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Abstract Background Emerging evidence has highlighted the therapeutic potential of human umbilical cord mesenchymal stem cells (UC-MSCs) in chemotherapy-induced premature ovarian failure (POF). This study was designed to investigate the appropriate timing and molecular mechanism of UC-MSCs treatment for chemotherapy-induced POF. Methods Ovarian structure and function of mice were assessed every 3 days after injections with cyclophosphamide (CTX) and busulfan (BUS). UC-MSCs and UC-MSCs-derived extracellular vesicles (EVs) were infused into mice via the tail vein, respectively. Ovarian function was analyzed by follicle counts, the serum levels of hormones and ovarian morphology. The apoptosis and proliferation of ovarian granulosa cells were analyzed in vitro and in vivo. Label-free quantitative proteomics was used to detect the differentially expressed proteins in UC-MSC-derived EVs. Results After CTX/BUS injection, we observed that the ovarian function of POF mice was significantly deteriorated on day 9 after CTX/BUS infusion. TUNEL assay indicated that the number of apoptotic cells in the ovaries of POF mice was significantly higher than that in normal mice on day 3 after CTX/BUS injection. Transplantation of UC-MSCs on day 6 after CTX/BUS injection significantly improved ovarian function, enhanced proliferation and inhibited apoptosis of ovarian granulosa cells, whereas the therapeutic effect of UC-MSCs transplantation decreased on day 9, or day 12 after CTX/BUS injection. Moreover, EVs derived from UC-MSCs exerted similar therapeutic effects on POF. UC-MSCs-derived EVs could activate the PI3K/AKT signaling pathway and reduce ovarian granulosa cell apoptosis. Quantitative proteomics analysis revealed that clusterin (CLU) was highly expressed in the EVs of UC-MSCs. The supplementation of CLU proteins prevented ovarian granulosa cells from chemotherapy-induced apoptosis. Further mechanistic analysis showed that CLU-knockdown blocked the PI3K/AKT signaling and reversed the protective effects of UC-MSCs-derived EVs. Conclusions Administration of UC-MSCs and UC-MSCs-derived EVs on day 6 of CTX/BUS injection could effectively improve the ovarian function of POF mice. UC-MSCs-derived EVs carrying CLU promoted proliferation and inhibited apoptosis of ovarian granulosa cells through activating the PI3K/AKT pathway. This study identifies a previously unrecognized molecular mechanism of UC-MSCs-mediated protective effects on POF, which pave the way for the use of cell-free therapeutic approach for POF. Graphical Abstract

Abstract Current studies have mainly focused on the effect of specific steel fibers on the shear performance of steel fiber-reinforced concrete (SFRC) slender beams. However, there has been a lack of in-depth research evaluating the effectiveness of different steel fibers through a statistically comparative analysis of experimental data from various researchers. Existing design methods do not fully account for the impact of all types of steel fibers on the shear capacity of SFRC slender beams, providing very limited guidance on selecting appropriate steel fibers. This highlights the need for research to verify the strengthening effectiveness of different steel fibers. This paper establishes databases comprising 232 shear-failed reinforced SFRC beams with four other types of steel fibers straight wire, deformed wire, deformed cut-sheet and ingot mill, based on a comprehensive review of published literature. These databases complement an existing database of 280 reinforced SFRC beams using hook-end wire steel fibers as shear reinforcement. The databases are used to evaluate the validity of several well-known existing formulas for predicting the shear capacity of beams and to determine the fiber bond factor values that reflect the diverse strengthening effects of different steel fibers. Utilizing a simi-empirical synergetic prediction model for the shear strength of reinforced SFRC slender beams with hook-end wire steel fibers, the shear resistances of test beams in databases with the other four types of steel fiber are analyzed. The primary contributors to shear capacity are identified as the uncracked shear-compression SFRC and the dowel action of longitudinal tensile steel bars. The contribution of steel fibers is linked to the shear resistance of uncracked shear-compression SFRC. From a practical design perspective, a conservative prediction formula is verified, aligning with the lower boundary of the tested shear strength obtained from the database of beams. Finally, suitable steel fibers for s enhancing the shear strength of reinforced SFRC beams without web rebars are suggested based on their effectiveness.

Abstract Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.

Abstract Present studies show that steel fibres can improve the bond of steel bar in steel fibre reinforced concrete (SFRC) with a correlation to the fibre factor and the fibre distribution uniformity. As a foundation of high-flowability SFRC working together with 400 MPa grade hot-rolled ribbed (HRB400) steel bar in reinforced structures, the bond between them was evaluated through a series of pull-out testing on 48 specimens with a central arranged steel bar. The bond behaviours of steel bar were estimated with a constant bond length of 5d (d is the diameter of steel bar) embedded in high-flowability SFRC, the main research parameters included the ingot mill steel fibres with a fibre volume fraction varied from 0.8 to 2.0%, the strength grade C40 and C50 of SFRC or referenced conventional concrete, and the diameter of steel bars varied from 14 to 20 mm. Results showed that the high-flowability SFRC compacted with a slight vibration is beneficial to improve the bond failure pattern since steel fibres effectively eliminate the crack appeared on the SFRC blocks during the pulling out of steel bar, leading to all specimens failed with the steel bar pull out of SFRC blocks. The bond strength was dominant by the SFRC strength, and obviously strengthened with the increase of fibre volume fraction, while the peak-slip was slightly influenced by the diameter of steel bar. By conducting analyses of test data, equations for calculating the bond strength and the peak-slip are proposed accounting for the effect of steel fibres. Then the predicting method for the anchorage length is suggested linking with different design codes for concrete structures. Compared with test results of this study, a little shorter anchorage length of steel bar in SFRC is obtained from the specification of Chinese code JGJ/T46, which should be noticed to ensure a rational anchorage of ribbed steel bar in SFRC with ingot mill steel fibres.

Abstract Tuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients. Schematic illustration of macrophage TSC1-mediated AKT/MST1/NRF2 signaling pathway in I/R-triggered liver inflammation. Macrophage TSC1 can be activated in I/R-stressed livers. TSC1 activation promotes phosphorylation of AKT and MST1, which in turn increases NRF2 expression and inhibits ROS production and TLR4/NF-κB activation, resulting in reduced hepatocellular apoptosis in I/R-triggered liver injury.

The traditional Harris Hawks optimization algorithm is prone to the local shortest path, slow search speed and poor path accuracy in indoor mobile robot path planning. For the above problems, a multi-strategy improvement of the Harris Hawks optimization algorithm (MIHHO) is proposed. In this study, a Chebyshev chaotic mapping strategy is used to increase the diversity of the Harris Hawk population, improve the global search performance of the Harris Hawk algorithm, and prevent being trapped in the locally optimal path. A fusion exploration mechanism is proposed to fuse the discovery mechanism of the sparrow algorithm with the exploration mechanism of the HHO. Then the influence factor E is improved to improve the algorithm’s search accuracy and search efficiency, and finally, in the design of a dynamic Lévy flight strategy, which accelerates the convergence speed of the algorithm and improves the robot planning speed. Simulation results show that the proposed MIHHO method exhibits better search performance in path planning, improved planning efficiency, and superior quality of planned paths.

