Biogenesis of circRBM33 mediated by N6-methyladenosine and its function in abdominal aortic aneurysm.

This study aimed to explore whether m6A modification affects the biogenesis of circRBM33, which is involved in the progression of abdominal aortic aneurysm (AAA). For in vitro experiments, vascular smooth muscle cells (VSMCs) were treated with Ang II. MeRIP‒PCR was used to assess m6A modification of circRBM33. Gene expression was measured using RT‒qPCR and Western blotting. For in vivo experiments, a mouse model of AAA was established via Ang II infusion. HE, Sirius Red and TUNEL staining was performed to evaluate pathological changes and cell apoptosis in aortic vessels. The results showed that the m6A level of circRBM33 was abnormally increased in Ang II-induced VSMCs. In addition, METTL3 positively regulated circRBM33 expression. YTHDC1 deficiency decreased circRBM33 expression but had no effect on RBM33 mRNA expression. Notably, neither METTL3 nor YTHDC1 influenced the stability of circRBM33 or RBM33 mRNA. The interaction between circRBM33 and METTL3/YTHDC1 was verified by RIP analysis. Moreover, the Ang II-induced increase in circRBM33 expression was reversed by cycloleucine (an inhibitor of m6A methylation). Importantly, the m6A modification and expression of circRBM33 in the circRBM33-m6A-mut2-expressing VSMCs were not altered by METTL3 silencing. Mechanistically, METTL3/YTHDC1 modulates the biogenesis of circRBM33 in an m6A-dependent manner. In addition, circRBM33 knockdown alleviated AAA by reducing ECM degradation in the Ang II-infused mice. In conclusion, this study demonstrated that METTL3/YTHDC1-mediated m6A modification modulates the biogenesis of circRBM33 from exons of the RBM33 gene. Moreover, knockdown of circRBM33 alleviated AAA by reducing ECM degradation, which may provide a novel therapeutic strategy for treating AAA.

A genetic variant in the TAPBP gene enhances cervical cancer susceptibility by increasing m6A modification.

Genetic variants can affect gene expression by altering the level of N6-methyladenosine (m6A) modifications. A better understanding of the association of these genetic variants with susceptibility to cervical cancer (CC) can promote advances in disease screening and treatment. Genome-wide identification of m6A-associated functional SNPs for CC was performed using the TCGA and JENGER databases, incorporating the data from RNA-seq and MeRIP-seq. The screened risk-associated SNP rs1059288 (A>G), which is located in the 3' UTR of TAPBP, was further validated in a case-control study involving 921 cases and 1077 controls. The results revealed a significant association between rs1059288 and the risk of CC (OR 1.48, 95% CI 1.13-1.92). Mechanistically, the presence of the risk G allele of rs1059288 was associated with increased m6A modification of TAPBP compared with the A allele. This modification was facilitated by the m6A methyltransferase METTL14 and the reading protein YTHDF2. Immunohistochemical staining of tissue microarrays containing 61 CC and 45 normal tissues showed an overexpression of TAPBP in CC. Furthermore, the upregulation of TAPBP promoted the growth and migration of CC cells as well as tumor-forming ability, inhibited apoptosis, and conferred increased resistance to commonly used chemotherapeutic drugs such as bleomycin, cisplatin, and doxorubicin. Knockdown of TAPBP inhibited the JAK/STAT/MICB signaling pathway in CC cells and upregulated certain immune genes including ISG15, IRF3, PTPN6, and HLA-A. These findings offer insights into the involvement of genetic variations in TAPBP in the development and progression of CC.

Historic dog Furs Unravel the Origin and Artificial Selection of Modern Nordic Lapphund and Elkhound dog Breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

A comprehensive review of m6A research in cervical cancer.

