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PubMed2001

Activation of frontoparietal cortices during memorized triple-step sequences of saccadic eye movements: an fMRI study.

To determine the cortical areas controlling memory-guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple-step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple-step visual stimulation, self-paced saccades in darkness, visually guided saccades and single memory-guided saccades. Triple-step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple-step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple-step sequence.

Adult↗

PubMed1993

[Magnetic resonance tomography using the fast STIR technique: optimization and a comparison with other sequences in a 0.5-Tesla system].

One disadvantage of the STIR sequence in MRI is its long acquisition time. A TR shortening for acceleration requires shortening of the inversion time depending upon the field strength. We optimized this "fast-STIR" technique at 0.5 T using calculations, phantom, volunteer, and patient measurements. This optimization procedure is transferable to other field strengths. The resulting sequence takes 4.5 minutes, fat is visualised signal-free. In the second part of our study we compared quantitatively and qualitatively the signal intensities, contrast, and sensitivity towards artifacts of this sequence with that of conventional SE and GRE sequences in 21 patients with neoplastic, inflammatory and traumatic disorders of the musculoskeletal system. The fast-STIR sequence showed similar or better lesion contrast as SE in 100% and as GRE in 88%. Decreased spatial resolution and higher sensitivity towards pulsatile artifacts of the fast-STIR sequence were only minor drawbacks.

Achilles Tendon↗

PubMed2005

Stimulus-specific sequence representation in serial reaction time tasks.

Some recent evidence has favoured purely response-based implicit representation of sequences in serial reaction time tasks. Three experiments were conducted using serial reaction time tasks featuring four spatial stimuli mapped in categories to two responses. Deviant items from the expected sequence that required the expected response resulted in increased response latencies. The findings demonstrated a stimulus-specific form of representation that operates in the serial reaction time task. No evidence was found to suggest that the stimulus-specific learning was contingent on explicit knowledge of the sequence. Such stimulus-based learning would be congruent with a shortcut within an information-processing framework and, combined with other research findings, suggests that there are multiple loci for learning effects.

Adult↗

PubMed2001

Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes.

BACKGROUND: The availability of complete genome sequences enables all the members of a gene family to be identified without limitations imposed by temporal, spatial or quantitative aspects of mRNA expression. Using the nearly completed human genome sequence, we combined in silico and experimental approaches to define the complete human nuclear receptor (NR) set. This information was used to carry out a comparative genomic study of the NR superfamily. RESULTS: Our analysis of the human genome identified two novel NR sequences. Both these contained stop codons within the coding regions, indicating that both are pseudogenes. One (HNF4 gamma-related) contained no introns and expressed no detectable mRNA, whereas the other (FXR-related) produced mRNA at relatively high levels in testis. If translated, the latter is predicted to encode a short, non-functional protein. Our analysis indicates that there are fewer than 50 functional human NRs, dramatically fewer than in Caenorhabditis elegans and about twice as many as in Drosophila. Using the complete human NR set we made comparisons with the NR sets of C. elegans and Drosophila. Searches for the >200 NRs unique to C. elegans revealed no human homologs. The comparative analysis also revealed a Drosophila member of NR subfamily NR3, confirming an ancient metazoan origin for this subfamily. CONCLUSIONS: This work provides the basis for new insights into the evolution and functional relationships of NR superfamily members.

Amino Acid Sequence↗

PubMed2026

Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues.

Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved transcriptomic analysis of single cells with high spatial resolution. Here, we introduce an in situ RNA amplification method and its integration with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to detect short RNA sequences and enable whole-transcriptome-scale, isoform-resolved spatial transcriptomics of individual cells in intact tissues. Using this approach, we imaged ∼33,000 distinct RNAs-including ∼23,000 genes and ∼10,000 isoforms-in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed rich spatial diversity and cell-type specificity in isoform usage across numerous genes, as well as brain structures particularly rich in isoform specificity. We anticipate broad application of this method for characterizing the molecular and cellular basis of tissue functions, unlocking previously inaccessible discoveries in cell and organismal biology.

Animals↗

PubMed1999

Comparison of three-dimensional visualization techniques for depicting the scala vestibuli and scala tympani of the cochlea by using high-resolution MR imaging.

