Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model.

BACKGROUND: Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes. METHODS: We created a cohort of genetically diverse XLAS male and female mice using the Diversity Outbred mouse resource and measured albuminuria, GFR, and gene expression. Using a quantitative trait locus approach, we mapped modifier genes that can best explain the underlying phenotypic variation measured in our diverse population. RESULTS: Genetic analysis identified several loci associated with the variation in albuminuria and GFR, including a locus on the X chromosome associated with X inactivation and a locus on chromosome 2 containing Fmn1. Subsequent analysis of genetically reduced Fmn1 expression in Col4a5 knockout mice showed a decrease in albuminuria, podocyte effacement, and podocyte protrusions in the glomerular basement membrane, which support the candidacy of Fmn1 as a modifier gene for AS. CONCLUSION: With this novel approach, we emulated the variability in the severity of kidney phenotypes found in human patients with Alport Syndrome through albuminuria and GFR measurements. This approach can identify modifier genes in kidney disease that can be used as novel therapeutic targets.

Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism.

Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4+ T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII-/-]) were created and metabolically characterized. FITC+ glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII-/- were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet-fed C57BL/6 mice. Unexpectedly, mMHCII-/- mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4+ T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8+ T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclusion, loss of either ATM or adipocyte APC function, but not both, improves systemic glucose metabolism because of maintenance of AT regulatory T cells.

Low visceral adipose tissue regulatory T cells are associated with higher comorbidity severity in patients undergoing bariatric surgery.

BACKGROUND: Adipose tissue (AT) inflammation is linked to the development of type 2 diabetes (T2DM) and atherosclerosis in murine models of obesity. Reduced AT regulatory T cells (Tregs), which are anti-inflammatory immune cells, play an important part in this pathogenesis, and we have shown that AT-Tregs are inversely correlated to increasing body-mass-index. The purpose of this study was to evaluate the association between AT-Treg abundance and comorbidity status in patients undergoing bariatric surgery (BS). METHODS: Visceral (intra-abdominal) AT was harvested at that time of primary BS (n = 80) and collagenase digested. AT-Treg abundance (CD4+/CD25+/FOXP3+) was characterized using flow cytometry from the AT stromal vascular fraction. The median AT-Treg abundance (3.03%) was utilized to define high (High-Tregs, n = 39) and low AT-Treg (low-Tregs, n = 38) abundance within this cohort. These two groups were compared in terms of baseline demographic data, preoperative obesity-related comorbidities, glycemic parameters, including insulin resistance (HOMA-IR). RESULTS: Age, excess body weight, and sex were not different between groups. Prevalence of hypertension, hyperlipidemia, or T2DM preoperatively were not different between groups. Compared to High-Tregs, patients with low-Tregs were more likely to have insulin-dependent type 2 diabetes (12.5% vs 2.9%, p = 0.04). Within patients with T2DM, low-Treg patients had higher plasma insulin levels compared to high-Tregs (31.8 (28.4-56.5) vs 15.5 (10.1-23.1), p = 0.04) and trended towards higher insulin resistance (HOMA-IR) (9.0 (5.3-18.3) vs 3.5 (2.2-7.7), p = 0.08). Within those diagnosed with hyperlipidemia, preoperative statin use was higher in Low-Treg patients compared to the control cohort (91% vs 50%, p = 0.056). Low-Treg patients with hypertension were more likely to need 2 + anti-hypertensive agents preoperatively compared to their counterparts (71% vs 44%, p = 0.058). CONCLUSION: Within bariatric candidates, lower visceral AT-Treg abundance was associated with increased baseline medication requirements for type 2 diabetes, hypertension, and hyperlipidemia. This suggests that reduced AT-Tregs may be associated with higher obesity-related comorbidity severity.

Supernatants from stored red blood cell (RBC) units, but not RBC-derived microvesicles, suppress monocyte function in vitro.

