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Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD.

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11 [3-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell--specific, 11β-HSD1--overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, [MIP-HSD1.sup.tg/+] mice exhibited a reversal of high fat-induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extraeellular signal-related kinase and p21 signaling pathways, [11β-HSD1.sup.-/-] mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1tg/tg mice and diabetic [Lep.sup.db/db] mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes., Type 2 diabetes prevalence has risen dramatically in parallel with the worldwide increase in obesity (1). Understanding and targeting the processes leading to β-cell exhaustion in the face of peripheral [...]

OBJECTIVE--The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11β-hydroxysteroid dehydrogenase type 1 knockout (11β-[HSD1.sup.-/-]) mice fed a high-fat (HF) diet. RESEARCH DESIGN AND METHODS--By focusing on the earliest divergence in visceral adiposity, subcutaneous and visceral fat depots from 11β-[HSD1.sup.-/-] and C57B1/6J control mice fed an HF diet for 4 weeks were used for comparative microarray analysis of gene expression, and differences were validated with real-time PCR. Key changes in metabolic signaling pathways were confirmed using Western blotting/immunoprecipitation, and fat cell size was compared with the respective chow-fed control groups. Altered adipose inflammatory cell content and function after 4 weeks (early) and 18 weeks (chronic) of HF feeding was investigated using fluorescence (and magnetic)-activated cell sorting analysis, immunohistochemistry, and in situ hybridization. RESULTS--In subcutaneous fat, HF-fed 11β-[HSD1.sup.-/-] mice showed evidence of enhanced insulin and β-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11β-[HSD1.sup.-/-] visceral fat accumulation was characterized by maintained AMP kinase activation, not insulin sensitization, and higher adipocyte interleukin-6 release. Intracellular glucocorticoid deficiency was unexpectedly associated with suppressed inflammatory signaling and lower adipocyte monocyte chemoattractant protein-1 secretion with strikingly reduced cytotoxic T-cell and macrophage infiltration, predominantly in visceral fat. CONCLUSIONS--Our data define for the first time the novel and distinct depot-specific mechanisms driving healthier fat patterning and function as a result of reduced intra-adipose glucocorticoid levels. Diabetes 60:1158-1167, 2011, Accumulation of visceral fat strongly increases the risk of cardiometabolic disease, whereas peripheral fat accretion is relatively protective (1-3). Pronounced visceral adiposity, loss of subcutaneous adipose tissue, and metabolic disease [...]

Corporate finance professionals are facing more complex landscapes than their predecessors saw 10 or 20 years ago. Hospital CFOs are no different. Hospitals are faced with capital pressures from many [...]

Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P< 0.001; 397 up, 531 down). These clustered in pathways involved in signalling, sterol/lipid metabolism, cell proliferation/hypertrophy and apoptosis. Signalling genes included some implicated in adrenal adenomas but also upregulated genes associated with cyclic AMP and downregulated genes associated with aldosterone synthesis. Sterol metabolism genes were those promoting cholesterol supply (Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P< 0.05; <1.3-fold). Increased Ki67, Ccna2, Ccnb2and Tk1expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1aand Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P< 0.001) and more widely distributed throughout the cortex. In summary, long-term steroidogenesis with ACTH excess is sustained by genes controlling cholesterol supply and adrenal mass. ACTH effects on adrenal morphology and genes controlling cell hypertrophy, proliferation and apoptosis suggest the involvement of different cell types and separate molecular pathways.

The ability to identify and stratify patients that will respond to specific therapies has been transformational in a number of disease areas, particularly oncology. It is anticipated that this will also be the case for cell‐based therapies, particularly in complex and heterogeneous diseases such as rheumatoid arthritis (RA). Recently, clinical results with expanded allogenic adipose‐derived mesenchymal stem cells (eASCs) have indicated clinical efficacy in highly refractory RA patients. In this study, we set out to determine if circulating microRNAs (miRNAs) could be identified as potential biomarkers associated with response to eASCs in these RA patients. The miRNA expression profiles of pre‐treatment plasma samples from responder and nonresponder patients were determined using microarrays. Ten miRNAs were identified that were differentially expressed in the responder group as compared to the nonresponder group. To confirm the differential expression of these 10 miRNA biomarkers, they were further assayed by quantitative reverse‐transcriptase polymerase chain reaction (QRT‐PCR). From this analysis, three miRNAs, miR‐26b‐5p, miR‐487b‐3p and miR‐495‐3p, were confirmed as being statistically significantly upregulated in the responder group as compared with the nonresponder group. Receiver operating characteristic analysis confirmed their diagnostic potential. These miRNAs could represent novel candidate stratification biomarkers associated with RA patient response to eASCs and are worthy of further clinical validation. StemCellsTranslationalMedicine2017;6:1202–1206

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.