Dolomite dust waste (DDW) has the potential to be used as an expansive agent for mortar due to its richness in magnesium and calcium. This paper reports the possibility of developing low-cost expansive agent for mortar using DDW through various activation methods. The changes in the physicochemical properties of the activated DDW and the shrinkage resistance, flexural strength, and compressive strength of the composite mortar prepared by partially replacing cement were systematically investigated. The hydration products and microstructure of DDW-composite mortar were investigated by XRD and SEM-EDS techniques. This study confirmed the feasibility of activated DDW as mortar expansion agents and the necessity of activation treatment for the resourceful use of DDW. The results showed that the activation treatment enhanced the activity of DDW, and the higher hydration reactivity significantly improved the shrinkage resistance and mechanical properties of composite mortar compared to raw DDW. The addition of 10% C800 DDW (thermal at 800 °C) showed a full-age compensatory effect on the volume shrinkage of the mortar. Substituting cement partially with 10% C900 DDW (thermal at 900 °C), the volume expansion rate of composite mortar after 28 d of standard curing exhibited 24.49% higher than normal, and its compressive strength (40.1 MPa) at 60 d exceeded 6.40% than normal mortar (37.7 MPa). The drying shrinkage of G30-10 (mechanically activated) and A0.1-10 (chemically activated) at 60 d resulted in 6.23% and 5.19% lower than normal mortar, respectively. Microanalysis revealed that the addition of DDW promoted the generation of C-M-S-H gels. The findings are instructive for the preparation of green and low-cost mortar expanders using DDW.

Background & Aims: Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive activation of liver macrophages are not completely understood. The Notch and Hippo-YAP signaling pathways have been implicated in immune homeostasis. In this study, we investigated the interactive cell signaling networks of Notch1/YAP pathway during acute liver injury. Methods: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to lipopolysaccharide/D-galactosamine toxicity. Some mice were injected via the tail vein with bone marrow–derived macrophages transfected with lentivirus-expressing YAP. Some mice were injected with YAP siRNA using an in vivo mannose-mediated delivery system. Results: We found that the activated Notch1 and YAP signaling in liver macrophages were closely related to lipopolysaccharide/D-galactosamine-induced acute liver injury. Macrophage/neutrophil infiltration, proinflammatory mediators, and hepatocellular apoptosis were markedly ameliorated in Notch1M-KO mice. Importantly, myeloid Notch1 deficiency depressed YAP signaling and facilitated M2 macrophage polarization in the injured liver. Furthermore, YAP overexpression in Notch1M-KO livers exacerbated liver damage and shifted macrophage polarization toward the M1 phenotype. Mechanistically, macrophage Notch1 signaling could transcriptionally activate YAP gene expression. Reciprocally, YAP transcriptionally upregulated the Notch ligand Jagged1 gene expression and was essential for Notch1-mediated macrophage polarization. Finally, dual inhibition of Notch1 and YAP in macrophages further promoted M2 polarization and alleviated liver damage. Conclusions: Our findings underscore a novel molecular insight into the Notch1-YAP circuit for controlling macrophage polarization in acute liver injury, raising the possibility of targeting macrophage Notch1-YAP circuit as an effective strategy for liver inflammation–related diseases.

Natural ecological protection changes the traditional practice for concrete production which faces a situation of the source exhaustion of natural materials, and the sufficient utilization of waste local materials becomes a strategy to reduce the carbon emission in infrastructure construction. This promotes a possible economic production of concrete with mixed-sand composited by coarse manufactured-sand and super-fine river-sand. Due to lack of study on the mixed-sand used for pumping concrete, an experimental study was carried out in this paper. The proportion of super-fine river-sand and manufactured-sand was determined at a target fineness modulus with a gradation in zone-II, the sand ratio of concrete was determined by the closed packing test of aggregates. Twelve mix proportions of mixed-sand concrete were designed by the absolute volume method, considering the content of super-fine river-sand and the sand ratio. The target cubic compressive strength of mixed-sand concrete was 48.2 MPa, while the target pumpability aimed at pumping height of 300 m. The pumpability of fresh mixed-sand concrete was evaluated by multi-indices including slump, slump flow, static segregation rate, pressure bleeding rate and air content, and explained by the rheological property including the indices of yield stress and plastic viscosity. The mechanical property was evaluated by the cubic and axial compressive strengths, the modulus of elasticity and the splitting tensile strength at curing age from 7 days to 56 days. Based on the test results, the absolute volume method for mix proportion design of mixed-sand concrete is rational to keep a consistent unit weight of fresh concrete, the optimal content of super-fine river-sand in mixed-sand is 25%− 35% with a rational sand ratio of 45%− 51%. The developments of compressive strength and tensile strength of mixed-sand concrete are identical to those of conventional concrete. The mixed-sand concrete presents the same relationships to the conventional concrete for the axial compressive strength, the splitting tensile strength and the modulus of elasticity with the cubic compressive strength. However, the splitting tensile strength of mixed-sand concrete is about 90% that of conventional concrete at the same strength grade. Further studies can be conducted to improve the flowability by adjusting superplasticizer and to enhance the tensile strength of mixed-sand concrete.

Abstract Background Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response. Methods Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry. Results MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity. Conclusions Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases.

Background and Aims: The immune-inflammatory cascade and pyroptosis play an important role in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). The maintenance of immune homeostasis is inextricably linked to the Notch signaling pathway, but whether myeloid Notch1 affects microglia polarization as well as neuronal pyroptosis in CIRI is not fully understood. This study was designed to clarify the role of myeloid Notch1 in CIRI, providing new therapeutic strategies for ischemic stroke. Methods and Results: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to middle cerebral artery occlusion (MCAO). After 3 days of CIRI, we evaluated the neurological deficit score and cerebral infarction volume. Immunofluorescence staining was used to detect the expression of Notch1 and microglial subtype markers. Cerebral infiltrating macrophages were detected by flow cytometry. RT-qPCR was used to detect pro-inflammatory cytokines. Western blot was used to detect the expression of pyroptosis related proteins. The Notch1-siRNA transfected BV2 cells were co-cultured with HT22 cells to investigate the potential mechanisms by which microglial Notch1 affects neuronal pyroptosis induced by anoxia/reoxygenation in vitro. We found that Notch1 was activated in cerebral microglia/macrophages after CIRI. Myeloid Notch1 deficiency decreased the cerebral infarct volume (24.17 ± 3.29 vs. 36.17 ± 2.27, p < 0.001), neurological function scores (2.33 ± 0.47 vs. 3.17 ± 0.37, p < 0.001) and the infiltration of peripheral monocytes/macrophages (3.26 ± 0.53 vs. 5.67 ± 0.57, p < 0.01). Strikingly, myeloid-specific Notch1 knockout alleviated pyroptosis. Compared with microglia M1, increased microglia M2 were detected in the ischemic penumbra. In parallel in vitro co-culture experiments, we found that Notch1 knockdown in microglial BV2 cells inhibited anoxia/reoxygenation-induced JAK2/STAT3 activation and pyroptosis in hippocampal neuron HT22 cells. Conclusions: Our findings elucidate the underlying mechanism of the myeloid Notch1 signaling pathway in regulating neuronal pyroptosis in CIRI, suggesting that targeting myeloid-specific Notch1 is an effective strategy for the treatment of ischemic stroke.

To promote the efficient utilization of bulk solid wastes, including superfine river sand and fly ash, high-flowing steel-fiber-reinforced mixed-sand concrete (SFRMC) was developed in this study. Superfine river sand and coarse manufactured sand were mixed in a proportion of 4:6 to make the mixed sand. Fly ash, with a content of 30~75%, was blended with 0~12% silica fume on the premise of equivalent activity. The water dosage and sand ratio were adjusted with the volume fraction of steel fiber, which varied from 0.4 to 1.6%, to ensure the high flowability of fresh SFRMC. The mechanical properties, including cubic and axial compressive strengths, modulus of elasticity, splitting tensile strength, and flexural strength and toughness of the SFRMC, were analyzed, accounting for the influences of the contents of fly ash and steel fiber. The predictive formulas for the splitting tensile strength, modulus of elasticity, and flexural strength were proposed by introducing the influencing factors of steel fiber. The SFRMC showed an increased modulus of elasticity with increases in the steel fiber factor, and flexural toughness was enhanced with increased contents of both steel fiber and fly ash.

