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PubMed2001

DNA binding chelates for nonviral gene delivery imaging.

Noninvasive in vivo monitoring of gene delivery would provide a critically important information regarding the spatial distribution, local concentration, kinetics of removal and/or biodegradation of the expression vector. We developed a novel approach to noninvasive gene delivery imaging using heterobifunctional peptide-based chelates (PBC) bearing double-stranded DNA-binding groups and a technetium-binding amino acid motif. One of such chelates: Gly-Cys(Acm)-Gly-Cys(Acm)-Gly-Lys(4)-Lys-(N-epsilon-[4-(psoralen-8-yloxy)]butyrate)-NH(2) has been characterized and labeled with reduced (99m)Tc pertechnetate (oxotechnetate). The psoralen moiety (a DNA binding group of PBC) allowed linking to double-stranded DNA upon short-term irradiation with the near UV range light (>320 nm). Approximately 30-40% of added (99m)Tc-labeled PBC was nonextractable and co-eluted with a model pCMV-GFP vector during the gel-permeation chromatography. Nuclear imaging of "naked" DNA and DNA complexes with lipid-based transfection reagents ("lipoplexes") has been performed after systemic or local administration of (99m)Tc-PBC-labeled DNA in mice. Imaging results were corroborated with the biodistribution using (99m)Tc-PBC and (32)P-labeled DNA and lipoplexes. A markedly different biodistribution of (99m)Tc PBC-labeled DNA and lipoplexes was observed with the latter being rapidly trapped in the liver, spleen and lung. (99m)Tc PBC-DNA was used as an imaging tracer during in vivo transfection of B16 melanoma by local injection of "naked" (99m)Tc PBC-DNA and corresponding lipoplexes. As demonstrated by nuclear imaging, (99m)Tc PBC-DNA lipoplexes showed a slower elimination from the site of injection than (99m)Tc PBC-DNA alone. This result correlated with a higher expression of marker mRNA and green fluorescent protein as determined using RT-PCR and immunohistochemistry, respectively.

Animals↗
PubMed2002

Visualization and characterization of electroactive defects in the native oxide film on aluminium.

Spatial!y localized electrochemical activity at Al/Al2O3 electrodes has been investigated using scanning electrochemical microscopy (SECM) in order to establish the relationship between localized corrosion of Al (and Al alloys) with the defect structure of the native Al2O3 film. Local electron transfer at microscopic defects (2 to 50 microm radius) was visualized in acetonitrile solutions using the nitrobenzene/nitrobenzene radical anion (Eo approximately -1.6 V vs. Ag/Ag+) and tetracyanoquinodimethane/tetracyanoquinodimethane radical anion couples (Eo approximately -0.3 V) as redox mediators for imaging. SECM investigations revealed no significant differences in electrochemical activity at Al/AI203 electrodes in the two mediator solutions, indicating that electrical conduction at the defect sites is weakly dependent on interfacial potential and the electric field across the Al2O3 film. The density of electroactive defects observed by SECM varied by 2 to 3 orders of magnitude between electrodes prepared from the same source of Al (either 99.450% and 99.9995%) suggesting that electrical conduction in the native oxide is very sensitive to surface preparation. Defect densities as low as approximately 3 sites cm(-2) were readily measured by SECM.

Journal Article↗
PubMed2004

Measurement and dynamics of the spatial distribution of an electron localized at a metal-dielectric interface.

The ability of time- and angle-resolved two-photon photoemission to estimate the size distribution of electron localization in the plane of a metal-adsorbate interface is discussed. It is shown that the width of angular distribution of the photoelectric current is inversely proportional to the electron localization size within the most common approximations in the description of image potential states. The localization of the n=1 image potential state for two monolayers of butyronitrile on Ag(111) is used as an example. For the delocalized n=1 state, the shape of the signal amplitude as a function of momentum parallel to the surface changes rapidly with time, indicating efficient intraband relaxation on a 100 fs time scale. For the localized state, little change was observed. The latter is related to the constant size distribution of electron localization, which is estimated to be a Gaussian with a 15+/-4 A full width at half maximum in the plane of the interface. A simple model was used to study the effect of a weak localization potential on the overall width of the angular distribution of the photoemitted electrons, which exhibited little sensitivity to the details of the potential. This substantiates the validity of the localization size estimate.

Journal Article↗
PubMed1993

Localization of sequences controlling the spatial, temporal, and sex-specific expression of the esterase 6 locus in Drosophila melanogaster adults.

