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PubMed2024

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↗

PubMed1978

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↗

PubMedDate not supplied

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↗

PubMed1975

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↗

PubMed1978

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↗

PubMed1976

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↗

PubMed1979

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↗

PubMed1978

Calcium-dependent protein modulator of cyclic nucleotide phosphodiesterases from mouse epidermis.

1. A heat-stable modulator protein was partially purified from mouse epidermis. The protein stimulated modulator-depleted cyclic AMP phosphodiesterase from bovine brain in the presence of Ca2+. 2. DEAE-cellulose chromatography of epidermal extracts demonstrated the presence of two main phosphodiesterase activities that hydrolysed both cyclic AMP and cyclic GMP. A minor peak was eluted between 0.1 and 0.3 M-sodium acetate and a major peak was eluted between 0.3 and 0.45 M-sodium acetate. 3. Cyclic AMP phosphodiesterase activity eluted at low salt concentrations was markedly activated by the epidermal modulator protein in the presence of Ca2+. Storage of the enzyme led to a decrease in its sensitivity to the protein modulator. 4. Treatment of mouse skin with the tumour promoter 12-O-tetradecanoylphorbol 13-acetate, which leads to an increase in epidermal cyclic nucleotide phosphodiesterase activity, did not alter the amount of modulator present in soluble epidermal extracts. The tumour promoter decreased the amount of modulator extractable from particulate epidermal preparations with Triton X-100.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1977

Receptor diffusion on cell surfaces modulated by locally bound concanavalin A.

In order to test the anchorage modulation hypothesis, the fluorescence photobleaching recovery method was used to measure the global inhibition of cell surface receptor mobility induced in 3T3 mouse fibroblasts by local binding of platelets labeled with concanavalin A (Con A). By measuring the diffusion of antibody-labeled cell surface receptors at various points on the cell surface, two states, immobile and mobile, were distinguished in the receptor population. Bound Con A-platelets, occupying between 4% and 30% of the cell surface, decreased the diffusion coefficient of the mobile population by a factor of 6. The magnitude of this effect was independent of distance from the sites of the bound Con A-platelets, demonstrating the propagated and nonlocal properties of the modulation effect. The immobile fraction of the population was not changed by Con A-platelet binding. Modulation of the diffusion constant of mobile receptors was partially reversed by treatment with microtubule-disrupting agents such as Colcemid and Vinca alkaloids. High doses of soluble Con A induced even higher levels of modulation than Con A-platelets, but reversal by microtubule-disrupting drugs was observed. These experiments provide additional support for the anchorage modulation hypothesis and provide a measure of the nature and degree of mobility at the molecular level. They also put important constraints on the hypothesized interactions among submembranous components (microtubules and microfilaments) of surface modulating assemblies.

Antigen-Antibody Complex↗

PubMed2026

Identifying multigenic modules under selection in the tumor genome.

MOTIVATION: Genomic alterations in cancer arise from selective pressures acting on hallmark molecular modules, layered over a background of random mutagenic events. Methods to detect selection at the level of modules, as opposed to genes or nucleotides, are relatively underdeveloped. RESULTS: Here we present CanSRMaPP (Cancer Selection Recovery by Maximum Posterior Probability), a Bayesian model of the cancer genome that infers mutational selection on single genes and multi-genic modules while simultaneously modeling background events. Applying CanSRMaPP to lung adenocarcinoma genomes, we identify positive selection on 63 modules, yielding a model that parsimoniously explains the observed pattern of genetic alterations observed in new cancer cohorts. We further show that CanSRMaPP is adaptable to more tumor types and to alternative module definitions. We show that these modules serve as an effective scaffold for translating the cancer genome to molecular states, with prediction of cancer biomarker status as demonstration. AVAILABILITY: CanSRMaPP is freely available on GitHub. SUPPLEMENTARY INFORMATION: Supplementary Figs. S1-5, Supplementary Tables S1-5, and Supplementary Notes 1 and 2 are available at Bioinformatics online.

Journal Article↗

PubMed1978

Circular dichroism studies on Ca2+-dependent protein modulator oxidized with N-chlorosuccinimide.

