Efficient and scalable synthesis of 3,4-dihydroisoquinolin-1(2H)-ones by benzylic oxidation of tetrahydroisoquinoline derivatives using cerium ammonium nitrate (CAN).

An efficient and scalable method for the synthesis of 3,4-dihydroisoquinolin-1(2H)-ones through benzylic oxidation of tetrahydroisoquinoline derivatives using a catalytic amount of cerium ammonium nitrate (CAN) and a stoichiometric amount of NaBrO3 as oxidants was developed. The reaction is significantly influenced by the substituent groups on the phenyl ring. While electron-withdrawing groups on the phenyl ring can lower the reactivities of the substrates, electron-donating groups on the phenyl ring can dramatically promote the oxidation rate.

See farther and more: a master-slave UAVs based synthetic optical aperture imaging system with wide and dynamic baseline.

An open challenge remained in designing an optical system to capture the aerial image with a wide field of view (FoV) and high resolution. The optical system of one camera from a single unmanned aerial vehicle (UAV) can hardly promise the FoV and resolution. The conventional swarm UAVs can form the camera array with a short or fixed baseline. They can capture the images with a wide FoV and high resolution, but the cost is the requirement of many UAVs. We aim to design a camera array with a wide and dynamic baseline to reduce the demand for UAVs to organize a synthetic optical aperture. In this thought, we propose a master-slave UAVs-based synthetic optical aperture imaging system with a wide and dynamic baseline. The system consists of one master UAV and multiple slave UAVs. Master and slave UAVs provide the global and local FoVs, respectively, and improve the efficiency of image acquisition. In such a system, fusing UAV images becomes a new challenge due to two factors: (i) the small FoV overlap of slave UAVs and (ii) the gap in resolution scale from slave to master UAV images. To deal with it, a coarse-to-fine stitching method is proposed to stitch up the multi-view images into one to obtain a wide FoV with high resolution. A video stabilization method has also been designed for the proposed imaging system. Challenges caused by wide and dynamic baselines can thus be solved by the above methods. Actual data experiments demonstrate that the proposed imaging system achieves high-quality imaging results.

Circulating cell-free DNA methylation-based multi-omics analysis allows early diagnosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC.

Causal association of smoking, blood lipids, and bladder cancer: Insights from a multivariable and mediation mendelian randomization investigation.

We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.

Blood metabolites mediate the impact of lifestyle factors on the risk of urolithiasis: a multivariate, mediation Mendelian randomization study.

Urolithiasis is closely linked to lifestyle factors. However, the causal relationship and underlying mechanisms remain unclear. This study aims to investigate the relationship between lifestyle factors and the onset of urolithiasis and explore potential blood metabolite mediators and their role in mediating this relationship. In this study, we selected single nucleotide polymorphisms (SNPs) as instrumental variables if they exhibited significant associations with our exposures in genome-wide association studies (GWAS) (p < 5.0 × 10-8). Summary data for urolithiasis came from the FinnGen database, including 8597 cases and 333,128 controls. We employed multiple MR analysis methods to assess causal links between genetically predicted lifestyle factors and urolithiasis, as well as the mediating role of blood metabolites. A series of sensitivity and pleiotropy analyses were also conducted. Our results show that cigarettes smoked per day (odds ratio [OR] = 1.159, 95% confidence interval [CI] = 1.004-1.338, p = 0.044) and alcohol intake frequency (OR = 1.286, 95% CI = 1.056-1.565, p = 0.012) were positively associated with increased risk of urolithiasis, while tea intake (OR = 0.473, 95% CI = 0.299-0.784, p = 0.001) was positively associated with reduced risk of urolithiasis. Mediation analysis identifies blood metabolites capable of mediating the causal relationship between cigarettes smoked per day, tea intake and urolithiasis. We have come to the conclusion that blood metabolites serve as potential causal mediators of urolithiasis, underscoring the importance of early lifestyle interventions and metabolite monitoring in the prevention of urolithiasis.

Comparison of Thulium Fiber Laser versus Holmium laser in ureteroscopic lithotripsy: a Meta-analysis and systematic review.

