Evolutionary medicine.
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Biological Evolution↗
Biomedical subjects
A Stevens
Publications and source records attributed to A Stevens.
An essential component of the decapping enzyme required for normal rates of mRNA turnover.
A major pathway of messenger RNA degradation in eukaryotic cells is initiated by shortening of the poly(A) tail, which, at least in yeast, triggers a decapping reaction, thereby exposing the mRNA to 5' --> 3' degradation. Decapping is the key step in this decay pathway because the transcript body is rapidly degraded following decapping. Accordingly, decapping is the site of numerous controls, including inhibition of decapping by the poly(A) tail and modulation of mRNA decapping rate by specific sequences. Moreover, a specialized decay pathway that degrades aberrant transcripts triggers rapid mRNA decapping independently of poly(A)-tail shortening. We have identified a yeast gene, termed DCP1, that encodes the decapping enzyme, or an essential component of a decapping complex. The protein Dcp1 is required for the normal decay of many unstable and stable yeast mRNAs, as well as mRNAs that are decapped independently of deadenylation. These results indicate that mRNA-specific rates of decapping, and thus decay, will result from differences in the interaction of the DCP1 decapping enzyme with individual transcripts.
Amino Acid Sequence↗
Morphometric evidence that epithelial basement membrane breaks are a feature of both squamous and basal cell carcinomas of the skin.
There have been reports that squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) are surrounded by continuous epithelial basement membranes (EBMs). This argues against the hypothesis that EBM breaks are required for tumour invasion. We have used morphometric techniques to re-examine the evidence for SCCs and BCCs as objectively as possible. We assessed sections stained for type-IV collagen from 12 SCCs, 14 keratoacanthomas (KAs), 9 morphoeic BCCs, 10 nodular BCCs and 7 superficial multifocal BCCs. In the centre of these tumours, the EBM was generally more continuous than at the periphery, and this difference was statistically significant for SCCs, KAs and morphoeic BCCs (p < 0.01 in all). By considering central and peripheral tumour regions separately, a significant difference was seen between SCCs and the difficult to distinguish benign tumour KA. In the centre of the KAs, EBM was significantly more continuous than than in SCCs (p = 0.0029), which may suggest new ways of distinguishing these lesions. All of the SCCs and morphoeic BCCs examined showed clear evidence of EBM breaks, but some nodular BCCs did not. As nodular BCCs show an expansile growth pattern without typical histological features of tumour invasion, we suggest that these tumours may be at a pre-malignant stage. In general, our findings are consistent with the hypothesis that EBM breaks are required for tumour invasion.
Basement Membrane↗
Search for the decay K+--> pi + nu nu -bar.
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Journal Article↗
The effect of concentration on the structure of alpha-crystallin.
Several models have been proposed for arrangement of the subunits in alpha-crystallin. These include the contrasting proposals that subunits are arranged in three layers and that subunits assemble into micelle-like structures. The validity of the micelle model was investigated by examining the effects of variations in protein concentration on the surface tension, conductivity, molecular weight and conformation of alpha-crystallin. The data were compared with those obtained for bovine serum albumin (BSA) and sodium dodecyl sulphate (SDS). Measurements of surface tension were conducted in the range, 10 micrograms ml-1 to 130 mg ml-1, in low and high ionic strength buffers. An apparent point of inflection, independent of ionic strength, was seen in alpha-crystallin's surface tension at around 1.9 mg ml-1 (95 microM). The surface tension did not plateau beyond this point, as is the case with surfactants, but continued to decrease up to 130 mg ml-1. BSA exhibited similar surface tension properties with an apparent inflection at 0.9 mg ml-1 (13 microM). The conductivity of alpha-crystallin and BSA solutions increased smoothly with no sign of any transition up to 96 mg ml-1 and 60 mg ml-1, respectively. In contrast, SDS showed a clear transition in this property at the concentration corresponding to its CMC. The aggregation state of the alpha-crystallin aggregates was examined by comparing molecular masses and Stokes radii. The size of the protein remained uniform over a wide concentration range and was unaffected by variations in ionic strength. Protein conformation, which was monitored by examining the microenvironment of tryptophan residues, was also found to be independent of protein concentration. It is concluded that over the concentration range that was investigated, alpha-crystallin does not exhibit any of the properties associated with classical micelles formed from small amphiphilic molecules.
Animals↗
Abnormal topography of EEG microstates in Gilles de la Tourette syndrome.
