Despite histone H2A variants and acetylation of histones occurring in almost every eukaryotic organism, it has been difficult to establish direct functional links between canonical histones or H2A ...variant acetylation, deposition of H2A variants and transcription. To disentangle these complex interdependent processes, we devised a highly sensitive strategy for quantifying histone acetylation levels at specific genomic loci. Taking advantage of the unusual genome organization in Trypanosoma brucei, we identified 58 histone modifications enriched at transcription start sites (TSSs). Furthermore, we found TSS-associated H4 and H2A.Z acetylation to be mediated by two different histone acetyltransferases, HAT2 and HAT1, respectively. Whereas depletion of HAT2 decreases H2A.Z deposition and shifts the site of transcription initiation, depletion of HAT1 does not affect H2A.Z deposition but reduces total mRNA levels by 50%. Thus, specifically reducing H4 or H2A.Z acetylation levels enabled us to reveal distinct roles for these modifications in H2A.Z deposition and RNA transcription.
Abstract
In recent years, the widespread use of drones for the transport of people and cargo in and between cities has become increasingly considered. From the point of view of airspace organization, ...world capitals with high potential for this operation mostly have one common parameter - airspaces defined as controlled zones are established above them, as an integral part of airspace around large international airports. Given the current state of knowledge and the global degree of implementation of unmanned traffic management, it is necessary to solve how to integrate the operation of drones alongside aircraft with crew on board, for which the current rules are defined. On the other hand, the rules for the joint operation of manned and unmanned aircraft, have not yet been sufficiently defined. The aim of this paper is to present the needs for individual solutions for this dedicated part of integration at the European Union member states level and to define the sub-areas that need to be defined and put into operation by regulators and interested institutions. This is achieved through analysis and a specific case study that identifies individual needs and helps to classify them. The combination of identified needs allow the creation of a flowchart showing the logical procedure for the gradual adaptation of Beyond Visual Line of Sight traffic in controlled zones.
We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 ...mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1
/ASXL1
(OS, P=0.004), RUNX1
/SRSF2
(OS, P=0.007) and RUNX1
/PHF6
(OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1
/IDH2
(OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.
We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in mutation analysis and had ...either high (TPS > 50%;
= 10) or negative (TPS < 1%;
= 10) PD-L1 status to be integrated into our study. To examine the methylation of 866,895 specific sites, we utilized the Illumina Infinium EPIC bead chip array. Both hypermethylation and hypomethylation play significant roles in tumor development, progression, and metastasis. They also impact the formation of the tumor microenvironment, which plays a decisive role in tumor differentiation, epigenetics, dissemination, and immune evasion. The gained methylation patterns were correlated with PD-L1 expression. Our analysis has identified distinct methylation patterns in lung adenocarcinomas with high and negative PD-L1 expression. After analyzing the correlation between the methylation results of genes and promoters with their pathobiology, we found that tumors with high expression of PD-L1 tend to exhibit oncogenic effects through hypermethylation. On the other hand, tumors with negative PD-L1 expression show loss of their suppressor functions through hypomethylation. The suppressor functions of hypermethylated genes and promoters are ineffective compared to simultaneously activated dominant oncogenic mechanisms. The tumor microenvironment supports tumor growth in both groups.
Histone variants play a crucial role in chromatin structure organization and gene expression. Trypanosomatids have an unusual H2B variant (H2B.V) that is known to dimerize with the variant H2A.Z ...generating unstable nucleosomes. Previously, we found that H2B.V protein is enriched in tissue-derived trypomastigote (TCT) life forms, a nonreplicative stage of Trypanosoma cruzi, suggesting that this variant may contribute to the differences in chromatin structure and global transcription rates observed among parasite life forms. Here, we performed the first genome-wide profiling of histone localization in T. cruzi using epimastigotes and TCT life forms, and we found that H2B.V was preferentially located at the edges of divergent transcriptional strand switch regions, which encompass putative transcriptional start regions; at some tDNA loci; and between the conserved and disrupted genome compartments, mainly at trans-sialidase, mucin and MASP genes. Remarkably, the chromatin of TCT forms was depleted of H2B.V-enriched peaks in comparison to epimastigote forms. Interactome assays indicated that H2B.V associated specifically with H2A.Z, bromodomain factor 2, nucleolar proteins and a histone chaperone, among others. Parasites expressing reduced H2B.V levels were associated with higher rates of parasite differentiation and mammalian cell infectivity. Taken together, H2B.V demarcates critical genomic regions and associates with regulatory chromatin proteins, suggesting a scenario wherein local chromatin structures associated with parasite differentiation and invasion are regulated during the parasite life cycle.