OBJECTIVES: To compare the efficacy and safety of thulium fiber laser (TFL) to holmium: YAG (Ho: YAG) laser in ureteroscopic lithotripsy for urolithiasis. METHODS: PubMed, Web of Science, Embase, CENTRAL, SinoMed, CNKI database, VIP and Wanfang Database were systematically searched for all relevant clinical trials until September 2023. References were explored to identify the relevant articles. Meta-analysis was carried out for the retrieved studies using RevMan5.4.1 software, and the risk ratio, mean difference and 95% confidence interval were expressed. Statistical significance was set at p < 0.05. The main outcomes of this meta-analysis were stone-free rate (SFR), perioperative outcomes and intraoperative or postoperative complications. RESULTS: Thirteen studies, including 1394 patients, were included. According to the results of pooled analysis, TFL was associated with significantly higher stone-free rate (SFR) [0.52, 95% CI (0.32, 0.85), P = 0.009], shorter operation time [-5.47, 95% CI (-8.86, -2.08), P = 0.002], and less stone migration [0.17, 95% CI (0.06, 0.50), P = 0.001]. However, there was no significant difference in terms of the laser time, duration of hospital stay, drop of hemoglobin level, total energy, postoperative ureteral stenting, the incidence of intraoperative complications or postoperative complications between TFL and Ho: YAGs. CONCLUSION: The findings of this study demonstrated several advantages of TFL in terms of higher SFR, shorter operative time and less stone migration. TRIAL REGISTRATION: The protocol of this systematic review was listed in PROSPERO ( www.crd.york.ac.uk/PROSPERO ) (Protocol number: CRD42022362550).

Kernel Bioassay Evaluation of Maize Ear Rot and Genome-Wide Association Analysis for Identifying Genetic Loci Associated with Resistance to Fusarium graminearum Infection.

Gibberella ear rot (GER) caused by Fusarium graminearum (teleomorph Gibberella zeae) is one of the most destructive diseases in maize, which severely reduces yield and contaminates several potential mycotoxins in the grain. However, few efforts had been devoted to dissecting the genetic basis of maize GER resistance. In the present study, a genome-wide association study (GWAS) was conducted in a maize association panel consisting of 303 diverse inbred lines. The phenotypes of GER severity were evaluated using kernel bioassay across multiple time points in the laboratory. Then, three models, including the fixed and random model circulating probability unification model (FarmCPU), general linear model (GLM), and mixed linear model (MLM), were conducted simultaneously in GWAS to identify single-nucleotide polymorphisms (SNPs) significantly associated with GER resistance. A total of four individual significant association SNPs with the phenotypic variation explained (PVE) ranging from 3.51 to 6.42% were obtained. Interestingly, the peak SNP (PUT-163a-71443302-3341) with the greatest PVE value, was co-localized in all models. Subsequently, 12 putative genes were captured from the peak SNP, and several of these genes were directly or indirectly involved in disease resistance. Overall, these findings contribute to understanding the complex plant-pathogen interactions in maize GER resistance. The regions and genes identified herein provide a list of candidate targets for further investigation, in addition to the kernel bioassay that can be used for evaluating and selecting elite germplasm resources with GER resistance in maize.

Identification of Crucial Genes and Signaling Pathways in Alectinib-Resistant Lung Adenocarcinoma Using Bioinformatic Analysis.

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has been shown to be effective for patients with ALK-positive non-small cell lung cancer (NSCLC). However, alectinib resistance is a serious problem worldwide. To the best of our knowledge, little information is available on its molecular mechanisms using the Gene Expression Omnibus (GEO) database. In this study, the differentially expressed genes (DEGs) were selected from the gene expression profile GSE73167 between parental and alectinib-resistant human lung adenocarcinoma (LUAD) cell samples. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) annotation enrichment analyses were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). The construction of protein-protein interaction (PPI) network was performed to visualize DEGs. The hub genes were extracted based on the analysis of the PPI network using plug-in cytoHubba of Cytoscape software. The functional roles of the key genes were investigated using Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer (UALCAN), Gene Set Enrichment Analysis (GSEA), and Tumor Immune Estimation Resource (TIMER) analysis. The networks of kinase, miRNA, and transcription-factor targets of SFTPD were explored using LinkedOmics. The drug sensitivity analysis of SFTPD was analyzed using the RNAactDrug database. Results showed a total of 144 DEGs were identified. Five hub genes were extracted, including mucin 5B (MUC5B), surfactant protein D (SFTPD), deleted in malignant brain tumors 1 (DMBT1), surfactant protein A2 (SFTPA2), and trefoil factor 3 (TFF3). The survival analysis using GEPIA displayed that low expression of SFTPD had a significantly negative effect on the prognosis of patients with LUAD. GSEA revealed that low expression of SFTPD was positively correlated with the pathways associated with drug resistance, such as DNA replication, cell cycle, drug metabolism, and DNA damage repair, including mismatch repair (MMR), base excision repair (BER), homologous recombination (HR), and nucleotide excision repair (NER). The SFTPD expression was negatively correlated with the drug sensitivity of alectinib according to RNAactDrug database. The expression of SFTPD was further validated in parental H3122 cells and alectinib-resistant H3122 cells by quantitative reverse transcription PCR (RT-qPCR). In conclusion, our study found that the five hub genes, especially low expression of SFTPD, are closely related to alectinib resistance in patients with LUAD.

