Heparan sulfate regulates amphiregulin signaling towards reparative lung mesenchymal cells during influenza A infection.

Amphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair/regeneration, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair/regeneration functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters downstream signaling and highlights the existence of HS-dependent vs. -independent Areg transcriptional signatures. Utilizing a panel of cell lines with targeted deletions in HS synthesis-related genes, we found that the presence of the glypican family of heparan sulfate proteoglycans is critical for Areg signaling and confirmed this dependency in primary LMC by siRNA-mediated knockdown. Furthermore, in the context of influenza A (IAV) infection in vivo , we found that an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS. Conditional deletion of HS primarily within this LMC subset resulted in reduced blood oxygen saturation following infection with IAV, with no changes in viral load. Finally, we found that co-culture of HS-knockout LMC with IAV-induced Treg cells results in reduced LMC responses. Collectively, this study reveals the essentiality of HS on a specific lung mesenchymal population as a mediator of Treg cell-derived Areg reparative signaling during IAV infection.

Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

Comorbidities associated with symptoms of subjective cognitive decline in individuals aged 45-64.

CONTEXT: Early-stage cognitive decline occurs when an individual experiences memory loss or other cognitive impairment but does not meet the criteria for Alzheimer's disease (AD) or other dementias. After diagnosis of mild cognitive impairment (MCI), approximately 5-15 % of cases progress to dementia per year. AD and many other causes of dementia are presently incurable. Early recognition of cognitive decline can allow healthcare providers to reduce the risk of disease progression. Literature is scarce on factors that can increase the incidence of cognitive decline, especially in early ages; this is further exacerbated by difficulty tracking the prevalence of mild cognitive symptoms. OBJECTIVES: This analysis aims to determine demographic and comorbid factors that predispose individuals to higher rates of early-stage subjective cognitive impairment in order to determine which individuals should be screened at earlier stages. METHODS: We conducted a cross-sectional analysis of data from the Subjective Cognitive Decline module of the 2017-2021 Behavioral Risk Factor Surveillance System (BRFSS). Applying survey design and sampling weights, we constructed binary logistic regression models to assess associations, via odds ratios (OR), between comorbidities and subjective cognitive decline (SCD). Alpha was set at 0.05 and confidence intervals (CIs) are reported at 95 %. RESULTS: Our sample included 110,305 participants representing 13.4 million US adults aged 45-64 years. Results showed that individuals with diabetes (OR: 2.29, CI: 2.09-2.51), hypertension (OR: 1.98, CI: 1.81-2.17), stroke (OR: 4.61, CI: 4.07-5.22), myocardial infarction (MI [OR: 3.09, CI: 2.73-3.49]), coronary heart disease (CHD [OR: 3.26, CI: 2.88-3.69]), depression (OR: 5.65, CI: 5.21-6.11), and chronic kidney disease (CKD [OR: 3.08, CI: 2.66-3.58]) experienced higher rates of SCD. Further, there were higher rates of SCD among individuals who identified as American Indian/Alaskan Native (AI/AN), those with low educational attainment, and those with lower incomes. CONCLUSIONS: Our findings show that all comorbidities listed were correlated with higher rates of memory loss or confusion. Investigation of factors that are associated with an increased risk of developing new or worsening cognitive decline allows healthcare professionals to properly screen and treat these individuals early, before progressing to conditions that are currently incurable. Future studies into the mechanisms of these diseases in contributing to cognitive decline can illuminate specific effective treatment options.

Research Note Showing That the Rural Mortality Penalty Varies by Region, Race, and Ethnicity in the United States, 1999-2016.

This research note presents a new perspective on the rural mortality penalty in the United States. While previous work has documented a growing rural mortality penalty, there has been a lack of attention to heterogeneity in trends at the intersection of region, race, and ethnicity. We use age-adjusted mortality rates from the Centers for Disease Control and Prevention to examine the rural mortality penalty by region, race, and ethnicity for 1999-2016 (N = 44,792,050 deaths) and stratify by 2006 National Center for Health Statistics metropolitan-nonmetropolitan classifications. We find substantial variation at the intersection of region, race, and ethnicity, revealing heterogeneity in the rural penalty and-in some cases-a rural mortality advantage. For the Black/African American population, the rural mortality penalty is observed only in the South. On the other hand, for Hispanic/Latino populations, a small but persistent rural mortality penalty is present only in the South and the West. There is a rural mortality penalty in all regions for White and American Indian/Alaska Native populations. However, for the latter, there is substantial variation in the magnitude of the penalty by region of residence. This research documents heterogeneous patterns when the rural mortality penalty is analyzed by region, race, and ethnicity in the United States.

Financial Hardship and Age-Related Decrements in Kidney Function among Black and White Adults in the Midlife in the United States (MIDUS) Study.

