Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential.

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.

Sequentially Processed Bulk-Heterojunction-Buried Structure for Efficient Organic Solar Cells with 500 nm Thickness.

Large-area printing fabrication is a distinctive feature of organic solar cells (OSCs). However, the advance of upscalable fabrication is challenged by the thickness of organic active layers considering the importance of both exciton dissociation and charge collection. In this work, a bulk-heterojunction-buried (buried-BHJ) structure is introduced by sequential deposition to realize efficient exciton dissociation and charge collection, thereby contributing to efficient OSCs with 500 nm thick active layers. The buried-BHJ distributes donor and acceptor phases in the vertical direction as charge transport channels, while numerous BHJ interfaces are buried in each phase to facilitate exciton dissociation simultaneously. It is found that buried-BHJ configurations possess efficient exciton dissociation and rapid charge transport, resulting in reduced recombination losses. In comparison with traditional structures, the buried-BHJ structure displays a decent tolerance to film thickness. In particular, a power conversion efficiency of 16.0% is achieved with active layers at a thickness of 500 nm. To the best of the authors' knowledge, this represents the champion efficiency of thick film OSCs.

E. hellem Ser/Thr protein phosphatase PP1 targets the DC MAPK pathway and impairs immune functions.

Microsporidia are difficult to be completely eliminated once infected, and the persistence disrupts host cell functions. Here in this study, we aimed to elucidate the impairing effects and consequences of microsporidia on host DCs. Enterocytozoon hellem, one of the most commonly diagnosed zoonotic microsporidia species, was applied. In vivo models demonstrated that E. hellem-infected mice were more susceptible to further pathogenic challenges, and DCs were identified as the most affected groups of cells. In vitro assays revealed that E. hellem infection impaired DCs' immune functions, reflected by down-regulated cytokine expressions, lower extent of maturation, phagocytosis ability, and antigen presentations. E. hellem infection also detained DCs' potencies to prime and stimulate T cells; therefore, host immunities were disrupted. We found that E. hellem Ser/Thr protein phosphatase PP1 directly interacts with host p38α (MAPK14) to manipulate the p38α(MAPK14)/NFAT5 axis of the MAPK pathway. Our study is the first to elucidate the molecular mechanisms of the impairing effects of microsporidia on host DCs' immune functions. The emergence of microsporidiosis may be of great threat to public health.

Halogenated Nonfused Ring Electron Acceptor for Organic Solar Cells with a Record Efficiency of over 17.

Three nonfused ring electron acceptors (NFREAs), namely, 3TT-C2-F, 3TT-C2-Cl, and 3TT-C2, are purposefully designed and synthesized with the concept of halogenation. The incorporation of F or/and Cl atoms into the molecular structure (3TT-C2-F and 3TT-C2-Cl) enhances the π-π stacking, improves electron mobility, and regulates the nanofiber morphology of blend films, thus facilitating the exciton dissociation and charge transport. In particular, blend films based on D18:3TT-C2-F demonstrate a high charge mobility, an extended exciton diffusion distance, and a well-formed nanofiber network. These factors contribute to devices with a remarkable power conversion efficiency of 17.19%, surpassing that of 3TT-C2-Cl (16.17%) and 3TT-C2 (15.42%). To the best of knowledge, this represents the highest efficiency achieved in NFREA-based devices up to now. These results highlight the potential of halogenation in NFREAs as a promising approach to enhance the performance of organic solar cells.

Harnessing multiplex crRNA enables an amplification-free/CRISPR-Cas12a-based diagnostic methodology for Nosema bombycis.

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.

Microsporidia persistence in host impairs epithelial barriers and increases chances of inflammatory bowel disease.

Microsporidia 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.

A bimolecular modification strategy for developing long-lasting bone anabolic aptamer.

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.

Chemically modified aptamers for improving binding affinity to the target proteins via enhanced non-covalent bonding.

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.

Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating protein: The present and the future.

Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (<20 kDa) is lower than the renal filtration threshold (30∼50 kDa), resulting in very short half-lives in vivo, which limit their druggability. The development of long-lasting modification approaches for aptamers can help address the druggability bottleneck of aptamers. This review summarized two distinct kinds of long-lasting modification approaches for aptamers, including macromolecular modification and low-molecular-weight modification. Though it is a current approach to extend the half-life of aptamers, the macromolecular modification approach could limit the space for the dosage increases, thus causing potential compliance concerns due to large molecular weight. As for the other modification approach, the low-molecular-weight modification approach, which uses low molecular weight coupling agents (LMWCAs) to modify aptamers, could greatly increase the proportion of aptamer moiety. However, some LMWCAs could bind to other proteins, causing a decrease in the drug amounts in blood circulation. Given these issues, the outlook for the next generation of long-lasting modification approaches was proposed at the end, including improving the administration method to increase dosage for aptamer drugs modified by macromolecule and developing Artificial intelligence (AI)-based strategies for optimization of LMWCAs.

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin's protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE-/- mice and hSOSTki.ApoE-/- mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOSTki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.

High-resolution computed tomography (HRCT) analysis in anti-synthase antibody syndrome with organizing pneumonia

Objective: The organizing pneumonia (OP) pattern is the second most common finding in anti-synthase antibody syndrome (ASS), and nonspecific interstitial pneumonia (NSIP) is the most common finding. This study analysed the OP score changes by semiquantitative and quantitative analysis methods and the correlation between the high-resolution computed tomography (HRCT) indexes and the pulmonary function test parameters (PFTs) in ASS patients.MethodsData from ASS-OP patients admitted to the respiratory department of Ping Jin Hospital from October 2014 to June 2020 were retrospectively reviewed and analysed.ResultsFourteen ASS-OP patients were recruited for this study. (1) In method-1, the consolidation (CO) score and the mean lung attenuation (MA) of poorly aerated and fibrosis lung fields (MAfibrosis) (r=0.56, P=0.04), the ground-glass opacity (GGO) score and the MA of non-aerated lung fields (MAnonaerated) (r=−0.64, P=0.01), and the CO plus the GGO (CG) score and the MAnonaerated (r=−0.59, P=0.03) of the lung fields had liner correlations. In method-2, the GGO score to the MAnonaerated (r=−0.58, P=0.03), and the CG (r=−0.68, P=0.01) score to the MAnonaerated had liner correlations. The FVC% (r=0.68, P=0.01) and FEV1% (r=0.64, P=0.01) to the MAfibrosis had good linear correlations. (2) Compared to the values before treatment, the CO pattern score, volume and weight percentages of the extracted whole lung volume with attenuation values of the nonaerated area (Vnonated%, Wnonaerated%), the volume of poorly aerated and fibrosis lung tissue (Vfibrosis%, Wfibrosis%), the weight percentages of normal aerated lung (Wnormal%), and the MAfibrosis exhibited significant differences during the 3–6 month follow-up period. (AU)

Objetivo: El patrón de neumonía organizada (PNO) es el segundo hallazgo más común en el síndrome de anticuerpos antisintasa (SAA), y la neumonía intersticial inespecífica es el hallazgo más común. Este estudio analizó los cambios en la puntuación de PNO mediante métodos de análisis semicuantitativos y cuantitativos, y la correlación entre los índices de la tomografía computarizada de alta resolución y los parámetros de las pruebas de función pulmonar en pacientes con SAA.MétodosSe revisaron y analizaron retrospectivamente los datos de los pacientes SAA-PNO ingresados en el departamento respiratorio del Hospital Ping Jin desde octubre de 2014 hasta junio de 2020.ResultadosSe reclutaron 14 pacientes SAA-PNO para este estudio. (1) En el método 1, la puntuación de consolidación (PC) y la atenuación pulmonar media (APM) de los campos pulmonares mal aireados y fibrosis (APMfibrosis) (r=0,56; p=0,04), la puntuación de la opacidad del vidrio molido (OVM) y la PC de los campos pulmonares no aireados (APMnoaireado) (r=−0,64; p =0,01), y la PC más la puntuación OVM (PV) y el APMnoaireado de los campos pulmonares tenían correlaciones de revestimiento. En el método 2, la puntuación de OVM para el APMnoaireado (r=−0,58; p =0,03) y la puntuación de PV (r=−0,68; p=0,01) para el APMnoaireado tenían correlaciones de revestimiento. El FVC% (r=0,68; p =0,01) y el FEV1% (r=0,64; p =0,01) a la APMfibrosis tuvieron buenas correlaciones lineales. (2) En comparación con los valores anteriores al tratamiento, la puntuación del patrón de PC, los porcentajes de volumen y peso del volumen pulmonar total extraído con los valores de atenuación del área no aireada (Vnoaireado%, Pnoaireado%), el volumen de tejido pulmonar poco aireado y fibroso (Vfibrosis%, Pfibrosis%), los porcentajes de peso del pulmón aireado normal (Pnormal%) y la APMfibrosis mostraron diferencias significativas durante el período de seguimiento de 3 a 6 meses. (AU)

High-resolution computed tomography (HRCT) analysis in anti-synthase antibody syndrome with organizing pneumonia.

