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Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.The Translational Potential of this Article.Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing the Wnt signal pathway, whereas it imposes severe cardiac ischemic events in clinic. Our team has screened an aptamer that could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (seven subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin toward the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in OI mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

ABSTRACTMicrosporidia are intracellular fungus-like pathogens and the infection symptoms include recurrent diarrhea and systematic inflammations. The major infection route of microsporidia is the digestive tract. Since microsporidia are hard to fully eliminate, the interactions and persistence of the pathogen within epithelium may modulate host susceptibility to digestive disorders. In this study, both in vitro and in vivo infection models were applied. The alterations of epithelial barrier integrity, permeability, and tight junction proteins after microsporidia infection were assessed on MDCK/Caco-2 monolayers. The fecal intestinal microbiota and tissue alterations after microsporidia infection were assessed on C57BL/6 mice. Moreover, the susceptibility to develop dextran sulfate sodium (DSS)-induced inflammatory bowel diseases (IBDs) was also analyzed by the murine infection model. The results demonstrated that microsporidia infection increased epithelium permeability, weakened wound healing capability, and destructed tight junction protein zonula occludens-1. Microsporidia infection also dysregulates intestinal microbiota. These impairing effects of microsporidia increased host vulnerability to develop enteritis as shown by the murine model of DSS-induced IBD. Our study is the first to elucidate molecular mechanisms of the damaging effects of microsporidia on host epithelium and pointed out the cryptic threats of latent microsporidia infection to public health as reflected by the increased chances of developing more severe diseases.IMPORTANCEMicrosporidia are widely present in nature and usually cause latent and persistent infections in hosts. Given the fact that the digestive tract is the major infection route, it is of great importance to explore the consequences of microsporidia infection on the intestinal epithelial barrier and the risks to the host. In this study, we demonstrated the destructing effects of microsporidium infection on epithelial barriers manifested as increased epithelial permeability, weakened wound healing ability, and disrupted tight junctions. Moreover, microsporidia made the host more susceptible to dextran sulfate sodium-induced inflammatory bowel disease. These findings provide new evidence for us to better understand and develop novel strategies for microsporidia prevention and disease control.

This study presents an innovative investigation into the wetting characteristic and flow behavior of sand particles, which have different shapes, sizes, and textures, when they bonded with silicate binder. The results revealed that the apparent contact angles of fine and angular particles with the binder are higher than those of coarse and circular particles. In addition, after modifying the four systems with anionic surfactants, the equilibrium contact angles decreased by 42.8%, 26.7%, 26.5%, and 7%. These findings suggest that coarse and circular particles demonstrate stronger wetting properties with the binder compared to fine and angled particles. Additionally, the cohesion and internal friction angle of the wet sand mixture can be measured through the ring shear test. Moreover, the unconfined yield strength and main consolidation stress can be calculated using the Mohr Coulomb model to obtain the yield locus and quantify the flowability of the wet sand mixture. The yield trajectory of sand mixtures at specific consolidation stresses suggests that the most important factor affecting the flowability of wet sand particles is particle size distribution. Wet mixtures of coarse and circular particles exhibit lower cohesive forces, indicating higher fluidity.

Microalloying is a cost-effective strategy to develop high performance nickel-based superalloys. Here, the mechanisms of rare earth Y in IN713C on purification, mechanical property improvement, and microstructure modification were systematically investigated. Via melt purification of Y, the O, N, and S elements are reduced to 5 ppm in the IN713C alloy. By adding Y to 74 ppm, the yield strength, tensile strength, and elongation of the IN713C alloy at 650 °C are increased by 12.2%, 14.5%, and 66%, respectively. Microstructure analysis indicated that the strength of the alloy is improved by refining the size and increasing the volume fraction of the γ’ phase. The plasticity of the alloy is improved by modifying the morphology and distribution of MC carbides. The modification of carbide morphology can be attributed to the enrichment of Y at the surface of carbides and the change of segregation of Nb, which is the main carbide-formation element.