The structural features and Ca2+-binding properties of native and N-chlorosuccinimide-oxidized modulator protein were compared by circular dichroism. In the presence of Ca2+,the far-UV spectra of native and oxidized modulator protein are virtually indistinguishable, indicating that oxidation of surface methionine residues does not alter the overall conformation of the molecule. In the absence of Ca2+, however, the circular dichroism spectra of native and oxidized modulator are different with calculated helical contents of 40% and 26%, respectively. As judged by circular dichroism titration studies, the native modulator contains both high-(Kd = 1.9 X 10(-7) M) and low-affinity (Kd = 4 X 10(-4) M) Ca2+-binding sites, whereas the modified modulator appears to possess only low-affinity sites (Kd = 3.8 X 10(-4) M). The reduced secondary structure in Ca2+-free oxidized modulator protein may account for the absence of high affinity Ca2+ binding sites.

Animals↗

PubMed1978

Regulation of allotype expression in heterozygous rabbits. I. Concomitant modulation of cell surface allotypes on peripheral blood lymphocytes from b4b6 rabbits.

Treatment of b4b6 rabbit peripheral blood lymphocytes with b5b5 anti-b4 antibodies at 4 degrees resulted in the modulation (disappearance) ob b4 and b6 cell surface allotype after subsequent incubation in serum-free medium for 1 h at 37 degrees. A clear dose dependence on the sensitizing anti-b4 antibody was observed. Similarly, b5b5 anti-b6 treatment demonstrated a dose dependence for b6 modulation and a threshold dose effect for b4 comodulation. Cells which formed rosettes with anti-b4-coupled SRBC (anti-b4 direct antiglobulin (DAG) rosettes) also demonstrated concomitant modulation of b4 and b6 allotype when incubated at 37 degrees. When cells formed anti-b6 DAG rosettes, subsequent b6 modulation could also be demonstrated, but no b4 comodulation occurred. Concomitant modulation did not occur when cells were incubated with anti-allotype antibodies at 37 degrees. Blocking studies disclosed that the two allotypes are not contiguous in the membrane since uptake of one antiallotype antibody did not block the uptake of another at 4 degrees. We therefore propose that concomitant modulation might occur during a process similar to patch formation.

Animals↗

PubMed1978

Modulator binding protein antagonizes activation of (Ca2+ + Mg2+)-ATPase and Ca2+ transport of red blood cell membranes.

Red blood cells contain a protein that activates membrane-bound (Ca2+ + Mg2+)-ATPase and Ca2+ transport. The red blood cell activator protein is similar to a modulator protein that stimulates cyclic AMP phosphodiesterase. Wang and Desai [Journal of Biological Chemistry 252:4175--4184, 1977] described a modulator-binding protein that antagonizes the activation of cyclic AMP phosphodiesterase by modulator protein. In the present work, modulator-binding protein was shown to antagonize the activation of (Ca2+ + Mg2+)-ATPase and Ca2+ transport by red blood cell activator protein. The results further demonstrate the similarity between the activator protein from human red blood cells and the modulator protein from bovine brain.

Biological Transport, Active↗

PubMed1976

Nystagmic modulation of neuronal activity in rabbit cerebellar flocculus.

1. The responses of neuronal elements in the flocculus of the awake, restrained rabbit were recorded during horizontal vestibular nystagmus in the dark. 2. Purkinje cells showed both vestibular (Types I and II) and eye movement modulation of simple spike activity. Type I Purkinje cells most commonly were inhibited in association with the ipsilaterally directed fast phase of nystagmus and excited during contralaterally directed fast phases. Type II Purkinje cells had a similar modulation but in the opposite direction. Variations on this pattern included an increase in firing during fast phases in both directions. 3. Presumed mossy fibers and granule cells also exhibited both vestibular and nystagmic modulation in various combinations. The nystagmic modulation often began during the fast phase and continued into the early part of the slow phase. Mossy fibers showing both vestibular and nystagmic modulation probably arise from the vestibular nuclei and/or the perihypoglossal nuclei. 4. Floccular control of brain stem nuclei utilizes not only vestibular but also eye movement signals and probably all sensory and internal signals involved in the regulation of gaze.

Animals↗

PubMed1992

Phasic modulation of transmission from vestibular inputs to reticulospinal neurons during fictive locomotion in lampreys.

