Antigenic modulation in vitro. II. Modulation of thymus-leukemia (TL) antigenicity requires complement component C3.
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Animals↗
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Human detectability of various modulation wave forms in frequency-modulated tones [proceedings].
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Humans↗
Circular dichroism studies of native and chemically modified Ca2+-dependent protein modulator.
The structural features of the native Ca2+-dependent protein modulator and two chemically modified derivatives, namely, nitrotyrosyl modulator and alkylated modulator, were examined by circular dichroism. The binding of Ca2+ to the native molecule was accompanied by an increase in helical content from 40 to 49%, with little effect on the local environments of aromatic residues in the modulator. The Mg2+ and Mn2+ do not elicit the conformational change induced by the binding of Ca2+, which also stabilizes the modulator against urea denaturation. The overall secondary structure of nitrotyrosyl modulator is indistinguishable from that of the native protein and undergoes a similar conformational change upon binding Ca2+. These observations are in agreement with the fact that nitration has no effect on modulator functions. Furthermore, nitrotyrosyl modulator interacts with troponin I only in the presence of Ca2+, as detected by circular dichroism (cd). On the other hand, alkylation of five methionine residues on the modulator with benzyl bromide affects protein conformation, as evidenced by a reduced helical content of only 35%. Alkylated modulator retains the ability of the native protein to bind Ca2+ although the affinity of this derivative for Ca2+ is reduced some three orders of magnitude relative to the native protein, with Kd = 3.2 X 10(-4) M. The results with the alkylated modulator, in conjunction with previous cd studies on N-chlorosuccinimide oxidized modulator are utilized to advance a model for the Ca2+ activation of modulator protein, based on three conformational states of the molecule.
Alkylation↗
Modulation of HL-A antigens by anti-HLA antiserum: effects on the cytotoxicity assay and mixed leukocyte reaction.
Modulation of human leukocyte antigen (HLA) was attempted by treating leukocytes with specific anti-HLA antiserum or by their passage through columns coated with anti-HLA or a double layer of HLA-anti-HLA. The modulated cells were resistant to the cytotoxic effects of the anti-HLA, and they were poor stimulators and good responders to allogeneic cells in the unidirectional mixed leukocyte reaction. Modulated cells regained their HLA 16 hr after modulation if kept in cell suspension alone. The proliferative responses of modulated cells to mitogens were as good as non-modulated cells, indicating that modulation was probably not caused by depletion of lymphoid cells. Supernatants of modulated cells that were incubated overnight or preformed HLA-anti-HLA complexes were capable of suppressing and enhancing the MLR of specific cells depending on the dose used. The similarities of modulation of HLA to other lymphocyte receptors and the limitation of application of the modulation phenomenon to transplantation of allogeneic cells are discussed.
Antibody Specificity↗
Prenatal pyrethroid exposure, placental gene network modules, and neonatal neurobehavior.
Prenatal pesticide exposure may adversely affect child neurodevelopment which may partly arise from impairing the placenta's vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N = 248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis, our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the interferon alpha response and Myc target modules, and the interferon alpha response module was correlated positively with attention, and negatively with arousal, and quality of movement. The analysis also highlighted the early and late trimesters as critical periods for the exposures influence on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the protein secretion module, and those measured later in pregnancy negatively associated with modules related to oxidative phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3-phenoxybenzoic acid across pregnancy was significantly negatively associated with the OXPHOS module. These findings suggest that prenatal exposure to pyrethroids may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression of metabolic pathways, and these effects may be pregnancy period specific. These results offer valuable insights for future risk assessment and intervention strategies.
Prenatal Exposure Delayed Effects↗
Role of surface modulating assemblies in growth control of normal and transformed fibroblasts.
