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Nowadays recording and sharing personal lives using mobile devices on the Internet is becoming increasingly popular, and successive POI recommendation is gaining growing attention from academia and industry. In mobile scenarios, multiple influencing factors including the diversity of user preferences, the changeability of user behavior and the dynamic of spatiotemporal context bring great challenges to the POI recommender system. In order to accurately capture both the stable and the contextual preferences of mobile users in dynamic contexts, we propose a fusion framework JANICP (Joint Attention Networks with Inherent and Contextual Preferences) for successive POI recommendation by jointly training an offline/nearline user inherent interest perception model and an online user contextual interest prediction model. The offline model is trained based on the global historical behavior data to achieve stable interest representation, while the online model is trained based on the instantly selected context-sensitive data to achieve dynamic interest perception. An attention aggregation and matching module is used to fully connect the two kinds of preference representations and generate the final POI recommendation. Extensive experiments were conducted on three real datasets and experimental results show that the proposed JANICP outperforms existing state-of-the-art methods.

Cardiac fibrosis is a hallmark of various cardiovascular diseases, which is quite commonly found in obesity, and may contribute to the increased incidence of heart failure arrhythmias, and sudden cardiac death in obese populations. As an endogenous regulator of adiposity metabolism, body mass, and energy balance, obesity, characterized by increased circulating levels of the adipocyte-derived hormone leptin, is a critical contributor to the pathogenesis of cardiac fibrosis. Although there are some gaps in our knowledge linking leptin and cardiac fibrosis, this review will focus on the interplay between leptin and major effectors involved in the pathogenesis underlying cardiac fibrosis at both cellular and molecular levels based on the current reports. The profibrotic effect of leptin is predominantly mediated by activated cardiac fibroblasts but may also involve cardiomyocytes, endothelial cells, and immune cells. Moreover, a series of molecular signals with a known profibrotic property is closely involved in leptin-induced fibrotic events. A more comprehensive understanding of the underlying mechanisms through which leptin contributes to the pathogenesis of cardiac fibrosis may open up a new avenue for the rapid emergence of a novel therapy for preventing or even reversing obesity-associated cardiac fibrosis.

To explore the effect and mechanism of the miR-339-3p/KAT6A/TRIM24 axis in nasopharyngeal carcinoma (NPC) cell growth and epithelial-mesenchymal transition (EMT) progression.CNE2 and 5-8F NPC cell lines were transfected with miR-339-3p-mimic or sh-KAT6A alone or co-transfected with miR-339-3p-mimic and oe-KAT6A. The expression levels of miR-339-3p, KAT6A, TRIM24, and EMT-related proteins were assessed, in addition to cell biological behaviors. Then, the relationship between miR-339-3p and KAT6A was predicted and validated. The correlations between miR-339-3p and KAT6A or between KAT6A and TRIM24 were analyzed by Pearson coefficient and the enrichment of H3K23ac in TRIM24 promoter region was measured by chromatin immunoprecipitation.miR-339-3p was downregulated, but KAT6A and TRIM24 were highly expressed in NPC cells and tissues. Upregulated miR-339-3p or downregulated KAT6A could inhibit the growth and EMT of NPC cells. Further experiments showed that miR-339-3p regulated NPC cell growth and EMT by mediating KAT6A in a targeted fashion. KAT6A was positively correlated with TRIM24, and the enrichment of H3K23ac was much higher in NPC tissues. miR-339-3p suppressed the growth and EMT of NPC cells by the KAT6A/TRIM24 axis. In a xenograft study, miR-339-3p overexpression inhibited NPC tumor growth in vivo.Conclusively, miR-339-3p inhibited the growth and EMT of NPC cells via the KAT6A/TRIM24 axis.

