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Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections.

Cross-correlation of low-frequency temporal fluctuations (<0.08 Hz) was used to correlate widely separated anatomic regions during continuous performance of a spatial working memory task. The regions of highest correlation to right-hemisphere dorsolateral prefrontal cortex correspond to the regions of largest baseline signal change in a conventional block-style functional MRI paradigm. Additionally, it is shown that the correlations between elements of the functional network increase during performance of a task that activates the network when compared to a task that does not directly stimulate the functionally connected network.

Attention↗

Construction of multi-layered cardiomyocyte sheets using magnetite nanoparticles and magnetic force.

Heart tissue engineering requires construction of three-dimensional (3-D) tissues composed of cardiomyocytes (CMs) that are tightly connected to each other. The aim of this study was to construct "scaffold-less" multi-layered 3-D CM sheets using magnetic force-based tissue engineering (Mag-TE) and to evaluate the cell-to-cell functional connections within the CM sheets. Original magnetite cationic liposomes (MCLs) with a positive surface charge (which facilitate adsorption to the target cell surface) were taken up by CMs that were isolated from 2-day-old Wistar rats. When MCLs were added to the medium of CMs at magnetite concentrations of 25, 50, and 100 pg per cell, subsequent measurements showed that 7.2, 13.2, and 27.3 pg of magnetite were taken up per cell, respectively, after 4 h incubation at 37 degrees C. Further, no toxicity was observed after a 24 h incubation period. Using magnetically labeled CMs (magnetite concentration, 100 pg/cell), multi-layered CM sheets were constructed. Immunofluorescent staining of connexin43 demonstrated the presence of gap junctions within the CM sheets that were constructed by Mag-TE. Moreover, electrical connections within the CM sheets constructed by Mag-TE were confirmed using extracellular potential mapping. These results indicate that Mag-TE is a viable methodology for heart tissue engineering.

Animals↗

Effects of iontophoretic administration of acetylcholine to rabbit motor cortex neurons on the functioning of intracortical connections.

Experiments were performed on eight rabbits to study the effects of acetylcholine on interneuronal intracortical interactions. Multineuronal activity was recorded in the motor cortex during local iontophoretic administration of acetylcholine and physiological saline. Interneuronal connections were identified by cross-correlation analysis. A role for acetylcholine in intracortical connection reorganization processes is proposed. These studies demonstrated that acetylcholine has an activating effect on intracortical connections; application of acetylcholine leads to increases in the intensity of short-latency, constantly functioning (stable) connections. Acetylcholine application also resulted in the formation of unstable, long-latency connections. Additionally, the data suggest that iontophoretic application of acetylcholine does not lead to the formation of new short-latency interneuronal connections. The modulatory effects of acetylcholine on the network activity of cortical neurons are discussed.

Acetylcholine↗

Lineage-specific loss and divergence of functionally linked genes in eukaryotes.

By comparing 4,344 protein sequences from fission yeast Schizosaccharomyces pombe with all available eukaryotic sequences, we identified those genes that are conserved in S. pombe and nonfungal eukaryotes but are missing or highly diverged in the baker's yeast Saccharomyces cerevisiae. Since the radiation from the common ancestor with S. pombe, S. cerevisiae appears to have lost about 300 genes, and about 300 more genes have diverged by far beyond expectation. The most notable feature of the set of genes lost in S. cerevisiae is the coelimination of functionally connected groups of proteins, such as the signalosome and the spliceosome components. We predict similar coelimination of the components of the posttranscriptional gene-silencing system that includes the recently identified RNA-dependent RNA polymerase. Because one of the functions of posttranscriptional silencing appears to be "taming" of retrotransposons, the loss of this system in yeast could have triggered massive retrotransposition, resulting in elimination of introns and subsequent loss of spliceosome components that become dispensable. As the genome database grows, systematic analysis of coordinated gene loss may become a general approach for predicting new components of functional systems or even defining previously unknown functional complexes.

Biological Evolution↗

Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3.

