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At least 721 records · Page 40Linked to original sources
PubMed2002

Cytokines and related receptor-mediated signaling pathways.

Cytokines represent a multi-diverse family of polypeptide regulators; they are of relatively low molecular weight, pharmacologically active proteins that are secreted by one cell for the purpose of altering either its own functions (autocrine effect) or those of adjacent cells (paracrine effect). Cytokines are small, non-enzymatic glycoproteins whose actions are both diverse and overlapping (specificity/redundancy) and may affect diverse and overlapping target cell populations. In many instances, individual cytokines have multiple biological activities. Different cytokines can also have the same activity, which provides for functional redundancy within the inflammatory and immune systems. As biological cofactors that are released by specific cells, cytokines have specific effects on cell-cell interaction, communication, and behavior of other cells. As a result, it is infrequent that loss or neutralization of one cytokine will markedly interfere with either of these systems. The biological effect of one cytokine is often modified or augmented by another. Because an inter-digitating, redundant network of cytokines is involved in the production of most biological effects, both under physiologic and pathologic conditions, it usually requires more than a single defect in the network to alter drastically the outcome of the process. This fact therefore may have crucial significance in the development of therapeutic strategies for bio-pharmacologic intervention in cytokine-mediated inflammatory processes and infections.

Animals↗
PubMed1998

Macromolecular diffusion of biological polymers measured by confocal fluorescence recovery after photobleaching.

Fluorescence recovery after photobleaching with an unmodified confocal laser scanning microscope (confocal FRAP) was used to determine the diffusion properties of network forming biological macromolecules such as aggrecan. The technique was validated using fluorescein isothiocyanate (FITC)-labeled dextrans and proteins (molecular mass 4-2000 kDa) at 25 degrees C and with fluorescent microspheres (207 nm diameter) over a temperature range of 5-50 degrees C. Lateral diffusion coefficients (D) were independent of the focus position, and the degree and extent of bleach. The free diffusion coefficient (Do) of FITC-aggrecan determined by confocal FRAP was 4.25 +/- 0.6 x 10(-8) cm2 s-1, which is compatible with dynamic laser light scattering measurements. It appeared to be independent of concentration below 2.0 mg/ml, but at higher concentrations (2-20 mg/ml) the self-diffusion coefficient followed the function D = Do(e)(-Bc). The concentration at which the self-diffusion coefficient began to fall corresponded to the concentration predicted for domain overlap. Multimolecular aggregates of aggrecan ( approximately 30 monomers) had a much lower free diffusion coefficient (Do = 6.6 +/- 1.0 x 10(-9) cm2 s-1) but showed a decrease in mobility with concentration of a form similar to that of the monomer. The method provides a technique for investigating the macromolecular organization in glycan-rich networks at concentrations close to those found physiologically.

Aggrecans↗
PubMed1998

Immune mechanisms of acute rejection.

An understanding of acute allograft rejection has eluded investigators for many years, despite major research efforts in this area. This understanding may not be achievable, given the current philosophic approach to the study of immune processes. An alternative approach, which is outlined here, would require investigators to develop an appreciation for the strengths and limitations of complex, adaptive networks like the interdigitated inflammatory, immune, and physiologic processes that are at work in transplanted allografts. This alternative approach is offered in the hope that it will provide new insights regarding the nature of immune responses and will be helpful in the design and interpretation of future studies of acute rejection and other transplant-related biologic processes.

Acute Disease↗
PubMed1998

Tracing of a neuronal network in the locust by pressure injection of markers into a synaptic neuropil.