BACKGROUND: We have previously shown that critically ill children transfused with red blood cells (RBCs) of longer storage durations have more suppressed monocyte function after transfusion compared to children transfused with fresher RBCs and that older stored RBCs directly suppress monocyte function in vitro, through unknown mechanisms. We hypothesized that RBC-derived microvesicles (MVs) were responsible for monocyte suppression. STUDY DESIGN AND METHODS: To determine the role of stored RBC unit-derived MVs, we cocultured monocytes with supernatants, isolated MVs, or supernatants that had been depleted of MVs from prestorage leukoreduced RBCs that had been stored for either 7 or 30 days. Isolated MVs were characterized by electron microscopy and flow cytometry. Monocyte function after coculture experiments was measured by cytokine production after stimulation with lipopolysaccharide (LPS). RESULTS: Monocyte function was suppressed after exposure to supernatants from 30-day RBC units compared to monocytes cultured in medium alone (LPS-induced tumor necrosis factor-α production, 17,611 ± 3,426 vs. 37,486 ± 5,598 pg/mL; p = 0.02). Monocyte function was not suppressed after exposure to MV fractions. RBC supernatants that had been depleted of MVs remained immunosuppressive. Treating RBC supernatants with heat followed by RNase (to degrade protein-bound RNA) prevented RBC supernatant-induced monocyte suppression. CONCLUSION: Our findings implicate soluble mediators of stored RBC-induced monocyte suppression outside of MV fractions and suggest that extracellular protein-bound RNAs (such as microRNA) may play a role in transfusion-related immunomodulation.

Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17~92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression. OBJECTIVES: We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue. METHODS: Expression and DNA methylation patterns of miR-17~92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17~92 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 5'-aza-2'-deoxycytidine. MEASUREMENTS AND MAIN RESULTS: Compared with control samples, miR-17~92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17~92 promoter was increased. Several miRNAs from the miR-17~92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17~92 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 5'-aza-2'-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17~92 cluster expression, and attenuated pulmonary fibrosis. CONCLUSIONS: This study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17~92 and DNMT-1 in lung fibrosis.

The Effect of Interprofessional Education on Student Readiness for Collaborative Practice.

BACKGROUND: Health care reform promotes interprofessional patient-centric health care models associated with improved population health outcomes. Interprofessional education (IPE) programs are necessary to cultivate collaborative care, yet little evidence exists to support IPE pedagogy within nursing and other health science academia. METHOD: This quasiexperimental study examined differences in pre- and posttest Readiness for Interprofessional Learning Scale (RIPLS) scores following an IPE intervention. The IPE intervention consisted of a video presentation and a debriefing session after a simulated interprofessional collaborative patient care conference that introduced baccalaureate nursing and health science students to the roles and responsibilities of clinicians in team-based primary care. Pre- and postintervention RIPLS scores were analyzed. RESULTS: Pre- and postintervention RIPLS scores increased across all subscales, with distinct variation between nursing and health science student subscales. CONCLUSION: This IPE intervention had positive effects on students' readiness for interprofessional learning. Additional research is warranted to support health science pedagogy. [J Nurs Educ. 2024;63(5):304-311.].

Evaluation of the Performance of a Card Game to Introduce Students to Interprofessional Collaboration: A Randomized 2-Group Comparison Study.

BACKGROUND: Gamification is an approach that can be used to introduce interprofessional collaboration in nursing and health science. Card games are an effective and convenient way to educate students about clinical professions. PURPOSE: We compared the perception of an experimental group of students who played an educational card game to a control group that played an uninstructive card game. METHODS: College students (n = 148) from nursing and health science majors consented to play a 30-minute card game and complete a 13-item survey. RESULTS: Perceptions of the card game were significantly better for students in the experimental group who played the interprofessional collaboration game than for those in the control group ( t = 10.33, P < .001). Survey subscales were rated significantly higher for respondents who played the interprofessional card game. CONCLUSIONS: The use of an innovative card game teaching strategy significantly increased the perception of interprofessional collaboration among college students.

