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1
Zhang, Jianing, Yanhuan Huang, Fuqiang Ye, Bibo Yang, Zengyong Li, and Xiaoling Hu. "Evaluation of Post-Stroke Impairment in Fine Tactile Sensation by Electroencephalography (EEG)-Based Machine Learning." Applied Sciences 12, no. 9 (May 9, 2022): 4796. http://dx.doi.org/10.3390/app12094796.
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Electroencephalography (EEG)-based measurements of fine tactile sensation produce large amounts of data, with high costs for manual evaluation. In this study, an EEG-based machine-learning (ML) model with support vector machine (SVM) was established to automatically evaluate post-stroke impairments in fine tactile sensation. Stroke survivors (n = 12, stroke group) and unimpaired participants (n = 15, control group) received stimulations with cotton, nylon, and wool fabrics to the different upper limbs of a stroke participant and the dominant side of the control. The average and maximal values of relative spectral power (RSP) of EEG in the stimulations were used as the inputs to the SVM-ML model, which was first optimized for classification accuracies for different limb sides through hyperparameter selection (γ, C) in radial basis function (RBF) kernel and cross-validation during cotton stimulation. Model generalization was investigated by comparing accuracies during stimulations with different fabrics to different limbs. The highest accuracies were achieved with (γ = 21, C = 23) for the RBF kernel (76.8%) and six-fold cross-validation (75.4%), respectively, in the gamma band for cotton stimulation; these were selected as optimal parameters for the SVM-ML model. In model generalization, significant differences in the post-stroke fabric stimulation accuracies were shifted to higher (beta/gamma) bands. The EEG-based SVM-ML model generated results similar to manual evaluation of cortical responses to fabric stimulations; this may aid automatic assessments of post-stroke fine tactile sensations.
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Suzuki, M., T. Asplund, H. Yamashita, C. H. Heldin, and P. Heldin. "Stimulation of hyaluronan biosynthesis by platelet-derived growth factor-BB and transforming growth factor-β1 involves activation of protein kinase C." Biochemical Journal 307, no. 3 (May 1, 1995): 817–21. http://dx.doi.org/10.1042/bj3070817.
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The intracellular signal transduction pathways that mediate the stimulatory effects of platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-beta on hyaluronan biosynthesis in human fibroblasts were investigated. The stimulatory effects of both PDGF-BB and TGF-beta 1 were dependent on protein kinase C (PKC), since the PKC inhibitor calphostin C inhibited the stimulation by the growth factors. Direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) also stimulated hyaluronan production, and the combination of either PDGF-BB or TGF-beta 1 and PMA gave an increased effect. One possible mechanism for activation of PKC is via induction of phospholipase C (PLC) activity; U-17322, an inhibitor of PLC-gamma, was found to inhibit partially PDGF-BB-stimulated hyaluronan synthesis. PDGF-BB is known to activate PLC-gamma through tyrosine phosphorylation; however, a PDGF beta-receptor mutant unable to interact with and activate PLC-gamma was still able to mediate induction of hyaluronan biosynthesis, indicating that PDGF-mediated stimulation is not entirely dependent on PLC-gamma. The stimulations by PDGF-BB and TGF-beta 1 were partly dependent on protein synthesis, since parts of the effects were inhibited by cycloheximide; in contrast, the effects mediated by PMA were not. Our results indicate that PKC is involved in the transduction of the effects of growth factors on hyaluronan biosynthesis, and that the effects involve direct or indirect activation of existing hyaluronan synthetase molecules, as well as induction of new enzyme molecules.
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Hui, C. S., and W. Chen. "Effects of conditioning depolarization and repetitive stimulation on Q beta and Q gamma charge components in frog cut twitch fibers." Journal of General Physiology 99, no. 6 (June 1, 1992): 1017–43. http://dx.doi.org/10.1085/jgp.99.6.1017.
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Charge movement was measured in frog cut twitch fibers with the double Vaseline-gap technique. Steady-state inactivation of charge movement was studied by changing the holding potential from -90 mV to a level ranging from -70 to -30 mV. Q beta and Q gamma at each holding potential were separated by fitting the Q-V plot with a sum of two Boltzmann distribution functions. At -70 mV Q beta and Q gamma were inactivated to 54.0% (SEM 2.2) and 82.7% (SEM 3.0) of the amounts at -90 mV. At holding potentials greater than or equal to -60 mV, more Q gamma was inactivated than Q beta, and at -30 mV Q gamma was completely inactivated but Q beta was not. There was no holding potential at which Q beta was unaffected and Q gamma was completely inactivated. The differences between the residual fractions of Q beta and Q gamma are significant at all holding potentials (P less than 0.001-0.05). The plot of the residual fraction of Q beta or Q gamma versus holding potential can be fitted well by an inverted sigmoidal curve that is a mirror image of the activation curve of the respective charge component. The pair of curves for Q gamma correlates well with those for tension generation or Ca release obtained by other investigators. The time courses of the inactivation of Q beta and Q gamma were studied by obtaining several Q-V plots with conditioning depolarizations lasting 1-20 s and separating each Q-V plot into Q beta and Q gamma components by fitting with a sum of two Boltzmann distribution functions. The inactivation time constant of Q beta was found to be 5-10 times as large as that of Q gamma. During repetitive stimulation, prominent I gamma humps could be observed in TEST-minus-CONTROL current traces and normal Q gamma components could be separated from the Q-V plots, whether 20 or 50 mM EGTA was present in the internal solution, whether 2 or 10 stimulations were used, and whether the stimuli were separated by 400 ms or 6 s. Repetitive stimulation slowed the kinetics of the I gamma hump and could shift the Q-V curve slightly in the depolarizing direction in some cases, resulting in an apparent suppression of charge at the potentials that fall on the steep part of the Q-V curve.
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Chen, Qi, Yue Dong, and Yan Gai. "Tactile Location Perception Encoded by Gamma-Band Power." Bioengineering 11, no. 4 (April 15, 2024): 377. http://dx.doi.org/10.3390/bioengineering11040377.
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Background: The perception of tactile-stimulation locations is an important function of the human somatosensory system during body movements and its interactions with the surroundings. Previous psychophysical and neurophysiological studies have focused on spatial location perception of the upper body. In this study, we recorded single-trial electroencephalography (EEG) responses evoked by four vibrotactile stimulators placed on the buttocks and thighs while the human subject was sitting in a chair with a cushion. Methods: Briefly, 14 human subjects were instructed to sit in a chair for a duration of 1 h or 1 h and 45 min. Two types of cushions were tested with each subject: a foam cushion and an air-cell-based cushion dedicated for wheelchair users to alleviate tissue stress. Vibrotactile stimulations were applied to the sitting interface at the beginning and end of the sitting period. Somatosensory-evoked potentials were obtained using a 32-channel EEG. An artificial neural net was used to predict the tactile locations based on the evoked EEG power. Results: We found that single-trial beta (13–30 Hz) and gamma (30–50 Hz) waves can best predict the tactor locations with an accuracy of up to 65%. Female subjects showed the highest performances, while males’ sensitivity tended to degrade after the sitting period. A three-way ANOVA analysis indicated that the air-cell cushion maintained location sensitivity better than the foam cushion. Conclusion: Our finding shows that tactile location information is encoded in EEG responses and provides insights on the fundamental mechanisms of the tactile system, as well as applications in brain–computer interfaces that rely on tactile stimulation.
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İMDAT, Nuray Nükhet, Özlem Tuğçe ÇİLİNGİR-KAYA, Zehra Nur TURGAN ÂŞIK, Tuğba KARAMAHMUTOĞLU, Medine GÜLÇEBİ İDRİZ OĞLU, Dilek AKAKIN, Filiz ONAT, and Serap ŞİRVANCI. "Electron microscopic GABA evaluation in hippocampal mossy terminals of genetic absence epilepsy rats receiving kindling stimulations." Clinical and Experimental Health Sciences 12, no. 4 (December 30, 2022): 981–87. http://dx.doi.org/10.33808/clinexphealthsci.1030132.
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Objective: The hypotheses related to the fact of epileptic mechanisms are mainly based on excitation-inhibition imbalance in central nervous system. GAERS (Genetic Absence Epilepsy Rats from Strasbourg) is a well-known animal model of absence epilepsy, and frequently used in experimental studies. In the present study, we aimed to examine possible morphological and gamma-aminobutyric acid (GABA) density changes in GAERS hippocampus after electrical kindling stimulations.
Methods: All control and test group rats received 6 kindling stimulations. Rats were decapitated 1 h after the last stimulation. Ultrastructural GABA immunocytochemistry was used to evaluate GABA density quantitatively in mossy terminals of hippocampal CA3 region.
Results: GABA levels were less in kindling groups compared to their controls, and in GAERS groups compared to Wistar groups; mitochondrial and dendritic spine area ratios were greater in GAERS groups compared to Wistar groups, although all these evaluations were statistically nonsignificant. Depletion of synaptic vesicles was evident in the mossy terminals of kindling groups.
Conclusion: The reason of decreased levels of GABA found in the present study might be that GABA has been released from the synaptic pool rapidly at an early time period after the last stimulation, for compansation mechanisms. Depletion of synaptic vesicles observed in kindling groups shows that even 6 kindling stimulations have an impact of changing hippocampal morphology in trisynaptic cycle. The increased mitochondrial area in GAERS might be related to the increased mitochondrial activity. The increased dendritic spine area might be related to the increased performance of learning in GAERS. Our findings indicating that absence epilepsy and temporal lobe epilepsy have different mechanisms of epileptogenesis might be a basis for further experimental studies
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Schoisswohl, Stefan, Berthold Langguth, Tobias Hebel, Mohamed A. Abdelnaim, Gregor Volberg, and Martin Schecklmann. "Heading for Personalized rTMS in Tinnitus: Reliability of Individualized Stimulation Protocols in Behavioral and Electrophysiological Responses." Journal of Personalized Medicine 11, no. 6 (June 9, 2021): 536. http://dx.doi.org/10.3390/jpm11060536.
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Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool potentially modulating pathological brain activity. Its clinical effectiveness is hampered by varying results and characterized by inter-individual variability in treatment responses. RTMS individualization might constitute a useful strategy to overcome this variability. A precondition for this approach would be that repeatedly applied protocols result in reliable effects. The condition tinnitus provides the advantage of immediate behavioral consequences (tinnitus loudness changes) after interventions and thus offers an excellent model to exemplify TMS personalization. Objective: The aim was to investigate the test–retest reliability of short rTMS stimulations in modifying tinnitus loudness and oscillatory brain activity as well as to examine the feasibility of rTMS individualization in tinnitus. Methods: Three short verum (1, 10, 20 Hz; 200 pulses) and one sham (0.1 Hz; 20 pulses) rTMS protocol were administered on two different days in 22 tinnitus patients. Before and after each protocol, oscillatory brain activity was recorded with electroencephalography (EEG), together with behavioral tinnitus loudness ratings. RTMS individualization was executed on the basis of behavioral and electrophysiological responses. Stimulation responders were identified via consistent sham-superior increases in tinnitus loudness (behavioral responders) and alpha power increases or gamma power decreases (alpha responders/gamma responders) in accordance with the prevalent neurophysiological models for tinnitus. Results: It was feasible to identify individualized rTMS protocols featuring reliable tinnitus loudness changes (55% behavioral responder), alpha increases (91% alpha responder) and gamma decreases (100% gamma responder), respectively. Alpha responses primary occurred over parieto-occipital areas, whereas gamma responses mainly appeared over frontal regions. On the contrary, test–retest correlation analyses per protocol at a group level were not significant neither for behavioral nor for electrophysiological effects. No associations between behavioral and EEG responses were found. Conclusion: RTMS individualization via behavioral and electrophysiological data in tinnitus can be considered as a feasible approach to overcome low reliability at the group level. The present results open the discussion favoring personalization utilizing neurophysiological markers rather than behavioral responses. These insights are not only useful for the rTMS treatment of tinnitus but also for neuromodulation interventions in other pathologies, as our results suggest that the individualization of stimulation protocols is feasible despite absent group-level reliability.