Central neuronal circuits of vertebrates have often been investigated using injection of markers into synaptic neuropils, whereas similar techniques have rarely been applied in invertebrates. In this study we tested several neuroanatomical tracers for their ability to mark central neuronal circuits in insects, using the well described auditory network of the locust, Locusta migratoria. After physiological localization of an auditory neuropil various tracers were pressure injected. Horseradish peroxidase, dextrans (3 and 10 kDa) and especially biocytin and neurobiotin were effectively incorporated by auditory interneurons, which resulted in their extensive labeling. Postsynaptic regions turned out to be the major, if not exclusive sites of uptake of injected markers, which is deduced from two lines of evidence: (i) for labeling of identified auditory neurons it was necessary to apply the tracer to postsynaptic sites of the neuron; (ii) only a few non-auditory neurons were labeled (probably by lesioning axons during electrode impalement). No evidence could be found for an activity dependent uptake. We conclude that pressure injection of certain tracers into synaptic areas can be used to identify central nervous circuits in insects.

Acoustic Stimulation↗
PubMed1998

mu-Opposing actions of the kappa-opioid receptor.

Pharmacological studies and recent research using genetic approaches have indicated that most actions of exogenous opioids, such as morphine, are mediated through the mu-opioid receptor. By contrast, the function of the kappa-opioid receptor in opioid actions largely remains unclear. In this article, Zhizhong Z. Pan discusses the accumulating evidence that activation of the kappa-receptor antagonizes various mu-receptor-mediated actions in the brain, including analgesia, tolerance, reward and memory processes. The neural mechanism for this potentially ubiquitous mu-opposing function of the kappa-receptor is believed to involve distinct locations of the two opioid receptors on physiologically different cell types in local neuronal networks that are implicated in an opioid action.

Analgesics, Opioid↗
PubMed2000

Changes of cytokine profiles during peritonitis in patients on continuous ambulatory peritoneal dialysis.

Continuous ambulatory peritoneal dialysis (CAPD) has emerged as an important dialysis treatment modality worldwide. One of the major complications is bacterial peritonitis, which may result in subsequent technique failure because of loss of peritoneal clearance or peritoneal fibrosis. Bacterial peritonitis leads to the release of proinflammatory cytokines from resident and infiltrating cells in the peritoneal cavity. We studied 35 patients undergoing CAPD with acute bacterial peritonitis. All patients treated with antibiotics for 2 weeks after the clinical diagnosis of peritonitis had a good recovery. Peritoneal dialysate effluent (PDE) was collected on days 1, 3, 5, 10, 21, and 42 after the start of treatment. Cell populations were monitored by flow cytometry. PDE levels of interleukin-1beta (IL-1), IL-6, transforming growth factor-beta (TGF-beta), and basic fibroblast growth factor (FGF) were measured by enzyme-linked immunosorbent assay. Gene transcription of TGF-beta in macrophages from PDE was measured by quantitative polymerase chain reaction. Bacterial peritonitis was associated with a sharp increase in total cell and neutrophil counts (400-fold) in PDE up to 3 weeks after peritonitis despite clinical remission (P < 0.0001). There was an increased absolute number of macrophages during the first 3 weeks despite the reduced percentage of macrophages among total cells in PDE compared with noninfective PDE. There was a progressive increase in the percentage of mesothelial cells or dead cells in the total cell population in PDE over the entire 6-week period. PDE levels of IL-1, IL-6, TGF-beta, and FGF increased markedly on day 1 before their levels decreased gradually. PDE levels of these cytokines or growth factors were significantly greater than those in noninfective PDE (n = 76) throughout the study period (P < 0.01). Similarly, TGF-beta complementary DNA (cDNA) molecules per macrophage were significantly greater than those of macrophages in noninfective PDE throughout this period (P < 0.01). There was no significant correlation between PDE levels of TGF-beta and TGF-beta cDNA molecules per macrophage, suggesting that peritoneal macrophages are not the only source of TGF-beta in PDE. We conclude there is an active release of proinflammatory cytokines and sclerogenic growth factors through at least 6 weeks despite apparent clinical remission of peritonitis. The peritoneal cytokine networks after peritonitis may potentially affect the physiological properties of the peritoneal membrane.