Development and Challenges of Cyclic Peptides for Immunomodulation.

Cyclic peptides are polypeptide chains formed by cyclic sequences of amide bonds between protein-derived or non-protein-derived amino acids. Compared to linear peptides, cyclic peptides offer several unique advantages, such as increased stability, stronger affinity, improved selectivity, and reduced toxicity. Cyclic peptide has been proved to have a promising application prospect in the medical field. In addition, this paper mainly describes that cyclic peptides play an important role in anti-cancer, anti-inflammatory, anti-virus, treatment of multiple sclerosis and membranous nephropathy through immunomodulation. In order to know more useful information about cyclic peptides in clinical research and drug application, this paper also summarizes cyclic peptides currently in the clinical trial stage and cyclic peptide drugs approved for marketing in the recent five years. Cyclic peptides have many advantages and great potential in treating various diseases, but there are still many challenges to be solved in the development process of cyclic peptides.

Erratum: Citrus genomic resources unravel putative genetic determinants of Huanglongbing pathogenicity.

[This corrects the article DOI: 10.1016/j.isci.2023.106024.].

[Spatial Distribution of Aerobic Bacteria, Sources and Risks of Nitrogen and Phosphorus in Taihu Lake Sediments].

The release of nitrogen and phosphorus from sediments into lake water will exacerbate the eutrophication of lakes and endanger ecological safety and human health. Microorganisms are indispensable in nitrogen and phosphorus conversion, and accurate analysis of the distribution characteristics and sources of nitrogen and phosphorus in sediments as well as their relationship with microorganisms is an important prerequisite for lake eutrophication control. Taking Taihu Lake as the study area, 30 surface sediment samples were collected, and the grain size, pH, organic matter (OM), dissolved organic carbon (DOC), total phosphorus (TP), total nitrogen (TN), nitrate nitrogen (NO3--N), and dissolved organic nitrogen (DON) along with some other index contents were measured and analyzed; accordingly, spatial distribution characteristics were analyzed. While using nutrient agar (NA), the number of aerobic bacteria (AB) was determined by plate counting in the medium. Combined with principal component analysis (PCA) and Pearson correlation analysis, the spatial distribution characteristics and sources of sediments and AB in Taihu Lake were explored. The characteristics of sediment pollution in Taihu Lake were studied using the comprehensive pollution index and the organic pollution index methods. The results revealed that the average sediment indicators of the surface layer of Taihu Lake were as follows:AB was 9.25×104 CFU·g-1, average particle size (MZ) was 17.59 µm, pH was 7.62, ω(OM) was 15.05 g·kg-1, ω(DOC) was 71.60 mg·kg-1, ω(TP) was 598.13 mg·kg-1, ω(TN) was 1113.92 mg·kg-1, ω(NO3--N) was 3.22 mg·kg-1, and ω(DON) was 22.60 mg·kg-1. The comprehensive pollution index (FF) showed that 13% of the Taihu Lake was moderately polluted, while 87% was heavily polluted. Excluding the area in the center of the lake, the southern lake area, and some lakes in the western part of the East Taihu Lake, TN in the rest of the area was moderately and severely polluted. In addition to the heavy pollution of Zhushan Bay, the TP in Taihu Lake was generally at light and moderate pollution. The organic pollution index (OI) showed that the organic pollution of the sediments of Taihu Lake was relatively light, majorly caused by organic nitrogen (ON) pollution. DOC, DON, TN, and OM in Taihu Lake were primarily derived from the influence of aquatic plants, and TP And AB were primarily derived from the influence of the external input of rivers. This research will provide theoretical support for lake eutrophication treatment and also provide new ideas for further analysis of AB to remove nitrogen and phosphorus pollution from sediments.

