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Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction-associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA-mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK knockdown decreased the de novo lipogenesis pathway, whereas the inhibitor increased the fatty acid oxidation pathway. Moreover, KHK knockdown completely prevented hepatic fructolysis and improved glucose tolerance. Conversely, the KHK inhibitor only partially reduced fructolysis, but it also targeted triokinase, mediating the third step of fructolysis. This led to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. Overexpression of wild-type, but not kinase-dead, KHK in cultured hepatocytes increased hepatocyte injury and glycogen accumulation after treatment with fructose. The differences between KHK inhibition and knockdown are, in part, explained by the kinase-dependent and -independent effects of KHK on hepatic metabolism.

Scholars have long considered the era of modern education in Nepal as inaugurated by foreign actors in the 1950s. Based on an analysis of two central publications of the relatively overlooked educator and intellectual Jaya Prithvi Bahadur Singh, this paper aims to shed new light on the educational history of the early twentieth century Himalaya. By employing a lens of global history, the study challenges the narrative of a 'sudden arrival' of modern education in Nepal in 1950s. In doing so, the paper aims to demonstrate the relevance of Singh's thought to the global emergence of modern, progressive, and humanistic forms of education in the early twentieth century.

ObjectivesMore knowledge about health related quality of life (HRQoL) among mothers with inflammatory joint disease (IJD) is needed to understand the complex challenges for this group of patients. The overall aim of this study was to investigate changes in HRQoL among mothers with IJD from year 2000 to year 2020.MethodsThis study had a comparative cross-sectional design with two study groups 20 years apart, year 2000 (n = 77) and year 2020 (n = 197). Patients were identified from RevNatus, a Norwegian nationwide medical quality register (2020 cohort) and from a national centre for pregnancy and rheumatic disease (2000 cohort). Mothers with the diagnoses of rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis and psoriatic arthritis with children aged 0–6 were included. Data on HRQoL were self-reported and assessed by the RAND-36 (SF-36) questionnaire, along with data on educational status, number of children, months since last childbirth and eight questions on experienced motherhood limitations and experienced anxiety and distress for the children. Descriptive statistics were performed using the Mann-Whitney U-test, the Pearson chi-squared test and independent samples t-test. Multivariable linear regression were used to investigate changes and association between the RAND36 (SF-36) scores and the two study groups and possible confouders.ResultsThe 2020 cohort had significantly higher scores on bodily pain (p

The aim of the paper was to analyse the ways in which collaborative governance appears in the context of lifelong guidance in Finland. The research question was ‘What are (in terms of problem-solving, collaborative process and multi-relational accountability) the challenges for collaborative governance of lifelong guidance in Finland?’ The analysis drew from ten in-depth thematic interviews with experts working on issues related to the governance of lifelong guidance at the central government of Finland and related interest groups. Our analysis showed that, despite the progress made, institutional structures, practices and perceptions challenge the implementation of collaborative governance. The results point out three key challenges: The first generally relates to the aim of increasing collaborative governance, the second to the creation of a collaborative network and the formation of shared objectives in lifelong guidance and the third to the concept of multi-relational accountability. A key question in addressing these challenges is how to evaluate and verify the benefits of collaborative governance.

Background: Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, resulting in long-term weight loss and rapid remission of type 2 diabetes mellitus. Improved glucagon-like peptide 1 (GLP-1) levels is one factor that contributes to the positive effects. Prior to RYGB, GLP-1 response is blunted which can be attributed to intestinal ketogenesis. Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via an unidentified G-protein coupled receptors (GPCRs). A possible class of GPCRs through which ketone bodies may reach are the free fatty acid receptors (FFARs) located at the basolateral membrane of enteroendocrine cells. Aim: To evaluate FFAR3 expression in enteroendocrine cells of the small intestine under different circumstances, such as diet and bariatric surgery, as well as explore the link between ketone bodies and GLP-1 secretion. Materials and methods: FFAR3 and enteroendocrine cell expression was analyzed using Western blot and immunohistochemistry in biopsies from healthy volunteers, obese patients undergoing RYGB and mice. GLUTag cells were used to study GLP-1 secretion and FFAR3 signaling pathways. Results: The expression of FFAR3 is markedly influenced by diet, especially high fat diet, which increased FFAR3 protein expression. Lack of substrate such as free fatty acids in the alimentary limb after RYGB, downregulate FFAR3 expression. The number of enteroendocrine cells was affected by diet in the normal weight individuals but not in the subjects with obesity. In GLUTag cells, we show that the ketone bodies exert its blocking effect on GLP-1 secretion via the FFAR3, and the Gαi/o signaling pathway. Conclusion: Our findings that ketone bodies via FFAR3 inhibits GLP-1 secretion bring important insight into the pathophysiology of T2D. This highlights the role of FFAR3 as a possible target for future anti-diabetic drugs and treatments.

Analogues of the hepatokine fibroblast growth factor 21 (FGF21) are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration, and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation, and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.

Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

This article draws on ethnographic data on the distribution of scholarship programs at two Nepali state-run schools. Anchored in the cross-field of educational anthropology and the anthropology of bureaucracy, this article examines schools not just as sites of learning but as institutions that control and regulate access through bureaucratized mechanisms. We draw attention to scholarship processes as inherently selective and requiring social and cultural capital, thus leading to what we term "the bureaucratization of social justice."

Abstract Objectives To explore myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients' experiences of a health psychological group intervention and its usefulness, non‐usefulness or harmfulness for illness management and adjustment. Design A qualitative longitudinal study using inductive content analysis. Methods Semistructured interviews were conducted with 10 adults. Interviews were conducted before the 16‐week intervention, immediately after its completion, and at 3 months after completion. Results Participants reported that the intervention was useful and not harmful. The model improved their ability to cope with ME/CFS by providing them with useful information about the illness along with peer support and professional guidance. Participants reported improved illness management and adjustment, which they perceived as an outcome of achieving new ways of thinking, feeling and acting. Conclusions Participants viewed the health psychological approach to group intervention as meeting their needs. To achieve better illness management and adjustment, more consideration should be given to supportive interactional processes with peers and healthcare professionals. Patient or Public Contribution The intervention was developed to meet patients' needs of finding ways to manage their illness. The research team consulted eight patients with ME/CFS and three clinical centres working with ME/CFS treatment and rehabilitation at the intervention planning stage. Their comments influenced the planning and content of the intervention as well as ethical issues that should be considered, such as potential harm to participants. All participants were informed about the theoretical foundations of the study and the principles guiding the intervention. Participants were not involved in the data analysis. Clinical Trial Registration NCT04151693

AIMS: Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive. METHODS AND RESULTS: Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index. CONCLUSION: FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease.

Abstract Background We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: “Pancreato-Hepato-Biliary”, “Retroperitoneum and Aorta”, “Head and Neck-limited” and “Mikulicz’ and Systemic” in a well-characterized patient cohort. Methods We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. Results The study cohort included 79 IgG4-RD patients assigned to the “Pancreato-Hepato-Biliary” (22.8%), Retroperitoneum and Aorta” (22.8%) “Head and Neck-limited” (29.1%), and “Mikulicz’ and Systemic” (25.3%) phenotype groups, respectively. While 7 2/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the “Retroperitoneum and Aorta” group ( 66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the “Retroperitoneum and Aorta” group (27.8%, p