Bacterial Infections↗
PubMed2002

Pharmaco-redox regulation of cytokine-related pathways: from receptor signaling to pharmacogenomics.

Cytokines represent a multi-diverse family of polypeptide regulators; they are relatively low molecular weight (< 30 kDa), pharmacologically active proteins that are secreted by one cell for the purpose of altering either its own functions (autocrine effect) or those of adjacent cells (paracrine effect). Cytokines are small, nonenzymatic glycoproteins whose actions are both diverse and overlapping (specificity/redundancy) and may affect diverse and overlapping target cell populations. In many instances, individual cytokines have multiple biological activities. Different cytokines can also have the same activity, which provides for functional redundancy (network) within the inflammatory and immune systems. As biological cofactors that are released by specific cells, cytokines have specific effects on cell-cell interaction, communication, and behavior of other cells. As a result, it is infrequent that loss or neutralization of one cytokine will markedly interfere with either of these systems. The biological effect of one cytokine is often modified or augmented by another. Because an interdigitating, redundant network of cytokines is involved in the production of most biological effects, both under physiologic and pathologic conditions, it usually requires more than a single defect in the network to alter drastically the outcome of the process. This fact, therefore, may have crucial significance in the development of therapeutic strategies for biopharmacologic intervention in cytokine-mediated inflammatory processes and infections.

Animals↗
PubMed2006

Tubulin polymerization promoting proteins (TPPPs): members of a new family with distinct structures and functions.

TPPP/p25 is a brain-specific protein, which induces tubulin polymerization and microtubule (MT) bundling and is enriched in Lewy bodies characteristic of Parkinson's disease [Tirián et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 13976-13981]. We identified two human gene sequences, CG1-38 and p25beta, which encoded homologous proteins, that we termed p20 and p18, respectively. These homologous proteins display 60% identity with tubulin polymerization promoting protein/p25 (TPPP/p25); however, the N-terminal segment of TPPP/p25 is missing. They could be clustered into three subfamilies present in mammals and other vertebrates. We cloned, isolated, and characterized the structural and functional properties of the recombinant human proteins at molecular, ultrastructural, and cellular levels using a number of tools. These data revealed that, while p20 behaved as a disorganized protein similarly to TPPP/p25, which was described as a flexible and inherently dynamic protein with a long unstructured N-terminal tail, p18 was featured in more ordered fashion. TPPP/p25 and p20 specifically attached to MTs causing MT bundling both in vitro and in vivo; p18 protein did not cross-link MTs, and it distributed homogeneously within the cytosol of the transfected HeLa cells. These data indicate that the two shorter homologues display distinct structural features that determine their associations to MTs. The properties of p20 resemble TPPP/p25. The bundling activity of these two proteins results in the stabilization of the microtubular network, which is likely related to their physiological functions.

Amino Acid Sequence↗
PubMed2004

Integrin and cytoskeleton behaviour in human neuroblastoma cells during hyperthermia-related apoptosis.

Hyperthermia induces several cellular responses leading to morphological changes, cell detachment and death. Loss of integrins from the cell surface after acute heat-treatment may block several physiological signalling pathways, but whether the assembly network between integrin and cytoskeletal actin is perturbed during hyperthermic treatment is unknown. In this study we tested this hypothesis by evaluating cell morphology, protein cytoskeletal profile and integrin CD11a content in both adherent and floating SK-N-MC human neuroblastoma cells. Morphological and cytometric analyses confirmed that hyperthermia is an effective apoptotic trigger, revealing the typical chromatin margination, cell shape changes and 7-AAD incorporation. After hyperthermia, cytoskeletal proteins showed an increase of high-molecular-weight aggregates and a significant decrease of both actin and CD11a content with respect to control cells. The integrin CD11a and membrane-bound actin alterations found in detached floating neuroblastoma cells recovered after heat-shock may cause the cytoskeletal abnormalities related to the observed surface cell rounding/blebbing and anoikis, early events of hyperthermia-induced programmed cell death.

