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At least 109 records · Page 6Linked to original sources

PubMed1979

In vitro functional studies of mononuclear cells in patients with CLL: evidence for functionally normal T lymphocytes and monocytes and abnormal B lymphocytes.

In vitro functional studies of mononuclear cells from 34 patients with B-cell type CLL were investigated and the results of these studies were as follows: 1) The T lymphocytes from patients with CLL were capable of responding normally to PHA or PWM, of inducing allogeneic normal B lymphocytes to respond to these mitogens and of stimulating normally to allogeneic lymphocytes in "one-way" mixed lymphocyte reaction; 2) The monocytes from these patients were capable of enhancing the T lymphocyte response to mitogens and of stimulating normally to allogeneic lymphocytes; and 3) The leukemic B lymphocytes were incapable of responding to mitogens even in the presence of normal T lymphocytes and their enhancer cell activity on T lymphocyte response or their stimulating capacity on allogeneic lymphocytes was depressed. These observations suggest that the T lymphocytes and monocytes from patients with CLL are functionally normal while the leukemic B lymphocytes from these patients are functionally abnormal.

Adult↗

PubMed2026

Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

ABL1↗

PubMed1976

Structural and functional changes in an identified cricket neuron after separation from the soma. II. Functional changes.

Physiological and behavioural effects of separation from the soma were examined in isolated arborization and isolated axon segments of an identified motor neuron in the Polynesian field cricket, Teleogryllus oceanicus. The identified neuron, the contralateral dorsal longitudinal motor neuron of the metathoracic ganglion (CDLM), has an arborization most of which lies contralateral to its soma within the ganglion. Midline lesions in the ganglion separated CDLM into a distal segment composed of the axon and most of the arborization, and a proximal segment made up of the remaining arborization, neurite and soma. Isolated axonal segments were produced by cutting the nerve containing the CDLM axon. The function of the neuron-muscle system composed of CDLM, its pre-synaptic inputs, and its innervated muscle bundle was examined in contrl and experimentally operated animals. Extracellular recording assessed function in the axon. Electrical or tactil stimulation was used to excite pre-synaptic inputs to the CDLM arborization. Intracellular recording determined changes in post-synaptic potentials and miniature end-plate potentials in the muscle bundle innervated by CDLM. Normal axonal conduction, competence to respond to pre-synaptic input, neuron-muscle transmission, and miniature end-plate potential appearance can remain in the isolated arborization preparation. Physiological viability is longer in the cricket isolated arborization than in other insect distal segments described. Survival times of axonal conduction and the competence of the isolated arborization to respond to pre-synaptic input are roughly correlated with disappearance of the whole distal segment at 100 or more postoperative days. A naturally-occurring breakdown of the metathoracic dorsal longitudinal muscles in Teleogryllus eventually prevents measurements of post-synaptic potentials and miniature end-plate potentials. Normal post-synaptic function mediated by the distal arborization is maintained up to this breakdown, to a maximum of 44 days postoperative. The distal axonal segment of CDLM degenerates physiologically within four days postoperative, a time course approximating that of degeneration in vertebrate peripheral nerve distal axons.

Animals↗

PubMed1989

Immunosuppression in experimental cryptococcosis in rats: modification of macrophage functions by T suppressor cells. Macrophages functions in cryptococcosis.

