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Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC. [ABSTRACT FROM AUTHOR]

Single-cell whole-genome sequencing methods have undergone great improvements over the past decade. However, allele dropout, which means the inability to detect both alleles simultaneously in an individual diploid cell, largely restricts the application of these methods particularly for medical applications. Here, we develop a new single-cell whole-genome sequencing method based on third-generation sequencing (TGS) platform named Refresh-seq (restriction fragment ligation-based genome amplification and TGS). It is based on restriction endonuclease cutting and ligation strategy in which two alleles in an individual cell can be cut into equal fragments and tend to be amplified simultaneously. As a new single-cell long-read genome sequencing method, Refresh-seq features much lower allele dropout rate compared with SMOOTH-seq. Furthermore, we apply Refresh-seq to 688 sperm cells and 272 female haploid cells (secondary polar bodies and parthenogenetic oocytes) from F1 hybrid mice. We acquire high-resolution genetic map of mouse meiosis recombination at low sequencing depth and reveal the sexual dimorphism in meiotic crossovers. We also phase the structure variations (deletions and insertions) in sperm cells and female haploid cells with high precision. Refresh-seq shows great performance in screening aneuploid sperm cells and oocytes due to the low allele dropout rate and has great potential for medical applications such as preimplantation genetic diagnosis. [ABSTRACT FROM AUTHOR]

An increasing body of research has demonstrated the significant role of long non-coding RNAs (lncRNAs) in the pathogenesis of stroke. They can actively contribute to the disease's progression either by directly participating in its pathogenesis or by acting as mediators through competing endogenous RNA (ceRNA) mechanisms. Concurrently, epigenetics plays a pivotal role in the pathological mechanisms underlying stroke. Epigenetic factors serve as valuable markers for disease progression, diagnostic biomarkers, and novel therapeutic targets. One of the most prevalent epigenetic modifications is 5-methylcytosine (m5C). However, the specific profiles of 5-methylcytosine in lncRNAs associated with stroke remain to be solved. Within the scope of this research, we performed a thorough transcriptome-wide analysis of m5C methylation within lncRNAs by methylated RNA immunoprecipitation sequencing (MeRIP-Seq), within a mouse stroke model induced by middle cerebral artery occlusion. Our findings reveal substantial disparities in both the quantity and distribution of m5C within the mouse stroke model compared to normal mice. This suggests a potential linkage between stroke and lncRNA m5C modifications, offering valuable insights into the mechanisms of stroke pathogenesis and the development of new drug targets. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop and externally validate a nomogram to accurately predict the overall survival (OS) of patients with gastric adenocarcinoma who underwent radical gastrectomy. A total of 3492 patients with gastric adenocarcinoma who underwent radical gastrectomy from 2012 to 2017 were included as the training cohort. Survival analysis was performed via Kaplan Meier method and log-rank test. Independent postoperative prognostic factors in patients with gastric adenocarcinoma were analyzed using univariate and multifactorial COX analysis methods. The prognosis nomogram was established in the training cohort and verified externally in the Surveillance, Epidemiology and End Results (SEER) database. According to the univariate and multifactorial COX analyses, metastatic lymph node ratio (MLNR) and five other independent prognostic factors (age at surgery, type of gastrectomy, tumor size, T stage, and pathological grade) were included in the prognostic nomogram. The nomogram had better prognostic predictive ability than the American Joint Committee on Cancer (AJCC) TNM staging in both the training (C-index: 0.736 VS. 0.668) and external validation cohort (C-index: 0.712 VS. 0.627). The calibration plots showed that the predicted survival rate was in good agreement with the actual survival rate. And the decision curve analysis (DCA) curves revealed that nomogram showed stronger ability in predicting 1-year, 3-year, and 5-year OS. This study estimated the excellent prognostic predictive power and clinical application potential of the MLNR-based nomogram, which may be used to facilitate postoperative clinical treatment decisions and potentially improve patient survival outcomes. [ABSTRACT FROM AUTHOR]

