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GLP-1 receptor agonists ((GLP-1 RAs) are currently receiving a lot of attention because of their impact in diabetes, weight loss and other areas. While GLP-1 RAs in injectable form are highly efficacious, further work is required to develop oral versions which can deliver these peptides efficiently without requiring use of excessively high doses. This paper describes the ability of an oral peptide delivery formulation, Axcess™, to enhance uptake of GLP-1 receptor agonists via the intestine, resulting in changes in insulin and glucose blood levels indicative of biopotencies of 9% for exendin-4 and 14.8% for semaglutide in preclinical models. The route of delivery suggests that the peptides will be able to interact with the GLP-1 receptors on the vagal afferents of the intestine, as is the case for native GLP-1 in healthy individuals. GLP-1 receptor agonists administered via this route will be a valuable addition to the therapeutic modalities available for treatment of diabetes and obesity.

In this study, a Finite Element Computational (FEC) model for automotive bellows exhaust pipes is established, and the impact of displacement loads on their fatigue life is investigated. The relationships between various structural parameters of the exhaust pipes and stress, strain, and cycle counts are elucidated. Furthermore, the bellows’ structure is optimized through an orthogonal experiment. A microscopic morphological analysis is conducted on 309S stainless steel automotive bellows exhaust pipes after fatigue failure. The findings indicate that as displacement loads increase, the fatigue life of the bellows exhaust pipes decreases. The error between finite element analysis and experimental results is found to be less than 8,8 %. During the water swell forming stage, partial martensite is produced due to cold deformation. Under alternating loads, with noticeable cracks at the wave peaks, indicating the presence of internal fatigue characteristics.

Abstract A pressing need in low energy spintronics is two-dimensional (2D) ferromagnets with Curie temperature above the liquid-nitrogen temperature (77 K), and sizeable magnetic anisotropy. We studied Mn3Br8 monolayer which is obtained via inducing Mn vacancy at 1/4 population in MnBr2 monolayer. Such defective configuration is designed to change the coordination structure of the Mn-d5 and achieve ferromagnetism with sizeable magnetic anisotropy energy (MAE). Our calculations show that Mn3Br8 monolayer is a ferromagnetic (FM) half-metal with Curie temperature of 130 K, large MAE of − 2.33 meV per formula unit, and atomic magnetic moment of 13/3μB for the Mn atom. Additionally, Mn3Br8 monolayer maintains to be FM under small biaxial strain, whose Curie temperature under 5% compressive strain is 160 K. Additionally, both biaxial strain and carrier doping make the MAE increases, which mainly contributed by the magneto-crystalline anisotropy energy (MCE). Our designed defective structure of MnBr2 monolayer provides a simple but effective way to achieve ferromagnetism with large MAE in 2D materials.

Quantum information scrambling has received tremendous attention owing to its key concept in the fields of quantum chaos and quantum gravity. Here, with exploiting a fully controllable superconducting quantum processor, we study the verified scrambling in a 1D spin chain by an analog superconducting quantum simulator with the signs and values of individual driving and coupling terms fully controllable. By engineering opposite Hamiltonians on two subsystems, we measure the temporal and spatial patterns of out-of-time ordered correlators (OTOC), with the Hamiltonian mismatch and the decoherence extracted quantitatively from the scrambling dynamics, providing a benchmarking tool for probing not only the spatial but the temporal patterns of scrambling dynamics in many-body systems. Our work demonstrates the superconducting system with strong controllability as a powerful quantum simulator.

Steroid hormones influence diverse biological processes throughout the animal life cycle, including metabolism, stress resistance, reproduction, and lifespan. In insects, the steroid hormone, 20-hydroxyecdysone (20E), is the central hormone regulator of molting and metamorphosis, and plays roles in tissue morphogenesis. For example, amnioserosa contraction, which is a major driving force in Drosophila dorsal closure (DC), is defective in embryos mutant for 20E biosynthesis. Here, we show that 20E signaling modulates the transcription of several DC participants in the amnioserosa and other dorsal tissues during late embryonic development, including zipper, which encodes for non-muscle myosin. Canonical ecdysone signaling typically involves the binding of Ecdysone receptor (EcR) and Ultraspiracle heterodimers to ecdysone-response elements (EcREs) within the promoters of responsive genes to drive expression. During DC, however, we provide evidence that 20E signaling instead acts in parallel to the JNK cascade via a direct interaction between EcR and the AP-1 transcription factor subunit, Jun, which together binds to genomic regions containing AP-1 binding sites but no EcREs to control gene expression. Our work demonstrates a novel mode of action for 20E signaling in Drosophila that likely functions beyond DC, and may provide further insights into mammalian steroid hormone receptor interactions with AP-1.

