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PubMed2000

Functional neuroimaging studies of reading and reading disability (developmental dyslexia).

Converging evidence from a number of neuroimaging studies, including our own, suggest that fluent word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system is functionally disrupted in developmental dyslexia. Reading disabled readers, relative to nonimpaired readers, demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers the dorsal circuit predominates at first, and is associated with analytic processing necessary for learning to integrate orthographic features with phonological and lexical-semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word identification system which underlies fluent word recognition in skilled readers.

Cerebral Cortex↗

PubMedDate not supplied

Neurobiological studies of reading and reading disability.

UNLABELLED: Evidence from neuroimaging studies, including our own, suggest that skilled word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system appears to be functionally disrupted in developmental dyslexia. Relative to nonimpaired readers, reading-disabled individuals demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers, the dorsal circuit predominates at first, and in conjunction with premotor systems, is associated with analytic processing necessary for learning to integrate orthographic with phonological and lexical semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word form system, which underlies fluency in word recognition. LEARNING OUTCOMES: As a result of this activity, (1) the participant will learn about a model of lexical processing involving specific cortical regions. (2) The participant will learn about evidence which supports the theory that two dorsal LH systems may be disrupted in developmental dyslexia. (3) The participant will learn that individuals with reading impairment may rely on other regions of the brain to compensate for the disruption of posterior function.

Brain↗

PubMed2001

Mutagenic and chemical modification of the ABA-1 allergen of the nematode Ascaris: consequences for structure and lipid binding properties.

The polyprotein allergens/antigens of nematodes (NPAs) are the only lipid binding proteins known to be produced as polyproteins. Cleavage of the large polyprotein precursors at regularly spaced proteinase cleavage sites produces 10 or 11 individual protein units of approximately 15 kDa. The sequences of these units are highly diverse within and between species, but there are five absolutely or strongly conserved amino acid positions (Trp15, Gln20, Leu42, Cys64, and Cys120). We have tested the role of these signature amino acids by mutational or chemical alteration of the ABA-1 protein of Ascaris, and examined the resulting modified proteins for perturbations of their lipid binding activities and structural integrity. Substitution of Trp15 and Gln20 both affect the stability of the protein in terms of resistance to thermal or chemical denaturation, but the ligand binding function is unaffected. Mutation of Leu42, however, disrupts both the protein's structural stability and functional integrity, as does chemical disruption of the disulfide bridge formed between Cys64 and Cys120. We also find that the C-terminal, but not the N-terminal, half of the protein binds fatty acids, indicating that the binding site may be confined to this part of the protein. This also supports the idea that the NPA units are themselves derived from an ancient duplication event, and that they may comprise two functionally distinct domains.

Allergens↗

PubMed2004

A pneumatic vibrotactile stimulation device for fMRI.

Mapping the functional response of the somatosensory cortex is useful both for characterizing normal brain activity and for determining the functional integrity of damaged cortex compromised by stroke or other neurological insults. A variety of stimulators have been used to produce somatosensory cortex activation in functional brain imaging, including brushes and swabs operated manually, pneumatically and mechanically powered mechanical vibrators, air puffs, and vibrating ceramic piezoelectric wafers and benders. A closed-system, pneumatically driven rubber diaphragm is reported that overcomes many of the limitations of existing vibrotactile devices and produces robust sensory cortex activation in an fMRI experiment.

Air↗

PubMed2000

Loss of large-diameter spindle afferent fibres is not detrimental to the control of body sway during upright stance: evidence from neuropathy.

Fifteen patients with Charcot-Marie-Tooth type 1A (CMT1A) disease and 46 normal controls were studied. In the patients, leg muscle strength, touch-pressure, vibration and joint position sense were reduced; lower limb tendon reflexes were absent in 12 or markedly decreased. Motor and sensory conduction velocity (CV) of leg nerves was either reduced or not measurable. The Neurological Disability Score and the Neuropathy Score were obtained from clinical and electrophysiological examination, respectively. Tilt of a supporting platform elicited short- (SLR) and medium-latency (MLR) responses to stretch in the foot muscle flexor digitorum brevis (FDB) in controls. In the patients, the former response was absent and the latter delayed. These findings are in keeping with the known loss of large-diameter myelinated fibres, with relative sparing of the smaller fibres. The MLR delay was fully accounted for by the slowed CV of the motor fibres. The MLR afferent time was similar to that in normal subjects. Body sway area (SA) during quiet stance was recorded with eyes open or closed, and with feet apart or together. Under all postural and visual conditions, SA was within normal range in the less severely affected patients, but was moderately increased in the patients with a more severe neuropathy score. Across all patients, no correlation was found between SA and muscle force, motor CV, touch pressure, vibration and joint position sense, considered either separately or as an aggregate. We suggest that: (1) functional integrity of the largest afferent fibres is not necessary for appropriate equilibrium control during quiet stance and (2) any unsteadiness is related to additional functional alterations in smaller fibres, most likely group II spindle afferent fibres.

