Functional genomics analysis reveals the evolutionary adaptation and demographic history of pygmy lorises.

Lorises are a group of globally threatened strepsirrhine primates that exhibit many unusual physiological and behavioral features, including a low metabolic rate, slow movement, and hibernation. Here, we assembled a chromosome-level genome sequence of the pygmy loris (Xanthonycticebus pygmaeus) and resequenced whole genomes from 50 pygmy lorises and 6 Bengal slow lorises (Nycticebus bengalensis). We found that many gene families involved in detoxification have been specifically expanded in the pygmy loris, including the GSTA gene family, with many newly derived copies functioning specifically in the liver. We detected many genes displaying evolutionary convergence between pygmy loris and koala, including PITRM1. Significant decreases in PITRM1 enzymatic activity in these two species may have contributed to their characteristic low rate of metabolism. We also detected many evolutionarily convergent genes and positively selected genes in the pygmy loris that are involved in muscle development. Functional assays demonstrated the decreased ability of one positively selected gene, MYOF, to up-regulate the fast-type muscle fiber, consistent with the lower proportion of fast-twitch muscle fibers in the pygmy loris. The protein product of another positively selected gene in the pygmy loris, PER2, exhibited weaker binding to the key circadian core protein CRY, a finding that may be related to this species' unusual circadian rhythm. Finally, population genomics analysis revealed that these two extant loris species, which coexist in the same habitat, have exhibited an inverse relationship in terms of their demography over the past 1 million years, implying strong interspecies competition after speciation.

Probing the Atomic Erosion Wear Characteristics of TiC-Coated Fe in Oil and Gas Drilling Environments.

The titanium carbide (TiC) coating is considered one of the key coating materials to resist erosion wear in oil and gas drilling environments due to its excellent impact and wear resistance. Based on molecular dynamics, the erosion wear resistance of TiC coatings and the pure Fe system in the simulation of nanoindentation, scratch, and particle impact was studied at the microscale. The results indicate that TiC coatings can effectively enhance the load-bearing capacity of the Fe substrate within the critical load range and exhibit low friction characteristics and erosion resistance. However, the protection is lost after the TiC coating cracks, leading to an increase in the tangential force. In addition, when TiC coatings and pure Fe systems exhibit typical erosion characteristics of brittle materials, the TiC coating will significantly reduce the erosion wear of the substrate.

What Determines the Low-Friction Mechanism of the Silicon-Doped Diamond-like Carbon Film in a Water Environment: An Atomic-Level Understanding.

It is widely acknowledged that doping silicon can significantly enhance the friction performance of diamond-like carbon (DLC) films in a water environment. However, the mechanism of low friction caused by doped silicon is still highly controversial. Therefore, this article compares the interface interaction between DLC and Si-DLC films in a water environment through first-principles calculations of physisorption and chemisorption effects. The results indicate that water molecules are predominantly chemically adsorbed rather than physically adsorbed on the Si-DLC surface. Further study reveals that when OH-termination is formed on the Si-DLC surface, water molecules are predominantly physically adsorbed rather than chemically adsorbed on the Si-DLC hydroxylation surface. Consequently, a more stable hydration layer is formed on the surface through the hydrogen bond network formed by Si-OH groups, ultimately leading to lower friction. Moreover, molecular dynamics simulations further suggest that the lower friction coefficient of Si-DLC films in a water environment may be due to more water molecules at the friction interface and fewer interface covalent bonds. In short, the low-friction coefficient of the Si-DLC film in a water environment may be caused not only by the chemisorption of water molecules on its surface but also by the physisorption of water molecules on the Si-DLC film after surface hydroxylation.

Gut symbiotic bacteria are involved in nitrogen recycling in the tephritid fruit fly Bactrocera dorsalis.

BACKGROUND: Nitrogen is considered the most limiting nutrient element for herbivorous insects. To alleviate nitrogen limitation, insects have evolved various symbiotically mediated strategies that enable them to colonize nitrogen-poor habitats or exploit nitrogen-poor diets. In frugivorous tephritid larvae developing in fruit pulp under nitrogen stress, it remains largely unknown how nitrogen is obtained and larval development is completed. RESULTS: In this study, we used metagenomics and metatranscriptomics sequencing technologies as well as in vitro verification tests to uncover the mechanism underlying the nitrogen exploitation in the larvae of Bactrocera dorsalis. Our results showed that nitrogenous waste recycling (NWR) could be successfully driven by symbiotic bacteria, including Enterobacterales, Lactobacillales, Orbales, Pseudomonadales, Flavobacteriales, and Bacteroidales. In this process, urea hydrolysis in the larval gut was mainly mediated by Morganella morganii and Klebsiella oxytoca. In addition, core bacteria mediated essential amino acid (arginine excluded) biosynthesis by ammonium assimilation and transamination. CONCLUSIONS: Symbiotic bacteria contribute to nitrogen transformation in the larvae of B. dorsalis in fruit pulp. Our findings suggest that the pattern of NWR is more likely to be applied by B. dorsalis, and M. morganii, K. oxytoca, and other urease-positive strains play vital roles in hydrolysing nitrogenous waste and providing metabolizable nitrogen for B. dorsalis.

