Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

Greenhouse covering cultivation promotes chlorophyll accumulation of tea plant (Camellia sinensis) by activating relevant gene expression and enzyme activity.

BACKGROUND: The tea plant (Camellia sinensis (L.) O. Kuntze) is one of the most economically important woody crops. Plastic greenhouse covering cultivation has been widely used in tea areas of northern China. Chlorophyll is not only the crucial pigment for green tea, but also plays an important role in the growth and development of tea plants. Currently, little is known about the effect of plastic greenhouse covering cultivation on chlorophyll in tea leaves. RESULTS: To investigate the effect of plastic greenhouse covering cultivation on chlorophyll in tea leaves, color difference values, chlorophyll contents, gene expression, enzyme activities and photosynthetic parameters were analyzed in our study. Sensory evaluation showed the color of appearance, liquor and infused leaves of greenhouse tea was greener than field tea. Color difference analysis for tea liquor revealed that the value of ∆L, ∆b and b/a of greenhouse tea was significantly higher than field tea. Significant increase in chlorophyll content, intracellular CO2, stomatal conductance, transpiration rate, and net photosynthetic rate was observed in greenhouse tea leaves. The gene expression and activities of chlorophyll-metabolism-related enzymes in tea leaves were also activated by greenhouse covering. CONCLUSION: The higher contents of chlorophyll a, chlorophyll b and total chlorophyll in greenhouse tea samples were primarily due to higher gene expression and activities of chlorophyll-metabolism-related enzymes especially, chlorophyll a synthetase (chlG), pheophorbide a oxygenase (PAO) and chlorophyllide a oxygenase (CAO) in tea leaves covered by greenhouse. In general, our results revealed the molecular basis of chlorophyll metabolism in tea leaves caused by plastic greenhouse covering cultivation, which had great significance in production of greenhouse tea.

Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

Saturated fatty acid intake, genetic risk and colorectal cancer incidence: A large-scale prospective cohort study.

Previous investigations mainly focused on the associations of dietary fatty acids with colorectal cancer (CRC) risk, which ignored gene-environment interaction and mechanisms interpretation. We conducted a case-control study (751 cases and 3058 controls) and a prospective cohort study (125 021 participants) to explore the associations between dietary fatty acids, genetic risks, and CRC. Results showed that high intake of saturated fatty acid (SFA) was associated with a higher risk of CRC than low SFA intake (HR =1.22, 95% CI:1.02-1.46). Participants at high genetic risk had a greater risk of CRC with the HR of 2.48 (2.11-2.91) than those at low genetic risk. A multiplicative interaction of genetic risk and SFA intake with incident CRC risk was found (PInteraction = 7.59 × 10-20 ), demonstrating that participants with high genetic risk and high SFA intake had a 3.75-fold greater risk of CRC than those with low genetic risk and low SFA intake. Furthermore, incorporating PRS and SFA into traditional clinical risk factors improved the discriminatory accuracy for CRC risk stratification (AUC from 0.706 to 0.731). Multi-omics data showed that exposure to SFA-rich high-fat dietary (HFD) can responsively induce epigenome reprogramming of some oncogenes and pathological activation of fatty acid metabolism pathway, which may contribute to CRC development through changes in gut microbiomes, metabolites, and tumor-infiltrating immune cells. These findings suggest that individuals with high genetic risk of CRC may benefit from reducing SFA intake. The incorporation of SFA intake and PRS into traditional clinical risk factors will help improve high-risk sub-populations in individualized CRC prevention.

Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility.

Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity. Importantly, genetic variants linked to PDAC are preferentially found at PDAC-associated lncRNA regions, supporting the biological and clinical relevance of PDAC-associated lncRNAs. Finally, we prioritized a novel transcript (MICT00000110172.1) of RP11-638I2.4 as a potential tumor promoter. MICT00000110172.1 is able to reinforce the interaction with YY1, which could reverse the effect of YY1 on pancreatic cancer cell cycle arrest to promote the pancreatic cancer growth. G > A change at rs2757535 in the second exon of MICT00000110172.1 induces a spatial structural change and creates a target region for YY1 binding, which enforces the effect of MICT00000110172.1 in an allele-specific manner, and thus confers susceptibility to tumorigenesis. In summary, our results extend the repertoire of PDAC-associated lncRNAs that could act as a starting point for future functional explorations, and the identification of lncRNA-based target therapy.

HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction.

Although genome-wide association studies (GWASs) have identified over 100 colorectal cancer (CRC) risk loci, an understanding of causal genes or risk variants and their biological functions in these loci remain unclear. Recently, genomic loci 10q26.12 with lead SNP rs1665650 was identified as an essential CRC risk loci of Asian populations. However, the functional mechanism of this region has not been fully clarified. Here, we applied an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk loci 10q26.12. Notably, HSPA12A had the most significant effect among the identified genes and functioned as a crucial oncogene facilitating cell proliferation. Moreover, we conducted an integrative fine-mapping analysis to identify putative casual variants and further explored their association with CRC risk in a large-scale Chinese population consisting of 4054 cases and 4054 controls and also independently validated in 5208 cases and 20,832 controls from the UK biobank cohort. We identified a risk SNP rs7093835 in the intron of HSPA12A that was significantly associated with an increased risk of CRC (OR 1.23, 95% CI 1.08-1.41, P = 1.92 × 10-3). Mechanistically, the risk variant could facilitate an enhancer-promoter interaction mediated by the transcriptional factor (TF) GRHL1 and ultimately upregulate HSPA12A expression, which provides functional evidence to support our population findings. Collectively, our study reveals the important role of HSPA12A in CRC development and illustrates a novel enhancer-promoter interaction module between HSPA12A and its regulatory elements rs7093835, providing new insights into the etiology of CRC.

New method for scaling nonpoint source pollution by integrating the SWAT model and IHA-based indicators.

Nonpoint source (NPS) pollution shows spatial scaling effects because it is affected by topography, river networks, and many other factors. Currently, the lack of an integrated methodology for quantifying the scaling effect has become a crucial barrier in evaluating NPS pollution. In this study, a new method was proposed for scaling NPS pollution by integrating hydrological model and hydrological alteration indicators. Nested catchments were delineated by eight-direction algorithm, and a semidistributed hydrological model was used to simulate the interannual process within the drainage area and to obtain data series of runoff, sediment, and total phosphorus (TP) at different spatial scales. In addition, the average, the extrema, the change rate and feature variables of each type of indicators were proposed to quantitatively describe the pattern of NPS pollution at different spatial scales. The results show the coefficients of variation (CVs) of most runoff and TP indicators are 0.6-0.8, while those of sediment vary greatly from 0.4 to 1.6 with the threshold of those indicators being 0.33. With the increase in drainage area, the NPS load-related indicators show an increasing trend, while load intensity indicators show a decreasing trend and their changing patterns are affected by the heterogeneity of topographic or hydrological information included. Based on logarithmic variance of the change rate, 825 km2 was identified as the turning point for scaling transformation where the slope changes dramatically. The proposed methodology comprehensively describes features of the NPS scaling effect that could be utilized for targeted monitoring and control of NPS pollution in other watersheds.

Source appointment at large-scale and ungauged catchment using physically-based model and dynamic export coefficient.

Data scarcity has caused enormous problems in non-point pollution predictions and the related source apportionment. In this study, a new framework was developed to undertake the source apportionment at a large-scale and ungauged catchment, by integrating the physically-based model and a surrogate model. The improvements were made, in terms of the application of a physically-based model in an ungauged area for the transfer process and the parametric transplantation process. The new framework was then tested in the Chaohu Lake basin, China. The result suggested that there has been a good match between simulated and observed data. Although the planting industry was the largest emission source with 48.16% of nitrogen (N), itonly contributed 12.61% of N flux to the Chaohu Lake. The ungauged catchments surrounding the Chaohu Lake were identified as non-negligible sources with 8.46% of phosphorus (P) contribution. The rainfall conditions could have great impacts on source apportionment results; e.g., the planting industry contributed from 68.17t of P in dry year to 436.02t in wet year. The new framework could be extended to other large-scale watersheds for source apportionment with data limitations.

Hepatocellular carcinoma risk variant modulates lncRNA HLA-DQB1-AS1 expression via a long-range enhancer-promoter interaction.

Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10-4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.

Mesenchymal stem cell therapies for Alzheimer's disease: preclinical studies.

Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder that is characterized by memory failure, cognitive impairment, as well as behavioral and psychological manifestations. Drugs can only moderately manage, but not alleviate, clinical symptoms. Results, based on animal models, have demonstrated that cell therapy is a promising strategy for treating neurodegenerative disorders. The homing effect of mesenchymal stem cells (MSCs) replaces damaged cells, while some scholars believe that the paracrine effects play a crucial role in treating diseases. In fact, these cells have rich sources, exhibit high proliferation rates, low tumorigenicity, and immunogenicity, and have no ethical concerns. Consequently, MSCs have been used across various disease aspects, such as regulating immunity, nourishing nerves, and promoting regeneration. Deterioration of public health status have exposed both Alzheimer's patients and researchers to various difficulties during epidemics. In this review, we discuss the advances and challenges in the application of mesenchymal stem cell therapy for treatment of Alzheimer's disease.

Improved analysis of propamocarb and cymoxanil for the investigation of residue behavior in two vegetables with different cultivation conditions.

BACKGROUND: A modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method was developed for the simultaneous determination of highly water-soluble propamocarb and hydrophobic cymoxanil in potato tuber and tomato fruit. Residue behaviors of the fungicides in open field or greenhouse were investigated for the safety evaluation of these two pesticides, and the effects of cultivation conditions, fungicide exposure and fruit size of tomato on residue level are discussed. RESULTS: Vegetable samples were extracted with ammonia-acetonitrile, further purified with multiwall carbon nanotubes and analyzed using high-performance liquid chromatography tandem mass spectrometry. The method was validated with fortified samples at different concentration levels (0.05-2.0 mg kg-1 ). Average recoveries ranged from 84 to 111% with relative standard deviations between 0.3 and 5.5%. Limits of quantification (LOQs) were set at the lowest spiking level of 0.05 mg kg-1 . In tomato and cherry tomato, initial residue level of cymoxanil was below LOQ at recommended good agricultural practices. Propamocarb residues were affected by the cultivation conditions, with highest levels of 0.52 and 0.72 mg kg-1 in open field and greenhouse, respectively. In addition, residues of propamocarb in cherry tomatoes were found to be present at 1.25 mg kg-1 . CONCLUSIONS: The field trial results showed that propamocarb and cymoxanil residues in potato tubers were below LOQ due to the tubers not being exposed to sprayed pesticides. The unexpected high residue levels in cherry tomato seem to indicate that cherry tomato with small size presents certain accumulative effects of propamocarb. © 2020 Society of Chemical Industry.

Is returning farmland to forest an effective measure to reduce phosphorus delivery across distinct spatial scales?

As one typical land use change, the mechanism of returning farmland to forests (RFF) on nonpoint source pollution (NPS) is not clear, especially at multiple spatial scales. In this study, by using the Soil and Water Assessment Tool (SWAT), the changes in several flow-related and NPS-related indicators across several nested catchments were quantified and compared in the Three Gorges Reservoir Region, China. The results indicated that RFF could reduce the total flow and total phosphorus (TP), which are higher in the dry season (41% and 79%, respectively) than in the wet season (21% and 47%, respectively) at the watershed with a total area of 2423.74 km2. In comparison, RFF has a larger impact on the baseflow index during the wet season (367.02%) than during the dry season (166.54%). The results also indicated that a spatial scaling effect did exist, while the reduction in TP increased from 24.57% to 48.46% as the drainage area increased from 65.92 km2 to 2104.35 km2. Specific thresholds of RFF efficiency were also observed (approximately 2000 km2 for the study area). It is suggested that other source control measures could supplement RFF by stabilizing the efficiency of RFF across different spatial scales. The results of this study could provide valuable suggestions for land use development and water quality protection, especially for large, complex watersheds.

Identification and validation of a copper homeostasis-related gene signature for the predicting prognosis of breast cancer patients via integrated bioinformatics analysis.