The influence of lymphocytes on the modulation of macrophage functions in altered immune states induced by Cryptococcus neoformans infection in rats has been investigated. In this report we observed a decrease of 'in vitro' phagocytic activity by peritoneal cells (PC) from rats that received T suppressor cells induced by cryptococcal infection, against both the same microorganism that stimulated this suppressor population (p less than 0.05) and another non-pathogenic primary yeast (Candida tropicalis), (p less than 0.02). The microbicide function of the PC from these animals present a significant decrease in challenge by C. tropicalis (p less than 0.002) when compared with PC from animals transferred with T normal cells. The transference of T suppressor cells induced by cryptococcal infection in animals immunized with human serum albumin-complete Freund's adjuvant (HSA-CFA) produces a significant alteration of the phagocytosis to HSA-human red cells (HSA-HRC) when compared with the phagocytosis observed in animals that received T normal cells or the phagocytosis of normal animals (p less than 0.001). We could also observe that the DTH to HSA studied during 30 days was negative in rats transferred with PC sensitizated with HSA and treated with suppressor T cells, when compared with the DTH response of animals transferred with PC-HSA cocultured with normal cells (p less than 0.05 21st day). The data presented in this paper illustrated that following infection of rats with C. neoformans there is a change in some population of accessory cells behavior reflected by the modification of several functions, such as phagocytosis, lytic activity and antigen presentation.

Animals↗

PubMed1992

Preferential expression and activity of multidrug resistance gene 1 product (P-glycoprotein), a functionally active efflux pump, in human CD8+ T cells: a role in cytotoxic effector function.

The multidrug resistance gene 1 (mdr 1) product, the P-glycoprotein (Pgp), is a 170-kD transmembrane transport protein, whose overexpression is associated with multidrug resistance in cancer cells and in chloroquine-resistant Plasmodium falciparum infection. In this study we show that normal freshly isolated human lymphocytes express low levels of mdr 1 mRNA and membrane Pgp. Although Pgp is expressed in both CD4+ and CD8+ T cells, it is preferentially expressed in CD8+ T cells. Activation of T lymphocytes with phytohemagglutinin leads to an amplification of both mdr 1 mRNA and membrane Pgp in T cells. P-glycoprotein in T cells is a functionally active efflux pump as demonstrated by decreased retention of rhodamine-123 and its increased accumulation by cyclosporin A, an inhibitor of Pgp function. In addition, MRK-16 antibody increased accumulation of Rh123 in CD8+ T cells. Furthermore, MRK16 anti-P-glycoprotein monoclonal antibody, in a concentration-dependent manner, inhibited T lymphocyte-mediated cytotoxicity. These data suggest a physiologic role of P-glycoprotein in cytotoxic T-lymphocyte effector function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1977

[Carbenicillin induced disturbance of platelet function: a study in patients with normal renal function (author's transl)].

After therapeutic doses of carbenicillin (3X10 g/24 h) prolongation of bleeding time, measured according to Ivy, was observed (median time prior to therapy 4 min 08 s-4 min 18 s; 24 h after therapy 15-20 min; 72 h after therapy greater than 30 min) in 5 patients with normal renal function and 2 patients with slight impairment of renal function (Ccr60-70 mlX1.73 m(2)). Prolongation of bleeding time was observed at serum concentrations between 13 and 180 microgram/carbenicillin/ml. After carbenicillin was withdrawn, prolongation of bleeding time was demonstrable for 4 days, i.v. even after the drug had been eliminated completely by urinary excretion. Higher doses of carbenicillin caused more severe disturbances of platelet function. The finding of prolonged bleeding time after carbenicillin may have clinical relevance (e.g. interaction with other anticoagulants, p.o. wound bleeding, gastro-intestinal hemorrhage, thrombopenia).

Adult↗

PubMed1979

Ovarian cancer: a solid tumor with evidence of normal cellular immune function but abnormal B cell function.

Immunologic assays of B and T lymphocyte function were performed on 21 patients with epithelial ovarian cancer prior to either chemotherapy or radiotherapy. The results were compared to similar studies on 12 age-matched normal women. The total peripheral blood lymphocyte counts, proportion of E rosette positive cells, stimulation of T cells by phytohemagglutinin and concanavalin A, recall skin tests, and the ability to have a primary delayed hypersensitivity response to keyhold limpet hemocyanin did not differ between patients and controls. However, patients with ovarian cancer had statistically significant reduction in surface immunoglobulin positive cells, proliferative response to pokeweed mitogen and primary antibody response to keyhole limpet hemocyanin. In contrast to results in patients with other solid tumors, these data indicate that untreated patients with ovarian cancer have evidence of normal cellular immune function but abnormal B cell function.