BACKGROUND AND PURPOSE: Cochlear implantation requires introduction of a stimulating electrode array into the scala vestibuli or scala tympani. Although these structures can be separately identified on many high-resolution scans, it is often difficult to ascertain whether these channels are patent throughout their length. The aim of this study was to determine whether an optimized combination of an imaging protocol and a visualization technique allows routine 3D rendering of the scala vestibuli and scala tympani. METHODS: A submillimeter T2 fast spin-echo imaging sequence was designed to optimize the performance of 3D visualization methods. The spatial resolution was determined experimentally using primary images and 3D surface and volume renderings from eight healthy subjects. These data were used to develop the imaging sequence and to compare the quality and signal-to-noise dependency of four data visualization algorithms: maximum intensity projection, ray casting with transparent voxels, ray casting with opaque voxels, and isosurface rendering. The ability of these methods to produce 3D renderings of the scala tympani and scala vestibuli was also examined. The imaging technique was used in five patients with sensorineural deafness. RESULTS: Visualization techniques produced optimal results in combination with an isotropic volume imaging sequence. Clinicians preferred the isosurface-rendered images to other 3D visualizations. Both isosurface and ray casting displayed the scala vestibuli and scala tympani throughout their length. Abnormalities were shown in three patients, and in one of these, a focal occlusion of the scala tympani was confirmed at surgery. CONCLUSION: Three-dimensional images of the scala vestibuli and scala tympani can be routinely produced. The combination of an MR sequence optimized for use with isosurface rendering or ray-casting algorithms can produce 3D images with greater spatial resolution and anatomic detail than has been possible previously.

Adult↗

PubMed1999

Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes.

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, show a limited amino acid sequence divergence. Their embryonic expression patterns overlap in spatial and temporal profiles with two major exceptions: until 8 days post coitum (d.p.c. ) only Otx2 is expressed in gastrulating embryos, and from 11 d.p.c. onwards only Otx1 is transcribed within the dorsal telencephalon. Otx1 null mice exhibit spontaneous epileptic seizures and multiple abnormalities affecting primarily the dorsal telencephalic cortex and components of the acoustic and visual sense organs. Otx2 null mice show heavy gastrulation abnormalities and lack the rostral neuroectoderm corresponding to the forebrain, midbrain and rostral hindbrain. In order to define whether these contrasting phenotypes reflect differences in expression pattern or coding sequence of Otx1 and Otx2 genes, we replaced Otx1 with a human Otx2 (hOtx2) full-coding cDNA. Interestingly, homozygous mutant mice (hOtx2(1)/hOtx2(1)) fully rescued epilepsy and corticogenesis abnormalities and showed a significant improvement of mesencephalon, cerebellum, eye and lachrymal gland defects. In contrast, the lateral semicircular canal of the inner ear was never recovered, strongly supporting an Otx1-specific requirement for the specification of this structure. These data indicate an extended functional homology between OTX1 and OTX2 proteins and provide evidence that, with the exception of the inner ear, in Otx1 and Otx2 null mice contrasting phenotypes stem from differences in expression patterns rather than in amino acid sequences.

Animals↗

PubMed2007

The acquisition and implementation of the smoothness maximization motion strategy is dependent on spatial accuracy demands.

We recently showed that extensive training on a sequence of planar hand trajectories passing through several targets resulted in the co-articulation of movement components and in the formation of new movement elements (primitives) (Sosnik et al. in Exp Brain Res 156(4):422-438, 2004). Reduction in movement duration was accompanied by the gradual replacing of a piecewise combination of rectilinear trajectories with a single, longer curved one, the latter affording the maximization of movement smoothness ("global motion planning"). The results from transfer experiments, conducted by the end of the last training session, have suggested that the participants have acquired movement elements whose attributes were solely dictated by the figural (i.e., geometrical) form of the path, rather than by both path geometry and its time derivatives. Here we show that the acquired movement generation strategy ("global motion planning") was not specific to the trained configuration or total movement duration. Performance gain (i.e., movement smoothness, defined by the fit of the data to the behavior, predicted by the "global planning" model) transferred to non-trained configurations in which the targets were spatially co-aligned or when participants were instructed to perform the task in a definite amount of time. Surprisingly, stringent accuracy demands, in transfer conditions, resulted not only in an increased movement duration but also in reverting to the straight trajectories (loss of co-articulation), implying that the performance gain was dependent on accuracy constraints. Only 28.5% of the participants (two out of seven) who were trained in the absence of visual feedback from the hand (dark condition) co-articulated by the end of the last training session compared to 75% (six out of eight) who were trained in the light, and none of them has acquired a geometrical motion primitive. Furthermore, six naive participants who trained in dark condition on large size targets have all co-articulated by the end of the last training session, still, none of them has acquired a geometrical motion primitive. Taken together, our results indicate that the acquisition of a geometrical motion primitive is dependent on the existence of visual feedback from the hand and that the implementation of the smoothness-maximization motion strategy is dependent on spatial accuracy demands. These findings imply that the specific features of the training experience (i.e., temporal or spatial task demands) determine the attributes of an acquired motion planning strategy and primitive.