Cellular microtubules, microfilaments, and surface receptors have been postulated to form a surface modulating assembly that regulates surface receptor mobility and cell growth. To test this hypothesis, we examined three agents known to affect cell growth [colchicine, concanavalin A (Con A), and the src gene product of Rous sarcoma virus] for their effects on chick embryo fibroblasts. Individual cells from serum-starved normal fibroblast populations became committed to enter S phase at various times over a 12 hr period after exposure to serum. Colchicine and other microtubule-disrupting agents blocked entry into S phase at a point close to the commitment point for each cell. The lectin Con A also blocked entry into the S phase when present in doses sufficient to modulate surface receptor mobility. In contrast, succinyl-Con A, which does not induce surface modulation, had no effect. Both Con A and colchicine blocked the appearance of cytoplasmic factors capable of stimulating DNA replication in a cell-free system. To study endogenous effects on the surface modulating assembly, we infected fibroblasts with a Rous sarcoma virus (tsNY68) having a temperature-sensitive mutation in the transforming (src) gene. We have previously shown that microtubular and microfilamentous structures of the surface modulating assembly are direct or indirect targets of the src gene product with consequent reduction in the capacity of Con A to induce surface modulation. TsNY68-infected fibroblasts shifted to the non-permissive temperature acquired normal microtubular morphology more rapidly (2 hr) than cells grown at the permissive temperature in the presence of protein synthesis inhibitors (7.5 hr). This suggests that the src gene product acts directly on the surface modulating assembly rather than via the nucleus or at the level of protein synthesis. Furthermore, "transformation" of the surface modulating assembly was partly blocked by treatment of the infected cells with Con A but not succinyl-Con A. Both Con A and colchicine inhibited entry into the S phase following a shift from nonpermissive to permissive growth conditions. All of these observations are in accord with the hypothesis that the surface modulating assembly acts as a signal regulator in growth control.
Animals↗
Dynamic properties of excitation and two-tone inhibition in the cochlear nucleus studied using amplitude-modulated tones.
The dynamic properties of excitation and two-tone inhibition in the cochlear nucleus were studied from extracellularly recorded unit responses to two simultaneously presented tones. One tone was presented at the unit's characteristic frequency, CF, the other at the unit's best inhibitory frequency, BIF. One or both of the tones were amplitude-modulated with pseudorandom noise. The system under study is in general nonlinear, but can be considered to function as a linear system for small changes in sound intensity around a certain operating point. The dynamic properties are likely to be different at different operating points. A suitable method for the study of dynamic properties of such a system employs tones that are amplitude-modulated with pseudorandom noise. In the present study, the dynamic properties were assessed by cross-correlating the unit discharge rate with the modulation. This was accomplished by computing the cross-covariance function between a period of noise and a period histogram of the discharges, the histogram being locked to the periodicity of the pseudorandom noise. In this way, it has been shown in previous works (Moller, 1973, 1974b), that the cross-covariance function is a valid approximation of the system's impulse response function at a certain sound intensity, provided the modulation is kept at a low value. In the present study the computed cross-covariance function is thus an approximation of the change in discharge rate of the cochlear nucleus units in response to a brief increase in stimulus intensity. As the response of the system under the given circumstances is approximately that of a linear system, the integrated cross-covariance is an approximation of the system's step response function, i.e the change in discharge rate that resulte from a hypothetical step increase in stimulus intensity. The results of the present study can be summarized as follows: 1. The impulse and step response functions computed from the responses to the modulated inhibitory tone of the great majority of units from which recording was made were found to be virtual mirror images of those obtained when the excitatory tone was modulated, the inhibitory response being somewhat smaller in amplitude than the excitatory. 2. When both tones were modulated simultaneously, the step response function was approximately the algebraic sum of the two responses obtained when the tones were modulated singly, further indicating that the system functions as a linear system when the stimulus amplitude is varied slightly around a certain operating point. 3. The shape of the cross-covariance functions is similar for all three stimulus situations, but varies with stimulus intensity and is different in different units. 4. The implication of the results is that the inhibition studied may either originate from the inhibition (suppression) seen in primary fibers or it may be the result of a true neural inhibition in the cochlear nucleus that occurs without any interneurons.
Animals↗
Coding of small sinusoidal frequency and amplitude modulations in the inferior colliculus of 'CF-FM' bat, Rhinolophus ferrumequinum.
Single neurons in the inferior colliculus of the Greater Horseshoe bat, Rhinolophus ferrumequinum, showed two broad categories of response patterns to sinusoidally frequency (SFM) or amplitude (SAM) modulated stimuli. Tonic responding cells (best excitatory frequency (BEF) between 10 and 90 kHz) showed a rough sinusoidal modulation of the discharge pattern to SFM. Transient responding neurons generally showing on- or off-responses to pure tones, (BEF between 65 and 88 kHz), displayed highly synchronized discharge patterns to SFM-cycles (Fig. 1). Modulation rates between 20 and 100 Hz were most effective and some neurons encoded modulation rates up to 350 Hz (Figs. 2 and 3). The SFM responses were best synchronized to the modulation envelope for center frequencies in the upper portion of the tuning curve (Figs. 4 and 5). Sharply tuned neurons with BEF around 80 kHz had the lowest threshold for modulation depth (+/- 10 Hz or 0.025%) (Fig. 6). In general, SAMs evoked the same type of response patterns and were encoded down to modulation index of 3% (Fig. 7). The fine frequency and amplitude discriminations for periodical modulations by collicular neurons is discussed as related to the detection and discrimination performance of bats, when preying on flying insects in clustered surroundings.
