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In the past decade or so, an increasing number of construction organizations have shifted from traditional CAD to BIM, which requires organizations to make corresponding changes and can be seen as a progressive organizational change. However, existing research knows little about the organizational management mechanisms for BIM implementation. From the perspective of organizational change, considering the role of transformational leadership and organizational unlearning, this study constructs a framework to explore the organizational mechanism of BIM implementation. Based on empirical analysis of 124 samples from mainland China, it was found that transformational leadership contributes to the improvement of an organization’s BIM implementation level and the pathway is mainly achieved through organizational unlearning. This study contributes to the construction industry’s organizational change and new technology implementation by inferring and validating the positive roles of transformational leadership and organizational unlearning in promoting BIM implementation. Research findings can also provide helpful guidance for industry participants to implement BIM within organizations successfully.

SNF1-related protein kinase 2 (SnRK2) family members are essential components of the plant abscisic acid (ABA) signaling pathway initiated by osmotic stress and triggering a drought stress response. This study characterized the molecular properties of TaSnRK2.4 and its function in mediating adaptation to drought in Triticum aestivum. Transcripts of TaSnRK2.4 were upregulated upon drought and ABA signaling and associated with drought- and ABA-responsive cis-elements ABRE and DRE, and MYB and MYC binding sites in the promoter as indicated by reporter GUS protein staining and activity driven by truncations of the promoter. Yeast two-hybrid, BiFC, and Co-IP assays indicated that TaSnRK2.4 protein interacts with TaPP2C01 and an ABF transcription factor (TF) TaABF2. The results suggested that TaSnRK2.4 forms a functional TaPP2C01-TaSnRK2.4-TaABF2 module with its upstream and downstream partners. Transgene analysis revealed that TaSnRK2.4 and TaABF2 positively regulate drought tolerance whereas TaPP2C01 acts negatively by modulating stomatal movement, osmotic adjustment, reactive oxygen species (ROS) homeostasis, and root morphology. Expression analysis, yeast one-hybrid, and transcriptional activation assays indicated that several osmotic stress-responsive genes, including TaSLAC1-4, TaP5CS3, TaSOD5, TaCAT1, and TaPIN4, are regulated by TaABF2. Transgene analysis verified their functions in positively regulating stomatal movement (TaSLAC1-4), proline accumulation (TaP5CS3), SOD activity (TaSOD5), CAT activity (TaCAT1), and root morphology (TaPIN4). There were high correlations between plant biomass and yield with module transcripts in a wheat variety panel cultivated under drought conditions in the field. Our findings provide insights into understanding plant drought response underlying the SnRK2 signaling pathway in common wheat.

Purpose: As the most common subset of breast cancer (BC), estrogen receptor positive (ER+) BC accounting for 80% of cases, has become a global public health concern. The female hormone estrogen (E2) unequivocally drives ER + breast malignancies. The reasons that estrogen affects BC development has long been considered, yet further study remains to be conducted of the molecular events in the E2-estrogen receptor α (ERα) signaling pathway in ER + BC progression, especially lipid metabolism, so providing more options for tailored and individualized therapy. Our aim is to find out new targets and clinical biomarkers for ER + breast cancer treatment from the perspective of lipid metabolism. Methods: Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. Some inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results: The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion: CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.

Abstract This study aimed to investigate the effects of ammonia addition on ethylene counter-flow diffusion flames with different diluents on the fuel or oxidizer side, using kinetic analyses. A special emphasis was put on assessing the coupled chemical effects of NH3 and CO2 on C2H4 combustion chemistry. The chemical effects could be evaluated by comparing fictitious inert NH3 or CO2 with normal active NH3 or CO2. The results revealed that the addition of NH3 decreased the mole fractions and production rates of key soot precursors, such as acetylene, propynyl, and benzene. When CO2 was used as the dilution gas, the coupled chemical effects of NH3 and CO2 were affected by the chemical effects of CO2 to varying degrees. With the oxidizer-side CO2 addition, the coupled chemical effects of NH3 and CO2 reduced the mole fractions of H, O, OH radicals, acetylene, propynyl, and benzene, while the effects differed from the fuel-side CO2 addition. The coupled chemical effects of NH3 and CO2 also promoted the formation of aldehyde contaminants, such as acetaldehyde, to some extent, particularly with CO2 addition on the oxidizer side.

Chinese work and lifestyle are undergoing dramatic changes caused by constantly changing technology and new policies. The demand-resource dynamic relationship, which leads to work-family conflict (WFC), has become increasingly complicated. However, very little is known about the combined effects of different factors from work and family spheres on WFC. This study aims to explore (1) the discrepancy between fit and misfit, (2) the discrepancy of the different degrees of fit, and (3) the discrepancy of the different degrees of misfit from two perspectives: work demand-family resource and work resource-family demand. Data were collected from 745 individuals in China and analyzed using polynomial regression and response surface. The results demonstrate that individuals having low work demand–high family resources experience the lowest WFC, and the fit between work demands and family resources impacts the conflict in a U way. Similarly, high work resource–low family demand results in the lowest WFC; however, the fit between work resources and family demands has negative effects on the conflict. This study took factors from both family and work domains into consideration and explored the effect of their interaction on WFC. By examining the dynamic relationship between demands and resources, adjustments can be made in both domains simultaneously, providing more flexible guidance for management practices that reduce WFC.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.

The regeneration of plant somatic cells is a prerequisite for their biological breeding. Identification of key genes controlling embryogenic callus (EC) differentiation and investigation of the genetic mechanism of cell fate determination are important for improving plant variety. In this study, we used the maize inbred line KN5585 and its gene-edited mutants Zmprx19-1, Zmprx19-2 and Zmprx19-3 as plant materials. Three somatic regeneration-related traits, the embryogenic callus induction rate (EIR), green callus rate (GCR) and plantlet regeneration rate (PRR), were identified by tissue culture of immature embryos. Additionally, the ECs at different differentiation stages (0 d, 5 d, 10 d and 15 d) were subjected to RNA-seq, and comparative transcriptome analyses were performed. The results showed that the somatic regeneration traits of the mutants were all highly significantly lower than those of the wild type (p < 0.01). The PRR value of KN5585 was 75.25%, while the highest PRR of the mutants was only 15.08%, indicating that knockdown of ZmPRX19 inhibited EC regeneration. Transcriptome sequencing yielded a total of 200.30 Gb of clean data from 24 libraries, with an average of 6.53 Gb of clean data per library. Mutant and wild-type gene expression data were compared separately at four differentiation stages, and 689 common differentially expressed genes (DEGs) were screened. WGCNA was used to classify these genes into nine modules, which were subsequently subjected to GO and KEGG enrichment analyses. In total, 40, 23, 17 and 5 genes were significantly (q < 0.05) enriched in plant hormone signal transduction, the MAPK signaling pathway-plant, phenylpropanoid biosynthesis and photosynthesis, respectively. Moreover, protein–protein interaction (PPI) network analysis revealed five MAPKKK17_18 hub nodes involved in the MAPK pathway-plant, which may be the key genes controlling plantlet differentiation from ECs. The above results provide a basis for the final elucidation of the molecular mechanism of plant somatic regeneration.

