Search

Abstract Fault fracture zones are rock formations commonly encountered in submarine tunnels, and the diffusion mechanism of slurry in fault fracture zones has a crucial impact on submarine tunnel reinforcement. Based on the seepage equation of Bingham fluid, the tortuosity parameter, fractal theory, and variable viscosity equation are introduced to establish a spherical permeation grouting model of Bingham fluid considering the slurry diffusion path and viscosity time variability. The viscosity variation law with time of sulfur aluminate cement slurry under different seawater admixture conditions was tested, and the time-varying equation of viscosity of sulfur aluminate cement slurry was obtained by fitting. A set of fault fracture zone permeation grouting test system was developed, and a fault fracture zone grouting simulation test was carried out. The study shows that the diffusion distance calculated without considering the influence of slurry diffusion path and seawater is 1.63–1.91 times of the test value, which obviously overestimates the diffusion distance; the diffusion distance calculated with considering the influence of diffusion path and seawater is 1.06–1.35 times of the test value, which is in good agreement with the test value. The research results can provide some theoretical support for the design of grouting in seawater environment.

Introduction: The Effective Management of Pain by Overcoming Worries to Enable Relief (EMPOWER) intervention is an evidence-supported approach for addressing barriers to pain management (e.g., patient/family concerns about addiction) at the end of life. Such barriers appear more pronounced among Spanish-speaking individuals. This study aimed to (1) translate EMPOWER materials into Spanish, (2) disseminate materials to hospices with ?25% Hispanic patients, and (3) survey hospices about the use and usefulness of materials. Methods: We back translated EMPOWER materials with harmonization, then disseminated materials to 242 hospices. Thereafter, we used a semistructured survey to assess use and usefulness of EMPOWER materials using univariate statistics and content analysis. Results: Thirty-eight hospice representatives responded (participation rate?=?15.7%). Respondents were primarily non-White (55.3%) and Hispanic (60.5%). Nealy half (47.4%) were nurses. A majority (81.6%) indicated they currently employ ?1 full-time English?Spanish bilingual team member. Among those who reported receiving the EMPOWER materials (n?=?29), 58.6% indicated they?or another staff member?used them with patients or families. Using a single-item rating (0?=?not useful to 10?=?very useful), respondents evaluated the English EMPOWER materials' usefulness as 7.6 (standard deviation [SD]?=?1.4) and Spanish materials as 8.4 (SD?=?1.4). Most (62.1%) indicated they would likely use EMPOWER materials in the future. Conclusion: Thematic findings suggest EMPOWER reinforces clinical education, promotes discussion about pain management, and helps address culturally specific barriers to care. EMPOWER appears to be a useful, easy to use, and promising intervention that can be implemented among both English- and Spanish-speaking populations.

City image is an important element in the design of urban features. Big data from social media has become a new way to perceive city image characteristics. Taking Nanjing (China) as a case study, we use social media data from the “Little Red Book” and “Sina Weibo” (similar to Twitter in China) and employ deep learning methods, multisource data semantic analysis, sDNA, and geographically weighted regression to analyze three aspects: the spatial distribution of hotspots, perception characteristics, and influencing factors. The hotspots are located in Nanjing’s old city, centered on Confucius Temple, and extend outward in a circular pattern. Regarding perception characteristics, the key characteristics that define the old city are “heritage monuments”, “long history”, and “culture”. The high functional perception area converged around the central urban area. The spatial distributions of closeness and betweenness under traffic perception showed opposite trends; emotional perception was mainly positive. Compared with visual and emotional perception, functional and traffic perception have greater impacts on city image hotspots. Our study constructs a model of city image perception from a new perspective. This approach bridges the gap that traditional city image research focuses only on objective environment descriptions and lacks subject-object relationship analysis, which can provide scientific value for decision makers in urban design management.

