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8-aryl or alkyl-naphthyl substituents are widely used as an effective axial shielding strategy for the suppression of chain transfer in late-transition metal-catalyzed ethylene (co)polymerization to yield high molecular weight polyethylene and copolymers. In this study, two 8-cycloalkylnaphthyl acenaphthene-based α-diimine ligands and the corresponding four nickel and palladium complexes were designed and synthesized to explore the effect of axial flexible shielding on ethylene (co)polymerization. In ethylene polymerization, the nickel complexes displayed high activities (up to 1.99 × 106 g mol-1 h-1) and generated lightly branched (34-54/1000 C) polyethylenes with high molecular weights (up to Mn = 1075 kg/mol), whereas the corresponding palladium complexes exhibited moderate activities (level of 104 g mol-1 h-1), producing highly branched (111-125/1000 C) polyethylenes with high molecular weights (up to Mn = 37.6 kg/mol). Highly branched (110-123/1000 C) E-MA copolymers with moderate insertion ratios (1.97-5.56 mol %) were produced by these palladium complexes in ethylene/methyl acrylate (MA) copolymerization. In addition, the size of the 8-cycloalkyl ring in these α-diimine catalysts strongly influences the ethylene (co)polymerization. Compared to cyclopentyl groups, cyclohexyl groups are more effective in suppressing chain transfer reactions in the polymerization of ethylene and the copolymerization of ethylene and MA, leading to higher molecular weight polyethylene and E-MA copolymers. Most interestingly, compared to the reported rigid planar 8-arylnaphthyl catalysts, the flexible 8-cyclohexylnaphthyl catalysts exhibited higher activity and produced higher molecular weight polyethylene in ethylene polymerization. Moreover, in nickel-catalyzed ethylene polymerization, the cyclohexyl catalyst produced significantly reduced branched polyethylene, while in palladium-catalyzed ethylene (co)polymerization, the cyclohexyl catalyst produced more highly branched polyethylene and copolymers. In contrast to the previously reported flexible 8-butylnaphthyl nickel catalysts, the 8-cycloalkylnaphthyl catalysts reported in this work yielded polyethylene with narrow unimodal molecular weight distributions.
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Psoroptes ovis, a common surface-living mite of domestic and wild animals worldwide, results in huge economic losses and serious welfare issues in the animal industry. P. ovis infestation rapidly causes massive eosinophil infiltration in skin lesions, and increasing research revealed that eosinophils might play an important role in the pathogenesis of P. ovis infestation. Intradermal injection of P. ovis antigen invoked massive eosinophil infiltration, suggesting that this mite should contain some relative molecules involved in eosinophil accumulation in the skin. However, these active molecules have not yet been identified. Herein, we identified macrophage migration inhibitor factor (MIF) in P. ovis (PsoMIF) using bioinformatics and molecular biology methods. Sequence analyses revealed that PsoMIF appeared with high similarity to the topology of monomer and trimer formation with host MIF (RMSD = 0.28 angstroms and 2.826 angstroms, respectively) but with differences in tautomerase and thiol-protein oxidoreductase active sites. Reverse transcription PCR analysis (qRT-PCR) results showed that PsoMIF was expressed throughout all the developmental stages of P. ovis, particularly with the highest expression in female mites. Immunolocalization revealed that MIF protein located in the ovary and oviduct of female mites and also localized throughout the stratum spinosum, stratum granulosum, and even basal layers of the epidermis in skin lesions caused by P. ovis. rPsoMIF significantly upregulated eosinophil-related gene expression both in vitro (PBMC: CCL5, CCL11; HaCaT: IL-3, IL-4, IL-5, CCL5, CCL11) and in vivo (rabbit: IL-5, CCL5, CCL11, P-selectin, ICAM-1). Moreover, rPsoMIF could induce cutaneous eosinophil accumulation in a rabbit model and increased the vascular permeability in a mouse model. Our findings indicated that PsoMIF served as one of the key molecules contributing to skin eosinophil accumulation in P. ovis infection of rabbits.
