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Abstract Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.

ObjectiveThe COVID-19 pandemic has prompted a surge in research focusing on mental health issues faced by society, with particular emphasis on the interplay between social support and anxiety. However, the results of these studies have often been controversial.MethodsTo address this, we conducted a meta-analysis of 104 studies (N = 107,660) to investigate the relationship between anxiety and social support and the potential moderate variables.ResultsOur meta-analysis revealed a negative correlation between social support and anxiety (r = −0.233). The study also demonstrated the variation in the relationship between social support and anxiety was moderated by cultural area (Q = 14.120, p

[Objective] To achieve non-stop aviation during the construction of a large-diameter shield tunnel crossing the airport flight zone in karst area, it is essential to study the construction scheme with non-stop aviation. [Method] Based on the construction of the No.2 and No.3 underpasses of the Phase III expansion project of Guangzhou Baiyun International Airport, the obstacle restrictions and runway land subsidence control requirements for non-stop aviation in airport flight zone are analyzed, and control standards for the runway area of this project are proposed. Combining the geological characteristics of engineering in karst area, a construction scheme for shallow-buried large-diameter shield tunnels is proposed. A three-dimensional refined numerical model is established to analyze the impact of shield tunneling on airport runway and validate the feasibility of the construction scheme. [Result & Conclusion] Efforts should be made to avoid tunneling into tunnel bottom bedrocks and meet the tunnel overall anti-floating requirements. Measures to increase shield tunnel overall stiffness should be taken to minimize the impact on airport operations to the greatest extent. The research results indicate that the design of tunnel crossing airport flight area mainly considers the impact of runway subsidence on aircraft operation safety during tunnel construction, so the runway subsidence control standard is set at the total subsidence within 30 mm, with a maximum differential subsidence rate not exceeding 1‰. According to numerical analysis results, the maximum subsidence of the airport runway during shield tunnel construction is 15.48 mm, with the maximum differential subsidence rate of 0.20‰, meeting the requirements for airport runway subsidence limits.

Abstract The Legume family (Leguminosae or Fabaceae), is one of the largest and economically important flowering plants. Heartwood, the core of a tree trunk or branch, is a valuable and renewable resource employed for centuries in constructing sturdy and sustainable structures. Hongmu refers to a category of precious timber trees in China, encompassing 29 woody species, primarily from the legume genus. Due to the lack of genome data, detailed studies on their economic and ecological importance are limited. Therefore, this study generates chromosome-scale assemblies of five Hongmu species in Leguminosae: Pterocarpus santalinus, Pterocarpus macrocarpus, Dalbergia cochinchinensis, Dalbergia cultrata, and Senna siamea, using a combination of short-reads, long-read nanopore, and Hi-C data. We obtained 623.86 Mb, 634.58 Mb, 700.60 Mb, 645.98 Mb, and 437.29 Mb of pseudochromosome level assemblies with the scaffold N50 lengths of 63.1 Mb, 63.7 Mb, 70.4 Mb, 61.1 Mb and 32.2 Mb for P. santalinus, P. macrocarpus, D. cochinchinensis, D. cultrata and S. siamea, respectively. These genome data will serve as a valuable resource for studying crucial traits, like wood quality, disease resistance, and environmental adaptation in Hongmu.

The stability of underground diaphragm walls is crucial for ensuring the safety and integrity of trench excavations in geotechnical engineering. This study addresses this critical issue by proposing a novel destabilization mechanism based on a sliding body model specifically designed for diaphragm wall trenching operations. The research employs an analytical framework rooted in soil mechanics and plasticity theory, utilizing limit equilibrium analysis to develop a method for calculating the minimum required slurry density and corresponding safety factor for trench stability. The study compares two distinct approaches to slurry density computation, analyzing their sensitivity to various influencing factors. Theoretical findings are validated through multiple real-world engineering case studies. Comparative analysis demonstrates the superiority of the proposed method, particularly in assessing trench stability within clay layers. Key variables influencing the safety factor are identified, including trench length, slurry density, soil friction angle, and the relative height difference between slurry and groundwater levels. Results indicate that actual slurry densities observed in practice consistently fall within the bounds predicted by the theoretical calculations. This research contributes a valuable theoretical framework to the field of diaphragm wall construction, offering improved accuracy in stability assessments and potentially enhancing safety in geotechnical engineering projects.