Adolescent↗

PubMed2026

Norgestrel drives mitochondrial collapse and plasma membrane impairment in Pacific oyster (Crassostrea gigas) sperm by triggering premature acrosome reaction.

The toxic mechanisms of norgestrel (NGT), an emerging marine pollutant, on the sperm from externally fertilized invertebrates remain elusive. This study employed an integrated physiological and multi-omics framework to elucidate how NGT (10 and 1000 ng/L) disrupts acrosome reaction (AR) signaling machinery, thereby impairing the functional integrity of Pacific oyster (Crassostrea gigas, also known as Magallana gigas) sperm. Exposure to NGT triggered a significant, dose-dependent premature AR, characterized by elevated acrosin activity and a loss of acrosomal integrity. Multi-omics integration supports a model in which this premature exocytosis is linked to signaling disturbances, including disruption of calcium signaling and reduced transcript abundance of calmodulin (CaM) and the primary recognition protein zonadhesin (Zan). This signaling interference induced an premature AR, subsequently driving a cascade of bioenergetic and structural failures. At the mitochondrial level, NGT induced abnormal mitochondrial permeability transition pore (mPTP) opening and elevated the transcript levels of antioxidant defense genes (e.g., peroxiredoxin-5, PRDX5). These alterations indicate the occurrence of mitochondrial collapse. Concurrently, scanning electron microscopy verified localized plasma membrane wrinkling and pore formation in sperm. In addition, NGT exposure decreased the transcript abundance of cytoskeleton-related genes, including solute carrier family 26 member 6 (SLC26A6), actin (ACT), and tubulin polymerization promoting protein family member 3 (TPPP3). These molecular changes further disrupted membrane phospholipid homeostasis, as represented by altered glycerophospholipid metabolism. At the same time, cumulative cellular stress was associated with decreased transcript abundance of cytoprotective factors (e.g., baculoviral IAP repeat-containing proteins, birc2) and changes in apoptosis-related genes consistent with activation of a caspase-8-mediated apoptotic programme. In conclusion, NGT, as a representative synthetic progestin, exerts reproductive toxicity by interfering with signaling mediators to induce premature AR, which subsequently exhausts metabolic energy and triggers plasma membrane impairment. These findings provide a critical mechanistic basis for the aquatic ecological risk assessment of synthetic progestins.

Animals↗

PubMed2004

DNA fragmentation, mitochondrial dysfunction and chromosomal aneuploidy in the spermatozoa of oligoasthenoteratozoospermic males.

PURPOSE: This study determined the incidence of sperm nuclear DNA fragmentation, mitochondrial dysfunction, and chromosomal aneuploidy. The results were correlated with the semen analysis parameters and fertilization rates. METHODS: Semen samples from 10 men showing oligoasthenoteratozoospermia (OAT) and undergoing ICSI treatment were analyzed. Another semen samples from 10 men showing normozoospermia and undergoing IVF treatment were analyzed for comparison. The samples were prepared using a two-step discontinuous Percoll gradient (80%-50%) and analyzed using a Hamilton-Thorne Integrated Visual Optical System (IVOS) Sperm Analyzer. DNA fragmentation was detected with a terminal deoxynucleotidyl transferase-mediated dUTP nick end label (TUNEL) assay. Functional integrity of mitochondria was detected using an Apoalert Mitochondrial Membrane Sensor Kit. Chromosomal aneuploidy was assayed by fluorescence in situ hybridization. RESULTS: Higher sperm DNA fragmentation rate (18.8% vs. 2.8%), mitochondrial dysfunction rate (24.9% vs. 5.7%), and chromosomal aneuploidy rate (0.12% vs. 0.06%) were found in the oligoasthenoteratozoospermic patients in comparison with the normozoospermic patients. CONCLUSIONS: The result indicates that spermatozoa from oligoasthenoteratozoospermic patients contain greater DNA fragmentation, mitochondrial dysfunction, and chromosomal aneuploidy. Because extremely poor semen samples are the indication for ICSI treatment, the result indicates the importance of selecting good quality sperm for oocyte injection.

Adult↗

PubMed2001

Disruption of T cell signaling networks and development by Grb2 haploid insufficiency.

The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2+/- mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal-regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Left ventricular remodeling and functional mitral regurgitation: mechanisms and therapy.