The esterase 6 gene (Est-6) of Drosophila melanogaster is expressed in a variety of tissues that differ between larval and adult stages and among related species. Variability in the level of expression of this locus among different species and strains and its species- and tissue-specific patterns of expression make it a useful system for studying the evolution of gene regulation in Drosophila. We have begun to determine the location of the regulatory regions of Est-6 by constructing deletion mutants of the 5' regions of the gene and transforming them back into flies. Deletion mutants of the putative 5' promoter regions of Est-6 were fused to the bacterial beta-galactosidase gene (lacZ) and assayed for their ability to direct tissue-specific expression in transformed D. melanogaster adults. We have identified four independently acting Est-6 regulatory regions that direct the expression of lacZ in (i) the ejaculatory duct; (ii) the adult salivary glands; (iii) the respiratory system, prefrons, antennae, and maxillary palps; and (iv) the ejaculatory bulb and prefrons. We also found a region near the start of transcription that directed expression of Est-6 in the cardia or proventriculus in some transformed lines.

Animals↗
PubMed2005

Subcellular targeting of oxidants during endothelial cell migration.

Endogenous oxidants participate in endothelial cell migration, suggesting that the enzymatic source of oxidants, like other proteins controlling cell migration, requires precise subcellular localization for spatial confinement of signaling effects. We found that the nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase adaptor p47(phox) and its binding partner TRAF4 were sequestered within nascent, focal complexlike structures in the lamellae of motile endothelial cells. TRAF4 directly associated with the focal contact scaffold Hic-5, and the knockdown of either protein, disruption of the complex, or oxidant scavenging blocked cell migration. An active mutant of TRAF4 activated the NADPH oxidase downstream of the Rho GTPases and p21-activated kinase 1 (PAK1) and oxidatively modified the focal contact phosphatase PTP-PEST. The oxidase also functioned upstream of Rac1 activation, suggesting its participation in a positive feedback loop. Active TRAF4 initiated robust membrane ruffling through Rac1, PAK1, and the oxidase, whereas the knockdown of PTP-PEST increased ruffling independent of oxidase activation. Our data suggest that TRAF4 specifies a molecular address within focal complexes that is targeted for oxidative modification during cell migration.

Cell Movement↗
PubMed2006

HIV outbreak among injecting drug users in the Helsinki region: social and geographical pockets.

BACKGROUND: Incidence of newly diagnosed HIV infections among injecting drug users (IDUs) in Helsinki rose from 0 per 100,000 inhabitants in 1997 to 2.9 in 1998 and to 11.1 in 1999. Thereafter incidence declined to 2.1 in 2003. METHODS: Data were collected from interviews with HIV-positive IDUs who attended the University Hospital in Helsinki from 1998 until 2003. We studied the sociodemographic profile and spatial distribution of IDUs who were diagnosed in the beginning of the outbreak and those diagnosed later. The indicator for the spatial differentiation within the metropolitan area is % employed males aged 25-64. RESULTS: The outbreak occurred among a marginalized population of IDUs characterized by a long history of injecting drug use (10.7 years), mean age 32 years, homelessness (66.3%), history of imprisonment (74.7%) and psychiatric hospital care (40.6%). Compared with 98 early cases diagnosed during the first 2 years until 2000, 47 recent cases diagnosed after 2001 were 4 years older, and as marginalized. Except for the city centre, both early and recent cases had been living or using drugs in the same deprived neighbourhoods with the highest unemployment rates. Up to 40% of cases in the two big geographical clusters did not have contact with the city centre, where the needle exchange services were available. CONCLUSIONS: The Finnish HIV outbreak is restricted socially to a very marginalized IDU population, and spatially to local pockets of poverty. In low prevalence countries, prevention programs should be targeted early at high-risk areas and populations.

Adult↗
PubMed2006

Structural and functional compartmentalization in pollen tubes.

Eukaryotic cellular functions are achieved by concerted activities in the cytosol and functions compartmentalized in the nucleus and other membrane-bound organelles. Moreover, the cytosol and nucleoplasm are populated with mega molecular ensembles that are specialized for different metabolic and biochemical processes. Pollen tubes are unique plant cells with a dramatic growth polarity. Tube growth is restricted to the tip and is supported by a polarized cytoplasmic organization. The apical region of elongating pollen tubes is a domain occupied exclusively by transport vesicles to support the secretion and endocytic activity needed for the rapid cell expansion at the apex. Larger organelles are predominantly segregated to the cytoplasm distal to the subapical region. Underlying the organelle compartmentalization is an elaborate actin cytoskeleton with distinct structural and dynamics properties at the tip, in the subapical region, and in the cytoplasm subtending it. Cytoplasmic domains with differential ionic conditions and spatially restricted localization of molecules in pollen tubes may also be important for regulating the polar cell growth process. The polarized cellular organization in pollen tubes drives an extremely efficient cell growth process that is responsive to extracellular signals, including directional cues. It may be an amplified framework of the cytoplasmic architecture that supports growth in other plant cell types that involves considerably more subtle and transient differential cell expansion.

Cell Compartmentation↗
PubMed2004

ARC3, a chloroplast division factor, is a chimera of prokaryotic FtsZ and part of eukaryotic phosphatidylinositol-4-phosphate 5-kinase.