Obesity-associated microbiomes instigate visceral adipose tissue inflammation by recruitment of distinct neutrophils.

Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.

Understanding Nuance and Ambivalence in Intergenerational Relationships Through Fiction.

BACKGROUND AND OBJECTIVES: The term "intergenerational relationships" is widely used in gerontological literature and age-related policies. However, discussions of the term often tell us surprisingly little about what it means or why it matters. We suggest that this is due to a reductivism and instrumentalism in 2 main discourses within which intergenerational relationships are usually discussed. First, intergenerational relationships are often conceptualized through a binary "conflict/solidarity" lens, reinforcing an entrenched "generationalism". Second, they are predominantly constructed as a problem to be addressed within debates on how to tackle intergenerational segregation. Neither of these discourses provides much room for a more nuanced understanding of how intergenerational relationships are experienced or why they are meaningful. In this paper, we discuss how fictional narratives can introduce imagination and a richer vocabulary into discourses concerning how people of different ages relate to each other. RESEARCH DESIGN AND METHODS: We present findings from reading groups where adults discussed novels depicting themes of older age, intergenerational relationships, and time. RESULTS: In discussing the fictional narratives and characters, participants reflected on the significance and meaning of intergenerational relationships in ways that went beyond dichotomous and instrumentalist discourses. Drawing on the concept of lived ambivalence, we argue that fictional representations of intergenerational themes can elicit more meaningful reflections on the complexities and contradictions of relationships across age groups. DISCUSSION AND IMPLICATIONS: We conclude that a more nuanced understanding of intergenerational interaction can inform gerontological discourses and policy, but also that gerontological awareness of social challenges concerning age relations can inform interpretations of fictional narratives.

Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity.

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.

Why is end-of-life care delivery sporadic?: A quantitative look at the barriers to and facilitators of providing end-of-life care in the neonatal intensive care unit.

PURPOSE: According to the Centers for Disease Control and Prevention Infant Mortality Statistics, 28 384 infants died in the United States in 2005. On examining the state of the science in providing end-of-life care for newborns, it is important to examine the practice of providing compassionate and dignified palliative care at the end of life. The purpose of this research study was to examine the barriers to and facilitators of providing a quality end-of-life care in one large Midwestern tertiary NICU. SUBJECTS: A convenience sample of 50 NICU registered nurses from a Level III Midwestern Facility participated. METHODS: A quantitative, prospective, cross-sectional design was used. Data were collected with the Neonatal Palliative Care Attitude Scale questionnaire. RESULTS: Five barriers and 8 facilitators to end-of-life care practice in the NICU were identified. The 5 barriers were the nurses' inability to express opinions values and beliefs regarding palliative care (M = 2.98, SD = 1.30), less than ideal physical environment (M = 2.70, SD = 1.31), technological imperatives (M = 3.22, SD = 1.11), parental demands (M = 3.46, SD = 1.07), and, finally, lack of education (M = 2.86, SD = 1.44). The 8 facilitators were supportive medical staff (M = 3.60, SD = 1.29), parental involvement of decisions (M = 3.76, SD = 1.17), parents informed of options (M = 3.32, SD = 1.22), support from medical team when palliative care is implemented (M = 3.20, SD = 1.28), staffing (M = 3.60, SD = 1.29), time spent with dying baby (M = 3.52, SD = 1.31), policies/guidelines supporting palliative care (M = 3.76, SD = 1.19), and available counseling (M = 3.566, SD = 1.26). CONCLUSIONS: Barriers and facilitators continue to exist within neonatal end-of-life care. There is significant importance for NICU nurses to recognize and understand the barriers to and facilitators of providing end-of-life care within their specific unit. Further research is warranted regarding implementation of end-of-life care education in the NICU to improve patient care.

Characterization of inflammatory changes in the breast cancer associated adipose tissue and comparison to the unaffected contralateral breast.

