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[The role of iron in immunologic processes].

Iron, apart a for long time well-known function connected with: transportation (hemoglobin), storage (myoglobin), and utilize (cytochromes, cytochrome oxidase) oxygen for respiration, has a critical role in host-pathogen interactions. Iron is essential for microbial growth, but also for immune function. The role of iron in infection, thermoregulation, acute lymphocytic leukemia, neoplasia, rheumatoid arthritis, stimulation of free radical reactions, and studies with iron chelation therapy are discussed.

Arthritis, Rheumatoid↗

[Functional relationships between the horizontal and vertical anterior semicircular canals in the labyrinth of the frog (Rana esculenta L.)].

We have studied the vestibular postrotatory reactions (reactions elicited by the stimulation of the horizontal semicircular canals) in the frog blinded by section of optic nerves, before and after section of the ampullary nerves of the vertical anterior semicircular canals (VAC). 90 frogs have been studied. In 30 frogs the ampullary nerves of the two VAC have been cut; in 60 animals either the ampullary nerve of the right VAC or of the left VAC has been cut. Both after section of the ampullary nerves of the two VAC and after section of the ampullary nerve of one VAC, the postrotatory reactions were decreased in about the half of the animals. The decrease of the postrotatory reactions is not due to a lesion of the ampullary nerves of the horizontal semicircular canals and it may be explained by the existence of functional connections between the VAC and the horizontal canal.

Animals↗

Learning letters in adulthood: direct visualization of cortical plasticity for forming a new link between orthography and phonology.

To identify which brain regions in adults show plasticity for learning letters, Hangul letters were experimentally associated with either speech sounds (HS condition) or nonspeech sounds (HN condition) in fMRI sessions over two consecutive days. Selective activations under the HS condition were found in several regions including the left posterior inferior temporal gyrus (PITG) and the parieto-occipital cortex (PO), as compared with activations under a condition for familiar letters and speech sounds, and with those under the HN condition. The left PITG showed a selective activation increase under the HS condition over two days, the degree of which predicted individual performance improvement. Further, functional connectivity between the left PITG and the left PO was selectively enhanced under the HS condition. These results demonstrate that a new link between orthography and phonology is formed by the plasticity of a functional system involving the left PITG in association with the left PO.

Acoustic Stimulation↗

[Determination of the functional activity, amount of C1 inhibitor, and autoantibodies as a tool for differential diagnosis of angioedema].

Aetiology of angioedema (and therefore the scheme of its treatment) can be different. Angioedema may be subdivided into four categories: hereditary and acquired angioedemas, allergies and vasculitis. To establish the reason of the hereditary and acquired form of angioedema analyses of functional activity of complement components, quantities and activity of C1 inhibitor, presence (or absence) autoantibodies to C1 inhibitor allow. Sorption of the puried enzymes of activated subcomponent C1s or plasmin on micropanels allows to connect specifically in cells of plate C1 inhibitor from serum and with the help conjugate of antibodies against C1 inhibitor with a horse-radish peroxidase to determine quantity of connected functionally active C1 inhibitor. Addition of this test-system ELISA system for determination of quantitative contents of C1 inhibitor in serum, and also systems for definition IgG, IgA and IgM autoantibodies against C1 inhibitor finishes creation of a necessary set of methods of differential diagnostics.

Angioedema↗

The machinery of mitochondrial fusion, division, and distribution, and emerging connections to apoptosis.

Mitochondrial undergo regulated fusion and division in many organisms and cell types, and each event is mediated by a different complex of proteins each containing at least one large GTPase. The mitochondrial fusion and division molecular machinery is in large part conserved; recent studies show a functional connection between some of these proteins and the apoptotic cascade. Mitochondria also undergo directed movement in cells, and the gene products that attach and propel mitochondria along cytoskeletal elements (actin filaments in some organisms, microtubules in others) are becoming gradually elucidated.

Journal Article↗

Drosophila melanogaster dihydroorotate dehydrogenase: the N-terminus is important for biological function in vivo but not for catalytic properties in vitro.