Background Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in previous literature. In this study, the mechanism of IL-17A that induces mitochondrial dysfunction promoted pyroptosis has been explored in colorectal cancer cells. Method The records of 78 patients diagnosed with CRC were reviewed via the public database to evaluate clinicopathological parameters and prognosis associations of IL-17A expression. The colorectal cancer cells were treated with IL-17A, and the morphological characteristics of those cells were indicated by scanning electron microscope and transmission electron microscope. After IL-17A treatment, mitochondrial dysfunction was tested by mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The expression of pyroptosis associated proteins including cleaved caspase-4, cleaved gasdermin-D (GSDMD), IL-1β, receptor activator of nuclear NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a card (ASC), and factor-kappa B was measured through western blotting. Results Positive IL-17A protein expression was observed in CRC compared to the non-tumour tissue. IL-17A expression indicates a better differentiation, earlier stage, and better overall survival in CRC. IL-17A treatment could induce mitochondrial dysfunction and stimulate intracellular reactive oxygen species (ROS) production. Furthermore, IL-17A could promote pyroptosis of colorectal cancer cells and significantly increase the secretion of inflammatory factors. Nevertheless, the pyroptosis induced by IL-17A could be inhibited through the pre-treatment with Mito-TEMPO (a mitochondria-targeted superoxide dismutase mimetic with superoxide and alkyl radical scavenging properties) or Z-LEVD-FMK (caspase-4 inhibitor, fluoromethylketone). Additionally, after being treated with IL-17A, an increasing number of CD8 + T cells showed in mouse-derived allograft colon cancer models. Conclusion IL-17A, as a cytokine mainly secreted by γδT cells in the colorectal tumour immune microenvironment, can regulate the tumour microenvironment in multiple ways. IL-17A could induce mitochondrial dysfunction and pyroptosis through the ROS/NLRP3/caspase-4/GSDMD pathway, and promote intracellular ROS accumulation. In addition, IL-17A can promote the secretion of inflammatory factors such as IL-1β、IL-18 and immune antigens, and recruit CD8 + T cells to infiltrate tumours. Graphical Abstract

Prognostic nutritional index (PNI) and age are effective prognostic factors for patients with non-metastatic nasopharyngeal carcinoma (NPC), and an interaction between them may exist. However, the age cutoff value is generally set at 45 years in current studies. The clinical implications of PNI in middle-aged and elderly patients are unclear. Therefore, we aimed to uncover this issue.We retrospectively collected data from 132 middle-aged and elderly (≥ 45 years old) patients with non-metastatic NPC. The association between covariates and the PNI was analyzed usingMedian age (61.0 years versus 59.5 years) and the proportion of patients aged ≥ 60 years (57.6% versus 50.0%) in the low-PNI group were higher than those in the high-PNI group (P 0.05). The patients with a low PNI had shorter overall survival (OS) (hazard ratio (HR) = 0.86, 95% confidence interval (CI) = 0.80-0.93; P 0.001) and progression-free survival (PFS) (HR = 0.93, 95% CI = 0.87-0.99; P = 0.034). The results remained stable after three adjusted models of covariates, including age (P 0.05). No significant interactions were observed in middle-aged (45-59 years) and elderly (≥ 60 years) subgroups for OS and PFS (P for interaction 0.05).Although there is an interaction between PNI and age, PNI is an independent prognostic factor in middle-aged and elderly patients with non-metastatic NPC.

Objectives This study aims to discuss the availability of robot-assisted percutaneous balloon compression (PBC) for trigeminal neuralgia (TN) and share our preliminary experiences. Methods Patients with TN who underwent robot-assisted PBC from June to September 2022 were enrolled. We designed a fixing plug for robot-assisted PBC, three-dimensional structured light registration was used, puncture trajectory was the line connects the medial third of inner and outer aperture of foramen ovale. Numerical Rating Scale (NRS), Barrow Neurological Institute (BNI) pain and numbness intensity score were used to evaluate the facial pain and numbness. Results Eventually, nine patients were enrolled, the structured light registrations were successfully finished in all patients with a mean registration error of 0.68 mm. All the punctures of foramen ovales were successfully done one-time. Of note, the balloons were all got pear-shaped followed by 150 to 180 s compression. Though, postoperatively, all the patients complained of facial numbness and four patients suffered from transient masseter weakness, all patients got fully or mostly pain relief. It should be noted that is the numbness and weakness gradually relieved during follow-up. Conclusion Three-dimensional structured light registration and robot assisted PBC is an effective choice for patients with TN. Extension line between the medial third of the inner and outer aperture of foramen ovale might be a safe and effective puncture trajectory to this procedure.

The relatively low output performance of triboelectric nanogenerator (TENG), which faces a challenge in performance improvement, limits its practical applications. Here, a high-performance TENG consisting of a silicon carbide@silicon dioxide nanowhiskers/polydimethylsiloxane (SiC@SiO2/PDMS) nanocomposite film and a superhydrophobic aluminum (Al) plate as triboelectric layers is demonstrated. The 7 wt% SiC@SiO2/PDMS TENG presents a peak voltage of 200 V and a peak current of 30 μA, which are ~ 300 and ~ 500% over that of the PDMS TENG, owing to an increase in dielectric constant and a decrease in dielectric loss of the PDMS film because of electric insulated SiC@SiO2 nanowhiskers. Furthermore, a 10 μF capacitor can be charged up to 3 V within ~ 87 s, which can be continuously operated on the electronic watch for 14 s. The work provides an effective strategy for improving output performance of TENG by adding core–shell nanowhiskers to modulate the dielectric properties of organic materials. Graphical abstract

