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At least 919 records · Page 51Linked to original sources
PubMed2005

Functional neuroanatomy of human vocalization: an H215O PET study.

Vocalization in lower animals is associated with a well-described visceromotor call system centered on the mesencephalic periacqueductal grey matter (PAG), which is itself regulated by paramedian cortical structures. To determine the role this phylogenetically older system plays in human phonation, we contrasted voiced and unvoiced speech using positron emission tomography and then evaluated functional connectivity of regions that significantly differentiated these conditions. Vocalization was associated with increased and highly correlated activity within the midline structures--PAG and paramedian cortices--described in lower mammalian species. Concurrent activation and connectivity of neocortical and subcortical motor regions--medial and lateral premotor structures and elements of basal ganglia thalamocortical circuitry--suggest a mechanism by which this system may have come under an increasing degree of voluntary control in humans. Additionally, areas in the temporal lobe and cerebellum were selectively activated during voiced but not unvoiced speech. These regions are functionally coupled to both visceromotor and neocortical motor areas during production of voiced speech, suggesting they may play a central role in self-monitoring and feedback regulation of human phonation.

Adult↗
PubMed2004

Restoring walking after spinal cord injury.

One of the most obvious deficits following a spinal cord injury is the difficulty in walking, forcing many patients to use wheelchairs for locomotion. Over the past decade considerable effort has been directed at promoting the recovery of walking and to find effective treatments for spinal cord injury. Advances in our knowledge of the neuronal control of walking have led to the development of a promising rehabilitative strategy in patients with partial spinal cord injury, namely treadmill training with partial weight support. The current focus is on developing more efficient training protocols and automating the training to reduce the physical demand for the therapists. Mechanisms underlying training-induced improvements in walking have been revealed to some extent in animal studies. Another strategy for improving the walking in spinal cord injured patients is the use of functional electric stimulation of nerves and muscles to assist stepping movements. This field has advanced significantly over the past decade as a result of developments in computer technology and the miniaturization of electronics. Finally, basic research on animals with damaged spinal cords has focused on enhancing walking and other motor functions by promoting growth and regeneration of damaged axons. Numerous important findings have been reported yielding optimism that techniques for repairing the injured spinal cord will be developed in the near future. However, at present no strategy involving direct treatment of the injured spinal cord has been established for routine use in spinal cord injured patients. It now seems likely that any successful protocol in humans will require a combination of a treatment to promote re-establishing functional connections to neuronal networks in the spinal cord and specialized rehabilitation training to shape the motor patterns generated by these networks for specific behavioral tasks.

Animals↗
PubMed2005

Human standing posture control system depending on adopted strategies.

Control of the standing posture of humans involves at least two distinct modes of operation to restore the body balance in the sagittal plane: the ankle strategy and the hip strategy. The objective of the study was to estimate the contribution of vestibular, visual and somatosensory feedbacks to these distinct strategies. The body dynamics was described as the motion of two linked rigid segments that represented the legs and the rest of the body. The posture controller received the inclination angles of the two body segments as inputs and regulated the moments around the ankle and hip joints. The controller had four feedback paths that were characterised by transfer functions connecting the two inputs and the two outputs. To evoke the distinct strategies, the floor conditions were varied by narrowing the support surface under the feet. A continuous pseudo-random external disturbing force was applied to the waist and the thigh independently. The inclination angles of the body segments and the ground reaction force were measured, and the transfer functions of the controller were estimated with the maximum-likelihood system identification procedure. Six healthy male adult subjects participated in the experiment. When the hip strategy became evident under the narrow support surface conditions, the transfer function relating the leg inclination angle and the ankle joint moment decreased its DC gain (16%), whereas the other three transfer functions increased the gains (20-140%) (ANOVA, p < 0.05). Based on a criterion for simplicity in the modification of the posture controller, these changes suggest a new hypothesis that, when posture control becomes difficult, the central nervous system selectively activates the somatosensory feedback paths from the hip joint angle to the moments around the ankle and hip joints.