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Eosinofilia , Factores Inhibidores de la Migración de Macrófagos , Infestaciones por Ácaros , Ácaros , Psoroptidae , Ratones , Animales , Conejos , Femenino , Ovinos , Psoroptidae/genética , Infestaciones por Ácaros/parasitología , Infestaciones por Ácaros/patología , Eosinófilos , Interacciones Huésped-Parásitos , Factores Inhibidores de la Migración de Macrófagos/genética , Interleucina-5 , Leucocitos Mononucleares/patologíaRESUMEN
Sertraline (SER) is one of the most commonly detected antidepressants in the aquatic environment that can negatively affect aquatic organisms at low concentrations. Despite some knowledge on its acute toxicity to fish, the effects of chronic SER exposure remain poorly understood along with any underlying mechanisms of SER-induced toxicity. To address this knowledge gap, the effects of chronic exposure to three SER concentrations from low to high were investigated in zebrafish. Juvenile zebrafish were exposed to three concentrations of 1, 10, or 100 µg/L of SER for 28 d, after which indicators of oxidative stress and neurotoxicity in the brain were measured. Superoxide dismutase (SOD) activity was significantly enhanced by SER at 1 up to 100 µg/L, and catalase (CAT) activity was significantly induced by SER at 1 or 10 µg/L. The activity of acetylcholinesterase (AChE) was significantly induced by 10 and 100 µg/L of SER, and the serotonin (5-HT) level was significantly increased by all three concentrations of SER. To ascertain mechanisms of SER-induced toxicity, transcriptomics was conducted in the brain of zebrafish following 100 µg/L SER exposure. The molecular signaling pathways connected with circadian system and the immune system were significantly altered in the zebrafish brain. Based on transcriptomic data, the expression levels of six circadian clock genes were measured, and three genes were significantly altered in relative abundance in fish from all experimental treatments with SER, including cryptochrome circadian regulator 2 (cry2), period circadian clock 2 (per2), and period circadian clock 3 (per3). We hypothesize that the circadian system may be related to SER-induced neurotoxicity and oxidative stress in the central nervous system. This study reveals potential mechanisms and key events (i.e., oxidative stress and neurotoxicity) associated with SER-induced toxicity, and improves understanding of the molecular and biochemical pathways putatively perturbed by SER.
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Contaminantes Químicos del Agua , Pez Cebra , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/metabolismo , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Estrés Oxidativo , Sertralina/toxicidad , Contaminantes Químicos del Agua/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. METHODS: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). RESULTS: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). CONCLUSIONS: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.
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Biomarcadores de Tumor/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Proteína Nuclear Ligada al Cromosoma X/genética , Anciano , Biopsia , Análisis Mutacional de ADN , Reparación del ADN/inmunología , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , RNA-Seq , Factores Sexuales , Estómago/inmunología , Estómago/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidadRESUMEN
8-Arylnaphthyl substituents are privileged motifs frequently integrated into late-transition-metal catalysts, endowing them with an ability to retard chain transfer in ethylene polymerization. In this contribution, we disclose a sort of novel α-diiminenickel and -palladium complexes containing flexible 8-alkylnaphthyl in lieu of rigid 8-arylnaphthyl and their catalytic performance in ethylene polymerization. An interesting feature of these 8-alkylnaphthyl-substituted α-(diimine)PdMeCl complexes is that they present as a mixture of syn and anti isomers (syn:anti = ca. 1:1 ratio, determined by 1H and 13C NMR spectroscopy). In ethylene polymerization, these nickel complexes displayed high activity (up to 3.37 × 106 g mol-1 h-1) and generated branched polyethylenes with broad or bimodal molecular weight distributions (4.6-29.3), while the corresponding palladium complexes exhibited moderate activity, producing highly branched polyethylenes with unimodal and narrow molecular weight distributions (<1.8). In ethylene (E)/methyl acrylate (MA) copolymerization, highly branched E-MA copolymers with considerable MA incorporations were achieved by these palladium complexes. Most interestingly, compared to rigid 8-arylnaphthyl-substituted α-diiminenickel and -palladium complexes, the flexible 8-alkylnaphthyl ones showed significantly improved activity and generated lower or comparable molecular weight polyethylenes or E-MA copolymers.
