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At least 1,729 records · Page 96Linked to original sources
PubMed2003

A multiplicity of coactivators is required by Gcn4p at individual promoters in vivo.

Transcriptional activators interact with multisubunit coactivators that modify chromatin structure or recruit the general transcriptional machinery to their target genes. Budding yeast cells respond to amino acid starvation by inducing an activator of amino acid biosynthetic genes, Gcn4p. We conducted a comprehensive analysis of viable mutants affecting known coactivator subunits from the Saccharomyces Genome Deletion Project for defects in activation by Gcn4p in vivo. The results confirm previous findings that Gcn4p requires SAGA, SWI/SNF, and SRB mediator (SRB/MED) and identify key nonessential subunits of these complexes required for activation. Among the numerous histone acetyltransferases examined, only that present in SAGA, Gcn5p, was required by Gcn4p. We also uncovered a dependence on CCR4-NOT, RSC, and the Paf1 complex. In vitro binding experiments suggest that the Gcn4p activation domain interacts specifically with CCR4-NOT and RSC in addition to SAGA, SWI/SNF, and SRB/MED. Chromatin immunoprecipitation experiments show that Mbf1p, SAGA, SWI/SNF, SRB/MED, RSC, CCR4-NOT, and the Paf1 complex all are recruited by Gcn4p to one of its target genes (ARG1) in vivo. We observed considerable differences in coactivator requirements among several Gcn4p-dependent promoters; thus, only a subset of the array of coactivators that can be recruited by Gcn4p is required at a given target gene in vivo.

Base Sequence↗
PubMed2005

Chromatin immunoprecipitation-based screen to identify functional genomic binding sites for sequence-specific transactivators.

In various human diseases, altered gene expression patterns are often the result of deregulated gene-specific transcription factor activity. To further understand disease on a molecular basis, the comprehensive analysis of transcription factor signaling networks is required. We developed an experimental approach, combining chromatin immunoprecipitation (ChIP) with a yeast-based assay, to screen the genome for transcription factor binding sites that link to transcriptionally regulated target genes. We used the tumor suppressor p53 to demonstrate the effectiveness of the method. Using primary and immortalized, nontransformed cultures of human mammary epithelial cells, we isolated over 100 genomic DNA fragments that contain novel p53 binding sites. This approach led to the identification and validation of novel p53 target genes involved in diverse signaling pathways, including growth factor signaling, protein kinase/phosphatase signaling, and RNA binding. Our results yield a more complete understanding of p53-regulated signaling pathways, and this approach could be applied to any number of transcription factors to further elucidate complex transcriptional networks.

Binding Sites↗
PubMed1991

Microbiological degradation of pesticides in yard waste composting.

Changes in public opinion and legislation have led to the general recognition that solid waste treatment practices must be changed. Solid-waste disposal by landfill is becoming increasingly expensive and regulated and no longer represents a long-term option in view of limited land space and environmental problems. Yard waste, a significant component of municipal solid waste, has previously not been separated from the municipal solid-waste stream. The treatment of municipal solid waste including yard waste must urgently be addressed because disposal via landfill will be prohibited by legislation. Separation of yard waste from municipal solid waste will be mandated in many localities, thus stressing the importance of scrutinizing current composting practices in treating grass clippings, leaves, and other yard residues. Yard waste poses a potential environmental health problem as a result of the widespread use of pesticides in lawn and tree care and the persistence of the residues of these chemicals in plant tissue. Yard waste containing pesticides may present a problem due to the recalcitrant and toxic nature of the pesticide molecules. Current composting processes are based on various modifications of either window systems or in-vessel systems. Both types of processes are ultimately dependent on microbial bioconversions of organic material to innocuous end products. The critical stage of the composting process is the thermophilic phase. The fate and mechanism of removal of pesticides in composting processes is largely unknown and in need of comprehensive analysis.

Biodegradation, Environmental↗
PubMed2006

Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study.

AIMS: To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. METHODS: As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth-Munsell 100 (FM-100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM-100 MS-Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non-blood relatives (off pedigree), who served as controls. RESULTS: 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a chi(2) test with one degree of freedom was statistically significant with a p value less that 0.001. CONCLUSIONS: Until now, LHON has always been characterised by a sudden, devastating vision loss. Asymptomatic carriers, those without vision loss, were considered unaffected by the disease. It now appears that asymptomatic carriers of the LHON mutation are affected by colour vision defects and may manifest other subtle, yet chronic, changes.