Abstract Thaw slumping is a periglacial process that occurs on slopes in cold environments, where the ground becomes unstable and the surface slides downhill due to saturation with water during thawing. In this study, GaoFen-1 remote sensing and fused multi-source feature data were used to automatically map thaw slumping landforms in the Beilu River Basin of the Qinghai–Tibet Plateau. The bi-directional cascade network structure was used to extract edges at different scales, where an individual layer was supervised by labeled edges at its specific scale, rather than directly applying the same supervision to all convolutional neural network outputs. Additionally, we conducted a 5-year multi-scale feature analysis of small baseline subset interferometric synthetic aperture radar deformation, normalized difference vegetation index, and slope, among other features. Our study analyzed the performance and accuracy of three methods based on edge object supervised learning and three preconfigured neural networks, ResNet101, VGG16, and ResNet152. Through verification using site surveys and multi-data fusion results, we obtained the best ResNet101 model score of intersection over union of 0.85 (overall accuracy of 84.59%).The value of intersection over union of the VGG and ResNet152 are 0.569 and 0.773, respectively. This work provides a new insight for the potential feasibility of applying the designed edge detection method to map diverse thaw slumping landforms in larger areas with high-resolution images.

ABSTRACT Nosema bombycis is transmitted horizontally and vertically from infected female moths to progeny eggs, bringing substantial economic losses to sericulture production. Timely and accurate detection of N. bombycis can effectively block the spread of silkworm pébrine disease, which is of great significance for its prevention and control. In this study, we established a multiplex-crRNA CRISPR/Cas12a nucleic acid amplification-free detection method for N. bombycis.. Specificity and sensitivity assessments confirmed that this method specifically detects N. bombycis without cross-reacting with other pathogens. It can detect N. bombycis at levels as low as 2 pg of genomic DNA. This method could also provide information on pathogen quantification, which will be important for in-field applications and promotions. IMPORTANCE The multiplex-crRNA CRISPR/Cas12a detection method saves hands-on time, reduces the risk of aerosol pollution, and can be directly applied to detecting silkworms infected with Nosema bombycis. This study provides a new approach for the inspection and quarantine of silkworm pébrine disease in sericulture and provides a new method for the detection of other pathogens.

The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30–50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life.

This study investigates the eco-geological environmental challenges faced by Jiangxia District, a mining region in Wuhan City. By combining field surveys, literature analysis and multi-source data such as remote sensing images and on-site monitoring data, an eco-geological environment quality (EGEQ) assessment system was developed. The system consists of six indicators representing biological abundance, vegetation cover, land erosion, water abundance, surface deformation and socio-economic characteristics of the assessed area. The grey relational analysis method was utilized to calculate the weights of each indicator, and the eco-geological environment quality index (EGQI) value was obtained through the linear weighted method. The assessment results indicated a moderate grade of overall eco-geological condition in Jiangxia District between 2017 and 2021, with an 8.56% increase in the EGQI during that period. This suggests a stable and favorable eco-geo logical environment situation in the district during the specified timeframe.

In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.

In this study, the effect of adding different contents of yttrium (Y) during vacuum induction melting in Al2O3 and Y2O3 crucibles on the purification of DD5 alloys was investigated. The results show that the Y2O3 crucible exhibited great crucible stability and an excellent desulfurization effect when melting a Y-containing DD5 alloy. The S content of the alloy was reduced from 5.03 ppm to 1.36 ppm with the addition of 0.50 wt.% Y. Element Y combined with free S in the melt to form the YS phase, which was removed from the condensate shell and slag during the vacuum induction melting (VIM) process. Meanwhile, when the alloy was melted in the Y2O3 crucible with 0.50 wt.% Y addition, there was a reduction in S content from 2.77 ppm to 1.36 ppm compared to the Al2O3 crucible. Additionally, the loss of Y decreased from 0.12 wt.% to 0.05 wt.%.

Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences.