OBJECTIVES: This analysis examined if financial hardship was associated with age-related decrements in kidney function using a material-psychosocial-behavioral framework. We also tested if this association was mediated by comorbidity of cardiometabolic risk factors (obesity, elevated blood pressure, and insulin resistance). METHODS: Data from 1,361 Non-Hispanic (NH) Black and white adults (ages 26-94; NH Black = 258) were obtained from the Wave 3 and Refresher phases of the Midlife in the United States (MIDUS) project. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (CKD-EPI formula without race adjustment). Financial hardship was evaluated in three domains: material (income to poverty line ratio, health insurance coverage, and public/government financial assistance), psychological (perceived financial status, control over financial status, and perceived financial strains), and behavioral responses (financial adjustment/coping such as sold possessions and cutting back on spending). RESULTS: More severe financial hardship (overall score and in each domain) was associated with age-related decrements in eGFR, even after adjusting for sociodemographic, education, and health-related covariates. The association between financial hardship and age-related decrements in eGFR was conditional on sex but not race. Finally, cardiometabolic risk factors mediated the association between financial hardship and age-related decrements in eGFR. CONCLUSIONS: These findings affirm the negative effects of financial hardship on age-related decrements in renal clearance. In addition to incorporating traditionally used indicators of SES, such as education and income, future research on social hallmarks of aging should also consider the role of financial hardship on the aging process and age-related diseases.

Probiotic-guided CAR-T cells for solid tumor targeting.

A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)-T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery. To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response.

Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity.

Tumors use multiple mechanisms to actively exclude immune cells involved in antitumor immunity. Strategies to overcome these exclusion signals remain limited due to an inability to target therapeutics specifically to the tumor. Synthetic biology enables engineering of cells and microbes for tumor-localized delivery of therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16K42A) offer therapeutic benefit in multiple mouse tumor models, an effect mediated via recruitment of CD8+ T cells. Furthermore, we target the presentation of tumor-derived antigens by dendritic cells, using a second engineered bacterial strain expressing CCL20. This led to type 1 conventional dendritic cell recruitment and synergized with hCXCL16K42A-induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to recruit and activate innate and adaptive antitumor immune responses, offering a new cancer immunotherapy strategy.

Dietary tryptophan deficiency promotes gut RORγt+ Treg cells at the expense of Gata3+ Treg cells and alters commensal microbiota metabolism.

Micronutrient deficiency is a major cause of disease throughout the world. Yet, how perturbations influence the immune-microbiome interface remains poorly understood. Here, we report that loss of dietary tryptophan (Trp) reshapes intestinal microbial communities, including the depletion of probiotic L. reuteri, drives transcriptional changes to immune response genes in the intestinal ileum, and reshapes the regulatory T cell (Treg) compartment. Dietary Trp deficiency promotes expansion of RORγt+ Treg cells and the loss of Gata3+ Tregs in a microbiota-dependent manner. In the absence of dietary Trp, provision of the AhR ligand indole-3-carbinol is sufficient to restore the Treg compartment. Together, these data show that dietary Trp deficiency perturbs the interaction between the host and its bacterial symbionts to regulate Treg homeostasis via the deprivation of bacterially derived Trp metabolites. Our findings highlight an essential role for immune-microbiome crosstalk as a key homeostatic regulator during nutrient deficiency.

Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells.

Following respiratory viral infection, regeneration of the epithelial barrier is required to preserve lung function and prevent secondary infections. Lung regulatory T (Treg) cells are critical for maintaining blood oxygenation following influenza virus infection through production of the EGFR ligand amphiregulin (Areg); however, how Treg cells engage with progenitors within the alveolar niche is unknown. Here, we describe local interactions between Treg cells and an Areg-responsive population of Col14a1+EGFR+ lung mesenchymal cells that mediate type II alveolar epithelial (AT2) cell-mediated regeneration following influenza virus infection. We propose a mechanism whereby Treg cells are deployed to sites of damage and provide pro-survival cues that support mesenchymal programming of the alveolar niche. In the absence of fibroblast EGFR signaling, we observe impaired AT2 proliferation and disrupted lung remodeling following viral clearance, uncovering a crucial immune/mesenchymal/epithelial network that guides alveolar regeneration.

daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71.

Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

Life course pathways from parental education to age-related decrements in kidney function among Black and white American adults.

OBJECTIVE: Using cross-sectional data on Black and white adults, this analysis examined whether age-related decrements in kidney function across adulthood were associated with parental education, and whether the association was differentially influenced by race. Further, this study assessed racial differences in life course pathways from parental education to age-related decrements in kidney function, through current SES and health-related risk factors. METHOD: Data from the main survey and the Biomarker Project of the Midlife in the United States (MIDUS) Wave 2 and Refresher samples were combined, resulting in 1861 adults (54.5% female; age 25-84, Mage = 53.37) who self-identified as non-Hispanic Black (n = 326) and non-Hispanic white (n = 1535). Estimated glomerular filtration rate (eGFR) was based on serum creatinine, calculated using the CKD-EPI formula. Adults SES was based on education, income, and financial strains. Health-related risk factors included obesity, elevated blood pressure (BP), and insulin resistance. Hypotheses were tested by utilizing multiple linear regression and regression-based moderated mediation analysis. RESULTS: Lower parental education was associated with steeper age-related decrements in eGFR (B = 0.38, SE = 0.15, p = .013, 95%CI = 0.08, 0.68), due to higher eGFR among younger participants and lower eGFR among older participants. In addition, age-related decrements in kidney function were steeper among Black relative to white adults (B = 0.41, SE = 0.13, p < .01, 95%CI = 0.16, 0.66), driven by higher proportion of younger Black adults that met criterion for renal hyperfiltration. Furthermore, parental education and race were associated with age-related decrements in kidney function in an additive rather than interactive way. There were some racial differences in the life course pathways from parental education to age-related differences in eGFR, glucoregulation, and hypertension. Among Black adults, lower parental education was associated with elevated eGFR among younger participants through insulin resistance. Among white adults, lower parental education was linked to higher eGFR among younger adults and lower eGFR among older adults, and the association was mediated by current SES, elevated BP, and insulin resistance. DISCUSSION: Early life SES can have a long-lasting influence on the preclinical renal senescence that is associated with the normal biology of aging for both Black and white adults.