This work investigates the chemical effects of ethane, propane, and butane substitution for methane on flame properties and sooting behaviors in inverse diffusion flames of natural gas in different ratios by a decoupling method. Results show that the influences of varying natural gas ratios on the concentration distributions of soot particles and soot gaseous precursors are greater than on temperature. After a certain amount of methane is replaced by C2–C4 alkanes, the soot volume fraction (SVF) becomes more centerline-dominated. Meanwhile, the average primary particle diameter increases while the number density of primary particles and the average number of primary particles per aggregate decrease. Due to their chemical effects, C2–C4 alkanes not only promote the formation of H2, C2H2, and C4H4 but also contribute to an increase in A2, A3, and A4 formation. As for the soot formation reaction rates, the condensation rates are promoted. However, under varying ratios, C2–C4 alkanes demonstrate diverse chemical effects on the coagulation rates. Among three alkanes, ethane has the most pronounced chemical suppression effect on soot inception, HACA surface growth, and oxidation process rates. The combined effects of increased condensation and delayed oxidation rates result in elevated SVF in natural gas flames.

Abstract Background Cardiac myxoma (CM) is the most common (58%–80%) type of primary cardiac tumours. Currently, there is a need to develop medical therapies, especially for patients not physically suitable for surgeries. However, the mechanisms that shape the tumour microenvironment (TME) in CM remain largely unknown, which impedes the development of targeted therapies. Here, we aimed to dissect the TME in CM at single‐cell and spatial resolution. Methods We performed single‐cell transcriptomic sequencing and Visium CytAssist spatial transcriptomic (ST) assays on tumour samples from patients with CM. A comprehensive analysis was performed, including unsupervised clustering, RNA velocity, clonal substructure inference of tumour cells and cell–cell communication. Results Unsupervised clustering of 34 759 cells identified 12 clusters, which were assigned to endothelial cells (ECs), mesenchymal stroma cells (MSCs), and tumour‐infiltrating immune cells. Myxoma tumour cells were found to encompass two closely related phenotypic states, namely, EC‐like tumour cells (ETCs) and MSC‐like tumour cells (MTCs). According to RNA velocity, our findings suggest that ETCs may be directly differentiated from MTCs. The immune microenvironment of CM was found to contain multiple factors that promote immune suppression and evasion, underscoring the potential of using immunotherapies as a treatment option. Hyperactive signals sent primarily by tumour cells were identified, such as MDK, HGF, chemerin, and GDF15 signalling. Finally, the ST assay uncovered spatial features of the subclusters, proximal cell–cell communication, and clonal evolution of myxoma tumour cells. Conclusions Our study presents the first comprehensive characterisation of the TME in CM at both single‐cell and spatial resolution. Our study provides novel insight into the differentiation of myxoma tumour cells and advance our understanding of the TME in CM. Given the rarity of cardiac tumours, our study provides invaluable datasets and promotes the development of medical therapies for CM.

The uneven spatial distribution of mineral resources necessitates the construction of mature global mineral governance system to ensure rational allocation of mineral resources. To this end, it is essential to analyze the structure of the global mineral governance system to provide a theoretical basis for the construction. The governance actor is the crucial element in driving the governance process, and country serves as the most central actor. Therefore, clarifying the roles and statuses of different countries in the governance system will be helpful to analyze the structure of the governance system. In the context of advancing globalization, a complex cooperative relationship has been presented between countries based on international organizations. Thus, we establish a national cooperation network based on the principle of the co-existence of countries in international organizations, to quantify these relationships between countries and identify the role and status of different countries, as well as the country communities in the cooperation network, by combining the characteristics of the countries in the network with the actual performance in the organizations. The research findings are as follow: (1) The UK, Germany, France, Sweden, and Canada play pivotal roles in promoting international cooperation as well as leading governance in the governance system. (2) Emerging economies are more actively engaged in these organizations and can promote international cooperation, but lack the capacity to assume leadership roles in governance. (3) The U.S. and China have a stronger ability to lead than to cooperate in the governance system. (4) Most African and South American countries, as well as some European nations, are marginalized in the governance system. (5) Countries with the same needs and similar economic and political conditions belong to the same community: The European countries and the U.S., consumer with a high level of economic and political development but low mineral resource endowment are in the first community. Canada, Australia, and certain African and South American countries, producers with high mineral resource endowments are in the second community. Most African and South American countries with lower levels of economic and political development are in the third group.

Abstract Wounds can lead to skin and soft tissue damage and their improper management may lead to the growth of pathogenic bacteria at the site of injury. Identifying better ways to promote wound healing is a major unmet need and biomedical materials with the ability to promote wound healing are urgently needed. Here, we report a thermosensitive black phosphorus hydrogel composed of black phosphorus nano-loaded drug silver sulfadiazine (SSD) and chitosan thermosensitive hydrogel for wound healing. The hydrogel has temperature-sensitive properties and enables the continuous release of SSD under near-infrared irradiation to achieve synergistic photothermal and antibacterial treatment. Additionally, it exerts antibacterial effects on Staphylococcus aureus. In a rat skin injury model, it promotes collagen deposition, boosts neovascularization, and suppresses inflammatory markers. In summary, the excellent thermosensitivity, biocompatibility, and wound-healing-promoting qualities of the reported thermosensitive hydrogel make it suitable as an ideal wound dressing in the clinic.

Abundant {10–12} twins appeared in an extruded Mg-2.8Y (wt. %) sheet with rare-earth (RE) texture under compression along the transverse direction (TD). Twinning-detwinning behavior during compression-tension loading was quantitatively investigated via quasi-in-situ EBSD observation. The evolution of deformation mechanisms was quantitatively studied by calculation of the plastic strain fraction of twinning, detwinning, and dislocation slip. Twinning and detwinning were the dominant deformation modes in compression and reverse tension, respectively, owing to their relatively higher Schmid factors (SF) and lowest activation stresses (τ). Twin variants with SF ranking 1st and 2nd were activated preferentially while detwinning with low SF ranking showed high activation. The impact of texture and load path on variant selection was systematically discussed. Moreover, short twin chains only passing through two or three grains caused by twinning transfer were observed. Grain boundary misorientation angle (GBMA) and geometric compatibility factor (m’) were introduced to analyze the crystallographic characteristics of twinning transfer. GBMA ≤34.5° or m’ ≥ 0.80 is a necessary condition for most twinning transfer events. RE texture as well as the nearly uniform distribution of GBMA gave rise to short twin chains and restricted the formation of long twin bands. The relationship between GBMA and m’ was also discussed.

Abstract Recent studies have reported that miRNA plays an important role in immune response and immune repair after trauma. By regulating the expression of related target genes, miRNA regulates the production, proliferation, development and immune response of immune cells. Therefore, it is in urgent demand to develop an novel method for miRNA analysis. Rolling circle amplification (RCA), as an attractive isothermal signal amplification strategy, has been widely utilized in constructing miRNA detection assays. However, accurate and sensitive miRNA quantitative determination remains a huge challenge for RCA based approaches. Herein, we propose a DSN enzyme based signal cycle initiated Rolling Circle Amplification assay (DiRCA) for sensitive and accurate miRNA detection. In DiRCA, target miRNA unfolds hairpin structure probe in the detection scaffold, forming a RNA–DNA duplex. DSN enzyme is utilized to specifically digest the DNA sequence in RNA–DNA duplex, releasing miRNA to form a signal cycle; its capability to distinguish one base pair mismatch in RNA–DNA duplex endows DiRCA a high selectivity. Meanwhile, DSN enzyme based cleavage initiates RCA, transcribing G-rich sequences for signal generation. Based on the DSN assisted signal cycle and RCA, DiRCA shows a low limit of detection of 0.43 fM and a superior capability in selectively detecting mismatched miRNA sequences, showing a promising prospect in the early-diagnosis of disease.