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To understand the epidemiology, evolutionary and transmission characteristics of HIV-1 CRF07_BC in Nanjing, China. One hundred and fifty-nine patients with HIV-1 CRF07_BC were recruited. DNA sequencing, phylogenetic analysis, and molecular transmission cluster analysis were conducted to determine the molecular epidemiology and evolutionary characteristics. Of these HIV-1-infected patients, 95.6% were male, and men who sex with men (76.7%) were the main transmission route. Only 34.0% of these cases were born in Nanjing, and most of them (64.8%) reported having multiple sex partners in the last 6 months. The maximum likelihood phylogenetic analyses of HIV-1 CRF07_BC revealed two lineages. Overall, 67.3% of Nanjing sequences were connected to at least one other individual distributed in 11 clusters, and the average degree was 21.2 with range (1-178). The clustered patients were more likely to be male. The time to a most recent common ancestor for the early HIV-1 CRF07_BC circulating in Nanjing was estimated to be 1998.71[1997.36-2001.07]. The mean estimated evolutionary rate for the epidemic cluster was slightly lower at 2.38[2.12-2.65] × 10-3 per site per year with the relaxed exponential clock model. HIV-1 CRF07_BC was transmitted into Nanjing more than 20 years ago from Yunnan and has become one of the most predominant subtypes with a higher evolutionary rate than before.
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Comprehensive data on hepatitis C virus (HCV) genotypes distribution is critical for treatment regimen selection, vaccine design, and drug development. This study aimed to understand the dynamic distribution of HCV genotypes in Mainland China. Three hundred sixty-two studies published from January 1993 to December 2017 involving 64 891 samples (5133 injecting drug users, 2748 volunteer blood donors, 1509 former paid plasma donors, 160 sexually encounters, and 1992 human immunodeficiency virus (HIV)/HCV coinfection patients) were eligible for the quantitative synthesis estimation. Pooled proportion of HCV genotypes (and 95% confidence intervals [CIs]) was estimated through the Freeman-Tukey double arcsine transformation by period, region, and risk group. A sharp decline of the subtype 1b was observed in all regions except in northwestern and central regions. The genotypes 3 and 6 showed an obvious increase in southern and southwestern regions and have already spread nationwide. After 2010, subtype 1b was the most dominant variant in all regions and risk groups, accounting for 54.0% (95% CI, 51.9-56.1) of all national infections. Subtype 2a was the second most prevalent strain in all regions except in the south and southwest, with 15.4% (95% CI, 13.1-17.8) national infections. The subtype 6a in southern region and 3b and 3a in southwestern region had a higher proportion of infections than that in other regions. In addition, the genotypes 3 and 6 are already prevalent in almost all risk groups. The distribution of HCV genotypes were sharply shifting in China in the past three decades. The HCV subtype 1b posed a sharp decline, whereas genotypes 3 and 6 played an increasing role in the regional and populational HCV pandemic.
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Variación Genética , Hepacivirus/genética , Hepatitis C/epidemiología , Hepatitis C/virología , China/epidemiología , Coinfección/epidemiología , Coinfección/virología , Evolución Molecular , Genotipo , Infecciones por VIH/epidemiología , Hepacivirus/clasificación , Humanos , Filogenia , Prevalencia , Análisis de Secuencia de ADN , Proteínas del Envoltorio Viral/genéticaRESUMEN
BACKGROUND The aim of this study was to identify biomarkers closely related to the pathogenesis and prognosis of oral squamous cell carcinoma (OSCC) by using weighted gene co-expression network analysis (WGCNA) based on integrative transcriptome datasets. MATERIAL AND METHODS Gene expression profiles of OSCC were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained and we then performed with Gene ontology (GO) and pathway enrichment analysis as well as protein-protein interactions (PPI) network analysis. WGCNA was used to construct the co-expression network. Multipart results were intersected to acquire the candidate genes, and survival analysis was used to identify the hub genes. RESULTS A total of 568 DEGs, including 272 upregulated genes and 296 downregulated genes, were identified. GO and pathway analyses revealed that these DEGs were mainly enriched in extracellular matrix (ECM), ECM organization, structural constituent of muscle, and ECM-receptor interaction. The PPI network of DEGs was established, comprising 428 nodes and 1944 edges. In the co-expression network, pink module was the key module, in which 34 genes with high connectivity were identified. After the intersection of multipart results, 24 common genes were chosen as the candidate genes, among which 7 hub genes (PLAU, SERPINE1, LAMC2, ITGA5, TGFBI, FSCN1, and HLF) were identified using survival analysis. CONCLUSIONS Seven potential biomarkers were identified as being closely related with the initiation and prognosis of OSCC and might serve as potential targets for early diagnosis and personalized therapy of OSCC.
