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Results for “Tissue Array Analysis”

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PubMed2026

Integrative transcriptomic, spatial and functional-genomic analysis identifies a UFMylation-related vascular-stromal program and prioritizes WWTR1 in glioblastoma.

Glioblastoma (GBM) contains spatially organized stress-adaptive and vascular niches. Because transcript abundance does not measure UFM1 conjugation, we asked whether a UFMylation-related transcriptional axis identifies a reproducible tissue program and alters candidate prioritization. In 518 unique primary TCGA-GBM tumors profiled on the Affymetrix HT Human Genome U133A array, weighted gene co-expression network analysis of 8,000 variable genes yielded 12 modules. The 278-gene green module ranked first across nine prespecified traits (mean |r|=0.637). Direct overlap comprised 1/3 measurable UFMylation-core, 5/19 ER-stress/UPR, and 2/15 proteostasis genes; after excluding overlapping genes, correlations with the green eigengene remained significant (r = 0.373, 0.831, 0.639, and 0.699 for UFMylation-core, ER-stress/UPR, proteostasis, and composite scores, respectively). The green score was associated with overall survival per standard-deviation increase (HR 1.17, 95% CI 1.07-1.28), although clinical adjustment attenuated the estimate. In a 10-sample single-cell dataset, sample-level scores were higher in pericytes and endothelial cells than in malignant cells. Donor-aware IvyGAP analysis supported regional organization, whereas one Visium section showed stronger concordance with ER-stress/UPR and mesenchymal scores than with the UFMylation-core score. CellChat indicated pathway-selective rather than global remodeling of inferred vascular communication. Layer ablation moved WWTR1 from rank 48 using WGCNA alone to rank 4 overall and rank 1 among non-common-essential genes after cross-platform integration. These findings define an ER-stress/mesenchymal-weighted, UFMylation-related vascular-stromal transcriptional association and nominate WWTR1 for experimental testing.

Humans↗

PubMed1991

Human fetal central nervous system organotypic cultures.

Many aspects of human neurodevelopment remain enigmatic. A main reason for this is, although there have been a significant number of morphologic and biochemical studies of neural tissues derived from human embryos and fetuses, this can only provide a static picture of the events at a given gestational age. Also, in vitro studies that focus on cells derived from these tissues have a limitation in that different cell types in dissociated tissue culture cannot interact in a 'normal' physiologic manner thereby, perhaps, altering their housekeeping and luxury functions. The present study focused on the development of a human explant organotypic culture model that may overcome the static limitation of the first example and permit a dynamic analysis of different cell types as they interact which may satisfy the second restriction. Because there is an array of developmental markers that define different cell phenotypes, this explant model may also provide a means of analyzing, for the first time, processes undefined in the human CNS. Human fetal CNS tissue obtained from second trimester abortuses was established in culture. The tissues were maintained for up to 12 weeks during which time they developed and differentiated. Sample cultures were harvested periodically and analyzed by light- and electron microscopy in combination with immunocytochemistry. Differentiation of neurons, astrocytes, oligodendrocytes and endothelial cells was documented using morphologic and biochemical criteria. As such, this model system may allow for the analysis of processes that occur during normal human fetal neurodevelopment and in pathologic conditions.

Central Nervous System↗

PubMed1987

Trace enrichment of biological folates on solid-phase adsorption cartridges and analysis by high-pressure liquid chromatography.

