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Results for “spatial sequencing”

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PubMed2005

Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model.

In Alzheimer disease, increased beta-secretase (BACE1) activity has been associated with neurodegeneration and accumulation of amyloid precursor protein (APP) products. Thus, inactivation of BACE1 could be important in the treatment of Alzheimer disease. In this study, we found that lowering BACE1 levels using lentiviral vectors expressing siRNAs targeting BACE1 reduced amyloid production and the neurodegenerative and behavioral deficits in APP transgenic mice, a model of Alzheimer disease. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.

Alzheimer Disease↗

PubMed1990

Structural analysis of the Hox-3.1 transcription unit and the Hox-3.2--Hox-3.1 intergenic region.

The mouse Hox gene family is a set of mammalian homeobox genes that may represent developmental control genes. Complete information about the primary structure of these genes is a prerequisite for a systematic analysis of the mechanisms that determine their complex tempero-spatial expression patterns. In this report we describe the complete sequence of the Hox-3.1 locus and provide evidence for several closely spaced transcriptional start sites. Sequence analysis of the 5' region of the Hox-3.1 gene extending to its nearest upstream neighbor, Hox-3.2, allowed us to identify sequences known to be capable of interactions with transcription factors. Several of these sequence motifs are similar to cis-regulatory elements found in the regulatory regions of other known developmentally regulated genes.

Amino Acid Sequence↗

PubMed2000

Probing the structure of the PI-SceI-DNA complex by affinity cleavage and affinity photocross-linking.

The PI-SceI protein is an intein-encoded homing endonuclease that initiates the mobility of its gene by making a double strand break at a single site in the yeast genome. The PI-SceI protein splicing and endonucleolytic active sites are separately located in each of two domains in the PI-SceI structure. To determine the spatial relationship between bases in the PI-SceI recognition sequence and selected PI-SceI amino acids, the PI-SceI-DNA complex was probed by photocross-linking and affinity cleavage methods. Unique solvent-accessible cysteine residues were introduced into the two PI-SceI domains at positions 91, 97, 170, 230, 376, and 378, and the mutant proteins were modified with either 4-azidophenacyl bromide or iron (S)-1-(p-bromoacetamidobenzyl)-ethylenediaminetetraacetate (FeBABE). The phenyl azide-coupled proteins cross-linked to the PI-SceI target sequence, and the FeBABE-modified proteins cleaved the DNA proximal to the derivatized amino acid. The results suggest that an extended beta-hairpin loop in the endonuclease domain that contains residues 376 and 378 contacts the major groove near the PI-SceI cleavage site. Conversely, residues 91, 97, and 170 in the protein splicing domain are in close proximity to a distant region of the substrate. To interpret our results, we used a new PI-SceI structure that is ordered in regions of the protein that bind DNA. The data strongly support a model of the PI-SceI-DNA complex derived from this structure.

Base Sequence↗

PubMed2003

Spatiotemporal characterization of paced cardiac activation with body surface potential mapping and self-organizing maps.

In this study self-organizing maps (SOM) were utilized for spatiotemporal analysis and classification of body surface potential mapping (BSPM) data. Altogether 86 cardiac depolarization (QRS) sequences paced by a catheter in 18 patients were included. Spatial BSPM distributions at every 5 ms over the QRS complex were first presented to an untrained SOM. The learning process of the SOM units organized the maps in such a way that similar BSPMs are represented in particular areas of the SOM network. Thereafter, time trajectories and distance maps were created on the trained SOM from sequential maps in a selected paced QRS. The trajectories and distance maps can be applied as such for the localization of abnormal ventricular activation, as well as quantitative input for statistical classification. The results indicate that the method has potential for locating endocardial sites of abnormal ventricular activation, despite the patient material being too limited to provide a reliable statistical evaluation of the source localization accuracy.

Algorithms↗

PubMed2003

Rer1p, a retrieval receptor for ER membrane proteins, recognizes transmembrane domains in multiple modes.

