Overexpression of proto-oncogene bcl-2 in rheumatoid synovium.
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Arthritis, Rheumatoid↗
Biomedical subjects
H M Chen
Publications and source records attributed to H M Chen.
DNA aneuploidy in benign tumors and normal tissues of the female genital tract.
Few flow cytometric DNA analyses have used sufficient normal tissues and benign tumors as controls. To establish a basis for the interpretation of DNA flow cytometric results of gynecologic neoplasms, paraffin blocks from 121 patients with a diagnosis of serous cystadenoma (n = 37), mucinous cystadenoma (n = 28), leiomyoma (n = 41), and fibrothecoma (n = 15), and normal tissue samples obtained from some of these patients, including ovary (n = 20), cervix (n = 20), and myometrium (n = 20) were analyzed for nuclear DNA content. Absence of DNA aneuploidy was confirmed in all the normal tissues analyzed. Three (7.3%) of the leiomyomas, three (10.7%) of the mucinous cystadenomas, and one (6.7%) of the fibrothecomas were DNA aneuploid, whereas no unequivocal aneuploidy was found in the serous cystadenomas. The DNA indices of the aneuploid peaks varied between 1.10 and 1.97. The frequency of aneuploidy was related to tumor size in leiomyoma (p < 0.05). Prominent myxoid degeneration was noted in two of the three aneuploid leiomyomas. One of the three aneuploid mucinous tumors had focal cellular atypia and increased mitotic activity, and another had prominent papillary infoldings, focal breakdown of cyst walls, and rupture of mucin into the ovarian stroma. There was no progression or recurrence in those patients who had histologically benign but DNA aneuploid tumors during a mean follow-up of 58.1 months.
Adult↗
CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter.
Transcription factors play a key role in the development and differentiation of specific lineages from multipotential progenitors. Identification of these regulators and determining the mechanism of how they activate their target genes are important for understanding normal development of monocytes and macrophages and the pathogenesis of a common form of adult acute leukemia, in which the differentiation of monocytic cells is blocked. Our previous work has shown that the monocyte-specific expression of the macrophage colony-stimulating factor (M-CSF) receptor is regulated by three transcription factors interacting with critical regions of the M-CSF receptor promoter, including PU.1 and AML1.PU.1 is essential for myeloid cell development, while the AML1 gene is involved in several common leukemia-related chromosome translocations, although its role in hematopoiesis has not been fully identified. Along with AML1, a third factor, Mono A, interacts with a small region of the promoter which can function as a monocyte-specific enhancer when multimerized and linked to a heterologous basal promoter. Here, we demonstrate by electrophoretic mobility shift assays with monocytic nuclear extracts, COS-7 cell-transfected factors, and specific antibodies that the monocyte-enriched factor Mono A is CCAAT enhancer-binding protein (C/EBP). C/EBP has been shown previously to be an important transcription factor involved in hepatocyte and adipocyte differentiation; in hematopoietic cells, C/EBP is specifically expressed in myeloid cells. In vitro binding analysis reveals a physical interaction between C/EBP and AML1. Further transfection studies show that C/EBP and AML1 in concert with the AML1 heterodimer partner CBF beta synergistically activate M-CSF receptor by more then 60 fold. These results demonstrate that C/EBP and AML1 are important factors for regulating a critical hematopoietic growth factor receptor, the M-CSF receptor, suggesting a mechanism of how the AML1 fusion protein could contribute to acute myeloid leukemia. Furthermore, they demonstrate physical and functional interactions between AML1 and C/EBP transcription factor family members.
Animals↗
Antimicrobial resistance and serotype distribution of Streptococcus pneumoniae strains isolated in southern Taiwan.