Adult↗
PubMed2003

Schizophrenia and Parkinson's disease lead to equal motor-related changes in cortical and subcortical brain activation: an fMRI fingertapping study.

In schizophrenia and Parkinson's disease, cortical and subcortical motor organization is influenced by primary disease conditions and neuroleptic treatment. Using functional magnetic resonance imaging patients with schizophrenia were compared, according to Diagnostic and Statistical Manual of Mental Disorders (4th edn), under stable treatment with olanzapine (n = 7; OL) or haloperidol (n = 7; HA) to healthy controls (n = 7; HC), patients with schizophrenia without any neuroleptic treatment (n = 7; UN) and to patients with left (n = 7; LHP)- and right (n = 7; RHP)-sided hemiparkinsonism. All subjects performed a unilateral left-handed fingertapping task. All groups had significant activation in the contralateral motor cortex and the putamen (P < 0.001). Different activation patterns between groups within cortical and subcortical regions of interest were revealed. In particular, different subcortical activation patterns were found between OL- and HA-treated patients with schizophrenia. Activation of the contralateral putamen was increased in right-sided hemiparkinsonism. Significant thalamus activation was found in patients under neuroleptic treatment as well as in hemiparkinsonism, whereas the thalamus was not activated in untreated patients with schizophrenia and in healthy controls. Comparing dopaminergic depletion in hemiparkinsonism and dopaminergic blockade in HA-treated patients, an increase in activation was found within the contralateral primary motorcortex, in the ipsilateral putamen and the contralateral thalamus in hemiparkinsonism. In contrast, activation of the contralateral putamen differed between OL and HA, LHP and RHP. These findings confirm that cortical and subcortical motor-related brain loop functions are influenced by both primary neuropsychiatric conditions as well as by treatment effects. It is hypothesized that dopaminergic depletion in hemiparkinsonism and dopaminergic blockade under neuroleptic agents influence basal ganglia activity in a different way; in particular regarding functional connectivity. Basal ganglia and thalamic interaction seems to have a key role in cortical-subcortical interaction.

Adult↗
PubMed1995

Inner connections within domain of dementia praecox: role of supervisory mental processes in schizophrenia.

Kraepelin's conclusion that there were underlying common features justifying the amalgamation of catatonia, hebephrenia and paranoia hallucinatoria to form a single illness is confirmed by factor analytic studies delineating the various dimensions of schizophrenic psychopathology. Neuropsychological studies reveal that the three cardinal dimensions reflect disorder of the supervisory mental processes responsible for initiation, selection and monitoring of self-generated mental activity. Brain-imaging studies indicate that the underlying neuropathology entails disordered functional connectivity within the neural networks in multimodal association cortex that are the substrate of the supervisory mental processes, consistent with Kraepelin's own speculation about the essential nature of the condition.

Humans↗
PubMed2000

Non-peptidic, non-prenylic bisubstrate farnesyltransferase inhibitors. Part 3: structural requirements of the central moiety for farnesyltransferase inhibitory activity.

Recently, we have described non-peptidic, non-prenylic bisubstrate analogues as a novel type of farnesyltransferase inhibitor composed of a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. With this study, we showed that the amide function connecting the farnesyl-mimetic and the linking substructures of our inhibitors is crucial for their activity. We suggest that the amide is bound to the essential zinc ion in the farnesyltransferases active center. We identified succinic and glutaric acid, respectively, in addition to the initially used 1-alanyl moiety as suitable linking structures. Glycine can also be used in this function provided the distance between the alpha-amide group and the center of the peptidomimetic substructure is enlarged by introduction of an additional methylene unit into the peptidomimetic substructure.

Alkyl and Aryl Transferases↗
PubMed2004

Depressed cortical excitability and elevated matrix metalloproteinases in remote brain regions following intracerebral hemorrhage.