Brazil↗
PubMed2004

Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearance.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection results in a high frequency of chronic disease. The aim of this study was to identify early prognostic markers of disease resolution by performing a comprehensive analysis of viral and host factors during the natural course of acute HCV infection. METHODS: The clinical course of acute hepatitis C was determined in 34 consecutive patients. Epidemiological and virological parameters, as well as cell mediated immunity (CMI) and distribution of human leukocyte antigens (HLA) alleles were analysed. RESULTS: Ten out of 34 patients experienced self-limiting infection, with most resolving patients showing fast kinetics of viral clearance: at least one negative HCV RNA test during this phase predicted a favourable outcome. Among other clinical epidemiological parameters measured, the self-limiting course was significantly associated with higher median peak bilirubin levels at the onset of disease, and with the female sex, but only the latter parameter was independently associated after multivariate analysis. No significant differences between self-limiting or chronic course were observed for the distribution of DRB1 and DQB1 alleles. HCV specific T cell response was more frequently detected during acute HCV infection, than in patients with chronic HCV disease. A significantly broader T cell response was found in patients with self-limiting infection than in those with chronic evolving acute hepatitis C. CONCLUSION: The results suggest that host related factors, in particular sex and CMI, play a crucial role in the spontaneous clearance of this virus. Most importantly, a negative HCV RNA test and broad CMI within the first month after onset of the symptoms represent very efficacious predictors of viral clearance and could thus be used as criteria in selecting candidates for early antiviral treatment.

Adult↗
PubMed2000

Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-gammadelta expression.

BACKGROUND AND AIMS: A histopathological feature considered indicative of ulcerative colitis (UC) is the so-called basal lymphoid aggregates. Their relevance in the pathogenesis of UC is, however, unknown. We have performed a comprehensive analysis of the immune cells in these aggregates most likely corresponding to the lymphoid follicular hyperplasia also described in other colitides. METHODS: Resection specimens of UC and normal colon were analysed by immunomorphometry, immunoflow cytometry, and immunoelectron microscopy, using a large panel of monoclonal antibodies. RESULTS: (1) In all cases of UC, colonic lamina propria contained numerous basal aggregates composed of lymphocytes, follicular dendritic cells, and CD80/B7.1 positive dendritic cells. (2) CD4(+)CD28(-) alphabeta T cells and B cells were the dominant cell types in the aggregates. (3) The aggregates contained a large fraction of cells that are normally associated with the epithelium: that is, gammadelta T cells (11 (7)%) and alpha(E)beta(7)(+) cells (26 (13)%). The gammadelta T cells used Vdelta1 and were CD4(-)CD8(-). Immunoelectron microscopy analysis demonstrated TcR-gammadelta internalisation and surface downregulation, indicating that the gammadelta T cells were activated and engaged in the disease process. (4) One third of cells in the aggregates expressed the antiapoptotic protein bcl-2. CONCLUSIONS: Basal lymphoid aggregates in UC colon are a consequence of anomalous lymphoid follicular hyperplasia, characterised by abnormal follicular architecture and unusual cell immunophenotypes. The aggregates increase in size with severity of disease, and contain large numbers of apoptosis resistant cells and activated mucosal gammadelta T cells. The latter probably colonise the aggregates as an immunoregulatory response to stressed lymphocytes or as a substitute for defective T helper cells in B cell activation. gammadelta T cells in the aggregates may be characteristic of UC.

Adult↗
PubMed2001

Upregulation of Reg 1alpha and GW112 in the epithelium of inflamed colonic mucosa.