To ensure a limited washout loss rate and the self-compaction of underwater concrete, the mix proportion design of underwater non-dispersible concrete is a key technology that has not been completely mastered. In view of this aspect, an orthogonal test study was carried out in this paper on the workability, washout resistance, and compressive strength of underwater non-dispersible concrete. Six factors with five levels were considered, which included the water/binder ratio, the sand ratio, the maximum particle size of the coarse aggregate, the content of the dispersion resistance agent, the content of superplasticizer, and the dosage of fly ash. Using a range and variance analysis, the sensitivity and significance of these factors were analyzed on the slump and slump-flow, the flow time, the washout loss rate, the pH value, and the compressive strength at the curing ages of 7 days and 28 days. The results indicated that the water/binder ratio and the content of the dispersion resistance agent were strong in terms of their sensitivity and significance on the workability and washout resistance, and the water/binder ratio and the dosage of fly ash were strong in terms of their sensitivity and significance on the compressive strength. With the joint fitness of the test results, formulas for predicting the slump-flow, washout loss rate, and compressive strength of underwater non-dispersible concrete were proposed considering the main impact factors.

Abstract Background Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and a common cause of end-stage renal disease (ESRD). Mesenchymal stem cells (MSCs) possess potent anti-inflammatory and immunomodulatory properties, which render them an attractive therapeutic tool for tissue damage and inflammation. Methods This study was designed to determine the protective effects and underlying mechanisms of human umbilical cord-derived MSCs (UC-MSCs) on streptozotocin-induced DN. Renal function and histological staining were used to evaluate kidney damage. RNA high-throughput sequencing on rat kidney and UCMSC-derived exosomes was used to identify the critical miRNAs. Co-cultivation of macrophage cell lines and UC-MSCs-derived conditional medium were used to assess the involvement of macrophage polarization signaling. Results UC-MSC administration significantly improved renal function, reduced the local and systemic inflammatory cytokine levels, and attenuated inflammatory cell infiltration into the kidney tissue in DN rats. Moreover, UC-MSCs shifted macrophage polarization from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. Mechanistically, miR-146a-5p was significantly downregulated and negatively correlated with renal injury in DN rats as determined through high-throughput RNA sequencing. Importantly, UC-MSCs-derived miR-146a-5p promoted M2 macrophage polarization by inhibiting tumor necrosis factor receptor-associated factor-6 (TRAF6)/signal transducer and activator of transcription (STAT1) signaling pathway. Furthermore, miR-146a-5p modification in UC-MSCs enhanced the efficacy of anti-inflammation and renal function improvement. Conclusions Collectively, our findings demonstrate that UC-MSCs-derived miR-146a-5p have the potential to restore renal function in DN rats through facilitating M2 macrophage polarization by targeting TRAF6. This would pave the way for the use of miRNA-modified cell therapy for kidney diseases.

Diabetic nephropathy (DN) is one of the microvascular complications of diabetes. Recent studies suggest that the pyroptosis of renal tubular epithelial cell plays a critical role in DN. Currently, effective therapeutic strategies to counteract and reverse the progression of DN are lacking. Mesenchymal stem cells (MSCs) represent an attractive therapeutic tool for tissue damage and inflammation owing to their unique immunomodulatory properties. However, the underlying mechanisms remain largely unknown. In the present study, we found that human umbilical cord MSCs (UC-MSCs) can effectively ameliorate kidney damage and reduce inflammation in DN rats. Importantly, UC-MSC treatment inhibits inflammasome-mediated pyroptosis in DN. Mechanistically, we performed RNA sequencing and identified that miR-342-3p was significantly downregulated in the kidneys of DN rats. Furthermore, we found that miR-342-3p was negatively correlated with renal injury and pyroptosis in DN rats. The expression of miR-342-3p was significantly increased after UC-MSC treatment. Moreover, miR-342-3p decreased the expression of Caspase1 by targeting its 3′-UTR, which was confirmed by double-luciferase assay. Using miRNA mimic transfection, we demonstrated that UC-MSC-derived miR-342-3p inhibited pyroptosis of renal tubular epithelial cells through targeting the NLRP3/Caspase1 pathway. These findings would provide a novel intervention strategy for the use of miRNA-modified cell therapy for kidney diseases.

With the success of several clinical trials of products based on human serum albumin (HSA) and the rapid development of nanotechnology, HSA-based nanodrug delivery systems (HBNDSs) have received extensive attention in the field of nanomedicine. However, there is still a lack of comprehensive reviews exploring the broader scope of HBNDSs in biomedical applications beyond cancer therapy. To address this gap, this review takes a systematic approach. Firstly, it focuses on the crystal structure and the potential binding sites of HSA. Additionally, it provides a comprehensive summary of recent progresses in the field of HBNDSs for various biomedical applications over the past five years, categorized according to the type of therapeutic drugs loaded onto HSA. These categories include small-molecule drugs, inorganic materials and bioactive ingredients. Finally, the review summarizes the characteristics and current application status of HBNDSs in drug delivery, and also discusses the challenges that need to be addressed for the clinical transformation of HSA formulations and offers future perspectives in this field.

Because researchers are aiming to restore the deformation and minimize the crack width of existing concrete structures, the strengthening technology of prestressed carbon-fiber-reinforced plastic (CFRP) is currently the focus of many studies and applications. In terms of the strengthening of a prestressed CFRP sheet on the flexural performance of cracked reinforced concrete beams under repeated loads, a four-point bending test of 12 beams was conducted considering the prestress degree reflected by the amount and the prestress force of the CFRP sheet. The longitudinal strengthened CFRP sheet was bonded on the bottom surface of the test beam and fixed by U-jacket CFRP sheets at the ends after tensioning. The strains of concrete, longitudinal tensile steel bars and CFRP sheets were measured at the pure bending segment of test beams, while the cracks, midspan deflection and failure pattern were recorded. The results show that the normal strain on the mid-span section of the strengthened beams by the prestress CFRP sheets was fitted for the assumption of plane section, the cracks and mid-span deflection decreased with the prestress degree of the CFRP sheets to provide better serviceability for the strengthened beams, the load capacity could be increased by 41.0–88.8% at the yield of longitudinal tensile steel bars and increased by 41.9–74.8% at the ultimate state and the ductility at the failure state was sharply reduced by 54.9–186%. The peeling off of broken CFRP sheets played a role in controlling the failure pattern of the strengthened beams under repeated loads. Finally, methods for predicting the bending performance of reinforced concrete beams strengthened by prestressed CFRP sheets were proposed. This study enriches the knowledge about damaged reinforced concrete beams that were strengthened with prestressed CFRP sheets.

Human pluripotent stem cell-derived liver organoids are emerging as more human-relevant in vitro models for studying liver diseases and hepatotoxicity than traditional hepatocyte cultures and animal models. The generation of liver organoids is based on the Matrigel dome method. However, the organoids constructed by this method display significant heterogeneity in their morphology, size, and maturity. Additionally, the formed organoid is randomly encapsulated in the Matrigel dome, which is not convenient for in situ staining and imaging. Here, we demonstrate an approach to generate a novel type of liver organoids via micropatterning technique. This approach enables the reproducible and high-throughput formation of bioengineered fetal liver organoids with uniform morphology and deterministic size and location in a multiwell plate. The liver organoids constructed by this technique closely recapitulate some critical features of human liver development at the fetal stage, including fetal liver-specific gene and protein expression, glycogen storage, lipid accumulation, and protein secretion. Additionally, the organoids allow whole-mount in-situ staining and imaging. Overall, this new type of liver organoids is compatible with the pharmaceutical industry’s widely-used preclinical drug discovery tools and will facilitate liver drug screening and hepatotoxic assessment.