Acoustic Stimulation↗
Serum requirements for in vivo modulation of thymus-leukemia antigens on mouse leukemia cells and thymocytes.
Mouse leukemia cells and normal thymocytes bearing thymus-leukemia (TL) cell surface antigens were previously shown to acquire resistance to lysis by guinea pig complement (C) during incubation with TL alloantiserum in vitro at 37 degrees C due to heat-labile serum activity resulting in deposition of mouse C3 onto the cell surface. The role of heat-labile serum activity and C3 in modulation of TL+ cells in vivo in mice actively or passively immunized against TL antigens was investigated. Mice of the TL-/TL+ C57BL/6J (B6) strain and the B6 congenic strain B6-Tiaa possessed poorly modulating sera, and the radiation-induced A-strain leukemia RADA1 transplanted into B6 mice passively immunized with heated (56 degrees C) TL antiserum failed to modulate; thymocytes of B6-Tiaa mice immunized similarly also did not modulate. A specific requirement for mouse C3 deposition onto RADA1 cells to achieve a modulated state was demonstrated in actively immunized TL- (B6 X A-Tiab)F1 mice in which circulating C3 and modulating activity were depleted by administration of cobra venom factor. In immunized (B6 X A-Tiab)F1 mice bearing RADA1 transplants and repeatedly given injections of B6 serum, tumor cells escaped immune destruction despite a lack of modulation. Thus modulation of TL antigenicity on tumor cells in vivo, but not tumor escape, required cell-bound C3.
Animals↗
ProgModule: A novel computational framework to identify mutation driver modules for predicting cancer prognosis and immunotherapy response.
BACKGROUND: Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability. METHODS: Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis. RESULTS: Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets. CONCLUSIONS: Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.
Humans↗
Responses of single units in the cat cochlear nucleus to sinusoidal amplitude modulation of tones and noise: linearity and relation to speech perception.
Responses to the sinusoidal modulation envelopes of amplitude-modulated tonend noise carriers were recorded from single units in the cochlear nucleus of the cat. The unit discharges were synchronized to the peaks of the modulation envelope. Population-averaged firing rate were independent of the modulation index of the stimulus. Temporal firing patterns, as represented by the shapes and magnitudes of modulation-cycle histograms, were strongly dependent on stimulus intesity and modulation index. Nonlinear nonsinusoidal responses to sinusoidal modulation envelopes were observed, but only at high values of sound intensity. These and other results are discussed in the context of psychological studies concerning the perception of speech information.
Acoustic Stimulation↗
Design and evaluation of antisense sequence length for modified mouse U7 small nuclear RNA to induce efficient pre-messenger RNA splicing modulation in vitro.
Pre-messenger RNA (pre-mRNA) splicing modulation is an attractive approach for investigating the mechanisms of genetic disorders caused by mis-splicing. Previous reports have indicated that a modified U7 small nuclear RNA (U7 snRNA) is a prospective tool for modulating splicing both in vitro and in vivo. To date, very few studies have investigated the role of antisense sequence length in modified U7 snRNA. In this study, we designed a series of antisense sequences with various lengths and evaluated their efficiency in inducing splicing modulation. To express modified U7 snRNAs, we constructed a series of plasmid DNA sequences which codes cytomegalovirus (CMV) enhancer, human U1 promoter, and modified mouse U7 snRNAs with antisense sequences of different lengths. We evaluated in vitro splicing modulation efficiency using a luciferase reporter system for simple and precise evaluation as well as reverse transcription-polymerase chain reaction to monitor splicing patterns. Our in vitro assay findings suggest that antisense sequences of modified mouse U7 snRNAs have an optimal length for efficient splicing modulation, which depends on the target exon. In addition, antisense sequences that were either too long or too short decreased splicing modulation efficiency. To confirm reproducibility, we performed an in vitro assay using two target genes, mouse Fas and mouse Dmd. Together, our data suggests that the antisense sequence length should be optimized for modified mouse U7 snRNAs to induce efficient splicing modulation.
RNA, Small Nuclear↗
Chemical modification studies on the Ca2+-dependent protein modulator: the role of methionine residues in the activation of cyclic nucleotide phosphodiesterase.
