RESUMO
Although CRISPR-Cas9 technology has been rapidly applied in soybean genetic improvement, it is difficult to achieve the targeted editing of the specific loci in the soybean complex genome due to the limitations of the classical protospacer adjacent motif (PAM). Here, we developed a PAM-less genome editing system mediated by SpRY in soybean. By performing targeted editing of representative agronomic trait targets in soybean and evaluating the results, we demonstrate that the SpRY protein can achieve efficient targeted mutagenesis at relaxed PAM sites in soybean. Furthermore, the SpRY-based cytosine base editor SpRY-hA3A and the adenine base editor SpRY-ABE8e both can accurately induce C-to-T and A-to-G conversion in soybean, respectively. Thus, our data illustrate that the SpRY toolbox can edit the soybean genomic sequence in a PAM-free manner, breaking restrictive PAM barriers in the soybean genome editing technology system. More importantly, our research enriches soybean genome editing tools, which has important practical application value for precise editing and molecular design in soybean breeding.
RESUMO
Global climate change has led to shifts in the distribution ranges of many terrestrial species, promoting their migration from lower altitudes or latitudes to higher ones. Meanwhile, successful invaders have developed genetic adaptations enabling the colonization of new environments. Over the past 40â years, Rattus tanezumi (RT) has expanded into northern China (Northwest and North China) from its southern origins. We studied the cold adaptation of RT and its potential for northward expansion by comparing it with sympatric Rattus norvegicus (RN), which is well adapted to cold regions. Through population genomic analysis, we revealed that the invading RT rats have split into three distinct populations: the North, Northwest, and Tibetan populations. The first two populations exhibited high genetic diversity, while the latter population showed remarkably low genetic diversity. These rats have developed various genetic adaptations to cold, arid, hypoxic, and high-UV conditions. Cold acclimation tests revealed divergent thermoregulation between RT and RN. Specifically, RT exhibited higher brown adipose tissue activity and metabolic rates than did RN. Transcriptome analysis highlighted changes in genes regulating triglyceride catabolic processes in RT, including Apoa1 and Apoa4, which were upregulated, under selection and associated with local adaptation. In contrast, RN showed changes in carbohydrate metabolism genes. Despite the cold adaptation of RT, we observed genotypic and phenotypic constraints that may limit its ability to cope with severe low temperatures farther north. Consequently, it is less likely that RT rats will invade and overlap with RN rats in farther northern regions.
Assuntos
Aclimatação , Temperatura Baixa , Animais , Ratos , Aclimatação/genética , China , Fenótipo , Variação Genética , Adaptação Fisiológica/genética , Regulação da Temperatura Corporal/genética , Mudança ClimáticaRESUMO
Fas-activated serine/threonine kinase domain 1 (FASTKD1), a known modulator of mitochondrial-mediated cell death and survival processes, has garnered attention for its potential role in various biological contexts. However, its involvement in gastric cancer remains unclear. Thus, the present study aimed to investigate the relationship between FASTKD1 expression and key factors, including clinicopathological characteristics, immune infiltration and m6A modification in stomach adenocarcinoma (STAD). The expression of FASTKD1 was analyzed in STAD and normal adjacent tissues to assess its association with clinicopathological characteristics and survival prognosis. Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used in this study. Additionally, the findings were validated through immunohistochemical staining. Co-expression analysis of FASTKD1 was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and LinkedOmics database analysis. An in-depth analysis was conducted using databases, such as Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), GEO and TCGA to explore the potential correlation between FASTKD1 expression and immune infiltration and m6A modification in STAD. The results revealed that FASTKD1 was significantly upregulated across different tumor types, including STAD. Notably, FASTKD1 was able to distinguish between tumor and normal tissue samples with accuracy. Furthermore, the expression levels of FASTKD1 were significantly associated with clinical stage and survival. Through GO/KEGG enrichment analysis and GSEA, it was revealed that the genes co-expressed with FASTKD1 were active in a variety of biological processes. Within the TIMER, GEPIA and TCGA databases, a notable inverse correlation was observed between FASTKD1 expression and the abundance of immune cell subsets. Notably, significant correlations were established between FASTKD1 and m6A modification genes, YTHDF1 and LRPPRC, in both TCGA and GEO datasets. In conclusion, FASTKD1 may serve a significant role in m6A modification and immune infiltration processes, making it a potentially valuable diagnostic and prognostic biomarker in STAD.