The absence of cortical responses to external stimuli is a dubious clinical sign during the first 1-2 days of brain injury. We previously showed that the amplitude of the somatic evoked potential (SEP) in the swine is diminished at the infarct site and perihematomal surround within the first 6 h of collagenase-induced intracerebral hemorrhage (ICH). We now report that this depressed SEP persists during the subchronic (48 h) period of ICH in the swine not only within the injured primary somatosensory (SI) cortex, but also in the contralateral homotopic SI cortex. This impairment of sensory responsiveness was accompanied by increases in various matrix metalloproteinases (MMPs) in different brain regions. By 24 h, a marked rise in MMP-9, an inflammatory marker, was detected in the white matter of the ipsilesional SI and secondary somatosensory cortex (SII), and in the contralesional SI gray matter, as compared to saline-injected controls. A subsequent increase in MMP-9 level was found in the ipsilesional SI and SII gray matter, and in the contralesional SI white matter by 48 h (P<0.05). By 7 days, significant levels of MMP-9 were detected only in the ipsilesional SI white and gray matter tissues. In contrast, the elevation of MMP-2, a marker of degeneration, was delayed until 7 days post-ICH in the ipsilesional SII gray matter. A significant rise in MMP-9 was also noted in CA1 of the ipsilesional and contralesional hemispheres during 1-2 days. Our MMP assay shows that the depressed cortical excitability seen in the contralateral SI cortex is a manifestation of the broad effect of a focal ICH that produces inflammatory and degenerative processes not only in the region adjacent to the focal ICH site, but also in remote regions that are functionally connected to the site of focal ICH.

Animals↗
PubMed2003

Ultrastructural study of gap junctions between dendrites of parvalbumin-containing GABAergic neurons in various neocortical areas of the adult rat.

Parvalbumin (PV)-containing GABAergic neurons in the hippocampus form dual networks linked by both dendrodendritic gap junctions and mutual inhibitory synapses. Recent physiological studies have demonstrated similar functional connectivity among cortical GABAergic neurons, but the corresponding structures have not been fully analyzed at the electron microscopic level. In this study we examined detailed ultrastructural features of gap junctions between PV neurons in the mature neocortex. Light microscopic observations and confocal laser scanning microscopy revealed frequent dendrodendritic contacts between PV neurons. Electron microscopic analysis provided direct morphological evidence for the existence of gap junctions between 22 pairs of PV-immunoreactive dendrites in the visual, auditory, and somatosensory cortices. Their ultrastructural features that were characteristic of immunolabeled profiles were consistent with the general structure of gap junctions. In one case a gap junction coexisted with a dendrodendritic chemical synapse, making a mixed synapse. Importantly, we also encountered a gap junction between PV positive and negative, presumptive non-principal cell-derived, dendrites. Quantitative analysis was made in 16 pairs of PV positive dendrites forming gap junctions in the infragranular layers of the somatosensory cortex. Diameters of these dendrites ranged from 0.3 to 2.7 microm, suggesting diverse locations of gap junctions along the proximal-distal axis of dendritic trees, but the majority (81%) were less than 1 microm. The mean size of gap junctions along apposing membranes was 0.22+/-0.09 microm. By using this size, the theoretical value of a junctional conductance was estimated to be 2.1-5.3 nS. Dendrites of PV neurons in the infragranular layers of the somatosensory cortex were reconstructed light microscopically and the sites of contacts with other PV neurons were mapped. Although these contacts do not necessarily imply gap junctional coupling, their number (5.3+/-2.3 per cell, n=11) suggested the degree of connectivity of less than 10 coupling from single PV neurons with others. Sholl analysis revealed that only 38% of their dendrites occurred within 200 microm from the soma. The present study demonstrated detailed ultrastructural features of gap junctions between mature cortical PV neurons. These features will facilitate not only identification of gap junctions in variously labeled neurons but also analysis of their functional aspects by enabling theoretical estimate of their junctional conductances.

Animals↗
PubMed2005

Optical studies of nicotinic acetylcholine receptor subtypes in the guinea-pig enteric nervous system.