The prognostic value of copper homeostasis-related genes in breast cancer (BC) remains largely unexplored. We analyzed copper homeostasis-related gene profiles within The Cancer Genome Atlas Program breast cancer cohorts and performed correlation analysis to explore the relationship between copper homeostasis-related mRNAs (chrmRNA) and lncRNAs. Based on these results, we developed a gene signature-based risk assessment model to predict BC patient outcomes using Cox regression analysis and a nomogram, which was further validated in a cohort of 72 BC patients. Using the gene set enrichment analysis, we identified 139 chrmRNAs and 16 core mRNAs via the Protein-Protein Interaction network. Additionally, our copper homeostasis-related lncRNAs (chrlncRNAs) (PINK1.AS, OIP5.AS1, HID.AS1, and MAPT.AS1) were evaluated as gene signatures of the predictive model. Kaplan-Meier survival analysis revealed that patients with a high-risk gene signature had significantly poorer clinical outcomes. Receiver operating characteristic curves showed that the prognostic value of the chrlncRNAs model reached 0.795 after ten years. Principal component analysis demonstrated the capability of the model to distinguish between low- and high-risk BC patients based on the gene signature. Using the pRRophetic package, we screened out 24 anticancer drugs that exhibited a significant relationship with the predictive model. Notably, we observed higher expression levels of the four chrlncRNAs in tumor tissues than in the adjacent normal tissues. The correlation between our model and the clinical characteristics of patients with BC highlights the potential of chrlncRNAs for predicting tumor progression. This novel gene signature not only predicts the prognosis of patients with BC but also suggests that targeting copper homeostasis may be a viable treatment strategy.

Defect-Engineered Tin Disulfide Nanocarriers as "Precision-Guided Projectile" for Intensive Synergistic Therapy.

Nanoformulations with endogenous/exogenous stimulus-responsive characteristics show great potential in tumor cell elimination with minimal adverse effects and high precision. Herein, an intelligent nanotheranostic platform (denoted as TPZ@Cu-SnS2-x /PLL) for tumor microenvironment (TME) and near-infrared light (NIR) activated tumor-specific therapy is constructed. Copper (Cu) doping and the resulting sulfur vacancies can not only improve the response range of visible light but also improve the separation efficiency of photogenerated carriers and increase the carrier density, resulting in the ideal photothermal and photodynamic performance. Density functional theory calculations revealed that the introduction of Cu and resulting sulfur vacancies can induce electron redistribution, achieving favorable photogenerated electrons. After entering cells through endocytosis, the TPZ@Cu-SnS2-x /PLL nanocomposites show the pH responsivity property for the release of the TPZ selectively within the acidic TME, and the released Cu2+ can first interact with local glutathione (GSH) to deplete GSH with the production of Cu+ . Subsequently, the Cu+ -mediated Fenton-like reaction can decompose local hydrogen peroxide into hydroxyl radicals, which can also be promoted by hyperthermia derived from the photothermal effect for tumor cell apoptosis. The integration of photoacoustic/computed tomography imaging-guided NIR phototherapy, TPZ-induced chemotherapy, and GSH-elimination/hyperthermia enhanced chemodynamic therapy results in synergistic therapeutic outcomes without obvious systemic toxicity in vivo.

Mesoscale eddy-strengthened deep-sea topographic Rossby waves in the southwestern South China Sea.

Topographic Rossby waves (TRWs) dominate the low-frequency variability of deep ocean currents and play a crucial role in energy exchange and material mixing. On the continental slope of the southwestern South China Sea, a deep-water mooring was deployed to observe TRWs for a period of ~ 40 days. The TRWs, with a wavelength of 109 km, account for 41.3% of the subinertial variations. A ray-tracing model was applied to investigate the propagation and energy source. The results showed that the TRWs propagated from the northeast of the mooring location and were most likely caused by the mesoscale eddy disturbances off the Vietnam coast. This study provides a new perspective on examining the impact of mesoscale eddies off Vietnam on abyssal currents.

Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers.

BACKGROUND: Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. METHODS: Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. RESULTS: A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88-0.95, P = 2.92 × 10-7) and Europe (OR = 0.92, 95%CI 0.88-0.95, P = 4.61 × 10-6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. CONCLUSION: Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

Coraliomargarita parva sp. nov., isolated from mangrove sediment and genome-based analysis of the class Opitutae revealed five novel families: Coraliomargaritaceae fam. nov., Pelagicoccaceae fam. nov., Cerasicoccaeae fam. nov., Oceanipulchritudinaceae fam. nov., and Alterococcaeae fam. nov.