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Hwang, Eun Jung, and Richard A. Andersen. "Effects of visual stimulation on LFPs, spikes, and LFP-spike relations in PRR." Journal of Neurophysiology 105, no. 4 (April 2011): 1850–60. http://dx.doi.org/10.1152/jn.00802.2010.
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Local field potentials (LFPs) have shown diverse relations to the spikes across different brain areas and stimulus features, suggesting that LFP-spike relationships are highly specific to the underlying connectivity of a local network. If so, the LFP-spike relationship may vary even within one brain area under the same task condition if neurons have heterogeneous connectivity with the active input sources during the task. Here, we tested this hypothesis in the parietal reach region (PRR), which includes two distinct classes of motor goal planning neurons with different connectivity to the visual input, i.e., visuomotor neurons receive stronger visual input than motor neurons. We predicted that the visual stimulation would render both the spike response and the LFP-spike relationship different between the two neuronal subpopulations. Thus we examined how visual stimulations affect spikes, LFPs, and LFP-spike relationships in PRR by comparing their planning (delay) period activity between two conditions: with or without a visual stimulus at the reach target. Neurons were classified as visuomotor if the visual stimulation increased their firing rate, or as motor otherwise. We found that the visual stimulation increased LFP power in gamma bands >40 Hz for both classes. Moreover, confirming our prediction, the correlation between the LFP gamma power and the firing rate became higher for the visuomotor than motor neurons in the presence of visual stimulation. We conclude that LFPs vary with the stimulation condition and that the LFP-spike relationship depends on a given neuron's connectivity to the dominant input sources in a particular stimulation condition.
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Sudha Kumari, Lekshmy, and Abbas Z. Kouzani. "A Miniaturized Closed-Loop Optogenetic Brain Stimulation Device." Electronics 11, no. 10 (May 17, 2022): 1591. http://dx.doi.org/10.3390/electronics11101591.
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This paper presents a tetherless and miniaturized closed-loop optogenetic brain stimulation device, designed as a back mountable device for laboratory mice. The device has the ability to sense the biomarkers corresponding to major depressive disorder (MDD) from local field potential (LFP), and produces a feedback signal to control the closed-loop operation after on-device processing of the sensed signals. MDD is a chronic neurological disorder and there are still many unanswered questions about the underlying neurological mechanisms behind its occurrence. Along with other brain stimulation paradigms, optogenetics has recently proved effective in the study of MDD. Most of these experiments have used tethered and connected devices. However, the use of tethered devices in optogenetic brain stimulation experiments has the drawback of hindering the free movement of the laboratory animal subjects undergoing stimulation. To address this issue, the proposed device is small, light-weight, untethered, and back-mountable. The device consists of: (i) an optrode which houses an electrode for collecting neural signals, an optical source for delivering light stimulations, and a temperature sensor for monitoring the temperature increase at the stimulation site, (ii) a neural sensor for acquisition and pre-processing of the neural signals to obtain LFP signals in the frequency range of 4 to 200 Hz, as electrophysiological biomarkers of MDD (iii) a classifier for classification of the signal into four classes: normal, abnormal alpha, abnormal theta, and abnormal gamma oscillations, (iv) a control algorithm to select stimulation parameters based on the input class, and (v) a stimulator for generating light stimulations. The design, implementation, and evaluation of the device are presented, and the results are discussed. The neural sensor and the stimulator are circular in shape with a radius of 8 mm. Pre-recorded neural signals from the mouse hippocampus are used for the evaluation of the device.
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Farrar, WL, and A. Harel-Bellan. "Myeloid growth factor(s) regulation of ornithine decarboxylase: effects of antiproliferative signals interferon-gamma and cAMP." Blood 73, no. 6 (May 1, 1989): 1468–75. http://dx.doi.org/10.1182/blood.v73.6.1468.1468.
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Abstract Colony-stimulating factors (CSFs) stimulate the activation and steady- state mRNA accumulation of an important regulatory enzyme for macromolecular synthesis, ornithine decarboxylase (ODC). Cloned murine CSF-dependent cell lines exhibited a rapid activation of ODC enzyme activity, detectable within ten minutes of stimulations with either interleukin-3 (IL-3), GM-CSF, or G-CSF. This early phase of enzyme activation did not require early protein or mRNA synthesis. The subsequent protracted rise in ODC activity occurring four to six hours after CSF treatment was dependent on increases in steady-state ODC mRNA accumulation and de novo protein synthesis. CSF, therefore, modulates both posttranslational activation of preexisting ODC and stabilization and accumulation of ODC mRNA. Antiproliferative signals, such as cAMP or interferon-gamma (IFN-gamma), effectively inhibited the CSF-directed increase in steady-state ODC mRNA. Cotreatment of the murine NSF 60.8 cell line with IFN-gamma and GM-CSF decreased steady-state ODC mRNA greater than 80% as compared with GM-CSF-treated cells alone. IFN treatment did not cause any appreciable destabilization of mature ODC mRNA, suggesting that its major effect may be at the level of ODC mRNA transcription or posttranscriptional processing. These data indicate that the ODC gene-protein system is an important molecular locus of the effects of myeloid proliferative and antiproliferation signals.
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Farrar, WL, and A. Harel-Bellan. "Myeloid growth factor(s) regulation of ornithine decarboxylase: effects of antiproliferative signals interferon-gamma and cAMP." Blood 73, no. 6 (May 1, 1989): 1468–75. http://dx.doi.org/10.1182/blood.v73.6.1468.bloodjournal7361468.
Full textAbstract:
Colony-stimulating factors (CSFs) stimulate the activation and steady- state mRNA accumulation of an important regulatory enzyme for macromolecular synthesis, ornithine decarboxylase (ODC). Cloned murine CSF-dependent cell lines exhibited a rapid activation of ODC enzyme activity, detectable within ten minutes of stimulations with either interleukin-3 (IL-3), GM-CSF, or G-CSF. This early phase of enzyme activation did not require early protein or mRNA synthesis. The subsequent protracted rise in ODC activity occurring four to six hours after CSF treatment was dependent on increases in steady-state ODC mRNA accumulation and de novo protein synthesis. CSF, therefore, modulates both posttranslational activation of preexisting ODC and stabilization and accumulation of ODC mRNA. Antiproliferative signals, such as cAMP or interferon-gamma (IFN-gamma), effectively inhibited the CSF-directed increase in steady-state ODC mRNA. Cotreatment of the murine NSF 60.8 cell line with IFN-gamma and GM-CSF decreased steady-state ODC mRNA greater than 80% as compared with GM-CSF-treated cells alone. IFN treatment did not cause any appreciable destabilization of mature ODC mRNA, suggesting that its major effect may be at the level of ODC mRNA transcription or posttranscriptional processing. These data indicate that the ODC gene-protein system is an important molecular locus of the effects of myeloid proliferative and antiproliferation signals.
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Morré, D. J., M. Davidson, C. Geilen, J. Lawrence, G. Flesher, R. Crowe, and F. L. Crane. "NADH oxidase activity of rat liver plasma membrane activated by guanine nucleotides." Biochemical Journal 292, no. 3 (June 15, 1993): 647–53. http://dx.doi.org/10.1042/bj2920647.
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The activity of a hormone- and growth-factor-stimulated NADH oxidase of the rat liver plasma membrane responds to guanine nucleotides, but in a manner that differs from that of the classic trimeric and low-molecular-mass monomeric G-proteins. In the absence of added bivalent ions, both GTP and GDP as well as guanosine 5′-[gamma-thio]triphosphate (GTP[gamma-S]) but not guanosine 5′[beta-thio]diphosphate (GDP[beta-S]) stimulate the activity over the range 1 microM to 100 microM. Other di- and tri-nucleotides also stimulate, but only at concentrations of 100 microM or higher. Added bivalent ions are not required either for NADH oxidation or guanine nucleotide stimulation. Bivalent ions (Mg2+ > Mn2+ > or = Ca2+) alone stimulate only slightly at low concentrations and then inhibit at high concentrations. The inhibitions are augmented by GDP or GTP [gamma-S] but not by GTP. Although the activity is the same, or less, in the presence of 0.5 mM MgCl2, GTP at 1-100 nM and other nucleotides at 0.1 mM or 1 mM still stimulate in its presence. The NADH oxidase is activated by mastoparan but aluminum fluoride is weakly inhibitory. Cholera and pertussis toxins elicit only marginal responses. Both the Mg2+ and the GDP and GTP[gamma-S] inhibitions (but not the GTP stimulations) shift to higher concentrations when the membrane preparations are first solubilized with Triton X-100. The results suggest a role for guanine nucleotides in the regulation of plasma membrane NADH oxidase, but with properties that differ from those of either trimeric or the low-molecular-mass G proteins thus far described.
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Shen, F., X. L. Xu, L. H. Graf, and A. S. Chong. "CD45-cross-linking stimulates IFN-gamma production in NK cells." Journal of Immunology 154, no. 2 (January 15, 1995): 644–52. http://dx.doi.org/10.4049/jimmunol.154.2.644.
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Abstract The in vitro demonstration of the ability of NK cells to secrete cytokines prompted in vivo studies that illustrated the importance of NK cell-derived cytokines in regulating immune responses. Cross-linking of CD16 on NK cells can stimulate cytokine production. CD16-independent interactions capable of stimulating cytokine production have also been described, but molecules mediating such stimulations remain to be biochemically defined. We report here that cross-linking of CD45 specifically stimulates IFN-gamma production in human NK cells. The NK cells used were IL-2-activated adherent NK cells and from the NK3.3 cell line. The ability of CD45 mAbs to stimulate NK cells appears not to be dependent on CD16, as CD45 mAbs of both IgG1 and IgG2a isotypes were equally stimulatory, as were F(ab')2 compared with whole anti-CD45 mAbs. Resting NK cells, like T cells, express predominantly CD45RA, whereas IL-2 activated adherent NK cells acquire expression of CD45RO. Abs specific for CD45RO, but not CD45RA, were able to stimulate IFN-gamma production in NK cells. It has been reported that one ligand for CD45RO is CD22 beta. We tested the ability of CD22-expressing transfectants to bind to and stimulate NK cells. Whereas NK cells bound to CD22 alpha and CD22 beta transfectants, this interaction was not inhibited by CD45RO Abs. In addition, neither of the CD22-transfectants were able to stimulate NK3.3 cells to secrete IFN-gamma. These observations collectively suggest that binding of NK3.3 cells to CD22 may be independent of CD45RO on NK3.3 cells.
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Vollebregt, M. M. G., A. Malfroot, M. De Raedemaecker, M. van der Burg, and J. E. van der Werff ten Bosch. "Immunodeficiency in a Child with Rapadilino Syndrome: A Case Report and Review of the Literature." Case Reports in Immunology 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/137368.
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Rapadilino syndrome is a genetic disease characterized by a characteristic clinical tableau. It is caused by mutations in RECQL4 gene. Immunodeficiency is not described as a classical feature of the disease. We present a 2-year-old girl with Rapadilino syndrome with important lymphadenopathies and pneumonia due to disseminatedMycobacterium lentiflavuminfection. An immunological work-up showed several unexpected abnormalities. Repeated blood samples showed severe lymphopenia. Immunophenotyping showed low T, B, and NK cells. No Treg cells were seen. T cell responses to stimulations were insufficient. The IL12/IL23 interferon gamma pathway was normal. Gamma globulin levels and vaccination responses were low. With this report, we aim to stress the importance of screening immunodeficiency in patients with RECQL4 mutations for immunodeficiency and the need to further research into its physiopathology.
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Zhu, Yan, Di Wu, Kewei Sun, Xianglong Chen, Yifan Wang, Yang He, and Wei Xiao. "Alpha and Theta Oscillations Are Causally Linked to Interference Inhibition: Evidence from High-Definition Transcranial Alternating Current Stimulation." Brain Sciences 13, no. 7 (July 4, 2023): 1026. http://dx.doi.org/10.3390/brainsci13071026.