BACKGROUND AND AIMS: Colonic epithelium is involved in the regulation of intestinal function and mucosal immune responses, and its function is altered in inflammatory bowel disease (IBD). However, a comprehensive analysis of the genetic alterations in inflamed colonic epithelium is not available at present. The aim of our study was to detect genes that are preferentially expressed in inflamed colonic epithelia and clarify the biochemical responses of epithelial cells in inflamed colonic mucosa. METHODS: cDNA representation difference analysis was used to identify candidate genes selectively expressed in inflamed colonic epithelia. Selective expression of these genes in the epithelium of inflamed colonic mucosa, including IBD and non-IBD tissues, was examined by real time polymerase chain reaction and in situ hybridisation. The effect of cell confluence and inflammatory mediators on Reg 1alpha gene expression was examined using a colon cancer cell line (HT29). RESULTS: We identified seven candidate genes that were presumed to be upregulated in the inflamed colonic epithelium. Of these, Reg 1alpha and GW112 were the dominant species and expression of these genes was confined to the crypt epithelium. In vitro studies using a colonic epithelial cell line suggested that cell confluence regulates Reg 1alpha gene expression. CONCLUSIONS: Selective expression of Reg 1alpha and GW112 genes in the crypt epithelium of inflamed colonic mucosa suggests the important regulatory functions of these genes.

Adult↗
PubMed2002

Associated changes of lipid peroxidation and transforming growth factor beta1 levels in human colon cancer during tumour progression.

BACKGROUND: During neoplastic progression, alterations in transforming growth factor beta1 (TGF-beta1) dependent control of cell growth may be an important mechanism of selective proliferation of transformed cellular clones. Defective regulation of TGF-beta1 receptors has been reported to occur in a number of human malignant tumours while little is known of the actual levels of this growth inhibitory cytokine in cancer. On the basis of the demonstrated ability of major lipid peroxidation products such as 4-hydroxynonenal to modulate TGF-beta1 expression and synthesis, we speculated that decreased lipid oxidation, as frequently observed in neoplastic tissues, would contribute to the selective promotion of tumour growth through decreased expression of the cytokine within the tumour mass. AIMS: To seek a possible association between steady state levels of major aldehydic end products of lipid peroxidation and TGF-beta1 content in human colon cancer at different stages of growth. PATIENTS AND METHODS: Tissue biopsies from 15 adult patients with colon adenocarcinoma of different TNM and G stagings were compared with regard to lipid peroxidation aldehydes and net TGF-beta1 levels. For a more comprehensive analysis, cytokine type I and II receptors were measured in tumour biopsies. In one set of experiments, to support the conclusions, the apoptotic effect of TGF-beta1 was evaluated in a human colon cancer cell line, CaCo-2, retaining receptor changes consistent with those observed in cancer patients. RESULTS: With the exception of two extremely advanced cases (T4/G3) in which tissue levels of lipid peroxidation were within the normal range, 4-hydroxynonenal was significantly decreased in all other cancer specimens. Consistent with lipid peroxidation levels, TGF-beta1 protein was markedly decreased or even negligible compared with the corresponding normal tissue surrounding the tumour in all tested biopsies except for the two T4/G3 colon cancers in which cytokine content was again within the normal range. As regards TGF-beta1 receptors, both in tumour sections and CaCo-2 cells, downregulation was greater for TGF-beta1 receptor I than for receptor II. Of note, in CaCo-2 cells, incubation with appropriate doses of TGF-beta1 led to marked nuclear fragmentation and apoptosis. CONCLUSIONS: Evasion of human colon cancer cells from TGF-beta1 mediated growth inhibition appears to be due not only to downregulation of TGF-beta1 receptors, which is inconsistent and unrelated to cancer development, but also to the constant low concentration of this cytokine in the tumour mass. The associated levels of lipid peroxidation aldehydes, much lower than in control tissue, probably represent a lower stimulus for TGF-beta1 production in the neoplastic area and thus a favourable condition for neoplastic progression.

Adenocarcinoma↗
PubMed1997

Estimating potential savings in cancer deaths by eliminating regional and social class variation in cancer survival in the Nordic countries.