Two types of photoreceptors, rods and cones, coexist in the vertebrate retina. An in-depth analysis of the retinal circuitry that transmits rod and cone signals has been hampered by the presence of intimate physical and functional connections between rod and cone pathways. By deleting the cyclic nucleotide-gated channel CNG3 we have generated a mouse lacking any cone-mediated photoresponse. In contrast, the rod pathway is completely intact in CNG3-deficient mice. The functional loss of cone function correlates with a progressive degeneration of cone photoreceptors but not of other retinal cell types. CNG3-deficient mice provide an animal model to dissect unequivocally the contribution of rod and cone pathways for normal retinal function.

Animals↗

Micropuncture analysis of tubuloglomerular feedback regulation in transgenic mice.

Micropuncture methods have been used widely as a means to define the function of single tubules and study the functional connection between tubules and afferent arterioles (so-called tubuloglomerular feedback [TGF]). Transgenic mouse strains have become a new research tool with the potential of shedding new light on the role of specific gene products in renal tubular and vascular function. The micropuncture approach has therefore been adapted to studies in the mouse kidney. Although the data presented here support the feasibility of using this technique in the mouse, technical improvements are desirable in the areas of anesthesia, ureteral urine collections, blood collections, volume replacement, and functional stability for extended time periods. During ketamine/inactin anesthesia, TGF responses could regularly be elicited in wild-type mice. In contrast, changes in loop flow did not alter stop-flow pressure in angiotensin II type 1A receptor and angiotensin-converting enzyme knockout mice. Infusion of angiotensin II in subpressor doses partially restored TGF responsiveness in angiotensin-converting enzyme knockout animals. Normal TGF responses compared to wild type were found in nitric oxide synthase I and thromboxane receptor knockout mice. Using free-flow micropuncture techniques, the proximal-distal single-nephron GFR difference was found to be augmented in aquaporin-1 and Na/H exchanger-3 knockout mice, suggesting TGF activation in these strains of mice. These results support an essential role of angiotensin II in TGF regulation mediated through the angiotensin II type 1A receptor. Chronic nitric oxide synthase I and thromboxane receptor deficiency did not change TGF responsiveness. Aquaporin-1 and Na/H exchanger-3 deficiency enhances TGF suppression of TGF probably by volume depletion-mediated TGF sensitization. The use of micropuncture methodology in transgenic mice combines old and new research tools in a way that promises to yield important new insights into single-nephron function in physiologic and pathophysiologic conditions.

Anesthesia↗

Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis.

Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O-water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non-IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.

Adult↗

Stimulating language: insights from TMS.

Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These 'virtual lesion' studies offer not only the ability to explore causal relations between brain regions and language functions absent in functional neuroimaging, but also spatial and temporal precision not typically available in patient studies. For instance, TMS has been used to demonstrate functionally distinct sub-regions of the left inferior frontal gyrus; to clarify the relationship between pre-morbid language organization and susceptibility to unilateral lesions and to investigate the contribution of both left and right hemisphere language areas in recovery from aphasia. When TMS is used as a measure of functional connectivity, it demonstrates a close link between action words and motor programmes; it suggests a potential evolutionary link between hand gestures and language and it suggests a role in speech perception for the motor system underlying speech production. In combination with functional neuroimaging, it can elucidate the circuits responsible for this involvement. Finally, TMS may even be useful for enhancing recovery in aphasic patients. In other words, TMS has already become an important tool for studying language at both the cognitive and neural levels, and it is clear that further developments in TMS methodology are likely to result in even greater opportunities for language research.

Aphasia↗

Phylogenetic detection of conserved gene clusters in microbial genomes.

BACKGROUND: Microbial genomes contain an abundance of genes with conserved proximity forming clusters on the chromosome. However, the conservation can be a result of many factors such as vertical inheritance, or functional selection. Thus, identification of conserved gene clusters that are under functional selection provides an effective channel for gene annotation, microarray screening, and pathway reconstruction. The problem of devising a robust method to identify these conserved gene clusters and to evaluate the significance of the conservation in multiple genomes has a number of implications for comparative, evolutionary and functional genomics as well as synthetic biology. RESULTS: In this paper we describe a new method for detecting conserved gene clusters that incorporates the information captured by a genome phylogenetic tree. We show that our method can overcome the common problem of overestimation of significance due to the bias in the genome database and thereby achieve better accuracy when detecting functionally connected gene clusters. Our results can be accessed at database GeneChords http://genomics10.bu.edu/GeneChords. CONCLUSION: The methodology described in this paper gives a scalable framework for discovering conserved gene clusters in microbial genomes. It serves as a platform for many other functional genomic analyses in microorganisms, such as operon prediction, regulatory site prediction, functional annotation of genes, evolutionary origin and development of gene clusters.

