Frequency-Domain Fusing Convolutional Neural Network: A Unified Architecture Improving Effect of Domain Adaptation for Fault Diagnosis.

In recent years, transfer learning has been widely applied in fault diagnosis for solving the problem of inconsistent distribution of the original training dataset and the online-collecting testing dataset. In particular, the domain adaptation method can solve the problem of the unlabeled testing dataset in transfer learning. Moreover, Convolutional Neural Network (CNN) is the most widely used network among existing domain adaptation approaches due to its powerful feature extraction capability. However, network designing is too empirical, and there is no network designing principle from the frequency domain. In this paper, we propose a unified convolutional neural network architecture from a frequency domain perspective for a domain adaptation named Frequency-domain Fusing Convolutional Neural Network (FFCNN). The method of FFCNN contains two parts, frequency-domain fusing layer and feature extractor. The frequency-domain fusing layer uses convolution operations to filter signals at different frequency bands and combines them into new input signals. These signals are input to the feature extractor to extract features and make domain adaptation. We apply FFCNN for three domain adaptation methods, and the diagnosis accuracy is improved compared to the typical CNN.

Catechol estrogens stimulate insulin secretion in pancreatic ß-cells via activation of the transient receptor potential A1 (TRPA1) channel.

Estrogen hormones play an important role in controlling glucose homeostasis and pancreatic ß-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic ß-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic ß-cells. We show that catechol estrogens, hydroxylated at positions C2 and C4 of the steroid A ring, rapidly potentiated glucose-induced insulin secretion via a nongenomic mechanism. 2-Hydroxyestrone, the most abundant endogenous estrogen metabolite, was more efficacious in stimulating insulin secretion than any other tested catechol estrogens. In insulin-secreting cells, catechol estrogens produced rapid activation of calcium influx and elevation in cytosolic free calcium. Catechol estrogens also generated sustained elevations in cytosolic free calcium and evoked inward ion current in HEK293 cells expressing the transient receptor potential A1 (TRPA1) cation channel. Calcium influx and insulin secretion stimulated by estrogen metabolites were dependent on the TRPA1 activity and inhibited with the channel-specific pharmacological antagonists or the siRNA. Our results suggest the role of estrogen metabolism in a direct regulation of TRPA1 activity with potential implications for metabolic diseases.

Synthetic protease-activated class B GPCRs.

G-protein coupled receptors (GPCRs) are the ligand detection machinery of a majority of extracellular signaling systems in metazoans. Novel chemical and biological tools to probe the structure-function relationships of GPCRs have impacted both basic and applied GPCR research. To better understand the structure-function of class B GPCRs, we generated receptor-ligand fusion chimeric proteins that can be activated by exogenous enzyme application. As a prototype, fusion proteins of the glucagon-like peptide-1 receptor (GLP-1R) with GLP-1(7-36) and exendin-4(1-39) peptides incorporating enterokinase-cleavable N-termini were generated. These receptors are predicted to generate fusion protein neo-epitopes upon proteolysis with enterokinase that are identical to the N-termini of GLP-1 agonists. This system was validated by measuring enterokinase-dependent GLP-1R mediated cAMP accumulation, and a structure-activity relationship for both linker length and peptide sequence was observed. Moreover, our results show this approach can be used in physiologically relevant cell systems, as GLP-1R-ligand chimeras were shown to induce glucose-dependent insulin secretion in insulinoma cells upon exposure to enterokinase. This approach suggests new strategies for understanding the structure-function of peptide-binding GPCRs.

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.

High-Performance Solid-State Supercapacitors Fabricated by Pencil Drawing and Polypyrrole Depositing on Paper Substrate.

A solid-state powerful supercapacitor (SC) is fabricated with a substrate of Xerox paper. Its current collector based on a foldable electronic circuit is developed by simply pencil drawing. Thin graphite sheets on paper provide effective channels for electron transmission with a low resistance of 95 Ω sq-1. The conductive organic material of polypyrrole coated on thin graphite sheets acts as the electrode material of the device. The as-fabricated SC exhibits a high specific capacitance of 52.9 F cm-3 at a scan rate of 1 mV s-1. An energy storage unit fabricated by three full-charged series SCs can drive a commercial light-emitting diode robustly. This work demonstrated a simple, versatile and cost-effective method for paper-based devices.

Ultrathin and lightweight 3D free-standing Ni@NiO nanowire membrane electrode for a supercapacitor with excellent capacitance retention at high rates.

A free-standing binder-free 3D Ni@NiO nanowire membrane is fabricated by a simple filtration method followed by thermal annealing. With an appropriate annealing temperature, the functional nanowires can keep their rough and echinate surface, and the conductive network composed of welded nickel nanowire cores is well-preserved without isolation (0.53 Ω/sq). The unique 3D multigrade mesporous structure not only accelerates the intercalation and deintercalation velocity of electrolyte ions but also provides numerous electroactive sites for the Faraday reaction. As a result, the supercapacitor electrode can preserve a capacitance retention of 96.1% (36.9 F/cm(3)) with a high discharge current density, indicating its wonderful rate capability. The fabricated membrane electrode exhibits high volumetric capacitance, stable cycling life, and remarkable retention of the capacitance at high rate, energy, and power density, making it a promising candidate for application in portable electronic products.