Understanding fundamental molecular mechanisms that govern the transmigration and interstitial migration of leukocytes to sites of tissue damage and infection is of potential significance in identifying novel therapeutic targets for the management of chronic inflammatory disorders. CD31 is a mammalian cell adhesion molecule that regulates the recruitment of leukocytes from the circulation. Our recent unpublished work has suggested that homophilic ligation of CD31 can negatively regulate the ether‐à‐go‐go‐related gene (ERG) current within leukocytes to regulate cell‐cell adhesion. To validate and probe the functional significance of ERG in leukocytes, we developed an infected wound model of inflammation in zebrafish and assessed the efficacy of two ERG‐specific inhibitors, dofetilide and E4031, as well as an ERG‐specific antisense RNA morpholino on neutrophil recruitment. Our data confirm a hitherto undescribed role for ERG in leukocytes, where inhibition or translational knockdown of ERG resulted in significant attenuation of the inflammatory response to an infectious stimulus. Inhibition of ERG was verified independently by a decrease in the ventricular heart rate, where ERG also functions in the repolarization of the cardiac action potential. Our results suggest that ERG‐specific Class III antiarrhythmic drugs can modulate inflammatory responses to infection.

Salivary fluid, the collective product of numerous major and minor salivary glands, contains a range of secretory proteins that play key defensive, digestive, and gustatory roles in the oral cavity. To understand the distinct protein “signature” contributed by individual salivary glands to salivary secretions, we studied a family of proteins shown by in vitro mRNA translation to be abundantly expressed in mouse sublingual glands. Molecular cloning, Southern blotting, and restriction fragment length polymorphism analyses showed these to represent one known and two novel members of the common salivary protein (CSP-1)/Demilune cell and parotid protein (Dcpp) salivary protein family, the genes for which are closely linked in the T-complex region of mouse chromosome 17. Bioinformatic analysis identified a putative human CSP-1/Dcpp ortholog, HRPE773, expressed predominantly in human salivary tissue, that shows 31% amino acid identity and 45% amino acid similarity to the mouse Dcppquery sequence. The corresponding human gene displays a similar structure to the mouse Dcppgenes and is located on human chromosome 16 in a region known to be syntenic with the T-complex region of mouse chromosome 17. The predicted mouse and human proteins both display classical NH2-terminal signal sequences, putative jacalin-related lectin domains, and potential N-linked glycosylation sites, suggesting secretion via sublingual saliva into the oral cavity where they may display antimicrobial activity or provide a defensive coating to enamel. Identification of a human CSP-1/Dcpp ortholog therefore provides a key tool for investigation of salivary protein function in human oral health and disease.

This corrects the article DOI: 10.1038/nm.4115

In the human fetal ovary, oocyte-derived activin A promotes somatic cell proliferation and survival, and regulates the expression of reciprocal signals to the oocyte such as BDNFand membrane-bound KITLG. The downstream targets of activin/TGF-beta (-B) signaling in the human fetal ovary remain broadly unknown, however. To identify novel gene targets of activin/TGF-B signaling, we performed an Illumina Ref-8 Beadchip array analysis of RNA from human fetal ovaries (17-19 weeks gestational age (wga)) cultured in serum free media in the presence or absence of recombinant human activin A or BMP2 (both 100ng/ml) for 24 hours. 35 genes were significantly differentially-expressed between both control (untreated) and activin A-treated ovaries, and between activin A and BMP2-treated ovaries (p<0.05, n=4). We selected the cell adhesion protein TGFBI, the serine peptidase inhibitor SERPINE2and the neuron-enriched signal protein BASP1for further analysis. qRT-PCR validation revealed 1.9- and 1.4-fold increases in SERPINE2and TGFBIexpression respectively in activin A-treated ovaries compared to controls (both p<0.01, n=6, 17-19wga). BASP1expression increased 1.4-fold but did not reach significance. Expression of these genes was unchanged in BMP2-treated ovaries, revealing these effects to be specific for activin/TGF-B signaling. Analysis of SERPINE2, BASP1and TGFBIexpression across a developmental window revealed the expression of all three genes to be greatest at 8-11wga (when the ovary contains only mitotic primordial germ cells (PGCs)), and downregulated significantly by 14-16wga (by which time meiosis has commenced), remaining low at 17-20wga (onset of follicle formation (all p<0.001, n=4-6/group)). Preliminary immunohistochemical analyses reveals SERPINE2, TGFBI and BASP1 to be expressed predominantly by somatic cells, consistent with these cells being the major target of activin/TGF-B action in the human fetal ovary (as indicated by our previous demonstration of SMAD2/3 protein in somatic cell nuclei). To establish whether activin/TGF-B signaling is important for regulating the expression of these genes at the earlier stage of ovarian development, we cultured human fetal ovaries (9-13wga) with the activin/TGF-B signaling inhibitor SB-431542 (10μM) for 24 hours. SB-431542 decreased expression of SERPINE2and TGFBIby 52% (p=0.02, n=3) and 50% (p=0.002) respectively, relative to DMSO-treated controls, demonstrating regulation of these genes by activin/TGF–B at this developmental stage. BASP1expression was also reduced by 32% (p=0.03) relative to controls, confirming this to be a genuine target of activin/TGF-B signaling. Levels of FOXL2(a somatic cell marker) and OCT4(a germ cell marker) mRNA were not affected by SB-431542 treatment, demonstrating the specificity of these effects. These data identify SERPINE2, TGFBIand BASP1as novel targets of activin/TGF-B signaling during human fetal ovarian development. The developmentally-regulated expression of SERPINE2, TGFBIand BASP1, coupled with roles for their encoded proteins in regulating growth factor availability, signaling and cell adhesion, suggests these genes may encode novel components of the human ovarian PGC niche and may contribute to the regulation of germ cell proliferation and differentiation in the human fetal ovary.