Transcriptome analysis uncovers different avenues for manipulating cold performance in Chrysomya megacephala (Diptera, Calliphoridae).

Temperature strongly impacts the rates of physiological and biochemical processes, which in turn can determine the survival and population size of insects. At low temperatures performance is limited, however, cold tolerance and performance at low temperature can be improved after short- or long-term acclimation in many insect species. To understand mechanisms underlying acclimation, we sequenced and compared the transcriptome of the blowfly Chrysomya megacephala under rapid cold hardening (RCH) and long-term cold acclimation (LCA) conditions. The RCH response was dominated by genes related to immune response, spliceosome, and protein processing in endoplasmic reticulum with up-regulation during recovery from RCH. In contrast, LCA was associated with genes related to carbohydrate metabolism and cytoskeleton branching and stabilizing. Meanwhile, mRNA levels of genes related to glycerophospholipid metabolism, and some heat shock proteins (Hsps) were collectively up-regulated by both RCH and LCA. There were more genes and pathway adjustments associated with LCA than RCH. Overall, the transcriptome data provide basic information of molecular mechanisms underpinning the RCH and LCA response. The partly independent molecular responses to RCH and LCA suggest that several avenues for manipulating cold performance exist and RCH might be more effective as it only triggers fewer genes and affects the general metabolisms less. These observations provide some appropriate methods to improve cold tolerance of C. megacephala, and hold promise for developing an extended use of mass-reared C. megacephala with better cold performance as a pollinator of crops at low temperatures.

Downregulation of PHF19 inhibits cell growth and migration in gastric cancer.

Objectives: The PHD Finger Protein 19 (PHF19), as a sub-component of polycomb repressive complex 2 (PRC2), has been identified to be associated with various biological processes. Aberrant expression of PHF19 has implicated in several cancer types. This study aims to investigate its function and clinical significance in gastric cancer for the first time.Methods: The expression of PHF19 was evaluated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. PHF19 was silenced by small interference RNAs and lentiviral particles in gastric cancer cells. Then cell growth was measured by CCK-8 assays, colony formation and in a mouse model. Transwell and wound healing assays were performed to detect cell migration. Western blot analysis was used to explore the downstream signaling factors in PHF19-silenced cells, xenograft tumors and gastric cancer samples.Results: PHF19 was frequently upregulated in gastric cancer tissues compared with adjacent normal stomach tissues and this upregulation was correlated with tumor cell differentiation and poor outcome of gastric cancer patients. Functionally, the silencing of PHF19 in gastric cancer cells led to decreased cell growth and migration. Stable knockdown of PHF19 inhibited the tumorigenicity of gastric cancer cells in nude mice model. Western blot results demonstrated that phosphorylated AKT and ERK were reduced upon PHF19 downregulation, implying the two signaling pathways possibly mediate the oncogenic roles of PHF19.Conclusions: We identified PHF19 as an oncogene candidate and provided a new potential drug target for gastric cancer.

Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway.

