14 research outputs found

    Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

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    Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.ISSN:0092-8674ISSN:1097-417

    Impact of caregivers' psychological and caregiving status on recruitment, conversion, and retention in stem cell therapy trials for cerebral palsy: A prospective survey analysis

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    Abstract Aim To examine specific correlates that may affect retention outcomes of neural stem cell therapy trials in families screened for cerebral palsy. Design A prospective correlational study. Methods Primary caregivers completed surveys of psychological resilience, care burden and family caregiver tasks. The overall data and differences between groups were analysed and compared. Results Resilience was negatively correlated with the care ability and closely related to the monthly household income and educational level of the caregivers. Factors affecting the final retention rate included the type of disease, number of combined disorders, monthly household income, primary caregivers' education level and resilience. Conclusion Economic level, literacy and psychological status may affect trial retention. These findings can provide tips for preparing for subsequent screening, identification and intervention in stem cell clinical trials. Implication for the Profession and/or Patient Care The study results may provide nursing care tips to make recruitment more efficient, reduce trial costs, support patient‐centredness and accelerate trial progress. No Patient or Public Contribution The target population involves the primary caregivers of children living with cerebral palsy. However, neither patients nor the public contributed to the design or conduct of the study, analysis, or interpretation of the data, or preparation of the manuscript

    Uric acid treatment decreases glucose-stimulated insulin secretion.

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    <p>(<b>A</b>) Min6 cells were treated with uric acid (5 mg/dL), uric acid+benzbromarone (50 µmol/L), uric acid+BAY 11–7082 (5 µmol/L), or uric acid+L-NMMA (1 mmol/L) for 24 h. (<b>B</b>) Isolated mouse islets (eight islets per well) were treated as above. After incubation for 1 h in glucose-free KRB buffer, Min6 cells or mouse islets were treated for 1 h with KRB buffer containing low (3.3 mmol/L) or high (16.7 mmol/L) concentrations of glucose, and the supernatant fractions were collected for insulin concentration analysis. Uric acid treatment reduced glucose-stimulated insulin secretion by both Min6 cells and islets, and in both cases insulin secretion was restored by all three inhibitors. *<i>P</i><0.05, **<i>P</i><0.01.</p

    Uric acid impairs β-cell viability by inducing apoptosis.

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    <p>(<b>A</b>) The viability of Min6 cells was measured using an MTT assay after treatment with different concentrations of uric acid. Uric acid (5 mg/dL) significantly reduced cell survival. (<b>B</b>) Bcl-2 protein levels in Min6 cells treated with different concentrations of uric acid were determined by Western blotting. Bcl-2 expression relative to control levels was significantly reduced by uric acid treatment (5 mg/dL). (<b>C</b>) Min6 cells were treated with uric acid (5 mg/dL) for 48 h, followed by staining with TUNEL and Hoechst. Apoptosis was determined by scoring cells displaying pycnotic nuclei. A significant increase in apoptotic cells induced by uric acid was attenuated by 50 µmol/L benzbromarone, 5 µmol/L BAY 11–7082, and 1 mmol/L L-NMMA. About 2000 cells were scored for each group in one experiment. Values are means ± SEM and are representative of three separate experiments. *<i>P</i><0.05, **<i>P</i><0.01.</p

    A hybrid sub-lineage of Listeria monocytogenes comprising hypervirulent isolates

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    The foodborne pathogen Listeria monocytogenes (Lm) is a highly heterogeneous species and currently comprises of 4 evolutionarily distinct lineages. Here, we characterize isolates from severe ovine listeriosis outbreaks that represent a hybrid sub-lineage of the major lineage II (HSL-II) and serotype 4h. HSL-II isolates are highly virulent and exhibit higher organ colonization capacities than well-characterized hypervirulent strains of Lm in an orogastric mouse infection model. The isolates harbour both the Lm Pathogenicity Island (LIPI)-1 and a truncated LIPI-2 locus, encoding sphingomyelinase (SmcL), a virulence factor required for invasion and bacterial translocation from the gut, and other non-contiguous chromosomal segments from another pathogenic species, L. ivanovii. HSL-II isolates exhibit a unique wall teichoic acid (WTA) structure essential for resistance to antimicrobial peptides, bacterial invasion and virulence. The discovery of isolates harbouring pan-species virulence genes of the genus Listeria warrants global efforts to identify further hypervirulent lineages of Lm.ISSN:2041-172
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