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Neoplasias de la Boca/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Biomarcadores de Tumor/sangre , Biología Computacional/métodos , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes/genética , Humanos , Neoplasias de la Boca/sangre , Pronóstico , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , TranscriptomaRESUMEN
OBJECTIVES: The epidemic of HIV-1 CRF01_AE has become a major public health issue in China. This study aimed to characterise the transmission patterns of genetic networks for CRF01_AE nationwide and elucidate possible opportunities for prevention. METHODS: We isolated and conducted genetic transmission network analysis of all available CRF01_AE pol sequences (n=4704) from China in the Los Alamos HIV sequence database. RESULTS: A total of 1391 (29.6%) sequences were identified as belonging to 400 separate networks. Of men who have sex with men (MSM) in the networks, 93.8% were linked to other MSM and only 2.4% were linked to heterosexual women. However, 11.8% heterosexual women in the networks were linked to MSM. Lineages composed mainly of MSM had higher transmission than those that were mostly heterosexuals. Of the 1391 individuals in networks, 513 (36.9%) were linked to cases diagnosed in different provinces. The proportion of individuals involved in inter-province links was interrelated with the number of migrant people (Spearman's r=0.738, p=0.001). CONCLUSIONS: The outcome of this study could help improve our ability to understand HIV transmission among various regions and risk groups in China, and highlighted the importance of targeting MSM and migrants by prevention and intervention efforts.
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Redes Reguladoras de Genes , Infecciones por VIH/transmisión , VIH-1/genética , Adulto , China/epidemiología , Epidemias/prevención & control , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/aislamiento & purificación , Heterosexualidad/estadística & datos numéricos , Homosexualidad Masculina/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Filogenia , ARN Viral/genética , Factores de Riesgo , Adulto JovenRESUMEN
Cyanobacterial blooms are worldwide distributed and threaten aquatic ecosystems and public health. The current studies mainly focus on the adverse impacts of planktonic cyanobacteria or pure cyanotoxins, while the benthic cyanobacteria-induced ecotoxic effects are relatively lacking. The cyanobacterial cell-induced toxic effects on aquatic organisms might be more serious and complex than the pure cyanotoxins and crude extracts of cyanobacteria. This study explored the chronic effects of toxin-producing planktonic Microcystis aeruginosa (producing microcystin) and benthic Oscillatoria sp. (producing cylindrospermopsin) on the behaviors, tissue structures, oxidative stress, apoptosis, and inflammation of the Asian clams (Corbicula fluminea) under 28-d exposure. The data showed that both M. aeruginosa and Oscillatoria sp. can decrease the behaviors associated with the feeding activity and induce tissue damage (i.e. gill and digestive gland) in clams. Furthermore, two kinds of cyanobacteria can alter the antioxidant enzyme activities and increase antioxidant, lipid oxidation product, and neurotransmitter degrading enzyme levels in clams. Moreover, two kinds of cyanobacteria can activate apoptosis-related enzyme activities and enhance the proinflammatory cytokine levels of clams. In addition, two kinds of cyanobacteria can disturb the transcript levels of genes linked with oxidative stress, apoptosis, and inflammation. These results suggested harmful cyanobacteria can threaten the survival and health of clams, while the benthic cyanobacteria-induced adverse effects deserve more attention. Our finding also indicated that it is necessary to focus on the entire algal cell-induced ecotoxicity when concerning the ecological impacts of cyanobacterial blooms.