The antimicrobial susceptibilities and serotypes of 115 Streptococcus pneumonia strains isolated in southern Taiwan from January 1990 to December 1993 were determined. All isolates were susceptible to cephalothin, cefotaxime, trimethoprim/sulfamethoxazole and vancomycin, and 14 of the isolates were resistant to penicillin G. The oxacillin disk method for presumptive detection of resistance to penicillin had a sensitivity of 85.7% and specificity of 97.0%. Resistance rates were as follows: erythromycin 62.2%, tetracycline 71.3%, clindamycin 46.1% and chloramphenicol 19.1%. Eighty-four percent of the isolates were resistant to one or more of the antibiotic tested. Multiple resistance (to three or more classes of antibiotics) was identified in 40.9% of all the isolates and 100% of penicillin-resistant isolates. The predominant serotypes were: 14 (19.1%), 3 (17.4%), 23 (15.7%), 6 (10.4%), and 15 (6.1%). Serotypes 14 and 63 most commonly caused childhood infections, while serotypes 3 and 23 were frequently encountered in adults. The proportion of coverage in 23-valent pneumococcal polysaccharide vaccine was 92.2%, if vaccine-related serotypes were considered to be cross-protecting. Seven (58%) of 12 typable penicillin-resistant isolates belonged to serotype 23 and two (16.7%) to serotype 6. All isolates of serotype 14, 23, 15 and 19 were resistant to one or more antibiotics. Multiple drug resistance was frequently associated with serotype 23 (31.9%), 14 (23.4%) and 6 (17.0%). Sixty-five percent of isolates of serotype 3 were susceptible to all antibiotics tested. The high level of antimicrobial resistance in S. pneumoniae mandates the continuous surveillance of resistance and the strict control of antibiotic use in Taiwan.
Adult↗
[Body image, cognition, behavior and social support of married pregnant adolescents during the third trimester].
In an attempt to compare the body image, cognition, behavior and social support in the third trimester of pregnancy between the pregnant adolescent and pregnant adult in the Tainan area, seventy-five pregnant adolescents during the third trimester were enrolled and matched to seventy-five pregnant adults who were also selected for this study. The results were as follows: The two groups were similar in their body image, cognition, and behavior. The order of sources from which the pregnant adult got information about infant's requirements was books, the neighborhood, friends, their mother, sisters, mother-in-law, and nurses. That for the pregnant adolescents was books, their mother, mother-in-law, neighborhood, friends, sisters, and nurses. The order of the preference for food of the pregnant adult was rice, pizza, sour food, sweet food, noodles, cookies, cola, hamburgers, and chocolates. That for the pregnant adolescents was noodles, sour food, pizza, sweet food, rice, hamburgers, cola, chocolates, and cookies. Both groups suffered from insomnia. However, the sleeping status of the pregnant adolescents was significantly worse than that of the pregnant adults. In both case, economic support came from spouse's income, but it was more obvious that pregnant adolescents relied on their parents' economic support more often than did normal pregnant women, the difference was statistically significant. The pregnant adult had a much higher score on social support than did the pregnant adolescents with a significant difference. Adolescents with unexpected pregnancies have lower social support scores than their adult counterparts.
Adolescent↗
[Compare stress and social support between adolescent and adult pregnant women during third trimester].
With the change of society, adolescent pregnancy is the issue for the professionals to face and be concerned about. The results of the study can be utilized to improve the prenatal care for adolescents. A total of 90 adolescents and 90 adults during third trimester were recruited to participate in this study. Three methods were used to collect data: the Demographic Data Form, the Pregnancy Stress Rating Scale, and the Interpersonal Support Evaluation List. Primiparas showed a significantly higher score on stress from seeking safe passage for herself and her child through pregnancy, labor and delivering than multiparas. Adult pregnant women had a higher score on social support than did pregnant adolescents. Results of the stepwise multiple regression indicated that the best subset to predict stress from identifying maternal role was social support and education. The best subset to predict stress from seeking safe passage for herself and her child through pregnancy, labor and delivery was parity and education, the best predictor of stress from altering body structure and body function was education.
Adolescent↗
Myasthenia gravis complicated with hyperthyroidism, thymoma and serological evidence of systemic lupus erythematosus: a case report.