Massive intra-articular infiltration of proinflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimately joint erosion. Here we report an efferocytosis-informed nanoimitator (EINI) for in situ targeted reprogramming of synovial inflammatory macrophages (SIMs) that thwarts their autoimmune attack and reestablishes articular immune homeostasis, which mitigates RA. The EINI consists of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH). When systemically administered, the LMWH on the EINI first binds to P-selectin overexpressed on the endothelium in subsynovial capillaries, which functions as an antagonist, disrupting neutrophil synovial trafficking. Due to the strong dysregulation of the synovial microvasculature, the EINI is subsequently enriched in the joint synovium where the shell is disassembled upon the reactive oxygen species stimulation, and PtdSer corona is then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by SIMs, which synergistically terminate SIM-initiated pathological cascades and serially reestablish intra-articular immune homeostasis, conferring a chondroprotective effect. These findings demonstrate that SIMs can be precisely remodeled via the efferocytosis-mimetic strategy, which holds potential for RA treatment.

Direct hydrogen peroxide (H2O2) electrosynthesis via the two-electron oxygen reduction reaction is a sustainable alternative to the traditional energy-intensive anthraquinone technology. However, high-performance and scalable electrocatalysts with industrial-relevant production rates remain to be challenging, partially due to insufficient atomic level understanding in catalyst design. Here we utilize theoretical approaches to identify transition-metal single-site catalysts for two-electron oxygen reduction using the *OOH binding energy as a descriptor. The theoretical predictions are then used as guidance to synthesize the desired cobalt single-site catalyst with a O-modified Co-(pyrrolic N)4 configuration that can achieve industrial-relevant current densities up to 300 mA cm−2 with 96–100% Faradaic efficiencies for H2O2 production at a record rate of 11,527 mmol h−1 gcat−1. Here, we show the feasibility and versatility of metal single-site catalyst design using various commercial carbon and cobalt phthalocyanine as starting materials and the high applicability for H2O2 electrosynthesis in acidic, neutral and alkaline electrolytes.

The necessity for safety in oil-gas storage and transportation has led to increasing technical requirements for on-line monitoring of damaged pores and oil leakage from tanks. In this study, the severity of damage of the oil tank at the micron level was detected by terahertz time-domain spectroscopy (THz-TDS), which is of great significance for the early detection and prevention of oil leakage. The THz amplitude ( E P) was related to the severity of damaged according to the THz-TDS measurement of oil tanks with various degrees of damage, including intact, partially damaged, completely damaged, and seriously damaged points. Absorption and scattering effects co-occurred when the THz wave penetrated the tanks, with the collective tendencies being used to expressly monitor oil leakage from tanks. When the oil tank was damaged to form micron-level pores and the crude oil had not overflowed, the pore size was close to THz wavelength and the Mie scattering effect was obvious. After further destruction of the pores, the crude oil gradually spilled over and the scattering effect was gradually transformed from Mie scattering to Rayleigh scattering. In addition, the polar molecules in crude oil have strong resonance under the irradiation of THz wave, and the THz wave has strong attenuation. Eventually, surface tension of the oil flattens the surface of the tank, the scattering effect is gradually suppressed and replaced by the absorption effect. Absorption and scattering caused by THz waves passing through tanks coexist and have competing relationships. The change rule of E P can successfully prove the phenomenon and can be considered as an important alternative for application to predict the degree of tank damage. Therefore, in this study, the detection of pores as small as micrometers on the oil tank was expected to greatly prevent oil leakage accidents and improve the safety of oil and gas storage and transportation.

The present study focuses on the investigation of the interfacial bond behavior of carbon fiber-reinforced polymer (CFRP)-concrete under dry-wet sulfate cycles by double-sided shear testing. Besides, the effects of fly ash content on the interfacial failure characteristics, interfacial debonding bearing capacity, CFRP strain distribution, and interfacial shear stress peak were analyzed. The interfacial debonding capacity, maximum CFRP strain, and peak value of interfacial shear stress of the CFRP-concrete interface decreased with increasing erosion time under the sulfate dry-wet cycle's action, according to the sulfate dry-wet cycle test results. The sulfate resistance of the CFRP-concrete interface increased after the addition of fly ash. However, the final decrease amplitude of interfacial debonding capacity, CFRP maximum strain, and maximum interfacial shear stress all reduced as the fly ash content increased. The effective bond length of the interface gradually increased with increasing erosion time; however, the change in fly ash content had little effect on the effective bond length, and the final effective bond length of the samples with different fly ash content was the same. Moreover, the CFRP-concrete interfacial bearing capacity model under the sulfate dry-wet cycle was established by introducing sulfate's comprehensive influence coefficient and considering fly ash content's influence. In conclusion, the comparative analysis of the prediction model and test results revealed that the prediction model could well reflect the degradation law of interfacial debonding bearing capacity with sulfate attack time.

