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Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.

Abstract The climate benefit of blue carbon sequestered by mangrove forests can be partially offset by CH4 emission, but this offset is rarely assessed using multi‐year high‐frequency measurements. Here, four‐year eddy covariance measurements were used to examine temporal patterns of CH4 flux and its blue carbon offset (i.e., reduced climate benefit) in a subtropical estuarine mangrove in China. We found both diel and seasonal CH4 fluxes were mainly driven by soil temperature and tidal activities, showing greater nighttime emission. On average, one‐tenth of CO2 uptake was offset by CH4 emission using the sustained‐flux global warming potential metric at a 20‐year time horizon, while this offset could vary over an order of magnitude due to asynchronous fluxes of CH4 and CO2 across diel and seasonal cycles. These results highlight the significant contribution of nighttime emission to mangrove CH4 budget and the importance of asynchronous flux variations in assessing mangrove's climate benefit.

Abstract For tumor treatment, the ultimate goal in tumor therapy is to eliminate the primary tumor, manage potential metastases, and trigger an antitumor immune response, resulting in the complete clearance of all malignant cells. Tumor microenvironment (TME) refers to the local biological environment of solid tumors and has increasingly become an attractive target for cancer therapy. Neutrophils within TME of gastric cancer (GC) spontaneously undergo ferroptosis, and this process releases oxidized lipids that limit T cell activity. Enhanced photodynamic therapy (PDT) mediated by di‐iodinated IR780 (Icy7) significantly increases the production of reactive oxygen species (ROS). Meanwhile, neutrophil ferroptosis can be triggered by increased ROS generation in the TME. In this study, a liposome encapsulating both ferroptosis inhibitor Liproxstatin‐1 and modified photosensitizer Icy7, denoted LLI, significantly inhibits tumor growth of GC. LLI internalizes into MFC cells to generate ROS causing immunogenic cell death (ICD). Simultaneously, liposome‐deliver Liproxstatin‐1 effectively inhibits the ferroptosis of tumor neutrophils. LLI‐based immunogenic PDT and neutrophil‐targeting immunotherapy synergistically boost the anti‐PD‐1 treatment to elicit potent TME and systemic antitumor immune response with abscopal effects. In conclusion, LLI holds great potential for GC immunotherapy.

Abstract Background Fruit expansion stage is crucial to fruit yield and quality formation, and auxin plays a significant role by mediating multi-hormone signals during fruit expansion. However, till now, it is still unclear of the molecular regulatory network during auxin-mediated peach fruit expansion. Results Here, exogenous NAA application markedly increased IAA content and drastically decreased ABA content at the fruit expansion stage. Correspondingly, NAA mainly induced the auxin biosynthesis gene (1 PpYUCCA) and early auxin-responsive genes (7PpIAA, 3 PpGH3, and 14 PpSAUR); while NAA down-regulated ABA biosynthesis genes (2 PpNCED, 1 PpABA3, and 1 PpAAO3). In addition, many DEGs involved in other plant hormone biosynthesis and signal transduction were significantly enriched after NAA treatment, including 7 JA, 7 CTK, 6 ETH, and 3 GA. Furthermore, we also found that NAA treatment down-regulated most of genes involved in the growth and development of peach fruit, including the cell wall metabolism-related genes (PpEG), sucrose metabolism-related genes (PpSPS), phenylalanine metabolism-related genes (PpPAL, Pp4CL, and PpHCT), and transcription factors (PpNAC, PpMADS-box, PpDof, PpSBP, and PpHB). Conclusion Overall, NAA treatment at the fruit expansion stage could inhibit some metabolism processes involved in the related genes in the growth and development of peach fruit by regulating multiple-hormone signaling networks. These results help reveal the short-term regulatory mechanism of auxin at the fruit expansion stage and provide new insights into the multi-hormone cascade regulatory network of fruit growth and development.

An automatic medical diagnosis service based on deep learning has been introduced in e-healthcare, bringing great convenience to human life. However, due to privacy regulations, insufficient data sharing among medical centers has led to many severe challenges for automated medical diagnostic services, including diagnostic accuracy. To solve such problems, swarm learning (SL), a blockchain-based federated learning (BCFL), has been proposed. Although SL avoids single-point-of-failure attacks and offers an incentive mechanism, it still faces privacy breaches and poisoning attacks. In this paper, we propose a new privacy-preserving Byzantine-resilient swarm learning (PBSL) that is resistant to poisoning attacks while protecting data privacy. Specifically, we adopt threshold fully homomorphic encryption (TFHE) to protect data privacy and provide secure aggregation. And the cosine similarity is used to judge the malicious gradient uploaded by malicious medical centers. Through security analysis, PBSL is able to defend against a variety of known security attacks. Finally, PBSL is implemented by uniting deep learning with blockchain-based smart contract platforms. Experiments based on different datasets show that the PBSL algorithm is practical and efficient.

Kale is a nutrient-dense leafy vegetable associated with wide-ranging health benefits. It is tolerant of drought and temperature fluctuations, and could thus serve an increasingly important role in providing a safe and nutritious food supply during the climate crisis, while kale's ease of cultivation and ability to be grown in a wide range of soils make it a good fit for urban agriculture. In this pilot study we explored potential differences between kale grown at urban versus rural farms. We planted kale seedlings (Darkibor variety) at three urban and four rural farms in and around Baltimore City, Maryland, instructed farmers to cultivate them using their usual growing practices, harvested the kale from fields and points of distribution, and analyzed it for concentrations of carotenoids, vitamins C and K1, ten nutritional elements, and eight non-essential metals. Although sample sizes for some analyses were in some cases too small to produce statistically significant results, we identified potentially meaningful differences in concentrations of several components between urban and rural kale samples. Compared to urban samples, mean concentrations of carotenoids and vitamins were 22-38% higher in rural field samples. By contrast, mean concentrations for eight nutritional elements were higher in urban field samples by as much as 413% for iron. Compared to rural field samples, mean concentrations of nine non-essential metals were higher in urban samples, although lead and cadmium concentrations for all samples were below public health guidelines. Some urban-rural differences were more pronounced than those identified in prior research. For six elements, variance within urban and rural farms was greater than variance between urban and rural farms, suggesting urbanicity may not be the primary driver of some observed differences. For some nutrients, mean concentrations were higher than upper ranges reported in prior estimates, suggesting kale may have the potential to be more nutrient-dense than previously estimated. The nutritive and metals composition of this important crop, and the factors that influence it, merit continued investigation given its growing popularity.