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Apoptosis , Corbicula , Microcystis , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Corbicula/efectos de los fármacos , Oscillatoria , Inflamación/inducido químicamente , Inflamación/patología , Microcistinas/toxicidad , Toxinas Bacterianas/toxicidad , Conducta Animal/efectos de los fármacos , Branquias/efectos de los fármacos , Branquias/patología , Branquias/metabolismo , Toxinas Marinas/toxicidad , Floraciones de Algas NocivasRESUMEN
BACKGROUND: The HIV-1 molecular network is an innovative tool, using gene sequences to understand transmission attributes and complementing social and sexual network studies. While previous research focused on static network characteristics, recent studies' emphasis on dynamic features enhances our understanding of real-time changes, offering insights for targeted interventions and efficient allocation of public health resources. OBJECTIVE: This study aims to identify the dynamic changes occurring in HIV-1 molecular transmission networks and analyze the primary influencing factors driving the dynamics of HIV-1 molecular networks. METHODS: We analyzed and compared the dynamic changes in the molecular network over a specific time period between the baseline and observed end point. The primary factors influencing the dynamic changes in the HIV-1 molecular network were identified through univariate analysis and multivariate analysis. RESULTS: A total of 955 HIV-1 polymerase fragments were successfully amplified from 1013 specimens; CRF01_AE and CRF07_BC were the predominant subtypes, accounting for 40.8% (n=390) and 33.6% (n=321) of the specimens, respectively. Through the analysis and comparison of the basic and terminal molecular networks, it was discovered that 144 sequences constituted static molecular networks, and 487 sequences contributed to the formation of dynamic molecular networks. The findings of the multivariate analysis indicated that the factors occupation as a student, floating population, Han ethnicity, engagement in occasional or multiple sexual partnerships, participation in anal sex, and being single were independent risk factors for the dynamic changes observed in the HIV-1 molecular network, and the odds ratio (OR; 95% CIs) values were 2.63 (1.54-4.47), 1.83 (1.17-2.84), 2.91 (1.09-7.79), 1.75 (1.06-2.90), 4.12 (2.48-6.87), 5.58 (2.43-12.80), and 2.10 (1.25-3.54), respectively. Heterosexuality and homosexuality seem to exhibit protective effects when compared to bisexuality, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. Additionally, the National Eight-Item score and sex education experience were also identified as protective factors against dynamic changes in the HIV-1 molecular network, with OR values of 0.12 (95% CI 0.05-0.32) and 0.26 (95% CI 0.11-0.64), respectively. CONCLUSIONS: The HIV-1 molecular network analysis showed 144 sequences in static networks and 487 in dynamic networks. Multivariate analysis revealed that occupation as a student, floating population, Han ethnicity, and risky sexual behavior were independent risk factors for dynamic changes, while heterosexuality and homosexuality were protective compared to bisexuality. A higher National Eight-Item score and sex education experience were also protective factors. The identification of HIV dynamic molecular networks has provided valuable insights into the characteristics of individuals undergoing dynamic alterations. These findings contribute to a better understanding of HIV-1 transmission dynamics and could inform targeted prevention strategies.
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Infecciones por VIH , VIH-1 , Humanos , Estudios Transversales , Infecciones por VIH/transmisión , Infecciones por VIH/epidemiología , Masculino , VIH-1/genética , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Lake Fuxian has the largest reserves of high-quality water resources in China, and understanding its ecological health status is the basis of its environmental protection. Based on a seasonal field investigation of the plankton community, we established a planktonic index of biotic integrity (P-IBI) evaluation system to assess the lake's ecosystem health. The biological integrity of Lake Fuxian was relatively good during winter and spring, but gradually deteriorated from summer to autumn. Areas with poor biological integrity were mainly distributed near tourist attractions along the lake's west coast. Redundancy analysis (RDA) was performed to explore the relationships between the P-IBI, its selected indicators, and the environmental variables. Water temperature (WT), pH, ammonia nitrogen (NH3-N), and dissolved oxygen (DO) significantly influenced the P-IBI and its selected indicators. NH3-N and DO were significantly positively correlated with the P-IBI, indicating that it could be used as a water quality indicator to indirectly reflect lake biological integrity. We demonstrated that the P-IBI can effectively reflect temporal and spatial variations of biological integrity and could be used as a potential tool to evaluate Lake Fuxian ecosystem health.
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Ecosistema , Plancton , Monitoreo del Ambiente , Lagos , ChinaRESUMEN
Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs' action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 µg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish.
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Anticonvulsivantes , Contaminantes Químicos del Agua , Animales , Anticonvulsivantes/toxicidad , Pez Cebra , Acetilcolinesterasa , Contaminantes Químicos del Agua/toxicidad , Hígado , Encéfalo , Carbamazepina/toxicidad , Ácido Glutámico , Superóxido DismutasaRESUMEN
Lead selenide (PbSe) colloidal quantum dots (CQDs) are suitable for the development of the next-generation of photovoltaics (PVs) because of efficient multiple-exciton generation and strong charge coupling ability. To date, the reported high-efficient PbSe CQD PVs use spin-coated zinc oxide (ZnO) as the electron transport layer (ETL). However, it is found that the surface defects of ZnO present a difficulty in completion of passivation, and this impedes the continuous progress of devices. To address this disadvantage, fluoride (F) anions are employed for the surface passivation of ZnO through a chemical bath deposition method (CBD). The F-passivated ZnO ETL possesses decreased densities of oxygen vacancy and a favorable band alignment. Benefiting from these improvements, PbSe CQD PVs report an efficiency of 10.04%, comparatively 9.4% higher than that of devices using sol-gel (SG) ZnO as ETL. We are optimistic that this interface passivation strategy has great potential in the development of solution-processed CQD optoelectronic devices.