Our understanding of full-thickness endometrial regeneration after injury is limited by an incomplete molecular characterization of the cell populations responsible for the organ functions. To help fill this knowledge gap, we characterized 10,551 cells of full-thickness normal human uterine from two menstrual phases (proliferative and secretory phase) using unbiased single cell RNA-sequencing. We dissected cell heterogeneity of main cell types (epithelial, stromal, endothelial, and immune cells) of the full thickness uterine tissues, cell population architectures of human uterus cells across the menstrual cycle. We identified an SFRP4+ stromal cell subpopulation that was highly enriched in the regenerative stage of the human endometria during the menstrual cycle, and the SFRP4+ stromal cells could significantly enhance the proliferation of human endometrial epithelial organoid in vitro, and promote the regeneration of endometrial epithelial glands and full-thickness endometrial injury through IGF1 signaling pathway in vivo. Our cell atlas of full-thickness uterine tissues revealed the cellular heterogeneities, cell population architectures, and their cell–cell communications during the monthly regeneration of the human endometria, which provide insight into the biology of human endometrial regeneration and the development of regenerative medicine treatments against endometrial damage and intrauterine adhesion.

Alamandine (Ala) is the newest identified peptide of the renin-angiotensin system and has protective effect on myocyte hypertrophy. However, it is still unclear whether Ala can alleviate heart failure (HF). The aim of this study was to explore the effects of Ala on HF and the related cardiac fibrosis, and to probe the mechanism. HF model was induced by myocardial infarction (MI) in mice. Four weeks after MI, Ala was administrated by intraperitoneal injection for two weeks. Ala injection significantly improved cardiac dysfunction of MI mice in vivo. The cardiac fibrosis and the related biomarkers were attenuated after Ala administration in HF mice in vivo. The increases of collagen I, alpha-smooth muscle actin and transforming growth factor-beta induced by oxygen–glucose deprivation (OGD) in neonatal rat cardiac fibroblasts (NRCFs) were inhibited by Ala treatment in vitro. The biomarkers of apoptosis were elevated in NRCFs induced by OGD, which were attenuated after treating with Ala in vitro. The enhancement of oxidative stress in the heart of MI mice or in the NRCFs treated with OGD was suppressed by treating with Ala in vivo and in vitro. These effects of Ala were reversed by tBHP, an exogenous inducer of oxidative stress in vitro. These results demonstrated that Ala could alleviate cardiac dysfunction and attenuate cardiac fibrosis via inhibition of oxidative stress.

Single crystalline BaMnSb2 is considered as a 3D Weyl semimetal with the 2D electronic structure containing Dirac cones from the Sb sheet. We report experimental investigation of low-temperature cleaved BaMnSb2 surfaces using scanning tunneling microscopy/spectroscopy and low energy electron diffraction. By natural cleavage, we find two terminations: one is Ba (above the orthorhombically distorted Sb sheet) and another Sb2 (at the surface of the Sb/Mn/Sb sandwich layer). Both terminations show the 2 × 1 surface reconstructions, with drastically different morphologies and electronic properties, however. The reconstructed structures, defect types and nature of the electronic structures of the two terminations are extensively studied. The quasiparticle interference (QPI) analysis is conducted at the energy range between −2 V and 2 V, although no interesting states are observed near the Fermi level, the surface-projected electronic band structures strongly depend on the surface termination above 1.6 V. The existence of defects can greatly modify the local density of states to create electronic phase separations on the surface in the order of tens of nm scale. Our observation on the atomic structures of the terminations and the corresponding electronic structures provides critical information towards an understanding of topological properties of BaMnSb2.

In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.

