Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers

Advanced fuel cell based on Perovskite La-SrTiO3 semiconductor as the electrolyte with superoxide-ion conduction

A solid oxide fuel cell’s (SOFC) performance is largely determined by the ionic-conducting electrolyte. A novel approach is presented for using the semiconductor perovskite LaR0.25RSrR0.75RTiOR3R (LST) as the electrolyte by creating surface superionic conduction, and the authors show that the LST electrolyte can deliver superior power density, 908.2 mW·cmP-2P at just 550 °C. The prepared LST materials formed a heterostructure including an insulating core and a super ionic conducting surface layer. The rapid ion transport along the surfaces or grain boundaries was identified as the primary means of oxygen ion conduction. The fuel cell-induced phase transition was observed from the insulating LST to a super OP2-P conductivity of 0.221 S·cmP-1P at 550 °C, leading to excellent current and power outputs

Surface Morphology Evolution Mechanisms of InGaN/GaN Multiple Quantum Wells with Mixture N2/H2-Grown GaN Barrier

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Surface morphology evolution mechanisms of InGaN/GaN multiple quantum wells (MQWs) during GaN barrier growth with different hydrogen (H2) percentages have been systematically studied. Ga surface-diffusion rate, stress relaxation, and H2 etching effect are found to be the main affecting factors of the surface evolution. As the percentage of H2 increases from 0 to 6.25%, Ga surface-diffusion rate and the etch effect are gradually enhanced, which is beneficial to obtaining a smooth surface with low pits density. As the H2 proportion further increases, stress relaxation and H2 over- etching effect begin to be the dominant factors, which degrade surface quality. Furthermore, the effects of surface evolution on the interface and optical properties of InGaN/GaN MQWs are also profoundly discussed. The comprehensive study on the surface evolution mechanisms herein provides both technical and theoretical support for the fabrication of high-quality InGaN/GaN heterostructures.Peer reviewe

Airborne Validation Experiment of 1.57-μm Double-Pulse IPDA LIDAR for Atmospheric Carbon Dioxide Measurement

The demand for greenhouse gas measurement has increased dramatically due to global warming. A 1.57-μm airborne double-pulse integrated-path differential absorption (IPDA) light detection and ranging (LIDAR) system for CO2 concentration measurement was developed. The airborne field experiments of this IPDA LIDAR system were conducted at a flight altitude of approximately 7 km, and the weak echo signal of the ocean area was successfully received. The matched filter algorithm was applied to the retrieval of the weak signals, and the pulse integration method was used to improve the signal-to-noise ratio. The inversion results of the CO2 column-averaged dry-air mixing ratio (XCO2) by the scheme of averaging after log (AVD) and the scheme of averaging signals before log were compared. The AVD method was found more effective for the experiment. The long-term correlation between the changing trends of XCO2 retrieved by the IPDA LIDAR system and CO2 dry-air volume mixing ratio measured by the in-situ instrument reached 92%. In the steady stage of the open area (30 km away from the coast), which is almost unaffected by the residential areas, the mean value of XCO2 retrieved by the IPDA LIDAR system was 414.69 ppm, with the standard deviation being 1.02 ppm. Compared with the CO2 concentration measured by the in-situ instrument in the same period, bias was 1.30 ppm. The flight path passed across the ocean, residential, and mountainous areas, with the mean value of XCO2 of the three areas being 419.35, 429.29, and 422.52 ppm, respectively. The gradient of the residential and ocean areas was 9.94 ppm, with that of the residential and mountainous areas being 6.77 ppm. Obvious gradients were found in different regions

Identification of a targeting-delivery peptide based on rhCNB

Calcineurin B subunit (CNB) is the regulatory subunit of calcineurin (CN), and its classical function is to regulate the activity of CN. Research in our laboratory has revealed that the recombinant human CNB (rhCNB) is a good antitumor candidate and can be internalized by tumor cells via TLR4 receptor complexes and targeted to tumor tissue in nude mice. However, the fragment or domain of rhCNB mediating internalization and target delivery has not been identified. To explore fragment- mediated rhCNB internalization and target delivery, we generated truncated derivatives of rhCNBs by recombinant DNA technology and examined their cellular uptake. Interactions between truncated rhCNBs and the TLR4 receptor were studied by ELISA and co-immunoprecipitation, and targeting of model tumors in nude mice was examined. The results showed that one truncated derivative, Trun3 (124-169aa), was taken up by cells and targeted tumors with almost the same efficiency as intact rhCNB. These results indicate that Trun3 (45aa) contains the major sequence responsible for rhCNB internalization and tumor targeting and might be developed for drug delivery to tumors

The immunostimulatory effects and pro-apoptotic activity of rhCNB against Lewis lung cancer is mediated by Toll-like receptor 4

Background Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune-stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll-like receptor 4 (TLR4) complex, but it was not known whether its immuno-modulatory and antitumor functions involved entry by this same route. Methods The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild-type (WT) mice, TLR4(-/-) mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB-stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up-regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4(+) cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4(+) and CD8(+)T cells in splenocytes from WT mice, but not from TLR4-deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4(-/-) littermates. Conclusions The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug

Micro-Motion Parameter Extraction of Multi-Scattering-Point Target Based on Vortex Electromagnetic Wave Radar