IntroductionGait impairment is a common symptom among individuals with cerebral small vessel disease (CSVD). However, performance differences between single-task walking (STW) and dual-task walking (DTW) among individuals with CSVD remain unclear. Therefore, we aimed to examine differences in gait characteristics during STW and DTW as well as the association between gait performance and neuroimaging markers.MethodsWe enrolled 126 older individuals with CSVD. The speed, cadence, stride length, stride time, and their dual-task cost (DTC) or variability were measured under the STW, motor-cognitive DTW (cognitive DTW), and motor-motor DTW (motor DTW) conditions. We examined neuroimaging features such as white matter hyperintensities (WMHs), lacunes, microbleeds, and total burden. Further, we analysed the association of neuroimaging markers with gait performance, including gait variability and DTC.ResultsAlmost all spatiotemporal characteristics, as well as their DTCs or variabilities, showed significant among-group differences according to disease severity in the cognitive DTW condition; however, relatively lesser differences were observed in the STW and motor DTW conditions. The total CSVD burden score was moderately correlated with all the spatial parameters, as well as their DTCs or variabilities, in the cognitive DTW condition. Moreover, WMHs showed a correlation with speed, stride time, and cadence, as well as their DTCs, in the cognitive DTW condition. Furthermore, lacunes showed a moderate correlation with speed, stride length, and the DTC of speed, whilst microbleeds were only related to the DTC of stride length in the cognitive DTW condition. Neuroimaging biomarkers were not correlated with spatiotemporal parameters in STW and motor DTW conditions after Bonferroni correction. Moreover, the correlation coefficient between the total CSVD burden score and gait parameters was greater than those of other biomarkers.DiscussionParameters in the cognitive DTW condition are more appropriate than those in the motor DTW condition for the evaluation of gait abnormalities in patients with CSVD. Moreover, the total CSVD burden score might have better predictive utility than any single neuroimaging marker. Patients with CSVD, especially those with moderate-to-severe disease, should concentrate more on their gait patterns and reduce the load of secondary cognitive tasks whilst walking in daily life.

Grain refinement could promote the activation of non-basal slip and enhance the strength and ductility of Mg alloy simultaneously. In this work, the grain size effect on deformation modes and deformation heterogeneity and its relations to crystallographic orientation in a rolled Mg–1.58Zn–0.1Ca alloy sheet with a weakened transverse direction (TD) spread texture were investigated via intragranular misorientation axis (IGMA) and high resolution-digital image correlation (HR-DIC) measurement. The results indicate that a decrease of the grain size from 55 to 13 μm increased the yield strength (YS) by 56.9%, from 72 MPa to 113 MPa, for the TD samples, but only by 8% for the rolling direction (RD) samples, from 125.7 to 135.7 MPa. Moreover, grain refinement enhanced the elongation by 76.4% for the TD samples, from 11% to 19.1%, and merely by 26.5% for the RD samples, from 16.6% to 21%. The transition in dominant deformation modes due to grain size decreasing can be summarized as: for the RD samples: basal slip → prismatic slip; for the TD samples: basal slip + tension twinning → prismatic slip. The enhanced activity of prismatic slip in the fine-grained (FG)-TD and FG-RD samples can be ascribed to the reduced ratio of critical resolved shear stress (CRSS)prismatic/CRSSbasal. For both the RD and TD samples, grain refinement facilitated deformation homogeneity, which could be related to the enhanced activity of basal slip and non-basal slip, as well as the resulting improved deformation compatibility across grain boundary.

Southeast Tibet in China is rich in clean energy such as water energy, light energy, and wind energy. As the key means of large-scale clean energy transmission in southeast Tibet, the ultra-high voltage (UHV) power transmission projects will be constructed at an altitude of nearly 4000 m. To accurately acquire the external insulation strength of electrical equipment operating at different altitudes, the standard positive switching impulse voltages were applied to a rod electrode and a 1.1 m diameter shielding sphere at the altitude of 3400, 2100, and 80 m. The switching impulse discharge characterization and altitude correction factors of the 1.1 m diameter shielding sphere-plate gap under different clearances at different altitudes were obtained. The discharge voltage of the rod-plate gap at the altitude of 80 m was corrected to the altitude of 3400 m using altitude correction methods recommended by GB 311.1, GB/T 16927.1, and DL/T 2305. Further comparison was made between the calculation results using the three altitude correction methods mentioned above and the test results at an altitude of 3400 m. The discharge characterization and the minimum clearance of the end fittings of the electrical equipment in the valve hall at the altitude of 3800 and 4500 m were obtained by fitting and extrapolating the test data. The research results provide important reference significance for the external insulation configuration of UHV converter stations constructed in areas with an altitude of 3000 m and above.

Abstract Background Lymphangioleiomyomatosis (LAM) is a female‐predominant interstitial lung disease, characterized by progressive cyst formation and respiratory failure. Clinical treatment with the mTORC1 inhibitor rapamycin could relieve partially the respiratory symptoms, but not curative. It is urgent to illustrate the fundamental mechanisms of TSC2 deficiency to the development of LAM, especially mTORC1‐independent mechanisms. Glutaredoxin‐1 (Glrx), an essential glutathione (GSH)‐dependent thiol‐oxidoreductase, maintains redox homeostasis and participates in various processes via controlling protein GSH adducts. Redox signalling through protein GSH adducts in LAM remains largely elusive. Here, we demonstrate the underlying mechanism of Glrx in the pathogenesis of LAM. Methods 1. Abnormal Glrx expression in various kinds of human malignancies was identified by the GEPIA tumour database, and the expression of Glrx in LAM‐derived cells was detected by real‐time quantitative reverse transcription (RT‐qPCR) and immunoblot. 2. Stable Glrx knockdown cell line was established to evaluate cellular impact. 3. Cell viability was determined by CCK8 assay. 4. Apoptotic cell number and intracellular reactive oxygen species (ROS) level were quantified by flow cytometry. 5. Cox2 expression and PGE2 production were detected to clarify the mechanism of Bim expression modulated by Glrx. 6. S‐glutathionylated p65 was enriched and detected by immunoprecipitation and the direct regulation of Glrx on p65 was determined. 7. The xenograft animal model was established and photon flux was analyzed using IVIS Spectrum. Results In LAM, TSC2 negatively regulated abnormal Glrx expression and activation in a mTORC1‐independent manner. Knockdown of Glrx increased the expression of Bim and the accumulation of ROS, together with elevated S‐glutathionylated proteins, contributing to the induction of apoptotic cell death and inhibited cell proliferation. Knockdown of Glrx in TSC2‐deficient LAM cells increased GSH adducts on nuclear factor‐kappa B p65, which contributed to a decrease in the expression of Cox2 and the biosynthesis of PGE2. Inhibition of PGE2 metabolism attenuated phosphorylation of ERK, which led to the accumulation of Bim, due to the imbalance of its phosphorylation and proteasome degradation. In xenograft tumour models, knockdown of Glrx in TSC2‐deficient LAM cells inhibited tumour growth and increased tumour cell apoptosis. Conclusions Collectively, we provide a novel redox‐dependent mechanism in the pathogenesis of LAM and propose that Glrx may be a beneficial strategy for the treatment of LAM or other TSC‐related diseases.