Ferroptosis is a form of cell death, i.e., programmed cell death characterized by lipid peroxidation and iron dependence, which has unique morphological and biochemical properties. This unique mode of cell death is driven by iron-dependent phospholipid peroxidation and regulated by multiple cell metabolic pathways, including redox homeostasis, iron metabolism, mitochondrial activity, and the metabolism of amino acids, lipids, and sugars. Many organ injuries and degenerative pathologies are caused by ferroptosis. Ferroptosis is closely related to central nervous system injury diseases and is currently an important topic of research globally. This research examined the relationships between ferroptosis and the occurrence and treatment of central nervous system injury diseases. Additionally, ferroptosis was assessed from the aspect of theory proposal, mechanism of action, and related signaling pathways per recent research. This review provides a relevant theoretical basis for further research on this theory, the prospect of its development, and the prevention and treatment of such diseases.

Abstract Mangrove ecosystems are becoming increasingly important in global climate mitigation. However, large gaps still exist in evaluating mangroves' gross primary productivity (GPP) due to reasons such as the specific influences, for example, temperature and salt stresses are poorly described in Earth System Models (ESMs). This study developed a process‐based biogeochemical model (Mango‐GPP) to improve the GPP simulation in natural and restored mangroves. The model integrates mangrove‐specific physiological processes, including the response to salt and temperature stresses, as well as the light‐use efficiency at different growing stages. Eddy covariance flux measurements at two natural sites and one restored site in China were used to calibrate and validate Mango‐GPP. The model was calibrated by inverse analysis approach based on two cases and independently validated against the other cases. The validation results showed that it was generally capable of simulating the seasonal and interannual GPP variations at different sites. The simulated daily and annual GPPs agreed well with the observations and yielded R2 of 0.67 and 0.96, with model efficiency of 0.64 and 0.93, respectively. In comparison, Mango‐GPP showed better performances than many current satellite‐based GPP products and ESMs. The model was more sensitive to solar radiation, carbon dioxide concentration, and leaf traits. Future improvements should focus on enhancing Mango‐GPP's descriptive power of key processes, and further simulating other carbon fluxes at regional scales. This work provides a model foundation for further simulating carbon exchanges between the atmosphere, mangrove, and ocean for studying the coastal wetland restoration on regional carbon neutrality.

Herein, a beech wood dowel reinforced with a self-tapping screw (composite dowel in brief) is proposed. Composite dowels were welded into the predrilled holes by high speed rotation. Force-displacement curves were obtained using a single-shear and dual connection. A double-peaked pattern was found in the bearing process, indicating that the wooden dowel and the self-tapping screw had a synergistic bearing effect in the bearing process. Regarding the failure mode, the self-tapping screw and the wooden dowel were bent, whilst the default wooden dowel fractured. Further, the numerical simulation was carried out using the finite element analysis software ABAQUS, and the result differed from the test value by only 4.30%, showing a high prediction accuracy. The study of the bearing capacity of the composite dowels provides a theoretical basis for the practical application of wooden dowels reinforced by self-tapping screws.

MYB is a common transcription factors widely involved in the regulation of anthocyanidin biosynthesis. In order to explore the regulatory role of MYB transcription factors in the biosynthesis of common buckwheat anthocyanidins, we screened and cloned a MYB gene associated with anthocyanin biosynthesis from the transcriptomic data of common buckwheat varieties of safflower common buckwheat and Beizaosheng, and named it FeR2R3-MYB, GenBank login number was MT151381.1. The sequence was analyzed by bioinformatics analysis and qRT-PCR was used to analyze the expression characteristics of FeR2R3-MYB gene in Beizaosheng and safflower common buckwheat. The results were as follows: (1) FeR2R3-MYB gene was 831 bp in total length, encoding 276 amino acids. The relative molecular mass of the protein was 30.95 kD, the theoretical isoelectric point (pI) was 8.73, and the instability index of the protein was 69.64, which belonged to the unstable protein. The total hydrophobic value was -0.679, and the whole peptide chain showed hydrophilic characteristics. (2) FeR2R3-MYB had a typical R2R3-MYB domain and belonged to the R2R3-MYB subfamily. (3) FeR2R3-MYB was closely related to common buckwheat and knotweed, belonging to the same family. (4) The promoter sequence of FeR2R3-MYB contained a total of nine light corresponding elements, 12 transcription factor binding sites, four abiotic corresponding elements and two hormone response elements. (5) Subcellular localization found that FeR2R3-MYB was only expressed in the nucleus. (6) The expression of FeR2R3-MYB gene of safflower common buckwheat was higher than that of Beizaosheng in leaves and inflorescences, and it was further speculated that FeR2R3-MYB gene could positively regulate the biosynthesis of common buckwheat anthocyanin. In summary, these results lay a foundation for further deepening the research on the function and expression regulation of FeR2R3-MYB gene in the biosynthetic pathway of common buckwheat anthocyanin.

Abstract Tumor immunotherapy exerts its anti-tumor effects by stimulating and enhancing immune responses of the body. It has become another important modality of anti-tumor therapy with significant clinical efficacy and advantages compared to chemotherapy, radiotherapy and targeted therapy. Although various kinds of tumor immunotherapeutic drugs have emerged, the challenges faced in the delivery of these drugs, such as poor tumor permeability and low tumor cell uptake rate, had prevented their widespread application. Recently, nanomaterials had emerged as a means for treatment of different diseases due to their targeting properties, biocompatibility and functionalities. Moreover, nanomaterials possess various characteristics that overcome the defects of traditional tumor immunotherapy, such as large drug loading capacity, precise tumor targeting and easy modification, thus leading to their wide application in tumor immunotherapy. There are two main classes of novel nanoparticles mentioned in this review: organic (polymeric nanomaterials, liposomes and lipid nanoparticles) and inorganic (non-metallic nanomaterials and metallic nanomaterials). Besides, the fabrication method for nanoparticles, Nanoemulsions, was also introduced. In summary, this review article mainly discussed the research progress of tumor immunotherapy based on nanomaterials in the past few years and offers a theoretical basis for exploring novel tumor immunotherapy strategies in the future.

The global construction industry is increasingly utilizing concrete prepared from recycled aggregate as a substitute for natural aggregate. However, the subpar performance of recycled fine aggregate (RFA) has resulted in its underutilization, particularly in the structural concrete exposed to challenging environments, including those involving chlorine salts and freeze–thaw climates. This study aimed to enhance the performance of RFA as a substitute for river sand in concrete as well as fulfill the present demand for fine aggregates in the construction sector by utilizing accelerated carbonation treatment to create fully recycled aggregate concrete (FRAC) composed of 100% recycled coarse and fine aggregates. The impacts of incorporating carbonated recycled fine aggregate (C-RFA) at various replacement rates (0%, 25%, 50%, 75%, and 100%) on the mechanical and durability properties of FRAC were investigated. The results showed that the physical properties of C-RFA, including apparent density, water absorption, and crushing value, were enhanced compared to that of RFA. The compressive strength of C-RFC100 was 19.8% higher than that of C-RFC0, while the water absorption decreased by 14.6%. In a comparison of C-RFC0 and C-RFC100, the chloride permeability coefficients showed a 50% decrease, and the frost resistance increased by 27.6%. According to the findings, the mechanical and durability properties, the interfacial transition zones (ITZs), and micro-cracks of the C-RFC were considerably enhanced with an increased C-RFA content.