Fluorinated organic compounds have superior physicochemical properties than general organic compounds due to the strong C-F single bond; they are widely used in medicine, biology, pesticides, and materials science. In order to gain a deeper understanding of the physicochemical properties of fluorinated organic compounds, fluorinated aromatic compounds have been investigated by various spectroscopic techniques. 2-fluorobenzonitrile and 3-fluorobenzonitrile are important fine chemical intermediates and their excited state S1 and cationic ground state D0 vibrational features remain unknown. In this paper, we used two-color resonance two photon ionization (2-color REMPI) and mass analyzed threshold ionization (MATI) spectroscopy to study S1 and D0 state vibrational features of 2-fluorobenzonitrile and 3-fluorobenzonitrile. The precise excitation energy (band origin) and adiabatic ionization energy were determined to be 36,028 ± 2 cm−1 and 78,650 ± 5 cm−1 for 2-fluorobenzonitrile and 35,989 ± 2 cm−1 and 78,873 ± 5 cm−1 for 3-fluorobenzonitrile, respectively. The density functional theory (DFT) at the levels of RB3LYP/aug-cc-pvtz, TD-B3LYP/aug-cc-pvtz, and UB3LYP/aug-cc-pvtz were used to calculate the stable structures and vibrational frequencies for the ground state S0, excited state S1, and cationic ground state D0, respectively. Franck–Condon spectral simulations for transitions of S1 ← S0 and D0 ← S1 were performed based on the above DFT calculations. The theoretical and experimental results were in good agreement. The observed vibrational features in S1 and D0 states were assigned according to the simulated spectra and the comparison with structurally similar molecules. Several experimental findings and molecular features were discussed in detail.

Remote-pumped concrete for infrastructure construction is a key innovation of the mechanized and intelligent construction technology. This has brought steel-fiber-reinforced concrete (SFRC) into undergoing various developments, from conventional flowability to high pumpability with low-carbon features. In this regard, an experimental study on the mixing proportion design and the pumpability and mechanical properties of SFRC was conducted for remote pumping. Using the absolute volume method based on the steel-fiber-aggregate skeleton packing test, the water dosage and the sand ratio were adjusted with an experimental study on reference concrete with the premise of varying the volume fraction of steel fiber from 0.4% to 1.2%. The test results of the pumpability of fresh SFRC indicated that the pressure bleeding rate and the static segregation rate were not the controlling indices due to the fact that they were far below the limits of the specifications, and the slump flowability fitted for remote-pumping construction was verified by a lab pumping test. Although the rheological properties of the SFRC charactered by the yield stress and the plastic viscosity increased with the volume fraction of steel fiber, those of mortar used as a lubricating layer during the pumping was almost constant. The cubic compressive strength of the SFRC had a tendency to increase with the volume fraction of steel fiber. The reinforcement effect of steel fiber on the splitting tensile strength of the SFRC was similar to the specifications, while its effect on the flexural strength was higher than the specifications due to the special feature of steel fibers distributed along the longitudinal direction of the beam specimens. The SFRC had excellent impact resistance with an increased volume fraction of steel fiber and presented acceptable water impermeability.

An improved whale optimization algorithm is proposed to solve the problems of the original algorithm in indoor robot path planning, which has slow convergence speed, poor path finding ability, low efficiency, and is easily prone to falling into the local shortest path problem. First, an improved logistic chaotic mapping is applied to enrich the initial population of whales and improve the global search capability of the algorithm. Second, a nonlinear convergence factor is introduced, and the equilibrium parameter A is changed to balance the global and local search capabilities of the algorithm and improve the search efficiency. Finally, the fused Corsi variance and weighting strategy perturbs the location of the whales to improve the path quality. The improved logical whale optimization algorithm (ILWOA) is compared with the WOA and four other improved whale optimization algorithms through eight test functions and three raster map environments for experiments. The results show that ILWOA has better convergence and merit-seeking ability in the test function. In the path planning experiments, the results are better than other algorithms when comparing three evaluation criteria, which verifies that the path quality, merit-seeking ability, and robustness of ILWOA in path planning are improved.

Abstract Background With the development of deep learning (DL), more and more methods based on deep learning are proposed and achieve state-of-the-art performance in biomedical image segmentation. However, these methods are usually complex and require the support of powerful computing resources. According to the actual situation, it is impractical that we use huge computing resources in clinical situations. Thus, it is significant to develop accurate DL based biomedical image segmentation methods which depend on resources-constraint computing. Results A lightweight and multiscale network called PyConvU-Net is proposed to potentially work with low-resources computing. Through strictly controlled experiments, PyConvU-Net predictions have a good performance on three biomedical image segmentation tasks with the fewest parameters. Conclusions Our experimental results preliminarily demonstrate the potential of proposed PyConvU-Net in biomedical image segmentation with resources-constraint computing.

Inspired by the animal upper digestive tract, a unique soft-elastic reactor (SER) has recently been researched whose mixing phenomena should be further investigated. Numerical simulation is an excellent method with which to explore the phenomena in SERs for a large number of conditions. It may also offer insights into the ways of effective mixing in this kind of reactor. The mixing processes in 2D SERs driven by bio-inspired wavelike boundary motions are systematically compared in this work. The influences of several key factors (i.e. the aspect ratios of rectangular SERs, the wavenumbers of moving walls, and the location and size of baffles) on the mixing performance are investigated. It has been found that mixing efficiency is better at an aspect ratio close to 1.0. The influence of wavenumber on mixing is not monotonic. Increasing the wavenumber speeds up mixing in parallel boundary type motion, while it slows it down in symmetrical-contraction boundary type motion. Mounting baffles on the left and right sides of the vessel wall (i.e. on the moving boundaries) promotes mixing. Lower porosity (≤ 0.4) of baffles benefits mixing. It has become clear that an efficient SER needs to be designed by considering not only its shape but also the wall moving mode. The work reported in this article has provided useful information on how it might be possible to improve SERs for industrial applications in future.

Producing concrete with large content of fly ash attracts increasing attention in low carbon building materials. In this paper, the fly-ash concrete (FAC) with a content of fly ash no less than 50% total weight of binders was developed. The adaptability of fly ash used for concrete was firstly examined by testing the water requirement of normal consistency and the setting time for cement fly-ash paste, and the strengths of cement fly-ash mortar at the curing age of 7 and 28 days. The factors of water-to-binder ratio from 0.3 to 0.5, the content of fly-ash from 40% to 80%, and the excitation measures with additional Ca(OH)2 and steam curing at initial were considered. After that, the FAC was designed by adding an excessive content of fly ash to reduce the water-to-binder ratio from 0.50 to 0.26, and the content of fly-ash varied from 52% to 60%. Results show that the cement fly-ash paste presented a reduction of water requirement and an elongation of setting time with the increased content of fly ash. This provides a foundation of maintaining the workability of fresh FAC with a decreased water-to-binder ratio by adding the excessive content of fly ash. The cement fly-ash mortar had a lower early strength due to the slow reaction of fly-ash with Ca(OH)2, which could be improved by steam curing at the initial 24 h due to the excitation of fly-ash activity. At curing age of 28 days, the FAC had the expected axial compressive strength and modulus of elasticity, but the tensile strength was lower than predicted. At the curing age of 56 days, all the basic mechanical properties of FAC reached the prediction. The resistances of FAC to chloride ion penetration and carbonization were realized at a very high level as specified in codes.

