Polymorphic Structures of Alzheimer's β-Amyloid Globulomers

Misfolding and self-assembly of Amyloid-β (Aβ) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation.Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR.Our computationally modeled Aβ globulomers provide useful insights into structure, dynamics, and polymorphic nature of Aβ globulomers which are completely different from Aβ fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between Aβ globulomers and fibrils

Hepatic FGF21 protects mice against diet-induced lipid dysregulation and insulin resistance

Fibroblast growth factor 21 (FGF21) is a potent metabolic hormone produced by a number of organs. It has been shown to confer multiple metabolic benefits on obesity. Therapeutic administration of FGF21 or its analog protects against diet-induced obesity and hyperglycemia in both rodents and humans. However, the physiological roles of FGF21 remain ambiguous. Since the liver is the major source of circulating FGF21, we propose that the endocrine actions of FGF21 derived from the liver may account for its metabolic effects on lipid metabolism. We therefore generated the liver-specific FGF21 KO (LiverKO) mice by utilizing the Cre-loxP recombination system. LiverKO mice and their age-matched wild-type (WT) littermates were fed a high fat diet (HFD) for 20 weeks and assessed for the metabolic phenotypes. Circulating FGF21 was significantly elevated in WT mice during fasting or HFD feeding. However, this elevation of circulating FGF21 was completely abolished in LiverKO mice, suggesting the liver is the major source of circulating FGF21. LiverKO mice treated with HFD showed a sign'5cant reduction in body fat mass when compared to WT mice, as revealed by NMR body composition analyzer suggesting resistance to obesity was mainly attributed to the loss at hepatic FGF21. Interestingly, although LiverKO mice were leaner, they developed more severe glucose intolerance and insulin resistance after HFD feeding as shown by GTT and ITT. In addition, LiverKO mice had higher serum triglyceride and free fatty acid levels suggesting that lipid homeostasis is lipid uptake in adipocytes. These data collectively suggest that circulating FGF21 is mainly derived from the liver. Hepatic FGF21 regulates lipid metabolism in adipocytes, and therefore protects mice against diet-induced hyperglycemia and insulin resistance possibly via reducing ectopic lipid accumulation in non-adipose tissues such as the liver and skeletal muscles. Supported By: Collaborative Research Fund Group Research Projects of Hong Kon

A novel lipocalin, LCN14, ameliorates hyperglycemia in diet-induced obese mice via reducing glycerol efflux from adipose tissue

Adipose tissue is an active endocrine organ that plays important roles in regulating energy metabolism in various organs, and dysreguation of adipose tissue-derived hormones may contribute to the pathogenesis of diabetic complications. In this study we identified a novel adipokine, lipocalin 14 (LCN 14), whose circulating level and expression in white adipose tissues are severely reduced in both diet-induced and genetically diabetic mice. This study aims to investigate whether over-expression of LCN14 could alleviate hyperglycemia, glucose intolerance and insulin resistance in obese mice. Mice (C57/BL6N) were fed with either chow diet (STC) or high-fat diet (HFD) for 10 weeks, followed by infection with recombinant adeno-associated virus (rAAV) encoding LCN14, or eGFP as a control. Our findings suggest that over-expressing LCN14 could lead to elevate circulating level of LCN14, which increase in insulin sensitivity in major metabolic tissues, including liver, muscle and adipose tissues. Interestingly, over-expressing LCN14 can also lower serum glycerol level by reducing the glycerol efflux from adipose tissue, which limited the availability of glycerol for hepatic gluconeogenesis, and hence reversing hyperglycemia. Collectively, our results provided the first evidence that LCN14 is a novel adipokine involved in glucose metabolism. The deficiency of LCN14 in diet-induced obese mice may contribute to the development of hyperglycemia and insulin resistance. LCN14, therefore, represents a promising molecular target for the development of new tools for blood-glucose-lowering therapy

Cotranscriptional recruitment of yeast TRAMP complex to intronic sequences promotes optimal pre-mRNA splicing

Most unwanted RNA transcripts in the nucleus of eukaryotic cells, such as splicing-defective pre-mRNAs and spliced-out introns, are rapidly degraded by the nuclear exosome. In budding yeast, a number of these unwanted RNA transcripts, including spliced-out introns, are first recognized by the nuclear exosome cofactor Trf4/5p-Air1/2p-Mtr4p polyadenylation (TRAMP) complex before subsequent nuclear-exosome-mediated degradation. However, it remains unclear when spliced-out introns are recognized by TRAMP, and whether TRAMP may have any potential roles in pre-mRNA splicing. Here, we demonstrated that TRAMP is cotranscriptionally recruited to nascent RNA transcripts, with particular enrichment at intronic sequences. Deletion of TRAMP components led to further accumulation of unspliced pre-mRNAs even in a yeast strain defective in nuclear exosome activity, suggesting a novel stimulatory role of TRAMP in splicing. We also uncovered new genetic and physical interactions between TRAMP and several splicing factors, and further showed that TRAMP is required for optimal recruitment of the splicing factor Msl5p. Our study provided the first evidence that TRAMP facilitates pre-mRNA splicing, and we interpreted this as a fail-safe mechanism to ensure the cotranscriptional recruitment of TRAMP before or during splicing to prepare for the subsequent targeting of spliced-out introns to rapid degradation by the nuclear exosome.link_to_OA_fulltex

The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT

Perspectives for IoT-Based Integration of Distributed and Automated Manufacturing Lines for Mass Customization

IoT (Internet-of-things) platforms can connect sensors and devices along supply chains of production and logistics systems, as well as end users of products, allowing for co-designed and customized solutions. This paper aims to present perspectives for the IoT-based integration of manufacturing lines. More specifically, it will address the implementation of these platforms for the cyberphysical integration of distributed and highly automated manufacturing lines of customized items. A Systematic Literature Review was conducted in order to identify the main characteristics of the research area and to cluster research and practical perspectives. As results, bibliometric analysis has evidenced the continuous growth of the research area and the most important scientific journals publishing content related to IoT-based platforms for distributed manufacturing lines. In the content analysis, the perspectives are clustered in: (i) conceptual propositions and requirements, (ii) new methods and models for supporting decision-making, (iii) development of technology-based approaches, and (iv) empirical studies. As conclusion, the paper wraps up with the description of interesting avenues from both a scientific and a praxis-oriented point-of-view