Adolescent↗

PubMed1987

Spatial structure of rabbit liver metallothionein-2 in solution by NMR.

Sequence-specific assignments of the proton spin systems of (Cd7) rabbit liver metallothionein-2 were obtained with homonuclear two-dimensional nuclear magnetic resonance techniques. On the basis of the NMR data the amino acid sequence had to be modified in six positions, and it was found that the protein consists of 62 rather than 61 residues. Through-bond connectivities between the metals and sequentially assigned cysteine residues were obtained with two-dimensional heteronuclear 1H-113Cd correlated spectroscopy. This information, and distance constraints obtained from nuclear Overhauser enhancement spectra were used as input for distance geometry calculations of the spatial polypeptide fold. The polypeptide chain forms two domains which enclose a three-metal cluster and a four-metal cluster, respectively. The metal coordination within the clusters is markedly different from that of (Cd5, Zn2)-MT-2 from rat liver as determined by X-ray crystallography (Furey, et al., 1986) i.e. in the two structures different metal-cysteine combinations prevail for 5 of the 12 connectivities in the three-metal cluster and for 14 of the 16 connectivities in the four-metal cluster.

Amino Acid Sequence↗

PubMed1991

Unusual codon bias occurring within insertion sequences in Escherichia coli.

The large open reading frames of insertion sequences from Escherichia coli were examined for their spatial pattern of codon usage bias and distribution of rarely used codons. There is a bias in codon usage that is generally lower toward the terminal ends of the coding regions, which is reflected in the occurrence of an excess of nonpreferred codons in the 3' portions of the coding regions as compared with the 5' portions. In contrast, typical chromosomal genes have a lower codon usage bias toward the 5' ends of the coding regions. These results imply that the selective forces reflected in codon usage bias may differ according to position within the coding sequence. In addition, these constraints apparently differ in important ways between genes contained in insertion sequences and those in the chromosome.

Chromosomes, Bacterial↗

PubMed2005

Hippocampal scrapie infection impairs operant DRL performance in mice.

In differential reinforcement of low rates of responding (DRL) tasks, animals are trained to respond for rewards that become available only after some set time has elapsed since the animal's previous response. DRL performance is impaired by hippocampal lesions regardless of their precise location, and can be measured using automated operant equipment, whereas spatial tasks are selectively impaired by dorsal, but not ventral hippocampal lesions, and are typically conducted by hand. Earlier studies of prion infection following dorsal hippocampal micro-injections of scrapie have shown clear impairments of spatial alternation, but these occurred significantly later than dysfunction in hippocampus-dependent 'domestic' tasks such as nesting or burrowing. In the present experiment, mice were trained to respond on an automated DRL schedule prior to dorsal hippocampal ME7 scrapie injection. Post-operative DRL performance was monitored, along with performance on 'domestic' and other tests, which provided additional measures of disease progression. Animals with scrapie developed a clear DRL deficit at approximately the same time as their deficits on the other tests became apparent, and long before clinical signs were detectable. DRL deficits thus appeared earlier in the sequence of disease progression than previously reported for spatial alternation, suggesting that early signs of scrapie infection are caused in part by neuronal dysfunction extending beyond the dorsal hippocampal region of initial infection.

Animals↗

PubMed1995

Echo-time reduction for submillimeter resolution imaging with a 3D phase encode time reduced acquisition method.

To achieve optimal image quality and highest spatial resolution for inner ear imaging with a 3D gradient echo sequence, it is necessary to minimize susceptibility dephasing effects by using very short TE. Fractional RF pulses and echoes can yield short TE for moderate spatial resolution; however, for voxel size of less than 1 mm, TE is limited by the phase encode gradients. We present a method to obtain very short effective TE by using short triangular shaped phase encode gradients to sample the central portions of k-space and progressively longer trapezoidal gradients for the outer portions of k-space. A 3D pulse sequence employing the modified phase encoding scheme for both in-plane and slice phase encoding directions was implemented and tested on phantoms and in vivo. The effective TE equals the minimal TE used for the central k-space portions. Submillimeter resolution (0.35 x 0.35 x 0.7 mm3) images of the inner ear were obtained with effective TE of 3.2 ms and were compared with standard 3D images with TE of 8 ms. With this pronounced TE reduction, the susceptibility artifacts at air/fluid interfaces are significantly reduced.

