Biomedical subjects
Publications and source records attributed to E W Jones.
We report a case of white fibrous papulosis of the neck in a 70-year-old Iranian woman. To date this recently reported entity has only been described in Japanese patients. This asymptomatic eruption characteristically affects the posterior neck. The pale papules are round to oval 2-3 mm in diameter, and not follicular. Histology shows thickened collagen bundles in the superficial and mid-dermis with a normal elastic pattern.
The Saccharomyces cerevisiae PEP3 gene was cloned from a wild-type genomic library by complementation of the carboxypeptidase Y deficiency in a pep3-12 strain. Subclone complementation results localized the PEP3 gene to a 3.8-kb DNA fragment. The DNA sequence of the fragment was determined; a 2,754-bp open reading frame predicts that the PEP3 gene product is a hydrophilic, 107-kDa protein that has no significant similarity to any known protein. The PEP3 predicted protein has a zinc finger (CX2CX13CX2C) near its C terminus that has spacing and slight sequence similarity to the adenovirus E1a zinc finger. A radiolabeled PEP3 DNA probe hybridized to an RNA transcript of 3.1 kb in extracts of log-phase and diauxic lag-phase cells. Cells bearing pep3 deletion/disruption alleles were viable, had decreased levels of protease A, protease B, and carboxypeptidase Y antigens, had decreased repressible alkaline phosphatase activity, and contained very few normal vacuolelike organelles by fluorescence microscopy and electron microscopy but had an abundance of extremely small vesicles that stained with carboxyfluorescein diacetate, were severely inhibited for growth at 37 degrees C, and were incapable of sporulating (as homozygotes). Fractionation of cells expressing a bifunctional PEP3::SUC2 fusion protein indicated that the PEP3 gene product is present at low abundance in both log-phase and stationary cells and is a vacuolar peripheral membrane protein. Sequence identity established that PEP3 and VPS18 (J. S. Robinson, T. R. Graham, and S. D. Emr, Mol. Cell. Biol. 11:5813-5824, 1991) are the same gene.
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Seventeen patients (six women and 11 men) with Jessner's lymphocytic infiltration of the skin were studied. Nineteen biopsy specimens were analyzed with the following monoclonal antibodies: UCHL1 (T cells), 4KB5, L26 (B cells), LN1 (germinal center B cells), and BerH2 (Ki-1+ cells). Routine direct immunofluorescence was performed on 15 specimens. In 10 of 19 specimens both B and T cells were demonstrated; the B cells were in close proximity to small blood vessels. In 50% of these cases the B cell component expressed LN1 positivity. We use the term perivascular lymphocytoma to describe this pattern. Nine specimens showed T cells only. No Ki-1+ cells were detected. Routine immunofluorescence studies were performed on 15 specimens. In six of seven specimens in which there was a mixed cell population of B and T cells, results were completely negative. In contrast, six of the remaining eight specimens with a predominantly T cell population revealed weak, patchy, granular, positive labeling for immunocomponents, particularly IgM and C3 at the basement membrane. These findings suggest that Jessner's lymphocytic infiltration is a heterogeneous disorder with at least two separate immunophenotypes. The finding of perivascular follicular center differentiation in more than half the specimens suggests a possible relationship in these cases to other benign lymphoid hyperplasias (pseudolymphomas).
We have studied eight cases of an acquired lymphatic endothelial lesion for which we propose the name "benign lymphangioendothelioma." The lesions developed as solitary, slowly extending, erythematous macules and plaques, usually occurring on the extremities or the shoulders in adolescents or adults. The characteristic histopathologic feature is permeation of the dermal collagen by flattened, endothelium-lined channels and spaces. Hemorrhage, iron deposition, and inflammation were not part of the lesion. Ulex europaeus agglutinin I labeled the lesional endothelial cells consistently, but factor VIII-related antigen labeling was negative. This histologic pattern and the special studies suggested a lymphatic lesion. Surgical excision, performed in six patients, was not followed by recurrence.