Abstract Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient‐derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d‐bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient‐derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient‐derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.

Abstract Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

This study examines whether and how risk disclosures in Management Discussion and Analysis (MD&A) affected the stock price crash risk of China’s publicly listed firms over the period of 2017–2021. The empirical results show that risk disclosures within the MD&A section are significantly and negatively associated with the future stock price crash risk, even after controlling for a broad set of well-known factors of crash risk. Additional tests revealed that the impact of MD&A risk disclosures on the stock price crash risk is accentuated when the MD&A disclosure contains more incremental information. The negative association between MD&A risk disclosures and stock price crash risk is also more pronounced for firms with poorer information environments, for firms with weaker external monitoring, and for firms with more investor attention. Our findings are robust to alternative measures of the stock price crash risk, controlling for firm-fixed effects and endogeneity issues, and excluding certain samples. The results indicate that MD&A risk disclosures could help alleviate information asymmetry and mitigate stock price crash risk.

Weiss–Kruszka syndrome (WSKA) is a rare disease most often caused by mutations in the ZNF462 gene. To screen for hereditary diseases, exons from the patient’s genome were sequenced. Genomic PCR experiments followed by Sanger sequencing were used to confirm the mutated genomic regions in the patient and his parents. We report a new mutation site, a heterozygous mutation (NM_021224.6:c.6311dup) in ZNF462 in a male patient of 8 years old. The mutation in the ZNF462 gene caused WSKA. This patient is the first case with WSKA characterized by attention-deficit hyperactivity disorder and complete growth hormone deficiency without pituitary lesions. Our results suggest that the heterozygous mutation in ZNF462 is the direct cause of WSKA in this patient. Mutations in other genes interacting with ZNF462 result in similar symptoms of WSKA. Furthermore, ZNF462 and its interacting proteins ASXL2 and VPS13B may form a protein complex that is important for normal development but awaits more studies to reveal its detailed functions.

The construction of railway and highway embankments has a significant influence on the behavior of existing pile foundations, especially in the situation of high embankments and extensively soft soils, which are commonly encountered in coastal areas. A high embankment might produce large lateral movement and bending moment to the existing adjacent piles, which would cause the failure of the pile if the surcharge loading is not properly considered. A field test was designed and performed to investigate the effect of lateral surcharge loading on the existing adjacent pile in extensively soft soils. A 4 m high embankment was constructed in five lifts and was close to the existing adjacent steel pipe pile with a length of 35 m. The deformation of the pile and the soft soils, the excess pore water pressure, and lateral earth pressures were measured during the surcharge loading test. The test results showed that the lateral displacement of the steel pipe pile at the ground surface exceeded 229.9 mm and could not maintain constant due to the surcharge loading. The lateral displacement decreased along with the pile depth and was relatively small when the pile depth exceeded 10 m. Large lateral displacements were observed in the soft soils at different locations. The surcharge loading zone showed obvious downward displacements, while the soft soils close to the loading zone showed upward displacements. The excess pore water pressure changed regularly with the construction of the embankment, and its maximum value reached 53.6 kPa. The lateral earth pressures that acted on the pile continuously increased with the increase in the embankment height, which caused large deformation of the pile.

Abstract Background Colorectal cancer (CRC) is one of the most common malignancies, and it’s expected that the CRC burden will substantially increase in the next two decades. New biomarkers for targeted treatment and associated molecular mechanism of tumorigenesis remain to be explored. In this study, we investigated whether PDCD6 plays an oncogenic role in colorectal cancer and its underlying mechanism. Methods Programmed cell death protein 6 (PDCD6) expression in CRC samples were analyzed by immunohistochemistry and immunofluorescence. The prognosis between PDCD6 and clinical features were analyzed. The roles of PDCD6 in cellular proliferation and tumor growth were measured by using CCK8, colony formation, and tumor xenograft in nude mice. RNA-sequence (RNA-seq), Mass Spectrum (MS), Co-Immunoprecipitation (Co-IP) and Western blot were utilized to investigate the mechanism of tumor progression. Immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) were performed to determine the correlation of PDCD6 and MAPK pathway. Results Higher expression levels of PDCD6 in tumor tissues were associated with a poorer prognosis in patients with CRC. Furthermore, PDCD6 increased cell proliferation in vitro and tumor growth in vivo. Mechanistically, RNA-seq showed that PDCD6 could affect the activation of the MAPK signaling pathway. PDCD6 interacted with c-Raf, resulting in the activation of downstream c-Raf/MEK/ERK pathway and the upregulation of core cell proliferation genes such as MYC and JUN. Conclusions These findings reveal the oncogenic effect of PDCD6 in CRC by activating c-Raf/MEK/ERK pathway and indicate that PDCD6 might be a potential prognostic indicator and therapeutic target for patients with colorectal cancer.