The arc3 (accumulation and replication of chloroplast) mutant of Arabidopsis thaliana has a small number of abnormally large chloroplasts in the cell, suggesting that chloroplast division is arrested in the mutant and ARC3 has an important role in the initiation of chloroplast division. To elucidate the role of ARC3, first we identified the ARC3 gene, and determined the location of ARC3 protein during chloroplast division because the localization and spatial orientation of such division factors are vital for correct chloroplast division. Sequencing analysis showed that ARC3 was a fusion of the prokaryotic FtsZ and part of the eukaryotic phosphatidylinositol-4-phosphate 5-kinase (PIP5K) genes. The PIP5K-homologous region of ARC3 had no catalytic domain but a membrane-occupation-and-recognition-nexus (MORN) repeat motif. Immunofluorescence microscopy, Western blotting analysis and in vitro chloroplast import and protease protection assays revealed that ARC3 protein was soluble, and located on the outer surface of the chloroplast in a ring-like structure at the early stage of chloroplast division. Prokaryotes have one FtsZ as a gene for division but have no ARC3 counterparts, the chimera of FtsZ and PIP5K, suggesting that the ARC3 gene might have been generated from FtsZ as another division factor during the evolution of chloroplast by endosymbiosis.

Amino Acid Motifs↗
PubMed2005

Spatially dependent inelastic tunneling in a single metallofullerene.

We have measured the elastic and inelastic tunneling properties of isolated Gd@C(82) molecules on Ag(001) using cryogenic scanning tunneling spectroscopy. We find that the dominant inelastic channel is spatially well localized to a particular region of the molecule. Ab initio pseudopotential density-functional theory calculations indicate that this channel arises from a vibrational cage mode. We further show that the observed inelastic tunneling localization is explained by strong localization in the molecular electron-phonon coupling to this mode.

Journal Article↗
PubMed1999

A model-based method for the reconstruction of total knee replacement kinematics.

A better knowledge of the kinematics behavior of total knee replacement (TKR) during activity still remains a crucial issue to validate innovative prosthesis designs and different surgical strategies. Tools for more accurate measurement of in vivo kinematics of knee prosthesis components are therefore fundamental to improve the clinical outcome of knee replacement. In the present study, a novel model-based method for the estimation of the three-dimensional (3-D) position and orientation (pose) of both the femoral and tibial knee prosthesis components during activity is presented. The knowledge of the 3-D geometry of the components and a single plane projection view in a fluoroscopic image are sufficient to reconstruct the absolute and relative pose of the components in space. The technique is based on the best alignment of the component designs with the corresponding projection on the image plane. The image generation process is modeled and an iterative procedure localizes the spatial pose of the object by minimizing the Euclidean distance of the projection rays from the object surface. Computer simulation and static/dynamic in vitro tests using real knee prosthesis show that the accuracy with which relative orientation and position of the components can be estimated is better than 1.5 degrees and 1.5 mm, respectively. In vivo tests demonstrate that the method is well suited for kinematics analysis on TKR patients and that good quality images can be obtained with a carefully positioning of the fluoroscope and an appropriate dosage. With respect to previously adopted template matching techniques, the present method overcomes the complete segmentation of the components on the projected image and also features the simultaneous evaluation of all the six degrees of freedom (DOF) of the object. The expected small difference between successive poses in in vivo sequences strongly reduces the frequency of false poses and both the operator and computation time.

Algorithms↗
PubMed2026

Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers.

BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C-reactive protein (CRP) and interleukin-6 (IL-6), yet the extent of their common genetic basis remains unclear. AIMS: We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. MATERIALS AND METHODS: We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL-6, fitted a single common factor, and performed multivariate GWAS followed by fine-mapping, transcriptome-wide association, gene-based analysis, pathway enrichment, and cell-type and spatial mapping. RESULTS: A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome-wide significant SNPs across 10 independent lead loci, including one novel signal. Fine-mapping prioritized high-confidence variants near PTPN22, the CRP gene cluster and a urate-associated locus. Gene-level analyses converged on DCLRE1B, PTPN22, IL6R, NLRP3 and HNF1A, with pathway enrichment implicating inflammasome assembly and metabolic-inflammatory overlap. Cell-type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. DISCUSSION: These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine-receptor and metabolic pathways. CONCLUSION: Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.

TWAS↗
PubMed1992

Oscillatory Neuronal Responses in the Visual Cortex of the Awake Macaque Monkey.