BACKGROUND: Adipose tissue has emerged as an important window into cancer pathophysiology, revealing potential targets for novel therapeutic interventions. The goal of this study was to compare the breast adipose tissue (BrAT) immune milieu surrounding breast carcinoma and contralateral unaffected breast tissue obtained from the same patient. MATERIALS AND METHODS: Patients undergoing bilateral mastectomy for unilateral breast cancer were enrolled for bilateral BrAT collection at the time of operation. After BrAT was processed, adipocyte and stromal vascular fraction (SVF) gene expression was quantified by PCR. SVF cells were also processed for flow cytometric immune cell characterization. RESULTS: Twelve patients underwent bilateral mastectomy for unilateral ductal carcinoma. BrAT adipocyte CXCL2 gene expression trended higher in the tumor-affected breast as compared to the unaffected breast. Macrophage MCP-1 and PPARγ gene expression also tended to be higher in the tumor-affected breasts. T cell gene expression of FOXP3 (p = 0.0370) were significantly greater in tumor-affected breasts than unaffected breasts. Affected BrAT contained higher numbers of Th2 CD4+ cells (p = 0.0165) and eosinophils (p = 0.0095) while trending towards increased macrophage and lower Th1 CD4+ cells infiltration than tumor-affected BrAT. CONCLUSION: This preliminary study aimed to identify the immunologic environment present within BrAT and is the first to directly compare this in individual patients' tumor-associated and unaffected BrAT. These findings suggest that cancer-affected BrAT had increased levels of T cell specific FOXP3 and higher levels of anti-inflammatory/regulatory cells compared to the contralateral BrAT.

Obesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance.

BACKGROUND: Obesity is characterized by visceral adipose tissue (AT) inflammation. Immunosuppressive regulatory T cells (Tregs), phagocytic M2-like macrophages, and innate lymphoid cells type 2 (ILC2) control lean AT inflammation to maintain systemic insulin sensitivity, while the loss of these cells in obesity leads to AT inflammation and insulin resistance (IR). OBJECTIVE: The objective of this study was to determine if weight loss following obesity would correct AT inflammation and systemic metabolism. RESULTS: After six months of high fat diet (HFD) in male C57/Bl6 mice, flow analyses of epidydimal AT stromal vascular fraction (SVF) revealed depleted Tregs by 50%, doubling of CD8+ T cells, tripling of pro-inflammatory M1-like macrophages, and an 80% drop in ILC2 cells associated with changes in pro-inflammatory adipocyte and macrophage gene expression. Despite normalization of body weight, fat, and adipocyte size, mice ingesting 3 months of high-fat diet (HFD) followed by 3 months of chow-diet remained more insulin resistant and glucose intolerant than chow-fed animals. Adipocytes, AT Tregs, CD8+ T cells, ILC2 cells, and M1-like macrophages all failed to normalize with weight loss. CONCLUSIONS: Persistent AT inflammation contributes to the maintenance of IR despite body weight and fat normalization in previously obese mice. These findings highlight the importance of obesity prevention to avoid the consequences of "obesogenic memory."

Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle.

