessed family conflict, both using different instruments. Regarding DV measurement, 43% of studies utilized the Safe Dates Abuse measures to assess various forms of DV perpetration. Findings from 3/4 (75%) studies that evaluated family conflict found it to be a significant predictor of DV perpetration. Additionally, 8/10 (80%) studies that assessed exposure to IPV reported significant associations with various forms of DV perpetration among adolescents. None of the included studies measured HD comprehensively; thus, measurement development is imperative. Findings from this review may help initiate the development of a more comprehensive HD measure, promote early intervention, and foster resilience among adolescents.

Correction: The effect of M. tuberculosis lineage on clinical phenotype.

[This corrects the article DOI: 10.1371/journal.pgph.0001788.].

Whole-of-School Physical Activity Promotion: Findings From Elementary Schools in the United States.

INTRODUCTION: Schools can support students' participation in physical activity by offering opportunities consistent with a Whole-of-School (WOS) approach; however, the extent to which physical activity opportunities are provided and how school-level characteristics associate with their use remains unclear. This study examined how elementary schools' use a WOS approach to promote physical activity, as well as associations between school-level characteristics and physical activity opportunities provided. METHODS: Survey data was collected from 162 elementary schools participating in the NFL PLAY 60 FitnessGram Project during the 2022-2023 school year. A WOS index (ranging from 0 to 12) was created from responses by school staff on questions about 6 physical activity practices (physical education, recess, before- and after-school programs, classroom-based approaches, active transport). Multivariable regression models examined associations between school characteristics and WOS index scores. Analyses were completed in Spring 2024. RESULTS: Fully adjusted models indicated a statistically significant difference between the percentage of economically disadvantaged students served and WOS index score. Schools serving between 20% and 39% (p<0.001), 40%-59% (p<0.01), 60%-79% (p<0.01) and ≥80% (p<0.001) economically disadvantaged students scored significantly lower on the WOS index compared to schools with 0%-19% economically disadvantaged students. CONCLUSIONS: Studies are needed to examine disparities in physical activity practices consistent with a WOS approach to understand the implications on health, academic performance, and other key outcomes. This information can inform the development of strategies to address disparities and ensure youth have equitable access to school-based physical activity opportunities.

Barriers to and facilitators of implementing colorectal cancer screening evidence-based interventions in federally qualified health centers: a qualitative study.

BACKGROUND: There is an urgent need to increase colorectal cancer screening (CRCS) uptake in Texas federally qualified health centers (FQHCs), which serve a predominantly vulnerable population with high demands. Empirical support exists for evidence-based interventions (EBIs) that are proven to increase CRCS; however, as with screening, their use remains low in FQHCs. This study aimed to identify barriers to and facilitators of implementing colorectal cancer screening (CRCS) evidence-based interventions (EBIs) in federally qualified health centers (FQHCs), guided by the Consolidated Framework for Implementation Research (CFIR). METHODS: We recruited employees involved in implementing CRCS EBIs (e.g., physicians) using data from a CDC-funded program to increase the CRCS in Texas FQHCs. Through 23 group interviews, we explored experiences with practice change, CRCS promotion and quality improvement initiatives, organizational readiness, the impact of COVID-19, and the use of CRCS EBIs (e.g., provider reminders). We used directed content analysis with CFIR constructs to identify the critical facilitators and barriers. RESULTS: The analysis revealed six primary CFIR constructs that influence implementation: information technology infrastructure, innovation design, work infrastructure, performance measurement pressure, assessing needs, and available resources. Based on experiences with four recommended EBIs, participants described barriers, including data limitations of electronic health records and the design of reminder alerts targeted at deliverers and recipients of patient or provider reminders. Implementation facilitators include incentivized processes to increase provider assessment and feedback, existing clinic processes (e.g., screening referrals), and available resources to address patient needs (e.g., transportation). Staff buy-in emerged as an implementation facilitator, fostering a conducive environment for change within clinics. CONCLUSIONS: Using CFIR, we identified barriers, such as the burden of technology infrastructure, and facilitators, such as staff buy-in. The results, which enhance our understanding of CRCS EBI implementation in FQHCs, provide insights into designing nuanced, practical implementation strategies to improve cancer control in a critical setting.

Loss of tumor suppressor TMEM127 drives RET-mediated transformation through disrupted membrane dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTKs) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumor pheochromocytoma (PCC) can be caused by activating mutations of the rearranged during transfection (RET) receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumor suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin-coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

Reliability and validity of the Patient Health Questionnaire-4 scale and its subscales of depression and anxiety among US adults based on nativity.