Nucleic acid aptamers are ssDNA or ssRNA fragments that specifically recognize targets. However, the pharmacodynamic properties of natural aptamers consisting of 4 naturally occurring nucleosides (A, G, C, T/U) are generally restricted for inferior binding affinity than the cognate antibodies. The development of high-affinity modification strategies has attracted extensive attention in aptamer applications. Chemically modified aptamers with stable three-dimensional shapes can tightly interact with the target proteins via enhanced non-covalent bonding, possibly resulting in hundreds of affinity enhancements. This review overviewed high-affinity modification strategies used in aptamers, including nucleobase modifications, fluorine modifications (2′-fluoro nucleic acid, 2′-fluoro arabino nucleic acid, 2′,2′-difluoro nucleic acid), structural alteration modifications (locked nucleic acid, unlocked nucleic acid), phosphate modifications (phosphorothioates, phosphorodithioates), and extended alphabets. The review emphasized how these high-affinity modifications function in effect as the interactions with target proteins, thereby refining the pharmacodynamic properties of aptamers.

Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (

Abstract Background There is an increasing trend on the practices of parental self-medication with antibiotics (PSMA) around world, accelerating the antibiotic abuse. This study aims to examine the nationality differences in the practices of PSMA and knowledge, attitudes and practices (KAP) toward antibiotic use, and understand the practices of PSMA among parents of various nationalities in China. Methods A cross-sectional study based on a structured questionnaire survey was conducted in Xi’an, Shaanxi Province, China, from September 2018 to October 2018. A total of 299 respondents participated in. The practices of PSMA (a dichotomous variable) and KAP toward antibiotic use (a continuous variable) served as dependent variables. Participant’s nationality was regarded as the independent variable. Binary logistic regression and ordinary least square regression were employed to examine the association between parent’s nationality and the practices of PSMA, and KAP toward antibiotic use, respectively. Results 121 (40.88%) Chinese, 100 (33.76%) other Asians and 75 (25.34%) Occidentals were included in final analysis, with a sample size of 296. Chinese were more likely to practice PSMA (OR = 7.070; 95% CI 1.315, 38.01), with worse knowledge (Coef. = − 0.549; 95% CI − 1.021, − 0.078), attitudes (Coef. = − 3.069; 95% CI − 4.182, − 1.956) and practices (Coef. = − 1.976; 95% CI − 3.162, − 0.790) toward antibiotic use, compared to their Occidental counterparts. The main reasons for the practices of PSMA were enough previous medication experience (80.49%) and same ailments with no need to see a doctor (39.02%), with common symptoms such as fever (60.98%) and cough (58.54%). Purchasing antibiotics at pharmacies (92.08%) and using leftover antibiotics (26.83%) were usual approaches. Conclusions The study highlights the gaps in the practices of PSMA and KAP toward antibiotic use among parents of different nationalities. The access to obtain antibiotics from pharmacies reflects the pharmacists’ unaware of laws on prescription of antibiotics, fierce competition in the pharmacy market, and the government’s lax supervision in China. It suggests the need to improve pharmacists’ training, enforce current legislations on pharmacy market regarding the sale of antibiotics, and provide practical and effective educational interventions for residents about antibiotic use.

Exosomes are small membrane vesicles released by most eukaryotic cells. They are considered to play an essential role in cell-to-cell communication, and It is also found that they serve as functional mediators in many severe diseases, including progression of various types of cancers. Inhibition of exosome release may slow the progression of some cancers; thus, exosome has been an attractive target for cancer treatment. Over the years, considerable efforts have been made to discover novel, highly potent and excellently selective exosome inhibitors. Most of these inhibitors are derived from synthetic compounds, some of which are currently existed drugs and found to have the potential to inhibit exosome release. In this review, we briefly discussed the development of exosome inhibitors that are currently discovered and provided guidance for the future development of inhibitors.