A procedure involving solid-phase adsorption on bonded silica has been developed for trace enrichment and selective recovery of folate monoglutamates from liver tissue. A variety of reverse-phase (ethyl, octyl, octadecyl, phenyl) and anion-exchange (aminopropyl, quaternary amine, primary/secondary amine) cartridges were tested for their potential to adsorb and elute folate monoglutamates from standard solutions (50 nmol each of H4-pteroylglutamic acid (H4PteGlu), 5-CHO-H4PteGlu, 10-CHO-H4PteGlu, PteGlu, and 5-CH3-H4PteGlu). Quantitative recoveries were obtained from aminopropyl (-NH2) and all reverse-phase cartridges. For the analyses of rat liver folates, 20 ml of clear supernatant obtained from 5 g of tissue was treated with conjugase, which released folate monoglutamates from endogenous stores. Folate monoglutamates were then separated from nonfolate material by selective adsorption and recovery from -NH2 extraction cartridges. The procedure also provided a 10-fold concentrate, which allowed direct analysis by HPLC, using C-18 reverse-phase ion-pair columns coupled with uv detection (290 nm). Experiments with standard folates (n = 3) mixed with liver tissue and carried through the extraction, incubation, and trace-enrichment steps showed the following recoveries: 10-CHO-H4PteGlu, 55 +/- 5.0%; H4PteGlu, 80 +/- 5.0%; 5-CHO-H4PteGlu, 123 +/- 12.0%; and 5-CH3-H4PteGlu, 89 +/- 3.0%. Endogenous compositions of liver folates (n = 5) were as follows: 10-CHO-H4PteGlu, 1.03 +/- 0.3 nmol/g (6.7%); H4PteGlu, 5.70 +/- 1.0 (36.4%); 5-CHO-H4Pte Glu, 1.34 +/- 0.4 (8.7%); and 5-CH3-H4PteGlu, 7.34 +/- 1.2 (48.0%). Chromatographic peaks were identified by their retention times and by comparing their spectral profiles (obtained by a diode array detector) with respective pure folates. We found trace enrichment of biological folates on solid-phase extraction cartridges to be rapid and quantitative. The method allowed, for the first time, direct analysis of tissue folates by HPLC/uv methods.

Adsorption↗

PubMed1992

Analysis of oxygen exchange between arterioles and surrounding capillary-perfused tissue.

A theoretical model is used to analyze oxygen transport in a three-dimensional tissue region containing an arteriole surrounded by an array of capillaries in planes perpendicular to the arteriole. Convective removal of oxygen from the vicinity of the arteriole by nearby capillaries is shown to increase diffusive oxygen loss from the arteriole. This effect depends on the locations of the capillaries, particularly those nearest to the arteriole. The arteriolar oxygen efflux is comparable to that predicted by a previous model which used a continuum approach, but the efflux does not increase with increasing perfusion as rapidly as predicted by the continuum model. Even a small capillary flow rate strongly influences the oxygen field surrounding the arteriole.

Arterioles↗

PubMed2026

CpGene: a web application for epigenetic signature identification from DNA methylation arrays.

MOTIVATION: DNA methylation (DNAme) is the best studied epigenetic mechanism that plays pivotal role in tissue differentiation and epigenetic disruption has been correlated to diverse disease types (e.g. cancer, metabolic disorders). While various DNAme array platforms have been discovered, data analysis remains a challenging task which often requires in-depth bioinformatic expertise. Here, we developed a user-friendly web-based application for data analysis and visualization that accommodates users ranging from early-career basic/translational researchers to experienced bioinformaticians. RESULTS: CpGene is a web application for analyzing DNA methylation array data. It supports Illumina 450K, EPIC, and EPICv2 methylation array platforms and processes .idat files with integrated preprocessing, normalization, and quality control. Biomarker discovery is available through either classic differential methylation point analysis or machine learning-based feature selection as well as gene enrichment analysis. Results are summarized with clear visualizations, to aid interpretation. By combining these functions in a unified interface, CpGene streamlines methylation analysis and helps identify CpG sites and genes with biological and clinical relevance. AVAILABILITY AND IMPLEMENTATION: CpGene is openly accessible as a web service through http://cpgene.duckdns.org:8001/ and it's source code is available on https://github.com/kostaslazaros/cpgenene.

DNA Methylation↗

PubMed1986

Procedures for respiratory function.

The emergency practitioner has a wide array of procedures in his armamentarium for the diagnosis of pulmonary dysfunction. The combination of blood gas analysis, spirometry, peak expiratory measurements, and trans-tissue monitors, coupled with clinical and radiographic findings, can offer a concise picture of pulmonary status. Further emergency medicine research in these areas will provide exciting methods of assessing and monitoring treatment responses for patients with pulmonary dysfunction.

Blood Gas Analysis↗

PubMed1978

[Overacidified tissue and microcirculation (author's transl)].