A novel humanized GLP-1 receptor model enables both affinity purification and Cre-LoxP deletion of the receptor.

Class B G protein-coupled receptors (GPCRs) are important regulators of endocrine physiology, and peptide-based therapeutics targeting some of these receptors have proven effective at treating disorders such as hypercalcemia, osteoporosis, and type 2 diabetes mellitus (T2DM). As next generation efforts attempt to develop novel non-peptide, orally available molecules for these GPCRs, new animal models expressing human receptor orthologs may be required because small molecule ligands make fewer receptor contacts, and thus, the impact of amino acid differences across species may be substantially greater. The objective of this report was to generate and characterize a new mouse model of the human glucagon-like peptide-1 receptor (hGLP-1R), a class B GPCR for which established peptide therapeutics exist for the treatment of T2DM. hGLP-1R knock-in mice express the receptor from the murine Glp-1r locus. Glucose tolerance tests and gastric emptying studies show hGLP-1R mice and their wild-type littermates display similar physiological responses for glucose metabolism, insulin secretion, and gastric transit, and treatment with the GLP-1R agonist, exendin-4, elicits similar responses in both groups. Further, ex vivo assays show insulin secretion from humanized islets is glucose-dependent and enhanced by GLP-1R agonists. To enable additional utility, the targeting construct of the knock-in line was engineered to contain both flanking LoxP sites and a C-terminal FLAG epitope. Anti-FLAG affinity purification shows strong expression of hGLP-1R in islets, lung, and stomach. We crossed the hGLP-1R line with Rosa26Cre mice and generated global Glp-1r-/- animals. Immunohistochemistry of pancreas from humanized and knock-out mice identified a human GLP-1R-specific antibody that detects the GLP-1R in human pancreas as well as in the pancreas of hGLP-1r knock-in mice. This new hGLP-1R model will allow tissue-specific deletion of the GLP-1R, purification of potential GLP-1R partner proteins, and testing of novel therapeutic agents targeting the hGLP-1R.

Solid-state high performance flexible supercapacitors based on polypyrrole-MnO2-carbon fiber hybrid structure.

A solid-state flexible supercapacitor (SC) based on organic-inorganic composite structure was fabricated through an "in situ growth for conductive wrapping" and an electrode material of polypyrrole (PPy)-MnO2 nanoflakes-carbon fiber (CF) hybrid structure was obtained. The conductive organic material of PPy greatly improved the electrochemical performance of the device. With a high specific capacitance of 69.3 F cm(-3) at a discharge current density of 0.1 A cm(-3) and an energy density of 6.16 × 10(-3) Wh cm(-3) at a power density of 0.04 W cm(-3), the device can drive a commercial liquid crystal display (LCD) after being charged. The organic-inorganic composite active materials have enormous potential in energy management and the "in situ growth for conductive wrapping" method might be generalized to open up new strategies for designing next-generation energy storage devices.

Development and validation of a 96-well cellular assay for the discovery of ALDH1A1 inhibitors.

Retinoic acid, the active metabolite of vitamin A, plays important roles in various physiological and pathological processes. The two-step production of retinoic acid from vitamin A (retinol) is catalyzed by alcohol dehydrogenases and aldehyde dehydrogenases, which are potential therapeutic targets for numerous diseases, such as obesity, diabetes, and cancer. Currently, the lack of a suitable high-throughput cellular assay hinders efforts to identify therapeutic small molecular inhibitors of aldehyde dehydrogenase, such as ALDH1A1. In this report, we utilized high-content imaging technology and a commercially available cell permeable ALDH substrate to develop a 96-well cellular ALDH1A1 assay. This assay has a robust and sensitive readout and is amenable to automation. With this cellular assay, we identified potent selective ALDH1A1 inhibitors to explore the role of retinoic acid production in various preclinical disease models.

Cable-type supercapacitors of three-dimensional cotton thread based multi-grade nanostructures for wearable energy storage.

A novel cable-type flexible supercapacitor with excellent performance is fabricated using 3D polypyrrole(PPy)-MnO2 -CNT-cotton thread multi-grade nanostructure-based electrodes. The multiple supercapacitors with a high areal capacitance 1.49 F cm(-2) at a scan rate of 1 mV s(-1) connected in series and in parallel can successfully drive a LED segment display. Such an excellent performance is attributed to the cumulative effect of conducting single-walled carbon nanotubes on cotton thread, active mesoporous flower-like MnO2 nanoplates, and PPy conductive wrapping layer improving the conductivity, and acting as pseudocapacitance material simultaneously.