Cervical cancer (CC) remains one of the most common malignancies among women worldwide, posing a serious threat to women's health. N6-methyladenosine (m6A) modification, as the most abundant type of RNA methylation modification, and has been found to play a crucial role in various cancers. Current research suggests a close association between RNA m6A modification and the occurrence and progression of CC, encompassing disruptions in m6A levels and its regulatory machinery. This review summarizes the current status of m6A modification research in CC, explores the mechanisms underlying m6A levels and regulators (methyltransferases, demethylases, reader proteins) in CC and examines the application of small-molecule inhibitors of m6A regulators in disease treatment. The findings provide new insights into the future treatment of CC.

The m⁶A modification participates in regulating the proliferation, migration, invasion, cell cycle, apoptosis, drug resistance and sensitivity to chemotherapy in cervical cancer cells.

Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration.

Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1ß-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.

Long-term 4-nonylphenol exposure drives cervical cell malignancy through MAPK-mediated ferroptosis inhibition.

4-NP (4-nonylphenol), a prevalent environmental endocrine disruptor with estrogenic properties, is commonly detected in drinking water and food sources. It poses a significant risk of endocrine disruption, thereby influencing the onset and progression of diverse diseases, including tumorigenesis. However, its specific impact on cervical cancer remains to be fully elucidated. Our study focused on the biological effects of sustained exposure to low-dose 4-NP on human normal cervical epithelial cells (HcerEpic). After a continuous 30-week exposure to 4-NP, the treated cells exhibited a significant malignant transformation, whereas the solvent control group showed limited malignant phenotypes. Subsequent analyses of the metabolomic profiles of the transformed cells unveiled marked irregularities in glutathione metabolism and unsaturated fatty acid metabolism. Analyses of transcriptomic profiles revealed significant activation of the MAPK signaling pathway and suppression of ferroptosis processes in these cells. Furthermore, the expression of MT2A was significantly upregulated following 4-NP exposure. Knockdown of MT2A restored the aberrant activation of the MAPK signaling pathway, elevated antioxidant capacity, ferroptosis inhibition, and ultimately the development of malignant phenotypes that induced by 4-NP in the transformed cells. Mechanistically, MT2A increased cellular antioxidant capabilities and facilitated the removal of toxic iron ions by enhancing the phosphorylation of ERK1/2 and JNK MAPK pathways. The administration of activators and inhibitors of the MAPK pathway confirmed that the MAPK pathway mediated the 4-NP-induced suppression of ferroptosis and, ultimately, the malignant transformation of cervical epithelial cells. Overall, our findings elucidated a dynamic molecular transformation induced by prolonged exposure to 4-NP, and delineated comprehensive biological perspectives underlying 4-NP-induced cervical carcinogenesis. This offers novel theoretical underpinnings for the assessment of the carcinogenic risks associated with 4-NP.

An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

Combined association of urinary volatile organic compounds with chronic bronchitis and emphysema among adults in NHANES 2011-2014: The mediating role of inflammation.

Evidence on the association of volatile organic compounds (VOCs) with chronic bronchitis (CB) and emphysema is spare and defective. To evaluate the relationship between urinary metabolites of VOCs (mVOCs) with CB and emphysema, and to identify the potential mVOC of paramount importance, data from NHANES 2011-2014 waves were utilized. Logistic regression was conducted to estimate the independent association of mVOCs with respiratory outcomes. Least absolute shrinkage and selection operator (LASSO) regression was performed to screen a parsimonious set of CB- and emphysema-relevant mVOCs that were used for further co-exposure analyses of weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR). Mediation analysis was employed to detect the mediating role of inflammatory makers in such associations. In single exposure analytic model, nine mVOCs were individually and positively associated with CB, while four mVOCs were with emphysema. In WQS regression, positive association between LASSO selected mVOCs and CB was identified (OR = 1.82, 95% CI: 1.25 to 2.69), and N-acetyl-S-(4-hydroxy-2-butenyl)-l-cysteine (MHBMA3) weighted the highest. Results from BKMR further validated such combined association and the significance of MHBMA3. As for emphysema, significantly positive overall trend of mVOCs was only observed in BKMR model and N-acetyl-S-(N-methylcarbamoyl)-l-cysteine (AMCC) contributed most to the mixed effect. White blood cell count (WBC) and lymphocyte number (LYM) were mediators in the positive pattern of mVOCs mixture with CB, while association between mVOCs mixture and emphysema was significantly mediated by LYM and segmented neutrophils num (NEO). This study demonstrated that exposure to VOCs was associated with CB and emphysema independently and combinedly, which might be partly speculated that VOCs were linked to activated inflammations. Our findings shed novel light on VOCs related respiratory illness, and provide a new basis for the contribution of certain VOCs to the risk of CB and emphysema, which has potential public health implications.