The classification of surrounding rock is crucial for formulating safe tunnel construction plans and support measures. However, the complex geological environment of tunnels presents a challenge in obtaining accurate drilling parameters for rock mass classification. This paper presents the development of a rock drilling testing system, which includes a propulsion speed acquisition system, oil pressure acquisition system, air pressure acquisition system, and an automatic data acquisition system. This system enables real-time, high-precision automatic collection and storage of parameters such as propulsion speed, with data collected twice per second for each parameter. Leveraging the Qingdao Metro Line 6 as a case study, we conducted rock mass drilling and constructed a rock mass classification database. By employing kernel density estimation and Pearson correlation analysis, we quantified the correlation between rock mass classification and the drilling parameters. The results indicated that relying on a single drilling parameter is insufficient for accurately determining rock mass classification. Both impact pressure and rotational pressure showed the strongest correlation with rock mass classification, each with a correlation coefficient below −0.8 (indicating a strong negative correlation). Outlier values of drilling parameters were excluded using the interval method. Based on the remaining data, we established an intelligent rock mass classification model using the random forest algorithm. This model demonstrated good accuracy and generalization performance, with an average accuracy exceeding 0.9. The proposed rock drilling testing system, combined with the intelligent rock mass classification model, forms an integrated system for the intelligent identification of rock mass grades. This system has significant implications for the intelligent and safe construction of drill-and-blast tunnels.

During the construction of underground engineering, the prediction of groundwater distribution and rock body permeability is essential for evaluating the safety of the project and guiding subsequent design and construction. This article proposes an objective function that solves an underdetermined inverse analysis problem based on the least-squares theory and regularization method and uses geostatistics theory and the variogram function to describe the spatial characteristics of the actual engineering system. It also establishes an optimization model of the analysis stratum seepage field and puts forward the method of using on-site test observation data to solve the stratum penetration coefficient. Relying on the foundation pit project of the Lingshanwei Station of Qingdao Metro, the on-site pumping and packer permeability test was conducted for different strata venues in the foundation pit, and the on-site water-head observation value was obtained. Physical detection of the influence area of foundation pit excavation confirms the correctness of the model from the region and verifies the accuracy of the model on the value through the on-site pumping test. Results show that the accuracy of the use of this objective function to solve the underdetermined inverse problem is above 85%, which proves the effectiveness of the method. The stratigraphic geological information obtained by the inverse analysis model provides an important basis for engineering design and security construction.

Abstract Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8+ lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.

Due to the hidden nature of the grouting project, it has not been possible to get a clear picture of the slurry transport law, and most of the existing permeation grouting theories have ignored the tortuous characteristics of the pore channels of porous media. Based on the fractal theory of porous media and the equation of seepage motion of viscous time-varying Bingham fluid, a theoretical model of permeation grouting with viscous time-varying Bingham fluid is established, and viscosity tests are carried out for C-S slurry to obtain the time-varying equation of viscosity of C-S slurry. A set of permeation grouting simulation experiment device was designed, and the permeation grouting simulation experiment of C-S slurry was carried out to obtain the variation curve of grouting pressure with time under different injection media and different grouting rates. The results show that the grouting pressure considering the diffusion path of the slurry is 0.9–1.1 times of the experimental results, the grouting pressure obtained from the experimental is 0.7–1.2 times of the theoretical value considering the diffusion path, and the calculated value considering the diffusion path agrees well with the experimental value. The theoretical model can provide scientific guidance for field grouting construction.

Abstract Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB–expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB–targeting approaches for metastasis treatment.