The yeast Golgi membrane protein Rer1p is required for the retrieval of various endoplasmic reticulum (ER) membrane proteins such as Sec12p and Sec71p to the ER. We demonstrate here that the transmembrane domain (TMD) of Sec71p, a type-III membrane protein, contains an ER localization signal, which is required for physical recognition by Rer1p. The Sec71TMD-GFP fusion protein is efficiently retrieved to the ER by Rer1p. The structural feature of this TMD signal turns out to be the spatial location of polar residues flanking the highly hydrophobic core sequence but not the whole length of the TMD. On the Rer1p side, Tyr152 residue in the 4th TMD is important for the recognition of Sec12p but not Sec71p, suggesting that Rer1p interacts with its ligands at least in two modes. Sec71TMD-GFP expressed in the Deltarer1 mutant cells is mislocalized from the ER to the lumen of vacuoles via the multivesicular body (MVB) sorting pathway. In this case, not only the presence of polar residues in the Sec71TMD but also the length of the TMD is critical for the MVB sorting. Thus, the Rer1p-dependent ER retrieval and the MVB sorting in late endosomes both watch polar residues in the TMD but in a different manner.

Amino Acid Sequence↗

PubMed2026

Genomic separation of Salish Sea and Pacific outer coast populations of the keystone sea star Pisaster ochraceus.

Environmental boundaries shape genetic diversity through the interacting effects of geographic distance, local adaptation, and constraints on gene flow. The ochre sea star (Pisaster ochraceus), an intertidal keystone predator, has long been considered to have limited spatial genetic structure along the North American Pacific coast, likely due to its extended larval dispersal period and high potential for gene flow. Here, we characterize spatial genomic variation in Pisaster ochraceus using whole-genome sequencing data from individuals spanning nearly 3000 kilometers of coastline from Alaska to southern California. Analyses of putatively neutral SNPs demonstrate considerable mixing across the latitudinal range, but also reveal substantial structure between outer Pacific coast populations and those within the semi-enclosed Salish Sea, suggesting restricted gene flow and demographic divergence between these regions. Genomic divergence is further supported by evidence of selection, with outlier loci highlighting extended regions of low diversity in the Salish Sea, consistent with recent selective sweeps and potential local adaptation to distinct estuarine conditions. These findings support the role of oceanographic barriers and environmental heterogeneity in shaping population structure in Pisaster ochraceus, challenging earlier expectations of range-wide homogeneity and providing insight into the persistence of this keystone marine species in a rapidly changing world.

Pisaster↗

PubMed2003

Dynamic control of neuronal morphogenesis by rho signaling.

Polarization of the neuronal cell body and initiation of the first neuritic process represent the starting point of a series of dynamic metamorphic events by which the newly acquired identity of a group of neurons can be translated into a morphologically complex web of three-dimensional neuronal circuit. Despite the critical importance of these events, little is known about the molecular signaling mechanisms that either regulate the temporal sequence of these steps or ensure the accuracy and the spatial consistency of the resulting circuits. In this review, based on recent findings from our group and others, we present a working model on how the initial events in neuronal morphogenesis in the CNS may be controlled by multiple Rho pathways.

Axons↗

PubMed2006

Genome-wide prediction and characterization of interactions between transcription factors in Saccharomyces cerevisiae.

Combinatorial regulation by transcription factor complexes is an important feature of eukaryotic gene regulation. Here, we propose a new method for identification of interactions between transcription factors (TFs) that relies on the relationship of their binding sites, and we test it using Saccharomyces cerevisiae as a model system. The algorithm predicts interacting TF pairs based on the co-occurrence of their binding motifs and the distance between the motifs in promoter sequences. This allows investigation of interactions between TFs without known binding motifs or expression data. With this approach, 300 significant interactions involving 77 TFs were identified. These included more than 70% of the known protein-protein interactions. Approximately half of the detected interacting motif pairs showed strong preferences for particular distances and orientations in the promoter sequences. These one dimensional features may reflect constraints on allowable spatial arrangements for protein-protein interactions. Evidence for biological relevance of the observed characteristic distances is provided by the finding that target genes with the same characteristic distances show significantly higher co-expression than those without preferred distances. Furthermore, the observed interactions were dynamic: most of the TF pairs were not constitutively active, but rather showed variable activity depending on the physiological condition of the cells. Interestingly, some TF pairs active in multiple conditions showed preferences for different distances and orientations depending on the condition. Our prediction and characterization of TF interactions may help to understand the transcriptional regulatory networks in eukaryotic systems.

Algorithms↗

PubMedDate not supplied

High-resolution MR venography at 3.0 Tesla.