The common optical path payload is a new type of imaging payload that can acquire LiDAR data and CCD images simultaneously. This new payload integrates the linear LiDAR and linear CCD images according to the common optical system, and achieves the registration of LiDAR point cloud and CCD images by the alignment of common aperture optical axis and time synchronization control in the front of hardware. Based on the fixed matching relationship between CCD probes and LiDAR probes offered by optical path of common, this paper proposes a joint calibration method, which reduces the ranging error and misalignment error. And the results verify that this method can effectively improve the quality of the three-dimensional images. The standard deviations of validation area and roof are improved from 0.54 m to 0.14 m and 1.83 m to 0.26 m respectively.

High-precision on-orbit geometric calibration of spaceborne laser altimetry data is essential to its effective applications. Firstly, the existing calibration methods for laser altimeter data are analyzed. Then, a geometric calibration method based on curve matching is proposed. Compared to the existing methods, the proposed method does not rely on ground calibration field. Thus, it is efficiency in expense and time. Notably, three factors, i.e. matching method, initial control point selection and the step size of matching step, which significantly affect the results of calibration are analyzed respectively. The analysis was validated based on the original laser altimetry data obtained by ZY3-02 satellite. According to the results, the following conclusions can be drawn preliminarily: (1) Both the correlation coefficient maximum (COR) criterion and the mean square error minimum (MSD) criterion in the curve matching can be used to correct the systematic error in altimetry data. (2) The initial control points of the selected track should have a significant change trend and the slope within the laser footprints should be less than 15°. (3) Current experimental data show that the best step size for matching search is 10 m. The relevant conclusions can provide reference for the research of geometrical calibration and data processing of the same type of laser altimetry satellite.

UAV LiDAR systems have unique advantage in acquiring 3D geo-information of the targets and the expenses are very reasonable; therefore, they are capable of security inspection of high-voltage power lines. There are already several methods for power line extraction from LiDAR point cloud data. However, the existing methods either introduce classification errors during point cloud filtering, or occasionally unable to detect multiple power lines in vertical arrangement. This paper proposes and implements an automatic power line extraction method based on 3D spatial features. Different from the existing power line extraction methods, the proposed method processes the LiDAR point cloud data vertically, therefore, the possible location of the power line in point cloud data can be predicted without filtering. Next, segmentation is conducted on candidates of power line using 3D region growing method. Then, linear point sets are extracted by linear discriminant method in this paper. Finally, power lines are extracted from the candidate linear point sets based on extension and direction features. The effectiveness and feasibility of the proposed method were verified by real data of UAV LiDAR point cloud data in Sichuan, China. The average correct extraction rate of power line points is 98.18%.

Arctium lappa and A. tomentosum are known medicinal plants in China. The complete chloroplast genomes from A. lappa and A. tomentosum were sequenced using Illumina sequencing technology. The total genome sizes of the complete chloroplast genomes of A. lappa and A. tomentosum were 152 767 bp and 152 688 bp, respectively, and contained a pair of inverted repeats of the same length (15,181 bp). The small single-copies were 18 584 bp and 18 582 bp, and the large single-copies were 83 821 bp and 83 744 bp, respectively. We identified and annotated 134 and 126 genes from A. lappa and A. tomentosum including, respectively, 90 and 89 protein-coding genes, 36 and 29 tRNAs, and eight rRNAs. A. lappa was found to have 10 tRNAs different from those in A. tomentosum, and A. tomentosum had three tRNAs different from those in A. lappa. There were only two types of simple sequence repeats of two species, mononucleotide and dinucleotide, and the sequences were A and T rich. In addition, the two ways of phylogenetic analysis show that the position of A. lappa and A. tomentosum is consistent within Asteraceae.

Neutrophilic inflammation occurs during asthma exacerbation, and especially, in patients with steroid-refractory asthma, but the underlying mechanisms are poorly understood. Recently, a significant accumulation of neutrophil extracellular traps (NETs) in the airways of neutrophilic asthma has been documented, suggesting that NETs may play an important role in the pathogenesis. In this study, we firstly demonstrated that NETs could induce human airway epithelial cell damage in vitro. In a mouse asthmatic model of neutrophil-dominated airway inflammation, we found that NETs were markedly increased in bronchoalveolar lavage (BAL), and the formation of NETs exacerbated the airway inflammation. Additionally, a small-molecule drug necrostatin-1 (Nec-1) shown to inhibit NETs formation was found to alleviate the neutrophil-dominated airway inflammation. Nec-1 reduced total protein concentration, myeloperoxidase activity, and the levels of inflammatory cytokines in BAL. Finally, further experiments proved that the inhibition of Nec-1 on NETs formation might be related to its ability to inhibiting mixed lineage kinase domain-like (MLKL) phosphorylation and perforation. Together, these results document that NETs are closely associated with the pathogenesis of neutrophilic asthma and inhibition of the formation of NETs by Nec-1 may be a new therapeutic strategy to ameliorate neutrophil-dominated airway inflammation.