Chondrocyte-Targeted Delivery System of Sortase A-Engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy.

Targeted drug delivery and the reduction of off-target effects are crucial for the promising clinical application of nucleic acid drugs. To address this challenge, a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase-13 (ASO-MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) are ligated with chondrocyte affinity peptide (CAP) using Sortase A and subsequently incubated with cholesterol-modified ASO-MMP13 to construct a chondrocyte-targeted drug delivery exo (CAP-exoASO). Compared with exos without CAP (ExoASO), CAP-exoASOs attenuate IL-1ß-induced chondrocyte damage and prolong the retention time of ASO-MMP13 in the joint without distribution in major organs following intra-articular injection. Notably, CAP-exoASOs decrease MMP13 expression (P < 0.001) and upregulate COL2A1 expression (P = 0.006), resulting in reorganization of the cartilage matrix and alleviation of progression in the OA model. Furthermore, the Osteoarthritis Research Society International (OARSI) score of articular cartilage tissues treated with CAP-exoASO is comparable with that of healthy rats (P = 0.148). A mechanistic study demonstrates that CAP-exoASO may reduce inflammation by suppressing the IL-17 and TNF signaling pathways. Based on the targeted delivery effect, CAP-exoASOs successfully accomplish cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy.

Comprehensive Analysis of the SUMO-related Signature: Implication for Diagnosis, Prognosis, and Immune Therapeutic Approaches in Cervical Cancer.

SUMOylation, an important post-translational protein modification, plays a critical role in cancer development and immune processes. This study aimed to construct diagnostic and prognostic models for cervical cancer (CC) using SUMOylation-related genes (SRGs) and explore their implications for novel clinical therapies. We analyzed the expression profiles of SRGs in CC patients and identified 15 SRGs associated with CC occurrence. After the subsequent qPCR verification of 20 cases of cancer and adjacent tissues, 13 of the 15 SRGs were differentially expressed in cancer tissues. Additionally, we identified molecular markers associated with the prognosis and recurrence of CC patients, based on SRGs. Next, a SUMOScore, based on SRG expression patterns, was generated to stratify patients into different subgroups. The SUMOScore showed significant associations with the tumor microenvironment, immune function features, immune checkpoint expression, and immune evasion score in CC patients, highlighting the strong connection between SUMOylation factors and immune processes. In terms of immune therapy, our analysis identified specific chemotherapy drugs with higher sensitivity in the subgroups characterized by high and low SUMOScore, indicating potential treatment options. Furthermore, we conducted drug sensitivity analysis to evaluate the response of different patient subgroups to conventional chemotherapy drugs. Our findings revealed enrichment of immune-related pathways in the low-risk subgroup identified by the prognostic model. In conclusion, this study presents diagnostic and prognostic models based on SRGs, accompanied by a comprehensive index derived from SRGs expression patterns. These findings offer valuable insights for CC diagnosis, prognosis, treatment, and immune-related analysis.

M6A plays a potential role in carotid atherosclerosis by modulating immune cell modification and regulating aging-related genes.