PURPOSE: The aim of this study was to investigate the visualization of small venous vessels in the normal human brain at a field strength of 3 Tesla. METHODS: T2*-weighted, three-dimensional gradient-echo images were acquired by exploiting the magnetic susceptibility difference between oxygenated and deoxygenated hemoglobin in the vasculature and microvasculature. The spatial resolution was 0.5 x 0.5 x 1 mm3, and sequence parameters were varied to obtain good vessel delineation. Improved visibility of venous vessels was obtained by creating phase mask images from the magnetic resonance phase images and multiplying these by the magnitude images. Venograms were created by performing a minimum intensity projection over targeted volumes. RESULTS: Highly detailed visualization of venous structures deep in the brain and in the superficial cortical areas were obtained without administration of an exogenous contrast agent; compared with similar studies performed at 1.5 T, the echo time could be reduced from typically 40-50 ms to 17-28 ms. CONCLUSION: Imaging at high-field strength offers the possibility of improved resolution and the delineation of smaller vessels compared with lower field strengths.

Adult↗

PubMed2003

Characterization of a nitrate-respiring bacterial community using the nitrate reductase gene (narG) as a functional marker.

Bacterial cultures capable of reducing nitrate to nitrite, or of complete denitrification, were established from 5, 10, 15 and 20 cm depths of a freshwater sediment. Taxonomic analysis of the 56 isolates using 16S rRNA gene sequences revealed an unexpected species richness, which included representatives of the gamma-Proteobacteria, Bacillus spp., Staphylococcus spp. and members of the Actinobacteria. Gram-positive species tended to predominate in the lower depths of the sediment, where there was evidence of active sulphate respiration. Sequences (from the narG gene) potentially encoding the catalytic subunit of the membrane-associated nitrate reductase were successfully amplified from 46 of the isolates, using a nested PCR with four degenerate primers. NarG sequences clustered into three major groupings that were supported by alternative phylogenetic analyses. The NarG sequences from Gram-positive isolates (according to rRNA gene phylogeny) clustered together within sequences from the low-G+C Gram-positive bacteria. However, this cluster also included two sequences from members of the genus Pseudomonas. Another group contained mostly NarG sequences from the Proteobacteria (according to rRNA gene phylogeny), but also included five sequences from Gram-positive species. The third group of NarG sequences contained three sequences from Gram-positive species. Thus, the NarG-derived phylogeny is not entirely consistent with 16S rRNA-based taxonomy, precluding the use of the narG gene as a taxonomically useful tool for the characterization of nitrate-respiring bacteria. Total DNA was also extracted from the four depth intervals of the sediment sample and used in similar narG amplifications. Most sequences amplified directly from environmental DNA clustered in the Gram-negative group, and none was in the predominantly Gram-positive group. The study also revealed a degree of spatial organization of a nitrate-respiring community in terms of both microbiology and narG sequences.

Bacteria↗

PubMed1994

The local distribution of highly divergent mitochondrial DNA haplotypes in toque macaques Macaca sinica at Polonnaruwa, Sri Lanka.

Surveys of mitochondrial DNA (mtDNA) variation in macaque monkeys have revealed extremely high levels of intraspecific divergence among haplotypes. One consistent pattern that has emerged from these studies is that divergent haplotypes are geographically segregated so that sampling a few matrilines from a given region shows them to be identical, or a closely related subset of haplotypes. Geographically structured mtDNA variation has also been commonly observed in other taxa. In this study, haplotype variation and distribution are studied in detail within a local population of toque macaques. The results show that highly divergent haplotypes, differing by 3.1% in their nucleotide sequences, coexist in this population and that they may be spatially segregated even on this micro-geographic scale. Furthermore, these differences are maintained between social groups that exchange male migrants, and thus nuclear genes, frequently.

Animals↗

PubMed1989

Molecular events in the organization of renal tubular epithelium: from nephrogenesis to regeneration.