Nicotinic transmission in the enteric nervous system (ENS) is extensive, but the role of individual nicotinic acetylcholine receptor (nAChR) subtypes in the functional connectivity of its plexuses has been elusive. Using monoclonal antibodies (mAbs) against neuronal alpha3-, alpha4-, alpha3/alpha5-, beta2-, beta4- and alpha7-subunits, combined with radioimmunoassays and immunocytochemistry, we demonstrate that guinea-pig enteric ganglia contain all of these nAChR-subunits with the exception of alpha4, and so, differ from mammalian brain. This information alone, however, is insufficient to establish the functional role of the identified nAChR-subtypes within the enteric networks and, ultimately, their specific contributions to gastrointestinal physiology. We have used voltage-sensitive dyes and a high-speed CCD camera, in conjunction with specific antagonists to various nAChRs, to elucidate some of the distinct contributions of the individual subtypes to the behaviour of enteric networks. In the guinea-pig, the submucous plexus has the extraordinary advantage that it is virtually two-dimensional, permitting optical recording, with single cell resolution, of the electrical activity of all of its neurones. In this plexus, the block of alpha3beta2-, alpha3beta4- and/or alpha7-nAChRs always results in a decrease in the magnitude of the synaptic response. However, the magnitude of the fast excitatory post-synaptic potentials (epsps) evoked by electrical stimulation of a neighbouring ganglion varies from cell to cell, reflecting the differential expression of subunits already observed using mAbs, as well as the strengths of the activated synaptic inputs. At the same time, we observe that submucous neurones have a substantial mecamylamine (Mec)-insensitive (non-nicotinic) component to their fast epsps, which may point to the presence of purinergic or serotonergic fast epsps in this system. In the myenteric plexus, on the other hand, the antagonist-induced changes in the evoked synaptic response vary depending upon the location of the stimulating electrode with respect to the ganglion under study. The range of activity patterns that follows sequential pharmacological elimination of individual subtypes suggests that nAChRs may be capable of regulating the activity of both excitatory and inhibitory pathways, in a manner similar to that described in the central nervous system.

Animals↗
PubMed1997

Interneuronal cortical connections and intertrial responses in appetitive instrumental learning.

The organization of interneuronal cortical connections in intertrial periods was studied in 4 cats trained to perform the delayed appetitive instrumental response to a visual conditioned stimulus (CS). Crosscorrelationl analysis revealed changes in intra- and intercortical neuronal networks of the visual and motor cortical projection areas. Depending on the form of behavior in the intertrial period, i.e., the presence or absence of the acquired instrumental response, the functional connections of either informational (time delays of less than 30 ms) or motivational (time delays in the range of 60-100 ms) character dominated between the neurons of the motor and visual cortical areas.

Animals↗
PubMedDate not supplied

[The frontal-motor interneuronal interactions in cats realizing a free choice of reinforcement].

Instrumental delayed reflexes with reinforcement of different quality were elaborated in six cats by the method of "active choice", where the time of delay of the motor reaction served as a signal of quality of the reinforcement. Individually varying ability to choose the quality of the reinforcement was used for classification of typological features of cats (self-control and impulsiveness). Multiunit activity was recorded by nichrome semimicroelectrodes from the frontal and motor cortical areas. Crosscorrelation analysis of interneuronal connections was carried out. The interneuronal frontal-motor relationships with different temporal delays (0-30; 30-60; 60-100 ms) were equally manifested in both groups of cats. We suggested that the organization of the frontal-motor relations did not characterize the individual typological features of the cats. During short-delayed reflexes in cats of both groups the identified functional connections with delays 0-30 ms were more significant. The question is discussed on the role of the frontal-motor coordination in definition of the kind of behaviour of cats to fulfil either short- or long-delayed conditioned reactions.

Animals↗
PubMed2000

Effects of reversible block of callosal afferent inputs on the response characteristics of single neurons in the cortical taste area in rats.