OBJECTIVE: The organizing pneumonia (OP) pattern is the second most common finding in anti-synthase antibody syndrome (ASS), and nonspecific interstitial pneumonia (NSIP) is the most common finding. This study analysed the OP score changes by semiquantitative and quantitative analysis methods and the correlation between the high-resolution computed tomography (HRCT) indexes and the pulmonary function test parameters (PFTs) in ASS patients. METHODS: Data from ASS-OP patients admitted to the respiratory department of Ping Jin Hospital from October 2014 to June 2020 were retrospectively reviewed and analysed. RESULTS: Fourteen ASS-OP patients were recruited for this study. (1) In method-1, the consolidation (CO) score and the mean lung attenuation (MA) of poorly aerated and fibrosis lung fields (MAfibrosis) (r=0.56, P=0.04), the ground-glass opacity (GGO) score and the MA of non-aerated lung fields (MAnonaerated) (r=-0.64, P=0.01), and the CO plus the GGO (CG) score and the MAnonaerated (r=-0.59, P=0.03) of the lung fields had liner correlations. In method-2, the GGO score to the MAnonaerated (r=-0.58, P=0.03), and the CG (r=-0.68, P=0.01) score to the MAnonaerated had liner correlations. The FVC% (r=0.68, P=0.01) and FEV1% (r=0.64, P=0.01) to the MAfibrosis had good linear correlations. (2) Compared to the values before treatment, the CO pattern score, volume and weight percentages of the extracted whole lung volume with attenuation values of the nonaerated area (Vnonated%, Wnonaerated%), the volume of poorly aerated and fibrosis lung tissue (Vfibrosis%, Wfibrosis%), the weight percentages of normal aerated lung (Wnormal%), and the MAfibrosis exhibited significant differences during the 3-6 month follow-up period. CONCLUSION: The GGO and CO scored by the semiquantitative or quantitative analysis methods was similar. The HRCT quantitative analysis parameters showed a good correlation with the PFTs in ASS-OP patients, can provide an accurate OP pattern interpretation, and may be used as a monitoring and therapeutic indicator for ASS-OP patients.

Understanding parental self-medication with antibiotics among parents of different nationalities: a cross-sectional study.

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.

Exosomal transfer of osteoclast-derived miRNAs to chondrocytes contributes to osteoarthritis progression.

Osteoarthritis (OA) is a prevalent aging-related joint disease lacking disease-modifying therapies. Here, we identified an upregulation of circulating exosomal osteoclast (OC)-derived microRNAs (OC-miRNAs) during the progression of surgery-induced OA in mice. We found that reducing OC-miRNAs by Cre-mediated excision of the key miRNA-processing enzyme Dicer or blocking the secretion of OC-originated exosomes by short interfering RNA-mediated silencing of Rab27a substantially delayed the progression of surgery-induced OA in mice. Mechanistically, the exosomal transfer of OC-miRNAs to chondrocytes reduced the resistance of cartilage to matrix degeneration, osteochondral angiogenesis and sensory innervation during OA progression by suppressing tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3. Furthermore, systemic administration of a new OC-targeted exosome inhibitor (OCExoInhib) blunted the progression of surgery-induced OA in mice. We suggest that targeting the exosomal transfer of OC-miRNAs to chondrocytes represents a potential therapeutic avenue to tackle OA progression.

Advances in the discovery of exosome inhibitors in cancer.

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.

Author Correction: HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.

Quantitative Relationship Analysis of Mechanical Properties with Mg Content and Heat Treatment Parameters in Al⁻7Si Alloys Using Artificial Neural Network.

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.

Behavior and Mechanism of High-Temperature Stability between Tial-Based Alloy and Y2O3-Al2O3 Composite Crucibles.

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.