Abstract Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation. Knockdown of SPHK1 showed reduced viability, migration and invasion in TSC2-deficient cells. Selective SPHK1 antagonist PF543 potently suppressed the viability of TSC2-deficient cells and induced autophagy-mediated cell death. Meanwhile, the cognate receptor S1PR3 was identified to mediating the tumorigenic effects of sphingosine-1-phosphate (S1P). Treatment with TY52156, a selective antagonist for S1PR3, or genetic silencing using S1PR3-siRNA suppressed the viability of TSC2-deficient cells. Both SPHK1 and S1PR3 inhibitors markedly exhibited antitumor effect in a xenograft model of TSC2-null cells, restored autophagy level, and triggered cell death. Together, we identified novel rapamycin-insensitive sphingosine metabolic signatures in TSC2-null LAM cells. Therapeutic targeting of aberrant SPHK1/S1P/S1PR3 signaling may have potent therapeutic benefit for patients with TSC/LAM or other hyperactive mTOR neoplasms with autophagy inhibition.

Abstract Porcine circovirus‐like virus P1, like porcine circovirus type 2 (PCV2), is a potential pathogen of post‐weaning multisystemic wasting syndrome in swine. Yaks are a valuable species and an iconic symbol of the Tibet Plateau which is the highest and largest plateau in the world. In this study, a total of 105 yak diarrheal samples, collected from 13 farms in Linzhi in the Tibet Plateau from January 2019 to December 2021, that were screened for P1 and PCV2 by polymerase chain reaction, 10.48% (n = 11) were positive for P1, 4.76% (n = 5) for PCV2, and 5.71% (n = 6) were positive for coinfection of P1 and PCV2. In addition, the whole genomes of eight P1 strains and eight PCV2 strains were sequenced. Alignment of deduced amino acid sequences of P1 ORF1 and PCV2 ORF2 gene revealed that ON012566 had one unique amino acid mutation at residues 137 (T to P). This mutation has important implication for the study of virus virulence, tissue tropism, and immune response. Phylogenetic analysis shows that the yak‐origin P1 strains in this study with cattle‐origin P1 reference strains were grouped into one cluster. The yak‐origin PCV2 (ON012566) and a buffalo‐origin PCV2 (KM116514) reference strain clustered in the same branch in the PCV2b regions. Meanwhile, the remaining PCV2 strains and buffalo‐origin PCV2 reference strain (ON012565) clustered in the PCV2d regions. To summarize, to our knowledge, this is the first report on the molecular prevalence and genome characteristics of P1 and PCV2 in yaks in the world and will contribute to further study of the molecular epidemiology, source, and evolution of P1 and PCV2 strains.

Abstract Background Abscisic acid receptors (ABR) involve transduction of the ABA signaling in plants, impacting largely on stress-defensive physiological processes and plant osmotic stress response. In this study, we characterized TaPYL4, a gene of ABR family in T. aestivum, in mediating plant drought tolerance given scarcity of functional characterization on wheat ABR members thus far. Results TaPYL4 harbors nine conserved domains shared by its PYL counterparts, targeting onto plasma membrane and nucleus after endoplasmic reticulum assortment. TaPYL4 interacts with TaPP2C2 whereas the latter with TaSnRK2.1, which establish a core module of the ABA signaling pathway. TaPYL4 expression was upregulated in root and aerial tissues upon drought stress. Overexpressing TaPYL4 conferred plants improved growth traits whereas knockdown expression of target gene alleviated growth feature compared with wild type under drought treatment. The TaPYL4-enhanced drought adaptation associates gene function in positively regulating stomata movement, osmolyte biosynthesis, and root system architecture (RSA) establishment. Expression analysis on the P5CS family genes involving proline biosynthesis indicated that TaP5CS1 exerts critical roles in promoting osmolytes accumulation in drought-challenged TaPYL4 lines. TaPIN9, a PIN-FORMED gene modulating cellular auxin translocation, was validated to function as a crucial mediator in defining RSA establishment underlying TaPYL4 regulation. Transcriptome analysis revealed that TaPYL4 controls transcription of numerous genes, which impact on physiological processes associated with ‘biological process’, ‘molecular component’, and ‘cellular process’. Moreover, the differentially expressed genes mediated by TaPYL4 were closely related to stress defensive pathways. Conclusions Our investigation suggested that TaPYL4 acts as a positive regulator in plant drought tolerance and a valuable target for engineering drought-tolerant cultivars in T. aestivum.

This work proposed a novel model to simultaneously reconstruct temperature distribution and soot volume fraction field for two-dimensional thin-slice flames using the knowledge of monochromatic radiation intensities at two wavelengths using a CCD camera. The deduction process and numerical analysis of the model were described. Effects of wavelength combinations and measurement errors on reconstruction accuracy were considered in detail. Numerical results have proven the model’s accuracy and showed that the temperature and soot volume fraction fields can be reconstructed well even with noisy input data from flame radiation. In addition, a series of experiments were conducted on a mesoscale combustor to obtain the real thin-slice flames for further experimental reconstruction via the model. The experimental results indicated that the proposed model can successfully reconstruct the flame temperature distribution and soot volume fraction field and the main features of thin-slice flames also can be reasonably reproduced.

Abstract Background Spermatogenesis is an intricate developmental process during which undifferentiated spermatogonia, containing spermatogonial stem cells (SSCs), undergo self-renewal and differentiation to generate eventually mature spermatozoa. Spermatogenesis occurs in seminiferous tubules within the testis, and the seminiferous tubules harbor Sertoli and germ cells. Sertoli cells are an essential somatic cell type within the microenvironment that support and steer male germ cell development, whereas spermatogonia are the primitive male germ cells at the onset of spermatogenesis. While the developmental progression of Sertoli cells and spermatogonia has been well established in mice, much less is known in other mammalian species including pigs. Results To acquire knowledge of Sertoli cell and spermatogonial development in pigs, here we collected as many as nine ages of Duroc porcine testes from the neonate to sexual maturity, i.e., testes from 7-, 30-, 50-, 70-, 90-, 110-, 130-, 150- and 210-day-old boars, and performed histological and immunohistochemical analyses on testis sections. We first examined the development of spermatogenic cells and seminiferous tubules in porcine testes. Then, by immunofluorescence staining for marker proteins (AMH, SOX9, DBA, UCHL1, VASA, KIT, Ki67 and/or PCNA), we delved into the proliferative activity and development of Sertoli cells and of spermatogonial subtypes (pro-, undifferentiated and differentiating spermatogonia). Besides, by immunostaining for β-catenin and ZO-1, we studied the establishment of the blood-testis barrier in porcine testes. Conclusions In this longitudinal study, we have systematically investigated the elaborate Sertoli cell and spermatogonial developmental patterns in pigs from the neonate to sexual maturity that have so far remained largely unknown. The findings not only extend the knowledge about spermatogenesis and testicular development in pigs, but also lay the theoretical groundwork for porcine breeding and rearing.