BACKGROUND: CircRNA has emerged as a new non-coding RNA that plays crucial roles in tumour initiation and development. 'MiRNA sponge' is the most reported role played by circRNAs in many tumours. The AKT/mTOR axis is a classic signalling pathway in cancers that sustains energy homeostasis through energy production activities, such as the Warburg effect, and blocks catabolic activities, such as autophagy. Additionally, the AKT/mTOR axis exerts a positive effect on EMT, which promotes tumour metastasis. METHODS: We detected higher circNRIP1 expression in gastric cancer by performing RNA-seq analysis. We verified the tumour promotor role of circNRIP1 in gastric cancer cells through a series of biological function assays. We then used a pull-down assay and dual-luciferase reporter assay to identify the downstream miR-149-5p of circNRIP1. Western blot analysis and immunofluorescence assays were performed to demonstrate that the circNRIP1-miR-149-5p-AKT1/mTOR axis is responsible for the altered metabolism in GC cells and promotes GC development. We then adopted a co-culture system to trace circNRIP1 transmission via exosomal communication and RIP experiments to determine that quaking regulates circNRIP1 expression. Finally, we confirmed the tumour suppressor role of microRNA-133a-3p in vivo in PDX mouse models. RESULTS: We discovered that knockdown of circNRIP1 successfully blocked proliferation, migration, invasion and the expression level of AKT1 in GC cells. MiR-149-5p inhibition phenocopied the overexpression of circNRIP1 in GC cells, and overexpression of miR-149-5p blocked the malignant behaviours of circNRIP1. Moreover, it was proven that circNRIP1 can be transmitted by exosomal communication between GC cells, and exosomal circNRIP1 promoted tumour metastasis in vivo. We also demonstrated that quaking can promote circNRIP1 transcription. In the final step, the tumour promotor role of circNRIP1 was verified in PDX models. CONCLUSIONS: We proved that circNRIP1 sponges miR-149-5p to affect the expression level of AKT1 and eventually acts as a tumour promotor in GC.

Synthesis of CF3CH2-Containing Indolines by Transition-Metal-Free Aryltrifluoromethylation of Unactivated Alkenes.

With an unactivated double bond as the radical acceptor, allyl amines underwent a metal-free trifluoromethylation/cyclization cascade with CF3SO2Na (Langlois' reagent), affording CF3CH2-containing indolines and tetrahydroisoquinolines, whose practical syntheses are significant challenges. This protocol features mild conditions, low cost, and a broad substrate scope.

Association between cytokine gene polymorphisms and ankylosing spondylitis susceptibility: a systematic review and meta-analysis.

PURPOSE OF THE STUDY: The aim of this study was to perform a meta-analysis to derive precise estimation of the association of interleukin-23 receptor (IL-23R), IL-1 receptor 2 (IL-1R2), IL-12 beta (IL-12B), IL-10 and tumour necrosis factor (TNF)-α polymorphisms with ankylosing spondylitis (AS) susceptibility. STUDY DESIGN: A systematic literature search was conducted to identify the relevant studies. Pooled OR with 95% CI was calculated to assess the strength of the association in a fixed or random-effects model. RESULTS: A total of 13 917 cases and 19 849 controls in 43 eligible studies were included in the meta-analysis. Seventeen single-nucleotide polymorphisms (SNPs) in the abovementioned five cytokine genes were evaluated. The results indicate that the nine SNPs (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs11209032, rs1495965, rs7517847, rs2201841) of IL-23R are associated with AS susceptibility in all study subjects in the allelic model. Moreover, stratification by ethnicity identified a significant association between seven SNPs of IL-23R and AS susceptibility in Europeans and Americans, but not in Asians. In addition, the IL-10-819 C/T and TNF-α-857 C/T polymorphisms also confer susceptibility to AS, especially in Asian population. CONCLUSION: The results suggested that the genetic susceptibility for AS is associated with the nine SNPs of IL-23R in overall population. In the subgroup analysis, significant associations were shown in European and American population, but not in Asian population. Our results also suggest that IL-10-819 C/T and TNF-α-857 C/T polymorphism might be associated with AS risk, especially in Asian population.

The Efficacy of Imrecoxib and Celecoxib in Axial Spondyloarthritis and Their Influence on Serum Dickopff-Related Protein 1 (DKK-1) Levels.

BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme-linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels.

A machine learning-based approach to predict energy layer for each field in spot-scanning proton arc therapy for lung cancer: A feasibility study.

