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At least 127 records · Page 7Linked to original sources
PubMed1977

[Characteristics of the structure and functional potentials of the metaepiphysis of tubular bones].

During early postnatal ontogenesis in the metaepiphyseal plate of the developing rat tibial bone, the borderline zone, the columnar cartilage zone and the zone of macrovesiculous cells differ in their cell composition, structure of basic substance and in functional and reactive potencies, which manifest themselves most distinctly after injection of growth-promoting hormones to the animals. The organic specificity of the metaepiphyseal borderline zone depends, first of all, on its intermediate position between the cartilage, fulfilling further bone growth lengthwise as an organ, and a developing endochondral bone substituting cartilage in the epiphysis. The borderline zone retains these features under hormonal effect. In the zone of columnar cells, it is reasonable to distinguish a layer of cuboidal cells--mature chondrocytes posessing great reactive and reparative possibilities, which become especially distincitive after prednisolon and TCT injection.

Animals↗
PubMed2001

minK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as beta subunit of cardiac transient outward channel?

Inherited mutations and a polymorphism in minK-related peptide 1 (MiRP1) have been linked to congenital or acquired long-QT syndrome, pointing to the importance of MiRP1 in maintaining the cardiac electrical stability. We tested whether MiRP1 could affect the function of Kv4.x (x=2 and 3), the major pore-forming (alpha) subunits of transient outward (I(to)) channels in the heart. We used the Xenopus oocyte expression system to examine the effects of MiRP1 on Kv4.x channel gating kinetics and current amplitude and correlated these effects with MiRP1 expression level. MiRP1 slowed the rates of Kv4.2 activation and inactivation and shifted the voltage dependence of channel gating in the positive direction. These effects had a similar "dose" dependence: they plateaued at a cRNA ratio (MiRP1:Kv4.2) of 13:1, with half-maximum effects at estimated cRNA ratios of 2 to 4. On the other hand, MiRP1 had no significant effects on Kv4.2 current amplitude in the same range of expression level. When expressed at a comparable low level, MiRP1 had similar (although smaller) effects on Kv4.3 but could not modulate Kv1.4 (another alpha subunit of I(to) channels in the heart). Kv4.2 could be coimmunoprecipitated with epitope-tagged MiRP1, indicating that the 2 could form a stable complex. Our data suggest that MiRP1 may serve as a regulatory (beta) subunit of I(to) channels in the heart. This is supported by the observation that MiRP1 induced an "overshoot" of Kv4.2 current amplitude during channel recovery from inactivation, similar to the overshoot of I(to) described for human epicardial myocytes.

4-Aminopyridine↗
PubMed1999

[Evaluation of functional potentials of microcirculation in patients with obliterating diseases of lower limb vessels].

An analysis of the data of laser doppler fluorometry in 136 patients has shown that different obliterating diseases have different typical fluorometric features of changes in microcirculation. Results of the postischemic test are of greater informative value in the noninvasive assessment of the functional state of microcirculation. The significance of the functional tests was particularly increasing in critical ischemia of the lower extremities. The intraoperative determination of the muscle blood flow allowed performing the control of the lower extremity revascularization and determining the optimum level of amputation.

Adult↗
PubMed2026

Long-read based detection of large copy number variants with potential functional significance using the ContextSV structural variant caller.

Long-read sequencing enables improved detection of structural variants (SVs) in the human genome due to its substantially increased read lengths. However, currently widely used long-read SV callers primarily rely on alignment-based evidence, limiting their ability to detect large and complex SVs and potentially missing disease-relevant events. To address these limitations, we developed ContextSV, a framework that integrates alignment evidence with copy number predictions derived from sequencing coverage and single-nucleotide variant allele frequencies to improve SV detection, particularly for large copy number variants (CNVs). We additionally developed ContextScore, a machine learning-based classification model to assign SV confidence scores based on genomic context features and integrated it within ContextSV. Through benchmarking analyses on both simulated and real datasets, we demonstrate that ContextSV improves detection of large CNVs and inversions that may be missed by existing long-read SV callers. We further illustrate its utility by identifying and experimentally validating multiple large SVs in the KOLF2.1J reference stem cell line that were not detected by other methods. Collectively, our results demonstrate that ContextSV serves as a valuable complement to existing long-read SV detection approaches by improving sensitivity for large and clinically relevant SVs.

Humans↗
PubMed1995

Biochemistry, regulation and potential function of kallistatin.

