Activation and the role of reinitiation in the control of transcription by RNA polymerase II.
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Animals↗
Biomedical subjects
S Hahn
Publications and source records attributed to S Hahn.
Architecture of protein and DNA contacts within the TFIIIB-DNA complex.
The RNA polymerase III factor TFIIIB forms a stable complex with DNA and can promote multiple rounds of initiation by polymerase. TFIIIB is composed of three subunits, the TATA binding protein (TBP), TFIIB-related factor (BRF), and B". Chemical footprinting, as well as mutagenesis of TBP, BRF, and promoter DNA, was used to probe the architecture of TFIIIB subunits bound to DNA. BRF bound to TBP-DNA through the nonconserved C-terminal region and required 15 bp downstream of the TATA box and as little as 1 bp upstream of the TATA box for stable complex formation. In contrast, formation of complete TFIIIB complexes required 15 bp both upstream and downstream of the TATA box. Hydroxyl radical footprinting of TFIIIB complexes and modeling the results to the TBP-DNA structure suggest that BRF and B" surround TBP on both faces of the TBP-DNA complex and provide an explanation for the exceptional stability of this complex. Competition for binding to TBP by BRF and either TFIIB or TFIIA suggests that BRF binds on the opposite face of the TBP-DNA complex from TFIIB and that the binding sites for TFIIA and BRF overlap. The positions of TBP mutations which are defective in binding BRF suggest that BRF binds to the top and N-terminal leg of TBP. One mutation on the N-terminal leg of TBP specifically affects the binding of the B" subunit.
Base Sequence↗
Chronic renal failure: an overview from a pediatric perspective.
We present data on the costs and impact of chronic renal failure, the primary renal diseases leading to end-stage renal disease in children, and review the adaptive responses and the pathophysiology and complications of uremia in experimental animals and in man. A treatment strategy is summarized.
Adaptation, Physiological↗
Glomerulosclerosis in the remnant kidney rat is modulated by dietary alpha-tocopherol.
Glomerulosclerosis and tubulointerstitial injury are characteristic features seen in the subtotal (5/6) nephrectomy remnant kidney model in the rat. Oxidative stress from renal mass reduction contributes to the glomerular and tubular injury. Previous studies have clearly demonstrated the prevention or inhibition of such injury by an antioxidant such as alpha-tocopherol. However, few data are available on the ability of alpha-tocopherol to modulate or arrest progression of the established disease. This study examines whether alpha-tocopherol modulates glomerulosclerosis and tubulointerstitial injury when it is given 2 wk after renal damage has been established. The findings indicate that alpha-tocopherol has the capacity to modulate both tubulointerstitial injury and glomerulosclerosis, lower the elevated expression of transforming growth factor-beta1, and reduce plasma and kidney malondialdehyde concentration, the end product of lipid peroxidation. The results support the potential utility of alpha-tocopherol in reversing established glomerulosclerosis and tubulointerstitial injury in a remnant kidney model.
Animals↗
Prenatal diagnosis using fetal cells enriched from maternal blood.
The ability to use fetal cells enriched from the blood of pregnant women for prenatal diagnosis has been a long-sought goal for those pursuing a non-invasive alternative to current methods, such as amniocentesis or chorionic villus sampling. Several new developments, which rely either on fluorescence in situ hybridization or the combination of single-cell manipulation and subsequent polymerase chain reaction practices, which are common to the field of preimplantation genetics, have been tested. We discuss the significance of these developments and the obstacles that still have to be surmounted before this technology becomes available in a broad diagnostic use. The research in the field yielded important observations regarding the traffic of cells between the fetus and the mother, which may provide a new insight into the development of disorders such as preeclampsia and the associated HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.
Aneuploidy↗
Hemofiltration in children.
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Acute Kidney Injury↗
Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.
Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism. We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells. Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.
Apoptosis↗
Molecular analysis of the SNF2/SWI2 protein family member MOT1, an ATP-driven enzyme that dissociates TATA-binding protein from DNA.
MOT1 is an essential Saccharomyces cerevisiae protein and a member of the SNF2/SWI2 family of ATPases. MOT1 functions by removing TATA-binding protein (TBP) from DNA, and as a consequence, MOT1 can regulate transcription both in vitro and in vivo. Here we describe the in vivo and in vitro activities of MOT1 deletion and substitution mutants. The results indicate that MOT1 is targeted to TBP both in vitro and in vivo via amino acids in its nonconserved N terminus. The conserved C-terminal ATPase of MOT1 appears to contribute to TBP-DNA complex recognition in the absence of ATP, but it appears to function primarily during the actual ATP-dependent dissociation reaction. Chimeric proteins in which homologous portions of SNF2/SWI2 have been substituted for the MOT1 ATPase can bind to TBP-DNA complexes but fail to dissociate these complexes in the presence of ATP, suggesting that the specificity of action of MOT1 is also conferred by the C-terminal ATPase. ATPase assays demonstrate that the MOT1 ATPase is activated by TBP. Thus, MOT1 undergoes at least two conformational changes: (i) an allosteric effect of TBP that mediates the activation of the MOT1 ATPase and (ii) an ATP-driven "power stroke" that causes TBP-DNA complex dissociation. These results provide a general framework for understanding how members of the SNF2/SWI2 protein family use ATP to modulate protein-DNA interactions to regulate many diverse processes in cells.
Adenosine Triphosphatases↗
Neonatal edema.
Edema develops in the neonate from diverse clinical conditions; sometimes it heralds serious underlying disorders. In this review, we discuss the diagnosis and treatment of edema in the neonate.
Edema↗
Edema in childhood.
There are two types of edema: localized edema and generalized edema. The causes of generalized edema in childhood are diverse. Formation of generalized edema involves retention of sodium and water in the kidney. The treatment of generalized edema depends on the primary etiology. Supportive nutritional and medical therapies are needed to prevent further edema. These and related features of edema in childhood are discussed in this review.
Child↗
Cloning and functional characterization of the gene encoding the TFIIIB90 subunit of RNA polymerase III transcription factor TFIIIB.
The yeast RNA polymerase III (pol III) general transcription factor TFIIIB is composed of three subunits; the TATA-binding protein (TBP)1, the TFIIB-related factor (BRF1), and a third factor termed TFIIIB90 or B". Here we report the purification of yeast TFIIIB90, cloning of the gene encoding TFIIIB90, and reconstitution of TFIIIB from recombinant polypeptides. The TFIIIB90 open reading frame encodes a 68-kDa polypeptide and has no obvious similarity to any other known protein sequences. The gene encoding TFIIIB90 is essential for viability of yeast. Using recombinant TFIIIB subunits, we found that TFIIIB90 interacts weakly with TBP in the absence of BRF1, and that this interaction is enhanced at least 25-fold by BRF1. In addition, TFIIIB90 showed pol III specificity as it could not interact with the pol II-specific TFIIB-TBP-DNA complex. To localize the regions of the TBP-DNA complex that interact with BRF1 and TFIIIB90, we tested whether the pol II factors TFIIA and TFIIB interfered with the binding of BRF1 and TFIIIB90 to TBP-DNA. Our results suggest that the binding sites for BRF1 and TFIIIB90 on TBP-DNA both overlap the binding sites for TFIIA and TFIIB.
Amino Acid Sequence↗
Crystal structure of the yeast TFIIA/TBP/DNA complex.
The crystal structure of the yeast TFIIA/TBP/TATA promoter complex was solved to 3 angstrom resolution by double-edge multiple wavelength anomalous diffraction from two different species of anomalous scattering elements in the same crystal. The large and small subunits of TFIIA associate intimately to form both domains of a two-domain folding pattern. TFIIA binds as a heterodimer to the side of the TBP/TATA complex opposite to the side that binds TFIIB and does not alter the TBP/DNA interaction. The six-stranded beta-sandwich domain interacts with the amino-terminal end of TBP through a stereospecific parallel beta-strand interface and with the backbone of the TATA box and the 5'-flanking B-DNA segment. The four-helix-bundle domain projects away from the TBP/TATA complex, thereby presenting a substantial surface for further protein-protein interactions.
Amino Acid Sequence↗
Filling-in percepts produced by luminance modulation.
We report that when the luminance of a homogeneous spot of light is gradually increased or decreased, there are conditions in which the brightness of the spot is spatially nonuniform. When the spot luminance is increased, brightness changes in the spot's center lag behind changes at the edge and brightness appears to sweep inward. Conversely, if the luminance of the spot is decreased, there is a relative lag in the darkening toward the center of the spot and darkness seems to spread inward. In Experiment 1 we found that with both increasing and decreasing luminance sweeps, the strength of the brightness filling effects was strongest with luminance sweep durations of 0.25-0.5 sec. In Experiment 2, the sweep duration was held constant at 0.5 sec; the filling effect was seen when the dwell time spent at each luminance step was less than about 100 msec, but nonuniformities were not observed at longer dwell times. In Experiment 3, a spot of light was positioned to surround the optic disk in one eye. Surprisingly, when the spot was luminance modulated from bright to dark, darkness appeared to sweep from the edge to the center of the modulated disk, even though most of the disk's interior was imaged on a portion of the retina devoid of photoreceptors. These findings are consistent with the hypothesis that a neural filling-in mechanism in visual cortex plays a key role in brightness perception.
Darkness↗
Gender, quality of life, and mental disorders in primary care: results from the PRIME-MD 1000 study.
BACKGROUND: Recently there has been increased interest in the special mental health needs of women. We used data from the PRIME-MD 1000 study to assess gender differences in the frequency of mental disorders in primary care settings, and to explore the potential impact of these differences on health-related quality of life (HRQL). SUBJECTS AND METHODS: One thousand primary care patients (559 women) were interviewed during the PRIME-MD study, which was conducted at four primary care clinics affiliated with university hospitals throughout the eastern United States. Patients completed a one-page questionnaire in the waiting room prior to being seen by the physician; patients and physicians then completed together a clinician evaluation guide that used DSM-III-R algorithms to diagnose mood, anxiety, somatoform, eating, and alcohol related disorders. Health-related quality of life was assessed with the Medical Outcomes Study SF-20 General Health Survey. RESULTS: Women were more likely than men to have at least one mental disorder (43% versus 33%, P < 0.05). Higher rates were particularly prominent for mood disorders (31% of women versus 19% of men, odds ratio [OR] = 1.9, 95% confidence interval [CI] 1.4 to 2.6), anxiety disorders (22% versus 13%, OR = 1.9, CI = 1.3 to 2.8), and somatoform disorders (18% versus 9%, OR = 2.2, CI = 1.5 to 3.4). Psychiatric comorbidity was also more common in women (26% of women had two or more mental disorders versus 15% of men, P < 0.05). Unadjusted HRQL scores, ranging from 0 to 100, with 100 = best health, were all significantly lower in women than in men (eg, physical function = 67 in women versus 76 in men, P < 0.0001; mental health = 69 in women versus 76 in men, P < 0.0001). Many HRQL differences persisted after controlling for age, education, ethnicity, marital status, and number of physical disorders; however, differences in HRQL were eliminated in 5 of 6 domains after controlling for number of mental disorders. When compared with female patients of male physicians, female patients of female physicians demonstrated similar satisfaction with care, health care utilization, HRQL, and recognition rate of mental disorders. CONCLUSIONS: In the 1,000 patients of the PRIME-MD study, mood, anxiety, and somatoform disorders and psychiatric comorbidity were all significantly more common in women than men. The HRQL scores were poorer in women than men, although most of this difference was accounted for by the difference in prevalence of mental disorders. These data suggest that one of the most important aspects of a primary care physician's care of female patients is to screen for and treat common mental disorders.
Adult↗
Transcription: basal factors and activation.
Much progress has been made in the past few years in understanding the mechanism and regulation of mRNA synthesis. This rapid progress has largely been due to the availability of cloned genes encoding components of the transcription machinery. Structural and biochemical studies are rapidly defining the architecture of components in the transcription complex. Highly purified biochemical systems are beginning to elucidate the role of the individual initiation factors. The identification of a large complex that contains a polymerase, termed holoenzyme, has provided a new way of thinking about how the transcription complex assembles at a promoter. The mechanism of transcription stimulation by activators is beginning to be unraveled but still appears to be a complex process. Finally, analyses of genes involved in DNA repair, cell cycle control and transcription have revealed similarities between transcription and other forms of cell regulation.
Animals↗
Protective effect of the specific endothelin-1 antagonist BQ610 on mechanical function and energy metabolism during ischemia/reperfusion injury in isolated perfused rat hearts.
Endothelin-1 (ET-1) has been suggested to be involved in the pathophysiology of ischemia/reperfusion injury, but direct proof for this is still sparse. We tested whether protection of high-energy phosphate metabolism contributes to the beneficial effects of ETA receptor antagonists during ischemia/reperfusion. In isolated, buffer-perfused rat hearts, isovolumic function was measured by a left ventricular (LV) balloon, and 31P nuclear magnetic resonance spectra were continuously recorded. Two protocols were performed: (a) 15-min control, 30-min total, global ischemia, and 15-min reperfusion; and (b) 15-min control, 15-min total, global ischemia, and 30-min reperfusion. Treatment with BQ610 (1.75 micrograms/min) or saline was started during control and continued throughout the protocol. BQ610 did not affect function or energy metabolism under control conditions. In BQ610-treated hearts subjected to 30-min ischemia, time to ischemic contracture was significantly delayed (treated 10.6 +/- 0.4 min; untreated 8.1 +/- 0.7 min), and end-diastolic pressure (EDP) remained lower (after 30-min ischemia 26 +/- 2 vs. 35 +/- 2 mm Hg). In addition, recovery of mechanical function in BQ610-treated hearts was accelerated during reperfusion. BQ610 did not affect ATP but significantly accelerated and increased creatine phosphate (51 +/- 7 vs. 37 +/- 3%) recovery on reperfusion after 30-min ischemia. BQ610-treated hearts subjected to 15-min ischemia also showed lower EDP during ischemia and accelerated recovery of mechanical function during reperfusion. However, in this case, there were no differences in high-energy phosphate concentrations between treated and untreated hearts. We conclude that the protective action of BQ610 on mechanical function during ischemia/reperfusion injury can be but is not consistently associated with beneficial effects on cardiac high-energy phosphate metabolism.
Adenosine Triphosphate↗
[Reflection of hygenic and anti-epidemic problems at international hygenic exhibitions in Dresden in 1911 and 1930].
Ist International Hygenic Exhibition took place in Dresden in 1911 and it was dedicated to communicable diseases. In period of three months when it was opened it was seen by 5 million people. Next, the second - in 1930, was including also the problems connected with neoplastic and psychic diseases, and also with diseases of circulatory system. Sections dedicated to different problems, have had a similar didactic plan. They have been presenting a disease prevalence in the world; how to recognize it and what the course of it is; how it comes to infection and how it is transmitted; what present medicine can do about its treatment; what everybody should do to prevent becoming ill. Exhibitions were one of the elements of communicable diseases prevention, and of health education propagation; they played a significant part in this field.
Communicable Disease Control↗
The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells.
OBJECTIVE: To analyse the role of the apoptosis-inducing Fas receptor in the depletion of CD4+ and CD8+ T cells in HIV-infected individuals. METHODS: Peripheral blood lymphocytes (PBL) obtained from HIV-infected subjects of all 1993 Centers for Disease Control and Prevention (CDC) stages and from non-infected controls were examined. A two-colour cytofluorometry was employed using monoclonal antibodies against Fas receptor (CD95) in combination with the surface markers CD4, CD8, CD28, CD26 and CD45RO. CD4+ and CD8+ T-cell-enriched PBL were used as target cells to assess their susceptibility to lysis by CD4+ cytotoxic T lymphocytes (CTL) which kill via the Fas pathway. RESULTS: Fas+PBL are more elevated in HIV-infected individuals than in HIV-negative controls and increase significantly from CDC stages A to C. Whereas Fas+CD4+ and Fas-CD4+ T-cell populations decline in parallel with the progression of HIV infection, the Fas+CD8+, but not of the Fas-CD8+ fraction, significantly increases. The Fas+CD8+ lymphocytes are susceptible to Fas-mediated lysis as they are efficiently killed by Fas-ligand+CD4+CTL. CONCLUSION: The Fas receptor may contribute, but not as a unique cause, to the decline of CD4+ T cells in HIV-infected individuals. This and the significant increase of the number of Fas+ CD8+ T cells indicates that Fas-mediated immune regulation is disturbed.
Animals↗