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Biomedical subjects

J Silver

Publications and source records attributed to J Silver.

At least 91 records · Page 5Linked to original sources

A molecular basis for species differences in Thy-1 expression patterns.

Thy-1 is a membrane glycoprotein that displays species-specific differences in its pattern of expression. Although it is expressed on thymocytes and splenocytes in mice, it is only expressed on thymocytes in rats. Based on previous studies suggesting that the third intron of the mouse Thy-1 gene is required for its expression in thymocytes, in vivo footprinting analysis was performed on the third introns of both the mouse and rat Thy-1 genes, and led to the identification of homologous 36 bp "footprinted" regions. The mouse 36 bp region was found to be capable of specifically binding an Ets-1-like nuclear factor present in both mouse thymocytes and splenocytes. In contrast, the homologous 36 bp region of the rat which differs from the mouse 36 bp region by three nucleotides resulting in the loss of the Ets-1 binding site, is unable to bind a similar Ets-1-like factor present in rat thymocytes. Instead, this region of the rat third intron binds another nuclear factor which is present in rat thymocytes but not splenocytes. These observations suggest that the differential expression of the mouse and rat Thy-1 genes in thymocytes and splenocytes is the result of differential expression of nuclear factors that bind to this 36 bp region.

Animals↗

Spontaneous priming for anti-viral envelope cytotoxic T lymphocytes in mice transgenic for a murine leukaemia virus envelope gene (Fv4).

Compared with non-transgenic controls, mice bearing an Fv4 murine retroviral env transgene resist infection and do not become immunosuppressed when inoculated with Friend virus (FV). When immunized with FV antigens in the absence of infectious virus, they make antibodies and cytotoxic lymphocytes (CTL) to FV comparably to non-transgenic controls. Unimmunized transgenic mice were found to have CTL precursors, which could be activated by in vitro stimulation, specific for viral (and self) envelope protein (Env). This "spontaneous priming' for antiviral CTL is surprising because the transgene Env is present on the surface of thymocytes and in serum from before birth. Our experiments demonstrate that T cells reactive with self-thymic and serum antigens sometimes avoid clonal elimination or inactivation.

Animals↗

Evidence that the receptor for soluble CD14:LPS complexes may not be the putative signal-transducing molecule associated with membrane-bound CD14.

Membrane-bound CD14 acts as a receptor for lipopolysaccharide (LPS) on monocytes/macrophages and neutrophils. Studies have suggested that the activation of monocytes/macrophages by the binding of LPS to membrane-bound CD14 may require the association of a signal-transducing molecule with membrane-bound CD14. The observation that non-CD14 expressing cells, such as endothelial cells, can nevertheless be activated by a complex of LPS and a soluble form of CD14 (sCD14) suggests that the receptor for this complex may be identical to the signal transducing molecule associated with membrane-bound CD14. The studies described show that two CD14-specific MoAb are able to block the LPS-induced activation of endothelial cells but do not affect the response of monocytes to LPS. This suggests that the interaction of the sCD14:LPS complex with endothelial cells is distinct from the interaction of membrane-bound CD14 with its putative signal-transducing molecule.

Antibodies, Monoclonal↗

Parathyroid hormone gene expression in Hyp mice fed a low-phosphate diet.

BACKGROUND: The murine analogue of X-linked hypophosphataemia is the Hyp mouse; it has chronic phosphate depletion from an inherited defect of renal tubular reabsorption. Phosphate directly regulates the parathyroid (PT) in normal rats and it is of interest whether this regulation is intact in Hyp mice. METHODS: Hyp mice were fed either a low-phosphate diet or control diet and PTH mRNA levels were measured. In addition changes in NMR-visible kidney and muscle intracellular phosphate potentials in normal and Hyp mice were determined. Mice were maintained on a low-phosphate (0.02%) or normal-phosphate (0.6%) diet for 24 and 72 h. RESULTS: On the normal diet, Hyp mice had hypophosphataemia, normocalcaemia, and normal PTH mRNA levels. Phosphate deprivation for 72 h led to a profound fall in plasma phosphate, a slight but significant rise in plasma calcium, and a dramatic decrease in PTH mRNA, similar to that of normal mice fed this diet. Changes in kidney and muscle intracellular phosphate measured by NMR spectroscopy were not affected by diet or genotype. CONCLUSION: Dietary phosphate deprivation decreased Hyp mice PTH mRNA levels and caused no change in intracellular phosphate potentials. Therefore Hyp mice parathyroids' adapt appropriately to phosphate deprivation albeit at a lower threshold compared to normal mice.

Animals↗

Regulation of parathyroid cell proliferation.

The parathyroid normally has very few cells in mitosis but it retains the potential to proliferate. In-vivo studies in rats have demonstrated that hypocalcaemia and high serum phosphate both lead to an increase in the number of proliferating cells, which is relevant to the increased parathyroid cell proliferation in chronic renal failure. Hypophosphataemia and 1,25(OH)2D3 decrease parathyroid cell proliferation. Genetic factors have been defined for multiple endocrine neoplasia which includes parathyroid cell hyperplasia, and in some parathyroid adenomas there are genetic rearrangements.

Adenoma↗

Rapid degradation of CD4 in cells expressing human immunodeficiency virus type 1 Env and Vpu is blocked by proteasome inhibitors.

