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PubMed2005

Numerical simulation of PRESS localized MR spectroscopy.

Numerical simulations of NMR spectra can provide a rapid and convenient method for optimizing acquisition sequence parameters and generating prior spectral information required for parametric spectral analysis. For spatially resolved spectroscopy, spatially dependent variables affect the resultant spectral amplitudes and phases, which must therefore be taken into account in any spectral simulation model. In this study, methods for numerical simulation of spectra obtained using the PRESS localization pulse sequence are examined. A comparison is made between three different simulation models that include different levels of detail regarding the spatial distributions of the excitation functions, and spin evolution during application of the pulses. These methods were evaluated for measurement of spectra from J-coupled spin systems that are of interest for in vivo proton spectroscopy and results compared with experimental data. It is demonstrated that for optimized refocusing pulses it is sufficient to account for chemical shift effects only, although there is some advantage to implementing a more general numerical simulation approach that includes information on RF pulse excitation profiles, which provides sufficient accuracy while maintaining moderate computational requirements and flexibility to handle different spin systems.

Aspartic Acid↗
PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗
PubMed2005

Comparison of melanin-concentrating hormone and hypocretin/orexin mRNA expression patterns in a new parceling scheme of the lateral hypothalamic zone.

A high-resolution spatial distribution analysis of hypothalamic neurons expressing melanin-concentrating hormone or hypocretin/orexin was performed in adult male rats with in situ hybridization cytochemistry. For the analysis, a new parcellation of the lateral zone with some two-dozen regions was used, and distributions were plotted on 15 transverse reference levels through the hypothalamus. Qualitatively the results confirm earlier, much lower resolution mapping studies, although some discrepancies are clarified. Previous work indicates that each of these cell populations is far from homogeneous, and the present results should help establish a framework for clarifying more precisely how they are differentiated and organized in terms of axonal input-output relationships and gene expression patterns, and for defining precise relationships with other hypothalamic neuron populations.

Animals↗
PubMed2006

Microvascular pathology in the aging human brain: evidence that senile plaques are sites of microhaemorrhages.

Amyloid-rich plaques are a feature of the aging human cerebral cortex. We have recently described another feature of aging human cortex, microhaemorrhages, identified by their content of haem, red blood cells, collagen and clotting factors, and their spatial relationship to capillaries. Here we relate microhaemorrhages to amyloid deposits. Observations were made in three groups: patients with no history of dementia, patients with Alzheimer's disease (AD) and patients with Down's syndrome (DS) and dementia. Amyloid deposits and microhaemorrhages were labelled in adjacent sections, amyloid deposits with antibodies to beta-amyloid (betaA), and microhaemorrhages by Prussian blue histochemistry for haem. The densities and sizes of betaA deposits and haem-rich deposits (HRDs), and their relationship to blood vessels, were surveyed in temporal, cingulate and superior frontal cortex. Our results suggest that HRDs and betaA deposits are the same sites of pathology. Their densities in the cortex and white matter of the regions surveyed varied markedly between cases, particularly between demented and non-demented cases, but they always co-varied; where haem deposits were sparse or numerous, so were betaA deposits. Both HRDs and betaA deposits formed adjacent to or encircling small vessels, often at branch points, and a spatial proximity analysis confirmed that both were found close to or colocalising with microvessels. Both HRDs and betaA deposits were associated with blood- or vessel-derived proteins (fibrinogen, von Willebrand factor and collagen VI). Since haem is an established marker of cerebral bleeding, and amyloid is a marker of senile plaques, our results indicate that senile plaques are sites of microhaemorrhages. This colocalisation raises the very testable questions of whether microhaemorrhages are early events in plaque formation and whether therapies which stabilise cerebral microvessels can prevent the onset or slow the progress of dementias associated with plaque formation.

Adult↗
PubMed2022

Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

Humans↗
PubMed2026

Multi-omics and experimental validation identify RAPGEF2 as a protective prognostic biomarker in clear cell renal cell carcinoma.