Socioeconomic status trajectories across the life course, daily discrimination, and inflammation among Black and white adults.

OBJECTIVE: This study replicates and expands Surachman et al.'s (2020) findings documenting socioeconomic status (SES) trajectories across the life course in an independent sample of Black (majority recruited from Milwaukee, WI) and white adults in the United States. We extend this work by examining whether SES trajectories and daily discrimination are independently associated with markers of inflammation. METHOD: Data were from 215 Black adults (188 recruited from Milwaukee, WI; 27 recruited from across the continental US) and 985 white adults (7 recruited from Milwaukee, WI; 978 recruited from across the continental US) who completed the baseline interview and biomarker assessment during the second wave of the Midlife in the United States (MIDUS) Study (ages = 34-84). SES life course trajectories were examined using latent class analysis based on objective (e.g., income and education) and subjective (e.g., social status and financial strain) indicators of SES. The association between life course SES trajectories and daily discrimination with markers of inflammation (IL-6, CRP, fibrinogen) were examined using multiple linear regression analyses, controlling for demographic, psychological, behavioral, and health-related covariates. RESULTS: Black and white participants showed different patterns of life course SES trajectories. Among Black participants, the trajectories were Objectively Stable Low (45.16%), Downwardly Mobile (18.05%), and Upwardly Mobile (36.79%). Compared to the Upwardly Mobile, the Objectively Stable Low class showed elevated IL-6 after controlling for all covariates. Further, daily discrimination, but not SES trajectories, was significantly associated with CRP and fibrinogen after controlling for demographic, psychological, and behavioral covariates. White participants' experiences of life course SES trajectories were characterized as Objectively Stable Low (7.02%), Subjectively Downward (12.48%), Upwardly Mobile (39.99%), and Stable High (40.51%). Among white participants, SES trajectories, but not daily discrimination, were associated with all markers of inflammation (controlling for age and sex). DISCUSSION: Consistent with the fundamental cause theory, multiple independent pathways link SES trajectories across the life course and daily discrimination to racial disparities in IL-6, CRP, and fibrinogen.

Burn Hand or Finger Goniometric Measurements: Sum of the Isolated Parts and the Composite Whole.

Accurate assessment of hand function following a burn is important for patient impairment determination. Goniometric measurement of hand or finger range of motion (ROM) is typically done measuring individual finger joints with the adjacent joint in extension (isolated) or measuring the joints in a fist position (composite). The purpose of this study was to compare if the total flexion motion of the summed angles of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints in burned hands were equal when performed in an isolated vs a composite manner. Passive flexion ROM angles were collected prospectively and measured at the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal with the adjacent joints extended to measure isolated angles and with the adjacent joints fully flexed for composite angles. Thumb joints were excluded. ROM for isolated and composite positions of eight fingers was compared individually and as an aggregate. Finger measurements from 145 adult patients were compared. The study population was predominately male (69%) with a mean age of 41 ± 16.6 years. Mean total burn size was 14.2 ± 13.2%. A total of 739 fingers contributed 2217 joint ROM comparisons. Aggregate analysis of isolated ROM was 235.5° ± 52.1° compared with composite ROM of 226.8° ± 53.2° (P < .0001). Individual fingers showed significant differences between the two measurement methods as well (P ≤ .0040). The methods used to measure hand or finger ROM profoundly influence how hand impairment is reported. Measurement of isolated joint angles results in greater ROM values compared with composite angles, which are often more relevant for functional hand positions. Therefore, composite angles are recommended.

Manifestações orais do pênfigo vulgar: relato de caso / Oral findings of penphigus vulgaris: case report

O pênfigo vulgar (PV) é uma doença auto-imune, de envolvimento mucocutâneo, com vários fatores considerados predisponentes. Como características clínicas destacam-se o aparecimento de lesões bolhosas, em diversas áreas da cavidade oral e pele, que se rompem facilmente, causando úlceras com bordas irregulares, com dor, e dificuldade de fala, além da possibilidade de infecções secundárias. Os autores relatam o caso de uma paciente do sexo feminino de 30 anos de idade, com queixa de "queimação" na boca. O caso apresentado tem como objetivo orientar o Cirurgião Dentista quanto ao reconhecimento de lesões de PV contribuindo assim para o seu diagnóstico precoce.