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Diabetic nephropathy is a leading cause of end‐stage renal disease globally. The vital role of circular RNAs (circRNAs) has been reported in diabetic nephropathy progression, but the molecular mechanism linking diabetic nephropathy to circRNAs remains elusive. In this study, we investigated the significant function of circ‐AKT3/miR‐296‐3p/E‐cadherin regulatory network on the extracellular matrix accumulation in mesangial cells in diabetic nephropathy. The expression of circ‐AKT3 and fibrosis‐associated proteins, including fibronectin, collagen type I and collagen type IV, was assessed via RT‐PCR and Western blot analysis in diabetic nephropathy animal model and mouse mesangial SV40‐MES13 cells. Luciferase reporter assays were used to investigate interactions among E‐cadherin, circ‐AKT3 and miR‐296‐3p in mouse mesangial SV40‐MES13 cells. Cell apoptosis was evaluated via flow cytometry. The level of circ‐AKT3 was significantly lower in diabetic nephropathy mice model group and mouse mesangial SV40‐MES13 cells treated with high‐concentration (25 mmol/L) glucose. In addition, circ‐AKT3 overexpression inhibited the level of fibrosis‐associated protein, such as fibronectin, collagen type I and collagen type IV. Circ‐AKT3 overexpression also inhibited the apoptosis of mouse mesangial SV40‐MES13 cells treated with high glucose. Luciferase reporter assay and bioinformatics tools identified that circ‐AKT3 could act as a sponge of miR‐296‐3p and E‐cadherin was the miR‐296‐3p direct target. Moreover, circ‐AKT3/miR‐296‐3p/E‐cadherin modulated the extracellular matrix of mouse mesangial cells in high‐concentration (25 mmol/L) glucose, inhibiting the synthesis of related extracellular matrix protein. In conclusion, circ‐AKT3 inhibited the extracellular matrix accumulation in diabetic nephropathy mesangial cells through modulating miR‐296‐3p/E‐cadherin signals, which might offer novel potential opportunities for clinical diagnosis targets and therapeutic biomarkers for diabetic nephropathy.

Diabetic nephropathy (DN) is still on the rise worldwide, and millions of patients have to be treated through dialysis or transplant because of kidney failure caused by DN. Recent reports have highlighted circRNAs in the treatment of DN. Herein, we aimed to investigate the mechanism by which high glucose‐induced exo‐circ_0125310 promotes diabetic nephropathy progression. circ_0125310 is highly expressed in diabetic nephropathy and exosomes isolated from high glucose‐induced mesangial cells (MCs). High glucose‐induced exosomes promote the proliferation and fibrosis of MCs. However, results showed that the effects of exosomes on MCs can be reversed by the knockdown of circ_0125310. miR‐422a, which targets IGF1R, was the direct target of circ_0125310. circ_0125310 regulated IGF1R/p38 axis by sponging miR‐422a. Exo‐circ_0125310 increased the luciferase activity of the WT‐IGF1R reporter in the dual‐luciferase reporter gene assays and upregulated the expression level of IGF1R and p38. Finally, in vivo research indicated that the overexpression of circ_0125310 promoted the diabetic nephropathy progression. Above results demonstrated that the high glucose‐induced exo‐circ_0125310 promoted cell proliferation and fibrosis in diabetic nephropathy via sponging miR‐422a and targeting the IGF1R/p38 axis.