Abstract Background Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the leading cause of end-stage chronic kidney disease. Currently, there are no effective drugs for treating DN. Therefore, novel and effective strategies to ameliorate DN at the early stage should be identified. This study aimed to explore the effectiveness and underlying mechanisms of human umbilical cord mesenchymal stem cells (UC-MSCs) in DN. Methods We identified the basic biological properties and examined the multilineage differentiation potential of UC-MSCs. Streptozotocin (STZ)-induced DN rats were infused with 2 × 106 UC-MSCs via the tail vein at week 6. After 2 weeks, we measured blood glucose level, levels of renal function parameters in the blood and urine, and cytokine levels in the kidney and blood, and analyzed renal pathological changes after UC-MSC treatment. We also determined the colonization of UC-MSCs in the kidney with or without STZ injection. Moreover, in vitro experiments were performed to analyze cytokine levels of renal tubular epithelial cell lines (NRK-52E, HK2) and human renal glomerular endothelial cell line (hrGECs). Results UC-MSCs significantly ameliorated functional parameters, such as 24-h urinary protein, creatinine clearance rate, serum creatinine, urea nitrogen, and renal hypertrophy index. Pathological changes in the kidney were manifested by significant reductions in renal vacuole degeneration, inflammatory cell infiltration, and renal interstitial fibrosis after UC-MSC treatment. We observed that the number of UC-MSCs recruited to the injured kidneys was increased compared with the controls. UC-MSCs apparently reduced the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and pro-fibrotic factor (TGF-β) in the kidney and blood of DN rats. In vitro experiments showed that UC-MSC conditioned medium and UC-MSC-derived exosomes decreased the production of these cytokines in high glucose-injured renal tubular epithelial cells, and renal glomerular endothelial cells. Moreover, UC-MSCs secreted large amounts of growth factors including epidermal growth factor, fibroblast growth factor, hepatocyte growth factor, and vascular endothelial growth factor. Conclusion UC-MSCs can effectively improve the renal function, inhibit inflammation and fibrosis, and prevent its progression in a model of diabetes-induced chronic renal injury, indicating that UC-MSCs could be a promising treatment strategy for DN.

Apart from the flexural performance of reinforced hybrid composite beams made of SFRELC (steel fiber reinforced expanded-shale lightweight concrete) and partial higher-strength conventional concrete, the shear properties are also essential to be understood for reliable application. To bridge this gap, sixteen reinforced hybrid composite beams compared with two reinforced SFRELC beams and two reinforced conventional concrete beams were experimentally studied under four-point test in this paper. The grades of SFRELC and partial conventional concrete were 40 MPa and 50 MPa respectively in cubic compressive strength. The composite depth ratio of conventional concrete to SFRELC varied from 0.3 to 0.5, the shear-span to depth ratio ranged from 1.5 to 3.0, and the volume fraction of steel fiber changed from 0.8% to 1.6%. The shear-cracking resistance, shear crack width, mid-span deflection and shear capacity of test beams were measured, and the crack distribution and failure modes were observed. Results indicate that the composition of SFRELC with higher-strength of conventional concrete confirmed a beneficial effect on the shear-cracking resistance and the shear capacity of reinforced hybrid composite beams. The interface of conventional concrete and SFRELC bonded well without any slip. The shear performance was slightly influenced by the composite depth ratio, and similar to reinforced SFRELC or conventional concrete beams with a varying of the shear-span to depth ratio and the volume fraction of steel fiber. Based on the test results, the tensile strength of SFRELC is used to predict the shear-cracking force of reinforced hybrid composite beams, while the equivalent tensile strength considering the combination of SFRELC and conventional concrete is used to calculate the shear capacity of reinforced hybrid composite beams. Finally, the design method is discussed for the shear capacity with the control of shear crack width of reinforced hybrid composite beams.

Aimed at improving the production efficiency of tetrahedron-like pervious frames for the river revetment, self-compacting steel fiber reinforced concrete (SFRC) was applied to strengthen the tensile resistance of concrete to remove conventional steel bars used as reinforcement. The workability and mechanical properties of self-compacting SFRC were experimentally studied with the volume fraction of steel fiber changed from 0.4% to 1.2%, and the rational volume fraction of 0.8% was determined for producing the pervious frames. Based on the flow-induced orientation of the steel fibers in the fresh mix, the casting process of self-compacting SFRC was optimal from one inclined rod to other two inclined rods and the horizontal rods of the pervious frame. The loading capacities of pervious frames during lifting and stacking were respectively detected by the simulation tests on the testing machine, which ensure the safety of pervious frames lifted six layers together and stacked for nineteen layers. By testing groups of pervious frames throwed in and then salvaged from the river, the quality of pervious frames without any damage was observed. Finally, the pervious frames were successfully applied in an engineering project for the river revetment.

The reliable bond of steel fibers to concrete matrix is fundamental to ensure they work together under internal and external actions throughout their service life. Due to the lack of research on the long-term bond property, this paper conducted an experimental study on the bond of hook-end steel fiber in the manufactured sand mortars with different water to binder ratios cured for different ages from 7 days to 360 days. The characteristic pull-out load-slip curves are measured, and bond performance indexes at different curing ages are analyzed by using the multi-index synthetical evaluation method. The results show that the bond strengths, the fiber strength use efficiency, the debonding work and the pull-out work increased with the increase in curing age up to to 90 days, which became stable with little variation with the follow-up curing age. The variations are closely associated with the development of mortar strength. Steel fibers embedded in high-strength mortar presented a higher debonding ductility and a lower slipping ductility. In addition, the prediction formulas of long-term debonding strength, bond strength and residual bond strength are proposed.

Aiming at achieving the beneficial effects from the lightened self-weight of structures, steel fiber reinforced expanded-shale lightweight concrete (SFRELC) is promoting to be applied in structural engineering. In this condition, proper design method needs to be built up for the reinforced SFRELC structures. In view of the shear performance of reinforced SFRELC beams, ten test beams were fabricated and tested by four-point bending test in this paper. The major variables were selected as the shear-span to depth ratio from 2 to 3 and the stirrups ratio of 0.19 % and 0.25 %. The shear-cracking resistance, the shear crack width and distribution, the mid-span deflection and the shear capacity of test beams were measured. Results indicate that the shear failure mode of reinforced SFRELC beams relied on the shear-span to depth ratio and can be modified to ductile with the increase of stirrups ratio, the shear-cracking resistance and the shear capacity reduced with the increase of shear-span to depth ratio. The beneficial effects of steel fiber and stirrups on the shear performance of SFRELC can be comprehensively reflected by the shear capacity provided by SFRELC of reinforced SFRELC beams. Based on test results and previous studies, formulas were proposed to calculate the shear-cracking resistance and shear capacity of reinforced SFRELC beams. Finally, the formulas expressed by the lower envelop curves of test date for conservative design of shear capacity of reinforced SFRELC beams are also suggested. In this condition, the shear crack width can be limited within 0.2 mm and 0.1 mm at normal serviceability.

Liver fibrosis is a common pathological process of end-stage liver diseases. However, the role of microRNA (miRNA) in liver fibrosis is poorly understood. The activated hepatic stellate cells (HSCs) are the major source of fibrogenic cells and play a central role in liver fibrosis. In this study, we investigated the differential expression of miRNAs in resting and transforming growth factor β1 (TGF-β1) activated HSCs by microarray analysis and found that miR-455-3p was significantly downregulated during HSCs activation. In addition, the reduction of miR-455-3p was correlated with liver fibrosis in mice with carbon tetrachloride (CCl4), bile duct ligation (BDL), and high-fat diet (HFD)-induced liver fibrosis. Our functional analyses demonstrated that miR-455-3p inhibited expression of profibrotic markers and cell proliferation in HSCs in vitro. Moreover, miR-455-3p regulated heat shock factor 1 (HSF1) expression by binding to the 3′ UTR of its mRNA directly. Overexpression of HSF1 facilitated HSCs activation and proliferation by promoting heat shock protein 47 (Hsp47) expression, leading to activation of the TGF-β/Smad4 signaling pathway. To explore the clinical potential of miR-455-3p, we injected ago-miR-455-3p into mice with CCl4-, BDL-, and HFD-induced hepatic fibrosis in vivo. The overexpression of miR-455-3p suppressed HSF1 expression and reduced fibrosis marker expression, which resulted in alleviated liver fibrosis in mice. In conclusion, our present study suggests that miR-455-3p inhibits the activation of HSCs through targeting HSF1 involved in the Hsp47/TGF-β/Smad4 signaling pathway. Therefore, miR-455-3p might be a promising therapeutic target for liver fibrosis. Keywords: miR-455-3p, HSF1, hepatic stellate cells, liver fibrosis