RESUMO
Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood-brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1ß(IL-1ß) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood-brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.
RESUMO
Purpose: To investigate the relationship between corneal volume (CV) at different zones and corneal biomechanics in keratoconus (KC) along with the significance of CV in diagnosing and staging KC. Methods: This prospective clinical study included 456 keratoconic eyes (Group B) and 198 normal eyes (Group A). Using the topographic KC classification method, Group B was divided into subgroups based on severity (mild, moderate, and severe). The CVs of the 3 mm, 5 mm, and 7 mm zones and biomechanical parameters were obtained by Pentacam and Corvis ST. The diagnostic utility of multirange CVs at different disease stages and severity was determined using a receiver operating characteristic (ROC) curve analysis. Results: The CV of the 7-mm zone had the strongest correlation with A1V, A2T, PD, DA ratio max (2 mm), DA ratio max (1 mm), ARTh, integrated radius, SPA1, and CBI (p < 0.01). The CVs of the Group B subgroups were significantly lower than those of Group A for each diameter range (p < 0.05). There were significant differences between the severe, mild, and moderate subgroups for the 3 mm zone (p < 0.05, all). The 3 mm zone CV exhibited better diagnostic ability in each group for distinguishing KC from the normal cornea (Groups A vs. B: area under the ROC curve (AUC) = 0.926, Groups A vs. B1: AUC = 0.894, Groups A vs. B2: AUC = 0.925, Groups A vs. B3: AUC = 0.953). Conclusion: The CV significantly decreased in keratoconic eyes. Progressive thinning in the 3 mm zone may be a valuable measurement for detecting and staging KC. Combining the CV examination with corneal biomechanical information may effectively enhance the ability to detect KC.
RESUMO
Rattus species are thought to live only at altitudes less than 2500 m, but the Asian house rat (R. tanezumi) (RT) has recently expanded to altitudes greater than 3500 m in China. Other Rattus species, especially brown rats (R. norvegicus) (RN), still reach only low altitudes on the Tibetan Plateau. Comparative genomics revealed the positive selection of hypoxia-inducible transcription factors 1 and 2 (HIFs) in RT, with the rapid evolution of HIF pathway genes in RT and Mus musculus (MM) but not RN or R. rattus. Population genomics revealed that genes associated with energy metabolism and oxygen transport were positively selected in RT compared with the other four Rattus species, and two specific substitutions (arginine 31 serine and leucine 33 methionine) were identified in the hemoglobin subunit beta (HBB) in RT. The above results suggested that RT possesses unique genetic adaptations to hypoxia, which was further confirmed by behavioral experiments on RT and RN. Normobaric hypoxia significantly reduced locomotion in RN but not in RT. Moreover, through intraspecific transcriptome analysis, the expression of Hbb and genes related to angiogenesis, oxygen transport, and glycolysis was upregulated, and the expression of genes associated with immunological functions in the liver, lungs, and/or sperm was downregulated in RT compared to those in RN. Interspecific transcriptome analysis further revealed that HIF-1α plays a role in modulating the hypoxic adaptation of RT rather than RN. Our work provides genomic, behavioral, and physiological insights into why RT, but not other Rattus species, could invade the Tibetan Plateau.
RESUMO
BACKGROUND: The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. METHODS: The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. RESULTS: HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. CONCLUSIONS: HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.