Myocardial damage that results in dysfunction and remodeling changes left ventricular shape and size. Mitral competence requires the functional integrity of all components of the mitral apparatus. Progressive remodeling ultimately leads to geometric distortion of multiple elements of the mitral apparatus, resulting in functional mitral regurgitation (MR). In this article, we examine the mechanisms of functional MR in the remodeled ventricle. Surgical treatment should aim to correct all abnormalities of the mitral apparatus. These include (1) revascularization of viable myocardium, (2) reduction of ventricular volume and restoration of shape, (3) realignment of papillary muscles, and (4) reduction of annular orifice size.

Humans↗

PubMed2002

[Language activation in ischemic stroke and brain tumor: a PET study].

Disturbance of neurologic function in disorders of the central nervous system is expressed as altered activation pattern in functional networks after specific tasks, and can be studied by functional imaging modalities, e.g. positron emission tomography (PET). Language, a complex brain function is based on the interplay of a distributed network in which partial functions are executed in various centers and tasks are hierarchically organized according to their complexity. The specialization of different centers and the lateralization of integrative functions into the dominant (usually left) hemisphere is achieved by collateral and transcallosal inhibition of structures of lower order in the network. Patients with ischemic stroke often suffer from aphasia; the features and the prognosis of this disturbance is determined by the localization and the extent of the infarct in the dominant hemisphere. The preservation of the left superior temporal gyrus or its functional reintegration, respectively, is of utmost importance for the recovery of the deficits and for a satisfactory outcome. Reactivation of this region in repeated PET-activation studies were related to a favorable outcome, activation of other eloquent regions or of contralateral areas were accompanied by some improvements, but never indicated recovery of sufficient speech production. Symptoms develop slowly in patients with tumors in the left hemisphere, and the functional network can adapt to the lesion. In these patients a dislocation of areas activated during language tasks was observed, either to ipsilateral regions usually not involved or to contralateral homotopic areas. Aphasia was frequent in cases with activation shift to the subdominant hemisphere, and the right over left asymmetry in activation of the cerebellum was correlated to the severity of language impairment. The shift of dominance in activation could be reversed after surgical resection of the tumor leading to improved speech performance. The patterns of intrahemispheric as well as interhemispheric compensation may be explained by reduction of collateral inhibition of specific centers on other structures within the network (disinhibition): circumscript and/or slowly developing lesions disinhibit surrounding areas leading to increases and to displacements of activated centers; large morphological defects reduce the transcallosal inhibition leading to the activation of contralateral regions.

Adult↗

PubMed2006

FuGE: Functional Genomics Experiment Object Model.

This is an interim report on the Functional Genomics Experiment (FuGE) Object Model. FuGE is a framework for creating data standards for high-throughput biological experiments, developed by a consortium of researchers from academia and industry. FuGE supports rich annotation of samples, protocols, instruments, and software, as well as providing extension points for technology specific details. It has been adopted by microarray and proteomics standards bodies as a basis for forthcoming standards. It is hoped that standards developers for other omics techniques will join this collaborative effort; widespread adoption will allow uniform annotation of common parts of functional genomics workflows, reduce standard development and learning times through the sharing of consistent practice, and ease the construction of software for accessing and integrating functional genomics data.

Computer Simulation↗

PubMed2003

14C-methylamine-glutaraldehyde conjugation as an alternative to iodination for protein labeling.

Radiolabeling of native proteins conventionally has required iodination using 125Iodine (125I). Although radioiodination can result in high specific activity, there are several drawbacks in the use of 125I (e.g., radiological hazards and short half-life). 14C-Methylamine-glutaraldehyde conjugation to proteins offers an alternative for radiolabeling of proteins that is safer and longer-lived alpha-2-Macroglobulin was radiolabeled by conjugation to a 14C-methylamine-glutaraldehyde conjugate. Analysis of the labeling procedure was performed using scintillation counting, gel filtration chromatography, and protein assays. The radiolabeled alpha-2-macroglobulin was activated using established protocols and tested for functional integrity using competitive binding assays in the presence of recombinant receptor associated protein, an alternative ligand for the alpha-2-macroglobulin cellular receptor. The function of alpha-2-macroglobulin was unaffected by the labeling procedure. Comparison of 14C-methylamine-labeling and iodination by Scatchard analysis yielded nonlinear plots that suggested the presence of two sets of receptors with different binding affinities but that do not show cooperativity. This technique offers an alternative to radioiodination for the sensitive labeling of proteins.

Binding, Competitive↗

PubMedDate not supplied

[Topical issues of the primary medical and sanitary care].

Issues related with transforming the functioning of the country's health care on the basis of the model of general practitioner (GP) are discussed in the article. It is concluded that there is need in a full-scale preparatory activity comprising both the optimization of the internal structural-and-functional relations and the ensuring of the health care readiness as whole, i.e. evolving the activity of its elements in the direction of an integrally functioning system.

First Aid↗

PubMed1987

Nutrition of the fetus and newborn.