We examined the change in magnitude of the taste responses of single neurons in the cortical taste area (CTA) in one side by reversibly blocking the CTA in the other side with a local anesthetic, procaine-HCl, in urethane-anesthetized rats. Taste responses of 68 taste neurons were continuously recorded for up to 2 h until recovery from the treatment, and those in 50 of them were found to be affected significantly. No remarkable difference was noted in the spatial distribution of the affected and non-affected neurons in the CTA. Many of the affected neurons were located in layers IV and V of area GI and in layer V of area DI. In most cases, changes in the taste responses of single neurons were in one direction, i.e., either a decrease or an increase, but in a few cases they decreased or increased depending on the stimulus. The taste profile of callosal inputs was estimated by subtracting responses after treatment from the control responses before treatment. The results suggest that the CTAs on both sides are functionally connected by way of callosal fibers as anatomical studies indicate, and that the CTA in one side receives excitatory or inhibitory inputs from the other side.

Anesthetics, Local↗
PubMed2026

Functional mapping of the Trypanosoma cruzi serinome by fluorophosphonate activity-based protein profiling.

Serine hydrolases (SHs) constitute one of the largest enzyme superfamilies in eukaryotes, yet their roles in Trypanosoma cruzi, the causative agent of Chagas disease, remain largely uncharacterized. Here, we report an activity-based chemoproteomic map of the T. cruzi epimastigote serinome by combining genome-informed in silico curation with whole-cell activity-based protein profiling (ABPP) using a panel of cell-permeable fluorophosphonate (FP)-alkyne probes. Whole-cell labelling followed by label-free quantitative proteomics (LFQ-MS) identified 37 enriched SH-like proteins, including 35 with conserved or partially conserved catalytic triad/dyad features, spanning lipases, peptidases, esterases, and previously uncharacterized hydrolases. The 35 SHs represent approximately 63% of the 56 predicted SHs retained after catalytic-site curation. Domain architecture analysis revealed broad structural diversity, while orthologue-based localization data suggested association with multiple subcellular compartments, including glycosomal, mitochondrial, and endosomal localizations. Gene Ontology enrichment highlighted lipid metabolic and catabolic processes as dominant functional themes, and protein-protein interaction network analysis supported functional connectivity among the captured enzymes. Several identified SHs, including oligopeptidase B, prolyl oligopeptidase Tc80, serine carboxypeptidase CPB1, and phospholipase A1 (PLA1) have previously been characterized in trypanosomatids, with roles linked to parasite virulence or host-pathogen interactions. Together, these findings establish a fluorophosphonate-based chemoproteomic resource for the kinetoplastid community and prioritize probe-accessible active T. cruzi SHs for future functional validation and antiparasitic inhibitor discovery.

Activity-based protein profiling↗
PubMedDate not supplied

Mapping cognition to the brain through neural interactions.

Brain imaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provide a unique opportunity to study the neurobiology of human memory. As these methods can measure most of the brain, it is possible to examine the operations of large-scale neural systems and their relation to cognition. Two neuroimaging studies, one concerning working memory and the other episodic memory retrieval, serve as examples of application of two analytic methods that are optimised for the quantification of neural systems, structural equation modelling, and partial least squares. Structural equation modelling was used to explore shifting prefrontal and limbic interactions from the right to the left hemisphere in a delayed match-to-sample task for faces. A feature of the functional network for short delays was strong right hemisphere interactions between hippocampus, inferior prefrontal, and anterior cingulate cortices. At longer delays, these same three areas were strongly linked, but in the left hemisphere, which was interpreted as reflecting change in task strategy from perceptual to elaborate encoding with increasing delay. The primary manipulation in the memory retrieval study was different levels of retrieval success. The partial least squares method was used to determine whether the image-wide pattern of covariances of Brodmann areas 10 and 45/47 in right prefrontal cortex (RPFC) and the left hippocampus (LGH) could be mapped on to retrieval levels. Area 10 and LGH showed an opposite pattern of functional connectivity with a large expanse of bilateral limbic cortices that was equivalent for all levels of retrieval as well as the baseline task. However, only during high retrieval was area 45/47 included in this pattern. The results suggest that activity in portions of the RPFC can reflect either memory retrieval mode or retrieval success depending on other brain regions to which it is functionally linked, and imply that regional activity must be evaluated within the neural context in which it occurs. The general hypothesis that learning and memory are emergent properties of large-scale neural network interactions is discussed, emphasising that a region can play a different role across many functions and that role is governed by its interactions with anatomically related regions.