Abstract Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

Abstract Background Cancer/testis antigens (CTAs) participate in the regulation of malignant biological behaviors in breast cancer. However, the function and mechanism of KK-LC-1, a member of the CTA family, in breast cancer are still unclear. Methods Bioinformatic tools, immunohistochemistry, and western blotting were utilized to detect the expression of KK-LC-1 in breast cancer and to explore the prognostic effect of KK-LC-1 expression in breast cancer patients. Cell function assays, animal assays, and next-generation sequencing were utilized to explore the function and mechanism of KK-LC-1 in the malignant biological behaviors of triple-negative breast cancer. Small molecular compounds targeting KK-LC-1 were also screened and drug susceptibility testing was performed. Results KK-LC-1 was significantly highly expressed in triple-negative breast cancer tissues than in normal breast tissues. KK-LC-1 high expression was related to poor survival outcomes in patients with breast cancer. In vitro studies suggested that KK-LC-1 silencing can inhibit triple-negative breast cancer cell proliferation, invasion, migration, and scratch healing ability, increase cell apoptosis ratio, and arrest the cell cycle in the G0–G1 phase. In vivo studies have suggested that KK-LC-1 silencing decreases tumor weight and volume in nude mice. Results showed that KK-CL-1 can regulate the malignant biological behaviors of triple-negative breast cancer via the MAL2/MUC1-C/PI3K/AKT/mTOR pathway. The small-molecule compound Z839878730 had excellent KK-LC-1 targeting ability and cancer cell killing ability. The EC50 value was 9.7 μM for MDA-MB-231 cells and 13.67 µM for MDA-MB-468 cells. Besides, Z839878730 has little tumor-killing effect on human normal mammary epithelial cells MCF10A and can inhibit the malignant biological behaviors of triple-negative breast cancer cells by MAL2/MUC1-C/PI3K/AKT/mTOR pathway. Conclusions Our findings suggest that KK-LC-1 may serve as a novel therapeutic target for triple-negative breast cancer. Z839878730, which targets KK-LC-1, presents a new path for breast cancer clinical treatment.

Abstract In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients’ survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, which can induce severe inflammatory responses. Notably, besides apoptosis, ferroptosis, necroptosis, and pyroptosis also contribute to the occurrence and development of gastrointestinal cancers. This review aims to provide a comprehensive summary on the biological roles and molecular mechanisms of ferroptosis, necroptosis, and pyroptosis, as well as their regulators in gastrointestinal cancers and hope to open up new paths for tumor targeted therapy in the near future.

Summary: Background: Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment. Methods: This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings: Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator’s decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion. Interpretation: Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial. Funding: This study was funded by CARsgen Therapeutics Co., Ltd.

The properties of single shear specimens connected by wooden nail frictional welding and twist nails were studied. The single shear properties of the specimens connected by wooden nail welding were lower than that of the twist nail specimens. The single shear capacity of the wooden nail welding specimen was determined by calculating the method of design value of the bearing capacity of the pin connection. Furthermore, the flexural properties of the wooden nail welding laminated timber were analyzed. Due to the larger diameter of the wooden nails compared with the twist nails, the wooden nail welding laminated timber in the elastic phase had higher stiffness. The elastic modulus of the wooden nail welding laminated timber exceeded the average elastic modulus of the constituent lumber pieces by 9.46%. The number of wood lumbers in wooden nail welding laminated timber had little effect on the elastic modulus of laminated timber, but the nail spacing had a certain effect. Therefore, in future research, it is recommended to use the construction method of twist nail connection to design the wooden nail welding laminated timber. In addition, the nail spacing should refer to the GB 50005 (2003) standard and the wood structure design manual.

Three kinds of L-shaped latticed joint were designed to study the shear bearing capacity of joints prepared by welding of wooden dowels prepared with self-tapping screws. The results showed that such composite dowels in all specimens showed varying degrees of bending and splitting on the surface of the beech dowel after the shear test. The bending bearing capacity of the joint was the bending moment at the geometric center of the four composite dowels. The shear force of each composite dowel generated from the bending moment was equal with the same direction. The ultimate standard value of the theoretical loading force (F) was equal to 4.44 kN and the calculated design value (Fd) was equal to 2.96 kN. The errors between the standard and design value and test value of 3.94 kN were 11.2% and 24.9%, respectively. The theoretical value was relatively consistent with the test value. If the calculated design value was applied to estimate the ultimate bearing capacity of the joint, it was on the conservative side.

Cross-laminated timber (CLT), a wood product with excellent shear resistance, is often used in modern timber constructions. Using the standards ASTM D1761-12 (2020) and NDS-2012 (2012), this study investigated the connection properties of shear bolts and screws in CLT panels. The specimens were made from spruce-pine-fir lumber and installed on a test platform using one high-strength bolt or eight screws, and then an upward load was applied to the top of the specimen. The results showed that the bolt connection provided a higher ultimate bearing capacity and elastic stiffness. The bolt exhibited virtually no deformation, and the CLT panel did not noticeably deteriorate when the connection was damaged. The distance between the bolt hole and the bottom of the CLT specimen and the angle between the outer-layer grain direction of the CLT panel and the load direction were both measured. Changes in the ductility coefficient value had an obvious effect on the connection performance of the shear bolts when the outer-layer grain direction of the CLT panel was consistent with the load direction. Contrastingly, when the outer-layer grain direction of the CLT panel was perpendicular to the load direction, the effect was negligible, and the yield load was nearly unchanged.