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(1) Background: The Go/NoGo task and color-word Stroop task were used to investigate the effect of applying different frequency bands of neural oscillations to the lDLPFC on inhibitory control modulation. (2) Methods: Participants were randomly categorized into four groups and received HD-tACS at 6, 10, and 20 Hz or sham stimulation at 1.5 mA for 20 min. All participants performed a color-word Stroop task and Go/NoGo task before and immediately after the stimulation; closed-eye resting-state EEG signals were acquired for 3 min before and after the tasks. (3) Results: There were no significant differences in the Go/NoGo behavioral indices task across the four groups. In the color-word Stroop task, the Stroop effect of response time was significantly reduced by 6 and 10 Hz stimulations compared to sham stimulation, and the Stroop effect of accuracy was significantly reduced by 10 Hz stimulation. There were no significant differences in the frequency range-specific (delta, theta, alpha, beta, or gamma) resting EEG power before and after stimulation. (4) Conclusions: HD-tACS at 6 and 10 Hz effectively improved participants’ performance on the color-word Stroop task, demonstrating the importance of the lDLPFC in interference inhibition and supporting a causal relationship between theta and alpha oscillations in interference inhibition.
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Arif, Yasra, Alex I. Wiesman, Nicholas J. Christopher-Hayes, and Tony W. Wilson. "Aberrant inhibitory processing in the somatosensory cortices of cannabis-users." Journal of Psychopharmacology 35, no. 11 (October 25, 2021): 1356–64. http://dx.doi.org/10.1177/02698811211050557.
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Background: Delta-9 tetrahydrocannabinol (THC) is a major exogenous psychoactive agent, which acts as a partial agonist on cannabinoid (CB1) receptors. THC is known to inhibit presynaptic neurotransmission and has been repeatedly linked to acute decrements in cognitive function across multiple domains. Previous electrophysiological studies of sensory gating have shown specific deficits in inhibitory processing in cannabis-users, but to date these findings have been limited to the auditory cortices, and the degree to which these aberrations extend to other brain regions remains largely unknown. Methods: We used magnetoencephalography (MEG) and a paired-pulse somatosensory stimulation paradigm to probe inhibitory processing in 29 cannabis-users (i.e. at least four times per month) and 41 demographically matched non-user controls. MEG responses to each stimulation were imaged in both the oscillatory and time domain, and voxel time-series data were extracted to quantify the dynamics of sensory gating, oscillatory gamma activity, evoked responses, and spontaneous neural activity. Results: We observed robust somatosensory responses following both stimulations, which were used to compute sensory gating ratios. Cannabis-users exhibited significantly impaired gating relative to non-users in somatosensory cortices, as well as decreased spontaneous neural activity. In contrast, oscillatory gamma activity did not appear to be affected by cannabis use. Conclusions: We observed impaired gating of redundant somatosensory information and altered spontaneous activity in the same cortical tissue in cannabis-users compared to non-users. These data suggest that cannabis use is associated with a decline in the brain’s ability to properly filter repetitive information and impairments in cortical inhibitory processing.
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Guy-Grand, D., B. Rocha, P. Mintz, M. Malassis-Seris, F. Selz, B. Malissen, and P. Vassalli. "Different use of T cell receptor transducing modules in two populations of gut intraepithelial lymphocytes are related to distinct pathways of T cell differentiation." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 673–79. http://dx.doi.org/10.1084/jem.180.2.673.
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Most gut intraepithelial cells (IEL) of the mouse are T cells that bear CD8 molecules, present either as alpha-beta chain heterodimers (CD8 beta+) or as alpha chain homodimers (CD8 beta-). All CD8 beta+ IEL bear alpha/beta T cell receptors (TCR); CD8 beta- IEL bear either alpha/beta or gamma/delta TCR and are considered to be a thymus-independent (TI) population, probably arising locally from a small fraction of CD3- IEL containing the recombinant activating gene RAG proteins. Here we report that TI CD8 beta- IEL, whether bearing alpha/beta or gamma/delta TCR, contain, in normal mice, mRNAs for both zeta and Fc epsilon RI gamma chains. These chains are present in their CD3-TCR complexes as homo- or heterodimers. In contrast, only zeta chain mRNA and homodimers are found in gut CD8 alpha/beta+ IEL and in peripheral T lymphocytes. Intestinal CD3- precursor cells contain only gamma chain, and CD3- IL-2R+ thymocyte precursors only zeta chain mRNAs. Only very primitive thymocyte precursors contain detectable gamma chain mRNA, and it thus appears that Fc epsilon RI gamma chain use is switched off at a very early stage during thymocyte differentiation. Thus, T cell differentiation in the gut epithelium differs from that occurring in the thymus, from which CD8 beta+ IEL appear to derive. Use of different TCR transducing modules and CD8 accessory molecules between the TI and the thymus-derived T cell populations provides an explanation for their difference in reactivity to antigenic stimulations and thus in selection of repertoires.
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Gorbatova, Irina V., Elizaveta A. Kazakova, Mikhail S. Podlutskii, Ivan A. Pishenin, Vladimir S. Bondarenko, Aleksandra A. Dontsova, Dmitriy P. Dontsov, et al. "Studying Gene Expression in Irradiated Barley Cultivars: PM19L-like and CML31-like Expression as Possible Determinants of Radiation Hormesis Effect." Agronomy 10, no. 11 (November 22, 2020): 1837. http://dx.doi.org/10.3390/agronomy10111837.
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Gamma (γ)-irradiation of plants at low doses can provoke a broad range of growth-stimulating effects. In order to reveal universal target genes that are involved in molecular pathways of radiation hormesis establishment, we studied nine barley cultivars for their tolerance to γ-irradiation of seeds. Four morphological traits were assessed in barley seedlings after γ-irradiation of seeds at 20 Gy. Nine cultivars were sorted according to the sensitivity to irradiation as γ-stimulated, “no morphological effect”, or γ-inhibited. Gene expression of 17 candidate genes was evaluated for the 7 most contrasting cultivars. Changes in expression of barley homologues of PM19L and CML31 were suggested as possible determinants of radiation hormesis effect. The possible role of jasmonate signaling in roots in radiation growth stimulations was revealed. Morphological analysis and gene expression study showed that the genetic background of a cultivar plays an important role in eustress responses to low-dose γ-irradiation of seeds.
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Shirakawa, F., Y. Tanaka, S. Eto, H. Suzuki, J. Yodoi, and U. Yamashita. "Effect of interleukin 1 on the expression of interleukin 2 receptor (Tac antigen) on human natural killer cells and natural killer-like cell line (YT cells)." Journal of Immunology 137, no. 2 (July 15, 1986): 551–56. http://dx.doi.org/10.4049/jimmunol.137.2.551.
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Abstract The effect of interleukin 1 (IL 1) on the expression of interleukin 2 receptor (IL 2R/Tac antigen) on human natural killer (NK) cells and the NK-like cell line, YT was studied with the use of a fluoresceinated anti-IL 2R monoclonal antibody and a Spectrum III flow cytofluorometer. IL 2R was expressed on approximately 10% of NK cells. The expression of IL 2R on NK cells was increased to approximately 25% by the in vitro culture with monocytes or IL 1 and to a less extent by the culture with IL 2 or interferon-gamma (IFN-gamma). IL 2R was expressed on approximately 50% of YT cells without any stimulations. The expression of IL 2R on YT cells was increased up to almost 100% by the culture with IL 1 or monocytes, but not with IL 2, IFN-alpha, IFN-beta, IFN-gamma, or lectins such as concanavalin A and phytohemagglutinin-P. IL 1 absorbed with YT cells or murine thymocytes lost both IL 1 activity detected by the stimulation of murine thymocyte proliferative response and enhancing activity of IL 2R expression on YT cells, suggesting that IL 1 has both activities. However, the assay system of the expression of IL 2R on YT cells is much more sensitive than the stimulation of murine thymocyte proliferative response. By the kinetic study, the enhancement of IL 2R expression was induced by only a 2-hr incubation of YT cells with IL 1. This enhancement did not proceed at 4 degrees C or by the treatment of YT cells with actinomycin D or cycloheximide, suggesting that this enhancement is energy dependent and requires the synthesis of RNA and protein but not DNA. Thus IL 1 plays an important role for the regulation of the expression of IL 2R on NK cells, and IL 1-dependent IL 2R expression on YT cells may give us a good model for the study of the molecular mechanism of the regulation of IL 2R expression.
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Tasnim, Israt, Nuri Ince, Sujit Prabhu, Kyle Noll, Chandra Swamy, Katherine Connelly, Priscella Asman, et al. "NIMG-64. INTRAOPERATIVE LANGUAGE MAPPING USING GAMMA-BAND MODULATIONS OF ELECTROCORTICOGRAM (ECOG) INDUCED BY WORD/SOUND CATEGORIZATION TASK: VALIDATION WITH REPRODUCIBLE SPEECH ARRESTS DURING LINGUISTIC TASKS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii178—vii179. http://dx.doi.org/10.1093/neuonc/noac209.682.
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Abstract OBJECTIVE Determination of the correlation between gamma-band modulations of electrocorticogram (ECoG) induced by linguistic tasks and reproducible speech arrests caused by bipolar direct cortical stimulations (DCS). METHODS 3 subjects (age 39, 56, 64 years) with left temporal lobe glioma underwent surgery involving awake craniotomy. A 4x8 ECoG electrode grid (2.3mm contact exposure, 1cm contact spacing) was placed above the respective tumor area. A MATLAB-Simulink based real-time software system running on a portable laptop computer was used to map gamma-band modulations as a 2D heat map while the subjects engaged in different linguistic tasks: word/sound categorization by pressing a button, object naming, action naming, written descriptive naming, and auditory descriptive naming. Auditory stimulus was applied during word/sound categorization task (duration 300 – 500ms), auditory descriptive naming ( > 1s); other tasks involved visual stimulus only. The subjects repeated the four naming tasks while bipolar DCS (2/4/6 mA, 60Hz, 2s) was applied at different electrode pairs. RESULTS The electrodes having stronger gamma-band modulations were distinct for different tasks. Reproducible speech arrests occurred during object, action, auditory naming tasks while stimulating specific electrode pairs, even though not all these electrodes had strong activations during these tasks. Across all subjects these electrodes had strong activations consistently during word/sound categorization tasks, starting as early as 250ms and lasting even after the auditory stimuli were terminated (~ 650ms). The longer activations can be associated with word recognition process. The subjects self-reported about having difficulty in comprehension rather than speech production during speech arrests. 3D brain rendering using MRI images showed that the speech arrest electrodes were identically located on the superior temporal gyrus, inferior to central sulcus for all 3 subjects. CONCLUSION Intraoperative language mapping guided by gamma-band ECoG modulations induced by word/sound categorization tasks can be utilized to localize eloquent cortex associated with auditory processing.
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Croft, M., and S. L. Swain. "Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines." Journal of Immunology 154, no. 9 (May 1, 1995): 4269–82. http://dx.doi.org/10.4049/jimmunol.154.9.4269.
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Abstract Development of T cells during primary responses was investigated using pigeon cytochrome C-specific naive Th from TCR transgenic mice. Naive CD4 cells did not activate and help resting B cells. This failure was found to be primarily because the resting B cells were incapable of stimulating the naive Th. Provision of a costimulatory signal such as anti-CD28, or addition of APCs that express costimulatory molecules, such as dendritic cells, activated B cells, and B7+ and B7+ICAM(+)-expressing fibroblasts, induced naive Th activation and promoted T cell-dependent help for IgM secretion. T cell activation for as little as 24 h promoted helper activity, and Ig secretion required production of small amounts of IL-4 by the activated naive Th. On initial stimulation, naive Th secrete only IL-2. By mRNA analysis, activated naive Th were also shown to produce IL-4, however induction of IL-4 message only occurred 24 h after initial activation and required additional stimulation with Ag. A single exposure of naive CD4 to Ag/APC followed by 4 to 12 days in culture led to generation of effector Th which secreted IL-2 and some IFN-gamma, and no detectable IL-4 or IL-5, and which could only help B cells to IgM secretion. In contrast, similar cultures that received Ag/APC one or more times during this period generated effector cells capable of secreting easily detectable titers of IL-4 and IL-5, as well as IL-2 and IFN-gamma, and able to now promote IgG1 and IgE responses. Generation of these Th0-like effectors was accompanied by increasing amounts of IL-4 secreted during the culture period after each restimulation, and addition of anti-IL-4 in culture inhibited development of the capacity to produce Th2 cytokines. These studies reinforce the notion that naive CD4 must interact with a costimulatory professional APC, rather than a resting B cell, for initiation of the primary response, but show that such an interaction can result in rapid development of the ability to interact with and provide cognate help to B cells. They also suggest that if activated naive CD4 cells receive multiple stimulations from Ag/APC, enough endogenous IL-4 can be produced to drive differentiation into effectors secreting type 2 cytokines. The existence of such an autocrine feedback mechanism suggests that the amount and availability of Ag could influence the nature and polarization of the Th response.