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Saccharomyces cerevisiae strains carrying a mutation in the clathrin heavy chain gene (CHC1) are genetically unstable and give rise to heterogeneous populations of cells. Manifestations of the instability include increases in genome copy number as well as compensatory genetic changes that allow better growing clathrin-deficient cells to take over the population. Increases in genome copy number appear to result from changes in ploidy as well as alterations in normal nuclear number. Genetic background influences the frequency at which cells with increased genome content are observed in different Chc- strains. We cannot distinguish whether genetic background affects the rate at which aberrant nuclear division events occur or a growth advantage of cells with increased nuclear and/or genome content. However, survival of chc1-delta cells does not require an increase in genome copy number. The clathrin heavy chain gene was mapped 1-2 cM distal to KEX1 on the left arm of chromosome VII by making use of integrated 2 mu plasmid sequences to destabilize distal chromosome segments and allow ordering of the genes.
Glucose represses PRB1 expression at the level of transcription. However, release from glucose repression initially does not result in accumulation of protease B (PrB) activity despite transcriptional derepression. PrB activity accumulates only upon a second transcriptional derepression as the cells approach stationary phase. Increasing the PRB1 gene dosage on 2 mu-based plasmids does not overcome glucose repression. Glucose-mediated repression of PRB1 is not subject to the same genetic controls as SUC2. Mutation of the HXK2 gene, which confers glucose-insensitive expression of secreted invertase, had no effect on PRB1 expression at the level of PrB activity. Strains bearing a mutation in any of the SNF1-SNF6 genes cannot derepress secreted invertase synthesis, but did derepress PrB synthesis when grown in the absence of glucose. Mutation of the SNF2 or SNF5 gene led to accumulation of PrB activity to levels ten times that of wild type. Polymorphism for a suppressor gene was observed: in snf5-bearing strains, one allele of this suppressor gene resulted in elevated levels of PrB and the other allele resulted in wild-type levels of PrB; neither allele suppressed the Suc- phenotype of the snf5 mutant. Re-examination of published data on SUC2 expression in snf2 and snf5 mutants and examination of PRB1 expression in these mutants paradoxically suggest that the SNF2 and SNF5 gene products might act as negative regulators of gene expression.
pep5 mutants of Saccharomyces cerevisiae accumulate inactive precursors to the vacuolar hydrolases. The PEP5 gene was isolated from a genomic DNA library by complementation of the pep5-8 mutation. Deletion analysis localized the complementing activity to a 3.3-kb DNA fragment. DNA sequence analysis of the PEP5 gene revealed an open reading frame of 1029 codons with a calculated molecular mass for the encoded protein of 117,403 D. Deletion/disruption of the PEP5 gene did not kill the cells. The resulting strains grow very slowly at 37 degrees. The disruption mutant showed greatly decreased activities of all vacuolar hydrolases examined, including PrA, PrB, CpY, and the repressible alkaline phosphatase. Apparently normal precursors forms of the proteases accumulated in pep5 mutants, as did novel forms of PrB antigen. Antibodies raised to a fusion protein that contained almost half of the PEP5 open reading frame allowed detection by immunoblot of a protein of relative molecular mass 107 kD in extracts prepared from wild-type cells. Cell fractionation showed the PEP5 gene product is enriched in the vacuolar fraction and appears to be a peripheral vacuolar membrane protein.
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As part of a genetic analysis of the biogenesis and function of the vacuole (lysosome) in the yeast Saccharomyces cerevisiae, assays of vacuolar pH were developed and used to identify mutants defective in vacuolar acidification. Vacuoles were labeled with 6-carboxyfluorescein with the membrane-permeant precursor 6-carboxyfluorescein diacetate. Dual-excitation flow cytometry was used to calibrate the pH-dependence of 6-carboxyfluorescein fluorescence in vivo. Vacuoles in wild-type yeast were mildly acidic, pH 6.2, in cells grown under several different conditions. Cultures labeled with 6-carboxyfluorescein were screened by fluorescence-ratio microscopy to detect mutants that had defects related to vacuolar acidification. A recessive nuclear mutation, vph1-1, caused an abnormally high vacuolar pH of 6.9, as assayed by flow cytometry, and eliminated vacuolar uptake of the weak base quinacrine. Acidification in a pep12::LEU2 mutant appeared defective by fluorescence-ratio microscopy and quinacrine-uptake assays, but the vacuolar pH in the pep12::LEU2 mutant was nearly normal (pH 6.3) in flow cytometric assays.