Abstract Background Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. Methods SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. Results We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. Conclusions Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Abstract Background Loss of G2-specific E3-like (G2E3) protein sensitizes tumor cells to chemotherapy. However, the role of G2E3 in breast cancer development and patient’s prognosis is unclear. Here, we explored the expression, prognostic significance, and regulatory pathway of G2E3 in breast cancer. Methods TCGA and UALCAN database were utilized to explore G2E3 expression in breast cancer and normal tissues and its expression in breast cancer based on clinicopathological characteristics, respectively. The Kaplan–Meier plotter database was utilized to determine the effect of G2E3 on the prognosis of breast cancer patients. RT-PCR was utilized to validate the G2E3 expression in cancerous and normal breast tissues. Immunohistochemistry analysis was utilized to validate the prognostic effect of G2E3 expression in breast cancer patients and the relationship between G2E3 expression and lymphocyte infiltration levels. Receiver operating characteristic (ROC) curves were also generated to validate the diagnostic value of G2E3 expression in recurrence/distant organ metastasis and death. The STRING database, DAVID database, and Sanger-box tools were utilized to perform GO functional, KEGG pathway enrichment, and GSEA analysis. The TISIDB database was utilized to determine the relationship between G2E3 expression and tumor immunity. Finally, CTD database was utilized to screen for potential therapeutic compounds that could reduce the G2E3 mRNA expression. Results TCGA data presented that G2E3 expression was higher in breast cancer tissues than in normal breast tissues. This result was further validated by RT-PCR (P = 0.003). The Kaplan–Meier plotter database suggested that patients with high G2E3 mRNA expression had significantly shorter RFS and OS than patients with low G2E3 mRNA expression. Immunohistochemistry analysis of 156 breast cancer clinical specimens also validated patients with G2E3-positive expression had a significantly shorter DFS and OS than patients with G2E3-negative expression. Thus, G2E3 expression was an independent prognostic predictor of DFS and OS. The G2E3-positive expression also has a high diagnostic value for recurrence/distant organ metastasis and death. GSEA analysis revealed that G2E3 might be enriched in the E2F, PI3K/AKT/mTOR signaling, DNA repair pathways, and other cancer-related signaling pathways. The TISIDB database showed that G2E3 expression was significantly negatively associated with lymphocyte infiltration. This result was further validated in clinical breast cancer samples (P = 0.048; R = −0.158). Using the CTD database, we found that (+)-JQ1 compound, 1,2-dimethylhydrazine, and other compounds may decrease the G2E3 mRNA expression. These compounds could serve as potential therapeutic compounds for the clinical treatment of breast cancer. Conclusions G2E3 expression was higher in breast cancer tissues than in normal tissues. G2E3-positive expression was related to a worse survival outcome in patients with breast cancer. Genes co-expressed with G2E3 may be enriched in the breast cancer-related signaling pathways. The G2E3 expression was significantly negatively associated with lymphocyte infiltration. G2E3 may serve as a novel prognostic biomarker and therapeutic target for breast cancer.

An increasing number of methods are being used to extract rock discontinuities from 3D point cloud data of rock surfaces. In this paper, a new method for automatic extraction of rock discontinuity based on an improved Naive Bayes classifier is proposed. The method first uses principal component analysis to find the normal vectors of the points, and then generates a certain number of random point sets around the selected training points for training the classifier. The trained, improved Naive Bayes classifier is based on point normal vectors and is able to automatically remove noise points due to various reasons in conjunction with the knee point algorithm, realizing high-precision extraction of the discontinuity sets. Subsequently, the individual discontinuities are segmented using a hierarchical density-based spatial clustering method with noise application. Finally, the PCA algorithm is used to complete the orientation by plane fitting the individual discontinuities. The method was applied in two cases, Kingston and Colorado, and the reliability and advantages of the new method were verified by comparing the results with those of previous research, and the discussion and analysis determined the optimal values of the relevant parameters in the algorithm.

Breast cancer is one of the leading causes of cancer-related death in women. Currently, the treatment of breast cancer is limited by the lack of effectively targeted therapy and patients often suffer from higher severity, metastasis, and resistance. Extracellular vesicles (EVs) consist of lipid bilayers that encapsulate a complex cargo, including proteins, nucleic acids, and metabolites. These bioactive cargoes have been found to play crucial roles in breast cancer initiation and progression. Moreover, EV cargoes play pivotal roles in converting mammary cells to carcinogenic cells and metastatic foci by extensively inducing proliferation, angiogenesis, pre-metastatic niche formation, migration, and chemoresistance. The present update review mainly discusses EVs cargoes released from breast cancer cells and tumor-derived EVs in the breast cancer microenvironment, focusing on proliferation, metastasis, chemoresistance, and their clinical potential as effective biomarkers.

Hepatocellular carcinoma (HCC), one of the most prevalent cancers, with a high mortality rate worldwide, seriously impairs patient health. The lack of accurate targets impedes the early screening and diagnosis of HCC and is associated with a poor response to routine therapies. Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are lipid bilayer membrane-derived nanometer-sized vesicles. EVs can be secreted from various cancer cells and release diverse biomolecules, such as DNA, RNA, proteins, metabolites, and lipids, making them a potential source of biomarkers and regulators of the tumor microenvironment. Emerging evidence suggests that EVs are involved in intercellular communication by carrying biological information. These EVs elicit physiological functions and are involved in the oncogenesis of HCC, such as proliferation, invasion, metastasis, and chemoresistance of HCC. EVs have also been considered promising biomarkers and nanotherapeutic targets for HCC. Therefore, this review sheds light on the current understanding of the interactions between EVs and HCC to propose potential biomarkers and nanotherapeutic strategies.

Abstract Chinese mangroves have been recovered in area over the past two decades from previous declining trend, and about half of existing mangroves are still in their young growth stage. This provides a unique opportunity to assess mangrove conservation by examining the growth dynamics of young mangroves over different conservation periods. However, we are currently short of effective assessment tools for spatially explicit quantification of mangrove conservation effects. To fill up this gap, we proposed a novel remote sensing approach using readily available unmanned aerial vehicle (UAV) and Landsat enhanced vegetation index (EVI) data to assess the spatial evolution of aboveground biomass (AGB) of young mangroves. With the space‐for‐time hypothesis, the approach implemented with an empirical EVI‐height‐AGB equation was tested in four subtropical estuarine mangroves in the southeastern coast of China. The results indicated: (a) the UAV‐based Structure from Motion (SfM) technology served as an effective and low‐cost means for capturing the spatial heterogeneity of mangrove canopy heights; (b) a maximum stand age of 15 years could be used to define the young growth stage of mangroves, for which the EVI‐height relationships could be described by exponential equations without suffering significant spectral saturation effects; (c) mangrove forests had overall faster annual AGB accumulation during the young growth stage over the post‐2000 versus pre‐2000 conservation period. This study is one of the first attempts to develop a remote sensing approach for quantifying spatially explicit AGB accumulation rates of young mangroves. It highlights the practicability and advantage of the UAV‐SfM technology and confirms that stronger conservation efforts promote mangrove AGB accumulation over the past two decades. The developed EVI‐height‐AGB framework fueled with readily available UAV and Landsat data provides a unique tool for assessing mangrove conservation effects from landscape to regional scales.