Research on the ovarian development of insect pests helps provide key information for predicting pest occurrences, and currently, there is very limited information about the reproductive system of Ceracris kiangsu Tsai. This study aimed to assess the reproductive fitness of 321 adult female insects by using traditional methods to dissect female adults, measure female ovaries, and assess the process of egg formation. The phenotypic traits including body weight and body length were also measured and used to estimate the model of ovarian developmental stages. Four ovarian developmental stages before the oviposition were identified, and the fundamental ovarian structure of C. kiangsu displayed red dots on the matured eggs inside the calyx at ovarian developmental stage V. The accessory glands of C. kiangsu had the deepest folds at stage Ⅲ. Redundancy analysis (RDA) was used to explore the correlation between ovarian development, body weight, and body length. A significant positive correlation was observed for body weight (p = 0.001) and body length (p = 0.009), which varied with the grade of ovarian development evaluated by the ovarian developmental stage, ovarian length, ovarian width, and ovarian cross-sectional area. A partial least square (PLS) regression was used to model the ovarian developmental stage, with a stage-based PLS being identified as the more effective method, which was y = 1.509x1 + 0.114x2. The model provides a potentially rapid way to identify the population source as either “native” or “immigrant” from the phenotypic traits without dissection. The aforementioned model may be used to estimate adult emergence periods and identify migratory populations from their ovarian development, potentially aiding in implementing proper prevention measures.

The flash ignition as a new ignition method has attracted lots of interest from researchers. The flash ignition can successfully achieve distributed ignition in a short time. To study the flash ignition and combustion characteristics of titanium dioxide mixed with iron nanoparticles and aluminum nanoparticles, an appropriate amount of titanium dioxide was added to the iron nanoparticles and aluminum nanoparticles to form the composite material. The ignition phenomenon of mixture materials was recorded by the high-speed camera and the temperature distribution of ignited materials was calculated by using the two-color method. The minimum ignition energy of mixture materials with different content of titanium dioxide and total mass was measured to analyze the method to decrease the minimum ignition energy. The results showed that the effect of the added titanium dioxide was insignificant on the combustion phenomenon of the iron nanoparticles. The temperature was still maintained at approximately 850 K compared with the pure iron nanoparticles. The minimum ignition energy of the mixture materials increased with the increasing content of titanium dioxide. As for the aluminum nanoparticles, titanium dioxide can enhance the explosion phenomenon occurring at the beginning of the flash ignition. In the exposure process. With the content of titanium dioxide in the range of 0%–20%, the minimum ignition energy of the mixture materials decreased greatly. The content increased to the range of 20%–40%, the minimum ignition energy was neglected. When the content was further increased to higher than 60%, the minimum ignition energy gradually increased until it gets the saturation condition.

Abstract Background The important role of long noncoding RNAs (lncRNAs) in cancer has been demonstrated in many studies. Prostate cancer gene expression marker 1 (PCGEM1) is a lncRNA specifically expressed within the prostate and overexpressed in many cancer cells. Numerous studies have shown that PCGEM1 promotes cell proliferation, invasion and migration. However, the specific mechanism of PCGEM1 within prostate cancer (PCa) has not been elucidated. MicroRNA-506-3p (miR-506-3p) is a noncoding RNA, and studies have indicated that miR-506-3p is downregulated in prostate cancer cell lines and functions as a tumor suppressor. Methods The TCGA (GEPIA) database ( http://gepia.cancer-pku.cn/ ) was employed to measure PCGEM1 levels in PCa. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the PCGEM1 gene level. CCK-8 (Cell Counting Kit-8) and colony formation assays were used to detect cell proliferation, and Transwell assays were applied to assess cell invasion and migration. The interacting ability of miR-506-3p with PCGEM1 or TRIAP1 was validated through a dual-luciferase reporter assay. TRIAP1 protein expression was detected by Western blotting. Results PCGEM1 expression was increased in PCa tissues and cells. In PCa tissues, High PCGEM1 expression was associated with high Gleason score, distant metastasis and extracapsular extension. In addition, PCGEM1 knockdown inhibited PCa cell (C4-2B and PC-3) proliferation, invasion and migration. miR-506-3p may interact with PCGEM1 or TRIAP1, and the suppressive effect of PCGEM1 knockdown was reversed when TRIAP1 or a miR-506-3p inhibitor was cotransfected. Conclusion PCGEM1 expression increased in PCa cells and tissues, enhancing PCa cell proliferation, migration and invasion by sponging miR-506 to upregulate TRIAP1.

Steel rebar corrosion is one of the predominant factors influencing the durability of marine and offshore reinforced concrete structures, resulting in economic loss and the potential threat to human safety. Distributed fiber optic sensors (DFOSs) have gradually become an effective method for structural health monitoring over the past two decades. In this work, a strain transfer model is developed between a steel rebar and a DFOS, considering pitting-corrosion-induced strain variation in the steel rebar. The Gaussian function is first adopted to describe the strain distribution near the corrosion pit of the steel rebar and then is substituted into the governing equation of the strain transfer model, and the strain distribution in the DFOS is analytically obtained. Tensile tests are also conducted on steel rebars with artificially simulated corrosion pits, which are used to validate the developed model. The results show that the Gaussian function can be used to describe the strain variation near a corrosion pit with a depth less than 50% of the steel rebar diameter, and the strain distribution in the DFOS analytically determined based on the developed strain transfer model agrees well with the tensile test results. The corrosion pit depth and loading force in the steel rebars estimated based on the proposed model agree well with the actual values, and therefore, the developed strain transfer model is effective in detecting pitting corrosion and loading force in steel rebars.

The mechanical properties and failure characteristics of columnar jointed rock mass (CJRM) are significantly influenced by its irregular structure. Current research on CJRMs is mainly under static loading, which cannot meet the actual needs of engineering. This paper adopts the finite element method (FEM) to carry out numerical simulation tests on irregular CJRMs with different dip angles under different dynamic stress wave loadings. The dynamic failure modes of irregular CJRMs and the influence law of related stress wave parameters are obtained. The results show that when the column dip angle α is 0°, the tensile-compressive-shear failure occurs in the CJRMs; when α is 30°, the CJRMs undergo tensile failure and a small amount of compressive shear failure, and an obvious crack-free area appears in the middle of the rock mass; when α is 60°, tensile failure is dominant and compressive shear failure is minimal and no crack area disappears; and when α is 90°, the rock mass undergoes complete tensile failure. In addition, in terms of the change law of stress wave parameters, the increase in peak amplitude will increase the number of cracks, promote the development of cracks, and increase the proportion of compression-shear failure units for low-angle rock mass. The changes in the loading and decay rate only affect the degree of crack development in the CJRMs, but do not increase the number of cracks. Meanwhile, the simulation results show that the crack expansion velocity of the CJRMs increases with the increase in dip angle, and the CJRMs with dip angle α = 60° are the most vulnerable to failure. The influence of the loading and decay rate on the rock mass failure is different with the change in dip angle. The results of the study provide references for related rock engineering.

