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1.
On the Role of Proteasomes in Cell Biology and Proteasome Inhibition as a Novel Frontier in the Development of Immunosuppressants 总被引:2,自引:0,他引:2
Jiangping Wu 《American journal of transplantation》2002,2(10):904-912
The proteasome, a large protease complex in cells, is the major machinery for protein degradation. It was previously considered a humble garbage collector, performing housekeeping duties to remove misfolded or spent proteins. Until recently, the interests of immunologists in proteasomes were focused largely on its role in antigen processing. Its real importance in cell biology has only been revealed contemporarily due to the availability of relatively specific inhibitors. It has now become increasingly clear that many aspects of immune responses highly depend on proper proteasome activity. Recently, a proteasome inhibitor has been successfully used to prevent acute as well as ongoing heart allograft rejection in mice. Such inhibitors are also efficacious in treating several autoimmune diseases, such as arthritis, psoriasis, and probably type I diabetes, in animal models. Phase II and III clinical trials of proteasome inhibitors in treating various tumors have shown promising results, and the side-effects of these drugs are tolerable. Therefore, proteasome inhibition represents a new and promising frontier in immunosuppressant development. 相似文献
2.
Deep brain stimulation, DBS, is an accepted technique for the treatment of Parkinson's disease. DBS affects the electrical functions of neurons, but exactly how it alters those functions is not clearly explained. An electrical model is determined to simulate treatment with DBS of the sub thalamic nucleus. This model shows the difference in electrical fields between the inside and the outside the neurons. The generated electrical field near the electrodes is high enough to perform an electropermeabilization of the cell membranes, which most likely blockade normal nerve pulses or reduce the nerve impulse speed. Further away from the electrodes activation of large axons is performed. 相似文献
3.
Cristian Sevcencu 《Neuromodulation》2007,10(2):100-112
Studies performed to date have shown that electrical stimulation of the stomach and intestines can create or modulate motility functions in the gastrointestinal (GI) tract. Therefore, electrical stimulation of GI organs may become a valuable alternative to medication and surgical approaches in the treatment of GI motor dysfunctions. However, the mechanisms underlying the effects induced by electrical stimulation of the gut wall are not totally understood, and such knowledge is important for further development of stimulation methods and devices. Presently, it is known that electrical stimulation of GI organs triggers complex reactions comprising excitatory and inhibitory responses of the excitable components performing or controlling motility in the GI tract. I present here a review of what is known of the mechanisms of GI organ stimulation. 相似文献
4.
Yannick Poquet Patricia Constant Franck Halary Marie-Alix Peyrat Martine Gilleron François Davodeau Marc Bonneville Jean-Jacques Fournié 《European journal of immunology》1996,26(10):2344-2349
The stimulation of human γδ T cells by mycobacteria occurs through recognition of four distinct nonpeptide phosphorylated antigens termed TUBag1–4. Among these latter, TUBag4 has already been biochemically characterized as a γ-X derivative of 5′-deoxythymidine triphosphate (Constant, P., Davodeau, F., Peyrat, M. A., Poquet, Y., Puzo, G., Bonneville, M. and Fournié, J.-J., Science 1994. 264: 267). However, despite chemical synthesis of weakly stimulatory nucleotide-containing analogs, these mycobacterial compounds remained the sole nucleotide-containing antigens actually isolated from natural sources. Here, we present the complete isolation of the TUBag3 antigen from Mycobacterium fortuitum and demonstrate that this nonpeptide molecule contains a 5′-UTP nucleotide moiety. On selected Vγ9/Vδ2 clones, T cell responses can be triggered with nanomolar concentrations of TUBag3. Like crude mycobacterial extracts, this purified nucleotide conjugate elicits a strong polyclonal response of γδ PBL from healthy donors. Furthermore, we present evidence that this compound is distinct from the recently synthesized γ-isopentenyl 5′-UTP, a nucleotide conjugate of isopentenyl pyrophosphate that was found to be stimulatory for human γδ T cells (Tanaka, Y., Morita, C. T., Tanaka, Y., Nieves, E., Brenner, M. B. and Bloom, B. R., Nature 1995. 375: 155). Since it appears that both mycobacterial nucleotide antigens are molecules structurally related to peculiar precursors of nucleic acid synthesis, we propose that TUBag-reactive T cells might be specifically devoted to surveillance of proliferating cells. 相似文献
5.
W. F. Genadry R. E. Kearney I. W. Hunter 《Medical & biological engineering & computing》1988,26(5):489-496
Stochastic system identification techniques were used to determine the dynamic relationship between the electromyogram (EMG)
and torque in the ankle muscles of normal human subjects. EMG and torque were recorded while subjects modulated ankle torque
by tracking a computer-generated stochastic waveform. Nonparametric impulse response functions (IRFs) relating EMG to ankle
torque were computed and parameterised by determining the parameters of the second-order system which provided the best least-squares
fit. Two sets of experiments were carried out. In the first, the mean level of torque was varied from 5 per cent of the maximum
voluntary contraction (MVC) to 30 per cent MVC while the depth of modulation was held constant at ±5 per cent of MVC. In the
second series of experiments the mean torque was held constant at 25 per cent MVC while the depth of modulation was varied
from ±2.5 per cent to ±25 per cent. The major findings were: (1) A second-order, low-pass filter provided a good quasilinear
model of the EMG/force dynamics under all conditions; (2) The model parameters depended only weakly on the mean level of torque;
(3) In contrast, the model parameters depended strongly on the amplitude with which the contraction was modulated; the natural
frequency increased significantly with the depth of modulation. 相似文献
6.