BackgroundIsovaleric acidaemia (IVA), characterized by an acute metabolic crisis and psychomotor delay, is a rare inherited metabolic disease caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD).MethodsWe report the case of a Chinese patient with IVA who was admitted to Tianjin Children's Hospital and followed up for 8 years. Genetic analysis of the patient and his parents was conducted using the whole-exome sequencing and Sanger sequencing. We searched for similar reported cases in the PubMed and Wanfang databases using the term “isovaleric acidaemia,” reviewed the related literature to obtain a summary of the clinical and genetic characteristics, and analyzed the genotype–phenotype correlations.ResultsThe patient presented with encephalopathic symptoms, such as vomiting, lethargy, and somnolence. We identified compound heterozygous variants of the IVD gene, including the unreported variant c.224A>G (p.Asn75Ser) and the reported variant c.1195G>C (p.Asp399His). The child was prescribed a low-protein diet supplemented with L-carnitine. During the 8-year follow-up, no metabolic disorder or encephalopathic symptoms recurred. At present, the child is 11 years of age and has normal mental and motor performance. Another 154 cases identified in 25 relevant references were combined with this case, resulting in a sample of 155 patients, including 52 asymptomatic patients, 64 with neonatal onset, and 39 with the chronic intermittent disease with onset from ages of 1 month to 10 years (median age, 2 years). Among articles that reported sex, the male-to-female ratio was 1:1.06. The cardinal symptoms included vomiting, lethargy, “sweaty foot” odor, poor feeding, developmental delay, and epilepsy. The proportion of variants in regions 123–159 and 356–403 of the IVD protein was greater in symptomatic patients than in asymptomatic patients. Conversely, in asymptomatic patients, the proportion of variants in the 282–318 region was greater than in symptomatic patients.ConclusionThis case report describes an unreported variant c.224A>G (p.Asn75Ser) of the IVD gene, and summarizes previously reported cases. Furthermore, the correlation between the genotype and clinical phenotype of IVA is analyzed to improve the understanding of this disease.

Cancer stem-like cells are the culprits of tumour recurrence and metastasis, but their regulatory mechanisms are not fully understood. Here, the authors show that the scaffold protein SH3RF3 enhances the stem-like properties of breast cancer by facilitating activation of the JNK-JUN pathway and PTX3 expression.

We explored the composition and roles of the protein phosphatase 2C (PP2C) family in Paulownia fortunei. The genome P. fortunei harbored 91 PfPP2C genes, encoding proteins with 120–1107 amino acids (molecular weight range, 13.51–124.81 kDa). The 91 PfPP2Cs were distributed in 12 subfamilies, with 1–15 PfPP2Cs per subfamily. The number and types of conserved structure domains differed among PP2Cs, but the distribution of conserved motifs within each subfamily was similar, with the main motif structure being motifs 3, 16, 13, 10, 2, 6, 12, 4, 14, 1, 18, and 8. The PfPP2C genes had 2 to 20 exons. There were ABA-response elements in the promoters of 42 PfPP2C genes, response elements to phytohormones, and stress in the promoters of other PfPP2C genes. A covariance analysis revealed that gene fragment duplication has played an important role in the evolution of the PfPP2C family. There were significant differences in the transcript levels of some PfPP2C genes in P. fortunei affected by witches’ broom (PaWB) and after treatment with rifampicin and methyl methanesulfonate. PfPP2C02, PfPP2C12, PfPP2C19, and PfPP2C80 were strongly related to PaWB. These findings provide a foundation for further studies on the roles of PP2Cs in PaWB.

Background: Mitochondrial dynamics, including mitochondrial fission and fusion, transport and distribution, biogenesis and degradation, are critical to neuronal function. The dynamin-1 like (DNM1L) gene encodes dynamin-related protein 1 (DRP1/DLP1), which is an evolutionarily conserved member of the dynamin family and is responsible for mitochondrial division. DNM1L variants can lead to mitochondrial fission dysfunction and neurological disorders.Methods: We report a case of DNM1L-related mitochondrial disease admitted to Tianjin Children's Hospital. We searched for similar reported cases in the PubMed database using the terms “DNM1L” and “mitochondrial,” reviewed recent literature to summarize the clinical and genetic characteristics, and analyzed genotype-phenotype correlations.Results: The patient presented with psychomotor retardation, motor disturbance (muscle weakness with paroxysmal hypermyotonia), and a de novo variant (c.116G>A, g.22229G>A, p.S39N) in the GTPase domain of DNM1L (reference sequence NM_012062), which has not previously been reported in the literature. This case was combined with an additional 35 cases identified in 20 relevant references in order to analyze a total of 36 patients. The male-to-female ratio was 1:1.06, and the median age of onset was 6 months (range, neonatal period to 9 years). The cardinal symptoms included psychomotor retardation in 77.8% (28/36), limb paralysis in 66.7% (18/27), dystonia in 82.8% (24/29), and epilepsy in 59.4% (19/32). The clinical manifestations of variants in the GTPase domain of DRP1 were milder than those identified in the middle domain.Conclusion: This case report describes a new variant of the DNM1L gene, and summarizes previously reported cases. Furthermore, the clinical phenotype and the genotype of DNM1L gene-associated mitochondrial disease was analyzed to improve the understanding of this disease.