This paper focuses on the study of elasto-plastic bending behaviors of steel fiber reinforced expanded-shale lightweight concrete (SFRELC) T-beams by using the nonlinear finite-element method. The nonlinear finite-element model of T-beams was built with the rational constitutive models of SFRELC, steel bars and their bond-slip. The finite-element dimension was taken as one-third of average crack spacing to reflect the actual crack distribution and crushed compression zone. The loading procedure was controlled by displacement to perform the complete loading procedure. The convergence tolerance was enlarged with the adjusted loading substep to solve non-convergent issue in the elasto-plastic portion. The numerical analysis and experimental work were performed for five reinforced SFRELC T-beams with a varying volume fraction of steel fiber from zero to 2.0%. Results indicated that except for about 22% higher cracking moment, the numerical results agreed well to the experimental in the bearing capacity, the strains of SFRELC and longitudinal tensile steel bars, the complete load-deflection curve and the flexural ductility. Identical crack distribution and failure pattern was given out. The total width of cracks computed by the displacement difference between the longitudinal steel bar and the SFRELC is almost equal to the sum of crack width measured within pure bending segment. This confirms the adaptability of the numerical model to be used for the virtual-test to investigate the complete bending performance of reinforced SFRELC T-beams.

It is well accepted that low-dose ionizing radiation (LDIR) modulates a variety of immune responses that have exhibited the properties of immune hormesis. Alterations in messenger RNA (mRNA) and long noncoding RNA (lncRNA) expression were to crucially underlie these LDIR responses. However, lncRNAs in LDIR-induced immune responses have been rarely reported, and its functions and molecular mechanisms have not yet been characterized. Here, we used microarray profiling to determine lncRNA in BALB/c mice exposed to single (0.5 Gy×1) and chronic (0.05 Gy×10) low-dose γ-rays radiation (Co 60 ). We observed that a total of 8274 lncRNAs and 7240 mRNAs were altered in single LDIR, while 2077 lncRNAs and 796 mRNAs in chronic LDIR. The biological functions of these upregulated mRNAs in both 2 groups using Gene Ontology functional and pathway enrichment analysis were significantly enriched in immune processes and immune signaling pathways. Subsequently, we screened out the lncRNAs involved in regulating these immune signaling pathways and examined their potential functions by lncRNAs-mRNAs coexpression networks. This is the first study to comprehensively identify lncRNAs in single and chronic LDIR responses and to demonstrate the involvement of different lncRNA expression patterns in LDIR-induced immune signaling pathways. Further systematic research on these lncRNAs will provide new insights into our understanding of LDIR-modulated immune hormesis responses.

Mesenchymal stem cells (MSCs) are shown to alleviate renal injury of diabetic nephropathy (DN) in rats. However, the underlying mechanism of this beneficial effect is not fully understood. The aims of this study are to evaluate effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on renal cell apoptosis in streptozotocin- (STZ-) induced diabetic rats and explore the underlying mechanisms. Characteristics of UC-MSCs were identified by flow cytometry and differentiation capability. Six weeks after DN induction by STZ injection in Sprague-Dawley rats, the DN rats received UC-MSCs once a week for consecutive two weeks. DN-related physical and biochemical parameters were measured at 2 weeks after UC-MSC infusion. Renal histological changes were also assessed. Moreover, the apoptosis of renal cells and expression of apoptosis-related proteins were evaluated. Compared with DN rats, rats treated with UC-MSCs showed suppressed increase in 24-hour urinary total protein, urinary albumin to creatinine ratio, serum creatinine, and blood urea nitrogen. UC-MSC treatment ameliorated pathological abnormalities in the kidney of DN rats as evidenced by H&E, PAS, and Masson Trichrome staining. Furthermore, UC-MSC treatment reduced apoptosis of renal cells in DN rats. UC-MSCs promoted expression of antiapoptosis protein Bcl-xl and suppressed expression of high mobility group protein B1 (HMGB1) in the kidney of DN rats. Most importantly, UC-MSCs suppressed upregulation of thioredoxin-interacting protein (TXNIP), downregulation of thioredoxin 1 (TRX1), and activation of apoptosis signal-regulating kinase 1 (ASK1) and P38 MAPK in the kidney of DN rats. Our results suggest that UC-MSCs could alleviate nephrocyte injury and albuminuria of DN rats through their antiapoptotic property. The protective effects of UC-MSCs may be mediated by inhibiting TXNIP upregulation in part.

Although studies have been performed on the recycled aggregate made of waste concrete for the production of new concrete, the new concrete with 100% recycled coarse aggregate and manufactured sand (abbreviated as RAMC) still needs to be researched for structural applications. In this paper, an experimental study was performed on seven groups, including fourteen reinforced RAMC beams under the simply supported four-point loading test, considering the factors of the strength of RAMC and the reinforcement ratio of longitudinal tensile rebars. Based on the test results, the cracking resistance, the bearing capacity, the crack width, the flexural stiffness and the mid-span deflection of reinforced RAMC beams in bending are discussed and examined by using the formulas of conventional reinforced concrete beams. Results show that an obvious effect of reinforcement ratio was present, while less so was that of the strength of RAMC. With the comparison of predicted values by the formulas of conventional reinforced concrete beams, the reinforced RAMC beams decreased cracking resistance by about 20%, increased crack width by about 15% and increased mid-span deflection by about 10%, although the same bearing capacity can be reached. The results directly relate to the lower tensile strength of RAMC which should be further improved.

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

In recent years, the sludge produced by municipal sewage treatment plants has become an important recyclable resource for producing green building materials. After the systematic processing of incineration and particle formation, the sintered sludge can be processed into fine lightweight aggregate to produce building mortar with the controlled leaching of heavy metals and radioactivity. In this paper, to increase its economic and environmental benefits, mortar with sintered sludge aggregate was made by cement admixing of fly ash or limestone powder. The water-to-binder ratio was set at three levels—0.82, 0.68, and 0.62—and either flay ash or limestone powder was used to replace equal masses of cement at 10%, 20%, or 30%. Eighteen groups of mortar were studied to evaluate their workability, air content, compressive strength, tensile adhesive strength, dry density, and thermal conductivity. The results indicate that with a proper water-to-binder ratio, and the replacement ratio of fly ash or limestone powder, the mortar can be produced with good workability, consistency, water-retention rate, layering degree, and setting time. The mortar made with sintered sludge lightweight aggregate, designated by the mix-proportion method for conventional lightweight aggregate mortar, did not meet the target strength, although the compressive strength of mortar was no less than 3.0 MPa, which meets the strength grade M2.5. The tensile adhesive strength reached 0.18 MPa. The mortar was super lightweight with a dry density less than 400 kg/m3, and a thermal conductivity within 0.30~0.32 W/(m⋅K). The effects of water-to-binder ratio and replacement ratio of fly ash or limestone powder on the above properties are discussed with test results. The study provides a basis for using sintered sludge lightweight aggregate for building mortar.

