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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↗
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↗
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↗
PubMed1977

Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.

Friend leukemia virus (FLV) erythroleukemic cells cultured in medium containing FLV-immune serum from dormant FLV-infected mice undergo modulation of FLV cell surface antigens. Modulation was determined by an increased resistance to FLV antibody-mediated complement-dependent lysis and was associated temporally with the capping of FLV-immune complexes at the cell surface. Modulated cells regained their susceptibility to FLV antibody-mediated complement-dependent lysis when transferred to medium containing normal mouse serum. After 48 h of culture in FLV-immune serum, 26% of the FLV erythroleukemic cells were devoid of FLV cell surface antigens as demonstrated by immunofluoresence. Antigenic modulation occurred to a greater extent in cells maintained in logarithmic growth than in cells in GO or resting phase. FLV-antigenic modulation is discussed as a possible mechanism by which antibody induces and maintains FLV-transformed cells in a dormant state.

Animals↗
PubMed2026

LCR-modules: a collection of workflows for cancer genome analysis.

MOTIVATION: The surge of genomic data from advanced sequencing technologies is outpacing current analytical pipelines. We introduce LCR-modules, an open-source suite of bioinformatics tools designed for flexible and automated cancer genome data analysis. LCR-modules enables reproducible analysis of diverse cancer genomics data at scale. The suite comprises 49 Snakemake-based workflows organized into three levels, facilitating tasks from low-level quality control to complex cohort-level analyses. LCR-modules supports various sequencing types and integrates pipelines such as mutation calling, expression quantification, and cohort-level aggregation, ensuring flexibility and reproducibility. LCR-modules represents a significant advancement in genomic data analysis, reducing barriers in reproducibility and scalability and has already been applied to a combination of exomes and genomes from over 10 800 samples. AVAILABILITY: No new data were generated in support of this research. The source code for the LCR-modules is openly available at https://github.com/LCR-BCCRC/lcr-modules.

Software↗
PubMed1978

Ca2+/protein modulator-dependent and -independent cyclic GMP phosphodiesterase from hog heart.

Ca2+/protein modulator-dependent and -independent guanosine 3':5'-monophosphate (cGMP) phosphodiesterases were separated from hog heart. The protein modulator-free Ca2+/protein modulator-dependent enzyme was partially purified by repeated DEAE-cellulose column chromatography and heat treatment. The final preparation of this enzyme showed no significant basal activity under the standard assay conditions. Lineweaver-Burk plots of the Ca2+/protein modulator-dependent enzyme activity indicated the presence of only a single kinetic form of the enzyme with Km=2.0 X 10(-6) M for for cGMP, whereas the plots for the independent enzyme were anomalous, showing both high and low K m values for cGMP. The Ca2+/protein modulator-dependent enzyme proved relatively stable at 48 degrees C for 1 h, but the independent form lost its activity under the same conditions. Furthermore, 50% inhibition of the dependent enzyme activity, but only 10% inhibition of the independent enzyme activity, was observed with 0.1 mM adenosine 3':5'-monophosphate (cAMP) when 1 muM cGMP was employed as a substrate.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1979

Cyclic nucleotide-dependent protein kinase modulators in thyroid tissue.

A heat-stable protein which inhibits cAMP dependent protein kinase was prepared from the bovine thyroid 100,000 X g supernatant. This protein inhibited the cAMP-dependent protein kinase both from bovine thyroid cytosol and bovine thyroid plasma membranes. The inhibitory effect was noncompetitive with histone as substrate of the cytosolic enzyme. The stimulatory modulator for cGMP-dependent protein kinase was separated from the 100,000 X g supernatant by Sephadex G-100 gel filtration. The stimulatory modulator had no stimulating effect on cAMP-dependent phosphorylation, and the inhibitory modulator of cAMP-dependent enzyme had no effect on cGMP-requiring phosphorylations. The inhibitory modulator may regulate cAMP-dependent protein kinase activity in cytosol and plasma membrane, and the stimulatory modulator for cGMP-dependent protein kinase may have a role in thyroid function independent of the cAMP-requiring system.

Animals↗
PubMedDate not supplied

Effect of protein kinase modulator on cAMP-dependent protein kinase-catalyzed phosphorylation of phospholamban and stimulation of calcium transport in cardiac sarcoplasmic reticulum.