Kidney Renal Clear Cell Carcinoma (KIRC) is characterized by marked molecular heterogeneity and metabolic reprogramming, underscoring the need for reliable biomarkers for prognostic assessment and individualized treatment. RAPGEF2, a guanine nucleotide exchange factor has been implicated in cell adhesion and differentiation, but its role in KIRC remains unclear. In this study, we systematically evaluated the expression pattern, prognostic significance, genomic associations, biological function, and therapeutic relevance of RAPGEF2 in KIRC through integrated multi-omics analyses and experimental validation. Pan-cancer single-cell and Spatial transcriptomic analysis revealed heterogeneous RAPGEF2 expression across tumor types, with a relatively prominent signal in KIRC, where RAPGEF2 was mainly enriched in endothelial cells. Survival analyses in the TCGA-KIRC showed that high RAPGEF2 expression was significantly associated with favorable overall survival, disease-specific survival, and progression-free interval, and these findings were validated in independent ICGC_RECA-EU and E-MTAB-1980 cohorts. Multivariate Cox regression further confirmed RAPGEF2 as an independent protective prognostic factor. Immunohistochemistry in a tissue microarray cohort demonstrated that higher RAPGEF2 protein expression was associated with improved overall survival. Genomic analyses showed that low RAPGEF2 expression was related to higher mutational burden. Functional assays demonstrated that RAPGEF2 knockdown promoted KIRC progression. Enrichment analyses indicated that RAPGEF2 may be associated with metabolic pathway remodeling, while immunotherapy cohort analyses suggested its potential association with therapeutic benefit. Collectively, RAPGEF2 is identified as a protective prognostic biomarker and potential functional regulator in KIRC.

Biomarker↗
PubMed2004

Tree diseases and landscape processes: the challenge of landscape pathology.

Forest pathology inherently involves a landscape perspective, because tree pathogens propagate according to heterogeneous spatial patterns of flow and isolation. Landscape pathology is a field that is now emerging from the transdisciplinary cooperation of forest pathologists with landscape ecologists. Here, we review recent broad-scale assessments of tree disease risk, investigations of site and host preferences for several root rot pathogens, and regional historical analyses of pathogen outbreak in plantations. Crucial topics include fragmentation effects on pathogen spread and geophysical features that predispose forest patches to disease expression. Recent methodological developments facilitate the spatially explicit analysis of reciprocal coarse-scale relationships among hosts and pathogens. Landscape pathology studies fill a significant research gap in the context of our understanding of sustainable forest management, the introduction of exotic organisms and how climate change might affect the spread of disease.

Journal Article↗
PubMed2004

Tissue displacements during acupuncture using ultrasound elastography techniques.

Acupuncture needle manipulation has been previously shown to result in measurable changes in connective tissue architecture in animal experiments. In this study, we used a novel in vivo ultrasound (US)-based technique to quantify tissue displacement during acupuncture manipulation in humans. B-scan ultrasonic imaging was performed on the thighs of 12 human subjects at different stages of needle motion, including varying amounts of rotation, downward and upward movement performed with a computer-controlled acupuncture needling instrument. Tissue displacements, estimated using cross-correlation techniques, provided successful mapping and quantitative analysis of spatial and temporal tissue behavior during acupuncture needle manipulation. Increasing amounts of rotation had a significant linear effect on tissue displacement during downward and upward needle motion, as well as on rebound tissue displacement after downward needle movement. In addition to being a valuable tool for studies of acupuncture's mechanism of action, this technique may have applications to other types of needling including biopsies.

Acupuncture Therapy↗
PubMed2001

Numerical and experimental models of post-operative realistic flows in stenosed coronary bypasses.

By means of both experimental and finite element methods, we simulated three-dimensional unsteady flows through coronary bypass anastomosis. The host artery includes a stenosis shape located at two different distances of grafting. The inflow rates are issued from in vivo measurements in patients who had undergone coronary bypass surgery a few days before. We provide a comparison between experimental and numerical velocity profiles coupled with the numerical analysis of spatial and temporal wall shear stress evolution. The interaction between the graft and coronary flows has been demonstrated. The phase inflow difference can partly be responsible for specific flow phenomena: jet deflection towards a preferential wall or feedback phenomenon that causes the flapping of the post-stenotic jet during the cardiac cycle. In conclusion, we showed the sensitivity of these typical flows to distance of grafting, inflows waveforms but also to their phase difference.