Photosensitized heterogeneous CO2 reduction (PHCR) has emerged as a promising means to convert CO2 into valuable chemicals, however, challenged by the relatively low carbonaceous product selectivity caused by the competing hydrogen evolution reaction (HER). Here, we report a PHCR system that couples Ru(bpy)32+ photosensitizer with {001} faceted LiCoO2 nanosheets photocatalyst to simultaneously yield 21.2 and 722 µmol·g−1·h−1 of CO, and 4.42 and 108 µmol·g−1·h−1 of CH4 under the visible light and the simulated sunlight irradiations, respectively, with completely suppressed HER. The experimental and theoretical studies reveal that the favored CO2 adsorption on the exposed Li sites on {001} faceted LiCoO2 surface is responsible for the completely suppressed HER.

Water splitting is considered as one of the recommendable techniques to realize clear and renewable hydrogen production. However, it suffers from lacking efficient and sustainable catalysts. Herein, a metal–organic framework/graphene oxide pyrolysis strategy was proposed to prepare nitrogen-doped porous carbon-stabilized alloys supported on reduced graphene oxide (PdCo@N–C/rGO) composite. When evaluated as an electrocatalyst for hydrogen evolution reaction (HER), the as-obtained PdCo@N–C/rGO shows an excellent performance in acidic media including positive onset potential close to that of commercial Pt/C (vs. SCE), low overpotential and Tafel slope, as well as long-term durability. Also, it delivers outstanding HER activities in alkaline and neutral conditions. The excellent performance could be mainly ascribed to their synergetic effect among alloy particles, nitrogen-doped porous carbon shell, and conductive rGO substrate. A metal-organic framework engineered strategy was proposed to prepare N-doped porous carbon-stabilized PdCo alloys supported on reduced graphene oxide nanocomposite. Specifically, the as-obtained catalyst delivers excellent electrochemical activity for hydrogen evolution reaction.

Pressure grouting method can significantly enhance the strength of soil, and is widely used in foundation reinforcement. There already have some theoretical studies on pressure grouting, but the actual diffusion process of grouting can not be reflected exactly. Firstly, this paper conducts a field permeation grouting test on undisturbed loess of late pleistocene of quaternary, and acquires the pressure effected relationships of quantity vs. time. The test reveals that the grout quantity approximately increases linearly with the pressure until a certain grouting time point. The time point increases with grouting pressure and we try to define the pressure effected time point as the effective grouting time. After the effective grouting time, the grouting quantity remains constant due to the approaching of max migration radius and the stopping of grout migration. And then, considering the piston-like displacement effect of grout on porous mediums due to pressure, this study introduced the effective grouting time into the theoretical derivation process based on porous mediums’ fluid percolation pore pressure equation and Darcy’s law. The author combined the initial conditions and boundary conditions of pore pressure with the continuity conditions of permeation velocity, and performed the Boltzmann’s transformation and reduced-order processing to derive the equation for the migration velocity of the grout front and the migration radius of grout. Finally, by substituting the effective grouting time and the effective grouting quantity into the equation, we could obtain the grouting reinforcement radius. The equation can accurately predict the actual grouting reinforcement radius, and the applicability of the equation is verified by verification test.

Pellino1 has been shown to regulate proinflammatory genes by activating the nuclear factor kappa B (NF-κB) and Toll-like receptor (TLR) signaling pathways, which are important in the pathological development of lipopolysaccharide (LPS)-induced myocarditis. However, it is still unknown whether silencing Pellino1 (si-Pellino1) has a therapeutic effect on this disease. Here, we showed that silencing Pellino1 can be a potential protective strategy for abnormal myocardial energy metabolism in LPS-induced myocarditis. We used liquid chromatography electrospray–ionization tandem mass spectrometry (LC–MS/MS) to analyze samples from si-Pellino1 neonatal rat cardiac myocytes (NRCMs) treated with LPS or left untreated. After normalization of the data, metabolite interaction analysis of matched KEGG pathway associations following si-Pellino1 treatment was applied, accompanied by interaction analysis of gene and metabolite associations after this treatment. Moreover, we used western blot (WB) and polymerase chain reaction (PCR) analyses to determine the expression of genes involved in regulating cardiac energy and energy metabolism in different groups. LC–MS-based metabolic profiling analysis demonstrated that si-Pellino1 treatment could alleviate or even reverse LPS-induced cellular damage by altering cardiomyocytes energy metabolism accompanied by changes in key genes (Cs, Cpt2, and Acadm) and metabolites (3-oxoocotanoyl-CoA, hydroxypyruvic acid, lauroyl-CoA, and NADPH) in NRCMs. Overall, our study unveiled the promising cardioprotective effect of silencing Pellino1 in LPS-induced myocarditis through fuel and energy metabolic regulation, which can also serve as biomarkers for this disease. Supplementary Information The online version contains supplementary material available at 10.1007/s00726-021-02978-w.