BACKGROUND: Determining the optimal energy layer (EL) for each field, under considering both dose constraints and delivery efficiency, is crucial to promoting the development of proton arc therapy (PAT) technology. PURPOSE: This study aimed to explore the feasibility and potential clinical benefits of utilizing machine learning (ML) technique to automatically select EL for each field in PAT plans of lung cancer. METHODS: Proton Bragg peak position (BPP) was employed to characterize EL. The ground truth BPPs for each field were determined using the modified ELO-SPAT framework. Features in geometric, water-equivalent thicknesses (WET) and beamlet were defined and extracted. By analyzing the relationship between the extracted features and ground truth, a polynomial regression model with L2-norm regularization (Ridge regression) was constructed and trained. The performance of the regression model was reported as an error between the predictions and the ground truth. Besides, the predictions were used to make PAT plans (PAT_PRED). These plans were compared with those using the ground truth BPPs (PAT_TRUTH) and the mid-WET of the target volumes (PAT_MID) in terms of relative biological effectiveness-weighted dose (RWD) distributions. One hundred ten patients with lung cancer, a total of 7920 samples, were enrolled retrospectively, with 5940 cases randomly selected as the training set and the remaining 1980 cases as the testing set. Nine patients (648 samples) were collected additionally to evaluate the regression model in terms of plan quality and robustness. RESULTS: With regard to the prediction errors, the root mean squared errors and mean absolute errors between the ML-predicted and ground truth BPPs for the testing set were 9.165 and 6.572 mm, respectively, indicating differences of approximately two to three ELs. As for plan quality, the PAT_TRUTH and PAT_PRED plans performed similarly in terms of plan robustness, target coverage and organs at risk (OARs) protection, with differences smaller than 0.5 Gy(RBE). This trend was also observed for dose conformity and uniformity. The PAT_MID plans produced the lowest robustness index and lowest doses to OARs, along with the highest heterogeneity index, indicating better protection for OARs, improved plan robustness, but compromised dose homogeneity. Additionally, for relatively small tumor sizes, the PAT_MID plan demonstrated a notably poor dose conformity index. CONCLUSIONS: Within this cohort under investigation, our study demonstrated the feasibility of using ML technique to predict ELs for each field, offering a fast (within 2 s) and memory-efficient reduced way to select ELs for PAT plan.

circVAPA-rich small extracellular vesicles derived from gastric cancer promote neural invasion by inhibiting SLIT2 expression in neuronal cells.

Gastric cancer (GC) is one of the most common cancer worldwide. Neural invasion (NI) is considered as the symbiotic interaction between nerves and cancers, which strongly affects the prognosis of GC patients. Small extracellular vesicles (sEVs) play a key role in intercellular communication. However, whether sEVs mediate GC-NI remains unexplored. In this study, sEVs release inhibitor reduces the NI potential of GC cells. Muscarinic receptor M3 on GC-derived sEVs regulates their absorption by neuronal cells. The enrichment of sEV-circVAPA in NI-positive patients' serum is validated by serum high throughput sEV-circRNA sequencing and clinical samples. sEV-circVAPA promotes GC-NI in vitro and in vivo. Mechanistically, sEV-circVAPA decreases SLIT2 transcription by miR-548p/TGIF2 and inhibits SLIT2 translation via binding to eIF4G1, thereby downregulates SLIT2 expression in neuronal cells and finally induces GC-NI. Together, this work identifies the preferential absorption mechanism of GC-derived sEVs by neuronal cells and demonstrates a previously undefined role of GC-derived sEV-circRNA in GC-NI, which provides new insight into sEV-circRNA based diagnostic and therapeutic strategies for NI-positive GC patients.

Associations of dietary factors with gastric cancer risk: insights from NHANES 2003-2016 and mendelian randomization analyses.

Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings.

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1.

Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo. Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.

Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer.

Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21-mediated ubiquitination/degradation of STAT1 in a GTP binding-dependent modality.

BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. METHODS: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. RESULTS: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo. CONCLUSIONS: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.

N6-methyladenosine modification of CENPF mRNA facilitates gastric cancer metastasis via regulating FAK nuclear export.

BACKGROUND: N6-methyladenosine (m6 A) modification is the most common modification that occurs in eukaryotes. Although substantial effort has been made in the prevention and treatment of gastric cancer (GC) in recent years, the prognosis of GC patients remains unsatisfactory. The regulatory mechanism between m6 A modification and GC development needs to be elucidated. In this study, we examined m6 A modification and the downstream mechanism in GC. METHODS: Dot blotting assays, The Cancer Genome Atlas analysis, and quantitative real-time PCR (qRT-PCR) were used to measure the m6 A levels in GC tissues. Methylated RNA-immunoprecipitation sequencing and RNA sequencing were performed to identify the targets of m6 A modification. Western blotting, Transwell, wound healing, and angiogenesis assays were conducted to examine the role of centromere protein F (CENPF) in GC in vitro. Xenograft, immunohistochemistry, and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo. Methylated RNA-immunoprecipitation-qPCR, RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m6 A modification sites of CENPF. Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase (MAPK) signaling pathway in GC cells. Coimmunoprecipitation, mass spectrometry, qRT-PCR, and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them. RESULTS: CENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo. Mechanistically, increased m6 A modification of CENPF was mediated by methyltransferase 3, and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), thereby promoting its mRNA stability. In addition, the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway. Furthermore, CENPF could bind to FAK and promote its localization in the cytoplasm. Moreover, we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients. CONCLUSIONS: Our findings revealed that increased m6 A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis. CENPF expression was correlated with the clinical features of GC patients; therefore, CENPF may serve as a prognostic marker of GC.