The heat-stable protein (protein kinase modulator), partially purified from fresh bovine heart, possessed the ability to inhibit and stimulate adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase and guanosine 3':5'-monophosphate (cGMP)-dependent protein kinase activities, respectively. The inhibitory activity of protein kinase modulator on cAMP-dependent protein kinase was abolished almost completely by trypsin treatment, while the ability to stimulate cGMP-dependent protein kinase activity was resistant to trypsin. Fractionation by a linear potassium phosphate gradient on DEAE-cellulose column did not clearly separate both activities. Phosphorylation of cardiac microsomal component, "phospholamban" (molecular weight = 22,000), was inhibited almost completely by the saturating amounts of protein kinase modulator. This inhibition of phospholamban phosphorylation by protein kinase modulator was accompanied by a decreased Ca uptake rate that had been stimulated by cAMP-dependent protein kinase. These findings indicate that protein kinase modulator is functional in controlling the cAMP-dependent protein kinase-catalyzed phosphorylation of phospholamban and the rate of calcium transport, lending further support for the previously proposed mechanism, in which phospholamban is assumed to serve as a regulator of calcium transport in cardiac sarcoplasmic reticulum.

Animals↗
PubMed1978

Learning modules as a supplement to existing audiovisual aids.

The development and use of supplementary learning modules for audiovisual aids designed for wider audiences was found to be a feasible approach for the education of family practice residents. This approach allows programs to direct learner attention to areas of greatest interest in family practice. It was not excessively time consuming to develop the two modules and extensive technical expertise with media was not required. It was found that the modules were adaptable to individual or group use. This teaching method appears to be an excellent learning tool for residents. Supplementary learning modules may be useful for medical students and other health-care providers in family practice. Further economy of time and other innovations using this basic approach could result from recruiting family practice residents and other students to develop their own learning modules on topics of individual interest.

Audiovisual Aids↗
PubMed1977

Regulation of allotype expression in heterozygous rabbits. III. Concomitant modulation and concomitant suppression oa a2 and a3 allotypes on individual peripheral blood lymphocytes.

Sensitization of peripheral blood lymphocytes from heterozygous a2/a3 rabbits with purified, monospecific anti-a3 antibodies, raised in a1/a1 rabbits, resulted in the disappearance of surface a2 and a3 allotypes (concomitant modulation) after subsequent incubation at 37 degrees C, as determined by the mixed antiglobulin (rosette) test. Similar results were obtained when anti-a2 antibodies were used. The dose dependence of modulation and comodulation were also studied. Testing of mixtures of homozygous a2/a2 plus a3/a3 cells never led to comodulation. Blocking studies, performed to determine the surface contiguity of a2 and a3 determinants, indicated that both allotypes are situated close together in the membrane on cells exhibiting allotype inclusion. Overnight culture in serum-free medium revealed that cells which underwent extensive modulation and comodulation were often suppressed for both homologous and alternate allotypes (concomitant suppression). These and other data suggest that a single modulation event, in which extensive removal of cell membrane Ig occurred, could serve to inhibit the re-expression of Ig. This may, in part, reflect interactions with membrane receptors involved in the regulation of expression of VH gene products. Implications of VH allotype inclusion are discussed.

Animals↗
PubMedDate not supplied

Evoked responses of the superior olive to amplitude-modulated signals.

Evoked potentials of some auditory centers of Rhinolophidae bats to amplitude-modulated signals were studied. A synchronization response was found in the cochlear nuclei (with respect to the fast component of the response) and in the superior olivary complex (with respect to both fast and slow components of the response) within the range of frequency modulation from 50 to 2000 Hz. In the inferior colliculus a synchronized response was recorded at modulation frequencies below 150 Hz, but in the medial geniculate bodies no such response was found. Evoked responses of the superior olivary complex were investigated in detail. The lowest frequencies of synchronization were recorded within the carrier frequency range of 15-30 and 80-86 kHz. The amplitude of the synchronized response is a function of the frequency and coefficient of modulation and also of the angle of stimulus presentation.

Animals↗
PubMed1979

Effects of modulated RF energy on the EEG of mammalian brains. Effects of acute and chronic irradiations.