Natural biotissues like muscles, ligaments, and nerves have highly aligned structures, which play critical roles in directional signal transport, sensing, and actuation. Inspired by anisotropic biotissues, composite hydrogels with outstanding mechanical properties and conductivity are developed by compositing thermo‐responsive poly (N‐isopropylacrylamide) (PNIPAM) hydrogels with highly aligned carbon fibers (CFs). The anisotropic hydrogels show superior tensile strength (3.0 ± 0.3), modulus (74 ± 7.0 MPa), excellent electrical conductivity (≈670 S m−1), and ultra‐high sensitivity (gauge factor up to 647) along CFs, with an anisotropic ratio (AR) up to 740 over those in perpendicular direction. The extremely high AR in conductivity (more than 400) produces high‐level output in parallel direction and low‐level output in perpendicular direction with a direct current (DC) power supply, which is used to fabricate AND and OR gates. Moreover, the composite hydrogels are converted into thermo‐responsive actuators with CFs twisted before compositing with PNIPAM/clay network. The pre‐twisted CF helices impart internal stress that drives reversible actuation of hydrogel helices upon thermo‐stimulating. The actuation is self‐sensed due to the extremely high sensitivity of the composite hydrogels. Such biomimetic anisotropic self‐sensing hydrogel actuators resemble natural biotissues with both actuation and sensing capabilities, and have promise applications for artificial robotics. [ABSTRACT FROM AUTHOR]

Gastric cancers are highly heterogeneous malignant tumors. To reveal the relationship between differentiation status of cancer cells and tumor immune microenvironments in gastric cancer, single-cell RNA-sequencing was performed on normal mucosa tissue, differentiated gastric cancer (DGC) tissue, poorly differentiated gastric cancer (PDGC) tissue and neuroendocrine carcinoma (NEC) tissue sampled from surgically resected gastric cancer specimens. We identified the signature genes for both DGC and PDGC, and found that signature genes of PDGC strongly enriched in the epithelial–mesenchymal transition (EMT) program. Furthermore, we found that DGC tends to be immune-rich type whereas PDGC tends to be immune-poor type defined according to the density of tumor-infiltrating CD8+ T cells. Additionally, interferon alpha and gamma responding genes were specifically expressed in the immune-rich malignant cells compared with immune-poor malignant cells. Through analyzing the mixed adenoneuroendocrine carcinoma, we identified intermediate state malignant cells during the trans-differentiation process from DGC to NEC, which showed double-negative expressions of both DGC marker genes and NEC marker genes. Interferon-related pathways were gradually downregulated along the DGC to NEC trans-differentiation path, which was accompanied by reduced CD8+ cytotoxic T-cell infiltration. In summary, molecular features of both malignant cells and immune microenvironment cells of DGC, PDGC and NEC were systematically revealed, which may partially explain the strong tumor heterogeneities of gastric cancer. Especially along the DGC to NEC trans-differentiation path, immune-evasion was gradually enhanced with the decreasing activities of interferon pathway responses in malignant cells. [ABSTRACT FROM AUTHOR]

The detailed analysis of the initial ground stress distribution law is an important work for the safety of tunnel construction and operation. Especially, the high ground stress phenomenon in the deep-buried tunnel area is common, which has a great impact on the tunnel construction. Based on the on-site measured ground stress data, the analysis of the initial ground stress field by numerical simulation and multiple linear regression is mainly described in this study. Following the comparison and selection of three coefficient estimation methods for the regression equation, the best regression method is selected for inversion and verification. The distribution characteristic of the initial ground stress at different buried depths of the tunnel line is obtained. The inversion results of the initial ground stress in a tunnel area, in China, show that the lateral pressure coefficient gradually decreases with the buried depth increasing, while the overall lateral pressure coefficient is in the range of 1.0–2.0, showing a more significant horizontal tectonic. At the area where the tunnel passes through the fault, a small amount of horizontal tectonic stress is released. The ratio of horizontal principal stress to vertical principal stress is smaller than that on both sides, which is different from the distribution characteristic of lateral pressure coefficient without the impact of fault. It shows that faults have a great influence on ground stress. The lateral pressure coefficient in the area near the fault must be determined according to the on-site measured results. [ABSTRACT FROM AUTHOR]

Small bowel adenocarcinomas (SBAs) are rare malignant tumors with a high mortality rate, and their molecular characteristics are still largely unexplored. Here we performed single-cell RNA sequencing for tumor samples from 12 SBA patients and predicted drug candidates for SBA. We identified four prevalent subtypes of malignant cells with distinct signatures including cell cycle program, mitochondria program, metabolism program and epithelial–mesenchymal transition (EMT) program. The progression relationships of these four subtypes of malignant cells were also revealed, which started from the cell cycle program, through the mitochondria program and then progressing into either the metabolism program or the EMT program. Importantly, ligand–receptor interaction pairs were found to be specifically enriched in pairs of EMT-program malignant cells and highly exhausted CD8+ T cells, suggesting that cancer cell subpopulations with EMT features may contribute most to the exhaustion of T cells. We also showed that the duodenal subtype of SBA exhibited molecular features more similar to gastric cancer whereas jejunal subtype of SBA more similar to colorectal cancer. Especially, we predicted specific drugs for SBA based on differential gene expression signatures between malignant cells and normal epithelial cells of SBA, and verified more potent inhibitory effects of volasertib and tozasertib for SBA cancer cells than conventional drugs of SBA at the same concentration, which provides new clues for treatments of SBA. In summary, our study provides a blueprint of the molecular signatures of both tumor cells and tumor microenvironment cells in SBA and reveals potential targets and drug candidates for its clinical treatments. [ABSTRACT FROM AUTHOR]