There is little current literature on the augmented-pressure distal colostogram, the single most important diagnostic study performed in boys with imperforate anus prior to definitive repair. ...Accurate understanding of the anatomy of the anorectal malformation including an associated fistulous communication between the rectum and the urogenital tract is essential for optimal surgical management. Specifically, the position of the rectal pouch and recto-urinary fistula relative to posterior sagittal structures of the perineum, especially the sacral spine, dictates the operative approach. This pictorial essay is a guide for those who encounter such children with relative infrequency to become more comfortable with the technique. We report how to perform this radiologic exam and the potential pitfalls from our experience of performing the technique in our large pediatric colorectal practice.
Per vehicle mile traveled, motorcycle riders have a 34-fold higher risk of death in a crash than people driving other types of motor vehicles. While lower-extremity injuries most commonly occur in ...all motorcycle crashes, head injuries are most frequent in fatal crashes. Helmets and helmet use laws have been shown to be effective in reducing head injuries and deaths from motorcycle crashes. Alcohol is the major contributing factor to fatal crashes. Enforcement of legal limits on the blood alcohol concentration is effective in reducing motorcycle deaths, while some alcohol-related interventions such as a minimal legal drinking age, increased alcohol excise taxes, and responsible beverage service specifically for motorcycle riders have not been examined. Other modifiable protective or risk factors comprise inexperience and driver training, conspicuity and daytime headlight laws, motorcycle licensure and ownership, riding speed, and risk-taking behaviors. Features of motorcycle use and potentially effective prevention programs for motorcycle crash injuries in developing countries are discussed. Finally, recommendations for future motorcycle-injury research are made.
Glioblastomas are the most frequent primary brain tumors in adults. They show highly malignant behavior and devastating outcomes. Since there are still no targeted therapies available, median ...survival remains in the range of 12 to 15 months for glioblastoma patients. Programmed Cell Death Ligand 1 (PD-L1) is a promising novel candidate in precision medicine. Here, we performed integrated epigenome-wide methylation profiling of 866,895 methylation-specific sites in 20 glioblastoma samples comparing PD-L1 high- (i.e., TPS (tumor proportion score) > 30%) and PD-L1 low-expressing glioblastomas (i.e., TPS < 10%). We found 12,597 significantly differentially methylated CpGs (DMCG) (Δβ ≥ 0.1 and p-value < 0.05) in PD-L1 high- compared with PD-L1 low-expressing glioblastomas. These DMCGs were annotated to 2546 tiling regions, 139 promoters, 107 genes, and 107 CpG islands. PD-L1 high-expressing glioblastomas showed hypomethylation in 68% of all DMCGs. Interestingly, the list of the top 100 significantly differentially methylated genes showed the enrichment of regulatory RNAs with 19 DMCGs in miRNA, snoRNAs, lincRNAs, and asRNAs. Gene Ontology analysis showed the enrichment of post-transcriptional and RNA-associated pathways in the hypermethylated gene regions. In summary, dissecting the methylomes depending on PD-L1 status revealed significant alterations in RNA regulation and novel molecular targets in glioblastomas.
Multigrid methods for isogeometric discretization Gahalaut, K.P.S.; Kraus, J.K.; Tomar, S.K.
Computer methods in applied mechanics and engineering,
01/2013, Letnik:
253, Številka:
100
Journal Article
Recenzirano
Odprti dostop
► Multigrid methods are presented for isogeometric discretization of elliptic problems. ► Eigen-values and the condition number of the stiffness matrix are discussed. ► Approximation property and ...smoothing property (with numerical results) are discussed. ► Various numerical results are provided for convergence factor and iterations count.
We present (geometric) multigrid methods for isogeometric discretization of scalar second order elliptic problems. The smoothing property of the relaxation method, and the approximation property of the intergrid transfer operators are analyzed. These properties, when used in the framework of classical multigrid theory, imply uniform convergence of two-grid and multigrid methods. Supporting numerical results are provided for the smoothing property, the approximation property, convergence factor and iterations count for V-, W- and F-cycles, and the linear dependence of V-cycle convergence on the smoothing steps. For two dimensions, numerical results include the problems with variable coefficients, simple multi-patch geometry, a quarter annulus, and the dependence of convergence behavior on refinement levels ℓ, whereas for three dimensions, only the constant coefficient problem in a unit cube is considered. The numerical results are complete up to polynomial order p=4, and for C0 and Cp-1 smoothness.
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