Algorithms↗

[Diaschisis phenomenon in different neurological diseases].

Diaschisis is based on reversible depression of functions anatomically or functionally connected to the damaged area. It was described for the first time in 1914 by von Monakow. There has been a rise in the studies on diaschisis over the past twenty years--what is closely related to the progress made in functional neuroimagining techniques. In this article we try to describe the diaschisis phenomenon, its types, the possibilities of its investigations and clinical implications.

Humans↗

Functional interplay between histone demethylase and deacetylase enzymes.

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.

Acetylation↗

Interaction of Munc-18-2 with syntaxin 3 controls the association of apical SNAREs in epithelial cells.

The docking/fusion of transport vesicles mediated by the soluble NSF attachment protein receptors (SNAREs) is thought to be regulated by Sec1-related proteins. Munc-18-2, a member of this family, is predominantly expressed in the epithelial cells of several tissues. We demonstrate here that Munc-18-2 colocalizes with syntaxin 3 at the apical plasma membrane of intestinal epithelium and Caco-2 cells. The presence of a physical complex of the two proteins is verified by 2-way coimmunoprecipitation. The quantity of the complex is reduced by treatment of Caco-2 cells with the alkylating agent N-ethylmaleimide which also has an inhibitory effect on the ability of Munc-18-2 to associate with syntaxin 3 in vitro. The amount of Munc-18-2 in the complex increases upon treatment of the cells with the protein kinase C activator phorbol myristate acetate, indicating a functional connection between the complex and cell signalling. Increasing the amount of Munc-18-2 bound to syntaxin 3 by overexpression results in a marked decrease in the SNARE proteins SNAP-23 and cellubrevin bound to the syntaxin. These results define a novel functional complex of Munc-18-2 and syntaxin 3 involved in the regulation of apical membrane transport.

Animals↗

Calcium signal communication between glial and vascular brain cells.

The brain is composed of neurons that communicate electrical signals over neurites and chemical signals across synapses, and non-neuronal cells like glial and vascular cells that communicate calcium signals among each other Calcium ions have an important signaling function in the cytoplasm that depends on their amplitude, time course of change and subcellular localisation. Work over the last decade has added an additional dimension to this rich repertoire by including the possibility that calcium signals can be communicated between cells. In astrocytes and endothelial cells, connexins appear to be at the crossroad of calcium signal communication pathways, because they are the building blocks of gap junction channels that functionally connect cells, and because they can arrange as hemichannels that act as a conduit for cellular ATP release, thus initiating paracrine purinergic signaling. The two pathways appear to be operational in astrocytes and endothelial cells and we review in this paper possible functions of astrocyte-to-blood vessel calcium signaling at the level of arterioles where blood flow is controlled, at the level of capillaries where the blood-brain barrier is located and at the level of blood immune cells.

Animals↗

Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism.

Recent functional neuroimaging work has suggested that interregional functional connectivity between the anterior cingulate cortex (ACC), other limbic, and prefrontal regions may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). However, less attention has been paid to the white matter network. Voxel-based analysis enables an exploration of morphological or functional changes throughout the entire brain. Here we undertook the first application of this technology to diffusion tensor data in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based analysis showed a significant fractional anisotropy increase in the left anterior cingulum, subjacent to the left ACC gray matter where we previously found a volume decrement, in PTSD subjects. Moreover, the severity was positively, but not significantly associated with the fractional anisotropy of the left anterior cingulum in the victims with PTSD, using the region of interest defined in the native space with the inverse normalization technique. The present study demonstrated further evidence of abnormalities of both the ACC, a structure that is pivotally involved in attention, emotional regulation, and fear conditioning, and of subjacent white matter in the pathology of PTSD.

Adult↗

Constitutive innate immunity is a component of the pace-of-life syndrome in tropical birds.