For hydrocarbon exploitation in tight glutenite, glutenite brittleness plays an important role in fracturing efficiency, but the detailed effect is not entirely clear. In this study, considering rock heterogeneity, RFPA (Rock Failure Process Analysis) was applied to establish the three-dimension computational model. An improved rock brittleness index considering post-peak properties in rock uniaxial compression test was proposed to quantify the glutenite brittleness. Results show that brittle glutenite can generate multiple failure surfaces under the exterior loadings, which can be a mirror to reveal the denser development of natural fractures in the brittle reservoir, while the ductile glutenite is prone to generate a simple shear failure. Hydraulic fractures propagate faster in more brittle glutenite and can generate short branches, which is beneficial to connect the reservoir natural fractures and form complex hydraulic fractures. Brittle glutenite requires a lower treatment pressure than the ductile glutenite, which can provide convenience for ground pumping operation. Hydraulic fractures prefer to propagate in brittle glutenite, rather than the ductile glutenite. The obtained conclusions can provide a reference for the similar practice.

In measuring the flame temperature and radiative properties, the light field camera is subject to the visible bands of the spectral snapshot measurement in a single shot. In this paper, the infrared light field camera is proposed to improve the spectral range of detection. The effects of the participating media on the infrared light field imaging are clarified. The temperature detection ranges of visible, near-infrared, and mid-infrared spectral bands are analyzed. The coupling effects of radiative properties of gas and soot on the mid-infrared light field imaging are compared. The light field imaging results show that the temperature detection range in the mid-infrared band is twice as much as that in the visible band. The gas and soot radiative properties have recognizable effects on the mid-infrared light field images. The absorption coefficient takes the primary role, while the scattering effects by 0.275. The mid-infrared light field camera is used to take snapshots of the flame. The temperature detection range is wider than the visible band, the gas and soot laden changes the flame structure. This work can be used as theoretical support for the design and application of infrared light field camera to diagnose the flame temperature and radiation properties.

BackgroundPulmonary atresia (PA) is a heterogeneous congenital heart defect and ventricular septal defect (VSD) is the most vital factor for the conventional classification of PA patients. The simple dichotomy could not fully describe the cardiac morphologies and pathophysiology in such a complex disease. We utilized the Human Phenotype Ontology (HPO) database to explore the phenotypic patterns of PA and the phenotypic influence on prognosis.MethodsWe recruited 786 patients with diagnoses of PA between 2008 and 2016 at Fuwai Hospital. According to cardiovascular phenotypes of patients, we retrieved 52 HPO terms for further analyses. The patients were classified into three clusters based on unsupervised hierarchical clustering. We used Kaplan–Meier curves to estimate survival, the log-rank test to compare survival between clusters, and univariate and multivariate Cox proportional hazards regression modeling to investigate potential risk factors.ResultsAccording to HPO term distribution, we observed significant differences of morphological abnormalities in 3 clusters. We defined cluster 1 as being associated with Tetralogy of Fallot (TOF), VSD, right ventricular hypertrophy (RVH), and aortopulmonary collateral arteries (ACA). ACA was not included in the cluster classification because it was not an HPO term. Cluster 2 was associated with hypoplastic right heart (HRH), atrial septal defect (ASD) and tricuspid disease as the main morphological abnormalities. Cluster 3 presented higher frequency of single ventricle (SV), dextrocardia, and common atrium (CA). The mortality rate in cluster 1 was significantly lower than the rates in cluster 2 and 3 (p = 0.04). Multivariable analysis revealed that abnormal atrioventricular connection (AAC, p = 0.011) and persistent left superior vena cava (LSVC, p = 0.003) were associated with an increased risk of mortality.ConclusionsOur study reported a large cohort with clinical phenotypic, surgical strategy and long time follow-up. In addition, we provided a precise classification and successfully risk stratification for patients with PA.

Gallium is deemed to be a critical mineral given its irreplaceable use in consumer electronics and clean energy technologies. China has become a significant consumer of gallium while also playing a leading role in global gallium production, accounting for more than 90% of the world’s primary output in recent years. However, the quantification and evolution of China’s gallium cycle is limited until now. This study aims to uncover the dynamic flows and stocks of gallium in China during the period of 2005–2020. The results reveal that: 1) From 2005 to 2020, China’s gallium demand increased more than 20-fold, as a result of the booming semiconductor industry and the surging use of gallium in some low-carbon technologies; 2) despite the inefficient recovery issues existed in the production stage, the supply of gallium extracted as a byproduct grew in tandem with the capacity of alumina production, resulting in a significant supply surplus of 948 t by 2020; 3) China exported nearly half of its gallium mainly as raw materials and final products, but still experienced a high reliance on imported gallium-containing intermediate products from abroad, such as integrated circuits; 4) the generations of in-use stocks and end-of-life flows of gallium have accelerated since 2005 and reached about 278 t and 169 t in 2020, respectively. These indicate a large amount of available secondary gallium resource, with nonexistent recycling. The results provide a basis for identifying gallium extraction, use, loss and recycling within its anthropogenic cycle in China, as well as guidance for stakeholders to make future decisions concerning ways to improve resource efficiency and promote sustainable gallium practices from a dynamic material cycle perspective.

Summary: Background: Previously, we uncovered a patient subgroup with highly malignant pancreatic cancer with serum markers CEA+/CA125+/CA19-9 ≥ 1000 U/mL (triple-positive, TP). However, the underlying immunosuppressive mechanism in the tumor immune microenvironment (TIME) of this subgroup is still unknown. Methods: Human tissues were analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Mouse pancreatic ILC2s were expanded in vivo and used for RNA sequencing, chromatin immunoprecipitation (ChIP), and chemotaxis assays. Findings: Through microarray data, we identified the accumulation of the hypoxia-induced factor-1α (HIF-1α) pathway in these TP patients. Via flow and mass cytometry, we discovered that a special subset of ILC2s were highly infiltrated in TP patients. Under the hypoxia microenvironment, ILC2s were found undergo a transition to a IL10+ regulatory phenotype, we named ILCregs which was correlated with pancreatic ductal adenocarcinoma (PDAC) progression. Further, neoadjuvant chemotherapy could ameliorate hypoxic tumor microenvironments so that significantly reverse the regulatory phenotype of ILCregs. Moreover, most tumor ILC2 were CD103−, which indicated its circulatory origin. The expression of Ccr2 was significantly upregulated on mouse ILCregs, and these cells selectively migrated to CCL2. Interpretation: Our results indicate that the hypoxia microenvironment creates an immunosuppressive TIME by inducing ILCregs from a population of circulating group 2 ILCs in TP PDAC patients. Funding: This study was jointly supported by the National Natural Science Foundation of China (U21A20374, 82173091, and 81701630)

Xanthomonas oryzae pv. textitoryzae (Xoo) is a causal agent of rice bacterial leaf blight (BLB), the major rice disease, which is seriously constraining rice production in Asia. The interaction between Xoo and rice is in a dynamic process, essentially the co-evolution. Tracking the occurrence of plant diseases and identifying the epidemic pathogens in time are critical to assessing the epidemic disease status and understanding the pathogen evolution. In 2020, the occurrences of rice BLB were spotted in many places of Guangxi, the major rice growing region in China. Two of the 2020-epidemic Xoo strains, namely, GXO20-01 and GXO20-06, were isolated from low land and high mountain paddies in Guangxi, respectively, and were demonstrated to be race R8 of Chinese Xoo strains, but with significantly different virulence on certain susceptible varieties of rice. The HiFi PacBio sequencing revealed that GXO20-01 and GXO20-06 share the highly syntenic genome structures and the major genome contents, but only differ in