A discussion of physiological fundamentals with respect to the inhibition of blood microcirculation in (tumor) tissue at reduced pH values around 6.0 is followed by a report on principles, design and results obtained with a light probe array which permits to determine in vivo reference values of the relative intensity of microcirulation in both normal and tumor tissues under various conditions. An analysis of the discussed records has shown that--as compared to a value of 80-66% without glucose infusion--the relative mean intensity of microcirculation in tumor tissue drops to approximately 8-4% about 300 min after the onset of glucose infusion under CMT administration at 37 degrees C. By adding the CMT step of hyperthermy, the relative mean intensity of microcirculation--compared to normal tissue at 37 degrees C--will further drop below 1%. With such a decline of microcirculation--and an adequate duration of, say, 8 hours--local hyperthermy at 41-42 degrees C is likely to cause a very pronounced damaging action on tumor tissue because the then noticeably reduced substrate offer proves to be insufficient to ensure the structure-maintaining metabolic rate of cancer cells.

Animals↗

PubMed2025

Methylation Signatures Identify Two Distinct Clusters of Uterine Leiomyosarcoma With Unique Histologic and Clinical Behaviors.

Uterine leiomyosarcoma (uLMS) is a rare and deadly gynecologic malignancy. uLMS is histologically heterogeneous and presents with a wide spectrum of tumor differentiation, with a broad range of genomic DNA instability, which can make the diagnosis and prognosis of uLMS challenging. Methylation has emerged as a useful molecular tool in tumor classification and diagnosis in certain neoplasms. We initiated this study to investigate the role of global methylation in the differential diagnosis of uLMS from its mimics in correlation with pathologic characteristics and clinical outcomes. In this study, we performed array-based global methylation profiling analysis in a total of 71 uLMS and compared the methylation signatures of uLMS with several other uterine mesenchymal tumors and soft tissue leiomyosarcoma. We found that uLMS demonstrated distinct methylation patterns differing from all other tumor types. Notably, methylation profiling defines 2 distinct subgroups of uLMS with differing copy number alterations, resulting in unique histologic and clinical behaviors, further emphasized by differences in methylation pathway analysis. This study is the first to report methylation profiling as a useful diagnostic tool in differentiating uLMS from mimics and defines 2 subtypes of uLMS based on methylation signatures.

Humans↗

PubMed1991

Cytokines: is there biological meaning?

In the immune system, amidst the bewildering array of cytokine functions, it is sometimes difficult to discern the relative physiological importance of functions that have been determined in tissue culture. Cytokine functions are indeed complex, but the analysis of relatively simple regulatory networks suggests that activities determined in vitro are highly relevant to genuine physiological functions.

Animals↗

PubMed1991

Cell rearrangement during gastrulation of Xenopus: direct observation of cultured explants.

We have analyzed cell behavior in the organizer region of the Xenopus laevis gastrula by making high resolution time-lapse recordings of cultured explants. The dorsal marginal zone, comprising among other tissues prospective notochord and somitic mesoderm, was cut from early gastrulae and cultured in a way that permits high resolution microscopy of the deep mesodermal cells, whose organized intercalation produces the dramatic movements of convergent extension. At first, the explants extend without much convergence. This initial expansion results from rapid radial intercalation, or exchange of cells between layers. During the second half of gastrulation, the explants begin to converge strongly toward the midline while continuing to extend vigorously. This second phase of extension is driven by mediolateral cell intercalation, the rearrangement of cells within each layer to lengthen and narrow the array. Toward the end of gastrulation, fissures separate the central notochord from the somitic mesoderm on each side, and cells in both tissues elongate mediolaterally as they intercalate. A detailed analysis of the spatial and temporal pattern of these behaviors shows that both radial and mediolateral intercalation begin first in anterior tissue, demonstrating that the anterior-posterior timing gradient so evident in the mesoderm of the neurula is already forming in the gastrula. Finally, time-lapse recordings of intact embryos reveal that radial intercalation takes places primarily before involution, while mediolateral intercalation begins as the mesoderm goes around the lip. We discuss the significance of these findings to our understanding of both the mechanics of gastrulation and the patterning of the dorsal axis.