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Neosalanx taihuensis is widely distributed in freshwater and brackish water areas in China. Due to its high commercial value, it has been artificially introduced into many lakes and reservoirs, showing strong ecological adaptability. Here, a gap-free chromosome-level reference genome was constructed by combining short reads, PacBio HiFi long reads, Nanopore ultralong reads and Hi-C data. The reference genome of N. taihuensis was 397.29 Mb with a contig N50 of 15.61 Mb. The assembled sequences were anchored to 28 chromosomes. Furthermore, 20,024 protein-coding genes and 98.16% of the predicted genes were annotated in publicly available biological databases. This high-quality gap-free assembled genome will provide an essential reference for studying the evolution and ecological adaptability of N. taihuensis.
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Cromosomas , Peces , Genoma , China , Anotación de Secuencia Molecular , Filogenia , AnimalesRESUMEN
We aimed to explore the impact of sexual transmission modes on immune reconstitution after combined antiretroviral therapy (cART). We have retrospectively analyzed longitudinal samples from 1557 treated male patients with virological suppression (HIV-1 RNA < 50 copies/ml) for at least 2 years. Both heterosexuals (HET) and men who have sex with men (MSM) patients showed an increasing annual trend in CD4+ T cell counts after receiving cART (HET, ß: 23.51 (cell/µl)/year, 95% CI: 16.70-30.31; MSM, ß: 40.21 (cell/µl)/year, 95% CI: 35.82-44.61). However, the CD4+ T cell recovery rate was much lower in HET patients than MSM patients, determined by both the generalized additive mixed model (P < 0.001) and generalized estimating equations (P = 0.026). Besides HIV-1 subtypes, baseline CD4+ T cell counts and age at cART initiation, HET was an independent risk factor for immunological non-responders (adjusted OR: 1.73; 95% CI: 1.28-2.33). HET was also associated with lower probability of achieving conventional immune recovery (adjusted HR: 1.37; 95%CI: 1.22-1.67) and optimal immune recovery (adjusted HR: 1.48, 95%CI: 1.04-2.11). Male HET patients might have poorer immune reconstitution ability even after effective cART. Early initiation of cART after diagnosis and clinical monitoring for male HET patients should be highly emphasized.
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Infecciones por VIH , VIH-1 , Reconstitución Inmune , Minorías Sexuales y de Género , Humanos , Masculino , Terapia Antirretroviral Altamente Activa , Homosexualidad Masculina , Infecciones por VIH/tratamiento farmacológico , Heterosexualidad , Estudios Retrospectivos , Recuento de Linfocito CD4 , Carga ViralRESUMEN
BACKGROUND: Based on the results of existing observational studies, it can be found that the association between serum vitamin D levels and the risk of Sjogren's syndrome (SS) in humans is still controversial. Based on this situation, this study aimed to assess the causal relationship between serum vitamin D levels and SS by using the Mendelian randomization (MR) approach. METHODS: In this study, genome-wide association studies (GWAS) summary statistics on serum vitamin D levels [sample size = 417,580 (UK Biobank)] and SS [sample size = 416,757 (cases = 2495, controls = 414,262) (FinnGen)] were used. The bi-directional MR analysis was then used to assess possible causal relationships. The major analysis method of MR was performed using inverse-variance weighted (IVW), supplemented by MR-Egger and the weighted median approaches. In addition, sensitivity analyses were used to ensure the stability of the results, including Cochran's Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out test. RESULTS: The MR suggested that no significant causal effects of serum 25(OH)D levels on SS risks were observed [odds ratio (OR) = 0.9824; 95% confidence interval (CI) = 0.7130 to 1.3538; P = 0.9137]. Similarly, no evidence supported the causal effects of SS on serum vitamin D levels (ß: 0.0076, 95% CI: - 0.0031 to 0.0183; P = 0.1640). CONCLUSION: This study found no obvious evidence that serum vitamin D level is causally associated with SS risks or vice versa. We call for larger sample size studies to further unravel the potential causal relationship and the exact mechanism.