Leaf aging is a significant process during herbaceous plant senescence, which is influenced by various internal and external factors. During leaf aging, chlorophyll catabolism is one of the most important metabolism pathways and results in leaf yellowing. Understanding the underlying mechanism is important for the regulation of senescence in tobacco leaf. However, there are few studies on explaining tobacco leaf senescence from the proteomics level. Here, photosynthesis experiments, cell ultrastructure, and proteomics were used to study tobacco leaves of different growth stages. We applied iTRAQ-based quantitative proteomics and parallel reaction monitoring (PRM) to determine the accumulation of proteins in aging tobacco leaves. Overall, we screened 4747 proteins. The result of KEGG pathways analysis showed that differently expressed proteins (DEPs) were involved in four pathways: metabolic pathways, biosynthesis of secondary metabolites, microbial metabolism in diverse environments, and starch and sucrose metabolism. This would be first report based on iTRAQ-PRM technique, in which we identified proteins related to photosynthesis showed a differently expressed during senescence stage in flue-cured tobacco plants.

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence of new variant lineages that have exacerbated the COVID-19 pandemic. Some of those variants were designated as variants of concern/interest (VOC/VOI) by national or international authorities based on many factors including their potential impact on vaccine-mediated protection from disease. To ascertain and rank the risk of VOCs and VOIs, we analyze the ability of 14 variants (614G, Alpha, Beta, Gamma, Delta, Epsilon, Zeta, Eta, Theta, Iota, Kappa, Lambda, Mu, and Omicron) to escape from mRNA vaccine-induced antibodies. The variants show differential reductions in neutralization and replication by post-vaccination sera. Although the Omicron variant (BA.1, BA.1.1, and BA.2) shows the most escape from neutralization, sera collected after a third dose of vaccine (booster sera) retain moderate neutralizing activity against that variant. Therefore, vaccination remains an effective strategy during the COVID-19 pandemic.

α-Synuclein (α-syn), as a primary pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies, exhibits a high potential to form polymorphic fibrils. Chemical ligands have been found to involve in the assembly of α-syn fibrils in patients’ brains. However, how ligands influence the fibril polymorphism remains vague. Here, we report the near-atomic structures of α-syn fibrils in complex with heparin, a representative glycosaminoglycan (GAG), determined by cryo-electron microscopy (cryo-EM). The structures demonstrate that the presence of heparin completely alters the fibril assembly via rearranging the charge interactions of α-syn both at the intramolecular and the inter-protofilamental levels, which leads to the generation of four fibril polymorphs. Remarkably, in one of the fibril polymorphs, α-syn folds into a distinctive conformation that has not been observed previously. Moreover, the heparin-α-syn complex fibrils exhibit diminished neuropathology in primary neurons. Our work provides the structural mechanism for how heparin determines the assembly of α-syn fibrils, and emphasizes the important role of biological polymers in the conformational selection and neuropathology regulation of amyloid fibrils.

We study a classic Darcy’s law model for tumor cell motion with inhomogeneous and isotropic conductivity. The tumor cells are assumed to be a constant density fluid flowing through porous extracellular matrix (ECM). The ECM is assumed to be rigid and motionless with constant porosity. One and two dimensional simulations show that the tumor mass grows from high to low conductivity regions when the tumor morphology is steady. In the one-dimensional case, we proved that when the tumor size is steady, the tumor grows towards lower conductivity regions. We conclude that this phenomenon is produced by the coupling of a special inward flow pattern in the steady tumor and Darcy’s law which gives faster flow speed in higher conductivity regions.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Misfolded Cu, Zn-superoxide dismutase (SOD1) has been linked to both familial and sporadic ALS. SOD1 fibrils formed in vitro share toxic properties with ALS inclusions. Here we produced cytotoxic amyloid fibrils from full-length apo human SOD1 under reducing conditions and determined the atomic structure using cryo-EM. The SOD1 fibril consists of a single protofilament with a left-handed helix. The fibril core exhibits a serpentine fold comprising N-terminal segment (residues 3–55) and C-terminal segment (residues 86–153) with an intrinsic disordered segment. The two segments are zipped up by three salt bridge pairs. By comparison with the structure of apo SOD1 dimer, we propose that eight β-strands (to form a β-barrel) and one α-helix in the subunit of apo SOD1 convert into thirteen β-strands stabilized by five hydrophobic cavities in the SOD1 fibril. Our data provide insights into how SOD1 converts between structurally and functionally distinct states.