Abstract Background Following acute infection, Herpes Simplex virus-1 (HSV-1) establishes lifelong latency and recurrent reactivation in the sensory neurons of trigeminal ganglia (TG). Infected tree shrew differs from mouse and show characteristics similar to human infection. A detailed transcriptomic analysis of the tree shrew model could provide mechanistic insights into HSV-1 infection in humans. Methods We sequenced the transcriptome of infected TGs from tree shrews and mice, and 4 human donors, then examined viral genes expression up to 58 days in infected TGs from mouse and tree shrew, and compare the latency data with that in human TGs. Results Here, we found that all HSV-1 genes could be detected in mouse TGs during acute infection, but 22 viral genes necessary for viral transcription, replication and viral maturation were not expressed in tree shrew TGs during this stage. Importantly, during latency, we found that LAT could be detected both in mouse and tree shrew, but the latter also has an ICP0 transcript signal absent in mouse but present in human samples. Importantly, we observed that infected human and tree shrew TGs have a more similar LAT region transcription peak. More importantly, we observed that HSV-1 spontaneously reactivates from latently infected tree shrews with relatively high efficiency. Conclusions These results represent the first longitudinal transcriptomic characterization of HSV-1 infection in during acute, latency and recurrent phases, and revealed that tree shrew infection has important similar features with human infection.

Background: Schizophrenia is associated with a significant increase in the risk of violence, which constitutes a public health concern and contributes to stigma associated with mental illness. Although previous studies revealed structural and functional abnormalities in individuals with violent schizophrenia (VSZ), the neural basis of psychotic violence remains controversial.Methods: In this study, high-resolution structural magnetic resonance imaging (MRI) data were acquired from 18 individuals with VSZ, 23 individuals with non-VSZ (NSZ), and 22 age- and sex-matched healthy controls (HCs). Whole-brain voxel-based morphology and individual morphological covariance networks were analysed to reveal differences in gray matter volume (GMV) and individual morphological covariance network topology. Relationships among abnormal GMV, network topology, and clinical assessments were examined using correlation analyses.Results: GMV in the hypothalamus gradually decreased from HCs and NSZ to VSZ and showed significant differences between all pairs of groups. Graph theory analyses revealed that morphological covariance networks of HCs, NSZ, and VSZ exhibited small worldness. Significant differences in network topology measures, including global efficiency, shortest path length, and nodal degree, were found. Furthermore, changes in GMV and network topology were closely related to clinical performance in the NSZ and VSZ groups.Conclusions: These findings revealed the important role of local structural abnormalities of the hypothalamus and global network topological impairments in the neuropathology of NSZ and VSZ, providing new insight into the neural basis of and markers for VSZ and NSZ to facilitate future accurate clinical diagnosis and targeted treatment.

In this paper, we consider the optimization of the quantum circuit for discrete logarithm of binary elliptic curves under a constrained connectivity, focusing on the resource expenditure and the optimal design for quantum operations such as the addition, binary shift, multiplication, squaring, inversion, and division included in the point addition on binary elliptic curves. Based on the space-efficient quantum Karatsuba multiplication, the number of CNOTs in the circuits of inversion and division has been reduced with the help of the Steiner tree problem reduction. The optimized size of the CNOTs is related to the minimum degree of the connected graph.