Apoptosis↗
PubMed2002

An auditory domain in primate prefrontal cortex.

Although neuroimaging studies confirm the frontal lobe's involvement in language processes and auditory working memory, the cellular and network basis of these functions is unclear. Physiological studies of the frontal lobe in non-human primates have focused on visual working memory and auditory spatial processing in dorsolateral prefrontal cortex (PFC), although the candidate PFC areas for non-spatial acoustic processing lie in the ventrolateral PFC (areas 12 and 45), which receives afferents from physiologically and anatomically defined auditory cortex. We recorded neuronal responses from ventrolateral PFC to auditory cues in awake monkeys under controlled conditions and report that the macaque ventrolateral PFC contains an auditory responsive domain in which neurons show responses to complex sounds, including animal and human vocalizations.

Acoustic Stimulation↗
PubMed2005

High-throughput discovery of germ-cell-specific genes.

As a specialized cell population that plays the unique role of transmitting genetic information to subsequent generations, germ cells have been intensively studied to unravel their unique physiology from the specification of primordial germ cells to the fateful reunion of gametes during fertilization. For their differential expression, germ-cell-specific genes are the keys to understanding these unique features. In the last decade, the emerging methodologies designed for large-scale and high-throughput analysis have created an ever-increasing amount of data. Among these methodologies, expressed sequence tag libraries, serial analysis of gene expression, and microarrays provide valuable expression data that can be further analyzed. Using the mouse as a model system, we describe a strategy starting from the quick identification of germ-cell-specific genes using public domain expression data to the functional characterization of the identified genes using targeted gene disruption. This strategy should accelerate the process to fill in the missing pieces of the germ cell physiology puzzle and the construction of genetic networks to help us to understand the etiology of infertility. Furthermore, these identified germ-cell-specific genes may lead to the development of new contraceptives targeted specifically to germ cells.

Animals↗
PubMedDate not supplied

Behavioral modulation induced by food odor aversive conditioning and its influence on the olfactory responses of an oscillatory brain network in the slug Limax marginatus.

We compared behaviorally and physiologically the olfactory responses of slugs (Limax marginatus) that had been subjected to aversive, appetitive, or unpaired training with food odors (carrot or cucumber). In the aversive training, the slugs were exposed to the food odor as a conditioned stimulus (CS), and then quinidine sulfate solution as an unconditioned stimulus (UCS) was immediately applied to the lip of the slugs. This training caused a decrease in preference level for the CS. The unpaired training, in which the CS and the UCS were presented to the slugs with a 5-min interval, induced no change in the preference level for the CS. In the appetitive training, the slugs were allowed to eat the CS odor source without UCS application. When we used nonstarved slugs, it was found that the preference level for the CS increased upon the appetitive training. These results indicate that each training changed the preference for the odors in a characteristic manner. In the physiological experiments, we used brain-inferior tentacular nose preparations isolated from slugs and investigated the olfactory responses of the oscillations in the local field potential (LFP) of the procerebral (PC) lobe. We found that odor presentation induced various types of changes in the LFP oscillation frequency, although the rate of occurrence of the frequency modulation differed between odors used in the aversive and the unpaired training (aversive-conditioned and unpaired odors). The aversive-conditioned odors induced a decrease in the oscillatory frequency. Unpaired odors did not change it. Moreover, odors used in the appetitive training (appetitive-conditioned odors) induced an increase in the frequency. Thus, it was considered that those modulations of PC lobe oscillatory activity were independent of odor and reflected learned preference for odors.

Animals↗
PubMed2004

The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones.