Animals↗

PubMed2004

Function-informed transcriptome analysis of Drosophila renal tubule.

BACKGROUND: Comprehensive, tissue-specific, microarray analysis is a potent tool for the identification of tightly defined expression patterns that might be missed in whole-organism scans. We applied such an analysis to Drosophila melanogaster Malpighian (renal) tubule, a defined differentiated tissue. RESULTS: The transcriptome of the D. melanogaster Malpighian tubule is highly reproducible and significantly different from that obtained from whole-organism arrays. More than 200 genes are more than 10-fold enriched and over 1,000 are significantly enriched. Of the top 200 genes, only 18 have previously been named, and only 45% have even estimates of function. In addition, 30 transcription factors, not previously implicated in tubule development, are shown to be enriched in adult tubule, and their expression patterns respect precisely the domains and cell types previously identified by enhancer trapping. Of Drosophila genes with close human disease homologs, 50 are enriched threefold or more, and eight enriched 10-fold or more, in tubule. Intriguingly, several of these diseases have human renal phenotypes, implying close conservation of renal function across 400 million years of divergent evolution. CONCLUSIONS: From those genes that are identifiable, a radically new view of the function of the tubule, emphasizing solute transport rather than fluid secretion, can be obtained. The results illustrate the phenotype gap: historically, the effort expended on a model organism has tended to concentrate on a relatively small set of processes, rather than on the spread of genes in the genome.

Animals↗

PubMed2026

GWAS Meta-analysis Identifies Novel Associated Loci and Points to Causal Tissues in Central Serous Chorioretinopathy.

OBJECTIVE: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. DATA SOURCES: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. STUDY SELECTION: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. DATA EXTRACTION AND SYNTHESIS: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. MAIN OUTCOMES AND MEASURES: Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. RESULTS: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5 × 10-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0 × 10-4) and vascular endothelial cells (P = 4.0 × 10-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). CONCLUSIONS AND RELEVANCE: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.

Journal Article↗

PubMed1990

Expression of human plasma protein genes in ageing transgenic mice.

Introduction of human plasma protein genes into the mouse genome to produce transgenic mice furnishes an in vivo model for correlating chromosomal DNA sequences with developmental and tissue-specific expression. The liver produces an array of plasma proteins that circulate throughout the body contributing to homeostasis. Non-hepatic tissue sites of synthesis have been identified where a local provision of plasma proteins is needed. Analysis of expression of human plasma protein genes in ageing transgenic mice appears especially promising in identifying DNA sequences that respond to environmental adversities such as inflammatory factors, hormonal changes and metal toxicity. The results indicate that human genes encoding and controlling liver plasma proteins serve as useful models for studying genetic regulation in the background of development and ageing.

Aging↗

PubMed1988

A rapid method for processing very large numbers of tissue sections for immunohistochemical hybridoma screening.

A hybridoma screening format which facilitates the processing of thousands of tissue sections for immunohistochemical analysis is described. The method utilizes sterile replica transfers of monoclonal antibody-containing test supernatants from 96-well culture plates to tissue sections mounted in appropriately sized 8 X 12 arrays, and is extremely rapid and inexpensive.

Animals↗

PubMed1987

Theory on thermal probe arrays for the distinction between the convective and the perfusive modalities of heat transfer in living tissues.

Recent suggestions for an improved model of heat transfer in living tissues emphasize the existence of a convective mode due to flowing blood in addition to, or even instead of, the perfusive mode, as proposed in Pennes' "classic" bioheat equation. In view of these suggestions, it might be beneficial to develop a technique that will enable one to distinguish between these two modes of bioheat transfer. To this end, a concept that utilizes a multiprobe array of thermistors in conjunction with a revised bioheat transfer equation has been derived to distinguish between, and to quantify the perfusive and convective contribution of blood to heat transfer in living tissues. The array consists of two or more temperature sensors one of which also serves to locally insert a short pulse of heat into the tissue prior to the temperature measurements. A theoretical analysis shows that such a concept is feasible. The construction of the system involves the selection of several important design parameters, i.e., the distance between the probes, the heating power, and the pulse duration. The choice of these parameters is based on computer simulations of the actual experiment.