Components of the tissue kallikrein-kinin system include tissue kallikrein, kallistatin (kallikrein-binding protein), kininogen, kinin, bradykinin B1 and B2 receptors, and kininases. Tissue kallikrein is a serine proteinase which is capable of cleaving kininogen substrate to release the vasoactive kinin peptide. The binding of kinin to its specific receptor at target organs can produce a wide spectrum of biological effects. Kinin generation is primarily determined by the activity and availability of kallikrein since the level of kininogen is not a rate-limiting factor. Kallikrein levels are controlled by its rate of synthesis, activation, inactivation and clearance. The synthesis of tissue kallikrein is regulated transcriptionally, and its activity is regulated through post-translational processing and inactivation by inhibitors. Kallistatin is a newly discovered serine proteinase inhibitor (serpin) which forms a specific and covalently-linked complex with tissue kallikrein. Kallistatin may regulate tissue kallikrein's activity, bioavailability and clearance rate at the post-translational level. The major site of kallistatin synthesis is the liver with lower expression levels in the pancreas and kidney. Unlike many other serpins which are only present in the plasma, kallistatin is found in various tissues, cells and bodily fluids. The fact that both tissue kallikrein and kallistatin are widely distributed in tissues suggests kallistatin's role as a potential regulator of kallikrein outside the circulation. Protein purification and molecular cloning techniques have been used to study the structure, regulation and function of the components of the kallikrein-kinin system and for exploring their roles in ion transport, inflammation and blood pressure regulation. Considerable progress has been made in recent years to achieve these goals. This article provides an overview of the biochemical properties and potential physiological and pathophysiological roles of kallistatin.

Animals↗
PubMed1992

Nonsteroidal estrogens bearing acyl azide functions: potential electrophilic and photoaffinity labeling agents for the estrogen receptor.

In an effort to develop novel affinity labeling agents for the estrogen receptor, we have synthesized two nonsteroidal ligands, a 1-aroyl-2-aryl tetralin system (1) and a 2-aryl-3-aroylbenzo[b]thiophene system (2). These agents, patterned after the Lilly antiestrogens trioxifene and LY 117018, respectively, embody acyl azide functions as part of a benzoyl chromophore. The acyl azide group has weak acylating activity, suitable for electrophilic affinity labeling, but this function is also photoreactive and, in its particular embodiment within these ligands, it could provide an efficient photochemical route to the highly reactive singlet acyl nitrene. The tetralin system (1) was prepared in nine steps from 6-methoxy-1-tetralone, and the benzothiophene system (2) was prepared in four steps from a known substituted benzo[b]thiophene precursor. In competitive binding assays, both compounds show reasonable binding affinity for the rat and lamb uterine estrogen receptor: estradiol = 100%, 1 = 3%, and 2 = 12%. When assayed by indirect receptor consumption assays, both compounds appear to have substantial capacity for irreversible binding (electrophilic reaction) with the receptor. This reactivity, which suggests that acylation of the receptor has occurred, is photoreversible. The nature of this ligand-receptor interaction is being investigated further.

Affinity Labels↗
PubMed1989

Negative regulatory element associated with potentially functional promoter and enhancer elements in the long terminal repeats of endogenous murine leukemia virus-related proviral sequences.

Three series of recombinant DNA clones were constructed, with the bacterial chloramphenicol acetyltransferase (CAT) gene as a quantitative indicator, to examine the activities of promoter and enhancer sequence elements in the 5' long terminal repeat (LTR) of murine leukemia virus (MuLV)-related proviral sequences isolated from the mouse genome. Transient CAT expression was determined in mouse NIH 3T3, human HT1080, and mink CCL64 cultured cells transfected with the LTR-CAT constructs. The 700-base-pair (bp) LTRs of three polytropic MuLV-related proviral clones and the 750-bp LTRs of four modified polytropic proviral clones, in complete structures either with or without the adjacent downstream sequences, all showed very little or negligible activities for CAT expression, while ecotropic MuLV LTRs were highly active. The MuLV-related LTRs were divided into three portions and examined separately. The 3' portion of the MuLV-related LTRs that contains the CCAAC and TATAA boxes was found to be a functional promoter, being about one-half to one-third as active as the corresponding portion of ecotropic MuLV LTRs. A MboI-Bg/II fragment, representing the distinct 190- to 200-bp inserted segment in the middle, was found to be a potential enhancer, especially when examined in combination with the simian virus 40 promoter in CCL64 cells. A PstI-MboI fragment of the 5' portion, which contains the protein-binding motifs of the enhancer segment as well as the upstream LTR sequences, showed moderate enhancer activities in CCL6 cells but was virtually inactive in NIH 3T3 cells and HT1080 cells; addition of this fragment to the ecotropic LTR-CAT constructs depressed CAT expression. Further analyses using chimeric LTR constructs located the presence of a strong negative regulatory element within the region containing the 5' portion of the enhancer and the immediate upstream sequences in the MuLV-related LTRs.

Animals↗
PubMed2002

Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes.