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Palmer, E. M., and G. A. van Seventer. "Human T helper cell differentiation is regulated by the combined action of cytokines and accessory cell-dependent costimulatory signals." Journal of Immunology 158, no. 6 (March 15, 1997): 2654–62. http://dx.doi.org/10.4049/jimmunol.158.6.2654.
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Abstract We have developed an in vitro differentiation model for human Th cells to study the role of cytokines and accessory cell-dependent costimulatory signals in this process. Peripheral blood-derived CD4+ "naive" (CD45RA+ RO-) T cells were stimulated in weekly intervals with immobilized anti-CD3 mAb, accessory cells, and exogenous cytokines, and were analyzed for cytokine secretion pattern. With the B cell line JY (B7-1+ B7-2+), as source of accessory cells, we could generate distinct Th subsets. Coculture with the combination of recombinant human (rh) IL-1beta and rhIL-6 gave rise to Th0-like cells, which secreted low levels of IFN-gamma and IL-5. The addition of rhIL-12 led to the generation of Th1-like cells, which secreted high levels of IL-2, IFN-gamma, TNF-alpha, and upon multiple stimulations, significant levels of IL-10. The presence of rhIL-4 induced Th2-like cells that secreted high levels of IL-5 and IL-13, but undetectable levels of IL-4. Only after stimulation with phorbol ester and calcium ionophore could these Th2-like cells be induced to secrete significant levels of IL-4, indicating distinct stimulatory requirements for the induction of IL-5 and IL-13 compared with IL-4. The B7-1-negative monocytic cell line U937 could only provide accessory cell-dependent costimulatory signals for the generation of Th1-like cells, while B7-1-transfected U937 cells acquired the capacity to provide costimulation for the generation of Th2-like cells. These results indicate a differential dependence on CD28-mediated costimulation for the generation of human Th1-like and Th2-like cells.
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Cheron, Julian, and Guy Cheron. "Beta-gamma burst stimulations of the inferior olive induce high-frequency oscillations in the deep cerebellar nuclei." European Journal of Neuroscience 48, no. 8 (March 9, 2018): 2879–89. http://dx.doi.org/10.1111/ejn.13873.
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Poccia, F., S. Boullier, H. Lecoeur, M. Cochet, Y. Poquet, V. Colizzi, J. J. Fournie, and M. L. Gougeon. "Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons." Journal of Immunology 157, no. 1 (July 1, 1996): 449–61. http://dx.doi.org/10.4049/jimmunol.157.1.449.
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Abstract Gamma delta T cells represent a minor population of human peripheral lymphocytes, the majority of them expressing the V delta 2/V gamma 9 TCR. Their accumulation in infectious disease lesions and their reactivity toward mycobacterial Ags suggest that V gamma 9/V delta 2 T cells play a role during infectious diseases. We have shown previously a significant expansion of the V delta 1 subset parallel to a dramatic decrease of the V delta 2 subset in PBMC from HIV-infected persons. To understand the mechanisms involved in the deletion of V delta 2 T cells, we analyzed their ability to respond in vitro to several V gamma 9/V delta 2 t cell-specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, V delta 2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since V delta 2 responsiveness to mycobacterial Ags was shown to be normally dependent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore V delta 2 T cells' responsiveness to TUBAg-1 was tested. V delta 2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulated V delta 2 T cells. Since V delta 2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell death could be involved in this process, particularly because of their activated phenotype. Although peripheral V delta 2 T cells from some HIV-infected persons showed an increased susceptibility to spontaneous and activation-induced apoptosis, statistical comparison between HIV+ and HIV- donors indicated that there was no difference between both groups in the rate of V delta 2 apoptosis. Finally, V delta 2 complementarity-determining region 3 TCR analysis indicated that, in vivo, the remaining V delta 2 T cells were still polyclonal. All together these results suggest that the qualitative and quantitative alterations of the V delta 2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribution of a cellular ligand induced or modified by chronic HIV infection.
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Kim, Woo Sik, DaeSeong Choi, Ji Min Park, Ha-Yeon Song, Ho Seong Seo, Dong-Eun Lee, and Eui-Baek Byun. "Comparison of Exosomes Derived from Non- and Gamma-Irradiated Melanoma Cancer Cells as a Potential Antigenic and Immunogenic Source for Dendritic Cell-Based Immunotherapeutic Vaccine." Vaccines 8, no. 4 (November 19, 2020): 699. http://dx.doi.org/10.3390/vaccines8040699.
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Cancer cells can secrete exosomes under various stressful conditions, whose functions are involved in the delivery of various biologically active materials into host cells and/or modulation of host immune responses. Therefore, an improved understanding of the immunological interventions that stress-induced tumor exosomes have may provide novel therapeutic approaches and more effective vaccine designs. Here, we confirmed the phenotypical and functional alterations of dendritic cells (DCs), which act as a bridge between the innate and adaptive arms of immunity, following non-irradiated (N-exo) and gamma-irradiated melanoma cancer cell-derived exosome (G-exo) stimulation, and evaluated the N-exo- and G-exo-stimulated DCs as therapeutic cancer vaccine candidates. We demonstrated that G-exo-stimulated DCs result in DC maturation by the upregulation of surface molecule expression, pro-inflammatory cytokine release, and antigen-presenting ability, and the downregulation of endocytic capacity. In addition, these cells promoted T cell proliferation and the generation of T helper type 1 (Th1) and interferon (IFN)-γ-producing CD8+ T cells. However, N-exo-stimulated DCs induced semi-mature phenotypes and functions, eventually inhibiting T cell proliferation, decreasing IFN-γ, and increasing IL-10-producing CD4+ T cells. In addition, although N-exo and G-exo stimulations showed similar levels of antigen-specific IFN-γ production, which served as tumor antigen sources in melanoma-specific T cells, G-exo-stimulated DC vaccination conferred a stronger tumor growth inhibition than N-exo-stimulated DC vaccination; further, this was accompanied by a high frequency of tumor-specific, multifunctional effector T cells. These results suggest that gamma irradiation could provide important clues for designing and developing effective exosome vaccines that can induce strong immunogenicity, especially tumor-specific multifunctional T cell responses.
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Claro, E., A. Garcia, and F. Picatoste. "Carbachol and histamine stimulation of guanine-nucleotide-dependent phosphoinositide hydrolysis in rat brain cortical membranes." Biochemical Journal 261, no. 1 (July 1, 1989): 29–35. http://dx.doi.org/10.1042/bj2610029.
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Guanine nucleotides have been shown to stimulate phosphoinositide breakdown in brain membranes, but no potentiation of such an effect by agonist was demonstrated. We have studied the effect of carbachol and histamine on guanosine 5′-[gamma-thio]triphosphate (GTP[S]) stimulation of inositol phosphates formation in [3H]inositol-labelled rat brain cortical membranes. In this preparation, GTP[S] enhancement of phosphoinositide hydrolysis required the presence of MgATP and low Ca2+ concentration (100 nM). Carbachol potentiation of the GTP[S] effect was only observed when 1 mM-deoxycholate was also added. Under these conditions, stimulated production of [3H]inositol phosphates was linear for at least 15 min, and [3H]inositol bisphosphate [(3H]IP2) accounted for approx. 80%, whereas the amount of [3H]inositol trisphosphate [(3H]IP3) was very low. Stimulation by GTP[S] was concentration-dependent (half-maximal effect at 0.86 microM), and its maximal effect (815% over basal) was increased by 1 mM-carbachol (1.9-fold) and -histamine (1.7-fold). Both agonists decreased the slope index of the GTP[S] concentration/effect curve to values lower than unity, suggesting the appearance of some heterogeneity in the population of guanine-nucleotide-binding proteins (G-proteins) involved. The carbachol and histamine effects were also concentration-dependent, and were inhibited by atropine and mepyramine respectively. Fluoroaluminate stimulated phosphoinositide hydrolysis to a higher extent than GTP[S] plus carbachol, and these stimulations were not additive, indicating that the same polyphosphoinositide phospholipase C-coupled G-protein mediates both effects.
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Thörn, Carolina Wilnerzon, Vasilios Kafetzopoulos, and Bernat Kocsis. "Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal–Hippocampal Coupling." International Journal of Molecular Sciences 23, no. 19 (October 3, 2022): 11705. http://dx.doi.org/10.3390/ijms231911705.
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Dopamine D4 receptor (D4R) mechanisms are implicated in psychiatric diseases characterized by cognitive deficits, including schizophrenia, ADHD, and autism. The cellular mechanisms are poorly understood, but impaired neuronal synchronization in cortical networks was proposed to contribute to these deficits. In animal experiments, D4R activation was shown to generate aberrant increased gamma oscillations and to reduce performance on cognitive tasks requiring functional prefrontal cortex (PFC) and hippocampus (HPC) networks. While fast oscillations in the gamma range are important for local synchronization within neuronal ensembles, long-range synchronization between distant structures is achieved by slow rhythms in the delta, theta, alpha ranges. The characteristics of slow oscillations vary between structures during cognitive tasks. HPC activity is dominated by theta rhythm, whereas PFC generates unique oscillations in the 2–4 Hz range. In order to investigate the role of D4R on slow rhythms, cortical activity was recorded in rats under urethane anesthesia in which slow oscillations can be elicited in a controlled manner without behavioral confounds, by electrical stimulation of the brainstem reticular formation. The local field potential segments during stimulations were extracted and subjected to fast Fourier transform to obtain power density spectra. The selective D4R agonist A-412997 (5 and 10 mg/kg) and antagonists L-745870 (5 and 10 mg/kg) were injected systemically and the peak power in the two frequency ranges were compared before and after the injection. We found that D4R compounds significantly changed the activity of both HPC and PFC, but the direction of the effect was opposite in the two structures. D4R agonist enhanced PFC slow rhythm (delta, 2–4 Hz) and suppressed HPC theta, whereas the antagonist had an opposite effect. Analogous changes of the two slow rhythms were also found in the thalamic nucleus reuniens, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; delta and theta oscillations were shown in particular, to entrain neuronal firing and to modulate gamma activity in interconnected forebrain structures with a relative HPC theta dominance over PFC. Thus, the results of this study indicate that D4R activation may introduce an abnormal bias in the bidirectional PFC–HPC coupling which can be reversed by D4R antagonists.
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Schumacher, Peter M., Jan Dossche, Eric P. Mortier, Martin Luginbuehl, Thomas W. Bouillon, and Michel M. R. F. Struys. "Response Surface Modeling of the Interaction between Propofol and Sevoflurane." Anesthesiology 111, no. 4 (October 1, 2009): 790–804. http://dx.doi.org/10.1097/aln.0b013e3181b799ef.
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Background Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. Methods Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). Results Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. Conclusion For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.
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Kim, Jieun, Ju Hwan Yang, In Soo Ryu, Sumin Sohn, Sunghyun Kim, and Eun Sang Choe. "Interactions of Glutamatergic Neurotransmission and Brain-Derived Neurotrophic Factor in the Regulation of Behaviors after Nicotine Administration." International Journal of Molecular Sciences 20, no. 12 (June 16, 2019): 2943. http://dx.doi.org/10.3390/ijms20122943.