An important step in early visual processing is the segmentation of scenes. Features constituting individual objects have to be grouped together and segregated from those of other figures or the background. It has been proposed that this grouping could be achieved by synchronizing the fine temporal structure of responses from neurons excited by an individual figure. In the cat visual cortex evidence has been obtained that responses of feature-selective neurons have a distinctive oscillatory structure and can synchronize both within and across cortical areas, the synchronization depending on stimulus configuration. Here we investigate the generality of oscillatory responses and their synchronization and specifically whether these phenomena occur in extrastriate areas of the visual cortex of the awake behaving primate. We find in the caudal superior temporal sulcus of the macaque monkey (Macaca fascicularis) that adjacent neurons can synchronize their responses, in which case their discharges exhibit an oscillatory temporal structure. During such periods of local synchrony spatially separated cell groups can also synchronize their responses if activated with a single stimulus. These findings resemble those described previously for the cat visual cortex, except that in the awake monkey the oscillatory episodes tend to be of shorter duration and exhibit more variability of oscillation frequency.

Journal Article↗
PubMed2004

Analysis of nonlinear responses of adherent epithelial cells probed by magnetic bead twisting: A finite element model based on a homogenization approach.

An original homogenization method was used to analyze the nonlinear elastic properties of epithelial cells probed by magnetic twisting cytometry. In this approach, the apparent rigidity of a cell with nonlinear mechanical properties is deduced from the mechanical response of the entire population of adherent cells. The proposed hyperelastic cell model successfully accounts for the variability in probe-cell geometrical features, and the influence of the cell-substrate adhesion. Spatially distributed local secant elastic moduli had amplitudes ranging from 10 to 400 Pa. The nonlinear elastic behavior of cells may contribute to the wide differences in published results regarding cell elasticity moduli.

Cell Adhesion↗
PubMed1988

Numerical solutions for steady and unsteady flow in a model of the pulmonary airways.

A computational model is presented for unsteady flow through a collapsible tube with variable wall stiffness. The one-dimensional flow equations are solved for inlet, outlet and external conditions that vary with time and for a tube with time-dependent, spatially-distributed local properties. In particular, the effects of nonuniformities and local perturbations in stiffness distribution in the tube are studied. By allowing the flow to evolve in time, asymptotically steady flows are calculated. When simulating a quasi-steady reduction in downstream pressure, the model demonstrates critical transitions, the phenomena of wave-speed limitation and the sites of flow limitation. It also exhibits conditions for which viscous flow limitation occurs. Computations of rapid, unsteady changes of the exit pressure illustrate the phenomena occurring at the onset of a cough, and the generation and propagation of elastic jumps.

Computer Simulation↗
PubMed2002

Statistically stable ultrasonic imaging in random media.

Analysis of array data from acoustic scattering in a random medium with a small number of isolated targets is performed in order to image and, thereby, localize the spatial position of each target. Because the host medium has random fluctuations in wave speed, the background medium is itself a source of scattered energy. It is assumed, however, that the targets are sufficiently larger and/or more reflective than the background fluctuations so that a clear distinction can be made between targets and background scatterers. In numerical simulations nonreflective boundary conditions are used so as to isolate the effects of the host randomness from those of the spatial boundaries, which can then be treated in a separate analysis. It is shown that the key to successful imaging is finding statistically stable functionals of the data whose extreme values provide estimates of scatterer locations. The best ones are related to the eigenfunctions and eigenvalues of the array response matrix, just as one might expect from prior work on array data processing in complex scattering media having homogeneous backgrounds. The specific imaging functionals studied include matched-field processing and linear subspace methods, such as MUSIC (MUtiple SIgnal Classification). But statistical stability is not characteristic of the frequency domain, which is often the province of these methods. By transforming back into the time domain after first diagonalizing the array data in the frequency domain, one can take advantage of both the time-domain stability and the frequency-domain orthogonality of the relevant eigenfunctions.

Models, Statistical↗
PubMed2006

Perceptual recalibration in human sound localization: learning to remediate front-back reversals.

The efficacy of a sound localization training procedure that provided listeners with auditory, visual, and proprioceptive/vestibular feedback as to the correct sound-source position was evaluated using a virtual auditory display that used nonindividualized head-related transfer functions (HRTFs). Under these degraded stimulus conditions, in which the monaural spectral cues to sound-source direction were inappropriate, localization accuracy was initially poor with frequent front-back reversals (source localized to the incorrect front-back hemifield) for five of six listeners. Short periods of training (two 30-min sessions) were found to significantly reduce the rate of front-back reversal responses for four of five listeners that showed high initial reversal rates. Reversal rates remained unchanged for all listeners in a control group that did not participate in the training procedure. Because analyses of the HRTFs used in the display demonstrated a simple and robust front-back cue related to energy in the 3-7-kHz bandwidth, it is suggested that the reductions observed in reversal rates following the training procedure resulted from improved processing of this front-back cue, which is perhaps a form of rapid perceptual recalibration. Reversal rate reductions were found to generalize to untrained source locations, and persisted at least 4 months following the training procedure.

Acoustic Stimulation↗