BACKGROUND: The burdens of anxiety and depression symptoms have significantly increased in the general US population, especially during this COVID-19 epidemiological crisis. The first step in an effective treatment for anxiety and depression disorders is screening. The Patient Health Questionnaire-4 (PHQ-4, a 4-item measure of anxiety/depression) and its subscales (PHQ-2 [a 2-item measure of depression] and Generalized Anxiety Disorder [GAD-2, a 2-item measure of anxiety]) are brief but effective mass screening instruments for anxiety and depression symptoms in general populations. However, little to no study examined the psychometric properties (i.e., reliability and validity) of the PHQ-4 and its subscales (PHQ-2 and GAD-2) in the general US adult population or based on US nativity (i.e., foreign-born vs. the US-born). We evaluated the psychometric properties of the PHQ-4 and its subscales in US adults, as well as the psychometric equivalence of the PHQ-4 scale based on nativity. METHODS: We conducted a cross-sectional survey of 5,140 adults aged ≥ 18 years. We examined the factorial validity and dimensionality of the PHQ-4 with confirmatory factor analysis (CFA). A multiple-group confirmatory factor analysis (MCFA) was used to evaluate the comparability of the PHQ-4 across nativity groups. Reliability indices were assessed. Also, the scales' construct validities were assessed by examining the associations of both the PHQ-4 and its subscales' scores with the sociodemographic characteristics and the 3-item UCLA Loneliness scale. RESULTS: The internal consistencies were high for the PHQ-4 scale (α = 0.92) and its subscales of PHQ-2 (α = 0.86) and GAD-2 (α = 0.90). The CFA fit indices showed evidence for the two-factor structure of the PHQ-4. The two factors (i.e., anxiety and depression) were significantly correlated (r = 0.92). The MCFA demonstrated measurement invariance of the PHQ-4 across the nativity groups, but the model fits the data better in the foreign-born group. There were significant associations of the PHQ-4 scale and its subscales' scores with the sociodemographic characteristics and the UCLA Loneliness scale (all p < 0.001). CONCLUSIONS: The PHQ-4 and its subscales are reliable and valid measures to screen anxiety and depression symptoms in the general US adult population, especially in foreign-born individuals during the COVID-19 pandemic.

Urban-Rural Differences in School Districts' Local Wellness Policies and Policy Implementation Environments.

Higher rates of obesity in rural compared to urban districts suggest environmental differences that affect student health. This study examined urban-rural differences in districts' local wellness policies (LWPs) and LWP implementation environments. Cross-sectional data from two assessments in Texas were analyzed. In assessment one, each district's LWP was reviewed to see if 16 goals were included. In assessment two, an audit was conducted to identify the presence of a wellness plan (a document with recommendations for implementing LWPs), triennial LWP assessment, and school health advisory councils (SHACs) on the district website. Rural districts' LWPs had a smaller number of total goals (B = -2.281, p = 0.014), nutrition education goals (B = -0.654, p = 0.005), and other school-based activity goals (B = -0.675, p = 0.001) in their LWPs, compared to urban districts. Rural districts also had lower odds of having a wellness plan (OR = 0.520, 95% CI = 0.288-0.939), p = 0.030) and a SHAC (OR = 0.201, 95% CI = 0.113-0.357, p < 0.001) to support LWP implementation, compared to urban districts. More resources may be needed to create effective SHACs that can help develop and implement LWPs in rural areas. Important urban-rural differences exist in Texas LWPs and LWP implementation environments.

Prediction of pyrazinamide resistance in Mycobacterium tuberculosis using structure-based machine-learning approaches.

Background: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in pncA, encoding an enzyme that converts pyrazinamide into its active form. Methods: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features. Results: The best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4027 samples harbouring 367 unique missense mutations in pncA derived from 24 231 clinical isolates. Conclusions: This work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs.

Rifampicin resistant Mycobacterium tuberculosis in Vietnam, 2020-2022.