Abstract Background Immunotherapy‐antiangiogenesis combination therapy has achieved excellent survival outcomes in hepatocellular carcinoma (HCC) in clinical trials. However, the combination therapy for HCC outside clinical trials is not well studied, and predictive factors are lacking. Here, we retrospectively analyzed the efficacy and safety of immunotherapy‐antiangiogenesis combination therapy in unresectable HCC patients in a real‐world setting. Methods We conducted a four‐center, retrospective study of unresectable HCC patients who received the combination of programmed death 1 (PD‐1) inhibitor and antiangiogenic agent between April 2018 and July 2021 in China. Results In total, 136 patients were enrolled in the cohort. The objective response rate (ORR) and disease control rate (DCR) were 38.0% and 81.8%, respectively. The median time to progression (TTP), progression‐free survival (PFS), and overall survival (OS) were 7.2, 7.3, and 19.6 months, respectively. The multivariate analysis indicated that ECOG performance status score (PS) 2 was a significantly independent negative factor of ORR. Moreover, ECOG PS 2, peritoneum metastasis and previous immunotherapy were found to be independent negative predictors of PFS. A shorter OS was associated with ECOG PS 2, peritoneum metastasis, the presence of previous immunotherapy, Child‐Pugh stage B, and high alpha‐fetoprotein (AFP) concentration. One hundred and twenty‐five patients (91.9%) reported adverse events (AEs) with any grade. Conclusion We elucidated the efficacy and safety of immunotherapy‐antiangiogenesis combination therapy and identified potential predictors for response and survival in a real‐world cohort of patients with unresectable HCC.

Since Internet of Things (IoT) has been widely used in our daily life nowadays, it is regarded as a promising and popular application of the Internet, and has attracted more and more attention. However, IoT is also suffered by some security problems which seriously affect the implementation of IoT system. Similar to traditional software, IoT software is always threated by many vulnerabilities, thus how to evaluate the security situation of IoT software chain becomes a basic requirement. In this paper, A framework of security situation awareness for IoT software chain is proposed, which mainly includes two processes: IoT security situation classification based on support vector machine and security situation awareness based on Markov game model. The proposed method firstly constructs a classification model using support vector machine (IoT) to automatically evaluates the security situation of IoT software chain. Based on the situation classification, we further proposed to adopt Markov model to simulate and predict the next behaviors of participants that involved in IoT system. Additionally, we have designed and developed a security situation awareness system for IoT software chain, the developed system supports the detection of typical IoT vulnerabilities and inherits more than 20 vulnerability detection methods, which shows great potential in IoT system protection.

Abstract Background Intraductal carcinoma of the prostate (IDC-P) is a subtype of prostate cancer featured by poor prognosis. Previous studies suggested IDC-P could have a potentially unstable genome. Homologous recombination deficiency (HRD) score is a result-oriented method to describe the genomic instability status. This study investigates the association of HRD scores with IDC-P and other clinicopathological factors and the prognostic implication of HRD scores in an aggressive prostate cancer cohort. Methods This study involved 123 PCa patients, including high-risk localized (M0) and de novo metastatic (M1) diseases. HRD score is calculated based on over 10,000 single-nucleotide polymorphisms distributed across the human genome. We explored the association between HRD scores and clinicopathological characteristics, genomic alterations, and patients’ prognoses using rank-sum tests, chi-square tests, Kaplan-Meier curves, and Cox proportional hazards method. Results The median HRD score of this cohort is 21.0, with 65 (52.8%) patients showing HRD score≥21. Tumors with IDC-P displayed higher HRD scores than adenocarcinoma (P=0.002); other high HRD score-related factors included M1 (P =0.008) and high ISUP grades (4–5) (P=0.001). MYC mutations were associated with high HRD scores (P

Abstract Background The FAM83 family plays a key role in tumorigenesis and cancer progression. However, the role of the FAM83 family in the development of breast tumors is unclear to date. This report explores the expression, prognostic significance, and function of the FAM83 family members in breast cancer using public databases. Methods UALCAN database was used to explore the expression of FAM83 family members in breast cancer. Furthermore, we validated the expression of FAM83 family members in twenty pairs of breast cancer and normal tissues by RT-PCR. Kaplan–Meier plotter database was used to explore the prognostic significance of FAM83 family members in breast cancer. GeneMANIA and DAVID databases were used for functional and pathway enrichment analysis of genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G. MEXPRESS and UALCAN databases were used to analyze the level of DNA promoter methylation of FAM83A, FAM83D, FAM83F, and FAM83G in breast cancer. TIMER database was utilized to explore the relationships between immune cell infiltration and FAM83A, FAM83D, FAM83F, and FAM83G expression. Results Among FAM83 family members, FAM83A, FAM83D, FAM83F, and FAM83G were higher expressed in breast cancer than in normal tissues. We also validated the significant high expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in breast cancer than in normal samples. Their increased expression has an adverse prognostic effect on breast cancer patients. These genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G might take part in cell proliferation, G2/M transition of the mitotic cell cycle, regulation of apoptosis process and other cancer-related biological processes. In addition, they were mainly enriched in the Hippo signaling pathway, Hedgehog signaling pathway, PI3K/AKT signaling pathway, and other cancer-related pathways. We also found that promoter DNA methylation might regulate the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in most CpG islands. At last, we found the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA was significantly related to immune cell infiltration. Conclusions FAM83A, FAM83D, FAM83F, and FAM83G were highly expressed in breast cancer tissues and had an adverse effect on the survival outcomes of breast cancer patients. Also, they were involved in breast cancer-related signal pathways. Therefore, they might serve as potential therapeutic targets for breast cancer clinical treatment.

Mucinous adenocarcinoma of the kidney is rarely reported in the literature. We present a previously unreported mucinous adenocarcinoma arising from the renal parenchyma. A 55-year-old male patient with no complaints showed a large cystic hypodense lesion in the upper left kidney on contrast-enhanced computed tomography (CT) scan. A left renal cyst was initially considered, and a partial nephrectomy (PN) was performed. During the operation, a large amount of jelly-like mucus and bean-curd-like necrotic tissue was found in the focus. The pathological diagnosis was mucinous adenocarcinoma, and further systemic examination revealed no clinical evidence of primary disease elsewhere. Then the patient underwent left radical nephrectomy (RN), and the cystic lesion was found in the renal parenchyma, while neither the collecting system nor the ureters were involved. Postoperative sequential chemotherapy and radiotherapy were administered, and no signs of disease recurrence were observed over 30 months of follow-up. Based on a literature review, we summarize the lesion with rarity and the associated dilemma in preoperative diagnosis and treatment. Given the high degree of malignancy, a careful history analysis accompanied by dynamic observation of imaging and tumor markers is recommended for the diagnosis of the disease. Comprehensive treatment based on surgery may improve its clinical outcomes.