SULF1 Activates the VEGFR2/PI3K/AKT Pathway to Promote the Development of Cervical Cancer.

BACKGROUND AND PURPOSE: Sulfatase 1 (SULF1) can regulate the binding of numerous signaling molecules by removing 6-O-sulfate from heparan sulfate proteoglycans (HSPGs) to affect numerous physiological and pathological processes. Our research aimed to investigate the effect of the SULF1-mediated VEGFR2/PI3K/AKT signaling pathway on tumorigenesis and development of cervical cancer (CC). METHODS: The expression and prognostic values of SULF1 in patients with CC were analyzed through bioinformatics analysis, RT-PCR, immunohistochemistry, and western blot assays. The function and regulatory mechanism of SULF1 in proliferation, migration, and invasion of cervical cancer cells were examined through lentivirus transduction, CCK8, flow cytometry analysis, plate colony formation assay, scratch assay, transwell assay, western blot, VEGFR2 inhibitor (Ki8751), and mouse models. RESULTS: SULF1 expression was significantly upregulated in CC tissues, which was significantly associated with poor prognosis of patients with CC. In vitro, the upregulation of SULF1 expression in cervical cancer HeLa cells promoted cell proliferation, colony formation, migration, and invasion while inhibiting apoptosis. Conversely, the downregulation of SULF1 expression had the opposite effect. In vivo, the upregulation of SULF1 expression resulted in a significant increase in both tumor growth and angiogenesis, while its downregulation had the opposite effect. Furthermore, western blot detection and cell function rescue assay confirmed that the upregulation of SULF1 in HeLa cells promoted the tumorigenic behaviors of cancer cells by activating the VEGFR2/PI3K/AKT signaling pathway. CONCLUSION: SULF1 plays an oncogenic role in the tumorigenesis and development of CC, indicating its potential as a novel molecular target for gene-targeted therapy in patients with CC.

Artificial Downregulation of Ribosomal Protein L34 Restricts the Proliferation and Metastasis of Colorectal Cancer by Suppressing the JAK2/STAT3 Signaling Pathway.

The highly conserved ribosomal protein L34 (RPL34) has been reported to play an essential role in the progression of diverse malignancies. RPL34 is aberrantly expressed in multiple cancers, although its significant in colorectal cancer (CRC) is currently unclear. Here, we demonstrated that RPL34 expression was higher in CRC tissues than in normal tissues. Upon RPL34 overexpression, the ability of proliferation, migration, invasion, and metastasis of CRC cells were significantly enhanced in vitro and in vivo. Furthermore, high expression of RPL34 accelerated cell cycle progression, activated the JAK2/STAT3 signaling pathway, and induced the epithelial-to-mesenchymal transition (EMT) program. Conversely, RPL34 silencing inhibited the CRC malignant progression. Utilizing immunoprecipitation assays, we identified the RPL34 interactor, the cullin-associated NEDD8-dissociated protein 1 (CAND1), which is a negative regulator of cullin-RING ligases. CAND1 overexpression reduced the ubiquitin level of RPL34 and stabilized RPL34 protein. CAND1 silencing in CRC cells resulted in a decrease in the ability of proliferation, migration, and invasion. CAND1 overexpression promoted CRC malignant phenotypes and induced EMT, and RPL34 knockdown rescued CAND1-induced CRC progression. In summary, our study indicates that RPL34 acts as a mediator, is stabilized by CAND1, and promotes proliferation and metastasis, in part, through the activation of the JAK2/STAT3 signaling pathway and induction of EMT in CRC.

Metallaphotoredox-Catalyzed Enantioselective Cross-Electrophile Coupling Using Alcohols as Reducing Agents.