Blood Flow Velocity↗
PubMed2003

Covariances among join-count spatial autocorrelation measures.

Spatial distributions of biological variables are often well-characterized with pairwise measures of spatial autocorrelation. In this article, the probability theory for products and covariances of join-count spatial autocorrelation measures are developed for spatial distributions of multiple nominal (e.g. species or genotypes) types. This more fully describes the joint distributions of pairwise measures in spatial distributions of multiple (i.e. more than two) types. An example is given on how the covariances can be used for finding standard errors of weighted averages of join-counts in spatial autocorrelation analysis of more than two types, as is typical for genetic data for multiallelic loci.

Analysis of Variance↗
PubMed2001

First tryptophan-containing weak neurotoxin from cobra venom.

With the purpose of studying structure-function relationships among weak neurotoxins (called so because of their low toxicity), we have isolated a toxin (WTX) from the venom of cobra Naja kaouthia using a combination of gel-filtration and ion-exchange chromatography. The amino acid sequence of the isolated toxin was determined by means of Edman degradation and MALDI mass spectrometry, the primary structure obtained being confirmed by 1H-NMR in the course of spatial structure analysis. The WTX sequence differs slightly from that of the toxin CM-9a isolated earlier from the same venom (Joubert and Taljaard, Hoppe-Seyler's Z. Physiol. Chem., 361 (1980) 425). The differences include an extra residue (Trp36) between Ser35 and Arg37 as well as interchanging of two residues (Tyr52 and Lys50) in the C-terminal part of the toxin molecule. These changes improve the alignment that can be made with other weak neurotoxin sequences. An extended sequence comparison reveals that WTX is the first case of a tryptophan-containing weak neurotoxin isolated from cobra venom. WTX was found to compete with radioiodinated alpha-bungarotoxin for binding to the membrane-bound nicotinic acetylcholine receptor from Torpedo californica.

Amino Acid Sequence↗
PubMed2000

Summation between nearby motion signals and facilitative/inhibitory interactions between distant motion signals.

To explain the finding that motion assimilation was dominant between nearby motion signals while motion contrast between distant ones, a center-surround antagonistic mechanism was proposed [Nawrot & Sekuler (1990). Vision Research, 30, 1439-1451]. However, motion assimilation occurred not only between nearby signals but also between distant ones, suggesting the existence of a center-surround non-antagonistic mechanism [Ido. Ohtani & Ejima (1997). Vision Research, 37, 1565-1574]. The present study was designed to provide direct evidence for the non-antagonistic mechanism, and to examine further the motion interactions which operate in different spatial scales. The nature of motion interaction between the test and the inducer was examined by varying the size, the number of frames, the frame duration and the inter-frame displacement of random-dot kinematograms. The results were consistent with the notion that there are three types of interactions in human motion processing; one is a summation process effective within nearby regions, and the other two are facilitative and inhibitory induction processes operating over larger spatial scales. Analysis of the results in terms of the Fourier components suggests that the facilitative and the inhibitory induction processes may be sensitive, respectively to the lower and the higher temporal frequency components of the stimulus.

Humans↗
PubMed2003

Diversity and structure of Chironomidae (Diptera) communities along a gradient of heavy metal contamination in a subarctic watercourse.

Community structure of chironomid larvae was investigated along a gradient of heavy metal pollution in the subarctic lakes of the Pasvik watercourse, bordering Northern Norway and Russia. Sixty taxa were present in the four investigated lakes. Species richness was lower in Lake Kuetsjarvi, nearest the main source of pollution, relative to the more distant lakes, and Simpson's diversity index was similarly highest in the less polluted site with higher maximum depth. The number of orthoclad chironomid species was considerably higher at the least contaminated sites, whereas the relative abundance of Orthocladiinae was highest at the most polluted site. Chironomid density increased with increasing distance from the main source of heavy metal pollution, especially in the subfamilies Tanypodinae and Chironominae, and total chironomid biomass was significantly higher at the least polluted site. Canonical correspondence analysis revealed spatial patterns consistent with species-specific tolerance to the heavy metal concentrations. Protanypus morio, Monodiamesa bathyphila, Chironomus spp., Polypedilum scalaenum gr. and Sergentia coracina seemed to be tolerant to heavy metal contamination, occurring most commonly at the most polluted sites. In contrast, Heterotrissocladius subpilosus, Psectrocladius semicirculatus/sp., Chironomus anthracinus, Pagastiella orophila, Cladotanytarsus iucundus, and Tanytarsus spp. appeared to be more sensitive taxa, being common at the least polluted sites, but rare or absent at the two sites close to the pollution sources. Densities of Procladius (Holotanypus) spp., Tanytarsus spp. and Chironomus anthracinus were negatively correlated with heavy metal concentrations and these taxa appeared to be the best indicators of heavy metal contamination.