STUDY OBJECTIVES: To examine equity in the health care system with regard to cancer patient care by estimating the level of systematic regional variation in cancer survival in the Nordic countries. Specifically, those cancer sites which exhibit high levels of systematic regional variation in survival and hence inequity were identified. Estimating the reduction in cancer deaths which could be achieved by eliminating this variation so that everyone receives effective care will provide a readily interpretable measure of the amount of systematic regional variation. A comprehensive analysis of regional variation in survival has not previously been conducted so appropriate statistical methodology must be developed. SETTING AND PARTICIPANTS: All those aged 0-90 years who had been diagnosed with at least one of 12 common malignant neoplasms between 1977 and 1992 in Denmark, Finland, Norway, and Sweden. DESIGN: A separate analysis was conducted for each country. Regression models for the relative survival ratio were used to estimate the relative risk of excess mortality attributable to cancer in each region after correcting for age and sex. An estimate of the amount of systematic regional variation in survival was obtained by subtracting the estimated expected random variation from the observed regional variation. An estimate was then made of the potential reduction in the number of cancer deaths for 2008-12 if regional variation in survival were eliminated so that everyone received the same level of effective care. MAIN RESULTS: Between 2008 and 2012, an estimated 2.5% of deaths from cancers in the 12 sites studied could be prevented by eliminating regional variation in survival. The percentage of potentially avoidable deaths did not depend on country or sex but it did depend on cancer site. There was no relationship between the level of regional variation in a given country and the level of survival. The cancer sites for which the greatest percentage savings could be achieved were melanoma (11%) and cervix uteri (6%). The sites for which the highest number of deaths could be prevented were prostate, colon, melanoma, and breast. CONCLUSIONS: This methodology showed a small amount of systematic regional variation in cancer survival in the Nordic countries. The cancer sites with high levels of regional variation identified are potential targets for cancer control programmes.

Adolescent↗
PubMed2005

STRA13 expression and subcellular localisation in normal and tumour tissues: implications for use as a diagnostic and differentiation marker.

BACKGROUND: STRA13 is a bHLH transcription factor that plays a crucial role in cell differentiation, proliferation, apoptosis, and response to hypoxia. OBJECTIVE: To assess STRA13 involvement in carcinogenesis and evaluate its diagnostic value. METHODS: A comprehensive analysis was undertaken of the endogenous protein expression in 389 normal and corresponding malignant specimens, using newly generated polyclonal antibodies. RESULTS: STRA13 was commonly expressed in epithelial cells of normal and neoplastic tissues where it was confined mostly to the nucleus. Intense cytoplasmic STRA13 immunoreactivity was characteristic of myoepithelial and differentiated squamous epithelial cells of all organ sites and their neoplastic counterparts, suggesting application of STRA13 as a myoepithelial cell marker. A distinctive apical granular cytoplasmic staining pattern observed in the pancreas and large intestine was retained in corresponding metastatic carcinomas, providing for identification of the primary sites of these disseminating tumours. In less differentiated tumours there was a tendency to lose the cytoplasmic staining or to switch to nuclear STRA13 staining. Analysis of STRA13, HIF-1alpha, and CAIX expression patterns in a large set of various tumours substantiated the association of STRA13 with HIF-1alpha expression and hypoxia in vivo. Investigation of the molecular mechanisms of STRA13 nucleo-cytoplasmic shuttling suggested that STRA13 employs nuclear import/export that utilises the NLS/NES motifs situated within the N-terminus and in the middle of the protein. CONCLUSIONS: STRA13 may serve as a marker for myoepithelial cells, for the degree of tumour differentiation, and for identification of the primary site of certain metastatic tumours. In combination with CAIX and CAXII markers, it may lead to a more accurate classification of all renal carcinomas.

Antibody Specificity↗
PubMed1979

Presystemic drug elimination.

The presystemic elimination of a large number of compounds is clearly established and represents a common and unavoidable cause of reduced bioavailability. The liver, intestine, and lungs have been identified as potential organs contributing to this effect but only in the case of the liver are sufficient data available for comprehensive analysis. More information on intestinal and pulmonary metabolism is clearly needed. Simple methods of kinetic analysis already exist, however, to assess the relative importance of these organs in presystemic elimination, especially in relation to the pre- and postabsorptive types of elimination that may occur.

Animals↗
PubMed2004

Evaluating metabolic syndrome in a medical physiology laboratory.