Dihydroorotate dehydrogenase (DHODH, EC 1.3.99.11), the fourth enzyme of pyrimidine de novo synthesis, is an integral flavoprotein of the inner mitchondrial membrane and is functionally connected to the respiratory chain. Here, experiments have been directed toward determining the roles of the N-terminal sequence motifs both in enzymatic properties of insect DHODH produced in vitro and the in vivo function of the protein. Full-length and three N-terminal truncated derivatives of the Drosophila melanogaster enzyme were expressed in Escherichia coli and purified. For identification on Western blots of recombinant DHODH as well as the native enzyme from flies polyclonal anti-DHODH immunoglobulins were generated and affinity-purified. The enzymatic characteristics of the four versions of DHODH were very similar, indicating that the N-terminus of the enzyme does not influence its catalytic function or its susceptibility to prominent DHODH inhibitors: A77-1726, brequinar, dichloroallyl-lawsone and redoxal. Whereas the efficacy of A77-1726 and dichloroallyl-lawsone were similar with Drosophila and human DHODH, that of brequinar and redoxal differed significantly. The differences in responses of insect DHODH and the enzyme from other species may allow the design of new agents that will selectively control insect growth, due to pyrimidine nucleotide limitation. In vivo expression of the full-length and N-truncated DHODHs from engineered transgenes revealed that the truncated proteins could not support normal de novo pyrimidine biosynthesis during development of the fly (i.e., failure to complement dhod-null mutations), apparently due to instability of the truncated proteins. It is concluded that the proper intracellular localization, directed by the N-terminal targeting and transmembrane motifs, is required for stability and subsequent proper biological function in vivo.

Amino Acid Sequence↗

Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation.

Modulation of cortico-cortical connectivity in specific neural circuits might underlie some of the behavioural effects observed following repetitive transcranial magnetic stimulation (rTMS) of the human frontal cortex. This possibility was tested by applying rTMS to the left mid-dorsolateral frontal cortex (MDL-FC) and subsequently measuring functional connectivity of this region with positron emission tomography (PET) and TMS. The results showed a strong rTMS-related modulation of brain activity in the fronto-cingulate circuit. These results were confirmed in a parallel experiment in the rat using electrical stimulation and field-potential recordings. Future studies are needed to provide a direct link between the rTMS-induced modulation of cortical connectivity and its effects on specific behaviours.

Adolescent↗

Visual cortical inputs to deep layers of cat's superior colliculus.

In the superior colliculi of cats anesthetized with ketamine, 84% of identified output cells of the deep layers could be driven by shocks to the contralateral optic disk, optic chiasm, or ipsilateral optic tract; 75% of these deep-layer cells had response latencies reflecting a polysynaptic influence of retinal Y-cells. Following large, acute lesions of the ipsilateral occipital cortex (including visual areas 17, 18, 19, and the posteromedial lateral suprasylvian area (PMLS), only 18% of deep-layer output cells were driven by electrical stimulation of the optic pathway and only 4% exhibited an indirect Y-cell influence. Thus, one or more of these visual areas may be important for the relay of retinal information, and particularly of Y-cell information, to the deep layers of the superior colliculus. This hypothesis is supported by the observation that intracortical stimulation in areas 17, 18, 19, and PMLS activated many cells of the ipsilateral, deep tectal layers at latencies consistent with those exhibited by the indirect Y-cell pathway. The distributions of activation latencies were similar to those observed in the superficial layers, raising the possibility that at least some of the cortical influence on the deep layers may be mediated by direct connections. Cells of the deep layers were more likely to be excited by a cortical stimulus that activated cells immediately above them in the superficial layers than by a stimulus that did not. This indicates that the functional connections between visual cortex and the deep collicular layers exhibit a topographic orderliness similar to that previously described for corticotectal projections to the superficial layers. These results provide further evidence that the visual cortex exerts a significant influence on cells of the deep collicular strata and that the pathways involved are capable of mediating the indirect, retinal Y-cell input to these neurons.

Animals↗

Metabolic control of neuronal pacemaker activity and the rhythmic organization of central nervous functions.

The endogenous rhythmic activity of isolated pacemaker neurones of Aplysia californica appears to be controlled by the operation of a substrate cycle. The recycling of fructose-6-phosphate is mediated by two membrane-bound enzymes: phosphofructokinase (PFK) and fructose-1,6-diphosphatase (FDPase). Allosteric effectors which promote the PFK-FDPase system either increase the regular beating activity or induce bursting discharges, while inhibitory effectors reduce pacemaker activity. Associated with the PFK-FDPase cycle are slow oscillations in membrane potential, the postulate being that changes in amplitude and time period of the waves are brought about by the cyclic fluctuations of H+ ions and ATP in the immediate vicinity of the membrane. Other enzyme reactions which affect the concentrations of gluconeogenic substrates or PFK effectors can modulate the oscillatory driving input, a good example being the neurogenic amino acid glutamate. Modifiers of FDPase and PFK are equally effective in changing pacemaker activity within the intact neuronal network and, hence, the rhythmic body function connected to this network. This has been demonstrated with pacemaker neurones governing cardiovascular activity in Apylsia, blood pressure or heart beat in the cat, and respiration or thermoregulation in the rabbit. Nature appears to have achieved a functional differentiation between different pacemaker neurones by altering their response to at least one or two of the PFK and FDPase effectors. New periodicities can be entrained by current stimuli on the pre-existing rhythms of isolated Aplysia pacemaker neurones. Stimulus-induced resetting of the discharges is in fact accompanied by a redistribution between two kinetically distinct forms of PRK, and modifiers of this enzyme can stabilize the new periodicities or facilitate the conditioning effect of a stimulus. Memory facilitation and consolidation under PFK modifiers could also be demonstrated in avoidance and discrimination learning trials with honey bees and rats, which are consistent with the metabolic nature of the slow-wave rhythmicity in vertebrate microneurones thought to be the site of memory storage.