Background: Post-surgical recurrence of the metastatic colorectal cancer (mCRC) remains a challenge, even with adjuvant therapy. Moreover, patients show variable outcomes. Here, we set to identify gene models based on the perspectives of intrinsic cell activities and extrinsic immune microenvironment to predict the recurrence of mCRC and guide the adjuvant therapy.Methods: An RNA-based gene expression analysis of CRC samples (total = 998, including mCRCs = 344, non-mCRCs = 654) was performed. A metastasis-evaluation model (MEM) for mCRCs was developed using the Cox survival model based on the prognostic differentially expressed genes between mCRCs and non-mCRCs. This model separated the mCRC samples into high- and low-recurrence risk clusters that were tested using machine learning to predict recurrence. Further, an immune prognostic model (IPM) was built using the COX survival model with the prognostic differentially expressed immune-related genes between the two MEM risk clusters. The ability of MEM and IPM to predict prognosis was analyzed and validated. Moreover, the IPM was utilized to evaluate its relationship with the immune microenvironment and response to immuno-/chemotherapy. Finally, the dysregulation cause of IPM three genes was analyzed in bioinformatics.Results: A high post-operative recurrence risk was observed owing to the downregulation of the immune response, which was influenced by MEM genes (BAMBI, F13A1, LCN2) and their related IPM genes (SLIT2, CDKN2A, CLU). The MEM and IPM were developed and validated through mCRC samples to differentiate between low- and high-recurrence risk in a real-world cohort. The functional enrichment analysis suggested pathways related to immune response and immune system diseases as the major functional pathways related to the IPM genes. The IPM high-risk group (IPM-high) showed higher fractions of regulatory T cells (Tregs) and smaller fractions of resting memory CD4+ T cells than the IPM-low group. Moreover, the stroma and immune cells in the IPM-high samples were scant. Further, the IPM-high group showed downregulation of MHC class II molecules. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and GDSC analysis suggested the IPM-low as a promising responder to anti-CTLA-4 therapy and the common FDA-targeted drugs, while the IPM-high was non-responsive to these treatments. However, treatment using anti-CDKN2A agents, along with the activation of major histocompatibility complex (MHC) class-II response might sensitize this refractory mCRC subgroup. The dysfunction of MEIS1 might be the reason for the dysregulation of IPM genes.Conclusions: The IPM could identify subgroups of mCRC with a distinct risk of recurrence and stratify the patients sensitive to immuno-/chemotherapy. Further, for the first time, our study highlights the importance of MHC class-II molecules in the treatment of mCRCs using immunotherapy.

Rapid urbanization on a global scale leads to a number of issues such as arable land occupation and ecological degradation. In this context, analyzing the driving mechanism of urban land expansion in complex urban systems facilitates sustainable urban development. Most relevant studies focused on the role of each driving factor and less considered the interaction between different factors spatially and temporally. In order to provide a deep insight into the complex driving mechanism of urban expansion, this study began with an analysis of the spatio-temporal characteristics of urban expansion in the Pearl River Delta (PRD) urban agglomeration in different periods. Then, the driving mechanism of urban expansion intensity (UEI) and urban expansion landscape pattern were analyzed, based on the interaction of different driving factors over space and time. The result showed as follows. (1) During the period of 2000–2008, the overall UEI in the PRD was higher than that of the period of 2008–2015. From 2000 to 2015, the most important source of urban land expansion was farmland, followed by forest land. Meanwhile, the decline in the proportion of outlying expansion type indicated that the urban land has gradually become more compact. (2) From 2000 to 2015, the socio-economic factors had a greater effect on UEI than natural factors. And the interaction between the pairs of factors on UEI during 2000–2008 was significantly stronger than that during 2008–2015. (3) The driving factors of the urban landscape expansion index during the period from 2008 to 2015 were far more powerful than 2000–2008. And the interaction between the pairs of factors on urban landscape expansion index during 2000–2008 was significantly stronger than that during 2008–2015.