The vacuolar protease B of Saccharomyces cerevisiae is a subtilisin-like protease encoded by the PRB1 gene. Antibodies raised against a synthetic peptide and an Escherichia coli-derived PRB1 open reading frame (ORF) protein cross-react with authentic protease B from yeast. By using these antibodies, the posttranslational biosynthetic pathway of protease B has been elucidated. Preproprotease B is a 76-kD unglycosylated precursor that enters the endoplasmic reticulum (ER), where it receives one asparagine-linked (Asn-linked) and an undetermined number of non-Asn-linked carbohydrate side chains. The large glycosylated intermediate is proteolytically processed to a 39-kD form before exiting the ER. In the Golgi complex, the 39-kD form becomes 40 kD, due to elaboration of the Asn-linked side chain. The carboxyterminal end of the 40-kD proprotease B undergoes protease A-mediated processing to a 37-kD intermediate, which in turn is quickly processed to 31-kD mature protease B. The ultimate processing step removes a peptide containing the Asn-linked chain; mature PrB has only non-Asn-linked carbohydrate.
This is a report of a previously undescribed type of histiocytoma distinguished clinically by its occurrence as a solitary elevated nodule often with a vascular appearance and cytologically by the presence of large angulated epithelioid cells. Nineteen lesions from 11 women and eight men have been studied. The lower limb was the commonest site for the nodules. The mean age at presentation was 42 years (range 23-63). Only one lesion recurred after attempted removal. This lesion in the past may, have been mistaken for a Spitz naevus. Immunohistochemical findings mirror those of ordinary histiocytomas. In particular approximately 50% of the constituent cells label with a polyclonal antibody directed against factor XIIIa--an antibody that labels dermal fixed connective tissue cells (fibrocytes) and cells in ordinary histiocytoma, but not the cells of Spitz or common melanocytic naevi.
The histogenesis of histiocytoma (dermatofibroma) was investigated using new antibodies that demonstrate factor XIIIa (FXIIIa) positive cells and the monocyte macrophage cell series (MAC 387), in formalin fixed tissue. The distribution of S100 protein, vimentin and Ulex europaeus agglutinin I (UEA-I) were also studied. The antibody against FXIIIa labelled the normal dermal population of fixed connective tissue cells (dermal dendrocytes) emphasizing their dendritic processes; cells that are widely distributed, but are most numerous in the papillary dermis. In contrast, the antibody, MAC 387 against monocyte derived macrophages, did not label this cell population. In 30 histiocytomas, intense labelling for FXIIIa was found peripherally, but labelling was rather weaker in cells situated centrally. Only a few cells labelled for S100 protein and with the monoclonal antibody MAC 387, but vimentin positivity was universal. UEA-I labelled only vessels in histiocytomas. However, FXIIIa labelling was negative in 16 dermatofibrosarcomas, three keloids and several other fibroproliferative lesions. These contrasting results with FXIIIa labelling have practical implications for diagnosis of benign and malignant spindle cell tumours of the skin. We conclude that histiocytomas (dermal dendrocytomas) take their origin from dermal fixed connective tissue cells, (dermal dendrocytes), but other spindle cell tumours may differ in histogenesis.
Twenty-five cases of fibrous papule of the nose were studied by light microscopy and by immunohistochemistry using a panel of 4 cell markers. These included polyclonal antibodies against S100 protein and Factor XIII-a (FXIII-a), and 2 monoclonal antibodies, MAC 387 which labels monocyte derived macrophage cells and Ulex Europaeus Agglutinin-1 (UEA-1) a pan endothelial cell marker. An increase in the number of S100 protein positive cells, particularly in the upper dermis, was observed in 3 lesions. Melanin was identified in phagocytes in the superficial dermis in 6 lesions, including those with S100 protein positive cells. In all of the papules there was a marked increase in FXIII-a labelling of dendritic connective tissue cells, including spindle, stellate and multinucleate stellate cells. Immunoreactivity with FXIII-a was especially strong in the increased mononuclear dendritic cell population (greater than 80%) seen in the mid- and upper dermis. However, only 15% of the larger multinucleate stellate cells were immunostained with FXIII-a. The results achieved with markers to the macrophage cell series (MAC 387) or endothelial cells (UEA-1) showed no significant increase in labelling of the dermal cell population compared to normal skin taken from the nose. Our study suggests that fibrous papule of the nose, a lesion of uncertain histogenesis, probably represents a proliferative reactive process consisting mainly of dermal dendritic cells as identified by FXIII-a in most of the lesions. There is some evidence that a small percentage of the dendritic cells may represent involuted naevi and be of melanocytic origin.