Diabetic nephropathy (DN) is a serious kidney disease resulted from diabetes. Dys‐regulated proliferation and extracellular matrix (ECM) accumulation in mesangial cells contribute to DN progression. In this study, we tested expression level of MIAT in DN patients and mesangial cells treated by high glucose (HG). Up‐regulation of MIAT was observed in DN. Then, functional assays displayed that silence of MIAT by siRNA significantly repressed the proliferation and cycle progression in mesangial cells induced by HG. Meanwhile, we found that collagen IV, fibronectin and TGF‐β1 protein expression was obviously triggered by HG, which could be rescued by loss of MIAT. Then, further assessment indicated that MIAT served as sponge harbouring miR‐147a. Moreover, miR‐147a was decreased in DN, which exhibited an antagonistic effect of MIAT on modulating mesangial cell proliferation and fibrosis. Moreover, bioinformatics analysis displayed that E2F transcription factor 3 (E2F3) could act as direct target of miR‐147a. We demonstrated that E2F3 was greatly increased in DN and the direct binding association between miR‐147a and E2F3 was evidenced using luciferase reporter assay. In summary, our data explored the underlying mechanism of DN pathogenesis validated that MIAT induced mesangial cell proliferation and fibrosis via sponging miR‐147a and regulating E2F3.

Aberrant variations in angiogenesis have been observed in tumor tissues with abnormal stiffness of extracellular matrix (ECM). However, it remains largely unclear how ECM stiffness influences tumor angiogenesis. Numerous studies have reported that vascular endothelial growth factor-A (VEGF-A) released from tumor cells plays crucial roles in angiogenesis. Hence, we demonstrated the role of ECM stiffness in VEGF-A release from neuroblastoma (NB) cells and the underlying mechanisms. Based on 17 NB clinical samples, a negative correlation was observed between the length of blood vessels and stiffness of NB tissues. In vitro, an ECM stiffness of 30 kPa repressed the secretion of VEGF165 from NB cells which subsequently inhibited the tube formation of human umbilical vein endothelial cells (HUVECs). Knocked down VEGF165 in NB cells or blocked VEGF165 with neutralizing antibodies both repressed the tube formation of HUVECs. Specifically, 30 kPa ECM stiffness repressed the expression and nuclear accumulation of Yes-associated protein (YAP) to regulate the expression of Serine/Arginine Splicing Factor 1 (SRSF1) via Runt-related transcription factor 2 (RUNX2), which may then subsequently induce the expression and secretion of VEGF165 in NB tumor cells. Through implantation of 3D col-Tgels with different stiffness into nude mice, the inhibitory effect of 30 kPa on NB angiogenesis was confirmed in vivo. Furthermore, we found that the inhibitory effect of 30 kPa stiffness on NB angiogenesis was reversed by YAP overexpression, suggesting the important role of YAP in NB angiogenesis regulated by ECM stiffness. Overall, our work not only showed a regulatory effect of ECM stiffness on NB angiogenesis, but also revealed a new signaling axis, YAP-RUNX2-SRSF1, that mediates angiogenesis by regulating the expression and secretion of VEGF165 from NB cells. ECM stiffness and the potential molecules revealed in the present study may be new therapeutic targets for NB angiogenesis.

Large-scale omics datasets from tumor samples are becoming ever easier to generate and analyze. As technology continues to push forward, how can this data be leveraged to help patients in the clinic?Large-scale omics datasets from tumor samples are becoming ever easier to generate and analyze. As technology continues to push forward, how can this data be leveraged to help patients in the clinic?

Senior housing with age-friendly design and elderly care services contributes to the health and well-being of older people. Previous research has evidenced that the immediate environment factors of senior housing, such as the design of housing features and facilities, have a direct bearing on the satisfaction and quality of life of older people. However, external environment factors, such as political, economic, and social ones that affect key stakeholders’ behaviors in senior housing development, are relatively under-researched. Accordingly, this study aimed to explore the external environmental factors influencing the development of senior housing. Taking Hong Kong as case study, this study first commenced with a systematic review to identify the factors in political, economic, and social domains from global evidence. Following this, we interviewed local experts from academia, industry, and government to solicit their opinions on the relative importance of these factors. We then determined the factor rankings using the analytical hierarchy process method. The results showed that local experts perceived economic factors as the most critical ones in influencing senior housing development in Hong Kong, including land costs, funding from financial institutions, and government incentives. If policymakers tend to promote senior housing in densely populated cities like Hong Kong, the policies should be attractive for housing developers, such as land premium concessions and innovative financial channels for supporting the long-term development of senior housing.