Premature senescence is a common occurrence in rice production, and seriously affects rice plants’ nutrient utilization and growth. A total of 120 recombinant inbred lines (RILs) were obtained from successive self-crossing of F12 generations derived from Huazhan and Nekken2. The superoxide dismutase (SOD) activity, malondialdehyde (MDA), content and catalase (CAT) activity related to the anti-senescence traits and enzyme activity index of rice were measured for QTL mapping using 4858 SNPs. Thirteen QTLs related to anti-senescence were found, among which the highest LOD score was 5.70. Eighteen anti-senescence-related genes were found in these regions, and ten of them differed significantly between the parents. It was inferred that LOC_Os01g61500, LOC_Os01g61810, and LOC_Os04g40130 became involved in the regulation of the anti-senescence molecular network upon upregulation of their expression levels. The identified anti-senescence-related QTLs and candidate genes provide a genetic basis for further research on the mechanism of the molecular network that regulates premature senescence.

Age-dependent decline in remyelination in the CNS is associated with declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). Here, the authors show nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing in mouse OPCs. β-nicotinamide mononucleotide (β-NMN) supplement delays myelin aging and enhances remyelination in the aged mice.

Sea-level rise (SLR) is expected to suppress the growth of tidal marshes due to prolonged inundation, but this can be compensated by increasing surface elevation with SLR. Warming-induced growth regulation could make it more complicated. We applied a spatially explicit individual-based model (IBM) with dynamic parameterization to predict the range expansion of Spartina alterniflora by 2100 over a low-latitude wetland, under one low-emission scenario (Shared Socioeconomic Pathway 1 [SSP1]: 0.28 m SLR and 0.55 °C warming) and one high-emission scenario (SSP5: 1.01 m and 3.55 °C). The results showed that (a) the simulations of an IBM with life-history-mediated biophysical feedbacks (IBM1) better tracked the actual range expansion of S. alterniflora over 2014 to 2017 (90.1% accuracy) than that without the feedbacks (IBM0) (83.0%); (b) under SSP1, most marshes were predicted to survive SLR by 2100 in both IBM0 and IBM1, while, under SSP5, the marshes were predicted to disappear much more in IBM0 (93.2% drowned) than IBM1 (31.9%); and (c) warming-induced growth inhibition of S. alterniflora leads to exacerbated disappearance and even collapse of the marshes under SSP5 in IBM1. This study highlights the importance of life-history-mediated biophysical and physiological feedbacks in regulating the response of tidal marshes to climate change. Warming-induced growth inhibition weakens low-latitude tidal marsh resilience to SLR.

Soil salinization has a serious influence on rice yield and quality. How to enhance salt tolerance in rice is a topical issue. In this study, 120 recombinant inbred line populations were generated through nonstop multi-generation selfing using a male indica rice variety Huazhan (Oryza sativa L. subsp. indica cv. ‘HZ’) and a female variety of Nekken2 (Oryza sativa L. subsp. japonica cv. ‘Nekken2’) as the parents. Germination under 80 mM NaCl conditions was measured and analyzed, and quantitative trait locus (QTL) mapping was completed using a genetic map. A total of 16 salt-tolerance QTL ranges were detected at bud stage in rice, which were situated on chromosomes 3, 4, 6, 8, 9, 10, 11, and 12. The maximum limit of detection was 4.69. Moreover, the qST12.3 was narrowed to a 192 kb region on chromosome 12 using map-based cloning strategy. Statistical analysis of the expression levels of these candidate genes under different NaCl concentrations by qRT-PCR revealed that qST12.3 (LOC_Os12g25200) was significantly down-regulated with increasing NaCl concentration, and the expression level of the chlorine-transporter-encoding gene LOC_Os12g25200 in HZ was significantly higher than that of Nekken2 under 0 mM NaCl. Sequencing analysis of LOC_Os12g25200 promoter region indicated that the gene expression difference between parents may be due to eight base differences in the promoter region. Through QTL mining and analysis, a plurality of candidate genes related to salt tolerance in rice was obtained, and the results showed that LOC_Os12g25200 might negatively regulate salt tolerance in rice. The results provide the basis for further screening and cultivation of salt-tolerant rice varieties and have laid the foundation for elucidating further molecular regulation mechanisms of salt tolerance in rice.

Abstract Circular RNAs (circRNAs) play a vital role in the occurrence and development of tumors, including gastric cancer (GC). However, there are still many circRNAs related to GC whose functions and molecular mechanisms remain undetermined. Herein, we discover circRNA RELL1, which has not been investigated in GC, and it is markedly downregulated in GC tissues, which is related with poor prognosis, more pronounced lymph node metastasis and poor TNM stage. After confirming the circular structure of circRELL1, we found that circRELL1 could block cell proliferation, invasion, migration, and anti-apoptosis in patients with GC by a series of in vivo and in vitro function-related studies. Further mechanism investigation demonstrated that circRELL1 could sponge miR-637 and indirectly unregulated the expression of EPHB3 via modulating autophagy activation in GC. Additionally, circRELL1 can be transmitted by exosomal communication, and exosomal circRELL1 suppressed the malignant behavior of GC in vivo and in vitro. Taken together, this study elucidates the suppressive roles of circRELL1/miR-637/EPHB3 axis through autophagy activation in GC progression, inspiring for further understanding of the underlying molecular mechanisms of GC and providing a promising novel diagnostic circulating biomarker and therapeutic target in GC.

Circular (circ)RNAs are widely involved in gastric cancer (GC) pathogenesis, and coiled-coil domain containing 6 (CCDC6) is a fused partner of multiple oncogenes; however, the underlying mechanisms of how circRNAs regulate CCDC6 expression in the progression and prognosis of GC remain unclear. Here, we discovered the circRNA derived from the DNA2 gene locus (circDNA2) through RNA sequencing. By performing quantitative real-time PCR and fluorescence in situ hybridization (FISH) assays with a human tissue microarray, circDNA2 was found to be highly expressed in GC tissues and associated with lymphatic invasion of GC patients. Knockdown of circDNA2 expression suppressed the proliferation of GC cells by reducing CCDC6 expression. Mechanistically, circDNA2 acted as a microRNA (miR)-149-5p sponge, which was confirmed to target CCDC6 by RNA pulldown and dual-luciferase reporter assays and rescue experiments. Both low miR-149-5p expression and high CCDC6 expression were related to unfavorable prognosis in GC patients. Moreover, GC patients with low miR-149-5p expression had shorter overall survival and a higher risk of chemotherapy resistance than those with high miR-149-5p expression. In summary, circDNA2 contributes to the growth and lymphatic metastasis of GC by upregulating CCDC6 expression by sponging miR-149-5p. The circDNA2/miR-149-5p/CCDC6 axis might be developed as a therapeutic target and prognostic indicator for GC.