Brain↗
PubMed2000

Matrix metalloproteinases 2 and 9 in indomethacin-induced rat gastric ulcer.

The restoration of functional connective tissue is a major goal of the wound healing process. The 72- and 92-kD gelatinases (MMP-2 and MMP-9) are extracellular matrix metalloproteinases (MMPs), which are known to degrade type IV and V collagens and gelatin, and have a potential role in wound healing. The spatial and temporal gelatinolytic activities of MMP-2 and MMP-9 were analyzed as a function of ulcer age, in homogenates of rat, indomethacin-induced, chronic gastric ulcers. The rats were sacrificed on 1, 3, 7, 12, 18, 24 and 28 days after subcutaneous indomethacin injections. Zymographic analyses revealed elevated activation of MMP-9 and latent and active MMP-2 in gastric ulcers, when compared to gastric tissue from non-indomethacin-treated rats. The intact tissue and tissue from ulcerous lesions contained MMP-2. The highest activity of MMP-2 was found in 3 day gastric ulcers and returned to the control level by day 24. MMP-9 was not present in the intact tissue and the highest gelatinolytic activity of MMP-9 was also observed on the 3rd day after administration of indomethacin. The activity thereafter decreased and returned to the control level by day 24. In situ hybridization was used to evaluate which cells synthesize MMP-2 and MMP-9. MMP-2 was seen mostly in fibroblast-like cells in the submucosa and MMP-9 in macrophage-like cells in the mucosa on the margins of the ulcers. Thus, we conclude that these two MMPs seem to have different functions during the gastric ulcer injury/healing process. MMP-2 may participate in the physiological turnover of the gastric extracellular matrix, whereas MMP-9 may be important in the early phase of gastric ulcer formation and also in the healing process.

Animals↗
PubMed1979

Innervation of hippocampal explants by central catecholaminergic neurons in co-cultured fetal mouse brain stem explants.

The ability of central catecholaminergic neurons to grow into and establish functional connections with the hippocampus in vitro was studied using organotypic tissue culture. Brain stem explanted from the region of the locus coeruleus and hippocampal explants, from 18-day fetal mice, were maintained as co-cultures and were also grown separately. After 1-4 weeks these tissues were analyzed by glyoxylic acid-induced histofluorescence, by light and electron microscopic radioautography after incubation with [3H]norepinephrine, and by electrophysiology. Brain stem explants exhibited specifically fluorescent catecholaminergic cell bodies and varicose fibers after 2-4 weeks in culture. In contrast, no fluorescent cells or neurites could be seen in isolated hippocampal cultures grown for 2-3 weeks in vitro. When hippocampal explants were grown near brain stem explants, catecholaminergic fibers grew out of the brain stem and entered the hippocampus. In additional experiments, co-cultures of brain stem and hippocampus were incubated with [3H]norepinephrine (0.5 micron) and the monoamine oxidase inhibitor nialamide (100 micron). Radioautographic analyses revealed that brain stem neurites which entered the hippocampus took up norepinephrine, whereas neurites in the isolated hippocampal explants did not. Electron microscopic studies of the hippocampus showed varicose axon terminals within the hippocampus to be preferentially labeled. Although close relationships could be seen between labeled axons and dendrites, junctions exhibiting the membranous modifications associated with synapses were never seen. Electrophysiological studies suggested that the catecholaminergic neurites within the hippocampus were functional. Complex synaptically mediated slow wave discharges could be evoked by electrical stimuli in isolated hippocampal explants. Introduction of the beta adrenergic antagonist propranolol (0.4-4.3 micron) did not alter, or slightly depressed, these hippocampal discharges. On the other hand, in hippocampus-brain stem co-cultures, these concentrations of propranolol enhanced the complex hippocampal responses to brain stem or hippocampal stimuli. Similar enhancement of hippocampal responses by propranolol also occurred in these cocultures after acute surgical extirpation of the brain stem explant. The data suggest, therefore, that the action of propranol was probably to block adrenergic inhibitory connections with hippocampal synaptic networks. These experiments provide morphological and electrophysiological evidence that catecholaminergic neurons from fetal mouse brain stem maintained in organotypic tissue culture can grow into and functionally innervate the hippocampus.