Homeodomain-interacting protein kinases (Hipks) have been previously associated with cell proliferation and cancer, however, their effects in the nervous system are less well understood. We have used Drosophila melanogaster to evaluate the effects of altered Hipk expression on the nervous system and muscle. Using genetic manipulation of Hipk expression we demonstrate that knockdown and over-expression of Hipk produces early adult lethality, possibly due to the effects on the nervous system and muscle involvement. We find that optimal levels of Hipk are critical for the function of dopaminergic neurons and glial cells in the nervous system, as well as muscle. Furthermore, manipulation of Hipk affects the structure of the larval neuromuscular junction (NMJ) by promoting its growth. Hipk regulates the phosphorylation of the synapse-associated cytoskeletal protein Hu-li tai shao (Hts; adducin in mammals) and modulates the expression of two important protein kinases, Calcium-calmodulin protein kinase II (CaMKII) and Partitioning-defective 1 (PAR-1), all of which may alter neuromuscular structure/function and influence lethality. Hipk also modifies the levels of an important nuclear protein, TBPH, the fly orthologue of TAR DNA-binding protein 43 (TDP-43), which may have relevance for understanding motor neuron diseases.

The zeppelin (zep) locus is known for its essential role in the development of the embryonic cuticle of Drosophila melanogaster. We show here that zep encodes Gfat1 (Glutamine: Fructose-6-Phosphate Aminotransferase 1; CG12449), the enzyme that catalyzes the rate-limiting step in the hexosamine biosynthesis pathway (HBP). This conserved pathway diverts 2%–5% of cellular glucose from glycolysis and is a nexus of sugar (fructose-6-phosphate), amino acid (glutamine), fatty acid [acetyl-coenzymeA (CoA)], and nucleotide/energy (UDP) metabolism. We also describe the isolation and characterization of lethal mutants in the euchromatic paralog, Gfat2 (CG1345), and demonstrate that ubiquitous expression of Gfat1+ or Gfat2+ transgenes can rescue lethal mutations in either gene. Gfat1 and Gfat2 show differences in mRNA and protein expression during embryogenesis and in essential tissue-specific requirements for Gfat1 and Gfat2, suggesting a degree of functional evolutionary divergence. An evolutionary, cytogenetic analysis of the two genes in six Drosophila species revealed Gfat2 to be located within euchromatin in all six species. Gfat1 localizes to heterochromatin in three melanogaster-group species, and to euchromatin in the more distantly related species. We have also found that the pattern of flanking-gene microsynteny is highly conserved for Gfat1 and somewhat less conserved for Gfat2.

Ethylene response factor (ERF) is a key transcription factor of plant ethylene signaling pathway, which plays an important role in plant response to abiotic and biotic stresses by regulating the expression of downstream genes. However, little is known about the mechanisms of the regulation of gene expression by ERF proteins. Chloroplast is an essential organelle that is important for photosynthesis and biosynthesis of many essential metabolites. There exists an interaction between chloroplasts and the nucleus. Chloroplasts can send multiple kinds of signals to regulate the nuclear gene expression known as retrograde signaling. In our study, we have analyzed the expression of the components related to plastid retrograde signaling pathway to elucidate the mechanism of tomato ethylene responsive factor 1 (TERF1) in response to drought stress. Our results showed that TERF1 can regulate different biogenic and operational retrograde signals to regulate nuclear genes expression, which can improve plant tolerance to drought stress. We also propose a new potential of TERF1 in regulating nuclear gene expression, including regulation of different phytohormone signaling pathways and gene posttranscriptional modification triggered by different retrograde signals. Our results have enriched our knowledge about the function of ERF proteins and ethylene signaling pathway.