Abstract Measuring the concentration and viability of fungal cells is an important and fundamental procedure in scientific research and industrial fermentation. In consideration of the drawbacks of manual cell counting, large quantities of fungal cells require methods that provide easy, objective and reproducible high‐throughput calculations, especially for samples in complicated backgrounds. To answer this challenge, we explored and developed an easy‐to‐use fungal cell counting pipeline that combined the machine learning‐based ilastik tool with the freeware ImageJ, as well as a conventional photomicroscope. Briefly, learning from labels provided by the user, ilastik performs segmentation and classification automatically in batch processing mode and thus discriminates fungal cells from complex backgrounds. The files processed through ilastik can be recognized by ImageJ, which can compute the numeric results with the macro ‘Fungal Cell Counter’. Taking the yeast Cryptococccus deneoformans and the filamentous fungus Pestalotiopsis microspora as examples, we observed that the customizable software algorithm reduced inter‐operator errors significantly and achieved accurate and objective results, while manual counting with a haemocytometer exhibited some errors between repeats and required more time. In summary, a convenient, rapid, reproducible and extremely low‐cost method to count yeast cells and fungal spores is described here, which can be applied to multiple kinds of eucaryotic microorganisms in genetics, cell biology and industrial fermentation.

Abstract Background To use ddPCR to quantify plasma exosomal class III β‐tubulin (βIII‐tubulin, TUBB3, encoded by the TUBB3 gene) mRNA expression in metastatic castration‐resistant prostate cancer (mCRPC) patients, and study the association of this expression with abiraterone efficacy. Methods Blood samples were prospectively collected from 52 mCRPC patients using abiraterone as first‐line therapy to measure plasma exosomal TUBB3 mRNA expression value before the initiation of abiraterone. Study endpoints were PSA response rate, PSA‐progression‐free survival (PSA‐PFS), and overall survival (OS, from CRPC to death). Results Patients with positive exosomal TUBB3 expression showed shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3: 11.0 vs. 7.9 months; p = 0.014). Further analysis demonstrated that patients with strongly positive exosomal TUBB3 (>20 copies/20 µl) was associated with even shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3 [20 copies/20 µl]: 11.0 vs. 8.3 vs. 3.6 months, p = 0.005). In multivariate analyzes, TUBB3 (+) (HR: 2.114, p = 0.033) and ECOG score >2 (HR: 3.039, p = 0.006) were independent prognosticators of poor PSA‐PFS. PSA response and OS did not present significant differences. Conclusion The exosomal TUBB3 mRNA expression level is associated with poor PSA‐PFS of abiraterone in mCRPC patients. The detection of exosomal TUBB3 can be valuable in their management.

Objective This study aimed to establish a prognostic model related to prostate cancer (PCa) recurrence-free survival (RFS) and identify biomarkers. Methods The RFS prognostic model and key genes associated with PCa were established using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression from the Cancer Genome Atlas (TCGA)-PRAD and the Gene Expression Omnibus (GEO) GSE46602 datasets. The weighted gene co-expression network (WGCNA) was used to analyze the obtained key modules and genes, and gene set enrichment analysis (GSEA) was performed. The phenotype and mechanism were verified in vitro. Results A total of 18 genes were obtained by LASSO regression, and an RFS model was established and verified (TCGA, AUC: 0.774; GSE70768, AUC: 0.759). Three key genes were obtained using multivariate Cox regression. WGCNA analysis obtained the blue module closely related to the Gleason score (cor = –0.22, P = 3.3e − 05) and the unique gene glutathione peroxidase 2 (GPX2). Immunohistochemical analysis showed that the expression of GPX2 was significantly higher in patients with PCa than in patients with benign prostatic hyperplasia (P

Background Onco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression.Methods CD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages.Results CRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155+ TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155+ macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155–⁄– bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155+ TAMs.Conclusions These findings indicated that CD155+ TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155+ TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.

Abstract Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

The history, status quo, and prospect of tiny houses in North America were reviewed. The market demand for tiny houses in North America was analyzed according to the needs in various market segments, such as shelters for low-income and homeless people, recreational housing for vacationers, and the restoration and reconstruction after disasters. This study also discussed tiny housing communities for retirees, tourism companies offering tiny housing accommodation, and government-sponsored tiny housing projects for post-disaster reconstruction. Throughout years of promotion by tiny house enthusiasts, medium advocators, and construction practitioners, more and more people have come to realize the advantages of the tiny houses made of wood, such as energy conservation, low carbon footprint, and sustainable development. In summary, the market for tiny house in North America is in a stage of rapid development.

The modulation of the function and expression of epigenetic regulators of RNA modification has gradually become the hotspot of cancer research. Studies have shown that alteration of epigenetic modifications can promote the development and metastasis of breast cancer. This review highlights the progress in characterization of the link between RNA modification and the prognosis, carcinogenesis and treatment of breast cancer, which may provide a new theoretical basis for development of effective strategies for monitoring of breast cancer based on epigenetics.

Phoma macdonaldii (teleomorph Leptosphaeria lindquistii) is the causal agent of sunflower (Helianthus annuus L.) black stem. In order to investigate the molecular basis for the pathogenicity of P. ormacdonaldii, genomic and transcriptomic analyses were performed. The genome size was 38.24 Mb and assembled into 27 contigs with 11,094 putative predicted genes. These include 1133 genes for CAZymes specific for plant polysaccharide degradation, 2356 for the interaction between the pathogen and host, 2167 for virulence factors, and 37 secondary metabolites gene clusters. RNA-seq analysis was conducted at the early and late stages of the fungal spot formation in infected sunflower tissues. A total of 2506, 3035, and 2660 differentially expressed genes (DEGs) between CT and each treatment group (LEAF-2d, LEAF-6d, and STEM) were retrieved, respectively. The most significant pathways of DEGs from these diseased sunflower tissues were the metabolic pathways and biosynthesis of secondary metabolites. Overall, 371 up-regulated DEGs were shared among LEAF-2d, LEAF-6d, and STEM, including 82 mapped to DFVF, 63 mapped to PHI-base, 69 annotated as CAZymes, 33 annotated as transporters, 91 annotated as secretory proteins, and a carbon skeleton biosynthetic gene. The most important DEGs were further confirmed by RT-qPCR. This is the first report on the genome-scale assembly and annotation for P. macdonaldii. Our data provide a framework for further revealing the underlying mechanism of the pathogenesis of P. macdonaldii, and also suggest the potential targets for the diseases caused by this fungal pathogen.