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity and pathological phenomena such as epilepsy. However, the physiological implications for single cells and neuronal networks of the distinct expression patterns of KAR subunits are unknown. One intriguing effect of KAR activation is a long-term change to intrinsic neuronal excitability and neuronal firing patterns, such as single-spike and spike-burst firing. In this study, we describe the role of kainate receptor subunits in the metabotropic regulation of the slow and medium afterhyperpolarization (AHP) currents (I(sAHP), I(mAHP)). Using whole-cell patch-clamp recordings from CA3 pyramidal cells of wild-type (WT) and KAR knockout mice, we show that the kainate-induced decrease of I(sAHP) and I(mAHP) amplitude is protein-kinase-C-dependent and absent in GluR6(-/-) but not GluR5(-/-) pyramidal neurones. Our findings suggest that activation of GluR6-containing KARs modulates AHP amplitude, and influences the firing frequency of pyramidal neurones.

Action Potentials↗
PubMed2002

Heat shock transcription factor 2 is not essential for embryonic development, fertility, or adult cognitive and psychomotor function in mice.

Members of the heat shock factor (HSF) family are evolutionarily conserved regulators that share a highly homologous DNA-binding domain. In mammals, HSF1 is the main factor controlling the stress-inducible expression of Hsp genes while the functions of HSF2 and HSF4 are less clear. Based on its developmental profile of expression, it was hypothesized that HSF2 may play an essential role in brain and heart development, spermatogenesis, and erythroid differentiation. To directly assess this hypothesis and better understand the underlying mechanisms that require HSF2, we generated Hsf2 knockout mice. Here, we report that Hsf2(-/-) mice are viable and fertile and exhibit normal life span and behavioral functions. We conclude that HSF2, most probably because its physiological roles are integrated into a redundant network of gene regulation and function, is dispensable for normal development, fertility, and postnatal psychomotor function.

Acetylcysteine↗
PubMed1998

Interleukin-4 inhibits spontaneous sleep in rabbits.

Proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL-4 provide additional evidence for the hypothesis that a brain cytokine network is involved in the regulation of physiological sleep.

Alpha Rhythm↗
PubMed1997

Prediction of complex two-dimensional trajectories by a cerebellar model of smooth pursuit eye movement.

A neural network model based on the anatomy and physiology of the cerebellum is presented that can generate both simple and complex predictive pursuit, while also responding in a feedback mode to visual perturbations from an ongoing trajectory. The model allows the prediction of complex movements by adding two features that are not present in other pursuit models: an array of inputs distributed over a range of physiologically justified delays, and a novel, biologically plausible learning rule that generated changes in synaptic strengths in response to retinal slip errors that arrive after long delays. To directly test the model, its output was compared with the behavior of monkeys tracking the same trajectories. There was a close correspondence between model and monkey performance. Complex target trajectories were created by summing two or three sinusoidal components of different frequencies along horizontal and/or vertical axes. Both the model and the monkeys were able to track these complex sum-of-sines trajectories with small phase delays that averaged 8 and 20 ms in magnitude, respectively. Both the model and the monkeys showed a consistent relationship between the high- and low-frequency components of pursuit: high-frequency components were tracked with small phase lags, whereas low-frequency components were tracked with phase leads. The model was also trained to track targets moving along a circular trajectory with infrequent right-angle perturbations that moved the target along a circle meridian. Before the perturbation, the model tracked the target with very small phase differences that averaged 5 ms. After the perturbation, the model overshot the target while continuing along the expected nonperturbed circular trajectory for 80 ms, before it moved toward the new perturbed trajectory. Monkeys showed similar behaviors with an average phase difference of 3 ms during circular pursuit, followed by a perturbation response after 90 ms. In both cases, the delays required to process visual information were much longer than delays associated with nonperturbed circular and sum-of-sines pursuit. This suggests that both the model and the eye make short-term predictions about future events to compensate for visual feedback delays in receiving information about the direction of a target moving along a changing trajectory. In addition, both the eye and the model can adjust to abrupt changes in target direction on the basis of visual feedback, but do so after significant processing delays.