In the monolithic precast concrete shear-wall structure, the bonding property of cast-in-situ joints to precast concrete walls is important to ensure the entire structural performance. Aiming to the vertical joint of precast concrete walls, an experimental study was carried out considering the factors including the strength of precast and joint concretes, as well as the interface processing and casting age of precast concrete. The micro-expansion self-compacting concrete was used for the cast-in-situ joints. The interfacial bonding strength between joint and precast concrete was measured by splitting tensile test. Results show that the interfacial bonding strength was benefited from the increasing strength of joint concrete and the spraying binder paste on the interface of precast concrete, and unbenefited from the overtime storage of precast concrete. The washed rough surface with exposed aggregates improved the interfacial bonding strength, which increased with the increasing roughness. Based on the test results, the limits of the strength grade of joint concrete and the roughness of washed rough surface are proposed to get the interfacial bonding strength equivalent to the tensile strength of precast concrete. Meanwhile, the spraying of binder paste on precast concrete is a good choice, the storage time of precast components is a better limit within 28 days.

This article presents 755 groups splitting tensile strength tests data of concrete with manufactured sand (MSC) in different curing age ranged from 1 day to 388 days related to the research article “Experimental study on tensile strength development of concrete with manufactured sand” (Zhao et al., 2017) [1]. These data were used to evaluate the precision of the prediction formulas of tensile strength of MSC, and can be applied as dataset for further studies.

Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains the leading complication for mortality caused by bacterial infection. The regulatory T (Treg) cells appear to be an important modulator in resolving lung injury. Despite the extensive studies, little is known about the role of macrophage HMGB1/PTEN/β-catenin signaling in Treg development during ALI.Objectives: This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/β-catenin signaling in mediating CD4+CD25+Foxp3+ Treg development in sepsis-induced lung injury in mice.Setting: University laboratory research of First Affiliated Hospital of Anhui Medical University.Subjects: PTEN/β-catenin Loxp and myeloid-specific knockout mice.Interventions: Groups of PTENloxp/β-cateninloxp and myeloid-specific PTEN/β-catenin knockout (PTENM−KO/β-cateninM−KO) mice were treated with LPS or recombinant HMGB1 (rHMGB1) to induce ALI. The effects of HMGB1-PTEN axis were further analyzed by in vitro co-cultures.Measures and Main Results: In a mouse model of ALI, blocking HMGB1 or myeloid-specific PTEN knockout (PTENM−KO) increased animal survival/body weight, reduced lung damage, increased TGF-β production, inhibited the expression of RORγt and IL-17, while promoting β-catenin signaling and increasing CD4+CD25+Foxp3+ Tregs in LPS- or rHMGB-induced lung injury. Notably, myeloid-specific β-catenin ablation (β-cateninM−KO) resulted in reduced animal survival and increased lung injury, accompanied by reduced CD4+CD25+Foxp3+ Tregs in rHMGB-induced ALI. Furthermore, disruption of macrophage HMGB1/PTEN or activation of β-catenin significantly increased CD4+CD25+Foxp3+ Tregs in vitro.Conclusions: HMGB1/PTEN/β-catenin signaling is a novel pathway that regulates Treg development and provides a potential therapeutic target in sepsis-induced lung injury.

To determine the validity of steel fiber reinforced expanded-shale lightweight concrete (SFRELC) applied in structures, the shear behavior of SFRELC structural components needs to be understood. In this paper, four-point bending tests were carried out on reinforced SFRELC beams with stirrups and a varying volume fraction of steel fiber from 0.4% to 1.6%. The shear cracking force, shear crack width and distribution pattern, mid-span deflection, and failure modes of test beams were recorded. Results indicate that the shear failure modes of reinforced SFRELC beams with stirrups were modified from brittle to ductile and could be transferred to the flexure mode with the increasing volume fraction of steel fiber. The coupling of steel fibers with stirrups contributed to the shear cracking force and the shear capacity provided by the SFRELC, and it improved the distribution of shear cracks. At the limit loading level of beams in building structures at serviceability, the maximum width of shear cracks could be controlled within 0.3 mm and 0.2 mm with the volume fraction of steel fiber increased from 0.4% to 0.8%. Finally, the formulas are proposed for the prediction of shear-cracking force, shear crack width, and shear capacity of reinforced SFRELC beams with stirrups.

Due to the mechanical properties related closely to the distribution of steel fibers in concrete matrix, the assessment of tensile strength of self-compacting steel fiber reinforced concrete (SFRC) is significant for the engineering application. In this paper, seven groups of self-compacting SFRC were produced with the mix proportion designed by using the steel fiber-aggregates skeleton packing test method. The hooked-end steel fibers with length of 25.1 mm, 29.8 mm and 34.8 mm were used, and the volume fraction varied from 0.4% to 1.4%. The axial tensile test of notched sectional prism specimen and the splitting tensile test of cube specimen were carried out. Results show that the axial tensile strength was higher than the splitting tensile strength for the same self-compacting SFRC, the axial tensile work and toughness was not related to the length of steel fiber. Finally, the equations for the prediction of tensile strength of self-compacting SFRC are proposed considering the fiber distribution and fiber factor, and the adaptability of splitting tensile test for self-compacting SFRC is discussed.

This paper presents 186 groups compressive strength tests data of concrete with manufactured sand (MSC) in different curing age and 262 groups compressive strength tests data of MSC at 28 days collected from authors’ experiments and other researches in China. Further interpretation and discussion were described in this issues. Keywords: Concrete with manufactured sand(MSC), Long-term compressive strength, Stone powder

A scientific and concise mix design method is an impending problem in the engineering application of self-compacting steel-fiber-reinforced concrete (SFRC). This paper focuses on the mix proportion of self-compacting SFRC, which is influenced by the steel fibers, along with its effects on the packing properties of the steel fiber aggregate skeleton. In total, 252 groups of packing tests were carried out for several main factors, including with various maximum particle sizes for the coarse aggregates, manufactured sand ratios ranging from 50% to 62%, and with different types of hooked-end steel fibers and crimped steel fibers, with volume fractions ranging from 0% to 2.0%. The results indicated that the void content and rational sand ratio of the steel fiber aggregate skeleton increased linearly with the fiber factor. These results provided a basis for the calculation of the binder content and rational sand ratio of the self-compacting SFRC. Combined with the absolute volume design method and the calculation formula for the water-to-binder ratio, a systematical procedure was proposed for the mix proportion design of the self-compacting SFRC. Based on the design method, eight groups of mixtures were cast and tested to verify the adaptability and practicability of the workability, air content, density, cubic compressive strength, and splitting tensile strength of the self-compacting SFRC. Meanwhile, the outcomes of this study confirmed the applicability of using manufactured sand as a complete replacement for natural sand for the self-compacting SFRC.

This paper is the outcome of experiments on the shear performance of reinforced concrete beams with approved composite-recycled aggregates. The strength grade of composite-recycled aggregate concrete (CRAC) was between 30 MPa and 60 MPa. The shear span-to-depth ratio varied from 1 to 3. The adaptability of HRB400 rebar, with critical yield strength of 400 MPa, used as stirrups was also verified. As the composite technology overcame the shortcomings of recycled coarse aggregate, CRAC had similar mechanical properties with those of conventional concrete. Details on the shear behaviors of test beams under a four-point loading test are presented. The results indicated that the changes of CRAC strain, stirrup strain, and shear-crack width depended on the failure patterns, which are controlled by the shear-span to depth ratio. The stirrups yield at the failure of reinforced CRAC beams. The shear cracking resistance and the shear capacity of reinforced CRAC beams can be predicted by the statistical equations. Based on the design codes GB50010, ACI318-19, Model Code 2010 and DIN-1045-1-2008 for conventional reinforced concrete beams, the shear strengths provided by CRAC and stirrups are statistical analyzed. The rationality of the design equations is examined by the utilization level of shear strength provided by CRAC. The maximum shear-crack widths are extracted from the test data of reinforced CRAC beams at normal service state. Comparatively, by specifying the lower limit of shear strength provided by the CRAC with various shear-span to depth ratios, China code GB50010 gives a rational method for utilizing CRAC. Under the premise that the design of shear capacity would give considerations to meet the normal serviceability, the factored strength of HRB400 rebar should be 360 MPa for the calculation of shear strength provided by stirrups. The design methods in codes of GB50010, ACI318-19 and Model Code 2010 are conservative for the shear capacity of reinforced CRAC beams.