Both the successful development of healthy, long-term animal models to study fetal nutrition and metabolism and the improved survival of low-birth-weight, preterm infants have focused interest and research on fetal and neonatal nutrition and metabolism. Such a focus is important, given the recent emphasis on promoting neonatal growth in preterm infants at "normal" in utero growth rates. Estimates of nutrient requirements for growth in a human fetus remain ill defined, however. Body composition data appear biased toward thin infants. Animal data suggest that fetal nutrition proceeds according to species-specific growth rates, with variations in fat content largely dependent on placental fat permeability and on maternal nutrient supply as regulated by the placenta. After birth, neonatal nutrition is affected primarily by food intake and the functional integrity and capacity of the gastrointestinal tract. Additionally, muscle activity, thermoregulation and stresses of various kinds and degrees modify a neonate's nutritional requirements. Functional deficits of the gastrointestinal tract have been circumvented by a more aggressive use of intravenous nutrition. Both intravenous and enteral nutrient mixtures have been substantially improved in the quantity of all nutrients and have been modified qualitatively toward compositions that are closer to those of human milk. These nutrient mixtures now produce plasma nutrient concentrations that approximate those of a healthy, breast-fed infant. Although such efforts to improve the nutritional balance and growth of preterm infants have been successful, much remains to be learned about the nutritional requirements of sick infants.

Animals↗

PubMed2006

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug-membrane interactions and the effect of agitation on the barrier integrity and on the permeability.

Recently, we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability. Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC). Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation >or=150rpm. When using agitation up to 100rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100microm thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles. Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Positron emission tomography in Shy-Drager syndrome.

We studied the nigrostriatal dopaminergic pathway in 3 patients with Shy-Drager syndrome, by using positron emission tomography and [18F]6-fluoro-1-dopa to determine whether their parkinsonism correlated with impaired functional integrity of the presynaptic nigrostriatal pathway. One patient had short duration of disease, mild parkinsonism, and a normal positron emission tomographic scan, suggesting pathological changes functionally distal to the nigrostriatal pathway. Two patients with longer duration of disease had more severe parkinsonism and reduced [18F]6-fluoro-1-dopa uptake, suggesting impaired nigrostriatal dopaminergic function with progression of Shy-Drager syndrome.

Aged↗

PubMed2005

Acyl transfer in clorobiocin biosynthesis: involvement of several proteins in the transfer of the pyrrole-2-carboxyl moiety to the deoxysugar.

Clorobiocin is an aminocoumarin antibiotic containing a pyrrole-2-carboxyl moiety, attached through an ester bond to a deoxysugar. The pyrrole moiety is important for the binding of the antibiotic to its biological target, gyrase. The complete biosynthetic gene cluster for clorobiocin has been cloned and sequenced from the natural producer, Streptomyces roseochromogenes DS 12.976. In this study, the genes cloN1 and cloN7 were deleted separately from a cosmid containing the complete clorobiocin cluster. The modified cosmids were introduced into the genome of the heterologous host Streptomyces coelicolor M512 by using the integration functions of the PhiC31 phage. While a heterologous producer strain harbouring the intact clorobiocin biosynthetic gene cluster accumulated clorobiocin, the cloN1- and cloN7-defective integration mutants accumulated a clorobiocin derivative that lacked the pyrrole-2-carboxyl moiety, while also producing free pyrrole-2-carboxylic acid. The structures of these metabolites were confirmed by NMR and MS analysis. These results showed that CloN1 and CloN7, together with the previously investigated CloN2, are involved in the transfer of the pyrrole-2-carboxyl moiety to the deoxysugar of clorobiocin. A possible mechanism for the role of these three proteins in the acyl-transfer process is suggested.

Acylation↗

PubMed2005

Functional disconnectivity of the medial temporal lobe in Asperger's syndrome.

BACKGROUND: Autistic spectrum disorders (ASD) are neurodevelopmental conditions that may be caused by abnormal connectivity between brain regions constituting neurocognitive networks for specific aspects of social cognition. METHODS: We used three-way multidimensional scaling of regionally parcellated functional magnetic resonance imaging (fMRI) data to explore the hypothesis of abnormal functional connectivity in people with ASD. Thirteen high-functioning individuals with Asperger's syndrome and 13 healthy volunteers were scanned during incidental processing of fearful facial expressions. RESULTS: Using permutation tests for inference, we found evidence for significant abnormality of functional integration of amygdala and parahippocampal gyrus (p < .05, false discovery rate [FDR] corrected) in people with Asperger's syndrome. There were less salient abnormalities in functional connectivity of anterior cingulate, inferior occipital, and inferior frontal cortex, but there was no significant difference between groups in whole brain functional connectivity. CONCLUSIONS: We conclude there is evidence that functional connectivity of medial temporal lobe structures specifically is abnormal in people with Asperger's syndrome during fearful face processing.

Adult↗