Methionine residues have been implicated in the activation of cyclic nucleotide phosphodiesterase by the Ca2+-dependent protein modulator [Walsh, M., & Stevens, F.C. (1977) Biochemistry 16,2742-2749]. Treatment of the modulator with N-chlorosuccinimide in the presence of Ca2+ resulted in selective oxidation of methionine residues at positions 71,72, 76, and, possibly, 109 in the modulator sequence. These residues lie on the surface of the molecule exposed to solvent. This modification has several effects on the modulator protein: (1) the Ca2+-binding properties of the oxidized modulator are changed with apparent loss of high-affinity binding sites, (2) the oxidized protein no longer interacts with phosphodiesterase, and (3) troponin C like activities, viz., Ca2+-dependent change in mobility on urea-polyacrylamide gel electrophoresis and formation of a urea-stable complex with troponin I, are lost upon oxidation of the modulator. The phosphodiesterase binding domain of the modulator protein appears to be located between the second and third Ca2+-binding loops, a region of the molecule known from previous partial proteolysis studies [Walsh, M., Stevens, F.C., Kuznicki, J., & Drabikowski, W.(1977), J. Biol. Chem. 252, 7440-7443] to be exposed in the presence of Ca2+.
3',5'-Cyclic-AMP Phosphodiesterases↗
Electro-cochlear potentials elicited by sinusoidally modulated signals.
Responses of the guinea pig cochlea to amplitude-modulated stimuli were measured with the aid of a gross electrode. The dynamic characteristics of this part of the auditory system was studied by varying several parameters of the applied signal. The signals used as carriers in our experiments were either white noise or pure tones of 1 and 4 kHz. The modulation frequency, dynamic and intensity characteristics were determined by varying the modulating frequency, the modulation depth and the intensity of the applied signal. To get an idea about possible non-linear aspects of the system under investigation, we always computed the Fourier transform of the response data and plotted the amplitude of the various harmonics and the phase of the fundamental separately as functions of the signal parameter in question. The greatest response was always found at a modulation frequency of about 200 Hz, with a relatively gradual rise up to this frequency and a sharper drop above 200 Hz. The phase of the fundamental changes very rapidly at frequencies above Hz. The distortion is mainly second-harmonic and has a maximum about 1 octave lower than the fundamental. The carrier frequency and the intensity of the stimulus were not found to have a great influence on the frequency characteristic. For small modulation depths, the system is nearly linear; at higher intensities and modulation depths saturation occurs, coinciding with a relative increase in the intensity of the second harmonic with respect to the fundamental.
Acoustic Stimulation↗
Modulation of cortical and pyramidal tract induced motor responses by electrical stimulation of the basal ganglia.
Two general mechanisms based on anatomical studies are possible for modulation of motor activity by the caudate nucleus and globus pallidus. These mechanisms are: (1) modulation of the output of cortical neurons that exert motor influences; and (2) modulation of subcortical neurons that exert motor influences. Differentiation between these two mechanisms was accomplished in the present study by two experimental approaches, both of which employed the conditioning-test paradigm. The first approach was an investigation of caudate nucleus or globus pallidus modulation (conditioning stimulus) of flexor responses of the anterior tibialis muscle elicited by electrical stimulation of the sensorimotor cortex (test stimulus) or pyramidal tract (test stimulus). These investigations were carried out in the intact and in decorticate cats. The second approach was an analysis of modulation or cortically induced pyramidal tract responses (direct and indirect, D-I potentials) by conditioning shock trains delivered to various loci within the caudate nucleus or globus pallidus. Both approaches were designed to determine whixh inhibitory and facilitatory motor influences of the basal ganglia occurred at a cortical or subcortical level. Simultaneous stimulation of a locus within the caudate nucleus and the sensorimotor cortex evoked either an enhancement, reduction or no alteration of the cortically induced increase in flexor responses (measured by Ia afferent activity, EMG, myogram). In contrast, no inhibitory influences occurred from caudate nucleus stimulation upon pyramidal tract induced flexor responses in either the intact or decorticate preparation. Inhibitory loci were distributed toward the rostral portion of the caudate nucleus, whereas facilitatory loci were distributed throughout; this distribution was statistically significant (chi2; P less than 0.01). Only enhancement or no influence upon cortical induced or pyramidal tract induced responses were obtained by conditioning stimuli to the globus pallidus. In the unanesthetized but immobilized cat, trains of shocks delivered to the caudate nucleus enhanced, reduced or had no influence upon the cortically evoked direct (D) and indirect (I) potentials recorded in the bulbar pyramidal tract. The distribution of facilitatory and inhibitory loci was organized in a similar fashion as in theanesthetized preparation. From these observations, a model was proposed in which the output of the caudate nucleus exerts both facilitatory or inhibitory modulation of the tonically active globus pallidus cells. The latter in turn predominantly or exclusively facilitate output of pyramidal tract neurons as well as the output of subcortical structures; both effects facilitate motor responses at the spinal level.