Objective: We conducted a descriptive analysis of multi-drug resistant tuberculosis (MDR-TB) in Vietnam's two largest cities, Hanoi and Ho Chi Minh city. Methods: All patients with rifampicin resistant tuberculosis were recruited from Hanoi and surrounding provinces between 2020 and 2022. Additional patients were recruited from Ho Chi Minh city over the same time period. Demographic data were recorded from all patients, and samples collected, cultured, whole genome sequenced and analysed for drug resistance mutations. Genomic susceptibility predictions were made on the basis of the World Health Organization's catalogue of mutations in Mycobacterium tuberculosis associated with drug resistance, version 2. Comparisons were made against phenotypic drug susceptibility test results where these were available. Multivariable logistic regression was used to assess risk factors for previous episodes of tuberculosis. Results: 233/265 sequenced isolates were of sufficient quality for analysis, 146 (63 %) from Ho Chi Minh City and 87 (37 %) from Hanoi. 198 (85 %) were lineage 2, 20 (9 %) were lineage 4, and 15 (6 %) were lineage 1. 17/211 (8 %) for whom HIV status was known were infected, and 109/214 (51 %) patients had had a previous episode of tuberculosis. The main risk factor for a previous episode was HIV infection (odds ratio 5.1 (95 % confidence interval 1.3-20.0); p = 0.021). Sensitivity for predicting first-line drug resistance from whole genome sequencing data was over 90 %, with the exception of pyrazinamide (85 %). For moxifloxacin and amikacin it was 50 % or less. Among rifampicin-resistant isolates, prevalence of resistance to each non-first-line drug was < 20 %. Conclusions: Drug resistance among most MDR-TB strains in Vietnam's two largest cities is confined largely to first-line drugs. Living with HIV is the main risk factor among patients with MDR-TB for having had a previous episode of tuberculosis.

Targeted sequencing from cerebrospinal fluid for rapid identification of drug-resistant tuberculous meningitis.

Mortality from tuberculous meningitis (TBM) remains around 30%, with most deaths occurring within 2 months of starting treatment. Mortality from drug-resistant strains is higher still, making early detection of drug resistance (DR) essential. Targeted next-generation sequencing (tNGS) produces high read depths, allowing the detection of DR-associated alleles with low frequencies. We applied Deeplex Myc-TB-a tNGS assay-to cerebrospinal fluid (CSF) samples from 72 adults with microbiologically confirmed TBM and compared its genomic drug susceptibility predictions to a composite reference standard of phenotypic susceptibility testing (pDST) and whole genome sequencing, as well as to clinical outcomes. Deeplex detected Mycobacterium tuberculosis complex DNA in 24/72 (33.3%) CSF samples and generated full DR reports for 22/24 (91.7%). The read depth generated by Deeplex correlated with semi-quantitative results from MTB/RIF Xpert. Alleles with <20% frequency were seen at canonical loci associated with first-line DR. Disregarding these low-frequency alleles, Deeplex had 100% concordance with the composite reference standard for all drugs except pyrazinamide and streptomycin. Three patients had positive CSF cultures after 30 days of treatment; reference tests and Deeplex identified isoniazid resistance in two, and Deeplex alone identified low-frequency rifampin resistance alleles in one. Five patients died, of whom one had pDST-identified pyrazinamide resistance. tNGS on CSF can rapidly and accurately detect drug-resistant TBM, but its application is limited to those with higher bacterial loads. In those with lower bacterial burdens, alternative approaches need to be developed for both diagnosis and resistance detection.

Genomic insights into anthropozoonotic tuberculosis in captive sun bears (Helarctos malayanus) and an Asiatic black bear (Ursus thibetanus) in Cambodia.

Contact between humans and wildlife presents a risk for both zoonotic and anthropozoonotic disease transmission. In this study we report the detection of human strains of Mycobacterium tuberculosis in sun bears and an Asiatic black bear in a wildlife rescue centre in Cambodia, confirming for the first time the susceptibility of these bear species to tuberculosis when in close contact with humans. After genotyping revealed two different strains of M. tuberculosis from cases occurring between 2009 and 2019, 100 isolates from 30 sun bear cases, a single Asiatic black bear case, and a human case were subjected to whole genome sequencing. We combined single nucleotide polymorphism analysis and exploration of mixed base calls with epidemiological data to indicate the evolution of each outbreak. Our results confirmed two concurrent yet separate tuberculosis outbreaks and established a likely transmission route in one outbreak where the human case acted as an intermediatory between bear cases. In both outbreaks, we observed high rates of transmission and progression to active disease, suggesting that sun bears are highly susceptible to tuberculosis if exposed under these conditions. Overall, our findings highlight the risk of bi-directional transmission of tuberculosis between humans and captive bears in high human tuberculosis burden regions, with implied considerations for veterinary and public health. We also demonstrate the use of standard genomic approaches to better understand disease outbreaks in captive wildlife settings and to inform control and prevention measures.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

Comparing the Use and Effectiveness of In-Person and Remote Physical Education Delivery During the COVID-19 Pandemic.