Strategic emerging industries (SEIs) are an important industrial policy to promote innovation, develop advanced manufacturing, and upgrade the economy in China. The research explores the impact of SEIs on urban economic growth in mainland China, from agglomeration externalities and network externalities. The results show that SEIs have a significant impact on growth, and network externalities are generally more important than agglomeration externalities. Although the agglomeration of large-scale listed enterprises in the city promotes growth, too many large enterprises in the cluster, that is, the lack of small and medium-sized supporting enterprises, will harm urban growth. Meanwhile, a city with a higher degree of centrality has a larger GDP, but the strength has a negative impact.

Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer's disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau's encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exon-intron junctions and within the 5' and 3' untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5' UTR contains one structured region, which lies within a known internal ribosome entry site. The 3' UTR contains eight structured regions, including one that contains a polyadenylation signal. A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3' UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases.

Analysis of D-loop of mitochondrial DNA of 4 populations of Mongolian horses from different origin was conducted. Nowadays Mongolian horses massive is divided to several countries. Among them there are Mongolia, Inner Mongolia part of China, and Kalmyk Republic of Russia. D-loop of mitochondrial DNA gives an inside into the maternal lines of population of horses. I was stated, that maternal lines of 4 populations from different territories have their similarities, as well as differences. More investigations are in need to understand, if similarities can be explained by the same origin of the populations, or due to other horse breeds, involved into the breed’s genesis.

Euchiloglanis davidi, an endemic species to China, is mainly distributed in the upper Yangtze River and its tributaries. In this study, the complete mitochondrial genome of E. davidi was first sequenced. The result showed that the circular mitogenome was 16,559 bp in length and contained 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, one origin of replication on the light-strand, and one control region. These genes were in the same order as in other vertebrate species. Except ND6 and eight tRNA genes, most mitochondrial genes were encoded on the H-strand. The whole mitogenome base composition of 31.18% A, 25.12% T, 28.09% C, 15.61% G, with 56.30% AT. Phylogenetic analyses using concatenated nucleotide sequences of the 13 protein-coding genes with two different methods (Maximum likelihood and neighbor-joining analysis) both highly supported that E. davidi showed a close relationship with E. kishinouyei. This work provides basic genetic data of E. davidi which will be helpful for further researches on conservation biology and species identification.

Biomolecule labeling using chemical probes with specific biological activities has played important roles for the elucidation of complicated biological processes. Selective bioconjugation strategies are highly-demanded in the construction of various small-molecule probes to explore complex biological systems. Bioorthogonal reactions that undergo fast and selective ligation under bio-compatible conditions have found diverse applications in the development of new bioconjugation strategies. The development of new bioorthogonal reactions in the past decade has been summarized with comments on their potentials as bioconjugation method in the construction of various biological probes for investigating their target biomolecules. For the applications of bioorthogonal reactions in the site-selective biomolecule conjugation, examples have been presented on the bioconjugation of protein, glycan, nucleic acids and lipids.

α-Synuclein is an important drug target for the treatment of Parkinson’s disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5′ untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5′ UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient–derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders. [ABSTRACT FROM AUTHOR]