Adult↗

PubMed1990

Chronic estradiol treatment alters central cholinergic function in the female rat: effect on choline acetyltransferase activity, acetylcholine content, and nicotinic autoreceptor function.

The purpose of the present study was to determine the effects of chronic (2-month) estradiol (E2) treatment on cholinergic function in the frontal cortex, hippocampus and hypothalamus of the female rat. Chronic E2 treatment selectively increased choline acetyltransferase (ChAT) activity in the frontal cortex and decreased ChAT activity in the hypothalamus: hippocampal ChAT activity was not significantly changed. The decrease of ChAT activity in the hypothalamus was paralleled by a significant reduction in the content and release (basal and evoked) of acetylcholine (ACh) in this structure. Neither the content nor the release of ACh was altered in the frontal cortex. In the hippocampus, there was a significant increase in spontaneous ACh release; however, hippocampal ACh content and evoked ACh release were not changed. Chronic E2 treatment also altered nicotinic binding sites in these same regions as determined by saturation analysis of [3H]methylcarbamylcholine (MCC) to membranes. There was a decrease in the affinity and an increase in the density of [3H]MCC binding sites in hippocampal membranes and an increase in the density of [3H]MCC binding sites was observed in hypothalamic membranes. These alterations were paralleled by changes in nicotinic autoreceptor function within these two structures. In the hippocampus, the increase in spontaneous ACh release induced by MCC in control animals was no longer apparent after chronic treatment with E2. In hypothalamus, higher concentrations of the nicotinic agonist were required to increase spontaneous ACh release in slices from E2-treated rats as compared to control rats. Taken together, these results suggest that chronic E2 treatment decreases presynaptic cholinergic function in the female rat hippocampus and hypothalamus.

Acetylcholine↗

PubMed1990

Lung cancer in patients with borderline lung functions--zonal lung perfusion scans at presentation and lung function after high dose irradiation.

We prospectively studied patients with lung carcinoma and borderline lung functions (forced expired volume [FEV1] of less than 1500 ml or a dyspnoea score of 2 [7] at presentation), who were treated with high dose irradiation. Patients were divided into those with suprahilar and hilar tumours. Lung perfusion was assessed in upper, middle and lower zones for each lung at presentation. The ipsi-lateral upper and middle zone were regarded as at risk from irradiation in patients with suprahilar tumors and the whole ipsi-lateral lung in patients with hilar tumors. Lung function was measured at presentation (18 patients) at 4-6 month follow up (16 evaluable patients = group 1) and again at 10-12 month follow up (10 evaluable patients = group 2). A worsening of the dyspnoea score (3 in group 1 and 2 in group 2) occurred only in patients with a greater than 10% decrease in transfer factor irrespective of the change in FEV1. A statistically significant correlation was found between decreased transfer factor at follow up and the perfusion in the lung zones regarded as at risk from irradiation at presentation (Spearman's rank correlation). There was no correlation between perfusion and changes in the FEV1. Patients in whom lung perfusion was less than 35% in the zones at risk tended not to have decreased transfer factor at follow up. These findings indicate that worsening in the patients' dyspnoea score after irradiation is dependent on decreased transfer factor rather than FEV1 and that patients with borderline lung functions may be treated with irradiation if the perfusion in the zones at risk from radiation is less than 35%.

Adult↗

PubMed1990

Do cardiotoxins possess a functional site? Structural and chemical modification studies reveal the functional site of the cardiotoxin from Naja nigricollis.