Animals↗

PubMed1992

Increase in myofilament separation in the "stunned" myocardium.

This study explores the effects of ischemic reperfusion injury on the radial separation distance between thick and thin myofilaments. The left anterior descending coronary artery was occluded for 5 mins and reperfused for 10 mins twelve times repetitively in 6 dogs. At the end of a final 90 min reperfusion period, the hearts were fixed by perfusion with glutaraldehyde, and subepicardial and subendocardial tissue from both normal and ischemic areas were prepared for transmission electron microscopy. Quantitative analysis of inter-filament distance (IFD) was performed on micrographs of transverse sections. The center-to-center IFD was calculated from the numerical density of thick filaments at the A band level using a hexagonal array conversion formula. Sarcomere length was measured on micrographs of longitudinal sections. The results showed that center-to-center thick IFD in the stunned subendocardium was 43.9 +/- 0.8 nm which was significantly greater than the control distance of 40.6 +/- 0.4 nm (P less than 0.001) from normal zone tissue. Thick IFD in the subepicardium was also significantly different: 43.4 +/- 0.6 nm in the stunned tissue as compared with 39.0 +/- 0.7 nm in the non-ischemic tissue (P less than 0.001). Sarcomere length in the normally perfused subendocardium was 2.01 +/- 0.07 micron and was increased to 2.20 +/- 0.08 micron in the stunned subendocardium (P less than 0.005). Sarcomere length in the normal and the stunned subepicardium was also different: 2.02 +/- 0.04 vs. 2.10 +/- 0.09 micron (P less than 0.005). The significant increase in spatial separation between the contractile filaments may affect optimal cross-bridge force generation at the molecular level.(ABSTRACT TRUNCATED AT 250 WORDS)

Actin Cytoskeleton↗

PubMed1992

Type VI collagen microfibrils: evidence for a structural association with hyaluronan.

Type VI collagen, a widespread structural component of connective tissues, has been isolated in abundance from fetal bovine skin by a procedure involving bacterial collagenase digestion under nonreducing, nondenaturing conditions and gel filtration chromatography. Rotary shadowing electron microscopic analysis revealed that the collagen VI was predominantly in the form of extensive intact microfibrillar arrays. These microfibrils were seen in association with hyaluronan, which was identified by its ability to bind the G1 fragment of cartilage proteoglycan. Treatment with highly purified hyaluronidase largely disrupted the collagen VI microfibrils into component tetramers, double tetramers, and short microfibrillar sections. Subsequent incubation of disrupted collagen VI in the presence of hyaluronan facilitated a partial repolymerization of the microfibrils. In vitro binding studies have also demonstrated that type VI collagen binds hyaluronan with a relatively high affinity. These studies demonstrate that a specific structural relationship exists between type VI collagen and hyaluronan. This association is likely to be of primary importance in the growth and remodeling processes of connective tissues.

Animals↗

PubMed1988

The molecular and fibrillar structure of collagen and its relationship to the mechanical properties of connective tissue.

The conformation of type I collagen molecules has been refined using a linked-atom least-squares procedure in conjunction with high-quality X-ray diffraction data. In many tendons these molecules pack in crystalline arrays and a careful measurement of the positions of the Bragg reflections allows the unit cell to be determined with high precision. From a further analysis of the X-ray data it can be shown that the highly ordered overlap region of the collagen fibrils consists of a crystalline array of molecular segments inclined by a small angle with respect to the fibril axis. In contrast, the gap region is less well ordered and contains molecular segments that are likely to be inclined by a similar angle but in a different vertical plane to that found in the overlap region. The collagen molecule thus has a D-periodic crimp in addition to the macroscopic crimp observed visually in the collagen fibres of many connective tissues. The growth and development of collagen fibrils have been studied by electron microscopy for a diverse range of connective tissues and the general pattern of fibril growth has been established as a function of age. In particular, relationships between fibril size distribution, the content and composition of the glycosaminoglycans in the matrix and the mechanical role played by the fibrils in the tissue have been formulated and these now seem capable of explaining many new facets of connective tissue structure and function.

Algorithms↗