Skeletal muscles produce transient reactive oxygen species (ROS) in response to intense stimulation, disuse atrophy, heat stress, hypoxia, osmotic stress, stretch and cell receptor activation. The physiological significance is not well understood. Protein phosphatases (PPases) are known to be highly sensitive to oxidants and could contribute to many different signalling responses in muscle. We tested whether broad categories of PPases are inhibited by levels of acute oxidant exposure that do not result in loss of contractile function or gross oxidative stress. We also tested if this exposure results in elevated levels of global protein phosphorylation. Rat diaphragm muscles were treated with either 2,3-dimethoxy-1-naphthoquinone (DMNQ; 1, 10, 100 microm; a mitochondrial O(2)(.-)/H2O2 generator) or exogenous H2O2 (5, 50, 500 microm) for 30 min. Supernatants were assayed for serine/threonine PPase (Ser/Thr-PPase) or protein tyrosine PPase (PTP) activities. With the exception of 500 microm H2O2, no other oxidant exposures significantly elevated protein carbonyl formation, nor did they alter the magnitude of twitch force. DMNQ significantly decreased all categories of PPase activity at 10 and 100 microm and reduced PTP at 1 microm. Similar reductions in Ser/Thr-PPase activity were seen in response to 50 and 500 microm H2O2 and PTP at 500 microm H2O2. ROS treatments resulted a dose-dependent increase in the phosphorylation states of many proteins. The data are consistent with the concept that PPases, within intact skeletal muscles, are highly sensitive to acute changes in ROS activity and that localized ROS play a critical role in lowering the barriers for effective phosphorylation events to occur in muscle cells, thus increasing the probability for cell signalling responses to proceed.

Deindustrialization, the Linwood Car Plant and Scotland's Political Divergence from England in the 1960s and 1970s.

Scotland's political divergence from England is a key theme in late twentieth century British history. Typically seen in terms of the post-1979 Thatcher effect, this in fact developed over a longer timeframe, rooted in industrial changes revealed by analysis of the Linwood car plant in Renfrewshire. Conservatism and Unionism was an eminent political force in Scotland in the 1940s and 1950s. But in all general elections from 1959 onwards the vote share of Conservative and Unionist candidates was lower in Scotland than in England. From the late 1960s onwards there were also ambitions for constitutional change. This article breaks new conceptual and empirical ground by relating these important markers of political divergence to popular understanding among Scottish workers of deindustrialization. A Thompsonian moral economy framework is deployed. Expectations were elevated by industrial restructuring from the 1950s, with workers exchanging jobs in the staples for a better future in assembly goods. Labour governments earned a reputation in Scotland as better managers of this process than Conservative governments. The 1979 general election showed that Labourism was growing in popularity in Scotland just as its appeal faded in England. At Linwood moral economy expectations were compromised, chiefly by intermittent redundancy and recurrent threat of closure, which was averted in 1975 by Labour government intervention. When the plant was shut in 1981 criticisms of UK political-constitutional structures and Conservativism were intensified.

Human Visceral Adipose Tissue Macrophages Are Not Adequately Defined by Standard Methods of Characterization.

Obesity is associated with a state of chronic low-grade inflammation both systemically and within specific tissues, including adipose tissue (AT). In murine models of obesity, there is a shift in the inflammatory profile of the AT immune cells, with an accumulation of proinflammatory M1 macrophages that surround the expanding adipocyte. However, much less is known about the immune cell composition and how to best define AT macrophages in humans. Objective. The goals of the current study were to determine the contribution of macrophages to the stromal vascular fraction (SVF) in lean versus obese human visceral AT (VAT); examine the expression of common M1, M2, and pan macrophage markers; and determine the association of specific macrophage types with known biomarkers of obesity-related cardiometabolic disease. Research Design and Methods. VAT biopsies were obtained from obese (n = 50) and lean (n = 8) patients during elective surgery. Adipocytes and SVF were isolated, and the SVF was subjected to flow cytometry analyses. Results. Our results indicate that VAT macrophages are increased in obesity and associate with biomarkers of CVD but that many macrophages do not fall into currently defined M1/M2 classification system based on CD206 receptor expression levels. Conclusions. VAT macrophages are increased in obese subjects, but the current markers used to define macrophage populations are inadequate to distinguish differences in human obesity. Further studies are needed to delineate the function of AT macrophages in the maintenance and progression of human AT inflammation in obesity.

Clusterin Impairs Hepatic Insulin Sensitivity and Adipocyte Clusterin Associates With Cardiometabolic Risk.

OBJECTIVE: Components of the adipose tissue (AT) extracellular matrix (ECM) are recently discovered contributors to obesity-related cardiometabolic disease. We identified increased adipocyte expression of ECM-related clusterin (apolipoprotein J) in obese versus lean women by microarray. Our objective was to determine 1) whether subcutaneous AT adipocyte (SAd) clusterin and serum clusterin are associated with insulin resistance (IR) and known markers of cardiometabolic risk and 2) how clusterin may contribute to increased risk. RESEARCH DESIGN AND METHODS: We validated increased clusterin expression in adipocytes from a separate group of 18 lean and 54 obese individuals. The relationship of clusterin gene expression and plasma clusterin with IR, cardiovascular biomarkers, and risk of cardiovascular disease (CVD) was then determined. Further investigations in human cultured cells and in aged LDLR-/- mice prone to development of obesity-associated complications were performed. RESULTS: SAd clusterin correlated with IR, multiple CVD biomarkers, and CVD risk, independent of traditional risk factors. Circulating human clusterin exhibited similar associations. In human adipocytes, palmitate enhanced clusterin secretion, and in human hepatocytes, clusterin attenuated insulin signaling and APOA1 expression and stimulated hepatic gluconeogenesis. LRP2 (megalin), a clusterin receptor, highly expressed in liver, mediated these effects, which were inhibited by LRP2 siRNA. In response to Western diet feeding, an increase in adipocyte clusterin expression was associated with a progressive increase in liver fat, steatohepatitis, and fibrosis in aged LDLR-/- mice. CONCLUSIONS: Adipocyte-derived clusterin is a novel ECM-related protein linking cardiometabolic disease and obesity through its actions in the liver.

Aspiration, Agency, and the Production of New Selves in a Scottish New Town, c.1947-c.2016.

Narratives of deindustrialization, urban decline and failing public housing and the negative outcomes associated with these processes dominate accounts of post-war Scotland, bolstering the interpretation of Scottish exceptionalism in a British context. Within these accounts working people appear as victims of powerful and long-term external forces suffering sustained and ongoing deleterious vulnerabilities in terms of employment, health, and housing. This article challenges this picture by focusing on the first Scottish new town which made space for working people's aspiration and new models of the self manifested in new lifestyles and social relations. Drawing on archival data and oral history interviews, we identify how elective relocation fostered and enabled new forms of identity predicated upon new housing, new social relations, and lifestyle opportunities focused on the family and home and elective social networks no longer determined by traditional class and gender expectations. These findings permit an intervention in the historical debates on post-war housing and social change which go beyond the materialistic experience to deeper and affective dimensions of the new town self.

Adipocyte DIO2 Expression Increases in Human Obesity but Is Not Related to Systemic Insulin Sensitivity.

Deiodinase type II (D2), encoded by DIO2, catalyzes the conversion of T4 to bioactive T3. T3 not only stimulates adaptive thermogenesis but also affects adipose tissue (AT) lipid accumulation, mitochondrial function, inflammation, and potentially systemic metabolism. Although better defined in brown AT, the precise role of DIO2 expression in white AT remains largely unknown, with data derived only from whole fat. Therefore, the purpose of this study was to determine whether subcutaneous (SAT) and visceral (VAT) adipocyte-specific gene expression of DIO2 differs between obese and lean patients and whether these differences relate to alterations in mitochondrial function, fatty acid flux, inflammatory cytokines/adipokines, and ultimately insulin sensitivity. Accordingly, adipocytes of 73 obese and 21 lean subjects were isolated and subjected to gene expression analyses. Our results demonstrate that obese compared to lean human individuals have increased adipocyte-specific DIO2 expression in both SAT and VAT. Although higher DIO2 was strongly related to reduced fatty acid synthesis/oxidation and mitochondrial function, we found no relationship to proinflammatory cytokines or insulin resistance and no difference based on diabetic status. Our results suggest that adipocyte-derived DIO2 may play a role in weight maintenance but is likely not a major contributor to obesity-related insulin resistance.