Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. ...We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15
macrophages, PRDM16
dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of T
17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9
IL-4
IL-13
T
2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4
T
cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.
Simultaneous interrogation of tumor genomes and transcriptomes is underway in unprecedented global efforts. Yet, despite the essential need to separate driver mutations modulating gene expression ...networks from transcriptionally inert passenger mutations, robust computational methods to ascertain the impact of individual mutations on transcriptional networks are underdeveloped. We introduce a novel computational framework, DriverNet, to identify likely driver mutations by virtue of their effect on mRNA expression networks. Application to four cancer datasets reveals the prevalence of rare candidate driver mutations associated with disrupted transcriptional networks and a simultaneous modulation of oncogenic and metabolic networks, induced by copy number co-modification of adjacent oncogenic and metabolic drivers. DriverNet is available on Bioconductor or at http://compbio.bccrc.ca/software/drivernet/ .
Due to its unique advantages such as driving comfort, shock absorption, noise reduction, and convenient management and maintenance, Asphalt Plug Joint has been rapidly developed and applied. However, ...subject to the long-term coupling action of traffic loads and environmental factors, the Asphalt Plug Joint is prone to interface effects and stress concentration resulting in damage, especially the stress concentration at the contact part between the expansion joint and the steel cover plate is more prominent. The interface between the bridge expansion joint and the pavement, as well as the interface between the bridge expansion joint and the edge of the spanning slab, is prone to stress concentration. To solve the above problems, proposed an improved design scheme of the Asphalt Plug Joint: (1) The bonding performance of the interface has a great impact on the service life of the expansion joint. Therefore, through the pull-off and oblique shear tests, the binder with good bonding performance is selected, and the test data is introduced into the cohesion model to simulate the interface contact. (2) Through the finite element simulation analysis, the main parameters of the Asphalt Plug Joint, such as friction coefficient and the cross section form of the cross-seam plate, are analyzed. The results show that the reasonable use of binder can effectively improve the bonding performance of asphalt binder interface; The debonding of the steel cover plate and asphalt mixture and the easing of the cross section form of the joint slab edge can better adapt to the stress caused by the bridge vehicle and temperature load. The optimization of the geometric design of the steel cover plate has a significant effect on improving the mechanical performance of the Asphalt Plug Joint, and has an important reference value for improving its service performance and extending its service life.
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Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thinopyrum intermedium
(2n=6x=42, StStJ
r
J
r
J
vs
J
vs
) is resistant or tolerant to biotic and abiotic stresses, making it suitable for developing perennial crops and forage. Through five cycles of ...selection, we developed 24 perennial wheatgrass lines, designated 19HSC-Q and 20HSC-Z, by crossing wheat-
Th. intermedium
partial amphiploids with
Th. intermedium
. The cold resistance, morphological performance, chromosome composition, and yield components of these perennial lines were investigated from 2019 to 2022. Six lines of 19HSC-Q had higher 1,000-kernel weight, grains per spike, and tiller number than
Th. intermedium
, as well as surviving -30°C in winter. Lines 19HSC-Q14, 19HSC-Q18, and 19HSC-Q20 had the best performances for grain number per spike and 1,000-kernel weight. The 20HSC-Z lines, 20HSC-Z1, 20HSC-Z2, and 20HSC-Z3, were able to survive in the cold winter in Harbin and had been grown for two years. Sequential multicolor GISH analysis revealed that the J
vs
subgenome of
Th. intermedium
were divided into two karyotypes, three pairs of type-I J
vs
chromosomes and four pairs of type-II J
vs
chromosomes. Both
Th. intermedium
and the 24 advanced perennial wheatgrass lines had similar chromosome compositions, but the translocations among subgenome chromosomes were detected in some lines with prominent agronomic traits, such as 19HSC-Q11, 19HSC-Q14, 19HSC-Q18, 19HSC-Q20, and the three 20HSC-Z lines. The chromosome aberrations were distinguished into two types: the large fragment translocation with St-J
r
, J
vs
-St, J
r
-IIJ
vs
, and J
vs
-J
r
and the small fragment introgression of J
r
-St, St-IJ
vs,
and J
vs
-J
r
. These chromosomal variations can be used to further analyze the relationship between the subgenomes and phenotypes of
Th. intermedium
. The results of this study provide valuable materials for the next selection cycle of cold-resistant perennial wheatgrass.
In this paper, we will represent several methods that can reduce the computational complexity to detect signals for Uplink Massive MIMO Systems. Then we will show the simulation performance of these ...methods and analyse them. Finally we will give improvement for better performance.
With the rapid increase of whole-genome sequencing of human cancers, an important opportunity to analyze and characterize somatic mutations lying within cis-regulatory regions has emerged. A focus on ...protein-coding regions to identify nonsense or missense mutations disruptive to protein structure and/or function has led to important insights; however, the impact on gene expression of mutations lying within cis-regulatory regions remains under-explored. We analyzed somatic mutations from 84 matched tumor-normal whole genomes from B-cell lymphomas with accompanying gene expression measurements to elucidate the extent to which these cancers are disrupted by cis-regulatory mutations.
We characterize mutations overlapping a high quality set of well-annotated transcription factor binding sites (TFBSs), covering a similar portion of the genome as protein-coding exons. Our results indicate that cis-regulatory mutations overlapping predicted TFBSs are enriched in promoter regions of genes involved in apoptosis or growth/proliferation. By integrating gene expression data with mutation data, our computational approach culminates with identification of cis-regulatory mutations most likely to participate in dysregulation of the gene expression program. The impact can be measured along with protein-coding mutations to highlight key mutations disrupting gene expression and pathways in cancer.
Our study yields specific genes with disrupted expression triggered by genomic mutations in either the coding or the regulatory space. It implies that mutated regulatory components of the genome contribute substantially to cancer pathways. Our analyses demonstrate that identifying genomically altered cis-regulatory elements coupled with analysis of gene expression data will augment biological interpretation of mutational landscapes of cancers.
While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence ...suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities.
In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis.
Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.
Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients ...remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss–associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Inde’low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies.
•Integration of genome-wide copy number and whole transcriptome data identifies key mutational events in the pathogenesis of DLBCL.•Genomic deletions in RCOR1 are associated with a specific gene expression signature and with unfavorable clinical outcomes in DLBCL patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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