Hypertension is a pathological condition of persistent high blood pressure (BP) of which the underlying neural mechanisms remain obscure. Here, we show that the afferent nerves in perirenal adipose tissue (PRAT) contribute to maintain pathological high BP, without affecting physiological BP. Bilateral PRAT ablation or denervation leads to a long-term reduction of high BP in spontaneous hypertensive rats (SHR), but has no effect on normal BP in control rats. Further, gain- and loss-of-function and neuron transcriptomics studies show that augmented activities and remodeling of L1-L2 dorsal root ganglia neurons are responsible for hypertension in SHR. Moreover, we went on to show that calcitonin gene-related peptide (CGRP) is a key endogenous suppressor of hypertension that is sequestered by pro-hypertensive PRAT in SHRs. Taken together, we identify PRAT afferent nerves as a pro-hypertensive node that sustains high BP via suppressing CGRP, thereby providing a therapeutic target to tackle primary hypertension.

Under the influence of deep learning, many trackers have emerged recently. Among them, Siamese network reaches a pleasant balance between accuracy and speed, but its tracking performance still lags behind other trackers. In this paper, we have proposed a Hierarchical Correlation Siamese Network (HC-Siam) for object tracking. The tracker uses convolutional features of each layer to compare the correlation and identifies the position of the tracking object depending on the greatest correlation. Meanwhile, we have designed a Correlation Attention Module (CA-Module). For various objects, this module can assign different weights to the hierarchical correlation and help the network choose the distinct correlation from the hierarchical correlation. Besides, objects’ size and scale constantly varied during tracking, we claimed to use the separate scale factor in the wide and high directions to decrease the deformation of bounding boxes and increase the accuracy of our tracker. On the OTB dataset, the accuracy of HC-Siam is 6.5% higher than the baseline, and the speed of our tracker can reach 85 fps. On the VOT dataset, HC-Siam also has better performance in speed and accuracy.

We aim to develop an immune-score nomograms for predicting overall survival (OS) of patients with HNSCC and assess the association of immune scores with prognosis. The data of 530 patients used in this study were retrieved from The Cancer Genome Atlas database. The optimization cut‐point for immune scores was expressed by X-tile 3.6.1 tool. Possible prognostic factors from univariate Cox analysis were further included in a multivariate Cox proportional hazards analysis to obtain significant risk factors. Prognostic nomograms were constructed based on the factors of significant multivariate prognostic using R version 3.5.1. A calibration map was generated by comparing the nomogram prediction probability and the observation for the 3-year and 5-year OS rates. We retrospectively analyzed 462 patients downloaded from TCGA dataset. Prognostic nomograms was integrated following risk factors of significant multivariate prognostic, such as age, angiolymphaic invasion (AI), perineura invasion(Per_invasion),tumor site, immune score, tumor-node-metastasis(TNM) stage. The concordance Index (C-index) for OS predictions was 0.723 (95% CI 0.671–0.785). Moreover, we compared the powerful efficiency of the nomograms with that of the TNM staging system. OS prediction determined on immune score set compared with the TNM staging with C-index = 0.723 vs 0.612. The calibration curves for the probability of OS of 3-year or 5-year showed no deviations between the prediction by nomograms and actual reference line. The present study indicate that high and intermediate immune scores are as independent prognostic variables for OS of head–neck squamous cell carcinoma patients. We constructed novel nomograms may has the potential to provide individualized survival risk assessments and guide treatment decisions.

To explore the regulatory relationship between Chloride intracellular channel 1 (CLIC1) and Angiomotin (AMOT)-p130, and reveal the role of AMOT-p130 in gastric cancer (GC). Immunohistochemistry was performed to analyze the expression of CLIC1 and AMOT-p130 in GC tissues and adjacent tissues. The expression of AMOT-p130 upon CLIC1 silencing was analyzed using RT-PCR, western blot, and immunofluorescence in GC cells. Transwell and wound-healing assays were performed to detect migration and invasion in GC cells. The changes in EMT-related proteins were detected using western blot. Our study found that high CLIC1 expression was significantly associated with low AMOT-p130 expression in GC tissues. Silencing CLIC1 expression in MGC-803 cells (MGC-803 CLIC1 KO) and AGS cells (AGS CLIC1 KO) decreased the invasive and migratory abilities of tumor cells, which were induced by the upregulation of AMOT-p130. Subsequently, we demonstrated that AMOT-p130 inhibits the invasive and migratory abilities of GC cells by inhibiting epithelial–mesenchymal transition. Our study suggests that AMOT-p130 could inhibit epithelial–mesenchymal transition in GC cells. CLIC1 may participate in the metastatic progression of GC by downregulating the expression of AMOT-p130.