Human immunodeficiency virus (HIV) type 1 encodes three genes, Vpu, Env and Nef, that decrease cellular CD4. Vpu and Env act cooperatively to accelerate degradation of CD4 in the endoplasmic reticulum. Here we report that Vpu/Env-induced CD4 degradation is inhibited by lactacystin, a specific inhibitor of the proteasome, and by other proteasome inhibitors, but not by non-proteasome protease inhibitors. We also note that Vpu has amino acid sequence homology with a segment of IkappaB known to be involved in proteasome-mediated degradation, suggesting that HIV-1 could have transduced cellular sequences to enhance down-regulation of CD4.

Acetylcysteine↗

Secretion of a murine retroviral Env associated with resistance to infection.

Fv4 is an endogenous defective murine leukaemia virus (MuLV) which expresses high levels of an envelope protein (Env) closely related to that of the ecotropic class of MuLVs. Mice bearing the natural Fv4 gene or a transgenic version are resistant to infection by ecotropic MuLVs. Fv4 mice secrete the surface peptide (SU) of the Fv4 Env in their serum and this secreted Env can block infection of NIH3T3 cells. To study the secretion of Fv4, we metabolically labelled cells expressing Fv4 Env or Env from infectious MuLVs and followed synthesis, glycosylation, proteolytic processing and secretion of Env species. We found no difference in the kinetics of synthesis or processing of Fv4 Env compared to the envelopes of infectious MuLVs, but Fv4 Env associated more weakly with its transmembrane anchor and was shed from the surface of cells.

Animals↗

Infectious particles derived from Semliki Forest virus vectors encoding murine leukemia virus envelopes.

Semliki Forest virus vectors encoding murine leukemia virus (MLV) envelope protein with a truncated cytoplasmic tail generate submicrometer, cell-associated, membranous particles that transmit replication-competent vector RNA specifically to cells bearing the MLV receptor. Such "minimal" viruses could have applications as retroviral vaccines or in the study of virus evolution.

3T3 Cells↗

Where is the "inverting factor" in hormone secretion from parathyroid cells?

Secretion of hormones and transmitters in the body fall into two general categories. In the majority of the secreting cells, including the presynaptic terminals in the nervous system, an increase in the extracellular calcium causes an increase in secretion. There are two notable exceptions to this general rule: the parathyroid cells and the renal juxtaglomerular cells, where an increase in extracellular calcium leads to a decrease in secretion. Because these two cell types have a cardinal role in a wide variety of physiological and pathophysiological functions, it is of great importance to understand the regulation of their hormone secretion process. A key element to such an understanding is the identification of the location of the "inverting step," which makes the parathyroid cells behave in a fashion contrary to most other secretory cells. Whole cell imaging studies strongly suggested that the inversion factor is between the changes in intracellular calcium concentration ([Ca2+]i) and the secretion of the hormone. Surprisingly, confocal calcium imaging of the parathyroid cells did not support this dogma. It revealed that the interior of the parathyroid cell is a nonhomogeneous medium and that an increase in the extra-cellular calcium concentration produces changes in [Ca2+]i, in both the same and opposite directions, in different parts of the parathyroid cell.

Animals↗

Tetracycline derivatives, alternative treatment for nocardiosis in transplanted patients.

Nocardiosis is a rare infection in patients with immunosuppression following transplantation. Thus far, treatment with sulfa derivatives, when combined with immunosuppressive agents, has been shown to carry an unacceptably high rate of toxic effects. Therefore, the possibility of using an alternative antimicrobial treatment was investigated. The treatment of disseminated Nocardia infection with doxycycline or minocycline in patients after either kidney, bone marrow or liver transplantation was investigated retrospectively. Three patients were treated at The Hadassah University Hospital in Jerusalem. Antibiotic treatment with tetracyclines was administered for one to 14 months at a dose of 100 to 600 mg/d. Additional seven patients were reviewed from previous published reports. Nine out of the ten treated patients had an uneventful recovery. One non-compliant patient died of disseminated nocardiosis. In conclusion, the favorable outcome of the patients treated with minocycline for Nocardia infection which developed after transplantation, suggests that this antibacterial agentis is both effective and safe. These data support the recommendation that tetracycline derivatives may be considered as an alternative treatment for Nocardia infections in transplanted patients.

Adult↗

Differences in risk of Crohn's disease in offspring of mothers and fathers with inflammatory bowel disease.

OBJECTIVE: To determine whether there are any unusual patterns of transmission of susceptibility to inflammatory bowel disease (IBD) within multiplex families. METHODS: Individuals with IBD were recruited for genome-wide screening of susceptibility genes. The extent of familial aggregation and blood relationships in multiplex families were determined by questionnaires given to participants followed up by confirmation of disease diagnosis by participants' physicians. RESULTS: Of 135 families identified in which both a parent and a child had IBD, 93 involved transmission of susceptibility to disease from mother to child versus 42 examples of transmission from father to child (p = 0.00001, exact two-tailed binomial test). This distortion in transmission on the basis of the sex of the parent was observed only among non-Jewish pairs with Crohn's disease (CD), in which, of 33 parent-child pairs with CD, disease susceptibility was transmitted from the mother 28 times (p = 0.00007). CONCLUSION: Susceptibility to CD in a subset of patients may involve a gene that is imprinted.

Child↗