Telomere Recombination Accelerates Cellular Aging in Saccharomyces cerevisiae

Telomeres are nucleoprotein structures located at the linear ends of eukaryotic chromosomes. Telomere integrity is required for cell proliferation and survival. Although the vast majority of eukaryotic species use telomerase as a primary means for telomere maintenance, a few species can use recombination or retrotransposon-mediated maintenance pathways. Since Saccharomyces cerevisiae can use both telomerase and recombination to replicate telomeres, budding yeast provides a useful system with which to examine the evolutionary advantages of telomerase and recombination in preserving an organism or cell under natural selection. In this study, we examined the life span in telomerase-null, post-senescent type II survivors that have employed homologous recombination to replicate their telomeres. Type II recombination survivors stably maintained chromosomal integrity but exhibited a significantly reduced replicative life span. Normal patterns of cell morphology at the end of a replicative life span and aging-dependent sterility were observed in telomerase-null type II survivors, suggesting the type II survivors aged prematurely in a manner that is phenotypically consistent with that of wild-type senescent cells. The shortened life span of type II survivors was extended by calorie restriction or TOR1 deletion, but not by Fob1p inactivation or Sir2p over-expression. Intriguingly, rDNA recombination was decreased in type II survivors, indicating that the premature aging of type II survivors was not caused by an increase in extra-chromosomal rDNA circle accumulation. Reintroduction of telomerase activity immediately restored the replicative life span of type II survivors despite their heterogeneous telomeres. These results suggest that telomere recombination accelerates cellular aging in telomerase-null type II survivors and that telomerase is likely a superior telomere maintenance pathway in sustaining yeast replicative life span

Estradiol regulates miR-135b and mismatch repair gene expressions via estrogen receptor-β in colorectal cells.

Estrogen has anti-colorectal cancer effects which are thought to be mediated by mismatch repair gene (MMR) activity. Estrogen receptor (ER) expression is associated with microRNA (miRNA) expression in ER-positive tumors. However, studies of direct link between estrogen (especially estradiol E2), miRNA expression, and MMR in colorectal cancer (CRC) have not been done. In this study, we first evaluated the effects of estradiol (E2) and its antagonist ICI182,780 on the expression of miRNAs (miR-31, miR-155 and miR-135b) using COLO205, SW480 and MCF-7 cell lines, followed by examining the association of tissue miRNA expression and serum E2 levels using samples collected from 18 colorectal cancer patients. E2 inhibited the expressions of miRNAs in COLO205 cells, which could be reversed by E2 antagonist ICI 182.780. The expression of miR-135b was inversely correlated with serum E2 level and ER-β mRNA expression in CRC patients' cancer tissues. There were significant correlations between serum E2 level and expression of ER-β, miR-135b, and MMR in colon cancer tissue. This study suggests that the effects of estrogen on MMR function may be related to regulating miRNA expression via ER-β, which may be the basis for the anti-cancer effect in colorectal cells

Saccharomyces cerevisiae Est3p dimerizes in vitro and dimerization contributes to efficient telomere replication in vivo

In Saccharomyces cerevisiae at least five genes, EST1, EST2, EST3, TLC1 and CDC13, are required for telomerase activity in vivo. The telomerase catalytic subunit Est2p and telomerase RNA subunit Tlc1 constitute the telomerase core enzyme. Est1p and Est3p are the other subunits of telomerase holoenzyme. In order to dissect the function of Est3p in telomere replication, we over-expressed and purified recombinant wild-type and mutant Est3 proteins. The wild-type protein, as well as the K71A, E104A and T115A mutants were able to dimerize in vitro, while the Est3p-D49A, -K68A or -D166A mutant showed reduced ability to dimerize. Mutations in Est3p that decreased dimerization also appeared to cause telomere shortening in vivo. Double point mutation of Est3p-D49A-K68A and single point mutation of Est3p-K68A showed similar telomere shortening, suggesting that the K68 residue might be more important for telomerase activity. The ectopic co-expression of K71A or T115A mutant with wild-type Est3p using centromere plasmids caused telomere shortening, while co-expression of the D49A, K68A, D86A or F103A mutants with wild-type Est3p had no effect on telomere length regulation. These data suggested that dimerization is important for Est3p function in vivo

Sub-channel analysis for LBE cooled fuel assembly with grid type spacers of China initiative accelerator driven system