Adenosine Triphosphate↗

Inference of disease-related molecular logic from systems-based microarray analysis.

Computational analysis of gene expression data from microarrays has been useful for medical diagnosis and prognosis. The ability to analyze such data at the level of biological modules, rather than individual genes, has been recognized as important for improving our understanding of disease-related pathways. It has proved difficult, however, to infer pathways from microarray data by deriving modules of multiple synergistically interrelated genes, rather than individual genes. Here we propose a systems-based approach called Entropy Minimization and Boolean Parsimony (EMBP) that identifies, directly from gene expression data, modules of genes that are jointly associated with disease. Furthermore, the technique provides insight into the underlying biomolecular logic by inferring a logic function connecting the joint expression levels in a gene module with the outcome of disease. Coupled with biological knowledge, this information can be useful for identifying disease-related pathways, suggesting potential therapeutic approaches for interfering with the functions of such pathways. We present an example providing such gene modules associated with prostate cancer from publicly available gene expression data, and we successfully validate the results on additional independently derived data. Our results indicate a link between prostate cancer and cellular damage from oxidative stress combined with inhibition of apoptotic mechanisms normally triggered by such damage.

Algorithms↗

Activity of medullary respiratory neurons regenerating axons into peripheral nerve grafts in the adult rat.

Autologous segments of peroneal nerve were implanted into the medulla oblongata of young adult rats. To investigate activity of medullary respiratory neurons regenerating axons into these grafts, unitary recording from single fibers was performed on small strands teased from the grafts. Spontaneous activity was observed in teased fibers in 7 of 9 grafts recorded 2-5 months after graft implantation. Respiratory-related activity was found in 5 of these grafts and could in most cases be characterized as emanating from medullary respiratory neurons other than cranial motoneurons. The integrity of the input connections to the neurons that had regenerated axons was manifested by normal patterns of unitary respiratory-related activity and by the responsiveness of firing patterns of these neurons to lung hyperinflation and to the inspiratory off-switch effect induced by vagal stimulation. No spontaneous respiratory activity was found in fibers teased from any of the 10 grafts studied 9-11 months after implantation. Five of these grafts were blind-ended as were the 2-5-month grafts; the other 5 grafts formed bridges between the medulla and C4 ventral horn. No physiologic evidence of functional connections with phrenic motoneurons was found in these bridge grafts. These experiments indicate that physiologic function is maintained or regained in some respiratory neurons regenerating axons into peripheral nerve grafts but that this function is not indefinitely preserved in the absence of functional reconnection with an appropriate target.

Action Potentials↗

Molecular and cellular properties of mammalian primary olfactory axons.

How are the axonal projections of olfactory and vomeronasal receptor neurons to the olfactory bulb formed during development? How are the primary olfactory axonal connections functionally organized? With progress in molecular biological techniques and histochemical methods, it became possible to study cellular strategies and molecular mechanisms which guide the primary olfactory axons of the main and accessory olfactory systems to the target glomeruli in the bulb. In addition, new methodologies have begun to elucidate various subsets of the primary olfactory axons with distinctive central connections. The aim of the present paper is to review (1) the characteristic organization of the projection of the primary olfactory axons, (2) projection patterns of histochemically defined subsets of primary olfactory axons, and (3) information on molecules expressed by the surface membrane of the primary olfactory axons. This knowledge gives insight into the functional organization of the primary olfactory axon projection, which is indispensable for understanding signal processing in the olfactory system. This knowledge also underscores the notion that the primary olfactory axon projection provides an excellent model system in which to study axonal guidance and the formation of specific synaptic connections.

Animals↗

A positron emission tomographic study of auditory localization in the congenitally blind.

We have used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in sighted and congenitally blind subjects performing auditory localization tasks. During scanning, the spectral and binaural cues of localized sound were reproduced by a sound system and delivered via headphones. During tasks that required auditory localization both the sighted and blind subjects strongly activated posterior parietal areas. In addition, the blind subjects activated association areas in the right occipital cortex, the foci of which were similar to areas previously identified in visual location and motion detection experiments in sighted subjects. The blind subjects, therefore, demonstrated visual to auditory cross-modal plasticity with auditory localization activating occipital association areas originally intended for dorsal-stream visual processing. To determine the functional connectivity of pre-selected brain regions in primary and non-primary auditory and posterior parietal cortex in the two cohorts, we performed an inter-regional correlation analysis on the rCBF data set. During auditory localization in the blind subjects, rCBF activity in the right posterior parietal cortex was positively correlated with that in the right occipital region, whereas in sighted subjects correlations were generally negative. There were no significant positive occipital correlations in either cohort when reference regions in temporal or left parietal cortex were chosen. This indicates that in congenitally blind subjects the right occipital cortex participates in a functional network for auditory localization and that occipital activity is more likely to arise from connections with posterior parietal cortex.