BACKGROUND: Physical Education is a key component to improve youth health, but there is limited information on Physical Education delivery in different formats. PURPOSE: We compared PE formats (in-person versus remote) across evaluation aspects: weekly minutes; perceived effectiveness; and student-to-teacher ratio. METHODS: We distributed questionnaires (2020-2021 school year) to school contacts who represented NFL Play 60 FitnessGram® Project (n=216) schools in multiple US cities. Questionnaires entailed learning format, weekly PE minutes, perceived effectiveness, and student-to-teacher ratio. We used linear mixed models to compare PE formats across evaluation variables. RESULTS: Among 165 schools, 10% (n=17) offered in-person instruction, 31% (n=51) offered remote instruction, and 59% offered both (n=97). Results revealed higher in-person PE minutes (77.2±7.3) compared to remote minutes (67.1±14.6), but results were not significantly different (p=0.19). School contacts reported significantly more effective in-person PE (4.0) than remote PE (2.8, p<0.001). In-person PE also had significantly smaller reported student-to-teacher ratio (16.7) compared to remote PE (23.7, p<0.001). DISCUSSION: Findings indicate PE was offered during the pandemic, but remote learning appeared less effective than in-person PE. TRANSLATION to HEALTH EDUCATION PRACTICE: Efforts are needed to improve remote PE to reinforce high-quality PE in the future.

Using the R = MC2 heuristic to understand barriers to and facilitators of implementing school-based physical activity opportunities: a qualitative study.

BACKGROUND: Schools are a key setting for supporting youth physical activity, given their broad reach and diverse student populations. Organizational readiness is a precursor to the successful implementation of school-based physical activity opportunities. The R = MC2 heuristic (Readiness = Motivation x Innovation-Specific Capacity x General Capacity) describes readiness as a function of an organization's motivation and capacity to implement an innovation and can be applied to better understand the implementation process. The purpose of this study was to explore the barriers to and facilitators of implementing school-based physical activity opportunities in the context of organizational readiness. METHODS: We analyzed interview data from 15 elementary school staff (principals, assistant principals, physical education teachers, and classroom teachers) from a school district in Texas. We focused on factors related to adopting, implementing, and sustaining a variety of school-based physical activity opportunities. We used the Framework Method to guide the analysis and coded data using deductive (informed by the R = MC2 heuristic) and inductive approaches. Themes were generated using the frequency, depth, and richness of participant responses. RESULTS: Four themes emerged from the data: (1) implementation is aided by the presence of internal and external relationships; (2) physical activity opportunities compete with other school priorities; (3) seeing the benefits of physical activity opportunities motivates school staff toward implementation; and (4) staff buy-in is critical to the implementation process. Themes 1-3 aligned with subcomponents of the R = MC2 heuristic (intra- and inter-organizational relationships, priority, and observability), whereas Theme 4 (staff buy-in) related to multiple subcomponents within the Motivation component but was ultimately viewed as a distinct construct. CONCLUSION: Our results highlight and explain how key readiness constructs impact the implementation of school-based physical activity opportunities. They also highlight the importance of obtaining staff buy-in when implementing in the school setting. This information is critical to developing readiness-building strategies that help schools improve their capacity to deliver physical activity opportunities effectively. TRIAL REGISTRATION: Not applicable.

Navigating COVID-19 and racial trauma as a Black student at predominantly White institutions.

Black students at predominantly White institutions (PWIs) contend with racial microaggressions that can lead to negative mental health and academic outcomes. The physical and mental health consequences of the novel coronavirus pandemic are well-known. What remains unknown is how targeted racial hate during a pandemic might have a compounded effect on Black essential workers. The current study examines how future essential workers in helping professions cope with dual crises as they navigate mostly White universities. Study participants were Black university students attending PWIs in the United States enrolled in social work, public health, or psychology programs during the 2020-2021 academic year. Participants completed an online survey that measured racial microaggressions, COVID distress, sense of belonging, engagement in activism, and well-being. Hierarchical regression models revealed COVID distress predicted poorer well-being. Also, COVID distress interacted with racial microaggressions to predict well-being. Findings have implications for developing decolonized learning communities with a liberation pedagogy in community psychology and other helping professions.

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics.

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.