Members of the class Opitutae are widely distributed in various environments such as rice paddy soil, freshwater lakes, seawater, marine sediment, and invertebrate digestive tracts. The class currently consists of two orders, Opitutales and Puniceicoccales, represented by the families Opitutaceae and Puniceicoccaceae, respectively, which are primarily delineated on the basis of 16S rRNA gene sequences and limited phenotypic characterizations of a few type strains. The scarcity of 16S rRNA gene and genome sequences generated from the type strains of the class Opitutae constrained our understanding of the ecological distribution and adequate resolution of its taxonomy. Here, an Opitutae strain designated WMMB3T, isolated from a mangrove sediment, was subjected to taxonomic characterization. The 16S rRNA gene of strain WMMB3T shared high sequence similarities with Coraliomargarita akajimensis DSM 45221T and C. sinensis WN38T of 96.1 and 95.9%, respectively. Phylogenetic analysis suggested that strain WMMB3T formed a monophyletic branch affiliated to the genus Coraliomargarita. The average nucleotide identity (ANI) values, digital DNA-DNA hybridization (dDDH) values and average amino acid identity (AAI) values of strain WMMB3T compared between Coraliomargarita members were 71.8-72.5, 20.7, and 68.2-68.7%, respectively, indicating that strain WMMB3T represented a novel species of Coraliomargarita. The genome of strain WMMB3T was 4.5 Mbp with a DNA G + C content of 56.0%. The respiratory quinone was menaquinone-7. The major fatty acids were iso-C14:0, and C18:1ω9c. Based on genomic, phenotypic, and chemotaxonomic characterizations, strain WMMB3T represents a novel species, and Coraliomargarita parva sp. nov. is proposed. Additionally, the phylogenomic analysis of more than 500 genomes of the class Opitutae, encompassing a majority of uncultivated bacteria and a few type strains, was performed using the Genome Taxonomic Database toolkit (GTDB-Tk) to present adequate resolution of the taxonomy. Combined with 16S rRNA gene sequence phylogeny and genomic relatedness, five novel families retrieved mainly from marine habitats were proposed: Coraliomargaritaceae fam. nov., Pelagicoccaceae fam. nov., Cerasicoccaeae fam. nov., Oceanipulchritudinaceae fam. nov., and Alterococcaeae fam. nov. AAI values of 58-60% could be considered as the boundary to delineate families of the class Opitutae. This study provided a new taxonomic framework of the class Opitutae based on the genomic data.

Novel PVA/carboxylated cellulose antimicrobial hydrogel grafted with curcumin and ε-polylysine for chilled chicken preservation.

PVA/CC/CUR/PL composite films containing curcumin (CUR) and ε-polylysine (PL) were prepared by casting and chemical grafting methods to address the threat to food spoilage. Morphological analysis showed that the grafting of CUR and PL resulted in a rough cross-section of the polymer matrix. Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis confirmed the grafting of CUR and PL into the polymer matrix via esterification and amidation reactions, respectively. Thermal weight loss analysis showed that grafting process positively improved the thermal stability. The PVA/CC/CUR/PL films exhibited strong bactericidal activity, reaching 99.0% and 99.8% for Pseudomonas lundensis and Shewanella putrefaciens, respectively. After 8 days of storage, the total number of colonies and the TVB-N content in the PVA/CC/CUR/PL group decreased by 1.51 lg CFU/g and 13.77 mg/100 g, respectively. Therefore, PVA/CC/CUR/PL films are considered as a promising bactericidal material with good mechanical properties, functionality, and other excellent characteristics.

Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci.

Alternative polyadenylation (APA) is emerging as a major mechanism of posttranscriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTL), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multiomics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA-binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in genome-wide association studies (GWAS)-identified cancer susceptibility loci. Moreover, apaQTL-related genes (aGene) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer tumor tissues and then screened for functional apaQTLs associated with colorectal cancer risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry-associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of colorectal cancer. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3'UTR. This stabilized DNM1L to upregulate its expression, provoking colorectal cancer cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology. SIGNIFICANCE: Cancer risk is mediated by alternative polyadenylation quantitative trait loci, including the rs1020670-G variant that promotes alternative polyadenylation of DNM1L and increases colorectal cancer risk.

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk.

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10-5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.