A 55-year-old woman with a several-decade history of thyroid goiter is presented here as a case of myasthenia gravis complicated with hyperthyroidism and thymoma with serological evidence of systemic lupus erythematous (SLE). She had had right eyelid ptosis since July 1992, with a positive tensilon test. The acetylcholine receptor antibody titer was 4.01 nmol/L. A thyroid function test revealed T3: 162 ngidl, T4: 14.98 micrograms/dl, TSH:0.09 microIU/ml and positive anti-microsomal antibody (1:400). An MRI of the chest showed a thymoma in the left thymus. Other autoantibody screenings include ANA (1:320, speckled pattern) and anti-ds DNA (+) suggesting a serological association with SLE. After three courses of plasmapheresis, she received an extended maximal thymomectomy and a subtotal thyroidectomy. She was then treated with prednisolone, Mestinon, Eltroxin and discharged without complications. The coexistence of myasthenia gravis, hyperthyroidism, thymoma and a serological evidence of SLE have not previously been documented in the literature.
Female↗
Propofol anesthesia in a patient with myasthenia gravis--a case report.
Experience with the use of propofol for induction and maintenance of anesthesia in patients with myasthenia gravis is limited in the literature. We report, in this case, the well prepared and successful use of continuous propofol infusion without conventional neuromuscular blocking agents in a patient with Ossermann stage IIb of myasthenia gravis undergoing laparoscopic cholecystectomy.
Anesthesia, Intravenous↗
Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B.
PU.1 (the Spi-1 oncogene) and Spi-B are closely related members of the ets transcription factor family, sharing similar DNA binding specificities mediated by similar DNA binding domains. PU.1 and Spi-B have been previously described as being predominantly expressed coordinately in macrophages and B cells, but their expression in early hematopoietic stages and during the course of myeloid differentiation to monocytes and macrophages or to neutrophils has not been extensively investigated. Here, we report that PU.1 mRNA is upregulated during myeloid differentiation of human purified CD34+ cells and murine multipotential FDCP-mix A4 cells, suggesting that PU.1 is upregulated as an early event during differentiation of multipotential progenitor cells. PU.1 expression is maintained at stable levels during differentiation of myeloid cell lines U937 and HL-60 to monocytic and neutrophilic cells. PU.1 is expressed at highest levels in mature human monocytes and human peripheral blood neutrophils. In contrast to PU.1, significant levels of Spi-B mRNA and protein are found only in some B-cell lines and spleen but are not found in myeloid cell lines, neutrophils, or macrophages. In vitro translated Spi-B protein can bind to PU.1 binding sites in myeloid promoters and transactivate these promoters in nonmyeloid cells. Therefore, although PU.1 and Spi-B may bind to similar DNA control elements and have redundancy of transactivation function in vitro, the lack of significant levels of Spi-B in myeloid cells makes it unlikely that Spi-B plays a significant role in myeloid lineage development and gene expression. In contrast, PU.1 is expressed at high levels not only in monocytes and macrophages but also in neutrophils, indicating that PU.1 can activate gene expression in both major myeloid lineages.
Animals↗
Identification of Sp1-binding sites in the CD11c (p150,95 alpha) and CD11a (LFA-1 alpha) integrin subunit promoters and their involvement in the tissue-specific expression of CD11c.
