Early-life inflammation primes a T helper 2 cell-fibroblast niche in skin.

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.

ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes.

The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of ß-amyloid (Aß). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aß degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aß degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.

Duplication and functional specialization of the telomere-capping protein Cdc13 in Candida species.

The budding yeast G-tail binding complex CST (Cdc13-Stn1-Ten1) is crucial for both telomere protection and replication. Previous studies revealed a family of Cdc13 orthologues (Cdc13A) in Candida species that are unusually small but are nevertheless responsible for G-tail binding and the regulation of telomere lengths and structures. Here we report the identification and characterization of a second family of Cdc13-like proteins in the Candida clade, named Cdc13B. Phylogenetic analysis and sequence alignment indicate that Cdc13B probably arose through gene duplication prior to Candida speciation. Like Cdc13A, Cdc13B appears to be essential. Deleting one copy each of the CDC13A and CDC13B genes caused a synergistic effect on aberrant telomere elongation and t-circle accumulation, suggesting that the two paralogues mediate overlapping and nonredundant functions in telomere regulation. Interestingly, Cdc13B utilizes its C-terminal OB-fold domain (OB4) to mediate self-association and binding to Cdc13A. Moreover, the stability of the heterodimer is evidently greater than that of either homodimer. Both the Cdc13 A/A homodimer and A/B heterodimer, but not the B/B homodimer, recognized the telomere G-tail repeat with high affinity and sequence specificity. Our results reveal novel evolutionary elaborations of the G-tail-binding protein in Saccharomycotina yeast, suggesting a drastic remodeling of CDC13 that entails gene duplication, fusion, and functional specialization. The repeated and independent duplication of G-tail-binding proteins such as Cdc13 and Pot1 hints at the evolutionary advantage of having multiple G-tail-binding proteins.

The social determinants of migrant domestic worker (MDW) health and well-being in the Western Pacific Region: A Scoping Review.

The health and well-being of transnational migrant domestic workers (MDWs) is a pressing but largely neglected public health concern. The Asia Pacific region is home to over 20% of the global MDW population. Living and working conditions, social contexts, political environments, and migration regimes are recognized as consequential to the health of this population, but currently no synthesis of available literature to prioritize research or policy agenda setting for MDW has yet been conducted. This scoping review screened 6,006 peer-reviewed articles and 1,217 gray literature sources, identifying 173 articles and 276 gray literature sources that reported key MDW health outcomes, social determinants of health, and related interventions. The majority of identified studies were observational and focused on the prevalence of common mental disorders and chronic physical conditions, with most studies lacking population representativeness. Identified social determinants of health were primarily concerned with personal social and financial resources, and health knowledge and behaviors, poor living and working conditions, community resources, experienced stigma and discrimination, poor healthcare access, exploitation within the MDW employment industry, and weak governance. Six interventional studies were identified that targeted individual-level health determinants such as financial and health knowledge with mixed effectiveness. Future population representative epidemiological and respondent driven sampling studies are needed to estimate population health burdens. In addition, randomized control trials and public health intervention studies are needed to improve women's health outcomes and address proximal health determinants to reduce health inequalities. Leveraging social networks and community facing non-governmental organizations (NGOs) are promising directions to overcome access to care for this population.

NOT gated T cells that selectively target EGFR and other widely expressed tumor antigens.

Here, we show that a NOT gated cell therapy (Tmod) can exploit antigens such as epidermal growth factor receptor (EGFR) and human leukocyte antigen-E (HLA-E) which are widely expressed on cancer cells. Noncancerous cells-despite high expression of these antigens-are protected from cytotoxicity by the action of an inhibitory receptor ("blocker") via a mechanism that involves blocker modulation of CAR surface expression. The blocker is triggered by the product of a polymorphic HLA allele (e.g., HLA-A∗02) deleted in a significant subset of solid tumors via loss of heterozygosity. Moreover, Tmod constructs that target mouse homologs of EGFR or HLA-E for activation, and a mouse-equivalent of HLA-A∗02 for inhibition, protect mice from toxicity caused by the CAR alone. The blocker also controls graft vs. host response in allogeneic T cells in vitro, consistent with the use of Tmod cells for off-the-shelf therapy without additional gene-editing.

The Sociostructural-Intersectional Body Image (SIBI) framework: Understanding the impact of white supremacy in body image research and practice.

White supremacy and racial inequities have long pervaded psychological research, including body image scholarship and practice. The experiences of white, heterosexual, able-bodied, cisgender (predominantly college) women from wealthy, Westernized nations have been centered throughout body image research and practice, thereby perpetuating myths of invulnerability among racialized groups and casting white ideals and experiences as the standard by which marginalized bodies are compared. Body image is shaped by multiple axes of oppression that exist within systemic and structural systems, ultimately privileging certain bodies above others. In this position paper, we highlight how white supremacy has shaped body image research and practice. In doing so, we first review the history of body image research and explain how participant sampling, measurement, interpretive frameworks, and dissemination of research have upheld and reinforced white supremacy. Next, grounded in inclusivity and intersectionality, we advance the Sociostructural-Intersectional Body Image (SIBI) framework to more fully understand the body image experiences of those with racialized and minoritized bodies, while challenging and seeking to upend white supremacy in body image research and practice. We encourage other scholars to utilize the SIBI framework to better understand body inequities and the body image experiences of all people, in all bodies.