Assuntos
Medicamentos de Ervas Chinesas , Inibidores de Checkpoint Imunológico , Melanoma , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Coptis chinensis , Receptor 7 Toll-Like , Melanoma/tratamento farmacológico , Transdução de SinaisRESUMO
MutL homolog 1 (MLH1), a member of the MutL homolog family, is required for normal recombination in most organisms. However, its role in soybean (Glycine max) remains unclear to date. Here, we characterized the Glycine max female and male sterility 1 (Gmfms1) mutation that reduces pollen grain viability and increases embryo sac abortion in soybean. Map-based cloning revealed that the causal gene of Gmfms1 is Glycine max MutL homolog 1 (GmMLH1), and CRISPR/Cas9 knockout approach further validated that disruption of GmMLH1 confers the female-male sterility phenotype in soybean. Loss of GmMLH1 function disrupted bivalent formation, leading to univalent mis-segregation during meiosis and ultimately to female-male sterility. The Gmmlh1 mutant showed about a 78.16% decrease in meiotic crossover frequency compared to the wild type. The residual chiasmata followed a Poisson distribution, suggesting that interference-sensitive crossover formation was affected in the Gmmlh1 mutant. Furthermore, GmMLH1 could interact with GmMLH3A and GmMLH3B both in vivo and in vitro. Overall, our work demonstrates that GmMLH1 participates in interference-sensitive crossover formation in soybean, and provides additional information about the conserved functions of MLH1 across plant species.
Assuntos
Troca Genética , Glycine max , Meiose , Proteínas de Plantas , Glycine max/genética , Glycine max/metabolismo , Meiose/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Infertilidade das Plantas/genética , Mutação/genética , Pólen/genética , Pólen/crescimento & desenvolvimentoRESUMO
PURPOSE: This study aimed to measure the Raman spectrum of the human corneal stroma lens obtained from small incision lenticule extraction surgery (SMILE) in Asian myopic eyes using a confocal Raman micro-spectrometer built in the laboratory. METHODS: Forty-three myopic patients who underwent SMILE with equivalent diopters between - 4.00 and - 6.00 D were selected, and the right eye data were collected. Corneal stroma lenses were obtained during surgery, and the Raman spectra were measured after air drying. The complete Raman spectrum of human myopic corneal stroma lens tissue was obtained within the range of 700-4000 cm-1. RESULTS: Thirteen characteristic peaks were found, with the stronger peaks appearing at 937 cm-1, corresponding to proline, valine, and the protein skeleton of the human myopic corneal stroma lens; 1243 cm-1, corresponding to collagen protein; 1448 cm-1, corresponding to the collagen protein and phospholipids; and 2940 cm-1, corresponding to the amino acid and lipids, which was the strongest Raman peak. CONCLUSION: These results demonstrated that Raman spectroscopy has much potential as a fast, cost-effective, and reliable diagnostic tool in the diagnosis and treatment of eye diseases, including myopia, keratoconus, and corneal infection.
Assuntos
Cirurgia da Córnea a Laser , Ceratomileuse Assistida por Excimer Laser In Situ , Miopia , Humanos , Substância Própria/cirurgia , Acuidade Visual , Miopia/diagnóstico , Miopia/cirurgia , Ceratomileuse Assistida por Excimer Laser In Situ/métodos , Colágeno , Lasers de Excimer , Refração OcularRESUMO
Soybean being a major cash crop provides half of the vegetable oil and a quarter of the plant proteins to the global population. Seed size traits are the most important agronomic traits determining the soybean yield. These are complex traits governed by polygenes with low heritability as well as are highly influenced by the environment as well as by genotype x environment interactions. Although, extensive efforts have been made to unravel the genetic basis and molecular mechanism of seed size in soybean. But most of these efforts were majorly limited to QTL identification, and only a few genes for seed size were isolated and their molecular mechanism was elucidated. Hence, elucidating the detailed molecular regulatory networks controlling seed size in soybeans has been an important area of research in soybeans from the past decades. This paper describes the current progress of genetic architecture, molecular mechanisms, and regulatory networks for seed sizes of soybeans. Additionally, the main problems and bottlenecks/challenges soybean researchers currently face in seed size research are also discussed. This review summarizes the comprehensive and systematic information to the soybean researchers regarding the molecular understanding of seed size in soybeans and will help future research work on seed size in soybeans.