The leukocyte integrins LFA-1 (CD11a/CD18) and p150,95 (CD11c/CD18) mediate cell-cell and cell-extracellular matrix interactions during inflammatory responses and signal transduction into the cytoplasm. While the CD11a integrin subunit is expressed on all leukocytes, CD11c is almost exclusively expressed on cells of the myeloid lineage and on activated B lymphocytes. Its expression is regulated during cell activation and differentiation by transcriptional mechanisms. We have previously demonstrated that the proximal region of the CD11c promoter directs tissue-restricted and developmentally-regulated expression of reporter genes. Structural studies by electrophoretic mobility shift assays have demonstrated the presence of two Sp1-binding sites at -70 (Sp1-70) and -120 (Sp1-120) which mediate the Sp1 transactivation of the CD11c promoter in Sp1-defective SL2 cells, and which are involved in cell lineage-specific DNA-protein interactions, as demonstrated by footprinting in vivo. More importantly, mutation of either Sp1 site inhibited the activity of the CD11c promoter both in myeloid U937 cells and the CD11c-expressing B lymphoblastoid JY cell line, while the opposite effect was observed in the CD11c-negative epithelial HeLa cell line, demonstrating the involvement of both Sp1-binding sites in the basal and the tissue-restricted expression of the CD11c integrin subunit gene. Interestingly, the analysis of the CD11a proximal promoter also revealed the existence of an Sp1-binding site at -70, indicating a common role for these cis-acting elements in the transcription of the leukocyte integrin alpha subunit genes. The binding of Sp1 to the regulatory regions of the leukocyte integrin genes raises the possibility that the retinoblastoma susceptibility gene product is implicated in integrin expression through its functional interaction with Sp1, thus establishing a link between integrin-dependent leukocyte adhesiveness and the state of cellular differentiation/proliferation.
Base Sequence↗
Serum responsiveness of the rat PCNA promoter.
Expression of proliferating cell nuclear antigen (PCNA) gene is growth-regulated. The growth dependence of the rat PCNA gene promoter activity was investigated. Cultured cells were transfected with the promoter containing plasmid and recovered for 48 h in serum-free medium to become quiescent. Cells were then cultured in serum-containing medium and harvested at certain intervals after serum-stimulation, and the promoter-directed chloramphenicol acetyltransferase activities in cell extracts were measured. The promoter used in this study contained sequences between -693 and +125 in relation to the transcription initiation site. The promoter activity was found to be serum-responsive. However, the serum-responsiveness of the promoter became less obvious when the amount of the promoter increased; meanwhile, the promoter became active in the control unstimulated (or quiescent) cells. It was suspected that the dosage effect was due to the titration of the negative regulatory factor in quiescent cells. The titration experiment with a reporterless construct as competitor for regulatory factors showed that the excess of promoter molecules reduced the promoter activity in serum-stimulated cells, while causing a transiently increase of promoter activity in quiescent cells. Based on these results, it is postulated that the serum-responsiveness of the rat PCNA promoter is controlled by both negative and positive regulatory factors. Consistent with this proposition, promoter binding proteins of 105 and 114 kDa were identified only in serum-stimulated and quiescent cells, respectively, in addition to several other promoter binding proteins (ranging from 76 to 110 kDa) which were seen in both serum-stimulated and quiescent cells.
Animals↗
Growth suppression of human colorectal carcinoma in nude mice by monoclonal antibody C27-abrin A chain conjugate.
PURPOSE: The aim of this study was to assess an immunotoxin, monoclonal antibody C27-abrin A chain conjugate (MAAAC), that might be effective in the treatment of colorectal carcinoma. METHODS: The immunotoxin was prepared by a specific monoclonal antibody against carcinoembryonic antigen (CEA), monoclonal antibody C27, linked to N-succinimidyl-3-(2-pyridyldithio)propionate and then coupled covalently to the toxic abrin-A chain to synthesize MAAC. The therapeutic role of this immunotoxin in suppressing the in vitro and in vivo growth of CEA-secreting human colorectal cancer cells (LS174T) was assayed by methods of protein biosynthesis inhibition, cell colony proliferation, and treatment of tumor cells before and after inoculation in nude mice. RESULTS: We found that MAAC effectively suppressed the growth of LS174T in culture medium and completely eradicated cells in inoculated nude mice. In contrast, irrelevant immunotoxin antiferritin-abrin A chain conjugate and isotype-matched monoclonal immunoglobin (MOPC21IgG1)-abrin A chain conjugate did not cause such effects. The in vitro toxicity was highly specific because the conjugate (MAAC) inhibited de novo protein biosynthesis, impeded growth, and caused death of cells possessing surface CEA determinants. The 50 percent inhibition dose values of the conjugate for colonogenic survival and for protein biosynthesis in LS174T cells were 0.09 microgram/ml and 0.06 microgram/ml, respectively. Colon survival was inhibited 96.3 percent after prolonged MAAC treatment. MAAC showed selective cytotoxicity; the inhibitory effect of MAAC to the CEA-secreting LS174T cells over the CEA-nonsecreting human embryonic kidney cells was 16-fold. CONCLUSION: These results indicate that MAAC may be of benefit in therapy during or soon after resection of colorectal carcinoma or in patients who have micrometastasis.