Examination of the literature has revealed that regarding the amino acid sequences, cardiotoxins constitute a family of homogeneous compounds. In contrast, cardiotoxins appear heterogeneous as far as their biological and spectroscopic properties are concerned. As a result, comparison between these molecules with a view to establishing structure-activity correlations is complicated. We have therefore reviewed recent works aiming at identifying the functional site of a defined cardiotoxin, ie toxin gamma from the venom of the spitting cobra Naja nigricollis. The biological and structural properties of toxin gamma are first described. In particular, a model depicting the 3-dimensional structure of the toxin studied by NMR spectroscopy is proposed. The toxin polypeptide chain is folded into 3 adjacent loops rich in beta-sheet structure connected to a small globular core containing the 4 disulfide bonds. A number of derivatives chemically modified at a single aromatic or amino group have been prepared. The structure of each derivative was probed by emission fluorescence, circular dichroism and NMR spectroscopy. Also tested was the ability of the derivatives to kill mice, depolarize excitable cell membranes and lyse epithelial cells. Modification of some residues in the first loop, in particular Lys-12 and at the base of the second loop substantially affected biological properties, with no sign of concomitant structural modifications other than local changes. Modifications in other regions much less affected the biological properties of the toxin. A plausible functional site for toxin gamma involving loop I and the base of loop II is presented. It is stressed that the functional site of other cardiotoxins may be different.

Amino Acid Sequence↗

PubMed1989

Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function.

Hepatocyte membranes from both lean and obese Zucker rats exhibited adenylate cyclase activity that could be stimulated by glucagon, forskolin, NaF and elevated concentrations of p[NH]ppG. In membranes from lean animals, functional Gi was detected by the ability of low concentrations of p[NH]ppG to inhibit forskolin-activated adenylate cyclase. This activity was abolished by treatment of hepatocytes with either pertussis toxin or the phorbol ester TPA, prior to making membranes for assay of adenylate cyclase activity. In hepatocyte membranes from obese animals no functional Gi activity was detected. Quantitative immunoblotting, using an antibody able to detect the alpha subunit of Gi, showed that hepatocyte plasma membranes from both lean and obese Zucker rats had similar amounts of Gi-alpha subunit. This was 6.2 pmol/mg plasma membrane for lean and 6.5 pmol/mg plasma membrane for obese animals. Using thiol pre-activated pertussis toxin and [32P]-NAD+, similar degrees of labelling of the 40 kDa alpha subunit of Gi were found using plasma membranes of both lean and obese Zucker rats. We suggest that liver plasma membranes from obese Zucker rats express an inactive Gi alpha subunit. Thus lesions in liver Gi functioning are seen in insulin-resistant obese rats and in alloxan- and streptozotocin-induced diabetic rats which also show resistance as regards the acute actions of insulin. Liver plasma membranes of obese animals also showed an impairment in the coupling of glucagon receptors to Gs-controlled adenylate cyclase, with the Kd values for activation by glucagon being 17.3 and 126 nM for lean and obese animals respectively. Membranes from obese animals also showed a reduced ability for high concentration of p[NH]ppG to activate adenylate cyclase. The use of [32P]-NAD+ and thiol-preactivated cholera toxin to label the 43 kDa and 52 kDa forms of the alpha-subunit of Gs showed that a reduced labelling occurred using liver plasma membranes from obese animals. It is suggested that abnormalities in the levels of expression of primarily the 52 kDa form of alpha-Gs may give rise to the abnormal coupling between glucagon receptors and adenylate cyclase in liver membranes from obese (fa/fa) Zucker rats.

Adenosine Diphosphate Ribose↗

PubMed1979

Augmentation of macrophage complement receptor function in vitro. I. Characterization of the cellular interactions required for the generation of a T-lymphocyte product that enhances macrophage complement receptor function.

The function of complement receptors of mouse peritoneal macrophages was converted in vitro from mediating only attachment of macrophage complement receptor function was achieved by treating freshly explanted macrophages with supernates from cultures containing T lymphocytes and appropriately triggered macrophages. Fc receptor-mediated phagocyctosis by macrophages was required for the production of active supernates, for neither ingestion via the cells' complement receptors nor ingestion via nonimmunologic means was a sufficient stimulus for the macrophages' participation in the generation of supernatant activity. Fc receptor-triggered macrophages interacted by a contact dependent, but histocompatibility independent, mechanism with T lymphocytes, thereby signalling the lymphocytes to elaborate the active product. The possible significance of enhanced macrophage complement receptor function in inflammation, host defense against microbial pathogens, immune complex disease, and neoplasia is discussed.