Assuntos
Glycine max , Proteínas de Plantas , Glycine max/genética , Fenótipo , Proteínas de Plantas/genética , Óleos de Plantas , Sementes/genéticaRESUMO
OBJECTIVE: Spindle pole body component 25 (SPC25) is an important cyclin involved in chromosome segregation and spindle dynamics regulation during mitosis. However, the role of SPC25 in lung adenocarcinoma (LAUD) is unclear. MATERIALS AND METHODS: The differential expression of SPC25 in tumor samples and normal samples was analyzed using TIMER, TCGA, GEO databases, and the correlation between its expression and clinicopathological features and prognosis in LUAD patients. Biological pathways that may be enriched by SPC25 were analyzed using GSEA. In vitro cell experiments were used to evaluate the effect of knocking down SPC25 expression on LUAD cells. Correlation analysis and differential analysis were used to assess the association of SPC25 expression with genes related to cell cycle, glycolysis, and ferroptosis. A ceRNA network involving SPC25 was constructed using multiple database analyses. RESULTS: SPC25 was highly expressed in LUAD, and its expression level could guide staging and predict prognosis. GSEA found that high expression of SPC25 involved multiple cell cycles and glycolytic pathways. Knocking down SPC25 expression significantly affected the proliferation, migration and apoptosis of LUAD cells. Abnormal SPC25 expression levels can affect cell cycle progression, glycolytic ability and ferroptosis regulation. A ceRNA network containing SPC25, SNHG15/hsa-miR-451a/SPC25, was successfully predicted and constructed. CONCLUSIONS: Our findings reveal the association of up-regulation of SPC25 in LUAD and its expression with clinical features, prognosis prediction, proliferation migration, cell cycle, glycolysis, ferroptosis, and ceRNA networks. Our results indicate that SPC25 can be used as a biomarker in LUAD therapy and a target for therapeutic intervention.
Assuntos
Adenocarcinoma de Pulmão , Ferroptose , Neoplasias Pulmonares , Humanos , Prognóstico , RNA Endógeno Competitivo , Ferroptose/genética , Corpos Polares do Fuso , Adenocarcinoma de Pulmão/genética , Mitose , Neoplasias Pulmonares/genética , Proteínas Associadas aos MicrotúbulosRESUMO
BACKGROUND: Sideroflexin 1 (SFXN1) has been discovered as a novel tumor marker for lung adenocarcinoma, but data on its importance in the development of lung adenocarcinoma is still limited. This study evaluated the correlation between SFXN1 and parameters related to 18F-flurodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), and further explored the role of SFXN1 in the value-added and glycolytic processes of LUAD. METHOD: The expression and prognostic value of SFXN1 mRNA in LUAD were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data base. Retrospective analysis of 18F-FDG PET imaging and metabolic parameters in 42 patients to explore the relationship between the expression of SFXN1 and glucose metabolism levels in lung adenocarcinoma and its clinical significance. H1975 cells were selected as the in vitro research object, and the biological effects of SFXN1 on LUAD were further elucidated through Edu proliferation assay, CCK8 activity assay, wound healing experiment, and cell flow cytometry. RESULT: SFXN1 is highly expressed in various tumors, including LUAD, and its high expression can serve as an independent predictor of overall survival in lung adenocarcinoma. In addition, the expression of SFXN1 in LUAD was significantly correlated with 18F-FDG PET/CT parameters: maximum and average standardized uptake values (SUVmax and SUVmean), as well as total lesion glycolysis (TLG) (rho = 0.574, 0.589, and 0.338, p < 0.05), which can predict the expression of SFXN1 with an accuracy of 0.934. In vitro functional experiments have shown that knocking down SFXN1 inhibits the proliferation and migration of LUAD cells, promotes cell apoptosis, and may inhibit tumor activity by regulating the expression of glycolytic related genes SLC2A1, HK2, GPI, ALDOA, GAPDH, ENO1, PKM, and LDHA. CONCLUSION: The overexpression of SFXN1 is closely related to FDG uptake, and SFXN1, as a promising prognostic biomarker, may mediate the development of LUAD through the glycolytic pathway.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Estudos Retrospectivos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , BiomarcadoresRESUMO
For multiple rare diseases as defined by a common biomarker signature, or a disease with multiple disease subtypes of low frequency, it is often possible to provide confirmatory evidence for these disease or subtypes (baskets) as a combined group. A novel drug, as a second generation, may have marginal improvement in efficacy overall but superior efficacy in some baskets. In this situation, it is appealing to test hypotheses of both non-inferiority overall and superiority on certain baskets. The challenge is designing a confirmatory study efficient to address multiple questions in one trial. A two-stage adaptive design is proposed to test the non-inferiority hypothesis at the interim stage, followed by pruning and pooling before testing a superiority hypothesis at the final stage. Such a design enables an efficient and novel registration pathway, including an early claim of non-inferiority followed by a potential label extension with superiority on certain baskets and an improved benefit-risk profile demonstrated by longer term efficacy and safety data. Operating characteristics of this design are examined by simulation studies, and its appealing features make it ready for use in a confirmatory setting, especially in emerging markets, where both the need and the possibility for efficient use of resources may be the greatest.