Green onion (Allium fistulosum L.) is mainly available as factory-produced seedlings. Although factory seedling production is highly automated, miss-seeding during the seeding process considerably affects subsequent transplanting and the final yield. To solve the problem of miss-seeding, the current main method is manual complementary seeding, which is labor-intensive and inefficient work. In this study, an automatic machine-vision-based complementary seeding device was proposed to reduce the miss-seeding rate and as a replacement of manual complementary seeding. The device performs several main functions, including the identification of miss-seeding holes, control of seed case movement, and the seed uptake and release from the seed suction nozzle array. A majority-mechanism-based miss-seeding tray hole rapid-detection method was proposed to enable the real-time identification of miss-seeding tray holes in the tray under high-speed moving conditions. The structural parameters of the vacuum-generated seed suction nozzle were optimized through numerical simulations and orthogonal experiments, and the seed suction nozzle array and seed case were produced using 3D-printing technology. Finally, the complementary seeding device was installed on the tray-type green onion seeding machine and the effectiveness of the complementary seeding was confirmed by experiments. The results revealed that the average values of the precision, recall, and F1 scores for identifying miss-seeding tray holes were 98.48%, 97.00%, and 97.73%, respectively. The results revealed that the rate of miss-seeding tray holes decreased from 5.37% to 0.89% after complementary seeding. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the prognostic value of Metastatic lymph node ratio (MLNR) after curative gastrectomy in patients with gastric cancer (GC) and the potential for new indicators to strengthen the current guidelines. We retrospectively researched 3864 GC patients with curative gastrectomy between February 2011 and February 2016. The following clinical data were collected from the included patients: gender, type of gastrectomy, tumor location, T stage, N stage, ELN, tumor size, age at surgery, perineural invasion, vascular invasion, TNM stage, survival time and survival status. Patients were divided into low-MLNR (L-MLNR), and high-MLNR (H-MLNR) groups based on adjusted the X-tile cutoff-value of 0.25 for MLNR, the survival rates and clinicopathological characteristics of each group were compared. For the assessment of significant associations between clinicopathological characteristics and patients' survival, univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazards analysis. The log-rank test was used to examine the statistical significance of differences among different survival curves. Clinicopathological features significantly associated with MLNR were assessed by the Chi-square test and multinomial logistic regression. The discriminative ability was measured by calculating the Bayesian Information Criterion (BIC) values for each category. Assessment of the effect of clinicopathological features on MLNR for predicting prognosis of GC patients used stratum analysis through Kaplan-Meier analysis and Cox proportional risk Analysis. Survival analysis indicated that MLNR was negatively associated with overall survival (OS) (p <.001) and was an independent prognostic predictor in 3864 GC patients (p <.001). MLNR had significant prognostic significance in various subgroups with clinicopathological characteristics (gender, type of gastrectomy, tumor location, T stage, N stage, ELN, tumor size, age at surgery, perineural invasion, vascular invasion, and TNM stage) (p <.001). The MLNR may become a new indicator to assess the prognosis of GC patients who underwent curative gastrectomy. The results may have potential clinical implications that should be considered when developing clinical practice guidelines or the design of the future investigation. [ABSTRACT FROM AUTHOR]

The multiple lights scattering stability analyzer (Turbiscan AGS, Formulaction Co., Ltd., French) was used to scan the emulsion, and the stability change curve of Pickering emulsion prepared with different particle size solid emulsifiers was analyzed. 2.6 Determination of emulsifying properties The freshly prepared solid emulsifier stabilized Pickering emulsions with different particle sizes were stored at 4 °C and 25 °C for 30 days, then the height of serum layer and total emulsions of the emulsions were recorded, and the relative ratio (×100) was used as the creaming index (CI). Keywords: insoluble dietary fiber; interfacial properties; Okara; Pickering emulsion EN insoluble dietary fiber interfacial properties Okara Pickering emulsion 359 369 11 06/01/22 20220501 NES 220501 1 Introduction Okara is the main by-products of soybean production and processing [[1]]. Graph: Figure 2: The CI images (a) of Pickering emulsion stabilized by solid emulsifiers of different particle sizes and appearance images (b) of Pickering emulsions stored at 4 °C and 25 °C for 30 days. [Extracted from the article]