Animals↗

PubMed1992

Transfection of HLA-DR-expressing DAP.3 cells with a cDNA clone encoding the glycosyl phosphatidylinositol-linked form of lymphocyte function associated antigen-3: biochemical features and functional consequences.

Structural and functional aspects of the accessory molecule lymphocyte function associated antigen (LFA)-3 (CD58) have been examined following the transfection of DAP.3 and P815 cells with a cDNA clone encoding the glycosyl phosphatidylinositol (GPI)-linked form of human LFA-3. Despite earlier observations that DAP.3 cells are deficient in GPI anchoring LFA-3 was expressed efficiently on DAP.3, as well as on P815 cells. Immunoprecipitation of LFA-3 from 35S-labelled cells revealed that the molecule expressed on the DAP.3 cells had a molecular weight intermediate between the transmembrane and GPI-linked forms expressed by human B cells. This suggests that the DAP.3 cells have a default pathway whereby the RNA transcript which encodes the GPI-linked form of the molecule can also encode an integral membrane protein. Functionally, expression of LFA-3 by DAP.3 which had previously been transfected with the genes encoding HLA-DR1 led to a marked augmentation of the proliferative response of five out of eight anti-DR1 human T cell clones. This effect was not reproduced when DR1 and LFA-3 were expressed by separate populations of DAP.3 cells, suggesting that the ligands for CD2 and for the T cell's receptor must be expressed on the same cell membrane. Expression of human LFA-3 also led to a substantial increase in the proliferative response of human peripheral blood T cells to a DR alloantigen. Separation of T cells into CD45RO+ and CD45RO- populations revealed that the augmentation was more marked for the memory than the virgin population. The mechanisms responsible for these differences are discussed.

Animals↗

PubMed1988

Conservation of short patches of amino acid sequence amongst proteins with a common function but evolutionarily distinct origins: implications for cloning genes and for structure-function analysis.

Small patches of identical amino acid sequences commonly occur in proteins that have the same function but are derived from evolutionarily distant organisms. Reverse translation of such patches into degenerate pools of oligonucleotides provide useful hybridization probes for cloning the gene for the corresponding protein from other organisms. Since the conserved patches of identical amino acid sequence are probably important for the protein's biological function, they are preferred targets for reverse genetic studies aimed at defining structure-function relationships.

Amino Acid Sequence↗

PubMed1991

Structure-function relationships of the C-terminal functional domain of hirudin and its variants.

The C-terminal functional domain of hirudin, hirudin variant 1 (residues 55-65), binds to a non-catalytic site on thrombin. In doing so, it is capable of inhibiting the procoagulant actions of thrombin. In terms of free energy of binding, this domain, which comprises 17% of the total sequence of the protein, contributes approximately half of the binding energy of the whole protein to thrombin. This situation also appears to hold true for the known variants of hirudin, some of which differ in the functional nature of their C-terminal regions. Extensive structure-function studies on this domain yield insights into the differences and similarities in the modes of thrombin interaction of hirudin and its variants. In particular, hirudin and hirudin PA have a similar and somewhat interchangeable structure-activity relationships (SAR) profile that indicates that they interact with thrombin in a similar manner. Hirullin P18, a 62 amino acid member of the hirudin family and isolated from Hirudinaria manillensis, is substantially different in sequence and its SAR, which shows that, although it seems to utilize the same non-catalytic binding domain as hirudin, it must utilize a different mode of interaction with thrombin.

Amino Acid Sequence↗

PubMed1986

Activated T cells with immunoregulatory functions at different sites of involvement in sarcoidosis. Phenotypic and functional evaluations.