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Nicotine causes tobacco dependence, which may result in fatal respiratory diseases. The striatum is a key structure of forebrain basal nuclei associated with nicotine dependence. In the striatum, glutamate release is increased when α7 nicotinic acetylcholine receptors expressed in the glutamatergic terminals are exposed to nicotine, and over-stimulates glutamate receptors in gamma amino-butyric acid (GABA)ergic neurons. These receptor over-stimulations in turn potentiate GABAergic outputs to forebrain basal nuclei and contribute to the increase in psychomotor behaviors associated with nicotine dependence. In parallel with glutamate increases, nicotine exposure elevates brain-derived neurotrophic factor (BDNF) release through anterograde and retrograde targeting of the synapses of glutamatergic terminals and GABAergic neurons. This article reviews nicotine-exposure induced elevations of glutamatergic neurotransmission, the bidirectional targeting of BDNF in the striatum, and the potential regulatory role played by BDNF in behavioral responses to nicotine exposure.
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Bewket, Gezahegn, Amare Kiflie, Fitsumbrhan Tajebe, Ebba Abate, Thomas Schön, and Robert Blomgran. "Helminth species dependent effects on Th1 and Th17 cytokines in active tuberculosis patients and healthy community controls." PLOS Neglected Tropical Diseases 16, no. 8 (August 17, 2022): e0010721. http://dx.doi.org/10.1371/journal.pntd.0010721.
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Despite that the impact of different helminth species is not well explored, the current dogma states that helminths affect the Th1/Th2 balance which in turn affects the risk of tuberculosis (TB) reactivation and severity of disease. We investigated the influence of helminth species on cytokine profiles including IL-17A in TB patients and healthy community controls (CCs). In total, 104 newly diagnosed pulmonary TB patients and 70 HIV negative and QuantiFERON negative CCs in Gondar, Ethiopia were included following helminth screening by stool microscopy. Plasma samples and ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with purified protein derivative (PPD) and Staphylococcus enterotoxin B (SEB) was used to determine cytokine profiles by cytometric bead array. In CCs, Ascaris lumbricoides or Schistosoma mansoni infections were associated with an impaired Th1-type response (IFN-gamma, IL-6 and TNF-alpha) in PBMCs mainly with SEB stimulations, whereas in TB patients only hookworm infection showed a similar pattern. Among CCs, the IL-17A response in PBMCs stimulated with SEB was higher only for S. mansoni, whereas in TB patients, the elevated systemic IL-17A plasma level was significantly suppressed in hookworm infected TB patients compared to patients without helminth coinfection. Following treatment of TB and helminth infection there was a general decrease in ex vivio IL-10 and TNF-alpha production in unstimulated, PPD or SEB stimulated PBMCs that was the most pronounced and significant in TB patients infected with S. mansoni, whereas the follow-up levels of IFN-gamma and IL-17A was significantly increased only in TB patients without helminth coinfection from PBMCs stimulated mainly with SEB. In summary, in addition to confirming helminth specific effects on the Th1/Th2 response before and after TB treatment, our novel finding is that IL-17A was impaired in helminth infected TB patients especially for hookworm, indicating a helminth species-specific immunoregulatory effect on IL-17A which needs to be further investigated.
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Butterfield, Lisa, and Hadas Naveh. "Adenovirus vector-specific cellular immunity induced by engineered human dendritic cells in vitro and in vivo (P4434)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 126.3. http://dx.doi.org/10.4049/jimmunol.190.supp.126.3.
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Abstract Recombinant adenovirus has been used in gene transfer applications, including cancer immunotherapy and infectious disease. Immunity to the adenoviral vector is known to include a potent humoral response; however, the cellular response is poorly characterized. Here, we evaluated the virus-specific response to an AdV encoding three melanoma tumor antigens (Tyrosinase, MART-1 and MAGE-A6 (AdVTMM2)) in healthy donors and patients with melanoma. CD4+ and CD8+ T cell responses were followed weekly by multi-cytokine ELISPOT assays (IFN-gamma, IL-2, IL-10 and TNF) and flow cytometric analysis in vitro. NK cells and Treg were also assessed. We found a strong type 1-skewed response with INFg secreted by CD4+ cells beginning within 7 days of stimulation and carrying through 3 weekly stimulations. Strong type 1 CD8+ T cell immunity was also detected to the virus. Treg increased transiently and an activated, INFg-producing subset of NK cells became evident. Melanoma patient cells also show a type-1 CD8+ T cell and CD4+ T cell response to the adenovirus. While strong, these virus-specific responses did not mask responses to the melanoma antigens. Melanoma patients vaccinated with the engineered DC vaccine in a new clinical trial respond immunologically to both the viral vector and encoded melanoma antigens, and show modulation of NK cells and Treg post-vaccination. Therefore, AdV-engineered DC promote a strong type 1 virus- and melanoma antigen-specific response, in vitro and in vivo.
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Flamand, V., D. Abramowicz, M. Goldman, C. Biernaux, G. Huez, J. Urbain, M. Moser, and O. Leo. "Anti-CD3 antibodies induce T cells from unprimed animals to secrete IL-4 both in vitro and in vivo." Journal of Immunology 144, no. 8 (April 15, 1990): 2875–82. http://dx.doi.org/10.4049/jimmunol.144.8.2875.
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Abstract Recently, functional heterogeneity among Th cells has been recognized. Based on pattern of lymphokine secretion, two mutually exclusive subsets of CD4+ cells have been defined and designated Th1 (secreting IL-2 and IFN-gamma) and Th2 (secreting IL-4 and IL-5). Identification of these subsets was mostly based on the study of long term cultured T cell lines and clones, and little is known about the Th heterogeneity in vivo. In particular, it has been suggested that IL-4 producing cells cannot be detected in vivo or in primary stimulations in vitro unless responder cells had been previously primed. Our data however, indicate that anti-CD3 mediated stimulation can induce T cells isolated from unprimed animals to IL-4 production. An assay system based on the ability of IL-4 to increase Ia expression of B cells present in the environment of activated T cells was found to be more sensitive than detection of secreted IL-4 in the supernatant by conventional bioassays and was used to study IL-4 production by unprimed lymphocytes polyclonally stimulated in vivo and in vitro by anti-CD3 mAb. The results obtained indicate that CD4+ CD8- T cells able to produce IL-4 upon receptor-specific stimulation exist in the preimmune pool of adult animals. Remarkably, these cells can also be stimulated in vivo by treating animals with anti-CD3 mAb, as indicated by the in vivo induction of IL-4 specific mRNA and hyper-Ia expression on B cells. These results indicate that the inability to detect IL-4 in primary cultures is not due to different activation requirements of Th2 cells but may simply result from their lower frequency in unprimed animals.
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Bonfiglio, Tommaso, Matteo Vergassola, Guendalina Olivero, and Anna Pittaluga. "Environmental Training and Synaptic Functions in Young and Old Brain: A Presynaptic Perspective." Current Medicinal Chemistry 26, no. 20 (September 13, 2019): 3670–84. http://dx.doi.org/10.2174/0929867325666180228170450.
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Background:Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in Central Nervous System (CNS), having profound implications for human well-being. The term “cognitive reserve” refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term “Cognitive training” indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. “Cognitive training” reinforces the “cognitive reserve” permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the “cognitive training” in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, from a preclinical point of view, whether “cognitive training” promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals.Conclusion:Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by “cognitive training”. The impact of “cognitive training” on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of “cognitive reserve” in young and old animals.
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Lucas, Kenneth G., Qi Sun, Nargisa Niyazova-Brewer, and Lei Bao. "Rapid Generation of Cytomegalovirus Specific T Lymphocytes Using Commercially Available CMV pp65 Peptides." Blood 108, no. 11 (November 16, 2006): 5144. http://dx.doi.org/10.1182/blood.v108.11.5144.5144.
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Abstract Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) can result in resolution of viremia and reconstiution of CMV specific immunity following allogeneic stem cell transplantation. Most recipients of allogeneic transplants who develop CMV reactivation are successfully treated with anti-viral agents, however some have persistent viremia or develop CMV disease despite these medications. In these situations the development of CMV specific T cells may be impractical due to time contraints or institutional limitations. We have expanded CMV pp65 specific CTL from 5/6 normal blood donors of diverse HLA backgrounds in 10–15 days using adherent cells (monocytes) as antigen presenting cells, pulsed with a commercially available source of CMV pp65 peptides, which includes 138 CMV pp65 15mers. These pulsed monocytes are incubated at a 1:5 ratio with non-adherent peripheral blood lymphocytes, resulting in a population of CD4 and CD8+ CMV pp65 specific T cells after 2 weekly stimulations. While >80% of these cells were CD3+, 29–78% were CD4+, and 15–55% were CD8+. These CTL have specific cytotoxicity against CMV pp65, and intracellular cytokine analysis showed specific interferon-gamma production in response to CMV pp65 target cells. Table I depicts the phenotype as well as interferon-gamma production and specific cytotoxicity in response to stimulation with B lymphoblastoid cell lines (BLCL) expressing pp65. There was no reactivity to allogeneic targets by cytokine analysis or in chromium release assays. CTL sufficient for a dose of 30–50 × 106 CTL were routinely generated from 40–50 cc of whole blood. Considering the short time frame and relative ease with which these CTL can be expanded, this methodology could be readily adopted in clinical situations of persistent or therapy refractory CMV infections in allogeneic stem cell transplant patients as an adjuvant to anti-viral therapy. Characteristics of CMVpp65 CTL Interferon production Cytotoxicity Donor CD4 CD8 BLCL-pp65 BLCL Allo BLCL 1 1% 23% 57% 1% 1% 2 2% 3% 75% 22% 6% 3 6% 1% 31% 7% 7% 4 9% 29% 47% 0% 0% 5 7% 15% 69% 1% 5% 6 24% 3% 10% 1% 6%
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Dwivedi, Alka, Lynn Fu, Chris Daniel Chien, Marie Pouzolles, Nirali N. Shah, and Naomi Taylor. "Engineering Off-the-Shelf Gamma Delta CAR T Cells for the Treatment of Acute Myeloid Leukemia." Blood 142, Supplement 1 (November 28, 2023): 4827. http://dx.doi.org/10.1182/blood-2023-190357.
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Chimeric antigen receptor T cell therapy (CART) therapy has shown remarkable success in the treatment of B cell acute lymphoblastic leukemias (B-ALL) and lymphomas. However, CART therapies for acute myeloid leukemia (AML), where 5-year survival rates are significantly lower than for B-ALL, are only in their infancy. CD33-CART have potent activity against AML in preclinical models and a first-in-child/first-in-human phase 1/2 CD33-CART clinical trial for AML is ongoing in the Pediatric Oncology Branch of the National Cancer Institute (NCT03971799). Nonetheless, published outcomes suggest a modest efficacy of approximately 50% (Shahzad et al., Front Immunol 2023), highlighting the critical need to develop new strategies to improve CART accessibility and a more robust anti-AML response. We hypothesized that off-the-shelf gamma delta (γδ) CD33 CART cells could potentially overcome current challenges for the treatment of AML. γδ lineage T cells are unconventional lymphocytes whose functions are not restricted to MHC-mediated antigen presentation; they are primed for immediate responses, including tumor killing. Furthermore, allogeneicγδ T cells have the potential to induce robust anti-tumor cytotoxicity without causing graft versus host disease (GVHD). Here, we generated γδ CAR T cells from healthy donor elutriated lymphocytes by activation with zoledronic acid and IL-2 for 7-14 days. Within 9 days post stimulation, the vast majority of lymphocytes were Vδ2+ and 30-40% were successfully transduced with a lentiviral CD33 CAR construct harboring the 4-1BB costimulatory domain. Importantly, and unlike conventional alpha beta (ab) T lymphocytes, >98% of these γδ CD33CAR T cells expressed IFNγ under basal conditions. This characteristic likely accounted for the efficient in vitro killing of AML cell lines by untransduced γδ T lymphocytes under conditions of high effector/target (E/T) ratios. While untransduced γδ T cells did not exhibit cytotoxicity following repeat AML stimulations, γδ CD33CAR T lymphocytes exhibited proficient in vitro cytotoxicity, with killing rates that were more rapid than those initiated by ab CD33 CART (Figure 1). These characteristics were associated with a prolonged metabolic activity of γδT cells; γδ CD33 CART expressed high levels of the GLUT1 glucose transporter for >14 days post activation whereas GLUT1 levels on ab CD33 CART returned to resting within 10 days. High GLUT1 levels were linked to efficient killing under conditions of basal glucose levels. Most notably, γδ CD33CAR T lymphocytes achieved high in vivo cytotoxicity, assessed using bioluminescent AML cell line xenografts in humanized NSG mice. Together, these data highlight the feasibility of generating allogeneic γδ CD33CART with a strong anti-AML cytotoxic response.