RNA N6-methyladenosine (m6A) regulators play essential roles in diverse biological processes, including immune responses. Mounting evidence suggests that their dysregulation is intricately linked to numerous diseases. However, the role of m6A-associated genes in carotid atherosclerosis and their relationship with aging and immune cells remain unclear. Analyze the expression profiles of m6A-related genes in carotid atherosclerosis-related datasets. Based on the expression patterns of m6A-related genes, perform consistent clustering analysis of carotid atherosclerosis samples and investigate associated immune cell infiltration patterns and aging characteristics. Develop an m6A prediction model specific to carotid atherosclerosis and analyze the relationships between immune cells infiltration and aging features. The m6A methylation modification level exhibited a substantial decrease in early-stage carotid atherosclerosis samples compared to late-stage carotid atherosclerosis samples. Subsequently, two distinct m6A subtypes were defined through consensus clustering analysis, with the lower m6A modification level group showing associations with heightened immune cell infiltration and increased expression of aging-related genes. A model composed of five m6A-related genes was formulated, and the results indicated that this model possesses effective predictive and therapeutic capabilities for carotid atherosclerosis. Furthermore, the downregulation of YTHDC1 expression resulted in elevated expression of inflammatory factors and a decrease in the expression of the aging-related gene RGN. Single-cell data analysis suggests that the reduced expression of YTHDC1 may decrease the degradation of inflammation-related factors in macrophages, leading to a highly inflammatory state in the carotid artery wall. Furthermore, the sustained release of inflammatory factors may increase the expression of the aging-related gene RGN in vascular smooth muscle cells, further exacerbating the progression of atherosclerosis. A reduced level of m6A methylation modification could enhance inflammation and expedite cellular aging, thereby contributing to the development of carotid atherosclerosis.

LINC00426, a novel m6A-regulated long non-coding RNA, induces EMT in cervical cancer by binding to ZEB1.

PURPOSE: To explore the function and molecular mechanism of LINC00426 in Cervical Cancer (CC), and to explore the clinical treatment strategy of LINC00426 for CC. METHODS: Bioinformatics analysis was used to explore the expression of LINC00426 and patient prognosis of CC. Cell function experiments were conducted to explore the potential effect of LINC00426 on CC malignant phenotypes. The difference in m6A modification level between the high and low expression groups of LINC00426 was analyzed by detecting the total m6A level. The luciferase reporter assay was used to confirm the binding of miR-200a-3p to LINC00426. The RIP assay was used to confirm the binding of LINC00426 to ZEB1. Cell viability assay was performed to detect the effect of LINC00426 on cellular drug resistance. RESULTS: LINC00426 is up-regulated in CC, which can enhance the proliferation, migration and invasion of CC cells. METTL3 promotes the expression of LINC00426 by m6A methylation modification. In addition, the LINC00426/miR-200a-3p/ZEB1 axis affects the proliferation, migration, and invasion of CC by regulating the expression of EMT markers. Through the detection of cell viability, we observed that overexpression LINC00426 in cells resulted in resistance to cisplatin and bleomycin, and more sensitive to imatinib. CONCLUSION: LINC00426 is a cancer-promoting lncRNA related to m6A modification. The process of EMT in CC is regulated by the LINC00426/miR-200a/3p/ZEB1 axis. LINC00426 can affect the sensitivity of CC cells to chemotherapy drugs, and is expected to become a therapeutic target for CC.

An improved UAV target detection algorithm based on ASFF-YOLOv5s.

Object detection in drone-captured scenarios is a recent popular task. Due to the high flight altitude of unmanned aerial vehicle (UAV), the large variation of target scales, and the existence of dense occlusion of targets, in addition to the high requirements for real-time detection. To solve the above problems, we propose a real-time UAV small target detection algorithm based on improved ASFF-YOLOv5s. Based on the original YOLOv5s algorithm, the new shallow feature map is passed into the feature fusion network through multi-scale feature fusion to improve the extraction capability for small target features, and the Adaptively Spatial Feature Fusion (ASFF) is improved to improve the multi-scale information fusion capability. To obtain anchor frames for the VisDrone2021 dataset, we improve the K-means algorithm to obtain four different scales of anchor frames on each prediction layer. The Convolutional Block Attention Module (CBAM) is added in front of the backbone network and each prediction network layer to improve the capture capability of important features and suppress redundant features. Finally, to address the shortcomings of the original GIoU loss function, the SIoU loss function is used to accelerate the convergence of the model and improve accuracy. Extensive experiments conducted on the dataset VisDrone2021 show that the proposed model can detect a wide range of small targets in various challenging environments. At a detection rate of 70.4 FPS, the proposed model obtained a precision value of 32.55%, F1-score of 39.62%, and a mAP value of 38.03%, which improved 2.77, 3.98, and 5.1%, respectively, compared with the original algorithm, for the detection performance of small targets and to meet the task of real-time detection of UAV aerial images. The current work provides an effective method for real-time detection of small targets in UAV aerial photography in complex scenes, and can be extended to detect pedestrians, cars, etc. in urban security surveillance.