The cross-electrophile coupling (XEC) represents a powerful strategy for C-C bond formation. However, controlling the enantioselectivity in these processes remains a challenge. Here, we report an unprecedented enantioselective XEC of α-amino acid derivatives with aryl bromides, enabled by alcohols as reducing agents via Ni/photoredox catalysis. This mechanistically distinct approach exploits the ability of photocatalytically generated α-hydroxyalkyl radicals to convert alkyl electrophiles to the corresponding alkyl radicals that are then enantioselectively coupled with aryl bromides. The readily scalable protocol allows modular access to valuable enantioenriched benzylic amines from abundant and inexpensive precursors, and is applicable to late-stage diversification with broad functional group tolerance. Mechanistic studies rationalize the versatility of this alcohol-based reactivity for radical generation and subsequent asymmetric cross-coupling. We expect that this alcohol-based cross-coupling will render a general platform for the development of appealing yet challenging enantioselective XECs.

Tumor budding and the prognosis of patients with metastatic colorectal cancer: a meta-analysis.

PURPOSE: Tumor budding has been suggested to be associated with poor survival of patients with colorectal cancer (CRC). However, it is unclear whether the association remains in patients with metastatic CRC (mCRC). The aim of the systematic review and meta-analysis was to investigate the potential predictive role of tumor budding for the prognosis of patients with mCRC. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched for relevant observational studies comparing the survival outcomes between mCRC patients with high versus low tumor budding. Data collection, literature searching, and statistical analysis were conducted independently by two authors. Using a heterogeneity-incorporating random-effects model, the results were pooled. RESULTS: In this meta-analysis, 1503 patients from nine retrospective cohort studies were included. Pooled results showed that compared to those with low tumor budding, mCRC patients with high tumor budding were associated with a poor progression-free survival (hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.31 to 2.07, p < 0.001; I2 = 30%) and overall survival (HR, 1.60; 95% CI, 1.33 to 1.93; p < 0.001; I2 = 0%). Influencing analysis by excluding one study at a time showed consistent results (p all < 0.05). Subgroup analyses showed consistent results in tumor budding evaluated from the primary cancer and metastases, in studies with a high tumor budding defined as ≥ 10 or 15 and ≥ 5 buds/HPF and in studies analyzed with univariate and multivariate regression models (p for subgroup difference all > 0.05). CONCLUSION: A high-degree tumor budding may be associated with poor prognosis in patients with mCRC.

Karyopherin Subunit Alpha 1 Enhances the Malignant Behaviors of Colon Cancer Cells via Promoting Nuclear Factor-κB p65 Nuclear Translocation.

BACKGROUND/AIMS: Aberrant nuclear factor-κB p65 (NF-κB p65) nuclear import commonly occurs in multiple cancers, including colon cancer. According to BioGRID, we noted that Karyopherin subunit alpha 1 (KPNA1), an important molecular transporter between the nucleus and the cytoplasm, may interact with NF-κB p65. KPNA1 itself is highly expressed in colon adenocarcinoma samples (N = 286) based on The Cancer Genome Atlas (TCGA) database. We aimed to explore the role of KPNA1 in colonic carcinogenesis and to determine whether NF-κB p65 nuclear translocation was involved. METHODS: KPNA1 expressions at mRNA and protein levels were analyzed in colon cancer tissues. The regulatory effect of KPNA1 on malignant biological properties was detected in SW480 and HCT116 colon cancer cells. Coimmunoprecipitation and immunofluorescence were performed to verify the relationship between KPNA1 and NF-κB p65. KPNA1 ubiquitination was also preliminarily investigated. RESULTS: KPNA1 was firstly confirmed as a significantly upregulated gene in our collected clinical colon cancer samples (N = 35). KPNA1 depletion inhibited cell proliferation, induced cell cycle arrest, and diminished migratory and invasive capacity of SW480 and HCT116 cells. Colon cancer cells overexpressing KPNA1 acquired more aggressive behaviors. KPNA1 acted as a transporter to induce the nuclear accumulation of NF-κB p65, thereby activating NF-κB signaling pathway in colon cancer cells. Furthermore, HECT, C2, and WW Domain-Containing E3 Ubiquitin (HECW2) interacted with KPNA1 to induce its ubiquitination. KPNA1 labeled with polyubiquitins was degraded through ubiquitin-proteasome system. CONCLUSION: The present study uncovers a role of KPNA1-NF-κB p65 axis in promoting colonic carcinogenesis.