Assuntos
Projetos de Pesquisa , Humanos , Simulação por ComputadorRESUMO
The effects of the interaction between polygenes and the parent-child relationship on junior high school students' aggressive behaviors were explored through the frameworks of gene-endophenotype-behavior and neurophysiological basis. A total of 892 junior high school students participated in this study. They were asked to complete self-reported questionnaires, and saliva samples were collected. Results showed that 5-HTTLPR, MAOA-uVNTR, COMT (rs4680), and Taq1 (rs1800497) of the DRD2 gene affected students' aggressive behaviors in an accumulative way. The polygenic risk score explained 3.4% of boys' aggression and 1.1% of girls' aggression. The interactions between polygenic risk score and parent-child conflict significantly affected the aggressive behaviors of male students, but did not show any significant effect on those of female students. The interactional effect of polygenic risk score and parent-child conflict on junior high school students' aggressive behaviors was completely mediated by frustration. However, the interaction effect of polygenic risk score and parent-child affinity on aggression was not affected by frustration. This study helps us better understand junior high school students' aggressive behaviors and promotes the prevention and correction of adolescents' problem behaviors.
Assuntos
Agressão , Frustração , Adolescente , Humanos , Masculino , Feminino , Estudantes , Relações Pais-Filho , Inquéritos e Questionários , Estratificação de Risco GenéticoRESUMO
BACKGROUND: In two pivotal phase 3 trials, up to 24â weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12â years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200â mg once daily, TEZ 100â mg once daily and IVA 150â mg every 12â h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1â weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1â s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.
Assuntos
Fibrose Cística , Humanos , Alelos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , MutaçãoRESUMO
The vesicular nucleotide transporter (SLC17A9) has been overexpressed in various cancers. Nonetheless, little is known about its influence on non-small cell lung cancer (NSCLC), including human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Integrative bioinformatics analysis was performed to investigate the prognostic significance and underlying mechanisms of SLC17A9 in patients with NSCLC. Here, we found that SLC17A9 up-regulation was significantly correlated with overall survival in LUAD and LUSC (P < 0.05). Gene set enrichment analysis and protein-protein interaction results revealed that SLC17A9 up-regulation was linked to metabolic process, the hallmark of MYC targets, DNA repair, coagulation and complement. SLC17A9 expression was negatively associated with overall survival and positively related to most LUSC immune cells and immunoinhibitor (20/23), particularly immuno A2aR, PD-1, and CTLA-4 (P < 0.001). High SLC17A9 was associated with infiltrating levels of B cells, CD4+ T cells, M1 macrophages, and T cell exhaustion checkpoints such as PD-1, CTLA4, and LAG3 in LUAD. Moreover, Real-time PCR, MTS assay, EdU assay, ATP production assays and cell cycle analysis were performed to validate SLC17A9 knockdown in LUAD cells. SLC17A9 knockdown significantly inhibited cell proliferation and ATP levels by affecting P2X1, Cytochrome C, and STAT3 expression in lung cancer cells. In conclusion, the present study suggested that SLC17A9 could potentially serve as a prognostic biomarker and correlated with immune infiltrates in LUAD and LUSC.