The metabolic syndrome, a cluster of factors linked to obesity that contribute to risk for atherosclerosis and Type 2 diabetes, may affect 20-25% of the adults in the United States. We designed a medical physiology laboratory to evaluate and discuss the physiological and nutritional principles involved in the metabolic syndrome. The five criteria used to diagnose this syndrome (fasting blood triglycerides, high-density lipoprotein cholesterol, and glucose, blood pressure, central obesity) were measured by students on each other either previously or during this exercise. In addition, to illustrate nutritional factors involved in causation and treatment of the metabolic syndrome, a meal was provided during the laboratory. Class members were randomized to groups allowed ad libitum meal composition, or constrained to the National Cholesterol Education Program Step I or Step II diets. The composition of the diet (including saturated fat, cholesterol, dietary fiber, and carbohydrate content) was discussed in the context of blood cholesterol, triglyceride, and glucose levels. This laboratory allows a comprehensive analysis of the physiological and nutritional factors involved in the development of the metabolic syndrome.

Curriculum↗
PubMed2007

The actin cytoskeleton regulates exocytosis of all neutrophil granule subsets.

A comprehensive analysis of the role of the actin cytoskeleton in exocytosis of the four different neutrophil granule subsets had not been performed previously. Immunoblot analysis showed that, compared with plasma membrane, there was less actin associated with secretory vesicles (SV, 75%), gelatinase granules (GG, 40%), specific granules (SG, 10%), and azurophil granules (AG, 5%). Exocytosis of SV, SG, and AG was measured as increased plasma membrane expression of CD35, CD66b, and CD63, respectively, with flow cytometry, and GG exocytosis was measured as gelatinase release with an ELISA. N-formylmethionyl-leucyl-phenylalanine (FMLP) stimulated exocytosis of SV, GG, and SG with an ED(50) of 15, 31, and 28 nM, respectively, with maximal response at 10(-7) M FMLP by 5 min, while no exocytosis of AG was detected. Disruption of the actin cytoskeleton by latrunculin A and cytochalasin D induced a decrease in FMLP-stimulated CD35 expression after an initial increase. Both drugs enhanced the rate and extent of FMLP-stimulated GG, SG, and AG exocytosis, while the EC(50) for FMLP was not altered. We conclude that the actin cytoskeleton controls access of neutrophil granules to the plasma membrane, thereby limiting the rate and extent of exocytosis of all granule subsets. Differential association of actin with the four granule subsets was not associated with graded exocytosis.

Actins↗
PubMed2001

Magnitude and variation of ratio of total body potassium to fat-free mass: a cellular level modeling study.

Potassium is an essential element of living organisms that is found almost exclusively in the intracellular fluid compartment. The assumed constant ratio of total body potassium (TBK) to fat-free mass (FFM) is a cornerstone of the TBK method of estimating total body fat. Although the TBK-to-FFM (TBK/FFM) ratio has been assumed constant, a large range of individual and group values is recognized. The purpose of the present study was to undertake a comprehensive analysis of biological factors that cause variation in the TBK/FFM ratio. A theoretical TBK/FFM model was developed on the cellular body composition level. This physiological model includes six factors that combine to produce the observed TBK/FFM ratio. The ratio magnitude and range, as well as the differences in the TBK/FFM ratio between men and women and variation with growth, were examined with the proposed model. The ratio of extracellular water to intracellular water (E/I) is the major factor leading to between-individual variation in the TBK/FFM ratio. The present study provides a conceptual framework for examining the separate TBK/FFM determinants and suggests important limitations of the TBK/FFM method used in estimating total body fat in humans and other mammals.

Adipose Tissue↗
PubMed2026

Combined high-fat, high-sucrose diet and streptozotocin treatment induces cardiometabolic heart failure with preserved ejection fraction in mice.

Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a nongenetic, inducible type 2 diabetes mellitus (T2DM) mouse model about its suitability as a preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6 mice by a high-fat/high-sucrose diet and a low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization and in vitro using the isolated perfused heart. Structural, molecular, and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, Western blot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids, and ketone body levels were elevated, and insulin levels were reduced in DIO-STZ compared with chow. DIO-STZ mice showed an HFpEF phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis or in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed toward disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for β-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models, making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutic interventions in diabetes-associated HFpEF.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome whose pathophysiological mechanisms are incompletely understood, potentially due to a lack of preclinical models reflecting the broad range of pathophysiological aspects. We describe a diabetic DIO-STZ mouse model showing a pronounced HFpEF with underlying mechanisms that remarkably differ from other HFpEF models, making this model a relevant extension of the range of HFpEF models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes.