Adult↗

Molecular cloning and expression of the chromatin insulator protein CTCF in Xenopus laevis.

The zinc finger protein CTCF has been shown to mediate multiple functions connected to gene repression. Transcriptional inhibition as well as enhancer blocking and chromatin insulation are documented for CTCF in men, mice and chickens. Additionally, hCTCF has been linked to epigenetics and disease. In line with these basic cellular functions, CTCF has been found to be expressed in every cell type and adult tissue tested and has thus been deemed an ubiquitous protein. Here, we report the identification of the CTCF homologue from Xenopus and the analysis of the spatio-temporal expression of xCTCF during embryogenesis. Within the DNA binding domain, xCTCF is virtually identical to other identified vertebrate CTCF proteins. Homology also extends to other conserved regions that are important for CTCF function. Although xCTCF mRNA is present during all stages of early Xenopus development, a remarkable increase in expression is observed in neuronal tissues. Early in development, xCTCF is highly expressed in the neural plate and later in the neural tube and developing brain. By tailbud stage, elevated expression is also seen in the developing sensory organs of the head. This is the first detailed description of the expression pattern of a vertebrate insulator protein during embryogenesis.

Amino Acid Sequence↗

Dual intracellular recording of neocortical neurons in a neuron-glia co-culture system.

Measurement of synchronized activities in neocortical networks is critical for understanding integrated brain function. We describe here a procedure for intracellular recording of activity in two functionally connected neurons using patch electrodes in neuron-glia co-cultures. Rat neocortical neurons survive on monolayers of astrocytes for far longer periods (3-4 weeks) than in their absence. This prolonged survival facilitates the detection of functional synapses which are readily identified in vitro by means of dual intracellular recording using two patch electrodes. The neuron-glia co-culture system appears to be useful not only for studying the formation of neural networks in vitro but also for determining the effects of physiologically active substances and chemicals on synapse formation.

Animals↗

[Interaction of psychoemotional state and activity of the immune system].

As shown, there are direct and reverse functional connections between nervous and immune systems. Different shifts in psychoemotional reactivity induced by chronic stress or mental depression are accompanied with immunological disturbance, and on the contrary, disorders of immune state may be source of changes in mental functions. The pineal hormone melatonin, anxiolytic and antidepressant drugs simultaneously influences on the cerebral structures and immune system. These effects may be important part of specific psychopharmacological activity of the drugs.

Animals↗

Is the cerebellum relevant in the circuitry of neuropsychiatric disorders?

Contemporary mechanistic models of several psychiatric disorders propose abnormalities in the structure and function of distinct neural networks. The cerebellum has both anatomic and functional connections to the prefrontal cortex, the subcortical limbic structures and monoamine-producing brainstem nuclei. Conspicuously, however, the cerebellum has been underemphasized in neuropsychiatric research. A growing confluence of scientific data indicate that the cerebellum may not be irrelevant, which suggests that an integrated model of neuropsychiatric disorders should include a role for the cerebellum and its relevant neural connections. This review summarizes the published data describing and characterizing the putative role of the cerebellum in normal and abnormal mood regulation, with specific attention to states of psychosis, depression and mania. The available evidence suggests that a functional role for the cerebellum should be considered in future neuropsychiatric studies.

Bipolar Disorder↗

[What is the cerebral amygdaloid complex?].

The amygdaloid complex (AC) is considered to be one the basal nuclei of the telencephalon. However, a combination of two principals of the grey substance organizations--nuclear and shielded--in its territory, distinguished AC from the group of the subcortical nuclei defines its specific position among other structures of the telencephalon. A peculiar structure of AC is a consequence of certain evolutionary rearrangements of the brain in the process of histological development of organisms; principally important among them is appearance of the ancient cortex formations (++semi-separated) from elements of the ganglionic tubercle. The latter explains existence of tight anatomical and functional connections between typical nuclei and the ancient cortex structures. The new notion of the AC substrate as a specific nucleolar-paleocortical integrative center of the telencephalon gives a clue for understanding a number of specific, still remaining enigmatic functional phenomena in this formation. They evidently reflect a close interaction of its nuclei and paleocortical structures, that makes the base of its activity.

Amygdala↗