Information from studies of embryonic nephrons and established renal tubular cell lines in culture can be integrated to derive a picture of how the renal tubule develops and regenerates after acute injury. During development, the formation of a morphologically polarized epithelium from committed nephric mesenchymal cells requires an external signal for mitogenesis and differentiation. Polypeptide growth factors, in some cases mediated through oncogene expression, act in an autocrine or paracrine fashion to stimulate the production of extracellular matrix proteins that probably provide the earliest orientation signal for the cell. Interaction of these proteins with cell surface receptors leads to early organization of the cytoskeletal actin network, which is the major scaffolding for further differentiation and for definition of plasma membrane domains. The formation of cell-cell contacts via specialized adhesion molecules integrates the epithelium into a polarized monolayer and maintains its fence function, i.e., separation of plasma membrane domains. Microtubules probably participate in the delivery of vesicles to specific plasma membrane domains and in the spatial organization of intracellular organelles. Following acute renal injury, this sequence of events appears to be reversed, resulting in partial or complete loss of differentiated features. Regeneration seems to follow the same pattern of sequential differentiation steps as nephrogenesis. The integrity of the epithelium is restored by reestablishing only those stages of differentiation that have been lost. Where cell death occurs, mitogenesis in adjacent cells restores the continuity of the epithelium and the entire sequence of differentiation events is initiated in the newly generated cells.

Animals↗

PubMed1993

Measurement of two-dimensional blood velocity vectors by the ultrasonic speckle projection technique.

A technique has been developed for measuring the two in-plane components of blood velocity using ultrasound. The principle is based on analyzing a time sequence of successive images of the speckle pattern, and forming spatial projections of the resulting three-dimensional data set. The mathematics may be understood in terms of sections through a three-dimensional Fourier transform of the original data. The technique has been tested with data from a computer-controlled scanner using a tissue-mimicking phantom, and with data from a commercial ultrasound scanner using images of flowing blood in a jugular vein. In both cases, velocity vectors with many different orientations were measured, demonstrating the feasibility of the method. A less restrictive real-time implementation is suggested.

Blood Flow Velocity↗

PubMed1992

Recent advances in primary palate and midface morphogenesis research.

During the sixth week of human development, the primary palate develops as facial prominences enlarge around the nasal pits to form the premaxillary region. Growth of craniofacial components changes facial morphology and affects the extent of contact between the facial prominences. Our recent studies have focused on developing methods to analyze growth of the primary palate and the craniofacial complex to define morphological phases of normal development and to determine alterations leading to cleft lip malformation. Analysis of human embryos in the Carnegie Embryology Collection and mouse embryos of cleft lip and noncleft strains showed that human and mouse embryos have similar phases of primary palate development: first, an epithelial seam, the nasal fin, forms; then a mesenchymal bridge develops through the nasal fin and enlarges rapidly. A robust mesenchymal bridge must form between the facial prominences before advancing midfacial growth patterns tend to separate the facial components as the medial nasal region narrows and elongates, the nasal pits narrow, and the primary choanae (posterior nares) open posterior to the primary palate. In mouse strains with cleft lip gene, maxillary growth, nasal fin formation, and mesenchymal replacement of the nasal fin were all delayed compared with noncleft strains of mice. Successful primary palate formation involves a sequence of local cellular events that are closely timed with spatial changes associated with craniofacial growth that must occur within a critical developmental period.

Animals↗

PubMed2003

Phylogenetically and spatially conserved word pairs associated with gene-expression changes in yeasts.

BACKGROUND: Transcriptional regulation in eukaryotes often involves multiple transcription factors binding to the same transcription control region, and to understand the regulatory content of eukaryotic genomes it is necessary to consider the co-occurrence and spatial relationships of individual binding sites. The determination of conserved sequences (often known as phylogenetic footprinting) has identified individual transcription factor binding sites. We extend this concept of functional conservation to higher-order features of transcription control regions. RESULTS: We used the genome sequences of four yeast species of the genus Saccharomyces to identify sequences potentially involved in multifactorial control of gene expression. We found 989 potential regulatory 'templates': pairs of hexameric sequences that are jointly conserved in transcription regulatory regions and also exhibit non-random relative spacing. Many of the individual sequences in these templates correspond to known transcription factor binding sites, and the sets of genes containing a particular template in their transcription control regions tend to be differentially expressed in conditions where the corresponding transcription factors are known to be active. The incorporation of word pairs to define sequence features yields more specific predictions of average expression profiles and more informative regression models for genome-wide expression data than considering sequence conservation alone. CONCLUSIONS: The incorporation of both joint conservation and spacing constraints of sequence pairs predicts groups of target genes that are specific for common patterns of gene expression. Our work suggests that positional information, especially the relative spacing between transcription factor binding sites, may represent a common organizing principle of transcription control regions.

Base Sequence↗

PubMed2000

The effect of transmission bandwidth on the quality of ophthalmological still and video images.