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Ko, Li-Wei, Rupesh Kumar Chikara, Po-Yin Chen, Ying-Chun Jheng, Chien-Chih Wang, Yi-Chiang Yang, Lieber Po-Hung Li, Kwong-Kum Liao, Li-Wei Chou, and Chung-Lan Kao. "Noisy Galvanic Vestibular Stimulation (Stochastic Resonance) Changes Electroencephalography Activities and Postural Control in Patients with Bilateral Vestibular Hypofunction." Brain Sciences 10, no. 10 (October 15, 2020): 740. http://dx.doi.org/10.3390/brainsci10100740.
Full textAbstract:
Patients with bilateral vestibular hypofunction (BVH) often suffer from imbalance, gait problems, and oscillopsia. Noisy galvanic vestibular stimulation (GVS), a technique that non-invasively stimulates the vestibular afferents, has been shown to enhance postural and walking stability. However, no study has investigated how it affects stability and neural activities while standing and walking with a 2 Hz head yaw turning. Herein, we investigated this issue by comparing differences in neural activities during standing and walking with a 2 Hz head turning, before and after noisy GVS. We applied zero-mean gaussian white noise signal stimulations in the mastoid processes of 10 healthy individuals and seven patients with BVH, and simultaneously recorded electroencephalography (EEG) signals with 32 channels. We analyzed the root mean square (RMS) of the center of pressure (COP) sway during 30 s of standing, utilizing AMTI force plates (Advanced Mechanical Technology Inc., Watertown, MA, USA). Head rotation quality when walking with a 2 Hz head yaw, with and without GVS, was analyzed using a VICON system (Vicon Motion Systems Ltd., Oxford, UK) to evaluate GVS effects on static and dynamic postural control. The RMS of COP sway was significantly reduced during GVS while standing, for both patients and healthy subjects. During walking, 2 Hz head yaw movements was significantly improved by noisy GVS in both groups. Accordingly, the EEG power of theta, alpha, beta, and gamma bands significantly increased in the left parietal lobe after noisy GVS during walking and standing in both groups. GVS post-stimulation effect changed EEG activities in the left and right precentral gyrus, and the right parietal lobe. After stimulation, EEG activity changes were greater in healthy subjects than in patients. Our findings reveal noisy GVS as a non-invasive therapeutic alternative to improve postural stability in patients with BVH. This novel approach provides insight to clinicians and researchers on brain activities during noisy GVS in standing and walking conditions in both healthy and BVH patients.
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Bergmann, Liane, Matthias Staudinger, Christiane Pott, Ingrid Bolz, Martin Gramatzki, Michael Kneba, and Benedikt Gahn. "Potent Activation of Healthy Donor T-Cells Specific for Mantle Cell Lymphoma Immunoglobulin Derived Peptides by CD40- and TLR7/8-Ligand Matured Dendritic Cells in Vitro." Blood 112, no. 11 (November 16, 2008): 3502. http://dx.doi.org/10.1182/blood.v112.11.3502.3502.
Full textAbstract:
Abstract Patients with mantle cell lymphoma (MCL) and MRD after intensive radiochemotherapy and autologous stem cell transplantation have a high risk of relapse. Allogeneic stem cell transplantation offers the possibility of cure but is associated with a high risk of severe “graft versus host disease”(GvHD). A way to decrease the risk of GvHD while augmenting the “graft versus lymphoma” effect may be the in vitro activation and subsequent transplantation of allogeneic idiotyp-specific T-cells. This study was set out to determine whether cytotoxic T-cell responses specific for peptides derived from the mantle cell idiotype immunoglobulin can be activated in healthy individuals. In four patients with MCL treated in the European Mantle Cell Lymphoma Study Group the immunoglobulin heavy chain (IgH) gene family was amplified in lymphoma samples by PCR and sequenced. Using bioinformatics, the corresponding aminoacid sequence was analyzed for nonapeptides potentially binding to the individual HLA-haplotype. Peptides with a Rammensee-score >20 were synthesized. To determine whether these peptides could indeed elicit CD8+ T-cell responses they were used for dendritic cell (DC) pulsation and subsequent T-cell activation. The specificity of the CD8+ T-cells was tested against idiotype-pulsed DC and measured by flow cytometric intracellular interferon (IFN)-gamma staining. The lymphoma specific IgH rearrangements were successfully amplified and sequenced in all patients. In a HLA-A3 positive patient who was in remission after intensive radiochemotherapy and autologous hematopoietic stem cell transplantation three different idiotype HLA-matching peptides with a HLA-A3 binding score >20 were predicted from the VH-region, one additional nonapeptide was overlapping to the N-region of the immunoglobulin, rendering this peptide lymphoma-specific. This pool of peptides was synthesized and used for pulsation of monocyte derived dendritic cells (moDC) in two healthy HLA-A3 positive individuals. The maturation of the DC was done according to a standard protocol using proinflammatory cytokines (IL-6, IL-1 beta, TNF-alpha, PGE2). After 2–3 weekly stimulations of lymphocytes that had been depleted of regulatory T-cells 2.1% idiotype-specific CD8+ T-cells were activated in both healthy donors. Interestingly, T-cell stimulation using moDC matured with CD40− and TLR7/8-ligands was more efficient in comparison to the standard protocol and resulted in 12.3% IFN-gamma positive CD8+ cells. In summary, these data suggest, that idiotype-specific T-cells can be activated from healthy individuals by standard lymphocyte stimulating protocols in vitro. Moreover, the ability of moDC to activate idiotype-specific T-cells is exceeded by DC maturation using CD40− in combination with TLR7/8-ligands. These findings may help to improve immunotherapy in the settings of allogeneic transplantation strategies in relapsed MCL patients.
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Weinberg, JB, MA Misukonis, PJ Shami, SN Mason, DL Sauls, WA Dittman, ER Wood, GK Smith, B. McDonald, and KE Bachus. "Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages." Blood 86, no. 3 (August 1, 1995): 1184–95. http://dx.doi.org/10.1182/blood.v86.3.1184.1184.
Full textAbstract:
Abstract Nitric oxide (NO) is produced by numerous different cell types, and it is an important regulator and mediator of many processes including smooth muscle relaxation, neurotransmission, and murine macrophage- mediated cytotoxicity for microbes and tumor cells. Although murine macrophages produce NO readily after activation, human monocytes and tissue macrophages have been reported to produce only low levels of NO in vitro. The purpose of this study was to determine if stimulated human mononuclear phagocytes produce inducible nitric oxide synthase (iNOS) mRNA, protein, and enzymatic activity. By reverse transcriptase- polymerase chain reaction (RT-PCR) analysis, we show that human monocytes can be induced to express iNOS mRNA after treatment with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma). By immunofluorescence and immunoblot analyses, we show monocytes and peritoneal macrophages contain detectable levels of iNOS antigen after stimulations with cytokines in vitro. Control monocytes or those cultured with LPS and/or various cytokines have low levels of NOS functional activity as measured by the ability of cell extracts to convert L-arginine to L-citrulline, and they produce low levels of the NO catabolites nitrite and nitrate. Peritoneal macrophages have significantly enhanced nitrite/nitrate production and NOS activity after treatment with LPS and/or IFN-gamma, whereas monocyte nitrite/nitrate production and NOS activity are not altered by the treatments. Monocytes cultured with various live or heat-killed bacteria, fungi, or human immunodeficiency virus (HIV)-1 do not produce high levels of nitrite/nitrate. Antibodies against transforming growth factor-beta (TGF-beta), a factor known to inhibit iNOS expression and NO production in mouse macrophages, do not enhance NO production in human monocytes or macrophages. Biopterin, an obligate cofactor of iNOS enzymatic activity, is undetectable in freshly isolated or cultured human monocytes and peritoneal macrophages. However, replenishment of intracellular levels of tetrahydrobiopterin by culture with the cell- permeable, nontoxic precursor sepiapterin does not enhance the abilities of the human mononuclear phagocytes to produce NO in vitro. Mixing experiments show no evidence of a functional NOS inhibitor in human mononuclear phagocytes. Thus, we demonstrate that human mononuclear phagocytes can produce iNOS mRNA and protein, and (despite this) their abilities to generate NO are very low.
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Weinberg, JB, MA Misukonis, PJ Shami, SN Mason, DL Sauls, WA Dittman, ER Wood, GK Smith, B. McDonald, and KE Bachus. "Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages." Blood 86, no. 3 (August 1, 1995): 1184–95. http://dx.doi.org/10.1182/blood.v86.3.1184.bloodjournal8631184.
Full textAbstract:
Nitric oxide (NO) is produced by numerous different cell types, and it is an important regulator and mediator of many processes including smooth muscle relaxation, neurotransmission, and murine macrophage- mediated cytotoxicity for microbes and tumor cells. Although murine macrophages produce NO readily after activation, human monocytes and tissue macrophages have been reported to produce only low levels of NO in vitro. The purpose of this study was to determine if stimulated human mononuclear phagocytes produce inducible nitric oxide synthase (iNOS) mRNA, protein, and enzymatic activity. By reverse transcriptase- polymerase chain reaction (RT-PCR) analysis, we show that human monocytes can be induced to express iNOS mRNA after treatment with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma). By immunofluorescence and immunoblot analyses, we show monocytes and peritoneal macrophages contain detectable levels of iNOS antigen after stimulations with cytokines in vitro. Control monocytes or those cultured with LPS and/or various cytokines have low levels of NOS functional activity as measured by the ability of cell extracts to convert L-arginine to L-citrulline, and they produce low levels of the NO catabolites nitrite and nitrate. Peritoneal macrophages have significantly enhanced nitrite/nitrate production and NOS activity after treatment with LPS and/or IFN-gamma, whereas monocyte nitrite/nitrate production and NOS activity are not altered by the treatments. Monocytes cultured with various live or heat-killed bacteria, fungi, or human immunodeficiency virus (HIV)-1 do not produce high levels of nitrite/nitrate. Antibodies against transforming growth factor-beta (TGF-beta), a factor known to inhibit iNOS expression and NO production in mouse macrophages, do not enhance NO production in human monocytes or macrophages. Biopterin, an obligate cofactor of iNOS enzymatic activity, is undetectable in freshly isolated or cultured human monocytes and peritoneal macrophages. However, replenishment of intracellular levels of tetrahydrobiopterin by culture with the cell- permeable, nontoxic precursor sepiapterin does not enhance the abilities of the human mononuclear phagocytes to produce NO in vitro. Mixing experiments show no evidence of a functional NOS inhibitor in human mononuclear phagocytes. Thus, we demonstrate that human mononuclear phagocytes can produce iNOS mRNA and protein, and (despite this) their abilities to generate NO are very low.
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Wang, Dingyan, A. Keith Stewart, Lihua Zhuang, Nancy Xiao, Mawmaw Hlaing, Changxin Shi, Yuanxiao Zhu, Youdong Wang, and Xiao-Yan Wen. "Genetic Disruption of the SH3 and SAM Domains of HACS1 Enhances Adaptive Immunity." Blood 110, no. 11 (November 16, 2007): 2299. http://dx.doi.org/10.1182/blood.v110.11.2299.2299.