The effects of modulated radio frequency fields on mammalian EEGs were investigated using acute and chronic irradiations at non-thermal level. The EEG signals were computer processed to obtain power spectra. Rabbits were exposed to the field for 2 h a day for 6 weeks at 1-10 MHz (15 Hz modulation) at the level of 0.5-1 kV/M. Silver electrodes placed on the skull surface were used for recording of the EEG. Usually they were removed immediately after initial recordings of the EEG and reinserted before the final and intermediate EEG recordings. With this arrangement, modulated RF fields produced a change in EEG patterns by enhancing the low frequency components and decreasing high frequency activities. On the other hand, acute irradiations did not produce noticeable changes in the EEG at the level of 0.5-1 kV/M (1-30 MHz, 60 Hz modulation) as long as the use of intracranial electrodes was avoided.

Animals↗
PubMed1978

Averaged evoked potentials and frequency modulation.

Frequency modulated (FM) auditory stimuli result in average vertex potentials similar to the usual auditory average evoked potential (AEP). For stepwise increase or decrease in tone frequency the AEPs are similar. For FM stimuli modulated by pulses of different durations 'on' responses are evoked by the transition of the stimulus from the longer duration to the shorter duration frequency tone while 'off' responses result when the frequency transition is from the shorter to the longer duration tone. Ramp modulation of the stimulus frequency results in average evoked responses; the amplitude of these responses is proportional to the slope of the ramp as well as the frequency of the tone that precedes the ramp. Thus, if the tone preceding the ramp is also a ramp but of smaller slope the AEP is attenuated and with sufficiently large slope the AEP can be completely extinguished. No AEPs were obtained at the offset of ramp modulated stimuli. The standard deviation (S.D.) of the reaction time (RT) distributions to stimulus onset indicate that the AEP amplitude is inversely proportional to the S.D. values. Thus, the attenuation phenomena appeared to be related to the uncertainty of the subject as to the exact time the stimulus occurred, both of which seem to be the result of sensory difficulty to the type of stimuli used. AEPs to negative ramps were smaller than AEPs to positive ramps; this may be on account of the psychological inequality between the stimuli.

Acoustic Stimulation↗
PubMed1979

Combined modulating effects of the general arousal and the specific hunger arousal on the olfactory bulb responses in the rat.

The combined modulating effects of the general level of arousal and specific hunger arousal on the olfactory bulb responses were investigated in the rat. Vigilance state parameters and multi-unit mitral cell activity were recorded in freely moving animals stimulated by control odours and by their usual food odour, either in the hungry or the satiated state. The nutritionally modulated bulb responses towards food odour were observed only for high arousal level (wakefulness). In rapid eye movement sleep (REMS), no olfactory response occurred. In slow wave sleep (SWS), one observed either a high bulb responsiveness to stimuli with neocortical arousal, or a general inexcitability. Each odorous stimulus in SWS elicited a higher neocortical arousal rate in the hungry than in the satiated state, as did food odour compared with control odours in both nutritional states. In SWS, a progressive alteration of the nutritionally modulated responses occurred at first at the bulb level and later for inner structures. Rats fed 2 h a day displayed a reversed circadian sleep-waking cycle and a lower SWS proportion compared with rats fed ad libitum. The hunger arousal could quantitatively and qualitatively modulate the activity of structures regulating the sleep-waking pattern.

Animals↗
PubMed1978

The effect of inhibitors of protein synthesis on the reexpression of surface immunoglobulin following antigenic modulation.

P3, a cell line derived from the plasmacytoma MOPC-21 secretes IgG1 (K) and is sensitive to complement (C')-mediated lysis by antibody directed against gamma1 or K. Sensitivity is attributed to the presence of immunoglobulin molecules on the surface membrane, designed Ig-mem. This sensitivity is abolished by antigenic modulation of Ig-mem. Modulated cells, when incubated in the absence of antibody, recover sensitivity to lysis in 4 hr. By measuring the rate of recovery, it has been possible to study the effects of various drugs on the reexpression of Ig-mem. Treatment of modulated cells with cycloheximide (Cx), pactamycin Pc), anisomycin (An), homoharringtonine (Ha) or sparsomycin (Sm), each a specific inhibitor of a different step in protein synthesis, produces a significant reduction in the rate of recovery. Paradoxically, puromycin (Pm), also a specific inhibitor of protein synthesis, does not reduce the rate of recovery. Studies were performed using Pm together with each of the other drugs to gain an understanding of the relationship between protein synthesis and recovery from modulation. Based upon these studies, we conclude that continued operation of the initiation cycle of protein synthesis is required for reexpression of Ig-mem in the absence of de novo protein formation.