The aim of this study was to determine whether the transmission from sensory inputs to reticulospinal neurons is modulated during fictive locomotion in lampreys. Reticulospinal neurons play a key role in the control of locomotion; modulation of sensory transmission to these neurons might be of importance for the adaptation of the control they exert during locomotion. In this series of experiments, intracellular synaptic responses of reticulospinal neurons of the posterior rhombencephalic reticular nucleus elicited by electrical stimulation of vestibular nerves on each side were studied during fictive locomotion induced by 50 microM N-methyl-D-aspartate (NMDA). Interestingly, shortly after NMDA had reached the bath and much before locomotor discharges were apparent in the recorded ventral roots, there was a significant depression of the synaptic transmission from vestibular nerves. The effect was reversed by washing out the NMDA and persisted in the isolated brainstem after spinal transection at the first segmental level. As locomotor discharges appeared in the ventral roots, synaptic responses elicited by vestibular nerve stimulation showed a clear phasic modulation of their amplitude during the locomotor cycle. Responses to stimulation of the ipsilateral vestibular nerve were smaller during the ipsilateral burst discharge than during the contralateral activity, whilst responses to stimulation of the contralateral vestibular nerve were minimal during contralateral activity and maximal during ipsilateral activity. This opposite pattern of modulation observed in the same reticulospinal neuron suggests that the phasic modulation of vestibular transmission is not due to changes in the membrane properties of the reticulospinal cell but is produced at a pre-reticular level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Divergent actions of protein kinase modulator in regulating mammalian cyclic GMP-dependent and cyclic AMP-dependent protein kinases.

Protein kinase modulator can either augment or depress phosphorylation of substrate proteins catalyzed by cyclic GMP-dependent and cyclic AMP-dependent protein kinases prepared from mammalian and arthropod tissues. Alteration by the modulator of the phosphorylating activity of the protein kinases is considered to be due to modification of protein substrate specificity subsequent to interaction of the modulator with the catalytic subunits of the enzymes. It is likely that the physiologic role of the modulator is to monitor the opposing effects of cyclic GMP and cyclic AMP by regulating the activity of respective protein kinases. Thus the modulator may function as a biologic "fine tuner" providing on additional mechanism by which the signals imparted to cells by physiologic stimuli can be correctly expressed.

Animals↗

PubMed1992

1H NMR assignment and secondary structure of the cell adhesion type III module of fibronectin.

The secondary structure of the tenth type III module from human fibronectin has been determined using NMR. This type of module appears many times in a wide variety of proteins. The type III module described here contains an Arg-Gly-Asp sequence known to be involved in cell-cell adhesion. The module was expressed in yeast and characterized by amino acid sequencing and mass spectrometry. 2D and 3D NMR spectroscopy of 15N-labeled protein was used to perform sequence-specific assignment of the spectrum. The secondary structure was defined by patterns of nuclear Overhauser effects, 3JNH-alpha CH spin-spin coupling constants, and amide proton solvent exchange rates. The molecule consists of seven beta-strands in two antiparallel beta-sheets with an immunoglobulin-like fold similar to that predicted for homologous modules in the cytokine receptor super family [Bazan, J. F. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 6934-6938]. The Arg-Gly-Asp sequence is located on a loop between the beta-strands F and G.

Amino Acid Sequence↗

PubMed1979

Isolation and characterization of baby hamster kidney (BHK-21) cell modulator protein.

A Ca2+-dependent modulator protein has been isolated from BHK-21 cells. The purification requires heat treatment, ion-exchange chromatography, and gel filtration. The protein appears homogenous on sodium dodecyl sulfate--polyacrylamide and isoelectric focusing gels. The protein comigrates with purified smooth muscle and brain modulators. BHK-21 modulator is characterized by a high content of aspartic and glutamic acids and by a high phenylalanine/tyrosine ratio. It lacks both cysteine and tryptophan. The protein is effective in activating brain-modulator-deficient phosphodiesterase. It can also be used in assay systems to generate Ca2+-sensitive actin activation of both BHK-21 and smooth muscle myosins. Therefore, it is proposed that the BHK-21 modulator protein is a component of the Ca2+-dependent mechanism involved in the regulation of actin--myosin interactions in BHK-21 cells.

3',5'-Cyclic-AMP Phosphodiesterases↗