Abstract Background Invasive candidiasis is the most common fungal disease among hospitalized patients and continues to be a major cause of mortality. Risk factors for mortality have been studied previously but rarely developed into a predictive nomogram, especially for cancer patients. We constructed a nomogram for mortality prediction based on a retrospective review of 10 years of data for cancer patients with invasive candidiasis. Methods Clinical data for cancer patients with invasive candidiasis during the period of 2010–2019 were studied; the cases were randomly divided into training and validation cohorts. Variables in the training cohort were subjected to a predictive nomogram based on multivariate logistic regression analysis and a stepwise algorithm. We assessed the performance of the nomogram through the area under the receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) in both the training and validation cohorts. Results A total of 207 cases of invasive candidiasis were examined, and the crude 30-day mortality was 28.0%. Candida albicans (48.3%) was the predominant species responsible for infection, followed by the Candida glabrata complex (24.2%) and Candida tropicalis (10.1%). The training and validation cohorts contained 147 and 60 cases, respectively. The predictive nomogram consisted of bloodstream infections, intensive care unit (ICU) admitted > 3 days, no prior surgery, metastasis and no source control. The AUCs of the training and validation cohorts were 0.895 (95% confidence interval [CI], 0.846–0.945) and 0.862 (95% CI, 0.770–0.955), respectively. The net benefit of the model performed better than “treatment for all” in DCA and was also better for opting low-risk patients out of treatment than “treatment for none” in opt-out DCA. Conclusion Cancer patients with invasive candidiasis exhibit high crude mortality. The predictive nomogram established in this study can provide a probability of mortality for a given patient, which will be beneficial for therapeutic strategies and outcome improvement.

Background & Aims: Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. Methods: Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. Results: Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. Conclusions: This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.

Tunnel excavation inevitably causes surface deformation. In urban areas, surface deformation could lead to the deformation of surrounding buildings, which may cause damage to communities when accumulated to a certain extent. However, the current construction organization and management mainly rely on on-site deformation measurements, and there is still a lack of reliable prediction methods. Here, we proposed an effective evaluation method for frame building deformation based on the stochastic medium theory and the equivalent beam theory. This method could effectively evaluate the surface and building deformation after a horseshoe tunnel excavation by considering the non-uniform convergence. Furthermore, its accuracy and practicability were verified using the Nanyan Fourth Circuit Transmission Reconstruction located in Dalian, China. The results show that the spatial distribution and characteristic values of the maximum tensile strains were closely related to the ratio of Young’s modulus to the shear modulus (E/G), the building height (h), the tunnel depth (H), the tangent of the tunnel influence angle (tan β) and the convergence radius (ΔR). These achievements can provide a theoretical basis and analytical ideas for investigating the influence of shallow buried tunnel excavation on frame structure buildings in cities.

To meet the current demand of assisted reproduction and animal breeding via superovulation and reduce the impact of hormone drugs, it is necessary to develop new superovulation drugs. This study examined the role of inflammation and steroids in ovulation. Sodium salicylate can regulate inflammation and steroids. However, the effect of sodium salicylate on ovulation has not been studied. In this study, mice were intraperitoneally injected with different concentrations of sodium salicylate for four consecutive days. The effects of sodium salicylate on oocyte quality and on the number of ovulations were examined, and these effects were compared with those of pregnant horse serum gonadotropin (PMSG)/follicle-stimulating hormone (FSH) treatment. We found that low-dose sodium salicylate increased the levels of ovulation hormones and inflammation by promoting the expression of CYP17A1. Sodium salicylate had the same effect as the commonly used superovulation drug PMSG/FSH and reduced the histone methylation level. Sodium salicylate can promote ovulation in mice and Awang sheep. It can greatly decrease the use of hormone drugs, reduce breeding costs and physical impacts, and can thus be used for livestock breeding.

AimsThoracic aortic dissection (TAD) is a life-threatening disease with no effective drug therapy thus far. New therapeutic targets and indications for timely surgical intervention are urgently needed. Our aim is to investigate new pathological mechanisms and potential biomarkers of TAD through global metabolomic profiling of aortic aneurysm and dissection patients.Methods and ResultsWe performed untargeted metabolomics to determine plasma metabolite concentrations in an aortic disease cohort, including 70 thoracic aortic aneurysm (TAA) and 70 TAD patients, as well as 70 healthy controls. Comparative analysis revealed that sphingolipid, especially its core metabolite C18-ceramide, was significantly distinguished in TAD patients but not in TAA patients, which was confirmed by subsequent quantitative analysis of C18-ceramide in a validation cohort. By analyzing our existing multiomics data in aortic tissue in a murine TAD model and TAD patients, we found that an enhanced ceramide de novo synthesis pathway in macrophages might contribute to the elevated ceramide. Inhibition of the ceramide de novo synthesis pathway by myriocin markedly alleviated BAPN-induced aortic inflammation and dissection in mice. In vitro studies demonstrated that exogenous C18-ceramide promoted macrophage inflammation and matrix metalloprotein (MMP) expression through the NLRP3-caspase 1 pathway. In contrast, inhibition of endogenous ceramide synthesis by myriocin attenuated lipopolysaccharide (LPS)-induced macrophage inflammation.ConclusionsOur findings demonstrated that ceramide metabolism disturbance might play a vital role in TAD development by aggravating aortic inflammation through the NLRP3 pathway, possibly providing a new target for pharmacological therapy and a potential biomarker of TAD.

The outbreak of viral pneumonia caused by the novel coronavirus SARS-CoV-2 that began in December 2019 caused high mortality. It has been suggested that the main protease (Mpro) of SARS-CoV-2 may be an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. Remdesivir, ritonavir and chloroquine have all been reported to play a role in suppressing SARS-CoV-2. Here, we applied a molecular docking method to study the binding stability of these drugs with SARS-CoV-2 Mpro. It appeared that the ligand–protein binding stability of the alliin and SARS-CoV-2 Mpro complex was better than others. The results suggested that alliin may serve as a good candidate as an inhibitor of SARS-CoV-2 Mpro. Therefore, the present research may provide some meaningful guidance for the prevention and treatment of SARS-CoV-2.

Northern China contains some of the world’s earliest farming societies. Here, authors use 55 ancient genomes to trace the genetic history of human migrations across northern China for the last 7500 years, and document genetic changes mirroring shifts in subsistence strategy.

For decades, China’s rural migrants have split their households between their rural origins and urban work locations. While the hukou system continues to be a barrier to urban settlement, research has also underscored split households as a migrant strategy that spans the rural and urban boundary, questioning if sustained migration will eventually result in permanent urban settlement. Common split-household arrangements include sole migration, where the spouse and children are left behind, and couple migration, where both spouses are migrants, leaving behind their children. More recently, nuclear family migration involving both the spouse and children has been on the rise. Based on a 2015 nationally representative “floating population” survey, this article compares sole migrants, couple migrants, and family migrants in order to examine which migrants choose which household arrangements, including whether specific household arrangements are more associated with settlement intention than others. Our analysis also reveals differences between work-related migrants and family-related migrants. The findings highlight demographic, gender, economic, employment, and destination differences among the different types of migrant household arrangements, pointing to family migration as a likely indicator of permanent settlement. The increase of family migration over time signals to urban governments an increased urgency to address their needs as not only temporary dwellers but more permanent residents.