A combination of insulin resistance and pancreatic beta-cell dysfunction underlies most cases of type 2 diabetes. While the interplay of these two impairments is believed to be important in the development and progression of type 2 diabetes, the mechanisms involved are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) have deleterious effects on both glucose homeostasis and beta-cell function, and can disrupt insulin signalling pathways in both pancreatic beta cells and liver and adipose tissue. The anti-inflammatory activity of the thiazolidinedione anti-diabetic agents is potentially beneficial, given the possible role of pro-inflammatory cytokines in linking insulin resistance with beta-cell dysfunction.

Adipocytes↗
PubMed2004

Involvement of nuclear factor kappa B in the regulation of rat luteal function: potential roles as survival factor and inhibitor of 20alpha-hydroxysteroid dehydrogenase.

Nuclear factor kappa B (NFkappaB) is an important intracellular conveyor of extracellular signals and modulates a number of gene responses. Due to the potential significance of NFkappaB in regulating ovarian gene expression, we examined in the rat: (i) whether NFkappaB is activated and developmentally regulated in the corpus luteum (CL) throughout pregnancy; (ii) the proteins forming the NFkappaB complex in luteal cells; and (iii) the role of this transcription factor in luteal function. Western analysis and immunohistochemistry revealed that p65 and p50 were highly expressed throughout pregnancy and were located in both the nucleus and cytoplasm of luteal cells. In addition, because NFkappaB is maintained in the cytoplasm bound to IkappaB, whose phosphorylation allows NFkappaB translocation to the nucleus, we studied the developmental expression of phosphorylated and nonphosphorylated forms of IkappaBalpha. Western analysis revealed that IkappaBalpha was present and phosphorylated throughout pregnancy in the CL whereas by protein/DNA array and electromobility shift assays we found that luteal nuclear extracts bind to an NFkappaB consensus sequence, and that the binding activity decreased along pregnancy. The specific binding was supershifted only by an anti-p65 antibody and not by antibodies against p50, p52, cRel, or RelB. Using day 4 postpartum ovaries, we found higher NFkappaB binding activity in the newly formed CL than in old CL of pregnancy. Furthermore, NFkappaB DNA binding activity was enhanced by prolactin in luteinized granulosa cells. In our first functional study, blockade of NFkappaB/p65 binding to DNA with the sesquiterpene lactone helenalin in luteinized granulosa cells correlated with induction of cell death in a dose-dependent manner. In a second functional study, overexpression of NFkappaB/p65 in luteal cells resulted in inhibition of 20alpha-hydroxysteroid dehydrogenase (20alphaHSD) promoter activity as well as endogenous 20alphaHSD mRNA expression. In summary, we have shown that: (i) NFkappaB is expressed within the CL, primary luteinized granulosa cells, and a rat luteal cell line; (ii) NFkappaB activation within the CL is developmentally regulated in pregnancy, depends on the age of the gland, and can be upregulated by prolactin; (iii) inhibition of NFkappaB/p65 binding to an NFkappaB DNA consensus sequence correlates with induction of cell death in ovarian luteinized granulosa cells; and (iv) overexpression of NFkappaB in luteal cells inhibits 20alphaHSD gene expression. The results further support a role for NFkappaB as a survival factor in the CL.

20-alpha-Hydroxysteroid Dehydrogenase↗
PubMed2002

JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction.

BRCA1 is involved in the regulation of multiple nuclear events including transcription. AD1, one of the two trans-activation domains in BRCA1, stimulates transcription in a cell context-dependent manner. Here, it is shown that BRCA1 interacts with Jun proteins via a coiled-coil motif in AD1 and the basic leucine zipper (bZIP) region of the Jun proteins. The Jun-interacting domain in BRCA1 is critical for AD1-mediated transcriptional activation. In particular, the strength of AD1 in transcriptional activation is limited by the JunB level and ectopic expression of JunB potentiates the transcriptional activity of AD1. Furthermore, JunB mRNA expression is down-regulated in many ovarian tumor tissues examined. Thus, the coiled-coil-mediated cooperation between BRCA1 and JunB may facilitate the function of these proteins in tissue-specific transcriptional regulation and tumor suppression.

BRCA1 Protein↗
PubMed1999

Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta.