Adult↗

PubMed2000

Spatial and temporal organization of pressure patterns throughout the unprepared colon during spontaneous defecation.

OBJECTIVE: The aim of this study was to examine colonic motor events associated with spontaneous defecation in the entire unprepared human colon under physiological conditions. METHODS: In 13 healthy volunteers a perfused, balloon-tipped, 17-lumen catheter (outer diameter, 3.5 mm; intersidehole spacing, 7.5 cm) was passed pernasally and positioned in the distal unprepared colon. RESULTS: In the hour before spontaneous defecation, there was an increase in propagating sequence frequency (p = 0.04) and nonpropagating activity when compared to basal conditions (p < 0.0001). During this hour the spatial and temporal relationships among propagating sequences demonstrated a biphasic pattern. Both the early (proximal) and late (distal) colonic phases involved the whole colon and were characterized by respective antegrade and retrograde migration of site-of-origin of arrays of propagating sequences. There was a negative correlation between propagating sequence amplitude and the time interval from propagating sequence to stool expulsion (p = 0.008). CONCLUSIONS: The colonic motor correlate of defecation is the colonic propagating sequence, the frequency and amplitude of which begin to increase as early as 1 h before stool expulsion. During the preexpulsive phase, the spatial and temporal relationship among the sites of origin of individual propagating sequences demonstrate a stereotypic anal followed by orad migration, which raises the possibility of control by long colocolonic pathways.

Adult↗

PubMed2025

Ovarian development is driven by early spatiotemporal priming of the coelomic epithelium.

Ovarian organogenesis requires the coordinated specification of supporting and steroidogenic cell lineages from multipotent coelomic epithelium (CE) progenitors. A longstanding question is whether the CE contains transcriptionally distinct, spatially organized progenitor subpopulations with predetermined lineage biases, or whether specification into supporting and steroidogenic lineages occurs only after delamination and integration into the bipotential gonad. The developmental origins of granulosa cells and the emergence of ovarian steroidogenic/stromal progenitors (SPs) also remain poorly defined. Here, we show that CE cells covering the fetal mouse ovary are transcriptionally heterogeneous and spatially organized into subdomains already primed toward supporting or steroidogenic fates. CE priming is dynamic, with transient coexistence of supporting- and steroidogenic-biased CE progenitors before resolving into a predominantly supporting-biased CE. Local delamination of these primed cells seeds intragonadal niches where pre-granulosa cells and SPs mirror the spatio-temporal arrangements of CE-primed progenitors. We further demonstrate a dual origin for the supporting lineage, with granulosa cells deriving from both the CE and supporting-like cells (SLCs). In parallel, we show that SPs arise from steroidogenic-primed CE cells, expand to represent 52% of ovarian somatic cells at birth, persist into adulthood and contribute to both theca and steroidogenic stromal cells. Together, these findings reveal transcriptionally and spatially distinct CE subpopulations that shape somatic lineage emergence with important implications for ovarian pathophysiology.

Ovarian development↗

PubMed2004

Breath-hold water and fat imaging using a dual-echo two-point Dixon technique with an efficient and robust phase-correction algorithm.

A two-point Dixon technique using a novel phase-correction algorithm and commercially available dual-echo fast gradient-echo pulse sequence is presented. The phase-correction algorithm determines the directional rather than phase distribution of signals due to field inhomogeneities. Specifically, a region-growing scheme uses precalculated spatial gradients of the signal phase to guide the growth sequence, so there is no need to manually select the seeds or use an empirical angular threshold. Further, the determination of the signal direction of a given pixel is based on both the amplitude and phase of the surrounding pixels, the direction of which has already been determined. The advantages of this algorithm include its easy implementation, computational efficiency, and robustness in the presence of pixels with large phase uncertainty. The feasibility and usefulness of the technique are demonstrated in vivo with artifact-free water and fat images of an entire abdomen in a single breath-hold.

Abdomen↗

PubMed1988

Rat growth hormone gene expression. Both cell-specific and thyroid hormone response elements are required for thyroid hormone regulation.