Earthquake recurrence is studied from the temporal variation in slip through numerical simulations based on the normalized form of equation of motion of a one-body spring-slider model with thermal-pressurized slip-weakening friction and viscosity. The wear process, whose effect is included in the friction law, is also taken into account in this study. The main parameters are the normalized characteristic displacement, Uc, of the friction law and the normalized damping coefficient (to represent viscosity), η. TR, D, and τD are the recurrence time of events, the final slip of an event, and the duration time of an event, respectively. Simulation results show that TR increases when Uc decreases or η increases, D and τD decrease with increasing η, and τD increases with Uc. The time- and slip-predictable model can describe the temporal variation in cumulative slip. When the wear process is considered, the thickness of slip zone, h, which depends on the cumulated slip, S(t)  =   ∑ D(t), i.e., h(t)  =  CS(t) (C is a dimensionless increasing rate of h with S), is an important parameter influencing TR and D. Uc is a function of h and thus depends on cumulated normalized slip, ∑ U, with an increasing rate of C. In the computational time period, the wear process influences the recurrence of events and such an effect increases with C when C  >  0.0001. When viscosity is present, the effect due to wear process becomes stronger. Both TR and D decrease when the fault becomes more mature, thus suggesting that it is more difficult to produce large earthquakes along a fault when it becomes more mature. Neither the time-predictable nor the slip-predictable model can describe the temporal variation in cumulative slip of earthquakes under the wear process with large C.

Geometric phase gates are promising tools toward robust quantum computing owing to their robustness against certain control errors and decoherence. Here, we propose a multiqubit architecture with a nonadiabatic geometric phase gate scheme that is feasible in widely used superconducting qubit designs such as transmon and fluxonium. Through segmented microwave drive on multiple qubits coupled off-resonantly to a common resonator, the geometric phase gate is obtained from the qubit-state-dependent displacement of the resonator without fine-tuning the qubit frequencies. Fidelity above 99.99% is achieved in simulation under the available experimental parameters. Our scheme uses all-microwave control and only exploits the lowest qubit levels with long coherence time; thus it is desirable for experiments. Together with the single-qubit holonomic gates demonstrated in earlier experiments, our scheme can realize universal all-geometric quantum computing, and it also finds applications in quantum simulation with many-body interactions.

This study is focused on multistable slip of earthquakes based on a one-degree-of-freedom spring-slider model in the presence of thermal-pressurized slip-weakening friction and viscosity by using the normalized equation of motion of the model. The major model parameters are the normalized characteristic displacement, Uc, of the friction law and the normalized viscosity coefficient, η, between the slider and background plate. Analytic results at small slip suggest that there is a solution regime for η and γ ( = 1∕Uc) to make the slider slip steadily. Numerical simulations exhibit that the time variation in normalized velocity, V∕Vmax (Vmax is the maximum velocity), obviously depends on Uc and η. The effect on the amplitude is stronger due to η than due to Uc. In the phase portrait of V∕Vmax versus the normalized displacement, U∕Umax (Umax is the maximum displacement), there are two fixed points. The one at large V∕Vmax and large U∕Umax is not an attractor, while that at small V∕Vmax and small U∕Umax can be an attractor for some values of η and Uc. When Uc<0. 55, unstable slip does not exist. When Uc ≥ 0. 55, Uc and η divide the solution domain into three regimes: stable, intermittent, and unstable (or chaotic) regimes. For a certain Uc, the three regimes are controlled by a lower bound, ηl, and an upper bound, ηu, of η. The values of ηl, ηu, and ηu − ηl all decrease with increasing Uc, thus suggesting that it is easier to yield unstable slip for larger Uc than for smaller Uc or for larger η than for smaller η. When Uc<1, the Fourier spectra calculated from simulation velocity waveforms exhibit several peaks, thus suggesting the existence of nonlinear behavior of the system. When Uc>1, the related Fourier spectra show only one peak, thus suggesting linear behavior of the system.

Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.

Biocompatible and biodegradable carboxymethyl cellulose (CMC) has been modified with 4-hydroxybenzylamine (CMC-Ph) in order to prepare CMC-based microgels through the horseradish peroxidise/hydrogen peroxide enzymatic reaction. CMC-Ph was identified as a blend, and the amount of the grafted 4-hydroxybenzylamine per 100 units of CMC was between 17 and 23 according to the molecular weight of CMC. Through a special designed co-flowing microfluidic device, CMC-Ph microgels were prepared with the radius from 100 to 500 μm via adjusting the flow rates of the disperse phase and the continuous phase, respectively. The chondrocytic cell line ATDC5 was encapsulated in the CMC-Ph microgels. The cell-laden microgels were cultured for up to 40 days, illustrating the biocompatibility of CMC-Ph and the microfluidic approach through the enzymatic crosslinking reaction primarily. CMC-Ph showed a great promise to encapsulate the cells for further fabrication of the injectable scaffolds.