With the premise of ensuring workability on a fresh mixture, the volume stability of hardened self-compacting steel fiber reinforced concrete (SFRC) becomes an issue due to the content of cementitious materials increased with the volume fraction of steel fiber. By using the expansive agent to reduce the shrinkage deformation of self-compacting SFRC, the strength reduction of hardened self-compacting SFRC is another issue. To solve these issues, this paper performed an experimental investigation on the workability, shrinkage, and mechanical properties of self-compacting SFRC compared to the self-compacting concrete (SCC) with or without an expansive agent. The calcium-sulfoaluminate expansive agent with content optimized to be 10% mass of binders and the steel fiber with a varying volume fraction from 0.4% to 1.2% were selected as the main parameters. The mix proportion of self-compacting SFRC with expansive agent was designed by the direct absolute volume method, of which the steel fibers are considered to be the distributed coarse aggregates. Results showed that rational high filling and passing ability of fresh self-compacting SFRC was ensured by increasing the binder to coarse-aggregate ratio and the sand ratio in the mix proportions; the autogenous and drying shrinkages of hardened self-compacting SFRC reduced by 22.2% to 3.2% and by 18.5% to 7.3% compared to those of the SCC without expansive agent at a curing age of 180 d, although the expansion effect of expansive agent decreased with the increasing volume fraction of steel fiber; the mechanical properties, including the compressive strength, the splitting tensile strength, and the modulus of elasticity increased with the incorporation of an expansive agent and steel fibers, which met the design requirements.

Concerning the structural applications of steel fiber reinforced expanded-shales lightweight concrete (SFRELC), the present study focuses on the flexural fatigue performance of SFRELC superposed beams with initial static-load cracks. Nine SFRELC superposed beams were fabricated with the SFRELC depth varying from 50% to 70% of the whole sectional depth, and the volume fraction of steel fiber ranged from 0.8% to 1.6%. The fatigue load exerted on the beams was a constant amplitude sinusoid with a frequency of 10 Hz and a fatigue characteristic value of 0.10; the upper limit was taken as the load corresponded to the maximum crack width of 0.20 mm at the barycenter of the longitudinal rebars. The results showed that with the increase of SFRELC depth and the volume fraction of steel fiber, the fatigue life of the test beams was prolonged with three altered failure modes due to the crush of conventional concrete in the compression zone and/or the fracture of the tensile rebar; the failure pattern could be more ductile by the prevention of fatigue fracture by the longitudinal tensile rebar when the volume fraction of steel fiber was 1.6% and the reduction of crack growth and concrete strain in the compression zone; the fatigue life of test beams was sensitive to the upper-limit of the fatigue load, a short fatigue life appeared from the higher stress level and larger stress amplitude of the longitudinal rebar due to the higher upper-limit of the fatigue load. The methods for predicting the stress level, the stress amplitude of the longitudinal tensile rebar, and the degenerated flexural stiffness of SFRELC superposed beams with fatigue life are proposed. With the optimal composites of the SFRELC depth ratio and the volume fraction of steel fiber, the controllable failure of reinforced SFRELC superposed beams could be a good prospect with the trend curves of fatigue flexural stiffness.

For the popularized structural application, steel fiber-reinforced expanded-shale lightweight concrete (SFRELC) with high freeze-thaw resistance was developed. The experimental study of this paper figured out the effects of air-entraining content, volume fraction of steel fibers, and fine aggregate type. Results showed that while the less change of mass loss rate was taken place for SFRELC after 300 freeze-thaw cycles, the relative dynamic modulus of elasticity and the relative flexural strength presented clear trends of freeze-thaw resistance of SFRELC. The compound effect of the air-entraining agent and the steel fibers was found to support the SFRELC with high freeze-thaw resistance, and the mechanisms were explored with the aid of the test results of water penetration of SFRELC. The beneficial effect was appeared from the replacement of lightweight sand with manufactured sand. Based on the test results, suggestions are given out for the optimal mix proportion of SFRELC to satisfy the durability requirement of freeze-thaw resistance.

In this paper, a new recycled aggregate concrete (RAC) was produced with composite coarse aggregate and fine recycled aggregate. The composite coarse aggregate was mixed into continuous gradation by large particle natural aggregate with small particle recycled aggregate. To explore the time-dependent developments of the compressive strength and splitting tensile strength of this new RAC, 320 groups of cubic specimens were tested at different curing ages from 3 days to 360 days to measure the compressive and splitting tensile strengths. The amount of large particle natural aggregate varied from zero to 70% in mass of the total coarse aggregate. The water/cement ratio was taken as 0.60, 0.49, 0.41 and 0.36 to represent four strength grades of the RAC at about C20, C30, C40 and C50. Based on the tested results, the curves of the compressive and tensile strengths of the RAC that changed with curing age are plotted, which clearly exhibit that the amount of large particle natural aggregate had a rational range in different strength grades of the RAC which had better aging strength. When the RAC was no larger than C30 with a water/cement ratio of 0.60 and 0.49, the amount of large particle natural aggregate should be no more than 30%; when the RAC was no less than C40 with a water/cement ratio of 0.41 and 0.36, the amount of large particle natural aggregate should be no less than 50%. Along with the general prediction of the strength development of all the tested RAC, the optimal predictive formulas are proposed for the strength development of RAC with a rational amount of natural aggregate. Meanwhile, the strength developments of RAC with a rational amount of natural aggregate are assessed by the time-dependent models proposed by the ACI Committee 209 and CEB-FIP MC 2010.

In this paper, for a wide application of high-performance steel fiber reinforced expanded-shale lightweight concrete (SFRELC) in structures, the shear behavior of reinforced SFRELC beams without web reinforcements was experimentally investigated under a four-point bending test. Twenty-six beams were fabricated considering the influencing parameters of SFRELC strength, shear-span to depth ratio, longitudinal reinforcement ratio and the volume fraction of the steel fiber. The statistical analyses based on the foundational design principles and the experimental results are made based on the shear cracking resistance, the shear crack distribution and width, the mid-span deflection, the patterns of shear failure, and the shear capacity of the specimens. This confirms the effective strengthening of steel fibers on the shear performance of reinforced SFRELC beams without web reinforcements. Based on the modifications to the formulas of reinforced conventional concrete, lightweight-aggregate concrete or steel fiber reinforced concrete (SFRC) beams, and the validation against the experimental findings, formulas are proposed for the prediction of shear cracking resistance and shear capacity of reinforced SFRELC beams without web reinforcements. Finally, formulas are discussed for the reliable design of the shear capacity of reinforced SFRELC beams without web reinforcements.

With the sustainable development of green construction materials in civil engineering, self-compacting steel fiber reinforced concrete (SC-SFRC) has attracted widespread attention due to its superior self-compacting performance and excellent hardened properties. In this paper, 301 groups of test data from published literatures were collected to quantify the characteristics of the mix proportion of SC-SFRC. The type, aspect ratio and volume fraction of steel fiber commonly used in SC-SFRC are discussed and the effects of steel fiber on the workability and mechanical properties of SC-SFRC are statistically studied. The relationship of cubic compressive strength and water-to-binder ratio and that of the splitting tensile strengths between SC-SFRC and referenced self-compacting concrete (SCC) are also evaluated. Based on these analyses, the reasonable ranges of material components in the mix proportion design of SC-SFRC are determined. The results showed that with several adjusted parameters, the calculation model of the water-to-binder ratio for the mix proportion design of ordinary concrete is suitable for SC-SFRC. The calculation model of tensile strength is suggested for SC-SFRC with various types of steel fiber.