MORC4 plays a tumor-promoting role in colorectal cancer via regulating PCGF1/CDKN1A axis in vitro and in vivo.

MORC family CW-type zinc finger 4 (MORC4) possessing nuclear matrix binding domains has been observed to be involved in multiple cancer development. By digging three gene expression omnibus (GEO) gene microarrays (GSE110223, GSE110224 and GSE24514), we found that MORC4 was overexpressed in colorectal cancer (CRC) samples (log2 Fold change >1, p < 0.05). We aimed to investigate the role of MORC4 in CRC malignant behaviors, with an emphasis on polycomb group ring finger 1 (PCGF1)/cyclin-dependent kinase inhibitor 1A (CDKN1A) axis. Firstly, we confirmed MORC4 as an upregulated gene in 60 pairs of frozen CRC and adjacent normal samples. MORC4 overexpression increased proliferation and metastasis, and decreased apoptosis in SW480 and HT29 cells, which was diminished by the knockdown of PCGF1, a transcriptional repressor of CDKN1A (a potent cyclin-dependent kinase inhibitor). MORC4 was further identified as a novel molecule that interacted with PCGF1 via coimmunoprecipitation. MORC4 itself did not substantially suppress CDKN1A transcriptional activity, but it augmented PCGF1's effect on CDKN1A. Additionally, MORC4 acted as the substrate of HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) and was degraded through ubiquitin-proteasome system. Collectively, our work suggested that MORC4 accelerated CRC progression via governing PCGF1/CDKN1A signaling.

Citrus genomic resources unravel putative genetic determinants of Huanglongbing pathogenicity.

Citrus HLB caused by Candidatus Liberibacter asiaticus is a pathogen-triggered immune disease. Here, we identified putative genetic determinants of HLB pathogenicity by integrating citrus genomic resources to characterize the pan-genome of accessions that differ in their response to HLB. Genome-wide association mapping and analysis of allele-specific expression between susceptible, tolerant, and resistant accessions further refined candidates underlying the response to HLB. We first developed a phased diploid assembly of Citrus sinensis 'Newhall' genome and produced resequencing data for 91 citrus accessions that differ in their response to HLB. These data were combined with previous resequencing data from 356 accessions for genome-wide association mapping of the HLB response. Genes determinants for HLB pathogenicity were associated with host immune response, ROS production, and antioxidants. Overall, this study has provided a significant resource of citrus genomic data and identified candidate genes to be further explored to understand the genetic determinants of HLB pathogenicity.

Adeno-Associated Virus-Mediated Knockdown of Agmatinase Attenuates Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Colorectal Cancer.

Agmatinase (AGMAT) is an enzyme that hydrolyzes agmatine to putrescine and urea. In this study, we explored the functions of AGMAT in colorectal cancer (CRC). By performing gain-of-function and loss-of-function experiments, we investigated the roles of AGMAT in proliferation, cell cycle progression, and apoptosis of CRC cells. We also established a colitis-associated colorectal cancer model by challenging mice with azoxymethane (AOM) and dextran sodium sulfate (DSS), and we subsequently silenced AGMAT expression in mice by adeno-associated virus 9 (AAV9)-mediated delivery of short hairpin RNA (shRNA). In vitro experiments showed that overexpression of AGMAT accelerated the proliferation and inhibited the apoptosis of CRC cells, and AGMAT knockdown exhibited the opposite effects. Interestingly, the oncogenic transcription factor, c-Myc, could bind to the AGMAT promoter and transcriptionally increase AGMAT expression in CRC cells. Additionally, c-Myc and AGMAT were upregulated in the colon of AOM/DSS-treated mice, and AGMAT silencing significantly mitigated colitis in AOM/DSS-treated mice, as evidenced by the increased colon length, attenuated crypt damage, and reduced levels of inflammatory indicators (myeloperoxidase, interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase, and phosphorylated p65) in colon tissues. Notably, AGMAT silencing decreased both the number and size of tumors, reduced expression of proliferating cell nuclear antigen, and inhibited phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase in the colon of AOM/DSS-treated mice. Overall, we determined that AGMAT facilitates tumor progression in CRC. Our findings will be helpful in the search for potential therapeutic targets for CRC.