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Resistance and empowerment against racism: A preregistered study of associations with body appreciation and body acceptance by others in racialised minority adults in the United Kingdom.

Research on body image and racism has largely focused on how individual experiences of racism are associated with detrimental body image outcomes. However, research has not yet examined how resistance and empowerment against racism (REAR) - a repertoire of proactive strategies aimed at preventing or challenging racism both at the individual and collective levels - shape positive body image outcomes. Here, 236 women and 233 men who identified as belonging to racialised minority groups in the United Kingdom completed the REAR Scale - which measures REAR along four dimensions - as well as measures of body appreciation and body acceptance by others. Correlational analyses indicated significant inter-correlations between nearly all REAR domains and body image-related variables in men, whereas relationships in women were largely non-significant. Linear model analyses indicated that greater leadership for resistance against racism was significantly associated with higher body appreciation in women and men. Greater interpersonal confrontation of racism was significantly associated with both body appreciation and body acceptance by others in men, but not in women. These results suggest that REAR may play a role in shaping body image-related outcomes in people of colour, but that these effects are also be shaped by the intersection of gender and race.

"You Can't Be Too Skinny. You Can't Be Too Fat. I Don't Know What You Are Supposed To Be.": A qualitative focus group study exploring body image experiences of South Asian women in the UK.

British South Asian women may experience unique appearance pressures associated with their intersecting (racialised and gendered) identities; yet qualitative investigations of intersectional understandings of their body image are scarce. The aim of this study was to explore sociocultural factors influencing British South Asian women's body image using an intersectional framework. Seven focus groups were conducted with 22 women of South Asian heritage living in the UK between the age of 18 and 48 years old who were comfortable speaking in English. Data were analysed using reflexive thematic analysis. We generated four themes (1) navigating (often marriage-related) appearance pressures from South Asian elders and aunties (2) negotiating cultural and societal standards across different aspects of one's identity (3) representation of South Asian women in the wider context and (4) forms of healing from the pressures imposed on South Asian women. The findings have important implications for the body image experiences of South Asian women by acknowledging the need for tailored and nuanced responses to their complex needs in the sociocultural, political and relational context such as family, peers, education, health, media and the wider consumer landscape.

South Asian women in the United Kingdom: The role of skin colour dissatisfaction in acculturation experiences and body dissatisfaction.

South Asian women living in Western cultures may experience skin colour dissatisfaction, as fair skin is an important South Asian appearance ideal, whilst visible ethnic differences in their skin colour may lead to appearance-related ethnic teasing from members from the mainstream culture. This study investigates whether appearance-related ethnic teasing is indirectly associated with body dissatisfaction via skin colour dissatisfaction and explores the relationship between appearance-related ethnic teasing, cultural identification and skin colour dissatisfaction amongst first-generation South Asian women living in the United Kingdom. South Asian women (N = 98; 18-55 years, M = 24.60) completed an online questionnaire that measured appearance-related ethnic teasing, skin colour dissatisfaction, cultural identification, and body dissatisfaction. Appearance-related ethnic teasing was indirectly linked with greater body dissatisfaction via greater skin colour dissatisfaction. Appearance-related ethnic teasing was linked with stronger British identification, a greater sense of having an integrated identity and greater skin colour dissatisfaction. South Asian identification was associated with greater skin colour dissatisfaction. These findings suggest that skin colour dissatisfaction is an important link between appearance-related ethnic teasing and acculturating South Asian women's body image.

The CDC13-STN1-TEN1 complex stimulates Pol α activity by promoting RNA priming and primase-to-polymerase switch.

Emerging evidence suggests that Cdc13-Stn1-Ten1 (CST), an RPA-like ssDNA-binding complex, may regulate primase-Pol α (PP) activity at telomeres constitutively, and at other genomic locations under conditions of replication stress. Here we examine the mechanisms of PP stimulation by CST using purified complexes derived from Candida glabrata. While CST does not enhance isolated DNA polymerase activity, it substantially augments both primase activity and primase-to-polymerase switching. CST also simultaneously shortens the RNA and lengthens the DNA in the chimeric products. Stn1, the most conserved subunit of CST, is alone capable of PP stimulation. Both the N-terminal OB fold and the C-terminal winged-helix domains of Stn1 can bind to the Pol12 subunit of the PP complex and stimulate PP activity. Our findings provide mechanistic insights on a well-conserved pathway of PP regulation that is critical for genome stability.