Animals↗
PubMed1995

Longitudinal gradients for endothelium-dependent and -independent vascular responses in the coronary microcirculation.

BACKGROUND: Coronary microvessels (< 300 microns in diameter) have been demonstrated to be important in the regulation of local resistance and flow. Recent studies also suggest that these microvessels are more responsive to physiological and pharmacological stimuli than conduit vessels. However, little is known regarding the relative sensitivity of different microvascular segments in response to flow (shear stress) and agonists. The goal of this study was to test the hypothesis that a longitudinal gradient for shear stress- and agonist-induced dilation exists in the coronary microcirculation. METHODS AND RESULTS: Experiments were performed in four different sizes of porcine subepicardial coronary arterial microvessels: small arterioles (40 +/- 1-micron ID with resting tone); intermediate arterioles (60 +/- 1 micron); large arterioles (106 +/- 4 micron); and small arteries (179 +/- 9 microns). Vessels were isolated and cannulated to allow luminal pressure and flow to be independently controlled. All vessels developed active tone (to approximately 65% to 75% of maximum diameter) at their control luminal pressures and showed graded dilations to stepwise increases in shear stress (0 to 10 dynes/cm2). For arterioles, the magnitude of the dilations increased as vessel size increased. The highest shear stress produced 21 +/- 3%, 32 +/- 2%, and 52 +/- 5% increases in diameter in small, intermediate, and large arterioles, respectively. Small arteries dilated only 22 +/- 6%. The endothelium-dependent vasodilator substance P (SP) produced dose-dependent dilation of all vessels with a threshold at 10(-16) mol/L. Arterioles were maximally dilated at 10(-9) mol/L SP. However, this dose produced only 80% dilation in small arteries. The ED50 for SP was shifted to the right by two orders of magnitude in small arteries compared with the arterioles. Adenosine preferentially dilated small arterioles, and the dose-response curves shifted to the right for larger vessels. The thresholds for adenosine-induced dilation were 10(-12), 10(-11), and 10(-9) mol/L for small, intermediate, and large arterioles, respectively. The endothelium-independent vasodilator nitroprusside produced identical dose-dependent dilations in all vessel segments. CONCLUSIONS: The results indicate that the pig coronary circulation exhibits a heterogeneity in physiological and pharmacological responses along the microvascular network. Small arterioles are more sensitive to adenosine, but large arterioles are more responsive to shear-stress stimulation. We speculate that site-specific preferential responses may play a crucial role in coordinating overall vascular function in the coronary microvascular network.

Adenosine↗
PubMed2000

The effects of pair-wise and higher order correlations on the firing rate of a post-synaptic neuron.

Coincident firing of neurons projecting to a common target cell is likely to raise the probability of firing of this postsynaptic cell. Therefore, synchronized firing constitutes a significant event for postsynaptic neurons and is likely to play a role in neuronal information processing. Physiological data on synchronized firing in cortical networks are based primarily on paired recordings and cross-correlation analysis. However, pair-wise correlations among all inputs onto a postsynaptic neuron do not uniquely determine the distribution of simultaneous postsynaptic events. We develop a framework in order to calculate the amount of synchronous firing that, based on maximum entropy, should exist in a homogeneous neural network in which the neurons have known pair-wise correlations and higher-order structure is absent. According to the distribution of maximal entropy, synchronous events in which a large proportion of the neurons participates should exist even in the case of weak pair-wise correlations. Network simulations also exhibit these highly synchronous events in the case of weak pair-wise correlations. If such a group of neurons provides input to a common postsynaptic target, these network bursts may enhance the impact of this input, especially in the case of a high postsynaptic threshold. The proportion of neurons participating in synchronous bursts can be approximated by our method under restricted conditions. When these conditions are not fulfilled, the spike trains have less than maximal entropy, which is indicative of the presence of higher-order structure. In this situation, the degree of synchronicity cannot be derived from the pair-wise correlations.

Animals↗