Animals↗
PubMed1998

Dynamics of spectral components of heart rate variability during changes in autonomic balance.

Frequency domain analysis of heart rate variability (HRV) has been proposed as a semiquantitative method for assessing activities in the autonomic nervous system. We examined whether absolute powers, normalized powers, and the low frequency-to-high frequency ratio (LF/HF) derived from the HRV power spectrum could detect shifts in autonomic balance in a setting with low sympathetic nervous tone. Healthy subjects were examined for 3 h in the supine position during 1) control conditions (n = 12), 2) acute beta-blockade (n = 11), and 3) chronic beta-blockade (n = 10). Heart rate fell during the first 40 min of the control session (72 +/- 2 to 64 +/- 2 beats/min; P < 0. 005) and was even lower during acute and chronic beta-blockade (56 +/- 2 beats/min; P < 0.005). The powers of all spectral areas rose during the first 60 min in all three settings, more so with beta-blockade (P < 0.05). LF/HF was found to contain the same information as powers expressed in normalized units. LF/HF detected the shift in autonomic balance induced by beta-blockade but not the change induced by supine position. In conclusion, none of the investigated measures derived from power spectral analysis comprehensively and consistently described the changes in autonomic balance.

Adrenergic beta-Antagonists↗
PubMed1998

Human surfactant proteins A1 and A2 are differentially regulated during development and by soluble factors.

An RT-PCR method for the relative quantitation of the mRNAs for human surfactant protein (SP) A1 and SP-A2 was developed, verified, and then utilized to determine the relative levels of these mRNAs in fetal and adult lung samples in vivo, as well as in cultured human fetal lung explants and H441 cells. For the cultured tissue and cells, we assessed the effects of a variety of soluble factors known to modulate total SP-A. Comprehensive analysis revealed many significant findings, including the following: both mRNAs were expressed as early as 15 wk of gestation; throughout midgestation, SP-A1 was present at higher levels than SP-A2, with an average ratio of 30:1. In the adult lung, SP-A1 mRNA was present at lower levels than SP-A2, with a ratio of 0.4:1, whereas in H441 cells, the ratio was 0.85:1. In fetal lung cultured for 4 days, both mRNAs increased, with a greater increase in SP-A2 (97-fold) than in SP-A1 (15-fold), resulting in a final ratio of 4:1. Differential regulation was demonstrated for 8-(4-chlorophenylthio)-cAMP, interferon (IFN)-gamma, tumor necrosis factor-alpha, and transforming growth factor (TGF)-beta in the human fetal lung explant system, with SP-A2 being more affected, and for IFN-gamma and TGF-beta in the H441 cells, where SP-A1 showed greater regulation. Of the soluble factors tested, IFN-gamma and TGF-beta had the most potent and consistent effects in both systems.

Adult↗
PubMed2005

Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease.

The propensity for developing atherosclerosis is dependent on underlying genetic risk and varies as a function of age and exposure to environmental risk factors. Employing three mouse models with different disease susceptibility, two diets, and a longitudinal experimental design, it was possible to manipulate each of these factors to focus analysis on genes most likely to have a specific disease-related function. To identify differences in longitudinal gene expression patterns of atherosclerosis, we have developed and employed a statistical algorithm that relies on generalized regression and permutation analysis. Comprehensive annotation of the array with ontology and pathway terms has allowed rigorous identification of molecular and biological processes that underlie disease pathophysiology. The repertoire of atherosclerosis-related immunomodulatory genes has been extended, and additional fundamental pathways have been identified. This highly disease-specific group of mouse genes was combined with an extensive human coronary artery data set to identify a shared group of genes differentially regulated among atherosclerotic tissues from different species and different vascular beds. A small core subset of these differentially regulated genes was sufficient to accurately classify various stages of the disease in mouse. The same gene subset was also found to accurately classify human coronary lesion severity. In addition, this classifier gene set was able to distinguish with high accuracy atherectomy specimens from native coronary artery disease vs. those collected from in-stent restenosis lesions, thus identifying molecular differences between these two processes. These studies significantly focus efforts aimed at identifying central gene regulatory pathways that mediate atherosclerotic disease, and the identification of classification gene sets offers unique insights into potential diagnostic and therapeutic strategies in atherosclerotic disease.

Animals↗