N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer.

Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m6A) methylation participates in tumor progression and tissue development. During tumor progression, DNA damage repair mechanisms can be reprogrammed to give new growth advantages on tumor clones whose genomic integrity is disturbed. Here we detected the elevated SUV39H2 expression in GC tissues and cell lines. Functionally, SUV39H2 promoted GC proliferation and inhibited apoptosis in vitro and in vivo. Mechanistically, METTL3-mediated m6A modification promotes mRNA stability of SUV39H2 in an IGF2BP2 dependent manner, resulting in upregulated mRNA expression of SUV39H2. As a histone methyltransferase, SUV39H2 was verified to increase the phosphorylation level of ATM through transcriptional repression of DUSP6, thereby promoting HRR and ultimately inhibiting GC chemosensitivity to cisplatin. Collectively, these results indicate the specific mechanism of m6A-modified SUV39H2 as a histone methyltransferase promoting HRR to inhibit the chemosensitivity of GC. SUV39H2 is expected to become a key target in the precision targeted therapy of GC.

High-Valence Mo Doping and Oxygen Vacancy Engineering to Promote Morphological Evolution and Oxygen Evolution Reaction Activity.

The rational design of high-efficiency, low-cost electrocatalysts for electrochemical water oxidation in alkaline media remains a huge challenge. Herein, combined strategies of metal doping and vacancy engineering are employed to develop unique Mo-doped cobalt oxide nanosheet arrays. The Mo dopants exist in the form of high-valence Mo6+, and the doping amount has a significant effect on the structure morphology, which transforms from 1D nanowires/nanobelts to 2D nanosheets and finally 3D nanoflowers. In addition, the introduction of vast oxygen vacancies helps to modulate the electronic states and increase the electronic conductivity. The optimal catalyst MoCoO-3 exhibits greatly increased active sites and enhanced reaction kinetics. It gives a dramatically lower overpotential at 50 mA cm-2 (288 mV), much smaller than that of the undoped counterpart (418 mV) and comparable to those of the recently reported electrocatalysts. Density functional theory results further verify that the increased electronic conductivity and optimized adsorption energy toward oxygen evolution reaction intermediates are mainly responsible for the enhanced catalytic activity. Moreover, the assembled two-electrode electrolyzer (MoCoO-3||Pt/C) exhibits superior performance with the cell potential decreased by 233 mV to reach a current density of 50 mA cm-2 with respect to the benchmark counterpart catalysts (RuO2||Pt/C). This work might contribute to the rational design of effective, low-cost electrocatalyst materials by combining multiple strategies.

MSC-NPRA loop drives fatty acid oxidation to promote stemness and chemoresistance of gastric cancer.

Cisplatin (CDDP)-based chemotherapy is the preferred treatment strategy for advanced stage gastric cancer (GC) patients. Despite the efficacy of chemotherapy, the development of chemoresistance negatively affects the prognosis of GC and the underlying mechanism remains poorly understood. Accumulated evidence suggests that mesenchymal stem cells (MSCs) play important roles in drug resistance. The chemoresistance and stemness of GC cells were observed by colony formation, CCK-8, sphere formation and flow cytometry assays. Cell lines and animal models were utilized to investigate related functions. Western blot, quantitative real-time PCR (qRT-PCR) and co-immunoprecipitation were used to explore related pathways. The results showed that MSCs improved the stemness and chemoresistance of GC cells and accounted for the poor prognosis of GC. Natriuretic peptide receptor A (NPRA) was upregulated in GC cells cocultured with MSCs and knockdown of NPRA reversed the MSC-induced stemness and chemoresistance. At the same time, MSCs could be recruited to GC by NPRA, which formed a loop. In addition, NPRA facilitated stemness and chemoresistance through fatty acid oxidation (FAO). Mechanistically, NPRA protected Mfn2 against protein degradation and promoted its mitochondrial localization, which consequently improved FAO. Furthermore, inhibition of FAO with etomoxir (ETX) attenuated MSC-induced CDDP resistance in vivo. In conclusion, MSC-induced NPRA promoted stemness and chemoresistance by upregulating Mfn2 and improving FAO. These findings help us understand the role of NPRA in the prognosis and chemotherapy of GC. NPRA may be a promising target to overcome chemoresistance.