Structural insight into selectivity of amylin and calcitonin receptor agonists.

Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, and San45 bound to AMY3R or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein.

Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor exists, the amylin (Amy) 1 receptor (AMY1R), yet its involvement in the pathology of migraine is poorly understood. AMY1R and CGRPR are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), respectively. Here, we present the structure of AMY1R in complex with CGRP and Gs protein and compare it with the reported structures of the AMY1R complex with rat amylin (rAmy) and the CGRPR in complex with CGRP. Despite similar protein backbones observed within the receptors and the N- and C-termini of the two peptides bound to the AMY1R complexes, they have distinct organization in the peptide midregions (the bypass motif) that is correlated with differences in the dynamics of the respective receptor extracellular domains. Moreover, divergent conformations of extracellular loop (ECL) 3, intracellular loop (ICL) 2, and ICL3 within the CTR and CLR protomers are evident when comparing the CGRP bound to the CGRPR and AMY1R, which influences the binding mode of CGRP. However, the conserved interactions made by the C-terminus of CGRP to the CGRPR and AMY1R are likely to account for cross-reactivity of nonpeptide CGRPR antagonists observed at AMY1R, which also extends to other clinically used CGRPR blockers, including antibodies.

Grazing practices affect soil microbial networks but not diversity and composition in alpine meadows of northeastern Qinghai-Tibetan plateau.

Livestock grazing is the primary practice in alpine meadows and can alter soil microbiomes, which is critical for ecosystem functions and services. Seasonal grazing (SG) and continuous grazing (CG) are two kinds of different grazing practices that dominate alpine meadows on the Qinghai-Tibetan Plateau (QTP), and how they affect soil microbial communities remains in-depth exploration. The present study was conducted to investigate the effects of different grazing practices (i.e., SG and CG) on the diversity, composition, and co-occurrence networks of soil bacteria and fungi in QTP alpine meadows. Soil microbial α- and ß-diversity showed no obvious difference between SG and CG grasslands. Grazing practices had little impact on soil microbial composition, except that the relative abundance of Proteobacteria and Ascomycota showed significant difference between SG and CG grasslands. Soil microbial networks were more complex and less stable in SG grasslands than that in CG grasslands, and the bacterial networks were more complex than fungal networks. Soil fungal diversity was more strongly correlated with environmental factors than bacteria, whereas both fungal and bacterial structures were mainly influenced by soil pH, total nitrogen, and ammonium nitrogen. These findings indicate that microbial associations are more sensitive to grazing practices than microbial diversity and composition, and that SG may be a better grazing practice for ecological benefits in alpine meadows.

Formation of Cr-based layered double hydroxide: effect of the amendments.

Chromium is one of the eight most popular inorganic soil pollutants in China, and its bioavailability is determined by the chemical states. Amendments, which are able to change the chemical forms of chromium and decrease its bioavailability, have received considerable attention in recent years. In this work, the formation of Cr-based layered double hydroxides (LDHs) and the immobilization of Cr in solution and soil were systemically investigated. The formation of Cr-based LDHs is strongly depended on the layer charges, aging temperatures and reaction time, as identified by X-ray diffraction (XRD), transmission electron microscope (TEM) and X-ray absorption fine structure (XAFS) spectrum. According to the pot experiment results, the concentration of Cr in the overground part of Brassica Chinensis L. was significantly decreased to 1.50-2.03 µg kg- 1 in the present of amendments. In total, the finding of LDHs formation on amendments and the thermodynamic stability of LDHs provides a new insight into the remediation of Cr-polluted soils.

Broadband achromatic metalens for linearly polarized light from 450 to 800 nm.

Metalens is a planar optical component that uses nanostructures with a thickness on the order of the wavelength to manipulate the wavefront of the incident light. A key problem, especially in color imaging and display applications, is the correction of chromatic aberration, which is an inherent effect caused by the dispersion of periodic lattices and resonance modes. However, the current achromatic metalenses either use the PB phase method that is only valid for circularly polarized light or nanostructures with complex cross sections that are difficult to manufacture. Here, we designed a broadband achromatic metalens for linearly polarized light from 450 to 800 nm. Rectangular titanium dioxide nanofins of various lengths and widths were applied to modulate the phase and dispersion of the incident light. The metalens can fulfill three target phases simultaneously by using an optimization method. The designed metalens has a stable focus from 450 to 800 nm with an average focusing efficiency of 64%. It can be potentially applied in microscopes, lithography machines, sensors, and displays.