Classic crystallization describes a burst nucleation followed by a layer-by-layer atom deposition. The non-classic crystallization refers to particle mediated crystallization process. Different crystallization routes lead to the formation of diverse structured materials. Here we report a rational synthesis of silver particles by selecting the crystallization routes. Silver particles were synthesized by a solution reduction approach. The crystallization routes were regulated by adding amino acids to stabilize silver ions which leads to the decrease of the reduction rate. Without amino acids, silver dendrites were largely formed. With the addition of amino acids, flower-like (low concentration of amino acids) and spherical silver (high concentration of amino acid) particles were synthesized. Three kinds of amino acids were tested and the similar results were obtained. The time-dependent characterization on the evolution of silver particles showed that silver dendrites were formed by the classic atom deposition while the other two morphologies were formed by the combination of classic and non-classic crystallization. The silver particles synthesized were evaluated for ethylene epoxidation and the dendritic particles demonstrated a high selectivity.

This paper proposes a new traffic assignment model, named an N-path logit-based stochastic user equilibrium (NPSUE), which considers not only road users' perceptual errors in path choices, but also users' heterogeneity that allows the numbers of the limited path sets for each user to be different. The property of the N-path user equilibrium (NPUE) proposed in Dung-Ying Lin (2014) is first reanalyzed, and then the optimization program for the NPSUE models as well as the property of the optimal solution are explicitly discussed. For each type of users, the NPSUE assignment results are consistent with the logit-assignment results in their limited path set. Both the NPUE and NPSUE models are tested in three road networks: an simple grid network, Nguyen and Dupuis' network and Sioux Falls network. The numerical results show that (1) the NPUE can be equivalent to the UE under certain conditions, although the users don't have full information on the available paths; (2) the proposed NPSUE may provide an ideal equilibrium state for both system managers and road users; (3) the provision of appropriate path guidance information is beneficial to both system managers and road users; otherwise, the provision of excessive information may decrease the performance of the road network, and (4) under the NPSUE conditions, the provision of excessive information may decrease users' satisfaction.

Synaptic adhesion molecules mediate synaptic differentiation and formation. Here the authors present the structures of the synaptic adhesion molecule SALM5 alone and in complex with the LAR family receptor protein tyrosine phosphatase (LAR-RPTP) PTPδ, which reveals how SALM5 dimerization facilitates higher-order signaling assembly of LAR-RPTPs.

An amendment to this paper has been published and can be accessed via the original article.

Soil nutrients are essential factors that reflect farmland quality. Nitrogen, phosphorus, and potassium are essential elements for plants, while silicon is considered a “quasi-essential” element. This study investigated the spatial distribution of plant nutrients in soil in a hilly region of the Pearl River Delta in China. A total of 201 soil samples were collected from farmland topsoil (0–20 cm) for the analysis of total nitrogen (TN), available phosphorus (AP), available potassium (AK), and available silicon (ASi). The coefficients of variation ranged from 47.88% to 76.91%. The NSRs of TN, AP, AK, and ASi were 0.15, 0. 07, 0.12, and 0.13, respectively. The NSRs varied from 0.02 to 0.20. All variables exhibited weak spatial dependence (R2 < 0.5), except for TN (R2 = 0.701). After comparing the prediction accuracy of the different methods, we used the inverse distance weighting method to analyze the spatial distribution of plant nutrients in soil. The uniform spatial distribution of AK, TN overall showed a trend of increasing from northeast to southwest, and the overall spatial distribution of AP and ASi showed that the northeast was higher than the southwest. This study provides support for the delimitation of basic farmland protection areas, the formulation of land use spatial planning, and the formulation of accurate farmland protection policies.

Environment accounting information disclosure is an important means for chemical companies to solve environmental pollution problems. However, currently, in China, the environment accounting information disclosure system of chemical companies has not been established, there are still many existing problems, however, it’s necessary to further study the company environment accounting information disclosure system in-depth. This paper mainly analyzes and studies the evaluation indicator system of accounting information disclosure of chemical companies based on the Analytic Hierarchy Process (AHP) theory. The research results show that, as a whole, the disclosure level of environment accounting information of chemical companies is not high, and there is a big gap between the levels of environment accounting information disclosure among different chemical companies. The 10 items of environment accounting information disclosure were divided into three dimensions: relevance, saliency, and reliability, and a quality evaluation system for the accounting information disclosure of chemical companies was established, through analysis, it’s found that the degree of importance was: relevance, reliability, saliency. In addition, out of the 10 indicators, corporate pollutant emissions and auditing of environment accounting information accounted for higher weights.