Animals↗
Interhemispheric relationships of reponses to sine wave modulated light in normal subjects and patients.
(1) The interhemispheric amplitude correlations of the fundamental (A1) and second harmonic (A2) components of responses to sine wave modulated light were determined in the occipital, parietal and temporal scalp areas of a group of normal subjects and a group of patients with unilateral irritative EEG phenomena. The interhemispheric amplitude correlation was computed at 10- and 16-c/sec stimulation frequencies and under 3 conditions: no modulation and no attention (M-, A-), modulation 30%, and no attention (M+, A-) and modulation 30% and attention (M+, A+). The correlations wre expressed in the rank correlation coefficient of Kendall (rK). (2) Analysis of variance revealed that the interhemispheric amplitude correlation of A1 in the normal group was significantly larger than that in the patient group at a stimulation frequency of 10 c/sec and under the conditions (M-, A-) and (M+, A-). (3) Both groups presented the largest correlation coefficients in the occipital scalp area. (4) In the normal group a significant increase of rK occurred under the influence of modulation. Attention caused a decrease of the correlation coefficient of A1. In the group of patients this influence was not clear. (5) The standard deviation of the mean interhemispheric phase differences was considered as a measure of synchrony of the response components between the two hemispheres. The smallest values of standard deviation were found in the occipital scalp area of the normal group at 10 c/sec stimulation frequency. Considerable variations between individuals were observed in both groups. (6) The correlation between the interhemispheric amplitude correlation (rK) and the interhemispheric synchrony was influenced by changing modulation depth from 0 to 30% and by introduction of attention, mostly in the group of normal subjects. This phenomenon was considered to support the theory that in patients with unilateral EEG disturbances the interhemispheric relations are different from those in normal subjects. (7) The findings as to amplitude correlation (rK) were the same under the condition (M-, A-) as under the condition (M+, A-).
Attention↗
Stimulatory modulator of guanosine 3':5'-monophosphate-dependent protein kinase from mammalian tissues.
The crude protein kinase modulator preparations obtained from several rat tissues (aorta, brain heart, liver, lung, skeletal muscle, small intestine and testis) were separated into their stimulatory and inhibitory modulator components by Sephadex G-100 gel filtration. The isolated stimulatory modulator augmented the activity of guanosine 3':5'-monophosphate-dependent protein kinase. The isolated inhibitory modulator, on the other hand, depressed the activity of cyclic AMP-dependent protein kinase; it was without effect on the activity of cyclic GMP-dependent protein kinease. The present findings indicate that in the mammal, apparently in contrast to the arthropoda, separate proteins are responsibile for the stimulatory and the inhibitory activities of protein kinase modulator and that the two classes of cyclic nucleotide-dependent protein kinase are regulated in an opposing manner by these two types of modulators.
Animals↗
Isolation and characterization of Ca2+-dependent modulator protein from the marine invertebrate Renilla reniformis.
An acidic, low molecular weight (18 400--19 100) protein capable of activating porcine brain phosphodiesterase in the presence of calcium has been purified 2700-fold from the anthozoan coelenterate, Renilla reniformis. The protein has physical, spectral, and chemical properties similar to those of modulator proteins isolated from mammalian species. Amino acid composition studies reveal no significant differences between the Renilla and mammalian modulator proteins. For example, we observed 1 mol of epsilon-N-trimethyllysine per mol of protein, no tryptophan or cysteine, and high levels of glutamic and aspartic acid residues. The protein from Renilla complexes with troponin I and T subunits in the presence of calcium and quantitatively replaces porcine brain modulator in the calcium-dependent activation of porcine brain phosphodiesterase. The protein has a high affinity for calcium as judged by the low levels of free calcium required for modulator-dependent activation of phosphodiesterase. The similarities in physical and chemical properties, high affinity for calcium, and identical calcium-dependent activities of this protein from Renilla (as compared with modulator protein purified from mammalian systems) suggest that a high degree of structural conservation has been retained in modulator proteins isolated from these diverse evolutionary forms.
Amino Acids↗