We report and analyse the characteristics of 1382 meteor trails based on a sodium data set of ~ 680 h. The observations were made at Yanqing (115.97° E, 40.47° N), China by a ground-based Na fluorescence lidar. The temporal resolution of the raw profiles is 1.5 s and the altitude resolution is 96 m. We discover some characteristics of meteor trails different from those presented in previous reports. The occurrence heights of the trails follow a double-peak distribution with the peaks at ~ 83.5 km and at ~ 95.5 km, away from the peak height of the regular Na layer. 4.7% of the trails occur below 80 km, and 3.25% above 100 km. 75% of the trails are observed in only one 1.5 s profile, suggesting that the dwell time in the laser beam is not greater than 1.5 s. The peak density of the trails as a function of height is similar to that of the background sodium layer. The raw occurrence height distribution is corrected taking account of three factors which affect the relative lifetime of a trail as a function of height: the meteoroid velocity (which controls the ratio of Na/Na+ ablated); diffusional spreading of the trail; and chemical removal of Na. As a result, the bi-modal distribution is more pronounced. Modelling results show that the higher peak corresponds to a meteoroid population with speeds between 20 and 30 km s−1, whereas the lower peak should arise from much slower particles in a near-prograde orbit. It is inferred that most meteoroids in this data set have masses of ~ 1 mg, in order for ablation to produce sufficient Na atoms to be detected by lidar. Finally, the evolution of longer-duration meteor trails is investigated. Signals at each altitude channel consist of density enhancement bursts with the growth process usually faster than the decay process, and there exists a progressive phase shift among these altitude channels.

Sporadic sodium (Nas) layers, occurring in roughly the same height range as ionospheric sporadic-E layers, were first detected by lidar some 30 yr ago. Nas layers have a typical thickness of a few hundred meters to a few km, with peak atom concentrations several times that of the background layer. Despite a great deal of excellent work over the past decades, the source of Nas layers is still not altogether clear, partly as a result of our incomplete knowledge of Nas layer characteristics. In this paper we concentrate on some typical case studies chosen from the ~127 h of sporadic sodium layer observations made at a time resolution of 1.5 s at Yanqing (115.97° E, 40.47° N), Beijing, China. This is a much better time resolution than what has been employed in most earlier measurements. The results show that the Nas layer peak heights are dispersed at slightly different although adjacent heights. When averaged over several minutes, as has been the case with most earlier measurements, the height scatter results in an apparent layer thickness of a few km. We conclude, therefore, that these dispersed peaks at different but adjacent heights constitute the 5 min Nas layer. Similar to the observations of sporadic-E-ion (Es) layers and meteor rate, we observe quasi-periodic fluctuations on a timescale on the order of several minutes in the peak height and the peak density of sporadic layers, which is a universal feature but concealed by the lower temporal resolution previously adopted. Spatially localized multiple scatterers and multiple thin layers with similar apparent movement in Nas layers are also found. We discuss the possible formation mechanism by the direct deposition of large swarms of micrometeoroids and demonstrate a typical example of meteor trails evolving into a Nas layer, which suggests that this mechanism might indeed occur.

When full-waveform LiDAR (FW-LiDAR) data are applied to extract the component feature information of interest targets, there exist a problem of components lost during the waveform decomposition procedure, which severely constrains the performance of subsequent targets information extraction. Focusing on the problem above, an enhance component detection algorithm, which combines Finite Mixed Method (FMM), Levenberg-Marquardt (LM) algorithm and Penalized Minimum Matching Distance (PMMD),is proposed in this paper. All of the algorithms for parameters initialization, waveform decomposition and missing component detection have been improved, which greatly increase the precision of component detection, and guarantee the precision of waveform decomposition that could help the weak information extraction of interest targets. The effectiveness of this method is verified by the experimental results of simulation and measured data.

The validation of remote sensing products (RSPs) is fundamental work before the proper use of RSPs. This paper mainly introduces the technical specification for the validation of remote sensing product, which is used to guide user how to validate the available products. The validation of remote sensing products (VRSP) mainly there are two levels. The first level focuses on the validation at pixel scale and the other is the product level which contains a number of pixels that are distributed in different land use types which are selected to represent both the space-time characteristics of surface parameters investigated. At pixel scale, the validation procedure mainly consists of three steps: sampling design for ground observation, data collection and estimation the mean value at pixel scale. The data types of ground observation include the wireless sensor network, which are used to capture multi-scale heterogeneities of surface parameters, and the footprint which could be a flux observation such as eddy covariance (EC) and large aperture scintillometer (LAS). After finishing the validation at pixel scale, the second-level validation for the whole remote sensing product is followed. The assessment with indexes is then used to evaluate the performance of the validation. Last, a validation report on the description of the validation will be included in the technical specification.