Lightweight alloys produced by pressurized castings suffer from flow-induced microstructural segregation due to the migration of externally solidified crystals (ESCs). Although some qualitative research has been carried out on ESCs migration, quantitative prediction of it is still demanded. In this respect, an ESCs migration model based on hydrodynamics and the rheological behaviour of semi-solid metals (SSMs) is proposed to estimate flow-induced microstructural segregation. By employing the model, a plug flow region having a decisive influence on ESCs migration is observed according to the flow simulation of yield-pseudoplastic SSMs. Good agreement between the experimental data and the simulation results is obtained, suggesting that such flow-induced microstructural segregation is controllable by manipulating process parameters such as solid fraction, cavity size and filling velocity. A real-time in situ synchrotron X-ray radiography experiment is carried out to reveal the nature of ESCs migration and provide evidence for the hypothesized flow-induced ESCs migration mechanism. A semi-empirical solid fraction-related rheological (SFR) model capable of relating rheological parameters with solid fraction of SSMs is also proposed, enabling the optimization of process parameters.

Leflunomide is used for the treatment of rheumatoid arthritis. Here, the authors show that effectiveness is limited in patients with higher levels of serum c-reactive protein (CRP). Using animal models, they show that higher CRP induces HIF1a expression, which in turn interferes with Leflunomide signalling, and that effectiveness of the drug is restored when HIF1a is pharmacologically inhibited.

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In this paper, an artificial neural network (ANN) model with high accuracy and good generalization ability was developed to predict and optimize the mechanical properties of Al–7Si alloys. The quantitative correlation formulas of the mechanical properties with Mg content and heat treatment parameters were established based on the transfer function and weight values. The relative importance of the input variables, Mg content and heat treatment parameters, on the mechanical properties of Al–7Si alloys were identified through sensitivity analysis. The results indicated that the mechanical properties of Al–7Si alloys were sensitive to Mg content and aging temperature. Then the individual and the combined influences of these input variables on the properties of Al–7Si alloys were simulated and the process parameters were optimized using the artificial neural network model. Finally, the proposed model was validated to be a robust tool in predicting the mechanical properties of the Al–7Si alloy by conducting experiments.

In this work, Y2O3 based composite crucibles with different Al2O3 contents were designed and characterized. The stability behaviors and interaction mechanisms between molten Ti-47Al-2Cr-2Nb alloy and Y2O3-Al2O3 composite crucibles were investigated at high temperature. Results showed that the surface morphology of crucibles and the degree of interfacial reactions between the composite crucibles and the metal melts varied with the change of Al2O3 content in the crucible matrix. The pure Y2O3 crucible was the densest and its chemical stability was the highest. With the increase in Al2O3 content, the number of pores on the crucibles surface gradually increased and the interfacial reactions between the composite crucibles and the molten alloys became weaker. When the content of Al2O3 in composite crucibles increased from 3.5 wt % to 10.5 wt %, the thickness of the interface layer of melt-crucible decreased from 150 µm to 50 µm, and the equilibrium contact angles between metal and crucibles gradually decreased from 69.3° to 64.2° at 1873 K.

To obtain appropriate crucible materials for vacuum induction melting of MCrAlY alloys, four different oxide ceramics, including MgO, Y2O3, Al2O3, and ZrO2, with various microstructures were designed and characterized. The high-temperature wettability and interactions between Ni-20Co-20Cr-10Al-1.5Y alloys and oxide ceramics were studied by sessile drop experiments under vacuum. The results showed that all the systems exhibited non-wetting behavior. The contact angles were stable during the melting process of alloys and the equilibrium contact angles were 140° (MgO), 148° (Y2O3), 154° (Al2O3), and 157° (ZrO2), respectively. The interfacial reaction between the ceramic substrates and alloys occurred at high temperature. Though the ceramics had different microstructures, similar continuous Y2O3 reaction layer with thicknesses of about 25 μm at the alloy-ceramic interface in MgO, Al2O3, and ZrO2 systems formed. The average area percentage of oxides in the alloy matrices were 0.59% (MgO), 0.11% (Al2O3), 0.09% (ZrO2), and 0.02% (Y2O3), respectively. The alloys, after reacting with MgO ceramic, had the highest inclusion content, while those with the lowest content were in the Y2O3 system. Y2O3 ceramic was the most beneficial for vacuum induction melting of high-purity Y-containing Ni-based alloys.