The rockefeller university

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or beta 3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite beta-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.

The dynamics of ecological change following a major perturbation, known

Prescription opioid abuse is a serious public health issue. Recently, we showed that female and male Sprague-Dawley rats acquire conditioned place preference (CPP) to the mu opioid receptor agonist oxycodone. Anatomical analysis of the hippocampus from these rats unveiled sex differences in the opioid system in a way that would support excitation and opiate associative learning processes especially in females. In this study, we examined the expression and protein densities of opioid, plasticity, stress and related kinase and signaling molecules in the hippocampus of female and male rats following oxycodone CPP. Oxycodone CPP females have: a) increases in ARC (activity regulated cytoskeletal-associated protein)-immunoreactivity (ir) in CA3 pyramidal cells; b) decreases in Npy (neuropeptide Y) gene expression in the medial hippocampus but higher numbers of NPY-containing hilar interneurons compared to males; c) increases in Crhr2 (corticotropin releasing factor receptor 2) expression in CA2/3; d) increases in Akt1 (AKT serine/threonine kinase 1) expression in medial hippocampus; and e) decreases in phosphorylated MAPK (mitogen activated protein kinase)-ir in CA1 and dentate gyrus. Oxycodone CPP males have: a) increases in Bdnf (brain derived-neurotrophic factor) expression, which is known to be produced in granule cells, relative to females; b) elevated Mapk1 expression and pMAPK-ir in the dentate hilus which harbors newly generated granule cells; and c) increases in CRHR1-ir in CA3 pyramidal cell soma. These sex-specific changes in plasticity, stress and kinase markers in hippocampal circuitry parallel previously observed sex differences in the opioid system after oxycodone CPP. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

Background: Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. Objectives: To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an antieinterleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. Methods: This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4: 1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. Results: The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. Limitations: Interpretation of efficacy data is limited by the small sample size. Conclusion: Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis.

Linked Article: Albrecht et al. Br J Dermatol 2019; 180:749-55.

Eukaryotic elongation factor 2 kinase (eEF-2K), an atypical

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Breaking the anterior-posterior symmetry in mammals occurs at gastrulation. Much of the signalling network underlying this process has been elucidated in the mouse; however, there is no direct molecular evidence of events driving axis formation in humans. Here, we use human embryonic stem cells to generate an in vitro three-dimensional model of a human epiblast whose size, cell polarity and gene expression are similar to a day 10 human epiblast. A defined dose of BMP4 spontaneously breaks axial symmetry, and induces markers of the primitive streak and epithelial-to-mesenchymal transition. We show that WNT signalling and its inhibitor DKK1 play key roles in this process downstream of BMP4. Our work demonstrates that a model human epiblast can break axial symmetry despite the absence of asymmetry in the initial signal and of extra-embryonic tissues or maternal cues. Our three-dimensional model is an assay for the molecular events underlying human axial symmetry breaking.

Craniosynostosis (CS) is a frequent congenital anomaly featuring the