Abstract Objective Our goal was to research and develop exploratory analysis tools for clinical notes, which now are underrepresented to limit the diversity of data insights on medically relevant applications. Results We characterize how exploratory analysis can affect representation learning on clinical narratives and present several self-developed tools to explore sepsis. Our experiments focus on patients with sepsis in the MIMIC-III Clinical Database or in our institution’s research patient data repository. We found that global embeddings assist in learning local representations of clinical notes. Second, aligning at any specific time facilitates the use of learning models by pooling more available clinical notes to form a training set. Furthermore, reconstruction of the timeline enhances downstream-processing techniques by emphasizing temporal expressions and temporal relationships in clinical documentation. We demonstrate that clustering helps plot various types of clinical notes against a scale, which conveys a sense of the range or spread of the data and is useful for understanding data correlations. Appropriate exploratory analysis tools provide keen insights into preprocessing clinical notes, thereby further enhancing downstream analysis capabilities, making data driven medicine possible. Our examples can help generate better data representation of clinical documentation for models with improved performance and interpretability.

Objective: Chronic inflammatory response plays a prominent role in obesity-related nonalcoholic fatty liver disease (NAFLD). However, the intrahepatic triggering mechanism of inflammation remains obscure. This study aimed to elucidate the role of serum amyloid A1 (SAA1), an acute-phase response protein, in the obesity-induced hepatic inflammation and NAFLD. Methods: Male mice were fed a high fat diet (HFD) for 16 weeks, and insulin resistance, hepatic steatosis, and inflammation in mice were monitored. Murine SAA1/2 was genetically manipulated to investigate the role of SAA1 in NAFLD. Results: We found that SAA1 was increased in the NAFLD liver in both humans and mice. Knockout of SAA1/2 or knockdown of hepatic SAA1/2 promoted energy expenditure and alleviated HFD-induced metabolic disorder, hepatic steatosis, and inflammation. Endogenous overexpression of SAA1 in hepatocytes by adeno-associated virus 8 (AAV8) transfection aggravated overnutrition-associated gain of body weight, insulin resistance, hepatic lipid accumulation, and liver injury, which were markedly alleviated by knockout of murine toll-like receptor 4 (TLR4). Mechanistically, SAA1 directly bound with TLR4/myeloid differentiation 2 (MD2) to induce TLR4 internalization, leading to the activation of nuclear factor (NF)-κB signaling and production of both SAA1 and other inflammatory cytokines, including interleukin (IL)-6 and C–C chemokine ligand (CCL2) in hepatocytes. Administration of HFD mice with an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression. Conclusions: These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-κB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention.

Background: Integrin family are known as key gears in focal adhesion for triple-negative breast cancer (TNBC) metastasis. However, the integrin independent factor TLN1 remains vague in TNBC. Methods: Bioinformatics analysis was performed based on TCGA database and Shengjing Hospital cohort. Western blot and RT-PCR were used to detect the expression of TLN1 and integrin pathway in cells. A small-molecule C67399 was screened for blocking TLN1 and integrin β1 through a novel computational screening approach by targeting the protein-protein binding interface. Drug pharmacodynamics were determined through xenograft assay. Results: Upregulation of TLN1 in TNBC samples correlates with metastasis and worse prognosis. Silencing TLN1 in TNBC cells significantly attenuated the migration of tumour cells through interfering the dynamic formation of focal adhesion with integrin β1, thus regulating FAK-AKT signal pathway and epithelial-mesenchymal transformation. Targeting the binding between TLN1 and integrin β1 by C67399 could repress metastasis of TNBC. Conclusions: TLN1 overexpression contributes to TNBC metastasis and C67399 targeting TLN1 may hold promise for TNBC treatment. Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81872159, 81902607, 81874301), Liaoning Colleges Innovative Talent Support Program (Name: Cancer Stem Cell Origin and Biological Behaviour), Outstanding Scientific Fund of Shengjing Hospital (201803), and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

Telocytes (TCs) are a new type of mesenchymal cells that have been discovered recently in many organs and tissues. However, studies of TCs in the avian reproductive system are still at the beginning. Chickens are one of the world's most popular domesticated animals, providing inexpensive but valuable proteins and nutrients from chickens and eggs to nourish the human bodies. Chickens have important scientific value; thus, understanding the reproductive system regulations seems to be important. The utero-vaginal junction is involved in the regulation of sperm storage. The sperm storage tube (SST) in the utero-vaginal junction stores sperm. The purpose of this study was to investigate the existence of TCs in the utero-vaginal junction of the chicken, and their structural relationships with the sperm storage tube and surrounding cell types. We studied the morphology, ultrastructure, and immune characterization of TCs.MethodsThe utero-vaginal junction of 4-month-old healthy adult chickens (n = 10) were used for Masson's staining, fluorescent in situ hybridization technique (FISH), and transmission electron microscopy (TEM) analysis. The results showed that TCs were present in the utero-vaginal junction. TCs appear as CD34 immunopositive and C-kit immunopositive. They were identified especially via small-body and long-protrusion telopodes (Tps) containing Podomers (Pm) and Podoms (Pd). The Tps were bent, folded, and intertwined with each other, sometimes in the shape of a labyrinth. The Tps were embedded between collagen fiber bundles, smooth muscle bundles, and around blood vessels and releasing vesicles. TCs surround these glands, forming heteromorphic cell connections with surrounding lymphocytes and plasma cells, smooth muscle cells, blood vessels, collagen fibers, and fibroblast-formed homotypic or allotypic connections in a complex three-dimensional network structure. This study provides a morphological basis for the possible role of TCs in regulating the utero-vaginal junction physiological role and in intercellular communication.

Postharvest ultraviolet B (UV-B) radiation has been used to control pathogen incidence on fresh produce, but little attention has been paid to preharvest UV-B effect on strawberry fruit quality and storage. In this study, strawberry (Fragaria × ananassa Duch. cv Albion) plants grown in greenhouse were irradiated with UV-B lamps with an intensity of 0.7362 J/s m2 for 1 and 2 h every day from 5–7 pm after flowering. Fruits were harvested at red stage for quality evaluation. The results indicated that the preharvest UV-B-treated fruits had lighter color (increased L*) than the control. Total soluble solids (TSS), total phenolics content (TPS) and total anthocyanin content (TAC) of UV-B-treated fruits were higher than for the control fruits. There were no significant differences in any of the quality traits between UV-B one-hour and two-hour treatments. We further evaluated the fruit quality when stored at 5 °C on day 7 and day 14. Compared to untreated control, UV-B-treated fruits retarded decrease in L*, TSS, TPS, TAC and firmness, and reduced fruit decay. Examination of expression of genes related to UV-B signaling indicated that HY5 was the major component of UV-B signaling during the green and white stages. However, anthocyanin genes were highly responsive to UV-B treatment during the red stage. Our results suggest that utilization of a low dose of UV-B radiation during the growth stage can improve strawberry fruit quality, and extend shelf life. This research facilitates the utilization of preharvest UV-B treatment for improving fruit quality in controlled environment agriculture.