Animals↗
PubMed1975

Variation in annual incidence of primary acute pancreatitis in Nottingham, 1969-74.

A review of the 202 patients admitted to Nottingham hospitals with primary acute pancreatitis during the six years 1969-74 has been undertaken. The City of Nottingham and the four adjacent former urban districts had a population of 469 720 in 1971, and an attempt was made to obtain details of all patients from within this defined population area. 134 of the 202 patients came from this area. The annual incidence varied by 4-fold throughout the six years of the survey from a peak incidence of 83-0 per million population in 1974 to a low incidence of 21-2 per million in 1970. There was no detectable pattern behind this variation and consideration of the individual figures did not suggest that any particular predisposing factor accounted for the variation. Spatial variation analysis is now being undertaken to see if population and environmental subgroups can be identified.

Acute Disease↗
PubMedDate not supplied

Mutations and modifications support a 'pitted-flexiball' model for alpha-crystallin.

alpha-Crystallin is renown for resisting crystallization and electron microscopic image analysis. The spatial conformation thus remaining elusive, the authors explored the structure and chaperone functioning by analyzing the effects of site-directed mutagenesis, the properties of naturally occurring aberrant forms of alpha-crystallin and the influence of chemical modifications. The authors observed that the globular multimeric structure, as well as the chaperoning capacity are remarkably tolerant towards changes and modifications in the primary structure. The essential features of the quaternary structure--globular shape, flexibility, highly polar exterior and accessible hydrophobic surface pockets--support a 'pitted-flexiball' model, which combines tetrameric subunit building blocks in an open micelle-like arrangement.

Amino Acid Sequence↗
PubMed2003

High-resolution voxelation mapping of human and rodent brain gene expression.

Voxelation allows high-throughput acquisition of multiple volumetric images of brain gene expression, similar to those obtained from biomedical imaging systems. To obtain these images, the method employs analysis of spatially registered voxels (cubes). For creation of high-resolution maps using voxelation, relatively small voxel sizes are necessary and instruments will be required for semiautomated harvesting of such voxels. Here, we describe two devices that allow spatially registered harvesting of voxels from the human and rodent brain, giving linear resolutions of 3.3 and 1 mm, respectively. Gene expression patterns obtained using these devices showed good agreement with known expression patterns. The voxelation instruments and their future iterations represent a valuable approach to the genome scale acquisition of gene expression patterns in the human and rodent brain.

Animals↗
PubMed1985

Analysis of the structure and spatial distribution of ultraviolet-induced DNA repair patches in human cells made in the presence of inhibitors of replicative synthesis.

The repair of ultraviolet-induced damage in the presence of hydroxyurea or hydroxyurea and arabinosylcytosine was investigated in confluent human fibroblasts at the level of DNA loops attached to the nuclear matrix. Estimation of single-strand break frequencies based on the release of DNA from the DNA-nuclear matrix complex after incubation with nuclease S1 revealed the occurrence of multiple incision events per DNA loop in the presence of inhibitors. When both inhibitors were employed, over 90% of the repair-labelled DNA was not ligated within 2 h post-incubation. In the absence of ligation of repair patches, we observed a preferential release of repair-labelled DNA from the nuclear matrix by nuclease S1 compared to prelabelled DNA, regardless of the period of post-UV incubation. The results suggest that repair events are clustered to some extent in a certain area of a DNA loop. However, the position of these clusters relative to the attachment sites of DNA loops at the nuclear matrix is random. The data are discussed in terms of denaturation of a putative repair complex in the presence of hydroxyurea resulting in an excess of incisions over repaired sites.

Cell Line↗