Abstract Background Spermatogonial stem cells (SSCs) are the cornerstone of sperm production and thus perpetual male fertility. In clinics, transplantation of patient’s own SSCs into testes is a promising technique to restore fertility when male germ cells have been depleted by gonadotoxic therapies. Auto-transplantation of genetically modified SSCs even has the potential to treat male infertility caused by genetic mutations. However, SSCs are refractory to transfection approaches. Poly(amidoamine) (PAMAM) dendrimers have the unique three-dimensional architecture, surface charge, and high density of surface groups that are suitable for ligand attachment, thereby facilitating target delivery. The goal of this study was to elucidate whether PAMAM dendrimers can efficiently deliver short interfering RNAs (siRNAs) to SSCs. Methods and results We introduced cyclic arginine-glycine-aspartic acid (cRGD) peptides to the fifth generation of PAMAM dendrimers (G5) to generate PAMAM-cRGD dendrimers (G5-cRGD). The characterization of G5-cRGD was detected by Fourier transform infrared spectroscope (FTIR), transmission electron microscope (TEM), and the Cell Counting Kit-8 (CCK-8) assay. Confocal microscopy and flow cytometry were used to evaluate the delivery efficiency of siRNA by G5-cRGD to SSCs. The results showed that G5-cRGD encompassing siRNA could self-assemble into spherical structures with nanoscale size and possess high transfection efficiency, excellent endosomal escape ability, and low cytotoxicity, superior to a commercial transfection reagent Lipofectamine® 2000. Moreover, we demonstrated that G5-cRGD efficiently delivered siRNAs and triggered gene silencing. Conclusions This study thus provides a promising nanovector for siRNA delivery in SSCs, facilitating the future clinical application of SSC auto-transplantation with genetically modified cells with a hope to cure male infertility that is caused by genetic disorders.

The latest industrial revolution, Industry 4.0, is driven by the emergence of digital manufacturing and, most notably, additive manufacturing (AM) technologies. The simultaneous material and structure forming in AM broadens the material and structural design space. This expanded design space holds a great potential in creating improved engineering materials and products that attract growing interests from both academia and industry. A major aspect of this growing interest is reflected in the increased adaptation of data‐driven tools that accelerate the exploration of the vast design space in AM. Herein, the integration of data‐driven tools in various aspects of AM is reviewed, from materials design in AM (i.e., homogeneous and composite material design) to structure design for AM (i.e., topology optimization). The optimization of AM tool path using machine learning for producing best‐quality AM products with optimal material and structure is also discussed. Finally, the perspectives on the future development of holistically integrated frameworks of AM and data‐driven methods are provided.

The additive manufacturing (AM) industry is rapidly developing and expanding, thereby becoming an important and integral component of the digital revolution in manufacturing practices. While the engineering aspects of AM are under intensive research, there still remain many chances to strengthen the sustainability of additive manufacturing (SAM). Cogently increasing the AM community's attention to SAM is vital for developing the AM industry sustainably from the bottom up. The digital nature of AM provides new opportunities for acquiring, storing, and utilizing data to strengthen SAM through data‐driven approaches. Herein, spotlight on SAM is shone upon and it is placed on a more concrete footing. The corresponding advances in data‐driven methods that can strengthen SAM are featured, such as optimizing designs for AM, reducing material waste, and developing databases. How the AM workforce can be developed and grown as a collaboration between the industry, government, and academia to extensively harness the full potential of AM as well as mitigate its adversarial social impact is discussed. Finally, several critical digital techniques that have the potential to further strengthen SAM in the factory of the future, including hybrid manufacturing, Internet of Things, and machine learning and artificial intelligence, are highlighted.

Summary: Anthropology began in the late nineteenth century with an emphasis on kinship as a key factor in human evolution. From the 1960s, archaeologists attempted increasingly sophisticated ways of reconstructing prehistoric kinship but ancient DNA analysis has transformed the field, making it possible, to directly examine kin relations from human skeletal remains. Here, we retrieved genomic data from four Late Neolithic individuals in central China associated with the Late Neolithic Longshan culture. We provide direct evidence of consanguineous mating in ancient China, revealing inbreeding among the Longshan populations. By combining ancient genomic data with anthropological and archaeological evidence, we further show that Longshan society household was built based on the extended beyond the nuclear family, coinciding with intensified social complexity during the Longshan period, perhaps showing the transformation of large communities through a new role of genetic kinship-based extended family units.

Patient-specific hiPSCs (NCCDFWi001-A) were generated from a patient with Marfan syndrome carrying a compound heterozygous variant (c.684_736 + 4del, p.Pro228fs and c.2613A>C, p.Leu871Phe). Here, we used CRISPR/ Cas9 to correct the FBN1 c.2613A>C variant, which generated an hiPSC line (NCCDFWi001-A-1) that maintained normal karyotype, pluripotency markers and demonstrated potential for trilineage differentiation.

In this paper, the influence of the edge effect on the simultaneous reconstruction of axisymmetric flame temperature and soot volume fraction profiles by a single CCD camera was investigated in detail. The reconstruction accuracy of the flame temperature profile and soot volume fraction was insensitive to the measurement error of the coefficient matrix. When the signal to ratio (SNR) of the measurement system for both the radiation intensity and coefficient matrix was as low as 46 dB, the reconstruction accuracy for both temperature and soot volume fraction was acceptable and was more influenced by the radiation intensity measurement error. The reconstruction of the flame temperature and soot volume fraction was greatly influenced by the edge effect. When the flame edge with weak radiation signals was ignored during the reconstruction, the relative reconstruction error for the temperature and soot volume fraction increased from the flame center to the edge, and reached an unacceptable value at the reconstruction boundary, especially for the soot volume fraction. The flame image boundary could be chosen as the unified reconstruction boundary to reconstruct the two-dimensional distribution of the temperature and soot volume fraction with satisfactory accuracy. The low soot volume fraction could influence the reconstruction accuracy for both the temperature and soot concentration in non-sooting regions. Moreover, there was no obvious regularity between the reconstruction accuracy of the temperature and soot volume fraction and the extension of the reconstruction boundary.

Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor, designed for the therapy of HER2-positive breast cancers. Inhibition of the epidermal growth factor receptor (EGFR, HER family) efficiently and selectively suppresses the proliferation of human TSC2-deficient smooth muscle cells and reverses lung changes in LAM/TSC. Our pilot study indicated that pyrotinib dramatically restrained the vitality of TSC2-deficient cells compared to its limited impact on TSC2-expression cells. Pyrotinib induced G1-phase arrest and triggered apoptosis by blocking abnormally activated CD24 in TSC2-deficient cells. CD24 is not only an important immune checkpoint, but is also involved in the regulation of signaling pathways. Pyrotinib inhibited the nuclear import of pEGFR and restrained the pEGFR/pSTAT3 signals, which directly boosted the transcriptional expression of CD24 by binding to its promoter region. In reverse, CD24 enhanced pEGFR function by directly binding. Pyrotinib specifically targeted TSC2-deficient cells, inhibited tumor cell viability and induced apoptosis through EGFR-STAT3/CD24 Loop in vivo and in vitro. Thus, pyrotinib may be a promising new therapeutic drug for TSC treatment.