Post-transcriptional regulation of tumor suppressor gene lncRNA CARMN via m6A modification and miRNA regulation in cervical cancer.

PURPOSE: The abnormal regulation of lncRNA CARMN has been proved to be a tumor suppressor gene of cervical cancer (CC). However, its role in CC is still elusive. The regulation of CARMN post-transcriptional level by m6A modification and miRNA has not been studied. This study aims to analyze the molecular mechanism of m6A modification and miRNA on the abnormal expression of CARMN in CC cells, so as to provide a new theoretical basis for the diagnosis and treatment of CC. METHODS: MeRIP-seq was used to identify the differential m6A-modified genes between tumor and normal cervical tissues. RT-qPCR assay was used to detect gene expression levels in tissues or cells. The m6A modification sites of CARMN was predicted by bioinformatics, and the modification of m6A and its regulatory effect on CARMN were analyzed by MeRIP-qPCR, Actinomycin D assay and RIP assay. RIP-microarray combined with bioinformatics methods to screen miRNAs that may target CARMN. The regulation mechanism between miRNA and CARMN was verified by RT-qPCR, nucleo-plasmic separation assay, mRNA stability assay, dual-luciferase reporter assay, and in vivo experiments. RESULTS: MeRIP-seq found that CARMN is a significant different gene in the abundance of m6A in CC, and the modification level of m6A in CC tissues was higher than that in normal cervical tissues. Further, this study verified that m6A reader YTHDF2 could recognize m6A-modified CARMN and promote its degradation in CC cells. miR-21-5p was proved to be the downstream target gene of CARMN, and miR-21-5p could negatively regulate the expression of CARMN. Further experiments showed that miR-21-5p could directly bind to CARMN and lead to the degradation of CARMN. The in vivo experimental results indicated that the level of miR-21-5p in the overexpressed CARMN group was significantly lower than that in the control group. CONCLUSION: m6A modification and miR-21-5p play important roles in promoting the occurrence and development of tumors by regulating CARMN, provide new potential targets for the treatment of CC.

Immune-Related Genes' Prognostic, Therapeutic and Diagnostic Value in Ovarian Cancer Immune-Related Gene Biomarker in Ovarian Cancer.

OBJECTIVES: The abnormal expression of immune-related genes (IRGs) plays an important role in the occurrence and progression of ovarian cancer (OC), which is the main cause of mortality among gynecological cancer patients. This study aims to establish a prognostic risk model and comprehensively analyze the relationship between OC risk score and prognosis, immune cell infiltration (ICI) and therapeutic sensitivity in OC. METHODS: We retrospectively evaluated the clinicopathological characteristics of consecutive OC patients in the Cancer Genome Atlas (TCGA) database. First, the prognostic risk model was constructed by bioinformatics methods. And then, we systematically assessed model robustness, and correlations between risk score and prognosis, and immune cell infiltration. The ICGC cohort was used to verify the prognostic risk model. Finally, we evaluated their value in the treatment of OC immunotherapy and chemotherapy. RESULTS: A total of 10 IRGs were identified to construct the prognostic risk model. Survival analysis revealed that patients in the low-risk group had a better prognosis (P < .01), and the risk score might be considered an independent predictor for predicting the prognosis. In addition, risk scores and patient clinical information were used to construct clinical nomograms, improving the prediction's precision. We also explored the relationship between the risk score and ICI, immunotherapy and drug sensitivity. CONCLUSIONS: Collectively, we identified a novel ten IRGs signature that may be applied as a prognostic predictor of OC, thereby benefiting clinical decision-making and personalized treatment of patients.