RESUMO
Pheromones and olfactory communication play vital roles in sex recognition and mate choice in rodents. Asian house rats (Rattus tanezumi) (RT) often startle easily, making behavioral measurements difficult to carry out accurately in the laboratory. Here, the behavioral and olfactory preferences of the female RT between males and females were not observed using a conventional two-choice device; we then explored the neuro-immunohistochemical evidence in the brains of RT females. We found that male urine elicited significantly higher c-fos expression in the accessory olfactory system and sex-related brain regions in females than female urine did. On the other hand, the differences of volatile compounds and major urinary proteins (MUPs) in both voided urine and preputial glands (PGs) of the RT were detected using gas chromatography-mass spectrometer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing electrophoresis, and liquid chromatography-electrospray ionization mass spectrometry. We found that PG-derived 1-(4,5-dihydro-2-thiazolyl)-ethanone and total MUPs were more abundant in males versus females, suggesting these sexually divergent components might activate the female's accessory olfactory system. In conclusion, the neuro-immunohistochemical evidence indicated that potential sex pheromones might exist in RT; however, the strength of the chemical signal might be too weak to cause behavioral responses in females.
RESUMO
For mammals that originate in the cold north, adapting to warmer environments is crucial for southwards invasion. The brown rat (Rattus norvegicus) originated in Northeast China and has become a global pest. R. n. humiliatus (RNH) spread from the northeast, where R. n. caraco (RNC) lives, to North China and diverged to form a subspecies. Genomic analyses revealed that subspecies differentiation was promoted by temperature but impeded by gene flow and that genes related to fatty acid metabolism were under the strongest selection. Transcriptome analyses revealed downregulated hepatic genes related to fatty acid metabolism and upregulated those related to pheromones in RNH vs. RNC. Similar patterns were observed in relation to cold/warm acclimation. RNH preferred mates with stronger pheromone signals intra-populationally and more genetic divergence inter-populationally. We concluded that RNH experienced reduced fat utilization and increased pheromone-mediated sexual selection during its invasion from the cold north to warm south.
RESUMO
Background: Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma. Methods: This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways. Results: The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001). Conclusion: Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.
Assuntos
Glioma , Telômero , Adulto , Humanos , Prognóstico , Biomarcadores , Telômero/genética , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Sistema Nervoso Central , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: This study investigated the correlation between the expression of DARS2 and metabolic parameters of 18F-FDG PET/CT, and explored the potential mechanisms of DARS2 affecting the proliferation and glycolysis of lung adenocarcinoma (LUAD) cells. METHODS: This study used genomics and proteomics to analyze the difference in DARS2 expression between LUAD samples and control samples. An analysis of 62 patients with LUAD who underwent 18F-FDG PET/CT examinations before surgery was conducted retrospectively. The correlation between DARS2 expression and PET/CT metabolic parameters, including SUVmax, SUVmean, MTV, and TLG, was examined by Spearman correlation analysis. In addition, the molecular mechanism of interfering with DARS2 expression in inhibiting LUAD cell proliferation and glycolysis was analyzed through in vitro cell experiments. RESULTS: DARS2 expression was significantly higher in LUAD samples than in control samples (p < 0.001). DARS2 has high specificity (98.4%) and sensitivity (95.2%) in the diagnosis of LUAD. DARS2 expression was positively correlated with SUVmax, SUVmean, and TLG (p < 0.001). At the same time, the sensitivity and specificity of SUVmax in predicting DARS2 overexpression in LUAD were 88.9% and 65.9%, respectively. In vitro cell experiments have shown that interfering with DARS2 expression can inhibit the proliferation and migration of LUAD cells, promote cell apoptosis, and inhibit the glycolytic activity of tumor cells by inhibiting the expression of glycolytic related genes SLC2A1, GPI, ALDOA, and PGAM1. CONCLUSIONS: Overexpression of DARS2 is associated with metabolic parameters on 18F-FDG PET/CT, which can improve LUAD diagnosis accuracy. DARS2 may be a useful biomarker to diagnose, prognosis, and target treatment of LUAD patients.