An accurate reconstruction of Sino-Tibetan language evolution would greatly advance our understanding of East Asian population history. Two recent phylogenetic studies attempted to do so but several of their conclusions are different from each other. Here we reconstruct the phylogeny of the Sino-Tibetan language family, using Bayesian computational methods applied to a larger and linguistically more diverse sample. Our results confirm previous work in finding that the ancestral Sino-Tibetans first split into Sinitic and Tibeto-Burman clades, and support the existence of key internal relationships. But we find that the initial divergence of this group occurred earlier than previously suggested, at approximately 8000 years before the present, coinciding with the onset of millet-based agriculture and significant environmental changes in the Yellow River region. Our findings illustrate that key aspects of phylogenetic history can be replicated in this complex language family, and calls for a more nuanced understanding of the first Sino-Tibetan speakers in relation to the “early farming dispersal” theory of language evolution.

Chirality is an indispensable integral of biological system. As an important part of organisms, chiral organic structure of bone has been extensively investigated. However, the chirality of bone minerals is unclear and not fully determined. Here, we report nine levels of fractal-like chirality of bone minerals by combining electron microscopic and spectrometric characterizations. The primary helically twisted acicular apatite crystals inside collagen fibrils and between fibrils merge laterally to form secondary helical subplatelets. The chiral arrangement of several subplatelets forms tertiary spiral mineral platelets. Further coherent stepwise stacking of mineral platelets with collagen fibrils leads to quaternary to ninth levels, which reconciled the previous conflicting models. The optical activities in the UV-visible, infrared and terahertz regions demonstrated chirality from atomic to macroscopic scales based on circularly selective absorption and Bragg resonance at different levels of chirality. Our findings provide new insight into the structural integrity of bone, osteology, forensic medicine and archaeology and inspire the design of novel biomaterials.

There is currently a pandemic of pseudorabies virus (PRV) variant strains in China. Despite extensive research on PRV variant strains in the past two years, few studies have investigated PRV pathogenicity-related genes. To determine which gene(s) is/are linked to PRV virulence, ten putative virulence genes were knocked out using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 technology. The pathogenicity of these mutants was evaluated in a mouse model. Our results demonstrated that of the ten tested genes, the thymidine kinase (TK) and glycoprotein M (gM) knockout mutants displayed significantly reduced virulence. However, mutants of other putative virulence genes, such as glycoprotein E (gE), glycoprotein I (gI), Us2, Us9, Us3, glycoprotein G (gG), glycoprotein N (gN) and early protein 0 (EP0), did not exhibit significantly reduced virulence compared to that of the wild-type PRV. To our knowledge, this study is the first to compare virulence genes from the current pandemic PRV variant strain. This study will provide a valuable reference for scientists to design effective live attenuated vaccines in the future.

Remanufacturing in reverse logistics can not only support sustainable development but also provide a tractable way to achieve carbon neutrality. This study evaluates whether an original equipment manufacturer (OEM) should remanufacture outsource or authorize this reverse channel activity in the presence of government subsidies. Additionally, the model considers the equilibrium acquisition quantities, collection rates, prices, and effects of government subsidy under three reverse channel options: centralizing remanufacturing, outsourcing remanufacturing, and authorization remanufacturing. The analysis indicates that (i) a centralized approach with manufacturing and remanufacturing operations under a fixed government subsidy is always in the interest of the supply chain; (ii) that for the profit-maximizing third-party remanufacturer (3PR), the differentials in variable collection costs drive the strategy choice, and that a higher fixed scaling parameter of the collection cost favors outsourcing; and (iii) when the government aspires to reduce environmental effects and subsidy payments, the OEM and government have different reverse channel choice preferences. Surprisingly, profitability and environmental goals align under a high consumer acceptance of the remanufactured product. This paper extends the understanding of the remanufacturing strategy of an OEM and provides new insights on which reverse channel is optimal.