Multi-omics analysis revealed NMBA induced esophageal carcinoma tumorigenesis via regulating PPARα signaling pathway.

As widespread environmental carcinogens causing esophageal carcinoma (EC), the effects of N-nitrosamines on human health hazards and accurate toxicity mechanisms have not been well-elucidated. In this study, we explored the tumorigenic mechanism of N-nitrosomethylbenzylamine (NMBA) exposure using both cell and rat models. It was found that NMBA (2 µM) exposure for 26 weeks induced malignant transformation of normal esophageal epithelial (Het-1A) cells. After then proteomics analysis showed that lipid metabolism disorder predominantly participated in the process of NMBA-induced cell malignant transformation. Further the integrated proteomics and lipidomics analysis revealed that the enhancement of fatty acid metabolism promoted the EC tumorigenesis induced by NMBA through facilitating the fatty acid-associated PPARα signaling pathway. The animal studies also revealed that accelerated fatty acid decomposition in the progression of NMBA-induced EC models of rats was accompanied by the activation of the PPARα pathway. Overall, our findings depicted the key dynamic molecular alteration triggered by N-nitrosamines, and provided comprehensive biological perspectives into the carcinogenic risk assessment of N-nitrosamines.

A 1.1 Mb duplication CNV on chromosome 17 contributes to skeletal muscle development in Boer goats.

The Boer goat is one of the top meat breeds in modern animal husbandry and has attracted widespread attention for its unique growth performance. However, the genetic basis of muscle development in the Boer goat remains obscure. In this study, we identified specific structural variants in the Boer goat based on genome-wide selection signals and analyzed the basis of the molecular heredity of related candidate genes in muscle development. A total of 9 959 autosomal copy number variations (CNVs) were identified through selection signal analysis in 127 goat genomes. Specifically, we confirmed that the highest signal CNV (HSV) was a chromosomal arrangement containing an approximately 1.11 Mb (CHIR17: 60062304-61171840 bp) duplicated fragment inserted in reverse orientation and a 5 362 bp deleted region (CHIR17:60145940-60151302 bp) with overlapping genes (e.g., ARHGAP10, NR3C2, EDNRA, PRMT9, and TMEM184C). The homozygous duplicated HSV genotype (+/+) was found in 96% of Boer goats but was not detected in Eurasian goats and was only detected in 4% of indigenous African goats. The expression network of three candidate genes ( ARHGAP10, NR3C2, and EDNRA) regulating dose transcription was constructed by RNA sequencing. Results indicated that these genes were involved in the proliferation and differentiation of skeletal muscle satellite cells (SMSCs) and their overexpression significantly increased the expression of SAA3. The HSV of the Boer goat contributed to superior skeletal muscle growth via the dose effects of overlapping genes.

An integrative approach for identification of smoking-related genes involving bladder cancer.

Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10-2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10-4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status.

The effects of the interaction of genetic predisposition with lifestyle factors on bladder cancer risk.

OBJECTIVES: To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. METHODS: Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). RESULTS: Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16-1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%-15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. CONCLUSION: This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.

A single-nucleus transcriptomic atlas of the dog hippocampus reveals the potential relationship between specific cell types and domestication.

The process of domestication has led to dramatic differences in behavioral traits between domestic dogs and gray wolves. Whole-genome research found that a class of putative positively selected genes were related to various aspects of learning and memory, such as long-term potentiation and long-term depression. In this study, we constructed a single-nucleus transcriptomic atlas of the dog hippocampus to illustrate its cell types, cell lineage and molecular features. Using the transcriptomes of 105 057 nuclei from the hippocampus of a Beagle dog, we identified 26 cell clusters and a putative trajectory of oligodendrocyte development. Comparative analysis revealed a significant convergence between dog differentially expressed genes (DEGs) and putative positively selected genes (PSGs). Forty putative PSGs were DEGs in glutamatergic neurons, especially in Cluster 14, which is related to the regulation of nervous system development. In summary, this study provides a blueprint to understand the cellular mechanism of dog domestication.