The elements involved in mediating cell-specific and thyroid hormone stimulation of rat growth hormone gene expression have been defined by transfection studies and by nuclease footprinting. 5'-Flanking DNA extending to -104 can mediate cell-specific expression, and this is enhanced 3- to 4-fold with DNA extending to -145. Cell-specific factors, found only in rat growth hormone producing cells, bind within the -137/-107 and -95/-65 regions, and competition studies suggest that the same factor binds to both sites. The sequence A (A or T) TAAAT is found at the center of both footprints at -80 and -122, suggesting that it is a core component of the recognition sequence of the cell-specific factor. Disruption of the spatial and/or distance relationships between the two regions eliminates the enhanced level of cell-specific expression, suggesting a cooperative interaction of the proteins which bind to these elements. Sequences located between -208 and -178 can confer thyroid hormone-regulated expression when linked in either orientation in close proximity to one or both cell-specific elements. The thyroid hormone and cell-specific elements function as an enhancer-like unit and are both required to confer regulated expression to heterologous promoters. We propose that thyroid hormone acts via its receptor to enhance the function of the cell-specific element by forming a more "active" transcription complex which stimulates the level of gene expression.

Animals↗

PubMed1994

Analysis of antibody-antigen and antibody-anti-(idiotypic antibody) cross-reactivity using synthetic peptide probes.

The extent, nature and structural basis of immunological cross-reactivity of an anti-synthetic peptide monoclonal antibody (MAb) with the parent antigen (influenza virus haemagglutinin) from which the peptide was derived, and with a paratope-directed anti-idiotypic (anti-Id) antibody was investigated. Use of synthetic homologs and analogs of the peptide indicated that the anti-peptide MAb utilizes a common binding site to complex with peptide, haemagglutinin (HA) and anti-Id antibody, and the affinity constants for the binding of the anti-peptide MAb to peptide and to the anti-Id MAb were found to differ only by three fold. Determination of the amino acid sequence of the heavy chain variable domain (VH) of the anti-Id MAb did not reveal any obvious sequence homology with the peptide. Consideration of the spatial arrangement of residues, however, disclosed a region within the framework of the anti-Id VH with similarity to the epitope recognized by the anti-peptide MAb. This region, formed from antiparallel chains, contains amino acid residues arranged in a conformation similar to that assumed by amino acid residues comprising the epitope within the intact HA.

Amino Acid Sequence↗

PubMed2002

No spatial working memory deficit in beta-amyloid-exposed rats. A longitudinal study.

Two experiments are described assessing whether long-term intraventricular or intrahippocampal administration of beta-amyloid protein 1-40 (beta A1-40) affects spatial working memory in rats monitored in a longitudinal study using the open-field water maze. A delayed matching-to-position procedure (DMTP) was employed in which platform locations were semi-randomly altered between days but were kept constant over the four trials on each day. Intertrial intervals (ITIs) were either 30 s or 1 h between Trials 1 and 2 (all other intervals = 30 s), with Trial 2 performance being an index for spatial working memory. Animals were trained before and tested repeatedly at various intervals after application of various compounds (see below) in five successive test sessions (TSs). In Experiment 1, beta A1-40 was applied after a challenge with long-term oral exposure to aluminium (Al; as 0.1% sulfate in drinking water). This in itself did not affect spatial working memory at any delay, despite of the more than 6 months of intake. beta A1-40 administered alone via intracerebroventricular (icv) minipumps (20 micrograms in 250 microliters) led to a small increase in latencies to find the platform, which recovered to control levels 3 months after minipumps were exhausted. Application of beta A1-40 in Al-exposed animals led to a subtle and progressive decline in working memory. This deterioration was reversed by the nootropic compound nefiracetam, which had no effect on the Al only group. In Experiment 2, well-trained rats were bilaterally implanted with intra-hippocampal minipumps containing beta A1-40 or reverse sequence beta A40-1. This did not impair spatial working memory in the DMTP task, measured either directly after minipumps were exhausted, or 2 weeks later. When intraperitoneally (i.p.) injected with a low concentration of the muscarinic antagonist scopolamine (0.2 mg/kg), a dose that was not effective alone, animals in the beta A1-40 group were amnesic. These data suggest that intra-hippocampal beta A1-40 administration alters cholinergic transmission, but these alterations may be mild and thus do not lead to obvious working memory deficits in a DMTP task in well-trained animals.

Administration, Oral↗