Pisetsky DS 《Immunologic research》2000,22(2-3):119-126
Because of structural microheterogeneity, DNA can exert powerful effects that lead to immune system activation as well as
antibody induction. These activating effects resemble those of endotoxin and result from sequences that occur much more commonly
in bacterial DNA than in mammalian DNA. In contrast, mammalian DNA can inhibit the response to bacterial DNA as well as other
stimuli and may serve a counterregulatory role during infection. The recognition of the immune effects of DNA is relevant
to the pathogenesis of a variety of infectious and inflammatory diseases including systemic lupus erythematosus, a prototypic
autoimmune disease characterized by anti-DNA autoantibodies. 相似文献
7.
Natural killer (NK) cells and cytotoxic T lymphocytes (CTL), the functional coordination of which are governed by various signal substances, are crucial in the body’s defense of tumor and virus-infected cells. We investigated the role of various neurotransmitters and hormones on the regulation of functional parameters, including NK cell cytotoxicity, and the migration of NK cells and CTL within a three-dimensional collagen lattice. Using peripheral blood CTL and NK cells, we show that the neurotransmitters endorphin, histamine and substance P increase NK cell cytotoxicity, while norepinephrine inhibits cytotoxicity. Moreover, substance P reduces migratory activity, while norepinephrine increases NK cell and CTL migration. Furthermore, all three steroid hormones which were investigated, namely cortisone, testosterone, and estradiol, had regulatory influence on both cytotoxicity and migration of NK cells. These results further specify the functional basis of the complex interconnection between the immune and neuro-endocrine systems. 相似文献
8.
L. Bon C. Lucchetti 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1992,89(3):571-580
Summary The activity of 249 neurons in the dorsomedial frontal cortex was studied in two macaque monkeys. The animals were trained to release a bar when a visual stimulus changed color in order to receive reward. An acoustic cue signaled the start of a series of trials to the animal, which was then free to begin each trial at will. The monkeys tended to fixate the visual stimuli and to make saccades when the stimuli moved. The monkeys were neither rewarded for making proper eye movements nor punished for making extraneous ones. We found neurons whose discharge was related to various movements including those of the eye, neck, and arm. In this report, we describe the properties of neurons that showed activity related to visual fixation and saccadic eye movement. Fixation neurons discharged during active fixation with the eye in a given position in the orbit, but did not discharge when the eye occupied the same orbital positions during nonactive fixation. These neurons showed neither a classic nor a complex visual receptive field, nor a foveal receptive visual field. Electrical stimulation at the site of the fixation neurons often drove the eye to the orbital position associated with maximal activity of the cell. Several different kinds of neurons were found to discharge before saccades: 1) checking-saccade neurons, which discharged when the monkeys made self-generated saccades to extinguish LED's; 2) novelty-detection saccade neurons, which discharged before the first saccade made to a new visual target but whose activity waned with successive presentations of the same target. These results suggest that the dorsomedial frontal cortex is involved in attentive fixation. We hypothesize that the fixation neurons may be involved in codifying the saccade toward a target. We propose that their involvement in arm-eye-head motor-planning rests primarily in targeting the goal of the movement. The fact that saccaderelated neurons discharge when the saccades are self initiated, implies that this area of the cortex may share the control of voluntary saccades with the frontal eye fields and that the activation is involved in intentional motor processes. 相似文献
9.
Stretch activation and myogenic oscillation of isolated contractile structures of heart muscle 总被引:8,自引:0,他引:8
G. J. Steiger 《Pflügers Archiv : European journal of physiology》1971,330(4):347-361
Summary Glycerinated or freeze-dryed fibre bundles of heart muscles (papillary and trabecular muscles of rabbit or guinea pig) show in ATP-salt solution with about 10–6M Ca2+ an active, delayed tension increment after quick or sinusoidal stretching. The active tension increase is completely different from the passive tension increment caused by stretching of the elastic structures of the muscle; this well known length dependence of tension is also in phase with the length changes (or the tension-phase preceeds the length-phase in visco-elastic bodies). On the other hand, the active tension increase is delayed with respect to the length change; this can be observed very well after rectangular changes in length. The delayed activation of the contractile bonds at stretch and the delayed deactivation at shortening induce the muscle-during sinusoidal length changes in a characteristic frequency range-to produce power output. The frequency range corresponds to the heart beat frequency of the living muscle. Temperature rise and inorganic phosphate accelerate, Mg-ions and ADP retard the contraction speed. Ca-ions influence only the amount of the isometric tension, but not the contractile velocity.Supported by the Deutsche Forschungsgemeinschaft (Grant RU 154/3). 相似文献
10.
Membrane tethers (thin, cylindrical pieces of membrane) have been implicated in the rolling of neutrophils along the endothelium. In our studies, these tethers were formed from passive, stimulated (0.1 M fMLP), and osmotically swollen (170–180 mOsm) human neutrophils; as well as neutrophils treated with 0.3 M latrunculin A to disrupt the cytoskeleton. This tether formation was accomplished by micropipette suction of latex beads coated with antibodies to proteins on the neutrophil membrane surface. From plots of force versus velocity for the tether formation process, we calculated adhesion energies per unit area of the lipid membrane to the cytoskeleton and the viscous resistance (effective viscosity) that occurs during the formation of these tethers at finite velocity. Most of the properties of the neutrophil were altered once it had been treated as described above. We were also able to show mechanical reversibility of membrane tethers, as well as an unexpected formation rate at high tether forces. Since membrane tethers have been implicated in the rolling of neutrophils, then the changes in tether formation may ultimately alter how these cells roll. © 2002 Biomedical Engineering Society.
PAC2002: 8716Dg 相似文献