Anisomycin↗
PubMed2026

Discovery of NAT-6-321056 as a novel modulator of VEGFR2 signaling to suppress tumor angiogenesis.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a master regulator of angiogenesis and cancer progression. However, current VEGFR2 modulators face significant challenges, including off-target toxicity and acquired resistance, underscoring the urgent need for novel therapeutic agents with improved efficacy and safety profiles. Here, we reported that virtual screening of 39,442 natural products from the ZINC natural products-derived library, coupled with molecular docking and molecular dynamics (MD) simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling. Biological evaluations demonstrated that NAT-6-321056 exerted potent inhibition on the growth of a broad spectrum of cancer cells, including both solid tumors and hematological malignancies. In EA.hy 926 endothelial cells and SK-N-DZ neuroblast cells, the compound significantly suppressed proliferation, migration, and invasion. Microscale thermophoresis (MST) confirmed direct binding of NAT-6-321056 to VEGFR2 with favorable affinity. Kinase profiling against a panel of 33 kinases indicated that NAT-6-321056 exhibited a multi-kinase modulation profile. Mechanistic studies revealed that NAT-6-321056 suppressed the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and was associated with reduced VEGFR2 phosphorylation and attenuation of the downstream ERK/JNK/AKT signaling pathways. Moreover, NAT-6-321056 exhibited robust in vivo anti-angiogenic effects in both the chick chorioallantoic membrane (CAM) assay and transgenic zebrafish vascular fluorescence imaging models. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction suggested acceptable drug-like properties. Collectively, these findings demonstrated that NAT-6-321056 is a promising modulator of VEGFR2 signaling with potent anti-angiogenic activity and represents a viable candidate for cancer therapy.

Vascular Endothelial Growth Factor Receptor-2↗
PubMed2026

Synergistic transcriptional modules in Trichoderma asperellum enhance glutathione detoxification to counteract fungal pathogen toxins.

Trichoderma fungi are potent biocontrol agents. However, their defence mechanisms against pathogen-derived toxins remain poorly understood. We identified two synergistic transcription factor modules in T. asperellum that orchestrate the detoxification of cytotoxic secondary metabolites from the poplar blight pathogen Alternaria alternata. Overexpression of the central regulator TasMYB46 reduced disease lesion area by approximately 22% and was associated with decreased pathogen-induced reactive oxygen species (ROS) accumulation. Mechanistically, TasMYB46 directly activates the glutathione S-transferases TasGST61.1 and TasGST56.1 through distinct promoter binding sites (G-box/as-1/MBS), forming dedicated detoxification modules. Crucially, we identified urolithin C as the most abundant phytotoxin in A. alternata metabolites, which is efficiently detoxified through the TasMYB46-TasGST61.1 module. The transcription enhancer TasbHLH53.8 amplifies this system by binding to TasMYB46, boosting TasGST expression and enhancing glutathione-dependent detoxification capacity. This coordinated response elevates glutathione pools and antioxidant enzyme activities (GST/GPx), conferring increased oxidative stress resistance. This study reveals a novel defence mechanism in Trichoderma in which MYB-bHLH-GST modules enable biocontrol agents to neutralise pathogen-derived toxins. Given that Alternaria toxins threaten crops globally (tomatoes, potatoes, citrus), the discovered regulatory synergy represents a strategic advance in developing next-generation biocontrol solutions against toxin-producing plant pathogens.

Alternaria↗
PubMed1978

Modulator protein as a component of the myosin light chain kinase from chicken gizzard.

The Ca2+-dependent regulation of smooth muscle actomyosin involves a myosin light chain kinase (ATP: myosin light chain phosphotransferase). It has been shown (Dabrowska, R., Aromatorio, D., Sherry, J.M.F., and Hartshorne, D.J. 1977, Biochem. Biophys. Res. Commun. 78, 1263) that the kinase is composed of two proteins of approximate molecular weights 105 000 and 17 000. In this communication it is demonstrated that the 17 000 component is the modulator protein. This conclusion is based on: (1) the identical behavior of the 17 000 kinase component and modulator protein in assays of actomyosin Mg2+-ATPase activity, phosphorylation of myosin, and phosphodiesterase activity, and, (2) the similarity of the 17 000 kinase component and the modulator protein with respect to amino acid composition, absorption spectrum, and electrophoresis in urea-polyacrylamide gels. It is shown also that the modulator protein from smooth muscle and troponin C are distinct proteins.

Adenosine Triphosphatases↗