Asunto(s)
Análisis de la Aleatorización Mendeliana , Síndrome de Sjögren , Humanos , Estudio de Asociación del Genoma Completo , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/genética , Nonoxinol , Vitamina D , Polimorfismo de Nucleótido SimpleRESUMEN
Identification and validation of bioactive small-molecule targets is a significant challenge in drug discovery. In recent years, various in-silico approaches have been proposed to expedite time- and resource-consuming experiments for target detection. Herein, we developed several chemogenomic models for target prediction based on multi-scale information of chemical structures and protein sequences. By combining the information of a compound with multiple protein targets together and putting these compound-target pairs into a well-established model, the scores to indicate whether there are interactions between compounds and targets can be derived, and thus a target prediction task can be completed by sorting the outputted scores. To improve the prediction performance, we constructed several chemogenomic models using multi-scale information of chemical structures and protein sequences, and the ensemble model with the best performance was used as our final model. The model was validated by various strategies and external datasets and the promising target prediction capability of the model, i.e., the fraction of known targets identified in the top-k (1 to 10) list of the potential target candidates suggested by the model, was confirmed. Compared with multiple state-of-art target prediction methods, our model showed equivalent or better predictive ability in terms of the top-k predictions. It is expected that our method can be utilized as a powerful computational tool to narrow down the potential targets for experimental testing.
RESUMEN
OBJECTIVES: The role of DNA damage repair deficiency in improving immune checkpoint inhibitors (ICIs) efficacy has been widely recognized. Studies have confirmed the association of gene mutations in homologous recombination (HR) with an immune-activated microenvironment. Given the crucial role of the tumor microenvironment in ICIs response, our study aimed to identify specific HR gene mutations that influence the tumor microenvironment and thus serve as potential biomarkers for ICIs in tumors that are prone to occur with microsatellite instability (MSI) events (MSI-prone tumors). METHODS: The multi-omics and clinical data of MSI-prone tumors were extracted from ICIs-treated and non-ICIs-treated cohorts. We depicted the mutation landscape of HR genes in MSI-prone tumors and identified the prognosis related HR gene mutations. We integrated multiple immunotherapy-related indicators by bioinformatics methods to characterize the anti-tumor immunity and tumor microenvironment. RESULTS: ATRX, ARID1A, BRCA2 and ATM were the common top four frequently mutated HR genes in MSI-prone tumors, among which ATRX mutations were identified to have prognostic value for ICIs treatment. The bioinformatics analyses suggested that patients with ATRX mutilations (ATRX-mt) have enhanced anti-tumor immunity and inflamed tumor microenvironment in MSI-prone tumors. MSI-stratified analyses revealed the immunologically active features in both microsatellite instability-high (MSI-H) and non-MSI-H populations. There may exist a synergistic effect between ATRX mutations and MSI-H status in immune activation. CONCLUSIONS: Our work found the association of ATRX mutations with immunologically active characteristics in MSI-prone tumors. The combined use of ATRX mutations and MSI-H status might have potential clinical utility for ICIs selection in MSI-prone tumors.
RESUMEN
Because of the limitations of therapeutic approaches, patients suffering from lung adenocarcinoma (LUAD) have unsatisfactory prognoses. Studies have shown that neurotransmitters participated in tumorigenesis and development. In LUAD, the expression of neurotransmitter release cycle-related genes (NRCRGs) has been reported to be disordered. This study aimed to study the correlation between NRCRGs and LUAD. In this study, based on the Cancer Genome Atlas cohort, consensus clustering analyses were performed on ten neurotransmitter release cycle-related (NRCR) differentially expressed genes. Neurotransmitter release cycle (NRC) scores were derived by the Least Absolute Shrinkage and Selection Operator-Cox regression model constituted by 3 NRCRGs. Univariate and multivariate Cox regression analyses were performed to evaluate the prognosis value of the NRC score. In addition, single-Sample Gene Set Enrichment Analysis and CIBERSORT were conducted in the Cancer Genome Atlas cohort. Finally, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were also performed. As a result, the NRC-low group showed a good prognosis instead of the NRC-high group. NRC score was identified to be an independent prognosis factor for LUAD. In general, the NRC score based on the prognostic model was found to be closely correlated with immunotherapy-related anti-cancer immunity and inflamed tumor microenvironment. Functional enrichment results demonstrated that differentially expressed genes between 2 NRC groups were closely correlated with DNA replication, cell-substrate adhesion, Golgi vesicle transport, MAPK signal pathway, and many others. Novel biomarkers were offered for predicting the prognoses of LUAD patients. The NRC score might contribute to guiding LUAD patients with immunotherapy selection.