Immunoassay-type biosensor based on magnetic nanoparticle capture and the fluorescence signal formed by horseradish peroxidase catalysis for tumor-related exosome determination.

A sandwich-type fluorescent biosensor for the determination of tumor-related exosome was designed. It is based on magnetic nanoparticle (MNP) capture and horseradish peroxidase (HRP) catalysis. MNPs were used as the substrate to capture exosomes by modifying the CD63 antibody on MNPs surface. After that, the biotinylated epithelial cell adhesion molecule (EpCAM) antibody was used to capture the tumor-related exosomes, which specifically express EpCAM. A novel method for the fluorescence measurement of tumor-associated exosome was achieved, with a detection limit as low as 200 (± 9) particles mL-1. The analytical range of this method is from 576 (± 15) particles mL-1 to 5.76 × 107 (± 5.1 × 105) particles mL-1. For the fluorescence measurement, the excitation wavelength was set to 320 nm. Fluorescent spectra were collected at emission wavelength in the range 370 to 550 nm; the data shown in the calibration plot were studied by using the fluorescence intensity at 406 nm. This sensor was also able to successfully detect the exosomes from the plasma of patients with hepatocellular carcinoma (HCC) and healthy humans. Graphical abstract Schematic representation of the sensing process of immunoassay-type biosensor based on magnetic nanoparticle capture and the fluorescence signal formed by the horseradish peroxidase (HRP) catalysis for tumor-related exosome determination.

Driving Factors and Future Prediction of Land Use and Cover Change Based on Satellite Remote Sensing Data by the LCM Model: A Case Study from Gansu Province, China.

Land use and cover change (LUCC) is an important issue affecting the global environment, climate change, and sustainable development. Detecting and predicting LUCC, a dynamic process, and its driving factors will help in formulating effective land use and planning policy suitable for local conditions, thus supporting local socioeconomic development and global environmental protection. In this study, taking Gansu Province as a case study example, we explored the LUCC pattern and its driving mechanism from 1980 to 2018, and predicted land use and cover in 2030 using the integrated LCM (Logistic-Cellular Automata-Markov chain) model and data from satellite remote sensing. The results suggest that the LUCC pattern was more reasonable in the second stage (2005 to 2018) compared with that in the first stage (1980 to 2005). This was because a large area of green lands was protected by ecological engineering in the second stage. From 1980 to 2018, in general, natural factors were the main force influencing changes in land use and cover in Gansu, while the effects of socioeconomic factors were not significant because of the slow development of economy. Landscape indices analysis indicated that predicted land use and cover in 2030 under the ecological protection scenario would be more favorable than under the historical trend scenario. Besides, results from the present study suggested that LUCC in arid and semiarid area could be well detected by the LCM model. This study would hopefully provide theoretical instructions for future land use planning and management, as well as a new methodology reference for LUCC analysis in arid and semiarid regions.

Rumor detection based on propagation graph neural network with attention mechanism.

Rumors on social media have always been an important issue that seriously endangers social security. Researches on timely and effective detection of rumors have aroused lots of interest in both academia and industry. At present, most existing methods identify rumors based solely on the linguistic information without considering the temporal dynamics and propagation patterns. In this work, we aim to solve rumor detection task under the framework of representation learning. We first propose a novel way to construct the propagation graph by following the propagation structure (who replies to whom) of posts on Twitter. Then we propose a gated graph neural network based algorithm called PGNN, which can generate powerful representations for each node in the propagation graph. The proposed PGNN algorithm repeatedly updates node representations by exchanging information between the neighbor nodes via relation paths within a limited time steps. On this basis, we propose two models, namely GLO-PGNN (rumor detection model based on the global embedding with propagation graph neural network) and ENS-PGNN (rumor detection model based on the ensemble learning with propagation graph neural network). They respectively adopt different classification strategies for rumor detection task, and further improve the performance by including attention mechanism to dynamically adjust the weight of each node in the propagation graph. Experiments on a real-world Twitter dataset demonstrate that our proposed models achieve much better performance than state-of-the-art methods both on the rumor detection task and early detection task.