Quantitative analysis of scalp EEGs was performed on 13 patients with Gilles de la Tourette syndrome (GTS) and 25 matched controls. The analysis method was adaptive segmentation, which describes the topography and sequence of brain electric fields in continuous EEG. The GTS patients showed an abnormal increase in fields with a right-frontal/left-posterior configuration. The GTS patient's EEGs did not differ from normal controls in the average duration of the brain electric microstates, field stability and EEG carrier frequency. To find out whether the abnormal activity is similar to movement-related activity a simple and a complex motor task were performed. Both tasks led to distinct changes of brain electric activity, but not to an increase in right-frontal-/left-posterior-oriented patterns. Motor-related activity was contrasted with two auditory tasks. We conclude that GTS patient's EEG show abnormal topographic patterns of brain electric activity. Unlike other psychiatric disorders, the temporal descriptors of the EEG aspects are unaffected. The abnormal EEG patterns in GTS patients are not similar to those elicited by simple or complex movements; thus, the presence of abnormally facilitated, near-threshold motor activity in GTS patients seems not a likely explanation.
Adult↗
The evaluation of diagnostic and prognostic criteria and the terminology of thin cutaneous malignant melanoma by the CRC Melanoma Pathology Panel.
Sections from 95 skin lesions excised at pigmented lesion clinics in England and Scotland were studied by eight histopathologists in order to evaluate consistency in the use of histopathological terms for features of diagnostic and prognostic importance for cutaneous malignant melanoma. The level of agreement (kappa) amongst the panel improved after discussion and re-definement of criteria for several features. These included, architectural and nuclear atypia, pagetoid infiltration and radial and vertical growth phases. A high level of agreement was achieved for an overall benign or malignant diagnosis (kappa = 0.77) but use of more specific terms such as benign naevi with atypia and melanoma < or = 0.76 mm thickness, was associated with only an intermediate level of agreement. Of the original diagnosis of melanoma, 17% were re-classified by the panel as benign with atypia and 2% reported to be benign were judged to be melanoma. This reflected the high proportion of borderline lesions in the study. The use of standardized diagnostic criteria with precise definitions has been shown to improve consistency in diagnosis and it is recommended for general application. From this should emanate more reliable incidence figures for thin melanoma, and improved understanding of the nature of these early lesions, to the benefit of patient and clinician alike. The poor concordance in distinguishing severe dysplasia in the junctional component of melanocyte proliferations from melanoma in situ and superficial dermal invasion improved only modestly despite intensive efforts. Since melanoma in situ and severe dysplasia cannot be distinguished by objective measurements and since their clinical management is the same, the panel suggests that attempts to separate them in diagnostic reports should be discontinued and they could both be referred to as melanocytic intraepidermal neoplasia (MIN). If it becomes accepted that dermal invasion without a vertical growth component can also be managed identically to MIN, then this invasive radial phase may be appropriately referred to as microinvasion and linked to MIN for the purposes of clinical management.
Biopsy↗
Mutations in trans-acting factors affecting mRNA decapping in Saccharomyces cerevisiae.
The decay of several yeast mRNAs occurs by a mechanism in which deadenylation precedes decapping and subsequent 5'-to-3' exonucleolytic decay. In order to identify gene products required for this process of mRNA turnover, we screened a library of temperature-sensitive strains for mutants with altered mRNA degradation. We identified seven mutations in four genes that inhibited mRNA turnover. Two mutations were alleles of the XRN1 5'-to-3' exoribonuclease known to degrade mRNAs following decapping. One mutation defined a new gene, termed DCP1, which in subsequent work was demonstrated to encode a decapping enzyme or a necessary component of a decapping complex. The other mutations defined two additional genes, termed MRT1 and MRT3 (for mRNA turnover). Mutations in the MRT1 and MRT3 genes slow the rate of deadenylation-dependent decapping, show transcript-specific effects on mRNA decay rates, and do not affect the rapid turnover of an mRNA containing an early nonsense codon, which is degraded by a deadenylation-independent decapping mechanism. Importantly, cell extracts from mrt1 and mrt3 strains contain normal levels of the decapping activity required for mRNA decay. These observations suggest that the products of the MRT1 and MRT3 genes function to modulate the rates of decapping that occur following deadenylation.
Alleles↗
Chronic flexor tenosynovitis: missed diagnosis for a decade.
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Adult↗
A sheet-like form of alpha-crystallin.
Complexes containing alpha-crystallin were isolated from crosslinked lens extract using an affinity column constructed with monoclonal antibodies specific for alpha-crystallin. The affinity-purified protein was compared with alpha-crystallins before and after crosslinking. Electron microscopy revealed sheet-like structures in the cross-linked protein from the lens extract compared with spherical structures for the others. Studies on the amino acid composition, tryptophan microenvironments and the interaction with a monoclonal antibody revealed that the complexes consist almost entirely of alpha-crystallin. These results indicate that under certain conditions, alpha-crystallin subunits can adopt a sheet-like form.
Amino Acids↗
Increased pigmentation in scleroderma.
OBJECTIVE: Increased pigmentation is found in patients with scleroderma (systemic sclerosis, SSc) even in areas that have never clinically been involved with skin thickening. We wanted to determine if the pigmentation is due to subclinical sclerodermatous changes, or a systemic factor such as an increase in adrenocorticotropic hormone (ACTH). METHODS: To determine if clinically uninvolved skin that is pigmented differs from nonpigmented skin, skin biopsies were taken from patients with scleroderma from 2 different sites: (1) from pigmented but otherwise clinically normal skin, and (2) from nonpigmented clinically normal skin adjacent to the first site. Biopsies were examined by a dermatopathologist for evidence of dermal and epidermal changes. Cosyntropin stimulation tests were performed after baseline cortisol and ACTH samples were obtained. RESULTS: Six patients with diffuse SSc (dSSc) and 4 with limited SSc (ISSc) had skin biopsies. Patients with dSSc were more likely than those with ISSc to have increased pigmentation in uninvolved skin. Pigmented skin specimens had either a higher content of epidermal melanin and/or a more severe degree of pigmentary incontinence with a higher number of dermal melanophages in the superficial dermis. The cosyntropin stimulation tests were normal and there were no differences between subjects with diffuse and limited SSc or between those with and without increases in pigmentation. CONCLUSION: Clinically uninvolved skin in many of these patients with SSc was abnormal, and subtle changes of SSc were present, especially in the pigmented biopsies. There was no evidence of adrenal deficiency in these patients. It is difficult pathologically to differentiate the changes in pigmented compared to unpigmented skin in patients with SSc, except for changes of increased melanin and pigmentary incontinence.
Adrenocorticotropic Hormone↗
The under-reporting of skin disease in association with squamous cell carcinoma of the vulva.
Histology sections from 61 cases of squamous cell carcinoma (SCC) of the vulva presenting after 1988 were reviewed for evidence of associated epithelial abnormality. Of the 50 patients with epithelium adjacent to the tumour, 24 had histological evidence of lichen sclerosus (LS), 20 of severe vulvar intraepithelial neoplasia (VIN 3), 22 of human papilloma virus (HPV) infection and three of lichen planus (LP). The clinical records and the original histology report were also subsequently reviewed and with the exception of VIN 3, these disorders were poorly reported by both clinicians and pathologists. Lichen sclerosus was diagnosed clinically in only two of the 36 hospital records available for inspection. Old terminology was used to describe some patients with epithelial disease (erythroleucoplakia in one patient with LS, leucoplakia in two patients with LS and one with LP). This study demonstrates the need to adopt standard nomenclature and increase the awareness of epithelial disease associated with SCC of the vulva among clinicians and pathologists.
Adult↗
Do schizophrenics not differentiate between perception and imagination? an EEG study using dimensional analysis.
The electroencephalograms (EEGs) of 18 chronic schizophrenic patients and 16 controls were compared during three experimental conditions: simple mental arithmetic, the perception of a moving double pendulum, and the imagination of it. An elevated dimensional complexity of the EEG of schizophrenic patients during perception as compared to normals and a failure to increase dimensional complexity during mental imagery was found. No differences were found during mental arithmetic. It is concluded that the brains of schizophrenics operate during perception in a functional state that is characterised by increased and apparently unnecessary complexity.
Adult↗
Dornase alfa for cystic fibrosis.
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Cystic Fibrosis↗
5'-exonuclease-2 of Saccharomyces cerevisiae. Purification and features of ribonuclease activity with comparison to 5'-exonuclease-1.
5'-Exonuclease-2 has been purified 17,000-fold from whole cell extracts of Saccharomyces cerevisiae. A 116-kDa polypeptide parallels the enzyme activity when the purified protein is examined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. Amino-terminal sequencing of the 116-kDa protein shows that the sequence agrees with that encoded by the HKE1 gene, previously reported to encode exonuclease-2. A 45-kDa polypeptide also parallels the enzyme activity upon purification, and Sephacryl S-200 molecular sieve chromatography of the purified enzyme shows a parallel elution of most of the 116- and 45-kDa polypeptides, suggesting a close association of the two. Enzyme instability has precluded a more detailed analysis of their associative properties. The enzyme hydrolyzes RNA substrates to 5'-mononucleotides in a processive manner. Measurements of its substrate specificity and mode of action are compared with 5'-exonuclease-1. Restriction cut single-stranded T7 DNA is hydrolyzed at approximately 5-7% of the rate of 18 S rRNA of yeast by both enzymes. That 5'-exonuclease-2 hydrolyzes in a processive manner and lacks endonuclease activity is shown by the finding that [5'-32P]GMP is the only product of its hydrolysis of [alpha-32P]GTP-labeled synthetic RNAs. That 5'-exonuclease-2 hydrolyzes by a 5'-->3' mode is shown by: 1) its poor hydrolysis of both 5'-capped and triphosphate-ended RNA substrates; 2) the products of its hydrolysis of [5'-32P,3H](pA)4; and 3) the accumulation of 3'-stall fragments when a strong artificial RNA secondary structure is present in synthetic RNAs. 5'-Exonuclease-1 hydrolyzes the synthetic RNAs and (pA)4 in an identical manner.
Amino Acid Sequence↗
13C-NMR off-resonance rotating frame spin-lattice relaxation studies of bovine lens gamma-crystallin self association: effect of 'macromolecular crowding'.
The NMR technique of 13C off-resonance rotating frame spin-lattice relaxation, which provides an accurate assessment of the effective rotational correlation time (tau 0, eff) for macromolecular rotational diffusion, was applied to the study of gamma-crystallin association as a function of protein concentration and temperature. Values of the effective rotational correlation time for gamma-crystallin rotational diffusion were obtained at moderate to high protein concentrations (80-350 mg/ml) and at temperatures above, and below, the cold cataract phase transition temperature. With increasing concentration gamma-crystallin was observed to increasingly associate as reflected by larger values of tau 0, eff Decreasing temperature in the range of 35 to 22 degrees C was found to result in no change in the temperature corrected value of tau 0, eff at a gamma-crystallin concentration of 80 mg/ml, whereas at temperatures of 18 degrees C or below, this parameter was approx. twofold larger, suggesting the occurrence of a well defined phase transition, which correlated well with the cold cataract phase transition temperature. At higher protein concentrations, by contrast, tau 0, eff (temperature corrected) was found to increase by approx. 1.6- to 2-times in the temperature interval 35 degrees C to 22 degrees C, a result consistent with the dependence of the cold cataract phase transition temperature on gamma-crystallin concentration. Analysis of intensity ratio dispersion curves, using an assumed model of isodesmic association, permitted the estimation of the association constant characterizing the aggregation under particular conditions of concentration and temperature. The significant increase in the value of the association constant with moderate increases in protein concentration was rationalized by invoking the effect of 'macromolecular crowding'. The results obtained in this study suggest that in the intact lens, where high protein concentrations prevail, gamma-crystallin is unlikely to be found in the monomeric state, but more likely, as a significantly aggregated species, representing a broad molecular weight distribution.
Animals↗
A germline substitution in the human MSH2 gene is associated with high-grade dysplasia and cancer in ulcerative colitis.
BACKGROUND & AIMS: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of > 8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. METHODS: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. RESULTS: After direct sequencing of exon 13 and flanking regions of human MSH2, a germline T to C substitution was shown at the -6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) (P < or = 0.04) and in 7 of 80 healthy adult blood donors (9%) (P < or = 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. CONCLUSIONS: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.
Adult↗
Acute graft-versus-host disease with unusual cutaneous intracellular vacuolation in an infant with severe combined immunodeficiency.
We report an infant with severe combined immunodeficiency (SCID) who had cutaneous manifestations of acute graft-versus-host disease (GVHD) due to maternofetal lymphocyte engraftment. Histologic and ultrastructural examinations of the skin revealed intracellular vacuoles resembling lipid droplets in the epidermis and dermis, which is not a recognized feature of acute GVHD or SCID.
Acute Disease↗