Cells from recovered BAL fluid and from infiltrates in different involved tissues (lungs, lymph nodes, conjunctiva, liver, spleen, and skin) were studied in 22 patients with active sarcoidosis in order to define the surface phenotype, functional in vitro properties, and topographic distribution of the cells in granulomatous lesions. Our data demonstrated a compartmentalization of activated T cells with immunoregulatory functions from the blood to all sites of disease activity. In fact, these cells were found to express the T4+ Leu 8- 5/9+ T17- phenotype, which belongs to cells with helper activity, and that provide heightened responses in functional assays of helper activity, IL-2 release, and the ability to respond in AMLR's. Both a cellular redistribution and a local in vitro replication account for this tissue compartmentalization in sarcoidosis. The microanatomic location of activated T cells, as defined by immunohistological evaluation, showed that the state of activation in these T cells may be a consequence of an intimate contact between helper cells and macrophages within the sarcoidosis granulomas.

Adult↗

PubMed1990

Analysis of E1A-mediated growth regulation functions: binding of the 300-kilodalton cellular product correlates with E1A enhancer repression function and DNA synthesis-inducing activity.

Adenovirus E1A transforming function requires two distinct regions of the protein. Transforming activity is closely linked with the presence of a region designated conserved domain 2 and the ability of this region to bind the product of the cellular retinoblastoma tumor suppressor gene. We have investigated the biological properties of the second transforming region of E1A, which is located near the N terminus. Transformation-defective mutants containing deletions in the N terminus (deletion of residues between amino acids 2 and 36) were deficient in the ability to induce DNA synthesis and repress insulin enhancer-stimulated activity. The function of the N-terminal region correlated closely with binding of the 300-kilodalton E1A-associated protein and not with binding of the retinoblastoma protein. These results indicate that transformation by E1A is mediated by two functionally independent regions of the protein which interact with different specific cellular proteins and suggest that the 300-kilodalton E1A-associated protein plays a major role in E1A-mediated cell growth control mechanisms.

Adenovirus Early Proteins↗

PubMed1989

Assessment of testicular function after acute and chronic irradiation: further evidence for an influence of late spermatids on Sertoli cell function in the adult rat.

To study cell to cell communications within the testis of adult Sprague-Dawley rats, we used acute whole body neutron plus gamma-irradiation (0.99 Gray of neutron and 0.24 Gray of gamma-rays, 3 min; Exp A) over 7-121 days postirradiation and chronic whole body gamma-irradiation (7 cGy/day 60Co gamma-rays; Exp B) over 14-84 days of irradiation and 7-86 days postirradiation. Neither irradiation protocol had an effect on the body weight of the animals. Neutron plus gamma-rays induced dramatic damages to spermatogonia, preleptotene spermatocytes, spermatozoa, and, to a lesser extent, pachytene spermatocytes. In contrast, gamma-rays induced a selective destruction of spermatogonia. Subsequently, in both experiments a maturation-depletion process led to a marked decrease in all germ cell types. A complete or near complete recovery of the different germ cell types and spermatozoa took place during the two postirradiation periods. Under both irradiation protocols Sertoli cells number was unchanged. Androgen-binding protein and FSH levels were normal in spite of the disappearance of most germ cells from spermatogonia to early spermatids. However, the decline of androgen-binding protein as well as the rise of FSH and their subsequent recovery were highly correlated to the number of late spermatids and spermatozoa. Moreover, it appeared that spermatocytes may also interfere with the production of inhibin (Exp B). With neither irradiation was Leydig cell function altered, except in Exp B in which elevated LH levels were temporarily observed. Correlation analysis suggested a relationship between preleptotene spermatocytes and Leydig cell function. In conclusion, this study establishes that chronic gamma-irradiation is particularly useful in the study of intratesticular paracrine regulation in vivo and provides further support to the concept that late spermatids play a major role in controlling some aspects of Sertoli cell function in the adult rat.

Animals↗