In addition to traditional linear Doppler shift, the angular Doppler shift in vortex electromagnetic wave (VEMW) radar systems carrying orbital angular momentum (OAM) can provide more accurate target identification micro-motion parameters, especially the detailed features perpendicular to the radar line-of-sight (LOS) direction. In this paper, a micro-motion feature extraction method for a spinning target with multiple scattering points based on VEMW radar is proposed. First, a multi-scattering-point spinning target detection model using vortex radar is established, and the mathematical mechanism of echo signal flash shift in time-frequency (TF) domain is deduced. Then, linear Doppler shift is eliminated by interference processing with opposite dual-mode VEMW. Subsequently, the shift in TF flicker is focused on the reference zero frequency by the iterative phase compensation method, and the number of scattering points is estimated according to the focusing effect. After this, through the constructed compensation phase, the angular Doppler shift is separated, then the angular velocity, rotation radiusand initial phase of the target are estimated. Theoretical and simulation results verify the effectiveness of the proposed method, and more accurate rotation parameters can be obtained in the case of multiple scattering points using the VEMW radar system

Contrasting diel hysteresis between soil autotrophic and heterotrophic respiration in a desert ecosystem under different rainfall scenarios

Diel hysteresis occurs often between soil CO2 efflux (R-S) and temperature, yet, little is known if diel hysteresis occurs in the two components of R-S, i.e., autotrophic respiration (R-A) and heterotrophic respiration (R-H), and how diel hysteresis will respond to future rainfall change. We conducted a field experiment in a desert ecosystem in northern China simulating five different scenarios of future rain regimes. Diel variations of soil CO2 efflux and soil temperature were measured on Day 6 and Day 16 following the rain addition treatments each month during the growing season. We found contrasting responses in the diel hysteresis of R-A and R-H to soil temperature, with a clockwise hysteresis loop for R-H but a counter-clockwise hysteresis loop for R-A. Rain addition significantly increased the magnitude of diel hysteresis for both R-H and R-A on Day 6, but had no influence on either on Day 16 when soil moisture was much lower. These findings underline the different roles of biological (i.e. plant and microbial activities) and physical-chemical (e.g. heat transport and inorganic CO2 exchange) processes in regulating the diel hysteresis of R-A and R-H, which should be considered when estimating soil CO2 efflux in desert regions under future rainfall regime

Simulated rain addition modifies diurnal patterns and temperature sensitivities of autotrophic and heterotrophic soil respiration in an arid desert ecosystem

The timing and magnitude of rainfall events in arid and semiarid regions are expected to change dramatically in future decades, which will likely greatly affect regional carbon cycles. To understand how increases in rainfall affect the diurnal patterns and temperature sensitivities (Q(10)) of soil respiration (R-S) and its key components (i.e. heterotrophic respiration (R-H) and autotrophic respiration (R-A)), we conducted a manipulative field experiment in a desert ecosystem of Northwest China. We simulated five different scenarios of future rain regimes (0%, 25%, 50%, 75% and 100% increase over local annual mean precipitation) each month from May to September in 2009. We measured R-S and R-H every three hours on 6 and 16 days after the rain addition, and estimated R-A by calculating the difference between R-S and R-H. We found that rain addition significantly increased the daily mean R-S and its components on the two measurement days during the growing season. However, the diurnal pattern was different between the two respiration components. Rain addition significantly increased the daily Q(10) value of R-H but suppressed that of R-A on Day 6. Rain addition had no influence on daily Q(10) value of both respiration components on Day 16 when soil moisture was lower. In addition, we observed significantly higher daily Q(10) of R-H than R-A under all five rain addition treatments, indicating that microbial respiration is more temperature sensitive than root respiration in a short-time scale in this desert ecosystem. Thus, partitioning soil respiration into its two components, and analyzing the differential responses of R-H and R-A to future climate changes should be considered for more accurate predictions of soil respiration and regional carbon cycle in these arid and semiarid regions. (c) 2015 Elsevier Ltd. All rights reserved

Spatio-temporal variation of species richness and phylogenetic diversity patterns for spring ephemeral plants in northern China

Understanding the spatiotemporal distribution of species diversity in response to climatic change is essential for the conservation and management of species resources. Spring ephemeral plants (SEs) have played a crucial role in sustaining the desert and woodland ecosystems of northern China. However, our knowledge regarding the spatiotemporal variation of species diversity in SEs is limited. In this study, we employed occurrence and phylogenetic data for 200 SEs, alongside 19 environmental variables, to model their geographical distribution during the Last Glacial Maximum (LGM), Current, and the year 2070 (considering two representative concentration pathway scenarios, SSP2–4.5 and SSP5–8.5). We also visualized the phylogenetic diversity patterns in the Current. Our findings revealed that more than half of the SEs notably expanded their range and continuously shifted northeastward from LGM to 2070. From LGM to Current and from Current to SSP2–4.5_2070, 64% and 54% of SEs shifted from higher to lower elevations, and 53% of them will slightly shift to higher elevations from Current to SSP5–8.5_2070. We identified three distinct bioregions corresponding to the core ranges of desert SEs and understory SE ecotypes. The Ili Valley, Tacheng Basin, northern and southern Junggar Basin, and Changbai Mountains were identified as hotspots for species richness, phylogenetic diversity, and endemism for the two SE ecotypes. Notably, these hotspots had limited overlap with existing nature reserves. Additionally, the suitable habitat of desert SEs was primarily determined by precipitation seasonality and precipitation of driest month, whereas the distribution of forest understory SEs was mainly influenced by annual precipitation and temperature seasonality. This study significantly contributes to a comprehensive understanding of the modern diversity distribution patterns and conservation priorities for SEs within a species distribution and phylogenetic framework