Anticancer IrIII -Aspirin Conjugates for Enhanced Metabolic Immuno-Modulation and Mitochondrial Lifetime Imaging.

The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.

The Sensitivity of Grating-Based SPR Sensors with Wavelength Interrogation.

In this paper, we derive the analytical expression for the sensitivity of grating-based surface plasmon resonance (SPR) sensors working in wavelength interrogation. The theoretical analysis shows that the sensitivity increases with increasing wavelength and is saturated beyond a certain wavelength for Au and Ag gratings, while it is almost constant for Al gratings in the wavelength range of 500 to 1000 nm. More importantly, the grating period (P) and the diffraction order (m) dominate the value of sensitivity. Higher sensitivity is possible for SPR sensors with a larger grating period and lower diffraction order. At long wavelengths, a simple expression of P/|m| can be used to estimate the sensor sensitivity. Moreover, we perform experimental measurements of the sensitivity of an SPR sensor based on an Al grating to confirm the theoretical calculations.

Photodamaging of Mitochondrial DNA to Overcome Cisplatin Resistance by a RuII -PtII Bimetallic Complex.

Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip)2 (µ-bpm)PtCl2 ]Cl2 (RuPt; dip=4,7-diphenyl-1,10-phenanthroline; bpm=2,2'-bipyrimidine) and the corresponding mononuclear complex [Ru(dip)2 (bpm)]Cl2 (Ru) have been designed and synthesized. RuPt can bind to mtDNA and damage it both in the dark and upon visible light irradiation. By using a variety of methods, it was demonstrated that RuPt can interfere with the function of mtDNA by decreasing the amplification and copy number of mtDNA, and affecting the transcriptional level of mitochondria-encoded genes. Furthermore, RuPt can disturb the physiological processes of mitochondria and induce caspase-dependent apoptosis in the presence of light. In addition, RuPt shows low systemic toxicity and potent in vivo anticancer potency upon light irradiation. This study provides strong evidence that mtDNA is an important molecular target of RuPt, and photodamaging mtDNA is an effective strategy to overcome cisplatin resistance.

Subwavelength imaging by a nonlinear negative refraction lens through four wave mixing.

We propose a new approach for subwavelength imaging using a nonlinear negative refraction lens based on four wave mixing process. Here a thin metal film is implemented as the nonlinear negative refraction lens to bend the incident signal waves to negatively refracted FWM ones according to the partial phase matching along its surface. The imaging process can be described by the nonlinear optical transfer function over the entire spatial spectra including the evanescent ones. Analytical calculations and numerical simulations are performed to demonstrate the capability of such imaging. Compared with the existing techniques, our method works on non-resonant condition over a broad range of spectrum, therefore, it may open up a new avenue for super-resolution imaging applications.

Valproic Acid-Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents.

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1 a-3 a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death-related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.

A human gut microbial gene catalogue established by metagenomic sequencing.

To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.

The sequence and de novo assembly of the giant panda genome.

Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.

Sum-frequency nonlinear Cherenkov radiation generated on the boundary of bulk medium crystal.

We demonstrated experimentally a method to generate the sum-frequency Nonlinear Cherenkov radiation (NCR) on the boundary of bulk medium by using two synchronized laser beam with wavelength of 1300 nm and 800 nm. It is also an evidence that the polarization wave is always confined to the boundary. Critical conditions of surface sum-frequency NCR under normal and anomalous dispersion condition is discussed.

Noninvasive prenatal testing for autosomal recessive conditions by maternal plasma sequencing in a case of congenital deafness.

PURPOSE: The goals of our study were to develop a noninvasive prenatal test for autosomal recessive monogenic conditions and to prove its overall feasibility and potential for clinical integration. METHODS: We recruited a pregnant woman and her spouse, who had a proband child suffering from congenital deafness, and obtained the target-region sequencing data from a semicustom array that used genomic and maternal plasma DNA from three generations of this family. A haplotype-assisted strategy was developed to detect whether the fetus inherited the pathogenic mutations in the causative gene, GJB2. The parental haplotype was constructed using a trio strategy through two different processes, namely, the grandparent-assisted haplotype phasing process and the proband-assisted haplotype phasing process. The fetal haplotype was deduced afterward based on both the maternal plasma sequencing data and the parental haplotype. RESULTS: The accuracy levels of paternal and maternal haplotypes obtained by grandparent-assisted haplotype phasing were 99.01 and 97.36%, respectively, and the proband-assisted haplotype phasing process yielded slightly lower accuracies of 98.73 and 96.79%, respectively. Fetal inheritance of the pathogenic gene was deduced correctly in both processes. CONCLUSION: Our study indicates that the strategy of haplotype-based noninvasive prenatal testing for monogenic conditions has potential applications in clinical practice.