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Abstract HACS1 is a SH3 (Src homology 3) and SAM (sterile alpha motif) domain containing adaptor protein that is expressed in activated B and dendritic cells, is up-regulated by Interleukin 4 in the process of B cell activation and likely serves to dampen the immune response. To elucidate the function of HACS1, we generated HACS1 gene knockout mice by deletion of the SH3 and SAM domains. HACS1−/− mice were viable and fertile and had normal bone marrow B cell development and normal splenic T and B cell populations. However, adult HACS1−/− mice had increased numbers of peritoneal B1 cells (IgM+CD5+). Upon LPS plus BCR or TCR stimulations, splenic cells from HACS1−/− mice demonstrated an upregulation of activation markers with increased intensity of CD23 expression or increased population of CD69 positive cells. Purified B220+ splenic B cells from HACS1−/− mice showed increased cell proliferation upon BCR stimulation. Both T helper type 1 (Th1) and T helper type 2 (Th2) humoral responses were enhanced in HACS1−/− mice upon immunization with T cell-dependent antigen NP-KLH, which resulted in increased production of interferon-gamma (IFN-γ), anti-NP IgG2a and IL-4, as well as anti-NP IgG1 and IgE. Upon immunization with T cell-independent antigens such as TNP-LPS and TNP-Ficoll, HACS1−/− mice had increased production of anti-TNP IgM and IgG3 as compared to normal controls. The in vitro maturation of bone marrow-derived dentritic cells from HACS1−/− mice was similar to wild-type mice but HACS1−/− dentritic cells showed increased IL-12 production upon stimulation with anti-CD40 or LPS. There was no significant difference in antigen uptake by cultured dentritic cells from non-immunized wild-type or knockout mice. However, in immunized mice, an increase in antigen uptake in HACS1−/− dentritic cells was observed. We further demonstrate that the HACS1−/− B cells had increased tyrosine phosphorylation in the resting state. As deletion of the SH3 & SAM domains of HACS1 appears to generate a hypersensitive immune response, our results collectively support that HACS1 negatively regulates adaptive immunity.
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Distler, Eva, Catherine Woelfel, Sylvia Pesth, Nina Kraus, Thomas C. Wehler, Ralf G. Meyer, Marion Nonn, Christoph Huber, Thomas Woelfel, and Wolfgang Herr. "Rapid Expansion of Acute Myeloid Leukemia-Reactive Cytotoxic T Cells from CD8+CD62L+ Blood Lymphocytes of HLA-Matched Healthy Donors In Vitro." Blood 108, no. 11 (November 16, 2006): 3238. http://dx.doi.org/10.1182/blood.v108.11.3238.3238.
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Abstract Allogeneic cytotoxic T-lymphocyte (CTL) therapy in acute myeloid leukemia (AML) is hampered by the poor efficiency of growing leukemia-reactive CTLs from healthy donors in vitro. We established an allogeneic mini-mixed lymphocyte-leukemia culture (MLLC) approach by stimulating comparably small numbers (104/well) of CD8+ T cells isolated from healthy donors against irradiated primary AML blasts in 96-well plates. Prior to use, CD8+ T cells were immunomagnetically separated into a CD62L(high)+ subset enriched for naive precursors and central memory cells as well as a CD62L(low)+/negative subset containing effector memory cells. The culture medium contained IL-7, IL-12, and IL-15. After 2 weeks, IL-12 was replaced by IL-2. Mini-MLLCs were performed in seven different healthy donor-AML pairs that were matched for HLA class I according to high-resolution molecular typing. Following 2 weekly re-stimulations with primary AML blasts, mini-MLLC responder populations were analyzed for reactivity on day 19 of culture using split-well IFN-gamma ELISPOT assays. AML-reactive CD8+ T-cell responders were obtained from all 7 donor-AML pairs. The majority of reactive cultures originated from the CD62L(high)+ subfractions. In 4 out of 7 pairs MLLC responder populations mainly recognized AML blasts, but not Epstein-Barr virus transformed B-lymphoblastoid cell lines of donor and patient origin. The AML-reactive CD8+ T cells were restricted by single HLA class I alleles as determined by blocking experiments using a panel of HLA allele-specific monoclonal antibodies. Representative mini-MLLC responders demonstrated strong cytotoxicity against primary AML blasts in 51Chromium-release assay. Cross-reactivity testing identified an HLA-A*0201-restricted CTL population that recognized AML blasts much stronger than non-malignant monocytes of the same patient. This CTL neither recognized recipient-derived primary fibroblasts nor other hematopoietic cells suggesting a leukemia-associated rather than a minor histocompatibility antigen as the target structure. Several MLLC-derived CTL populations expressed unique T cell receptor Vbeta chains consistent with clonal origin from AML-reactive precursors. Multiple CTL responders reached a cell yield exceeding 108 after 6 to 10 weekly re-stimulations with AML blasts. Our results suggest that in healthy individuals most AML-reactive CD8+ CTLs originate from the CD62L(high)+ peripheral blood subpopulation containing naive precursor and central memory T cells. This mini-MLLC approach allows the rapid expansion of AML-reactive CD8+ CTLs from HLA-matched healthy donors to cell numbers sufficient for antigen identification strategies or adoptive immunotherapy trials.
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Hunt, Lee, Scott Hadley, Scott Reynolds, Regan Gilbert, Jon Rule, and Michael Kinzikeev. "Precise 3D seismic steering and production rates in the Wilrich tight gas sands of West Central Alberta." Interpretation 2, no. 2 (May 1, 2014): SC1—SC18. http://dx.doi.org/10.1190/int-2013-0086.1.
Full textAbstract:
We evaluate the controls on production performance of the Wilrich tight gas sand play in West Central Alberta, and show that careful steering using 3D seismic to place the wellbore within the upper reservoir is the most important geophysical contribution to production outcomes. Geologic, geophysical, drilling, and production data from more than 20 wells are used in the analysis. The completion and production parameters within the study area are relatively invariant, creating a control experiment relative to other productivity factors. We thus isolate the effects of varying bottom hole pressures, porosity, wellbore length, number of stimulations, mud gas response, gamma ray measurements while drilling, mud weight, curvature, amplitude versus offset (AVO), amplitude versus azimuth (AVAz), velocity versus azimuth (VVAz), and position of the horizontal wellbore within the reservoir. These variables are treated separately and in a multivariate fashion to determine their relative and combined effect on the productivity of the wells. Several methods of statistical evaluation are used to test confidence in the results. The Wilrich sand is approximately 20-m thick, and it was expected that the multistage fracture stimulation would have minimized the importance of vertical permeability variations by adequately accessing the entire vertical reservoir section. Such is not the case; precise placement of the wellbore in the most permeable stratigraphy of the thin reservoir is of material importance. The pressure and porosity strongly affect the production performance, but to a lesser degree than vertical position within the reservoir. This suggests that stratigraphic concerns as they relate to permeability variation can be critical, even in thin fracture-stimulated reservoirs. Interesting relationships were observed between the AVAz and curvature measures, but neither they nor the AVO or VVAz attributes yielded statistically significant correlations to the production data.
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Zhang, Cenrong, Yuemin Wang, Meng Wang, Xiaoyan Su, Yisong Lu, Fei Su, and Songhua Hu. "Rapeseed Oil and Ginseng Saponins Work Synergistically To Enhance Th1 and Th2 Immune Responses Induced by the Foot-and-Mouth Disease Vaccine." Clinical and Vaccine Immunology 21, no. 8 (June 11, 2014): 1113–19. http://dx.doi.org/10.1128/cvi.00127-14.
Full textAbstract:
ABSTRACTPrevious investigations demonstrated that saponins isolated from the root ofPanax ginsengC. A. Meyer (i.e., ginseng root saponin [GS-R]) had adjuvant activity. In the present study, the combined effects of rapeseed oil (RO) and GS-R on the immune responses elicited by foot-and-mouth disease (FMD) vaccine were investigated by measuring FMD virus (FMDV)-specific antibody levels, cytokine levels, lymphocyte proliferation, and long-lived IgG-secreting plasma cells from bone marrow in a mouse model. The results indicated that RO in combination with GS-R significantly enhanced serum IgG and isotype concentrations, gamma interferon (IFN-γ) and interleukin 5 (IL-5) levels, splenocyte proliferative responses to stimulations with concanavalin A (ConA), lipopolysaccharide (LPS), and FMDV antigen, and the numbers of IgG-secreting plasma cells in the bone marrow, suggesting that RO/GS-R enhanced both Th1 and Th2 immune responses. In addition, no significant difference was found between RO/GS-R and the commercial adjuvant oil ISA 206 in the promotion of FMD vaccine-induced immune responses. Considering the vegetable origin of RO and GS-R and the potent adjuvant activity, RO/GS-R should be studied further for the development of veterinary vaccines, especially for use in food animals in order to promote food safety.
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Bacchetta, R., R. de Waal Malefijt, H. Yssel, J. Abrams, J. E. de Vries, H. Spits, and M. G. Roncarolo. "Host-reactive CD4+ and CD8+ T cell clones isolated from a human chimera produce IL-5, IL-2, IFN-gamma and granulocyte/macrophage-colony-stimulating factor but not IL-4." Journal of Immunology 144, no. 3 (February 1, 1990): 902–8. http://dx.doi.org/10.4049/jimmunol.144.3.902.
Full textAbstract:
Abstract In the present study, we investigated the lymphokine production patterns in a series of CD4+ and CD8+ host-reactive T cell clones isolated from PBL of a SCID patient, who was immunologically reconstituted by two allogeneic fetal liver and thymus transplantations 13 years ago. We demonstrate that these donor-derived T cell clones, specifically reacting with the MHC Ag expressed on the recipient cells, do not produce IL-4 and do not express IL-4 mRNA upon Ag or polyclonal stimulations. In contrast, CD4+ tetanus toxin-specific T cell clones isolated from the same patient and having the same HLA phenotype produced normal amounts of IL-4 upon activation. These data suggest that the failure to produce IL-4 is a specific characteristic of these host-reactive clones and is not due to a genetic defect of the transplanted cells. Furthermore, different modes of activation resulted in simultaneous production of IL-5, IL-2, IFN-gamma, granulocyte/macrophage-CSF, and transcription of the TNF-beta gene by the host-reactive clones, indicating that the lack of IL-4 production is not related to the mode of activation. The finding that some of these clones produce significant levels of IL-5 but no IL-4 indicates that the IL-4 and IL-5 genes are not always coexpressed in activated human T cells.
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Udompornpitak, Kanyarat, Thansita Bhunyakarnjanarat, Awirut Charoensappakit, Cong Phi Dang, Wilasinee Saisorn, and Asada Leelahavanichkul. "Lipopolysaccharide-Enhanced Responses against Aryl Hydrocarbon Receptor in FcgRIIb-Deficient Macrophages, a Profound Impact of an Environmental Toxin on a Lupus-Like Mouse Model." International Journal of Molecular Sciences 22, no. 8 (April 18, 2021): 4199. http://dx.doi.org/10.3390/ijms22084199.
Full textAbstract:
Fc gamma receptor IIb (FcgRIIb) is the only inhibitory-FcgR in the FcgR family, and FcgRIIb-deficient (FcgRIIb−/−) mice develop a lupus-like condition with hyper-responsiveness against several stimulations. The activation of aryl hydrocarbon receptor (Ahr), a cellular environmental sensor, might aggravate activity of the lupus-like condition. As such, 1,4-chrysenequinone (1,4-CQ), an Ahr-activator, alone did not induce supernatant cytokines from macrophages, while the 24 h pre-treatment by lipopolysaccharide (LPS), a representative inflammatory activator, prior to 1,4-CQ activation (LPS/1,4-CQ) predominantly induced macrophage pro-inflammatory responses. Additionally, the responses from FcgRIIb−/− macrophages were more prominent than wild-type (WT) cells as determined by (i) supernatant cytokines (TNF-α, IL-6, and IL-10), (ii) expression of the inflammation associated genes (NF-κB, aryl hydrocarbon receptor, iNOS, IL-1β and activating-FcgRIV) and cell-surface CD-86 (a biomarker of M1 macrophage polarization), and (iii) cell apoptosis (Annexin V), with the lower inhibitory-FcgRIIb expression. Moreover, 8-week-administration of 1,4-CQ in 8 week old FcgRIIb−/− mice, a genetic-prone lupus-like model, enhanced lupus characteristics as indicated by anti-dsDNA, serum creatinine, proteinuria, endotoxemia, gut-leakage (FITC-dextran), and glomerular immunoglobulin deposition. In conclusion, an Ahr activation worsened the disease severity in FcgRIIb−/− mice possibly through the enhanced inflammatory responses. The deficiency of inhibitory-FcgRIIb in these mice, at least in part, prominently enhanced the pro-inflammatory responses. Our data suggest that patients with lupus might be more vulnerable to environmental pollutants.