The present study focuses on the thermal hydraulic characteristics of fuel assemblies in the China Initiative Accelerator Driven subcritical System (CiADS), which utilizes grid-type spacers to support lead bismuth eutectic (LBE) cooled fast reactors. While the structural design and mechanical analysis of CiADS triangular fuel assemblies with grid-type spacers have been preliminarily investigated, there is a pressing need to study the thermal hydraulic behavior of liquid LBE within these fuel assemblies. This analysis is crucial for assessing the safety and economy of the CiADS subcritical reactor. The sub-channel analysis code, based on the lumped parameter method, plays a vital role in rapidly evaluating the safety features of LBE-cooled fast reactor fuel assemblies. To comprehensively evaluate the thermal hydraulic performance of fuel assemblies with grid-type spacers in the CiADS LBE cooling system, the flow pressure drop model, turbulent mixing model, and convective heat transfer model for the fuel assembly structure with grid-type spacers were incorporated into the existing CiADS sub-channel analysis code. This enhanced code has been successfully employed in the thermal hydraulic analysis of fuel assemblies utilizing wire-type spacers in the CiADS system. To verify the validity and accuracy of the modified CiADS sub-channel analysis code in calculating triangular fuel assemblies with grid-type spacers, the code was first utilized to replicate a 19-rods flow heat transfer experiment with grid-type spacers cooling liquid LBE. A comparison between the simulation and experimental results confirms that the CiADS sub-channel analysis code can predict the coolant temperature and fuel rod surface temperature in fuel assemblies with grid-type spacers. Subsequently, the structure and thermal hydraulic design of the latest CiADS fuel assembly with grid-type spacers were reviewed. Finally, taking into account the aforementioned enhancements to the CiADS sub-channel analysis code, a comprehensive thermo-hydraulic calculation of the CiADS fuel assembly with grid-type spacers was conducted. The results demonstrate that the coolant outlet temperature, maximum cladding temperature, and maximum fuel pellet temperature all fall within the design parameters of CiADS. Furthermore, the impact of the number of rods in different rod bundles (91, 61, 37, and 7 rods) on thermal hydraulic performance was analyzed. The findings indicate that, while ensuring calculation accuracy and efficiency, the results obtained from the 37-rod bundle can effectively reflect the thermal hydraulic behavior of the reactor core

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10-19 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC

Evolutionary trajectories of snake genes and genomes revealed by comparative analyses of five-pacer viper

Snakes have numerous features distinctive from other tetrapods and a rich history of genome evolution that is still obscure. Here, we report the high-quality genome of the five-pacer viper, Deinagkistrodon acutus, and comparative analyses with other representative snake and lizard genomes. We map the evolutionary trajectories of transposable elements (TEs), developmental genes and sex chromosomes onto the snake phylogeny. TEs exhibit dynamic lineage-specific expansion, and many viper TEs show brain-specific gene expression along with their nearby genes. We detect signatures of adaptive evolution in olfactory, venom and thermal-sensing genes and also functional degeneration of genes associated with vision and hearing. Lineage-specific relaxation of functional constraints on respective Hox and Tbx limb-patterning genes supports fossil evidence for a successive loss of forelimbs then hindlimbs during snake evolution. Finally, we infer that the ZW sex chromosome pair had undergone at least three recombination suppression events in the ancestor of advanced snakes. These results altogether forge a framework for our deep understanding into snakes' history of molecular evolution

The establishment and validation of a prediction model for traumatic intracranial injury patients: a reliable nomogram

ObjectiveTraumatic brain injury (TBI) leads to death and disability. This study developed an effective prognostic nomogram for assessing the risk factors for TBI mortality.MethodData were extracted from an online database called “Multiparameter Intelligent Monitoring in Intensive Care IV” (MIMIC IV). The ICD code obtained data from 2,551 TBI persons (first ICU stay, >18 years old) from this database. R divided samples into 7:3 training and testing cohorts. The univariate analysis determined whether the two cohorts differed statistically in baseline data. This research used forward stepwise logistic regression after independent prognostic factors for these TBI patients. The optimal variables were selected for the model by the optimal subset method. The optimal feature subsets in pattern recognition improved the model prediction, and the minimum BIC forest of the high-dimensional mixed graph model achieved a better prediction effect. A nomogram-labeled TBI-IHM model containing these risk factors was made by nomology in State software. Least Squares OLS was used to build linear models, and then the Receiver Operating Characteristic (ROC) curve was plotted. The TBI-IHM nomogram model's validity was determined by receiver operating characteristic curves (AUCs), correction curve, Hosmer-Lemeshow test, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision-curve analysis (DCA).ResultThe eight features with a minimal BIC model were mannitol use, mechanical ventilation, vasopressor use, international normalized ratio, urea nitrogen, respiratory rate, and cerebrovascular disease. The proposed nomogram (TBI-IHM model) was the best mortality prediction model, with better discrimination and superior model fitting for severely ill TBI patients staying in ICU. The model's receiver operating characteristic curve (ROC) was the best compared to the seven other models. It might be clinically helpful for doctors to make clinical decisions.ConclusionThe proposed nomogram (TBI-IHM model) has significant potential as a clinical utility in predicting mortality in TBI patients

Serum metabolomic analysis reveals key metabolites in drug treatment of central precocious puberty in female children

Precocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl–tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid–biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice