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1.  Tuberculosis and silica exposure in South African gold miners 
To examine the effect of silica exposure, in the absence of silicosis, on the prevalence of pulmonary tuberculosis (PTB), which is epidemic among South African gold miners.
Cross‐sectional study of 520 gold miners over 37 years of age. Length of service, and cumulative and average dust and quartz exposure indices were derived for each miner. Chest radiographs were read for PTB by two NIOSH “B” readers. PTB was defined as a self‐reported history of PTB or PTB on chest radiograph. Logistic regression was used to adjust for age, smoking, and silicosis. PTB effects of different exposure metrics for silica, scaled on their interquartile range (IQR), were compared.
Means (ranges) were: age 46.7 (37.1–59.9) years; length of service 21.8 (6.3–34.5) years; average intensity of respirable quartz 0.053 (0–0.095) mg/m3. PTB prevalence was 19.4% (95% CI 16.0 to 22.8) on history alone, and 35.2% (95% CI 31.1 to 39.3) on history or on chest radiograph. Length of service was poorly predictive of PTB, while all exposure indices which included dust or quartz yielded prevalence odds ratios (PORs) of approximately 1.4 (95% CI ∼1.1 to 1.8) for changes of one interquartile range in exposure. Controlling for silicosis—by adjustment or restriction—did not modify these results. Drillers and winch operators had the highest PTB prevalences and the highest dust and silica exposures.
Older in‐service gold miners in South Africa have a high prevalence of PTB, which is significantly associated with dust and silica exposure, even in the absence of silicosis. Limitations include a survivor workforce and the use of cumulative exposures based on current exposures. Dust control is an important component in control of the PTB epidemic in South African gold mines.
PMCID: PMC2078150  PMID: 16497860
dust; mining; quartz; silicotuberculosis; tuberculosis
2.  Wheeze, asthma diagnosis and medication use: a national adult survey in a developing country 
Thorax  2005;60(11):895-901.
Background: As relatively little is known about adult wheeze and asthma in developing countries, this study aimed to determine the predictors of wheeze, asthma diagnosis, and current treatment in a national survey of South African adults.
Methods: A stratified national probability sample of households was drawn and all adults (>14 years) in the selected households were interviewed. Outcomes of interest were recent wheeze, asthma diagnosis, and current use of asthma medication. Predictors of interest were sex, age, household asset index, education, racial group, urban residence, medical insurance, domestic exposure to smoky fuels, occupational exposure, smoking, body mass index, and past tuberculosis.
Results: A total of 5671 men and 8155 women were studied. Although recent wheeze was reported by 14.4% of men and 17.6% of women and asthma diagnosis by 3.7% of men and 3.8% of women, women were less likely than men to be on current treatment (OR 0.6; 95% confidence interval (CI) 0.5 to 0.8). A history of tuberculosis was an independent predictor of both recent wheeze (OR 3.4; 95% CI 2.5 to 4.7) and asthma diagnosis (OR 2.2; 95% CI 1.5 to 3.2), as was occupational exposure (wheeze: OR 1.8; 95% CI 1.5 to 2.0; asthma diagnosis: OR 1.9; 95% CI 1.4 to 2.4). Smoking was associated with wheeze but not asthma diagnosis. Obesity showed an association with wheeze only in younger women. Both wheeze and asthma diagnosis were more prevalent in those with less education but had no association with the asset index. Independently, having medical insurance was associated with a higher prevalence of diagnosis.
Conclusions: Some of the findings may be to due to reporting bias and heterogeneity of the categories wheeze and asthma diagnosis, which may overlap with post tuberculous airways obstruction and chronic obstructive pulmonary disease due to smoking and occupational exposures. The results underline the importance of controlling tuberculosis and occupational exposures as well as smoking in reducing chronic respiratory morbidity. Validation of the asthma questionnaire in this setting and research into the pathophysiology of post tuberculous airways obstruction are also needed.
PMCID: PMC1747242  PMID: 16263947
3.  Augmented trabeculectomy in paediatric glaucoma 
Aims: To report the experience with trabeculectomy augmented with mitomycin C and 5-fluorouracil for the treatment of paediatric glaucoma.
Methods: Retrospective, interventional case series design was used. The sample included 17 children (29 eyes) with primary (19 eyes) or secondary (10 eyes) glaucoma who were treated with augmented trabeculectomy as the primary procedure between 1990 and 2002. Data were collected on age and family history, preoperative and end of follow up intraocular pressure, cup/disc ratio (evaluated by drawing), visual acuity, complications, and post-surgery treatment.
Results: Patient age at surgery ranged from 1 month to 8 years; most patients (n = 14, 82.3%) were aged less than 1 year (range 1 month–8 months, mean 3.95 (SD 2.56) months); three patients (17.7%) were aged 3, 5, and 8 years. The duration of follow up was 3–120 months (mean 46 months). Intraocular pressure significantly improved from 21 mm Hg to 60 mm Hg (mean 33.1 (10) mm Hg) before surgery to 6–26 mm Hg (mean 17.1 (6) mm Hg) after, (p <0.0001). There was no significant change in cup/disc ratio: 0.1–0.8 (mean 0.42 (0.26)) before and 0.1–1.0 (mean 0.511 (0.27)) after (p = 0.45). In 22 eyes (75.8%), intraocular pressure was controlled at less than 20 mm Hg and the cup/disc ratio remained stable or improved. The life table success rate for intraocular pressure control remained stable at 86% at the 12, 24, and 36 months and after 48 months decreased to 53%. There was no significant difference in the life table results between primary and secondary glaucoma. 14 eyes (48.2%) had a visual acuity better than 20/120 by the end of follow up. Repeated surgery was necessary in eight eyes (27.5%), and additional antiglaucoma treatment in 13 (44.8%). Complications included retinal detachment 1 year after surgery, choroidal detachment, and blebitis (one eye each).
Conclusions: Augmented trabeculectomy with mitomycin C and 5-fluorouracil may serve as the primary procedure in a selected group of paediatric patients with glaucoma.
PMCID: PMC1772527  PMID: 15665346
paediatric glaucoma; children; trabeculectomy; antimetabolites
4.  Silicosis prevalence and exposure-response relations in South African goldminers 
Aims: To measure the prevalence of silicosis among black migrant contract workers on a South African goldmine and to investigate exposure-response relations with silica dust.
Methods: In a cross sectional study, 520 black goldminers (aged >37 years) were interviewed and had chest radiographs taken. Silicosis was defined as International Labour Organisation Classification radiological profusion of 1/1 or greater.
Results: Mean length of service was 21.8 years (range 6.3–34.5). The mean intensity of respirable dust exposure was 0.37 mg/m3 (range 0–0.70) and of quartz 0.053 mg/m3 (range 0–0.095). The prevalence of silicosis was 18.3–19.9% depending on reader. Significant trends were found between the prevalence of silicosis and length of service, mean intensity of exposure, and cumulative exposure.
Conclusion: Results confirm a large burden of silicosis among older black workers in the South African goldmining industry, which is likely to worsen as such miners spend longer periods in continuous employment in dusty jobs. An urgent need for improved dust control in the industry is indicated. If the assumption of stability of average dust concentrations on this mine over the working life of this group of workers is correct, these workers developed silicosis while exposed to a quartz concentration below the recommended occupational exposure limit (OEL) of 0.1 mg/m3. This accords with a mounting body of evidence that an OEL of 0.1 mg/m3 is not protective against silicosis.
PMCID: PMC1740677  PMID: 15377766
5.  Pupillary block following posterior chamber intraocular lens implantation in adults 
The British Journal of Ophthalmology  2003;87(9):1109-1111.
Background: Pupillary block rarely occurs after cataract extraction with posterior chamber intraocular lens implantation.
Methods: A series of six patients (seven eyes) treated for pupillary block after posterior chamber intraocular lens implantation between 1990 and 2001 is described; in one eye, the attack occurred after phacoemulsification.
Results: The interval between pupillary block development and the cataract surgery ranged from 1 day to 5 years. In all eyes, treatment consisted of neodymium-YAG laser peripheral iridotomy. In four eyes, the laser peripheral iridotomy relieved the block (one procedure in two; two to three procedures in two). One patient was also treated with YAG capsulotomy, and two patients needed additional surgical intervention.
Conclusion: Despite the rarity of the complication of pupillary block after posterior chamber intraocular lens implantation, physicians should be aware of the sometimes difficult course of recovery after treatment.
PMCID: PMC1771845  PMID: 12928277
intraocular lens implantation; pupillary block
7.  Lead absorption and renal dysfunction in a South African battery factory 
OBJECTIVES: To test the association between inorganic lead (Pb) exposure, blood pressure, and renal function in South African battery factory workers, with both conventional and newer measures of renal function and integrity. METHODS: Renal function measures included serum creatinine, urea, and urate (n = 382). Urinary markers (n = 199) included urinary N-acetyl-beta-D-glucosaminidase (NAG), retinol binding protein, intestinal alkaline phosphatase, tissue non-specific alkaline phosphatase, Tamm-Horsfall glycoprotein, epidermal growth factor, and microalbuminuria. RESULTS: Mean current blood Pb was 53.5 micrograms/dl (range 23 to 110), median zinc protoporphyrin 10.9 micrograms/g haemoglobin (range 1.9 to 104), and mean exposure duration 11.6 years (range 0.5 to 44.5). Mean historical blood Pb, available on 246 workers, was 57.3 micrograms/dl (range 14 to 96.3). After adjustment for age, weight and height, positive exposure response relations were found between current blood Pb, historical blood Pb, zinc protoporphyrin (ZPP), and serum creatinine and urate. Blood pressure was not associated with Pb exposure. Among the urinary markers, only NAG showed a positive association with current and historical blood Pb. CONCLUSION: An exposure-response relation between Pb and renal dysfunction across the range from < 40 to > 70 micrograms/dl blood Pb was found in this workforce, with conventional measures of short and long term Pb exposure and of renal function. This could not be explained by an effect on blood pressure, which was not associated with Pb exposure. The findings probably reflect a higher cumulative renal burden of Pb absorption in this workforce in comparison with those in recent negative studies. The results also confirm the need for strategies to reduce Pb exposure among industrial workers in South Africa.
PMCID: PMC1757610  PMID: 9816378
8.  Regression of polyvinylchloride polymer pneumoconiosis 
Thorax  1997;52(8):748-749.
A 35 year old man heavily exposed to polyvinylchloride (PVC) polymer dust developed dyspnoea and a mild restrictive lung disorder consistent with PVC pneumoconiosis. Clinical and radiological abnormalities cleared on removal from exposure, suggesting that in its early stages PVC pneumoconiosis is reversible. 

PMCID: PMC1758620  PMID: 9337840
9.  Silent mutations in the Escherichia coli ompA leader peptide region strongly affect transcription and translation in vivo. 
Nucleic Acids Research  1998;26(20):4778-4782.
In order to test the effect of silent mutations on the regulation of gene expression, we monitored several steps of transcription and translation of the ompA gene in vivo , in which some or all codons between codons 6 and 14, frequently used in Escherichia coli , had been exchanged for infrequent synonymous codons. Northern blot analysis revealed an up to 4-fold reduction in the half-life of the mutated messengers and a >10-fold reduction in their steady-state amounts. Western blot analysis showed a 10-fold reduction in the amount of OmpA protein. Use of a system expressing a Rho-specific anti-terminator allowed us to detect a strong transcription polarity effect in the silent mutants. These results demonstrate that silent mutations can severely inhibit several steps of gene expression in E. coli and that code degeneracy is efficiently exploited in this species for setting signals for gene control and regulation.
PMCID: PMC147888  PMID: 9753749
10.  Expression and immunogenicity of an Echinococcus granulosus fatty acid-binding protein in live attenuated Salmonella vaccine strains. 
Infection and Immunity  1997;65(6):2402-2412.
Fatty acid-binding proteins (FABPs) are candidate molecules for vaccines against several parasitic platyhelminths. A FABP from the cestode Echinococcus granulosus (EgDf1) was expressed in Salmonella vaccine strains as a C-terminal fusion to fragment C of tetanus toxin (TetC) by using expression vector pTECH. The fusion protein was equally expressed in several attenuated vaccine strains derived from bacteria with different genetic backgrounds and different attenuating mutations. Single-dose immunization experiments with the aroA Salmonella typhimurium strain SL3261 carrying the pTECH-EgDf1 construct were conducted with mice, using both the intravenous and the oral routes. Surprisingly, the antibody response to EgDf1 and the antigen-specific cytokine production in spleen cells were stronger in mice immunized orally. Furthermore, immune mouse sera strongly reacted with fixed sections of the worm's larval stage. Analysis of the isotype distribution of the specific anti-EgDf1 antibodies showed similar production of immunoglobulin G1 (IgG1) and IgG2a together with specific IgA antibodies. In addition, stimulation of spleen cells from mice immunized with the different constructs with either Salmonella lysate, TetC, or EgDf1 showed that, together with Th1-related cytokines (gamma interferon and interleukin 2 [IL-2]), significant levels of a Th2 cytokine (IL-5) were produced specifically, indicating a Th2 component to the response to the Salmonella carrier and to the recombinant antigens. Salmonellae expressing the TetC-rEgDfl fusion are currently under evaluation as potential vaccines against E. granulosus.
PMCID: PMC175333  PMID: 9169781
11.  Prevalence of occupational lung disease among Botswana men formerly employed in the South African mining industry. 
OBJECTIVE: To determine whether previous health experiences affect the prevalence of occupational lung disease in a semirural Botswanan community where there is a long history of labour recruitment to South African mines. METHOD: A cross sectional prevalence study of 304 former miners examined according to a protocol including a questionnaire, chest radiograph, spirometry, and medical examination. RESULTS: Overall mean age was 56.7 (range 28-93) years, mean duration of service 15.5 (range 2-42) years. 26.6% had a history of tuberculosis. 23.3% had experienced a disabling occupational injury. Overall prevalence of pnemoconiosis (> 1/0 profusion, by the International Labour Organisation classification) was 26.6%-31.0%, and 6.8% had progressive massive fibrosis (PMF). Many were entitled to compensation under South African law. Both radiograph readers detected time response relations between pneumoconiosis and PMF among the 234 underground gold miners. PMF could result from < 5 years of exposure, but was not found < 15 years after first exposure. Both pulmonary tuberculosis (PTB) and pneumoconiosis were found to be associated with airflow limitation. CONCLUSIONS: Former miners in Botswana have a high prevalence of previously unrecognised pneumoconiosis, indicative of high previous exposures to fibrogenic respirable dust. Their pneumoconiosis went unrecognised because they had no access to surveillance after employment. Inadequate radiographic surveillance or failure to act on results when employed or when leaving employment at the mines could have contributed to under recognition. Community based studies of former miners are essential to fully evaluate the effects of mining exposures. Our findings indicate a failure of established measures to prevent or identify pneumoconiosis while these miners were in employment and show that few of the social costs of occupational lung diseases are borne by mining companies through the compensation system.
PMCID: PMC1128630  PMID: 9072029
12.  Synonymous codon selection controls in vivo turnover and amount of mRNA in Escherichia coli bla and ompA genes. 
Journal of Bacteriology  1996;178(9):2718-2720.
A number of silent codon changes were made in two Escherichia coli genes. For the ompA gene, the replacement of seven consecutive frequently used codons with synonymous infrequently used codons reduced the ompA mRNA level and its half-life. For the bla gene, the exchange of 24 codons for the most frequently used synonymous codons extended the bla mRNA half-life. A modification of ribosome traffic could account for these observations.
PMCID: PMC178002  PMID: 8626345
13.  Long term radiological effects of short term exposure to amosite asbestos among factory workers. 
Chest radiographs were read from a sub-cohort of 386 factory workers with short term exposure to amosite asbestos (median exposure six months) and long follow up (median 25 years). Prevalence of abnormality was determined independently by two readers from the first film available after 20 years from first employment. Serial films were obtainable for 238 men (median interval from first to last film: nine years). Progression was classified with a direct progression scoring scale. Individual dust exposure estimates were derived from dust counts from two similar plants. With as little as one month or less of employment, about 20% of the films showed parenchymal abnormality and about a third showed pleural abnormality. Those in the lowest cumulative exposure stratum (less than 5 fibre-years/ml) were similarly found to have high rates of abnormality. Dose-response relations were present in the data of both readers. Smokers had higher rates of parenchymal abnormality. On multivariate analysis, cumulative exposure was the exposure variable most closely related to parenchymal abnormality, and time from first employment was the variable most closely related to pleural abnormality. Progression (including first attacks) 20 or more years after ceasing employment occurred and was more common for pleural than for parenchymal abnormality. It is concluded that with exposure to high concentrations to amosite such as existed in this factory and with follow up for at least 20 years, (1) exposure for as little as a month was sufficient to produce radiological signs of parenchymal and pleural fibrosis, (2) no cumulative exposure threshold for parenchymal and pleural fibrosis was detectable, and (3) parenchymal and pleural progression were still detectable >/= 20 years after the end of exposure.
PMCID: PMC1012109  PMID: 1315154
14.  Transcriptional and posttranscriptional regulation of class I major histocompatibility complex genes following transformation with human adenoviruses. 
Journal of Virology  1991;65(10):5544-5548.
Transformation of rodent cells by human adenoviruses is a well-established model system for studying the expression, regulation, and function of class I antigens. In this report, we demonstrate that the highly oncogenic adenovirus type 12 operates at the transcriptional and posttranscriptional levels in regulating the activity of major histocompatibility complex class I genes and products in transformed cells. Adenovirus type 12 suppresses the cell surface expression of class I antigens in most cell lines. Nevertheless, in a number of cell lines suppression is the result of reduction in the amount of stable specific mRNA, while in another group of cell lines suppression involves interference with processing of a posttranscriptional product. The two mechanisms operate both for the endogenous H-2 genes and for a miniature swine class I transgene that is expressed in the cells.
PMCID: PMC249056  PMID: 1895404
15.  Identification of negative and positive regulatory elements associated with a class I major histocompatibility complex gene. 
Molecular and Cellular Biology  1988;8(2):695-703.
Regulatory DNA sequence elements were functionally identified in the 5'-flanking region of a gene, PD1, which encodes a porcine classical transplantation antigen. Both a positive regulatory element and a novel negative regulatory DNA element were mapped within 1.1 kilobases upstream of exon 1. The negative regulatory element reduced the activity of both the homologous PD1 promoter and a heterologous simian virus 40 promoter. In vivo competition experiments indicated that the functions of the PD1 positive and negative regulatory elements are mediated by distinct cellular trans-acting factors. The PD1 positive regulatory element interacted with cellular factors in common with those binding to the simian virus 40 enhancer. Finally, the negative regulatory element required the presence of a positive regulatory element to function. This interaction between positive and negative regulatory elements represents a novel mechanism for regulating gene expression.
PMCID: PMC363195  PMID: 2832733
16.  B16 melanoma development, NK activity cytostasis and natural antibodies in 3 and 12 month old mice. 
British Journal of Cancer  1984;49(6):769-777.
Three types of natural immune responses against malignant cells were studied in vitro: Cytotoxicity mediated by splenic NK cells; cytostasis mediated by splenocytes and binding of naturally occurring antibodies to various tumour targets. These responses were studied in untreated 3 and 12 month old mice and in mice of both age groups inoculated with B16 melanoma cells. The results showed that in normal mice NK activity decreases with age, cytostatic activity remains unchanged and the titre of natural antibodies increases. Twelve-month old mice were shown to be appreciably more resistant than 3 month old mice to the development of tumours from subthreshold numbers of B16 tumour cells. In mice injected with threshold amounts of the B16 tumour, there was no change in any of the responses in the tumour-free period, but there was a decrease in NK activity and an increase in cytostatic activity when a large tumour mass developed. An increase in the titre of natural antibodies in young mice injected with the tumour was also seen. The correlation between these changes and tumour appearance and development is discussed.
PMCID: PMC1976857  PMID: 6733023
17.  Interaction between environmental pollutants and respiratory infections. 
The major aspects that must be considered in studies of the health effects of environmental pollutants are: the direct damage due to the exposure, the role of pre-existing disease, and effects of the exposure on the response to secondary stresses. In experimental studies at concentrations of air pollutants found in urban environments frank toxicological responses are rarely observed. However, exposure to a secondary stress, i.e. respiratory challenge with infectious bacteria, can exacerbate the response of the experimental host. Changes in the resistance to respiratory infections provide a highly sensitive experimental animal model system, which is increasingly used in studies of health effects of air pollutants. This model indicates the impairment of the basic defense mechanisms of the respiratory system by the combined exposure to low concentrations of pollutants and the superimposed bacterial infection. Changes in the resistance to respiratory infections were studied in various species of laboratory animals. S. pyogenes and K. pneumoniae are the bacteria of choice to induce the pulmonary infection. Included in the studies are short-term single and multiple exposures as well as long-term exposures to gaseous pollutants such as O3 and NO2 and particulate pollutants such as sulfates and nitrates. Changes in the resistance are measured as excess mortalities and reduced survival time as compared to those in infected animals not exposed to the pollutants. Other parameters measured ranged from changes in the immune response to changes in retention rates of bacteria in lungs.
PMCID: PMC1568456  PMID: 6997030
18.  Nerve conduction in childhood diabetes 
Canadian Medical Association Journal  1973;108(9):1116-1119.
Sixty-nine diabetic children were studied with respect to the motor nerve conduction velocities, duration of illness and adequacy of control.
As a group there was a trend for children with diabetes to have slower MNCV than non-diabetic children, and for the slowing to become progressive as the duration of their disease increased. Poorer quality of diabetes control was also associated with progressive slowing of conduction but the exact relationship is uncertain, since no patient who had diabetes for more than four years was well controlled.
Theories of causation of peripheral neuropathy in diabetic patients are reviewed; metabolic changes, rather than other factors, are thought most likely in children.
PMCID: PMC1941401  PMID: 4704891
19.  Hypoglycaemia in infancy and childhood. 
Archives of Disease in Childhood  1971;46(249):716-719.
PMCID: PMC1647831  PMID: 4330193
20.  Juvenile Diabetes Mellitus 
Canadian Family Physician  1970;16(7):43-45.
Juvenile diabetes, although less common than the adult form, presents unique problems which make management more difficult. The basic principles of diet, insulin and exercise apply but the application must be individualized. A constant diet is the aim but with variations in growth and activity this is more difficult to achieve. A child's caloric intake is often greater than anticipated. Children are insulin sensitive and the amounts required to control diabetes and treat acidosis are much less than for adults. Hypoglycemic reactions are disturbing and may mimic or cause behavior problems. The rebound phenomena is common particularly when post prandial blood sugars are used to adjust insulin dose. Thorough understanding by the parents as well as acceptance of the condition are the keys to good control.
PMCID: PMC2281756  PMID: 20468531
22.  In vivo gene expression directed by synthetic promoter constructions restricted to the -10 and -35 consensus hexamers of E. coli. 
Nucleic Acids Research  1989;17(8):2933-2945.
Two synthetic DNA sequences, carrying no other known E. coli promoter element than the consensus hexamers (CH) TTGACA (CH-35) and TATAAT CH(-10), spaced by 17 bp, were inserted in pBR329, in a position enabling transcription of the complete Cmr gene. The region upstream of the Cmr transcription start was carefully cleared of w.t. promoter elements (full deletion of the wild type (w.t.) Cmr promoter upstream +2 and large portion of an upstream coding sequence). Both synthetic promoters, which differ only by the sequences of the spacers (non consensus, constrained in AT or GC) support in vivo high level Cmr gene expression. The GC rich spacer is associated with transcription start at the usual +1 position, but with the AT rich spacer, transcription starts at several places, mainly in CH(-10). Rearranged promoter sequences derived from the synthetic ones upon transformation with partly ligated plasmids, yield new insights on the role of the standard CH pair, the size of the spacer and the sequence downstream of CH(-10).
PMCID: PMC317703  PMID: 2657651
23.  Key for protein coding sequences identification: computer analysis of codon strategy. 
Nucleic Acids Research  1982;10(1):391-402.
The signal qualifying an AUG or GUG as an initiator in mRNAs processed by E. coli ribosomes is not found to be a systematic, literal homology sequence. In contrast, stability analysis reveals that initiators always occur within nucleic acid domains of low stability, for which a high A/U content is observed. Since no aminoacid selection pressure can be detected at N-termini of the proteins, the A/U enrichment results from a biased usage of the code degeneracy. A computer analysis is presented which allows easy detection of the codon strategy. N-terminal codons carry rather systematically A or U in third position, which suggests a mechanism for translation initiation and helps to detect protein coding sequences in sequenced DNA.
PMCID: PMC326141  PMID: 7038623
24.  Physical characteristics in eucaryotic promoters. 
Nucleic Acids Research  1983;11(13):4521-4540.
For a series of wild type and mutated eucaryotic gene prelude sequences (mainly "promoters" of SV40 early gene (Benoist and Chambon, Nature 290, 304 (1981); Moreau et al., Nuc. Acids Res. 9, 6047 (1982)) and of Herpes Simplex Virus TK gene (McKnight and Kingsbury, Science 217, 316 (1982)), in vivo promoter activity and local stability (denaturability) have been correlated. In agreement with the conclusions drawn in these papers, the correlation points to three major eucaryotic promoter elements and loci: (i) enzyme enabling by an enhancer sequence; SV40 and Moloney Sarcoma Virus enhancers have a striking stability homology; (ii) enzyme activation, occurring 50-70 b.p. upstream the cap site in a high stability domain; the enzyme apparently deactivates exponentially upon moving away to trap site; (iii) enzyme positioning at trap site, 30 +/- 5 b.p. upstream the cap site. The trap site contains the TATA box, or, when absent, other low stability domains downstream the activator. The number and occupancy of cap sites may depend on the stability and size of the trap site-cap site couple and its distance from the activator.
PMCID: PMC326062  PMID: 6306592
25.  An algorithm for studying cooperative transitions in DNA. 
Nucleic Acids Research  1986;14(1):551-558.
Cooperative transitions in DNA (B to Z, B to A, helix to coil, etc.) are known to depend strongly on nucleotide sequence. In general the change in free energy involved in the transition can be expressed as: delta G(seq) = 2RT log (sigma) where sigma is a factor arising from the free energy associated with boundaries of different conformations along the molecule. This formula allows to infer a general algorithm with which DNA sequences can be partitioned into well defined domains in which, under suitable conditions, base pairs change state cooperatively. The different partitions of the sequence that can be generated by varying the values of the physical parameters involved in the above formula, are shown to be embedded into a binary tree hierarchy. Application to a reliable prediction of Z-DNA antibody binding sites will be illustrated for the 0X174 genome. Possible biological implications are briefly discussed.
PMCID: PMC339440  PMID: 3484817

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