HIERARCHICAL LOOP STRUCTURES REGULATE CHROMOSOME ORGANIZATION

The study of chromatin dynamics and motion is essential to the understanding of the rules of life; indeed, the dynamic organization of chromatin plays a unique role in nearly all DNA metabolic processes. It has been hypothesized, and heavily explored experimentally, that various classes of proteins participate in managing the geometrical structure and dynamics of chromosomes throughout the cell cycle. While histones effectively compact chromosomes, the extent of compaction (7-fold) does not account for the greater than 1000-fold compaction required to reduce the genome (length ~1 meter) to the size of the nucleus (radius ~2 micron). It has recently been shown that condensins, one class of structural maintenance of chromosome (SMC) proteins, are able to extrude loops along the chromatin fiber, providing a mechanism to further compact the genome. The role of condensins during mitosis is a potential means for the 10,000-fold compaction attained at the time of chromosome segregation to daughter cells. Condensin and the loop-extrusion mechanism may also be responsible for the heterogeneous shape of chromosomes. In this work, a real-time numerical simulation model is introduced to simulate chromosome dynamics in the presence of histones and condensins to provide a realistic model based on physical principles of polymer dynamics and loop formation. We show that chromosome compaction and variance in compaction result from the coupled hierarchical loop structures created by both histones and condensins, and not from either individual effect. To study the existence of sub-nuclear domains in the nucleus, another coarse-grained polymer model that incorporates chromosomal crosslinks was examined. The model replicates the phase separation of the nucleolus, reveals dynamic self-organized clustering of genes within the nucleolus, and accurately predicts that multiple rDNA loci positioned on more than one chromosome will behave remarkably similarly to a single, intact nucleolus, despite varying the geometric positions of the loci. In this work, a new numerical method to identify the 3D territory is developed to measure the volume of the nucleolus. Simulation results reveal that the nucleolus gains compaction due to high frequency binding-unbinding kinetics of dynamic crosslinks, and the multiple-loci nucleolus gains comparable volume with the single-locus case.Doctor of Philosoph

Individualized analysis reveals CpG sites with methylation aberrations in almost all lung adenocarcinoma tissues

Additional file 1: Table S1. Stable and reversal CpG site pairs identified in the samples measured by two platforms

High expression level of the FTH1 gene is associated with poor prognosis in children with non-M3 acute myeloid leukemia

Acute myelogenous leukemia (AML) is a disease that severely affects the physical health of children. Thus, we aimed to identify biomarkers associated with AML prognosis in children. Using transcriptomics on an mRNA dataset from 27 children with non-M3 AML, we selected genes from among those with the top 5000 median absolute deviation (MAD) values for subsequent analysis which showed that two modules were associated with AML risk groups. Thus, enrichment analysis was performed using genes from these modules. A one-way Cox analysis was performed on a dataset of 149 non-M3 AML patients downloaded from the TCGA. This identified four genes as significant: FTH1, RCC2, ABHD17B, and IRAK1. Through survival analysis, FTH1 was identified as a key gene associated with AML prognosis. We verified the proliferative and regulatory effects of ferroptosis on MOLM-13 and THP-1 cells using Liproxstatin-1 and Erastin respectively by CCK-8 and flow cytometry assays. Furthermore, we assayed expression levels of FTH1 in MOLM-13 and THP-1 cells after induction and inhibition of ferroptosis by real-time quantitative PCR, which showed that upregulated FTH1 expression promoted proliferation and inhibited apoptosis in leukemia cells. In conclusion, high expression of FTH1 promoted proliferation and inhibited apoptosis of leukemic cells through the ferroptosis pathway and is thus a potential risk factor that affects the prognosis of non-M3 AML in children

A kognitív készségek rendszere és fejlődése

Additional file 7: Figure S1. The KEGG pathways separately enriched with hypermethylated (a) and hypomethylated (b) genes in at least 10% of the 539 TCGA lung adenocarcinoma samples

Hyperprogressive disease in non-small cell lung cancer after PD-1/PD-L1 inhibitors immunotherapy: underlying killer

Immune checkpoint inhibitors (ICIs) target the negative regulatory pathway of T cells and effectively reactive the anti-tumor immune function of T cells by blocking the key pathway of the immune escape mechanism of the tumor—PD-1/PD-L1, and fundamentally changing the prospect of immunotherapy for non-small cell lung cancer patients. However, such promising immunotherapy is overshadowed by Hyperprogressive Disease, a response pattern associated with unwanted accelerated tumor growth and characterized by poor prognosis in a fraction of treated patients. This review comprehensively provides an overview of Hyperprogressive Disease in immune checkpoint inhibitor-based immunotherapy for non-small cell lung cancer including its definition, biomarkers, mechanisms, and treatment. A better understanding of the black side of immune checkpoint inhibitors therapy will provide a more profound insight into the pros and cons of immunotherapy

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety

PURPOSE: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety.METHODS: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations.RESULTS: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression.CONCLUSIONS: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.</p

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety

PURPOSE: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety.METHODS: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations.RESULTS: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression.CONCLUSIONS: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.</p

ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs.

peer reviewedThe composition of the intestinal microbiome varies considerably between individuals and is correlated with health1. Understanding to what extend and how host genetics contributes to this variation is paramount yet has proven difficult as few associations have been replicated, particularly in humans2. We herein study the effect of host genotype on the composition of the intestinal microbiota in a large mosaic pig population. We show that, under conditions of exacerbated genetic diversity and environmental uniformity, microbiota composition and abundance of specific taxa are heritable. We map a quantitative trait locus affecting the abundance of Erysipelotrichaceae species and show that it is caused by a 2.3-Kb deletion in the N-acetyl-galactosaminyl-transferase gene underpinning the ABO blood group in humans. We show that this deletion is a ≥3.5 million years old trans-species polymorphism under balancing selection. We demonstrate that it decreases the concentrations of N-acetyl-galactosamine in the gut thereby reducing the abundance of Erysipelotrichaceae that can import and catabolize N-acetyl-galactosamine. Our results provide very strong evidence for an effect of host genotype on the abundance of specific bacteria in the intestine combined with insights in the molecular mechanisms that underpin this association. They pave the way towards identifying the same effect in human rural populations

Price discovery in Chinese PVC futures and spot markets: Impacts of COVID-19 and benchmark analysis

Despite being a minor futures category, Polyvinyl chloride (PVC) futures have emerging as a vital element in energy and chemical futures domain. Employing three benchmark models component share (CS), information share (IS), and information leadership share (ILS), this study explores the price discovery function of Chinese PVC futures and spot markets. It assesses whether PVC futures have matured into an effective hedging tool and reference point for spot markets, and also examines the impact of the COVID-19 pandemic on this price discovery relationship. Empirical analysis reveals that the futures market has become the primary site for price discovery in the Chinese PVC market. All the models consistently demonstrate a mature price discovery function in PVC futures, providing risk mitigation tools for industry players. However, post-pandemic dynamics indicate that price discovery in PVC markets primarily occurs within the spot market. This suggests that compared to the futures market, the PVC spot market is able to respond more quickly to the strong signals of industrial recovery after the end of the pandemic. The feedback and pricing efficiency of the PVC futures market in response to new market information are also influenced. Furthermore, our study offers better anticipation of future market prices