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Pinus armandiiseed kernel is a nutrient-rich and widely consumed nut whose yield and quality are affected by, among other things, harvesting time and climatic conditions, which reduce economic benefits. To investigate the optimal harvesting period of P. armandiiseed kernels, this study determined the nutrient composition and seed kernel morphology and analyzed the gene expression and metabolic differences of P. armandiiseed kernels during the harvesting period by transcriptomics and metabolomics. The results revealed that during the maturation of P. armandiiseed kernels, there was a significant increase in the width, thickness, and weight of the seed kernels, as well as a significant accumulation of sucrose, soluble sugars, proteins, starch, flavonoids, and polyphenols and a significant decrease in lipid content. In addition, transcriptomic and metabolomic analyses of P. armandiiseed kernels during the harvesting period screened and identified 103 differential metabolites (DEMs) and 8899 differential genes (DEGs). Analysis of these DEMs and DEGs revealed that P. armandiiseed kernel harvesting exhibited gene–metabolite differences in sugar- and lipid-related pathways. Among them, starch and sucrose metabolism, glycolysis, and gluconeogenesis were associated with the synthesis and catabolism of sugars, whereas fatty acid degradation, glyoxylate and dicarboxylic acid metabolism, and glycerophospholipid metabolism were associated with the synthesis and catabolism of lipids. Therefore, the present study hypothesized that these differences in genes and metabolites exhibited during the harvesting period of P. armandiiseed kernels might be related to the accumulation and transformation of sugars and lipids. This study may provide a theoretical basis for determining the optimal harvesting time of P. armandiiseed kernels, changes in the molecular mechanisms of nutrient accumulation, and quality directed breeding.

Hierarchical organization of intestine relies on the self-renewal and tightly regulated differentiation of intestinal stem cells (ISCs). Although signals like Wnt are known to sustain the continued intestinal renewal by maintaining ISCs activity and lineage commitment, molecular mechanisms underlying ISCs ‘stemness’ and supportive niche have not been well understood. Here, we found that CUL4B-RING ubiquitin ligase (CRL4B) regulates intestinal homeostasis by targeting immunity-related GTPase family M member 1 (IRGM1) for proteasomal degradation. CUL4B was mainly expressed at ISCs zone. Deletion of Cul4bled to reduced self-renewal of ISCs and a decreased lineage differentiation towards secretory progenitors through downregulated Wnt signals. Besides, Cul4b-null mice exhibited impaired Paneth cells number and structure. Mechanistically, CRL4B complex were associated with WD40 proteins and targeted IRGM1 at K270 for ubiquitination and proteosomal degradation. Impaired intestinal function caused by CUL4B deletion was rescued by down-regulation of its substrate IRGM1. Our results identified CUL4B as a novel regulator of ISCs and revealed a new 26 S proteasome degradation mechanism in intestine self-renewal and lineage commitment.

Targeted delivery of chemotherapeutic agents to the cancerous cells is of fundamental importance and the key step of the targeted delivery system design is to choice a specific receptor. Glypican-3 (GPC3) is a known cell membrane-associated oncofetal proteoglycan that is specifically up-regulated in the fast-growing hepatocarcinoma cells but rarely expressed in the normal healthy liver. Therefore, GPC3 may be a perfect targeting receptor for delivery treatment of hepatocellular carcinoma (HCC). In the present study, a GPC3 specific-targeting nanoliposomal drug delivery system was constructed with GPC3 targeting peptide (named as L5 peptide) modification and anticancer drug cantharidin encapsulation, which aims to realize cantharidin targeted treatment of liver cancer. In our study, nanoliposome specifically targeting GPC3 receptor was successfully constructed with particle size of 127.9 nm and a spherical shape. The targeted liposomes were stable under 4 °C or room temperature for almost 15 days. The drug release from L5-modified liposomes was controlled and delayed. Their targeted delivery properties were characterized by relatively more accumulation in the GPC3 highly expressed HepG2 cells than that of GPC3 lowly expressed Huh-7 cells. The competition results also indicated that the liposomes with L5 peptide modification could competitively bind to GPC3 receptor. Moreover, the liposomes showed colocalization with the lysosome after 3 h incubation. The L5-modified liposomal CTD had an augmented cell growth inhibition and tumor inhibition than that of the free CTD on HepG2 cells and GPC3 highly expressed tumor mice. Our study establishes a new strategy for improving HCC treatment and chemotherapeutic agent targeting delivery.

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB–target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner—that is, by activating YAP—may be a strategy for slowing tumor growth in patients.

The emergence of drug‐resistant bacteria poses a significant threat to people's lives and health as bacterial infections continue to persist. Currently, antibiotic therapy remains the primary approach for tackling bacterial infections. However, the escalating rates of drug resistance coupled with the lag in the development of novel drugs have led to diminishing effectiveness of conventional treatments. Therefore, the development of nonantibiotic‐dependent therapeutic strategies has become imperative to impede the rise of bacterial resistance. The emergence of chemodynamic therapy (CDT) has opened up a new possibility due to the CDT can convert H2O2into •OH via Fenton/Fenton‐like reaction for drug‐resistant bacterial treatment. However, the efficacy of CDT is limited by a variety of practical factors. To overcome this limitation, the sterilization efficiency of CDT can be enhanced by introducing the therapeutics with inherent antimicrobial capability. In addition, researchers have explored CDT‐based combined therapies to augment its antimicrobial effects and mitigate its potential toxic side effects toward normal tissues. This review examines the research progress of CDT in the antimicrobial field, explores various strategies to enhance CDT efficacy and presents the synergistic effects of CDT in combination with other modalities. And last, the current challenges faced by CDT and the future research directions are discussed. In this review, the recent progress of CDT in the antimicrobial therapy has been introduced. Then the strategies to boost the therapeutic effect of CDT and the CDT‐based combined therapeutic strategies are outlined. Finally, the challenges and opportunities of CDT are also discussed.

Purpose: To evacuate passengers arriving at intercity railway stations efficiently, metros and intercity railways usually share the same station or have stations close to each other. When intercity trains arrive intensively, a great number of passengers will burst into the metro station connecting with the intercity railway station within a short period, while the number of passengers will decrease substantially when intercity trains arrive sparsely. The metro timetables with regular headway currently adopted in real-world operations cannot handle the injected passenger demand properly. Timetable optimization of metro lines connecting with intercity railway stations is essential to improve service quality. Design/methodology/approach: Based on arrival times of intercity trains and the entire process for passengers transferring from railway to metro, this paper develops a mathematical model to characterize the time-varying demand of passengers arriving at the platform of a metro station connecting with an intercity railway station. Provided the time-varying passenger demand and capacity of metro trains, a timetable model to optimize train departure time of a bi-direction metro line where an intermediate station connects with an intercity railway station is proposed. The objective is to minimize waiting time of passengers at the connecting station. The proposed timetable model is solved by an adaptive large neighborhood search algorithm. Findings: Real-world case studies show that the prediction accuracy of the proposed model on passenger demand at the connecting station is higher than 90%, and the timetable model can reduce waiting time of passengers at the connecting station by 28.47% which is increased by 5% approximately than the calculation results of the generic algorithm. Originality/value: This paper puts forward a model to predict the number of passengers arriving at the platform of connection stations via analyzing the entire process for passengers transferring from intercity trains to metros. Also, a timetable optimization model aiming at minimizing passenger waiting time of a metro line where an intermediate station is connected to an intercity railway station is proposed.

Regulating cell migration dynamics is of significance in tissue engineering and regenerative medicine. A 3D scaffold was created to provide various topographies based on a poly(ε-caprolactone) (PCL) self-induced nanohybrid shish-kebab structure, which consisted of aligned PCL nanofibers and spaced PCL crystal lamellae grown on the fibers. Electrospinning was applied followed by self-induced crystallization. The results resembled natural collagen fibrils in an extracellular matrix. This variable microstructure enabled control of cell adhesion and migration. The kebab size was controlled by initial PCL concentrations. The geometry of cells seeded on the fibers was less elongated, but the adhesion was more polarized with a higher nuclear shape index and faster migration speed. These results could aid in rapid endothelialization in tissue engineering.

Photocatalytic oxidation desulfurization has become a research hotspot in recent years because of mild reaction conditions, less energy consumption and high selectivity. In this paper, TiO2was loaded onto SBA-15 molecular sieves and sensitized with organic dyes (2, 9-dichloroquinacridone, DCQ) to extend its spectral response range from ultraviolet light to visible light. The catalyst DCQ-X%TiO2@SBA-15 was characterized by BET measurements, X-ray diffraction, Fourier transform infrared spectroscopy and Ultraviolet–visible diffuse reflection spectra, and then it was applied for photocatalytic oxidation desulfurization of gasoline. The effects of different catalytic systems, TiO2concentration, catalyst dosage, and different model sulfur compounds on catalytic desulfurization performance were investigated. Experimental results show that DCQ-TiO2@SBA-15 has a better performance than the unsensitized TiO2@SBA-15, and the desulfurization rate can reach up to 96.1% in a reaction time of 90 min.

Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.

The dysregulation of some solute carrier (SLC) proteins has been linked to a variety of diseases, including diabetes and chronic kidney disease. However, SLC-related genes (SLCs) has not been extensively studied in acute myocardial infarction (AMI). The GSE66360 and GSE60993 datasets, and SLCs geneset were enrolled in this study. Differentially expressed SLCs (DE-SLCs) were screened by overlapping DEGs between the AMI and control groups and SLCs. Next, functional enrichment analysis was carried out to research the function of DE-SLCs. Consistent clustering of samples from the GSE66360 dataset was accomplished based on DE-SLCs selected. Next, the gene set enrichment analysis (GSEA) was performed on the DEGs-cluster (cluster 1 vs cluster 2). Three machine learning models were performed to obtain key genes. Subsequently, biomarkers were obtained through receiver operating characteristic (ROC) curves and expression analysis. Then, the immune infiltration analysis was performed. Afterwards, single-gene GSEA was carried out, and the biomarker-drug network was established. Finally, quantitative real-time fluorescence PCR (qRT-PCR) was performed to verify the expression levels of biomarkers. In this study, 13 DE-SLCs were filtered by overlapping 366 SLCs and 448 DEGs. The functional enrichment results indicated that the genes were implicated with amino acid transport and TNF signaling pathway. After the consistency clustering analysis, the samples were classified into cluster 1 and cluster 2 subtypes. The functional enrichment results showed that DEGs-cluster were implicated with chemokine signaling pathway and so on. Further, SLC11A1 and SLC2A3 were identified as SLC-related biomarkers, which had the strongest negative relationship with resting memory CD4 T cells and the strongest positive association with activated mast cells. In addition, the single-gene GSEA results showed that cytosolic ribosome was enriched by the biomarkers. Five drugs targeting SLC2A3 were predicted as well. Lastly, the experimental results showed that the biomarkers expression trends were consistent with public database. In this study, 2 SLC-related biomarkers (SLC11A1 and SLC2A3) were screened and drug predictions were carried out to explore the prediction and treatment of AMI.

Background: Expression quantitative trait locus (eQTL) analysis has emerged as an important tool in elucidating the link between genetic variants and gene expression, thereby bridging the gap between risk SNPs and associated diseases. We recently identified and validated a specific case where the methylation of a CpG site influences the relationship between the genetic variant and gene expression. Results: Here, to systematically evaluate this regulatory mechanism, we develop an extended eQTL mapping method, termed DNA methylation modulated eQTL (memo-eQTL). Applying this memo-eQTL mapping method to 128 normal prostate samples enables identification of 1063 memo-eQTLs, the majority of which are not recognized as conventional eQTLs in the same cohort. We observe that the methylation of the memo-eQTL CpG sites can either enhance or insulate the interaction between SNP and gene expression by altering CTCF-based chromatin 3D structure. Conclusions: This study demonstrates the prevalence of memo-eQTLs paving the way to identify novel causal genes for traits or diseases associated with genetic variations.

Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survival. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three-dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic-related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senescent cells. Cellular senescence induced by replication and an AKT inhibitor in ex-vivo spheroid leiomyomas was examined in this work. Several dysregulated genes in the ROS, hypoxic and AKT pathways were identified, including WIPI1 and SLITKR4. Induced senescence in spheroids can be reversed by ABT263, a BH3 mimetic, which may be therapeutic modality for treatment of leiomyoma.

Cellular senecence is an important biologic endpoint. Naturally occuring (aging) senescence is common in uterine leiomyoma (ULM). AKT is one of major pathways in promoting ULM growth and survival. Inactivation of AKT by MK2206 in ULM resulted in stress-induced senescence in vitro. Study of the senescent phenotypes and molecular changes in ULM may greatly facilitate the understanding of the tumor biology and potential clinical therapy for this common disease associated with high morbidity. To study senescence in a model system that closely resembles primary ULM in vivo, we applied an ex vivo model of three-dimensional (3D) spheroid culture system which maintained the molecular and cellular characteristics of primary ULM and matched myometrium as seen in vivo. Gene expression profiling done on ULM induced to undergo replication (passaging) or stress-induced (MK2206) senescence revealed that ROS and hypoxic-related genes were upregulated in the two types of senescences. Overexpression of two selected genes, WIPI1 and SLITKR4, induced cellular senescence in ULM spheroids. Additionally, administration of ABT263 (a BH3 mimetic) effectively reduced the senescent cells induced in ULM spheroids. This study identified novel genes associated with senescence in ULM and demonstrated a BH3 mimetic to act as a senolytic to remove senescent cells.

With the successive advent of piezoelectric nanogenerator (PENG) and triboelectric nanogenerator (TENG), the harvest of ambient mechanical energy has become more high-efficient, low-lost and simpler for self-powered systems. Introducing lightweight alternative power source to bionic micro aerial vehicle (BMAV) which is widely used for military surveillance or monitoring air pollution and so on, is the forefront of the research hotspots. However, there is still no design applying the two kinds of nanogenerator (NG) together in BMAV to collect the flapping mechanical energy more efficiently. In this paper, we demonstrate a hybrid flexible nanogenerator (HFNG) based on the combination of triboelectric and piezoelectric devices in BMAV. It not only can solve the problem of power supply, but also make the BMAV intelligent to monitor the changes of specific environmental factors. The newly designed HFNG can produce a maximum open-circuit voltage of 80 V, short-circuit current of 3.0 μA with the instantaneous output power density of 34.1 mW/m2when the flapping frequency of BMAV (f) is 14 Hz. The rectified output of HFNG has been applied to charge the commercial capacitor, rechargeable battery and drive light-emitting diodes. It was also demonstrated that HFNG can be used for testing the lift force (L) of BMAV. Moreover, the output performances of HFNG have been proved to be sensitive to temperature, humidity, alcohol concentration and PM2.5 in the environment.

Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.

ABSTRACTDue to increased glycolysis and poor local perfusion, solid tumors are usually immersed in an acidic microenvironment. While extracellular acidosis is cytotoxic, cancer cells eventually become acclimated to it. While previous studies have addressed the acute effect of acidosis on cancer cells, little is known about how cancer cells survive chronic acidosis. In this study we exposed colorectal cancer (CRC) cells (HCT15, HCT116 and LoVo) to acidic pH (pH 6.5) continuously for over three months and obtained CRC cells that become acclimated to acidic pH, designated as CRC-acidosis-acclimated or CRC-AA. We unexpectedly found that while acute exposure to low pH resulted in an increase in the level of intracellular reactive oxygen species (ROS), CRC-AA cells exhibited a significantly reduced level of ROS when compared to ancestor cells. CRC-AA cells were found to maintain a higher level of reduced glutathione, via the upregulation of CD44 and glutathione reductase (GSR), among others, than their ancestor cells. Importantly, CRC-AA cells were more sensitive to agents that deplete GSH. Moreover, downregulation of GSR by RNA interference was more deleterious to CRC-AA cells than to control cells. Together, our results demonstrate a critical role of glutathione-dependent antioxidant defense in acclimation of CRC cells to acidic extracellular pH.

Artesunate, a semi-synthetic derivative of arteminisin originally developed for the treatment of malaria, has recently been shown to possess antitumor properties. One of the cytotoxic effects of artesunate on cancer cells is mediated by induction of oxidative stress and DNA double-strand breaks (DSBs). We report here that in addition to inducing oxidative stress and DSBs, artesunate can also downregulate RAD51 and impair DSB repair in ovarian cancer cells. We observed that the formation of RAD51 foci and homologous recombination repair (HRR) were significantly reduced in artesunate-treated cells. As a consequence, artesunate and cisplatin synergistically induced DSBs and inhibited the clonogenic formation of ovarian cancer cells. Ectopic expression of RAD51 was able to rescue the increased chemosensitivity conferred by artesunate, confirming that the chemosensitizing effect of artesuante is at least partially mediated by the downregulation of RAD51. Our results indicated that artesunatecan compromise the repair of DSBs in ovarian cancer cells, and thus could be employed as a sensitizing agent in chemotherapy.

Here, we report a novel and facile protocol for the synthesis of benz[c,d]indol-2-imines viapalladium-catalyzed C–C and C–N coupling of 8-halo-1-naphthylamines with isocyanides in a single step. The reaction features broad substrate scopes and mild conditions, providing an efficient alternative for the construction of antiproliferative agents and BET bromodomain inhibitors. If 0.1 mL of H2O was added to this reaction, the N-substituted amino-1-naphthylamides could be obtained easily.

Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.