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Cheever, A. W., M. E. Williams, T. A. Wynn, F. D. Finkelman, R. A. Seder, T. M. Cox, S. Hieny, P. Caspar, and A. Sher. "Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis." Journal of Immunology 153, no. 2 (July 15, 1994): 753–59. http://dx.doi.org/10.4049/jimmunol.153.2.753.
Full textAbstract:
Abstract Increasing evidence suggests that schistosome egg granulomas are primarily Th2 cellular reactions. Mice infected with Schistosoma mansoni were treated with a neutralizing mAb against IL-4 to evaluate the role of this cytokine in the generation of parasite egg-induced cell-mediated responses and hepatic pathology. Animals treated with anti-IL-4 before egg deposition showed decreased IL-4, IL-5, and IL-10 production in response to in vitro antigenic stimulations and decreased IL-5 and IL-13 mRNA levels in the liver. As observed previously, non-B, non-T cells were a major source of IL-4 in infected mice treated with control mAb, and the diminished IL-4 response in anti-IL-4-treated animals was shown to be caused at least in part by a reduction in the number of these cells, as well as by decreased secretion of IL-4 per cell. In contrast, production of the Th1 cytokines IL-2 and IFN-gamma was elevated in anti-IL-4-treated infected mice in vitro, and the corresponding mRNAs in the liver were increased. Anti-IL-4 treatment did not consistently reduce the size of hepatic granulomas around S. mansoni eggs, but markedly inhibited granuloma formation in the lungs of the same animals after i.v. egg injection. Nevertheless, anti-IL-4-treated infected mice showed consistent and marked reductions in hepatic collagen deposition. These findings indicate that IL-4 plays a major role in the development of the Th2 response in S. mansoni-infected mice and contributes to the pathogenesis of hepatic fibrosis.
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Barber, K. E., P. S. Crosier, and J. D. Watson. "The differential inhibition of hemopoietic growth factor activity by cytotoxins and interferon-gamma." Journal of Immunology 139, no. 4 (August 15, 1987): 1108–12. http://dx.doi.org/10.4049/jimmunol.139.4.1108.
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Abstract The effects of recombinant human tumor necrosis factor (TNF), lymphotoxin (LT), and interferon-gamma (IFN-gamma) on the growth of human hemopoietic progenitor cells in clonal culture have been examined. Colony growth was induced by using granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony-stimulating factor (GM-CSF). A suppressive effect of TNF, LT, and IFN-gamma on the development of granulocyte, macrophage, and mixed granulocyte/macrophage colonies was shown. Suppression of colonies formed after stimulation with G-CSF was greater than that observed after stimulation with GM-CSF. In the presence of a monoclonal antibody to TNF, or polyclonal antibodies to either LT or IFN-gamma, the inhibitory effect of the molecule to which the antibody was directed was abrogated. These findings suggest that progenitor cells responsive to G-CSF or GM-CSF have different sensitivities to the effects of TNF, LT, and IFN-gamma. Defining the interactions of growth factors and inhibitors should increase understanding of mechanisms underlying diseases associated with suppression of normal hemopoiesis, and in predicting the effects in vivo of these bioregulatory molecules in clinical medicine.
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Novelli, F., M. M. D'Elios, P. Bernabei, L. Ozmen, L. Rigamonti, F. Almerigogna, G. Forni, and G. Del Prete. "Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones." Journal of Immunology 159, no. 1 (July 1, 1997): 206–13. http://dx.doi.org/10.4049/jimmunol.159.1.206.
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Abstract The mRNA and protein expression of the alpha- and beta-chains of IFN-gammaR were evaluated on a panel of human Th1 and Th2 clones. When cultured in IL-2-conditioned medium, both types of clones expressed mRNA for the alpha- and beta-chains, and both chains were present in the cytoplasm. Membrane expression of the alpha-chain was higher on Th2 than on Th1, whereas the beta-chain was poorly expressed on both types but increased following IL-2 withdrawal or PHA stimulation. In addition, both types of clones overexpressed MHC class I glycoproteins following IFN-gammaR triggering by exogenous IFN-gamma, although the kinetics was slower in Th1, and this exposure induced mRNA for IRF-1. When their TCR was triggered in the absence of APC, Th1 only underwent apoptosis. This activation-induced apoptosis was prevented by blocking of the alpha-chain or by IFN-gamma neutralization. Addition of IFN-gamma triggered the apoptosis of Th2 clones. Apoptosis of both types of clones was mediated by autocrine or exogenous IFN-gamma through the up-regulation of Fas-L expression, since anti-IFN-gammaR alpha mAb inhibited its expression on Th1 and exogenous IFN-gamma increased its expression on Th2. These results indicate that activated human Th1 and Th2 lymphocytes express IFN-gammaR alpha- and beta-chains and are both sensitive to signals provided by IFN-gamma. Data also suggest that IFN-gamma is critical for switching off their responses.
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Leclercq, G., and J. Plum. "Stimulation of TCR V gamma 3 cells by gram-negative bacteria." Journal of Immunology 154, no. 10 (May 15, 1995): 5313–19. http://dx.doi.org/10.4049/jimmunol.154.10.5313.
Full textAbstract:
Abstract A distinct feature of most murine TCR-gamma delta cells is that they localize in epithelial tissues that cover the internal and external surface of the body. Therefore, TCR-gamma delta cells have been hypothesized to represent a first line of defense against invading pathogens. In this study, it is shown that TCR V gamma 3 cells are activated to produce cytokines upon interaction with Gram-negative bacteria, whereas Gram-positive bacteria have no effect. Accessory cells are not required. LPS of Gram-negative bacteria is shown to be the stimulating structure for TCR V gamma 3 cells, as the stimulation is inhibited by addition of polymyxin B or anti-LPS Ab and as purified LPS stimulates V gamma 3 T cells. Blocking of the V gamma 3 TCR does not inhibit stimulation by Gram-negative bacteria, whereas suboptimal triggering of the TCR is synergistic. These results demonstrate that LPS is an important stimulus for TCR V gamma 3 cells. This indicates that skin-located V gamma 3 T cells might play a role in the defense against Gram-negative bacteria.
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Piacibello, W., L. Lu, D. Williams, M. Aglietta, BY Rubin, S. Cooper, M. Wachter, F. Gavosto, and HE Broxmeyer. "Human gamma interferon enhances release from phytohemagglutinin- stimulated T4+ lymphocytes of activities that stimulate colony formation by granulocyte-macrophage, erythroid, and multipotential progenitor cells." Blood 68, no. 6 (December 1, 1986): 1339–47. http://dx.doi.org/10.1182/blood.v68.6.1339.1339.
Full textAbstract:
Abstract Human gamma interferon (HuIFN gamma) was evaluated for its effects on the release from human peripheral blood T lymphocytes (greater than 98% pure) stimulated by phytohemagglutinin (PHA) of activities that can stimulate granulocyte-macrophage (CFU-GM) colonies and clusters, erythroid (BFU-E) bursts, and mixed (CFU-GEMM) colonies. T lymphocytes did not release these activities in the absence of PHA with or without HuIFN gamma. In the presence of PHA, pure natural HuIFN gamma at concentrations of 0.1 to 100 U/mL significantly enhanced release of these colony-stimulating activities. Although enhanced release of granulocyte-macrophage colony-stimulating activities were noted when T lymphocytes were added to the conditioning medium in the presence of 0.1%, 0.5%, and 1% PHA, enhanced release of burst-promoting and mixed colony activities was seen only in the presence of 0.1% and 0.5% PHA. The enhanced release of colony-stimulating activities was not due to HuIFN gamma-suppression of the release from PHA-stimulated T lymphocytes of suppressor molecules. The enhancing effects of natural HuIFN gamma were neutralized with a monoclonal anti-natural HuIFN gamma, and recombinant HuIFN gamma mimicked the enhancing effects of the natural HuIFN gamma. This enhancing effect was noted only when HuIFN gamma was added with the T lymphocytes and PHA during the first 24 hours of incubation. T lymphocytes were separated into T4+, T8-, T8+, and T4- subsets (greater than 98% pure for the appropriate phenotypes) after incubation with OKT4- and OKT8- monoclonal antibodies and sorting on a fluorescence-activated cell sorter (FACS). All types of colony-stimulating activities were released from each population after stimulation with PHA, but enhanced release of these activities in the presence of HuIFN gamma was only detected with the T4+ or T8- subsets of lymphocytes. It cannot be concluded from these studies whether HuIFN gamma is enhancing the release of one or several types of colony-stimulating activities, but these studies suggest a role for HuIFN gamma and T4+ lymphocyte subsets in the regulation in vitro of the release of colony-stimulating activities.
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Piacibello, W., L. Lu, D. Williams, M. Aglietta, BY Rubin, S. Cooper, M. Wachter, F. Gavosto, and HE Broxmeyer. "Human gamma interferon enhances release from phytohemagglutinin- stimulated T4+ lymphocytes of activities that stimulate colony formation by granulocyte-macrophage, erythroid, and multipotential progenitor cells." Blood 68, no. 6 (December 1, 1986): 1339–47. http://dx.doi.org/10.1182/blood.v68.6.1339.bloodjournal6861339.
Full textAbstract:
Human gamma interferon (HuIFN gamma) was evaluated for its effects on the release from human peripheral blood T lymphocytes (greater than 98% pure) stimulated by phytohemagglutinin (PHA) of activities that can stimulate granulocyte-macrophage (CFU-GM) colonies and clusters, erythroid (BFU-E) bursts, and mixed (CFU-GEMM) colonies. T lymphocytes did not release these activities in the absence of PHA with or without HuIFN gamma. In the presence of PHA, pure natural HuIFN gamma at concentrations of 0.1 to 100 U/mL significantly enhanced release of these colony-stimulating activities. Although enhanced release of granulocyte-macrophage colony-stimulating activities were noted when T lymphocytes were added to the conditioning medium in the presence of 0.1%, 0.5%, and 1% PHA, enhanced release of burst-promoting and mixed colony activities was seen only in the presence of 0.1% and 0.5% PHA. The enhanced release of colony-stimulating activities was not due to HuIFN gamma-suppression of the release from PHA-stimulated T lymphocytes of suppressor molecules. The enhancing effects of natural HuIFN gamma were neutralized with a monoclonal anti-natural HuIFN gamma, and recombinant HuIFN gamma mimicked the enhancing effects of the natural HuIFN gamma. This enhancing effect was noted only when HuIFN gamma was added with the T lymphocytes and PHA during the first 24 hours of incubation. T lymphocytes were separated into T4+, T8-, T8+, and T4- subsets (greater than 98% pure for the appropriate phenotypes) after incubation with OKT4- and OKT8- monoclonal antibodies and sorting on a fluorescence-activated cell sorter (FACS). All types of colony-stimulating activities were released from each population after stimulation with PHA, but enhanced release of these activities in the presence of HuIFN gamma was only detected with the T4+ or T8- subsets of lymphocytes. It cannot be concluded from these studies whether HuIFN gamma is enhancing the release of one or several types of colony-stimulating activities, but these studies suggest a role for HuIFN gamma and T4+ lymphocyte subsets in the regulation in vitro of the release of colony-stimulating activities.