DNA methylation, chromatin accessibility, and gene expression represent different levels information in biological process, but a comprehensive multiomics analysis of the mammalian heart is lacking. Here, we applied nucleosome occupancy and methylome sequencing, which detected DNA methylation and chromatin accessibility simultaneously, as well as RNA-seq, for multiomics analysis of the 4 chambers of adult and fetal human hearts, and adult mouse hearts. Our results showed conserved region-specific patterns in the mammalian heart at transcriptome and DNA methylation level. Adult and fetal human hearts showed distinct features in DNA methylome, chromatin accessibility, and transcriptome. Novel long noncoding RNAs were identified in the human heart, and the gene expression profiles of major cardiovascular diseases associated genes were displayed. Furthermore, cross-species comparisons revealed human-specific and mouse-specific differentially expressed genes between the atria and ventricles. We also reported the relationship among multiomics and found there was a bell-shaped relationship between gene-body methylation and expression in the human heart. In general, our study provided comprehensive spatiotemporal and evolutionary insights into the regulation of gene expression in the heart. Multi-omic analyses of the four chambers of the human and mouse heart, including transcriptome, DNA methylation and chromatin accessibility, reveals characteristic patterns of gene regulation at the level of heart regions. [ABSTRACT FROM AUTHOR]

Biotissue-Inspired Anisotropic Carbon Fiber Composite Hydrogels for Logic Gates, Integrated Soft Actuators, and Sensors with Ultra-High Sensitivity (Adv. Funct. Anisotropic hydrogels, carbon fibers, logic gates, sensors, thermo-responsive actuators Keywords: anisotropic hydrogels; carbon fibers; logic gates; sensors; thermo-responsive actuators EN anisotropic hydrogels carbon fibers logic gates sensors thermo-responsive actuators 1 1 1 03/15/23 20230309 NES 230309 B Thermo-Responsive Actuators b In article 2211189, Jun Fu and co-workers study carbon fiber composited hydrogels that show extremely high anisotropy in mechanical properties, conductivity, and sensitivity. [Extracted from the article]

The aim of this study was to analyze the effects of ultrasound bath intensity, CaCl2 and sodium tripolyphosphate (STPP) concentration on the ultrastructure of longissimus muscle fiber from milk goats. The sarcomere length was measured by atomic force microscopy. According to the results of AFM images, the sarcomere length is longest when the conditions were an intensity of 100 W ultrasound bath (42.77% increment), a concentration of 300 mM CaCl2 injection (44.68% increment) or 90 mM STPP injection (19.41% increment). Apart from the sarcomere length, the study put forward a potential index (roughness) to represent tenderness of meat which was treated by ultrasound bath. Among different methods, ultrasound bath was chosen as the preferred tenderization method. SCANNING 38:545-553, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Saussurea involucrata (S. involucrata) had been reported to have anti-hepatoma function. However, the mechanism is complex and unclear. To evaluate the anti-hepatoma mechanism of S. involucrata comprehensively and make a theoretical basis for the mechanical verification of later research, we carried out this work. In this study, the total phenolic acids from S. involucrata determined by a cell suspension culture (ESPI) was mainly composed of 4,5-dicaffeoylquinic acid, according to the LC-MS analysis. BALB/c nude female mice were injected with HepG2 cells to establish an animal model of liver tumor before being divided into a control group, a low-dose group, a middle-dose group, a high-dose group, and a DDP group. Subsequently, EPSI was used as the intervention drug for mice. Biochemical indicators and differences in protein expression determined by TMT quantitative proteomics were used to resolve the mechanism after the low- (100 mg/kg), middle- (200 mg/kg), and high-dose (400 mg/kg) interventions for 24 days. The results showed that EPSI can not only limit the growth of HepG2 cells in vitro, but also can inhibit liver tumors significantly with no toxicity at high doses in vivo. Proteomics analysis revealed that the upregulated differentially expressed proteins (DE proteins) in the high-dose group were over three times that in the control group. ESPI affected the pathways significantly associated with the protein metabolic process, metabolic process, catalytic activity, hydrolase activity, proteolysis, endopeptidase activity, serine-type endopeptidase activity, etc. The treatment group showed significant differences in the pathways associated with the renin-angiotensin system, hematopoietic cell lineage, etc. In conclusion, ESPI has a significant anti-hepatoma effect and the potential mechanism was revealed. [ABSTRACT FROM AUTHOR]