We studied the relationship between one component of immune function and basal metabolic rate (BMR), an indicator of the 'pace-of-life syndrome', among 12 tropical bird species and among individuals of the tropical house wren (Troglodytes aedon), to gain insights into functional connections between life history and physiology. To assess constitutive innate immunity we introduced a new technique in the field of ecological and evolutionary immunology that quantifies the bactericidal activity of whole blood. This in vitro assay utilises a single blood sample to provide a functional, integrated measure of constitutive innate immunity. We found that the bactericidal activity of whole blood varied considerably among species and among individuals within a species. This variation was not correlated with body mass or whole-organism BMR. However, among species, bacteria killing activity was negatively correlated with mass-adjusted BMR, suggesting that species with a slower pace-of-life have evolved a more robust constitutive innate immune capability. Among individuals of a single species, the house wren, bacteria killing activity was positively correlated with mass-adjusted BMR, pointing to physiological differences in individual quality on which natural selection potentially could act.

Animals↗

Lack of centripetal connection between the lateral olfactory tract and the caudate nucleus. Evoked potential study in the rat.

In rats under alpha-chloralose or without general anesthesia the effect of a lateral olfactory tract stimulus on the caudate nucleus electric activity was explored by bipolar macroelectrodes. The stimulation effectiveness and the reactivity of recording sites to somatic stimuli were systematically tested. Under these conditions, no functional connection from the lateral olfactory tract to the caudate nucleus was demonstrated.

Animals↗

[Feasibility of establishing genetic homeostasis in human populations using a complex of genetic markers].

The information that we have about functional connection of different phenotypes of independent loci served for identification of their reciprocal behavior in cohorts differed in healthy status from the same population. Coefficients of correlation were computed between phenotypes according to the scheme: everyone with all in a Buryat, on the basis of the distribution of 17 genetic loci. Their space was transformed to a standardized one of eigenvectors. Calculation of the distances between genotypes was performed using the Euclidean formula. The same distances were estimated using an alternative formula of reverse cosine from correlation. It was determined: 1) subgroups of ecological risk and adaptive norm have peculiarities of phenotypical combinations; 2) the number of reliable correlations between phenotypes 2.5 times exceeded that in the adaptive part of the population as compared with unfavourable cohort (according to the health status); 3) the proportion of attractably connected phenotypes (the effect of their interaction) was higher than the corresponding repulsive connected ones (the effect of their repulsion) in the adaptive standard subgroup; 4) on the contrary, the proportion of repulsively connected phenotypes prevailed over the corresponding attractably associated ones in the ecological risk subgroup; 5) there were smaller genetic distances between phenotypes in the adaptive norm subgroup as compared with those in the ecological risk cohort. All these data permit to narrate about considerably greater functional balance of the studied portion of the genome in the clinically healthy subgroups that express the display of genetic homeostasis in complex discrete nonlinked characters. Interloci correlation between Hp and Cerumen systems in the three populations studied were obtained.

Adaptation, Physiological↗

Architectonic organization of the inferior parietal convexity of the macaque monkey.

The inferior parietal lobule (IPL) of the macaque monkey constitutes the largest part of Brodmann's area 7. Functional, connectional, and architectonic data have indicated that area 7 is comprised of several distinct sectors located in the lateral bank of the intraparietal sulcus and on the IPL cortical convexity. To date, however, attempts to parcellate the IPL based on architectonic criteria have been controversial, and correlation between anatomical and functional data has been inadequate. In the present study we aimed to determine the number and extent of cytoarchitectonically distinct areas occupying the IPL convexity. To this end, we studied the cytoarchitecture and myeloarchitecture of this region in 28 hemispheres of 17 macaque monkeys. Four distinct areas were identified at different rostrocaudal levels along the IPL convexity and were defined as PF, PFG, PG, and Opt, with area PF corresponding to the rostralmost area and area Opt to the caudalmost one. All areas extend dorsally up to the lateral bank of the intraparietal sulcus, for about 1-2 mm. Areas PF, PFG, and PG border ventrally on opercular areas, whereas area Opt extends ventrally into the dorsal bank of the superior temporal sulcus. Analysis of the distribution of SMI-32 immunoreactivity confirmed the proposed parcellation scheme. Some additional connectional data showed that the four areas project in a differential way to the premotor cortex. The present data challenge the current widely used subdivision of the IPL convexity into two areas, confirming, but also extending the subdivision originally proposed by Pandya and Seltzer.

Animals↗