Metal-free flat lens using negative refraction by nonlinear four-wave mixing.

A perfect lens with unlimited resolution has always posed a challenge to both theoretical and experimental physicists. Recent developments in optical metamaterials promise an attractive approach towards perfect lenses using negative refraction to overcome the diffraction limit, improving resolution. However, those artificially engineered metamaterials are usually accompanied by high losses from metals and are extremely difficult to fabricate. An alternative proposal using negative refraction by four-wave mixing has attracted much interest recently, though most existing experiments still require metals and none of them have been implemented for an optical lens. Here, we experimentally demonstrate a metal-free flat lens for the first time using negative refraction by degenerate four-wave mixing with a thin glass slide. We realize an optical lensing effect utilizing a nonlinear refraction law, which may have potential applications in microscopy.

Characteristics of coal crack development and gas desorption in the stress affected zone of rock pillar.

Coal (Rock) pillar retaining in the mining of protective layer would cause gas dynamic disaster in the protected layer. Based on the gas geological conditions of the two-layer coal seam in Jinhe Coal Mine of Yaojie Mining District, the stress evolution law of coal seam in the rock pillar affected area was studied by theoretical analysis and numerical simulation, and the crack development law of coal seam in different loading stages under conventional triaxial loading was studied by CT scanning technology. With the analysis of the stress evolution and crack development of coal in rock pillar affected area, the gas extraction effect under different stress states and the gas desorption law after pressure relief antireflection were studied on site. The results showed that the stress of coal in the rock pillar affected area is in the approximate elastic stage of the conventional triaxial stress-strain curve, and the cracks of coal are mainly closed at this stage. Meanwhile, the increase of stress leaded to the decrease of coal permeability and the poor gas extraction effect. CT scanning tests under conventional triaxial loading were carried out in the laboratory, and three-dimensional visual models of coal sample cracks were constructed at different loading stages. When loading to the linear elastic stage, the crack volume and surface area were reduced by 74% and 71% compared with the ones in initial state. At the same time, the expression between stress σ and crack density T was further established. After comprehensive control measures such as intensive drilling discharge, presplitting blasting and coal water injection were taken to the coal in rock pillar affected area, the crack density T could reach the crack development level of the conventional triaxial loading softening stage, realizing the crack development of the coal under low stress. The enclosed gas in front of the coal could desorption flow during the roadway driving. And the predict index value K1 also decreased from 0.57 mL/(g·min1/2) to 0.17 mL/(g·min1/2) continuously. The safety of coal roadway in rock pillar affected area was realized, and the accuracy of numerical simulation and laboratory test results was verified, which had certain reference significance for coal roadway excavation under this similar conditions.

Color Generation and Polarization-Sensitive Encryption by Laser Writing on Plasmonic Reflector Arrays.

Plasmonic color printing presents a sustainable solution for vibrant and durable color reproduction by leveraging the light-manipulating properties of nanostructures. However, the fabrication of plasmonic nanostructures has posed challenges, hindering widespread adoption. In this paper, we introduce plasmonic reflector arrays (PRAs) composed of three layers─Ag nanoparticles (NPs), an Al2O3 spacer, and an Ag reflector─deposited via physical vapor deposition (PVD). By employing nanosecond and femtosecond laser writing techniques, we manipulate the surface morphology of silver nanoparticles on PRAs, resulting in a diverse range of structural colors that are both polarization-insensitive and polarization-sensitive. Furthermore, we demonstrate the versatility of nanosecond laser writing in creating intricate patterns on PRAs. Additionally, we propose a novel two-step method combining nanosecond and femtosecond laser processing to embed QR code patterns into PRAs, showcasing their potential for secure data encryption and transmission. This research underscores the promising applications of PRAs in advanced color printing and secure optical data encoding.