Talaromyces marneffei is an important opportunistic pathogen mainly afflicting the HIV-infected patients, in rare instance, it could cause infection in non-HIV-infected individuals. We report a 51-year-old Chinese woman who, with histories of SLE for 14 years and disseminated talaromycosis for 4 years, occurred partial intestinal obstruction that was demonstrated to be caused by Talaromyces marneffei infection. The randomly amplified polymorphic DNA results of paraffin-embedded tissues from both the present episode and the previous infection suggested that the present infection was a recurrent. The patient was performed excision of involved intestine and treated with oral itraconazole at a daily dose of 400 mg for 3 months, leading to an excellent response. However, she died with unknown reason more than a year later. We also reviewed the literature on Talaromyces marneffei infection associated with SLE as well as intestinal talaromycosis alone.

Three new metal complexes, namely: [Mn(AIDB)Cl2]·DMF (1), [Zn(AIDB)Br2]·CH3OH (2) and [Co(AIDB)Cl2]·CH3OH (3) having a ligand bis(benzimidazol-2-ylmethyl)allylamine (AIDB), have been synthesized in high yields and characterized by elemental analyses, molar conductivities, IR, UV–Vis spectra and single-crystal X-ray diffraction. The structural analysis revealed that all the three complexes 1–3 have five-coordinated trigonal bipyramid geometry where the degree of distorting is 1>3>2. In vitro antioxidant activity assay demonstrates that the complexes 1 and 3 display high scavenging activity against hydroxyl (OH·) and superoxide (O2−·) radicals.

A novel fluorescent probe, 2-allyl-6-((2-((2-hydroxy-5-nitrobenzylidene)amino)ethyl)amino)-1H-benzo[de]isoquinoline- 1,3(2H)-dione (ABID), based on naphthalimide-Schiff base, has been designed and synthesized for the monitoring of Cu2+ ions. In solution (DMSO/HEPES, 1:1, v/v, pH 7.4), ABID displayed fluorescence quenching towards Cu2+ ions over other important metal ions. A good linearity with a correlation coefficient (R2) of 0.99 validated that the ABID probe could be used to detect Cu2+ ions in 0.5–5.0 μM concentrations. The limit of detection of ABID for Cu2+ could reach at 3.4 × 10–7 M level, and the quenching constant (KSV) of ABID towards Cu2+ was calculated to be 3.4 × 104 M–1. The 2:1 stoichiometry and the binding mode between ABID and Cu2+ were studied by a Job plot and UV-Vis and fluorescence titration. Additionally, ABID was successfully employed to monitor Cu2+ in the Yellow River and tap water samples.

Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrPSc) that are able to template the conversion of the native form of the protein (PrPC), a property shared by in vitro–produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrPC (residues 23–231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170−229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrPC, we propose that two α-helices in the C-terminal domain of PrPC are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion. A cryo-EM structure of amyloid fibrils formed in vitro with recombinant human PrP provides insights into fibril architecture and the potential role of disease mutations.

With the development of urbanization, whether precipitation characteristics in Guangdong Province, China, from 1981 to 2015 have changed are investigated using rain gauge data from 76 stations. These characteristics include annual precipitation, rainfall frequency, intense rainfall (defined as hourly precipitation ⩾ 20 mm), light precipitation (defined as hourly precipitation ⩽ 2.5 mm), and extreme rainfall (defined as hourly rainfall exceeding the 99.9th percentile of the hourly rainfall distribution). During these 35 years, the annual precipitation shows an increasing trend in the urban areas. While rainfall frequency and light precipitation have a decreasing trend, intense rainfall frequency shows an increasing trend. The heavy and extreme rainfall frequency both exhibit an increasing trend in the Pearl River Delta region, where urbanization is the most significant. These trends in both the warm seasons (May−October) and during the pre-flood season (April−June) appear to be more significant. On the contrary, the annual precipitation amount in rural areas has a decreasing trend. Although the heavy and extreme precipitation also show an increasing trend, it is not as strong and significant as that in the urban areas. During periods in which a tropical cyclone makes landfall along the South China Coast, the rainfall in urban areas has been consistently more than that in surrounding areas. The precipitation in the urban areas and to their west is higher after 1995, when the urbanization accelerated. These results suggest that urbanization has a significant impact on the precipitation characteristics of Guangdong Province.