We have examined the minimum realtime transmission speed for video-angiography with the Rodenstock scanning laser ophthalmoscope (SLO) with respect to spatial and contrast resolution. An SLO fluorescein video-angiography sequence was recorded using high-quality media and relayed to a remote site at transmission speeds ranging from T3 (4.5 Mbit/s) to 0.125 T (197 kbit/s). Images were compared with each other subjectively by an ophthalmologist and objectively with image processing software. When compared qualitatively there was little difference between the T3 and T1 images. The T1 images scored well on clarity and contrast, while 0.5 T was satisfactory but inferior to T1. Transmission speeds below 0.5 T were inadequate. The digital analysis showed a slight difference between T3 and T1. We calculated that there was up to a 92% loss of resolution at 0.25 T and up to a 98% loss at 0.125 T. Based on our quantitative and qualitative analysis, a T3 line provided the highest bandwidth and best resolution, as expected. However, 0.5 T gave satisfactory results for realtime consultations and appears to be the minimum speed required for ophthalmic purposes, producing few motion artefacts and good resolution.

Cataract Extraction↗

PubMed2004

Decreased pulmonary perfusion in pulmonary vein stenosis after radiofrequency ablation: assessment with dynamic magnetic resonance perfusion imaging.

STUDY OBJECTIVES: The functional impact of pulmonary vein (PV) stenosis on pulmonary perfusion after radiofrequency ablation (RFA) for atrial fibrillation (AF) has not been systematically evaluated previously. Therefore, we correlated magnetic resonance (MR) pulmonary perfusion imaging with single-photon emission CT (SPECT) perfusion and with the degree of PV stenosis (PVS) apparent on MR angiography (MRA) after RF ablation. SETTING: Joint radiology-cardiology collaborative magnetic resonance unit at the Kerckhoff Heart Center. DESIGN AND PATIENTS: This was a cohort study of 110 patients who were routinely examined by MRA after RFA for AF, whereby 51 patients with a PV diameter reduction of > 25% or with clinical symptoms (ie, dyspnea and cough) were enrolled into the study. Patients were examined at follow-up by MR perfusion imaging and MRA, and the results were compared to those from patients who underwent SPECT scanning and from a control group of 26 untreated patients. Twelve patients underwent PVS dilatation as well as 22 sequential follow-up examinations. METHODS: Pulmonary perfusion was evaluated using a dynamic contrast-enhanced three-dimensional MR perfusion sequence (1.5 T, 2.5-s temporal resolution, and 0.05 cm spatial resolution), and high-resolution, contrast-enhanced MRA was performed to measure PV diameter. PV dilatation was performed using an angioplasty catheter that was 8 to 10 mm in diameter. RESULTS: The localization and extent of perfusion defects measured by MRI or SPECT scanning were precisely matched. MR perfusion imaging detected 20 of 21 perfusion defects (sensitivity, 95.2%; specificity, 100%). PVSs and perfusion deficits correlated closely and showed the following threshold: perfusion decreased substantially in PVs 6 mm in diameter. After PVS dilatation, perfusion was restored partially after weeks, and complete normalization was seen in 4 of 12 patients (33%). CONCLUSIONS: PVSs caused severe perfusion deficits, which were reliably demonstrated by MR perfusion imaging. Clinical symptoms correlated better with MR perfusion than they did with MRA. The combination with MRA to assess underlying PVS allowed a "one-stop-shopping" MRI procedure to be carried out. The results led to alterations of RFA techniques, and therefore MRA and MR perfusion imaging may be beneficial in patient follow-up and in evaluating new ablation techniques.

Atrial Fibrillation↗

PubMed2002

Aiding planning in air traffic control: an experimental investigation of the effects of perceptual information integration.

Prior research examined how controllers plan in their traditional environment and identified various information uncertainties as detriments to planning. A planning aid was designed to reduce this uncertainty by perceptually representing important constraints. This included integrating spatial information on the radar screen with discrete information (planned sequences of air traffic). Previous research reported improved planning performance and decreased workload in the planning aid condition. The purpose of this paper was to determine the source of these performance improvements. Analysis of computer interactions using log-linear modeling showed that the planning interface led to less repetitive--but more integrated--information retrieval compared with the traditional planning environment. Ecological interface design principles helped explain how the integrated information retrieval gave rise to the performance improvements. Actual or potential applications of this research include the design and evaluation of interface automation that keeps users in active control by modification of perceptual task characteristics.

Aerospace Medicine↗