Animals↗
PubMed2003

Repression of the luteinizing hormone receptor gene promoter by cross talk among EAR3/COUP-TFI, Sp1/Sp3, and TFIIB.

Transcription of luteinizing hormone receptor (LHR) gene is activated by Sp1/Sp3 at two Sp1 sites and is repressed by nuclear orphan receptors EAR2 and EAR3 through a direct-repeat (DR) motif. To elucidate the mechanism of the orphan receptor-mediated gene repression, we explored the functional connection between the orphan receptors and Sp1/Sp3 complex, and its impact on the basal transcription machinery. The Sp1(I) site was identified as critical for the repression since its mutation reduced the inhibition by EAR2 and abolished the inhibition by EAR3. Cotransfection analyses in SL2 cells showed that both Sp1 and Sp3 were required for this process since EAR3 displayed a complete Sp1/Sp3-dependent inhibitory effect. Functional cooperation between Sp1 and DR domains was further supported by mutual recruitment of EAR3 and Sp1/Sp3 bound to their cognate sites. Deletion of EAR3 N-terminal and DNA-binding domains that reduced its interaction with Sp1 impaired its inhibitory effect on human LHR (hLHR) gene transcription. Furthermore, we demonstrate interaction of TFIIB with Sp1/Sp3 at the Sp1(I) site besides its association with EAR3 and the TATA-less core promoter region. Such interaction relied on Sp1 site-bound Sp1/Sp3 complex and adaptor protein(s) present in the JAR nuclear extracts. We further demonstrated that EAR3 specifically decreased association of TFIIB to the Sp1(I) site without interfering on its interaction with the hLHR core promoter. The C-terminal region of EAR3, which did not participate in its interaction with Sp1, was required for its inhibitory function and may affect the association of TFIIB with Sp1. Moreover, perturbation of the association of TFIIB with Sp1 by EAR3 was reflected in the reduced recruitment of RNA polymerase II to the promoter. Overexpression of TFIIB counteracted the inhibitory effect of EAR3 and activated hLHR gene transcription in an Sp1 site-dependent manner. These findings therefore indicate that TFIIB is a key component in the regulatory control of EAR3 and Sp1/Sp3 on the initiation complex. Such cross talk among EAR3, TFIIB, and Sp1/Sp3 reveals repression of hLHR gene transcription by nuclear orphan receptors is achieved via perturbation of communication between Sp1/Sp3 at the Sp1-1 site and the basal transcription initiator complex.

Animals↗
PubMed2025

Microbiota and kidney disease: the road ahead.

More than 850 million individuals worldwide, accounting for 10-15% of the adult population, are estimated to have chronic kidney disease. Each of these individuals is host to tens of trillions of microorganisms that are collectively referred to as microbiota - a dynamic ecosystem that both influences host health and is itself influenced by changes in the host. Available evidence supports the existence of functional connections between resident microorganisms and kidney health that are altered in the context of specific kidney diseases, including acute kidney injury, chronic kidney disease and renal stone disease. Moreover, promising data from preclinical studies suggest that targeting of gut microbial pathways may provide new therapeutic opportunities for the treatment of kidney disease. This Roadmap describes current understanding of the mechanisms by which microorganisms regulate host organ function, the effects of kidney disease on the gut microbiome, and how these insights may contribute to the development of microbe-targeted therapeutics. We highlight key knowledge gaps that remain to be addressed and strategies for addressing these, outlining both the promise and the potential pitfalls of leveraging our understanding of the gut microbiota to better understand and treat kidney disease.

Humans↗