Skeletal muscle and myocardium express microNOS I, an elongated splice variant of neuronal-type nitric oxide (NO) synthase (NOS I), and NOS III, endothelial-type NO synthase, respectively. This study was designed to elucidate whether vascular smooth muscle also contains a constitutively expressed NO synthase isoform. In the rat, microNOS I contains an insert of 102 nucleotides after nucleotide 2865 of the cDNA, yielding a protein of 164 kd. Reverse transcription-polymerase chain reaction with primers flanking this insert and with insert-specific primers indicated that endothelium-denuded rat aorta expresses both brain-type NOS I and microNOS I. RNase protection analyses with an antisense RNA probe overlapping the microNOS I insert detected significant amounts of NOS I mRNA and lesser amounts of microNOS I mRNA in endothelium-denuded aorta. Western blots using a specific polyclonal antibody recognizing NOS I and microNOS I showed a major band of the 160-kd NOS I and a lesser band of a slightly larger protein in endothelium-denuded aorta. Immunohistochemistry demonstrated low levels of NOS I/microNOS I immunoreactivity in the medial layer of rat aorta, whereas the endothelium expressed only NOS III immunoreactivity. When the adventitia also was removed, NOS I and microNOS I mRNA decreased markedly but remained detectable in the medial layer. In functional experiments with endothelium-denuded rat aortic rings (that contained no NOS III), contractions induced by KCl were markedly increased in the presence of the NOS inhibitor N(G)-nitro-L-arginine. These data demonstrate that 2 subforms of NOS I are expressed in nonendothelial components of rat aorta: NOS I and lesser amounts of microNOS I. Under certain conditions, this NOS I/microNOS I expression could serve as a backup system to the functionally predominant NOS III.

Animals↗
PubMed1994

Simulation study on the effect of external vibration on left ventricular function: potential indicator of LV tolerance to the sudden reduction of myocardial contractility.

In a previous study the authors reported that external mechanical vibration applied to the left ventricular (LV) epicardium induces contractility-dependent depression in LV pressure, stroke volume and stroke work. It was suggested that this depression may be caused by the direct effect of external vibration on contractile protein. In another paper in this issue, it is proved that LV function with various myocardial contractilities and the actual process of deterioration in heart failure are well simulated in the model proposed by Beyar and Sideman, after some modifications have been made. In the study reported here it is assumed that an external mechanical vibration induces sudden reduction in myocardial active stress in the model of Beyar and Sideman; in this way the contractility-dependent effect of external vibration on LV function has been simulated. The results of this simulation support the suggestion that external mechanical vibration directly affects contractile protein and reduces LV function, and it is further suggested that the reduction of LV function induced by external vibration reflects the reserve or tolerance capacity of LV to a sudden reduction of myocardial contractility.

Animals↗
PubMed1999

Liquid junction potential in potentiometric titrations. 5. Deduction of the potential functions for E.M.F. cells with complex formation and with liquid junctions of the type AY [symbol: see text] AY + BYz(B) + HY + AyL.

Equations were derived, in a general form, for the calculation of the total cell e.m.f. for cells containing liquid junctions of constant ionic medium type, where formation of strong complexes takes place. The total cell e.m.f. is: EJ = E0J + (g/zJ) log cJfJTS2 + ED + EDf Here, (A+, Y-) is the ionic medium, J is the potential-determining ion, Bz(B)+ is the central metal ion, ED is the ideal diffusion potential (Henderson term), EDf is the contribution of the activity coefficients to the diffusion potential, AyL is the ligand. fJTS2 denotes the activity coefficients in the terminal solution TS2. The concentration of a chosen ion of the ionic medium, C, should be in the range 0.5 < or = C < or = 3 mol dm-3. The charge of the metal ion Bz(B)+ should be < or = 3. The total potential anomalies in the cells are delta EJ = (g/zJ) log fJTS2 + ED + EDf

Algorithms↗
PubMed2003

Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty.

Decorin is a small proteoglycan that binds to transforming growth factor-beta (TGF-beta) and inhibits its activity. However, its interaction with platelet-derived growth factor (PDGF), involved in arterial repair after injury, is not well characterized. The objectives of this study were to assess decorin-PDGF and decorin-PDGF receptor (PDGFR) interactions, the in vitro effects of decorin on PDGF-stimulated smooth muscle cell (SMC) functions and the in vivo effects of decorin overexpression on arterial repair in a rabbit carotid balloon-injury model. Decorin binding to PDGF was demonstrated by solid-phase binding and affinity cross-linking assays. Decorin potently inhibited PDGF-stimulated PDGFR phosphorylation. Pretreatment of rabbit aortic SMC with decorin significantly inhibited PDGF-stimulated cell migration, proliferation, and collagen synthesis. Decorin overexpression by adenoviral-mediated gene transfection in balloon-injured carotid arteries significantly decreased intimal cross-sectional area and collagen content by approximately 50% at 10 weeks compared to beta-galactosidase-transfected or balloon-injured, non-transfected controls. This study shows that decorin binds to PDGF and inhibits its stimulatory activity on SMCs by preventing PDGFR phosphorylation. Decorin overexpression reduces intimal hyperplasia and collagen content after arterial injury. Decorin may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty.

Angioplasty, Balloon↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH-cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Here, Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