Abrin↗
Localization of 102 exons to a 2.5 Mb region involved in Down syndrome.
Exon amplification has been applied to a 2.5 Mb region of chromosome 21 that has been associated with some features of Down syndrome (DS). Identification of the majority of genes from this region will facilitate the correlation of the over-expression of particular genes with specific phenotypes of DS. Over 100 gene fragments have been isolated from this 2.5 Mb segment. The exons have been characterized by sequence analysis, comparison with public databases and expansion to cDNA clones. Localization of the exons to chromosome 21 has been determined by hybridization to genomic Southern blots and to YAC and cosmid clones representing the region. This has resulted in a higher resolution physical map with a marker approximately every 25 kb. This integrated physical and transcript map will be valuable for fine mapping of DNA from individuals with partial aneuploidy of chromosome 21 as well as for assessing and ultimately generating a complete gene map of this segment of the genome.
Base Sequence↗
Identification and elimination by site-directed mutagenesis of thermolabile aspartyl bonds in Aspergillus awamori glucoamylase.
Both native Aspergillus niger glucoamylase and wild-type Aspergillus awamori glucoamylase expressed in Saccharomyces cerevisiae, which have identical primary structures, undergo hydrolysis at aspartyl bonds at low pH values and elevated temperatures. In native A.niger enzyme the Asp126-Gly127 bond was preferentially cleaved at pH 3.5, while at pH 4.5 cleavage of the Asp257-Pro258 and Asp293-Gly294 bonds was dominant. In wild-type A.awamori glucoamylase, cleavage of the latter was dominant at both pH 3.5 and 4.5. Site-directed mutations Asp126-->Glu and Gly127-->Ala in wild-type enzyme decreased specific activities by approximately 60 and 30%, respectively, and increased irreversible thermoinactivation rates 3- to 4-fold at pH 4.5. Replacement of Asp257 with Glu and Asp293 with Glu or Gln decreased specific activities by approximately 20%, but greatly reduced cleavage of the Asp257-Pro258 and Asp293-Gly294 bonds. The Asp257-->Glu mutant was produced very slowly and was more thermostable than wild-type glucoamylase at pH 4.5 up to 70 degrees C. Replacement of Asp293 with either Glu or Gln significantly raised protein production and slightly increased thermostability at pH 3.5 and 4.5, but not at pH 5.5.
Aspergillus↗
Validated fluorimetric HPLC analysis of acetaldehyde in hemoglobin fractions separated by cation exchange chromatography: three new peaks associated with acetaldehyde.
Stable hemoglobin-acetaldehyde adducts present in hemoglobin fractions separated by polyaspartic acid cation exchange chromatography were quantified by fluorimetric HPLC. The fluorescent species eluted from the HPLC was confirmed by mass spectrometry to be consistent with the expected product from reaction of acetaldehyde, 1,3-cyclohexanedione (CHD), and ammonium ion. Hemolysate (2.2 mM hemoglobin) was incubated in equivalent volumes of either phosphate-buffered saline or 5 mM acetaldehyde at 37 degrees C for 30 min and washed three times with H2O to remove free acetaldehyde and labile adducts before the injection of 14.7 mg hemoglobin onto the cation exchange column. Fluorimetric HPLC analysis of hemolysate samples either with or without in vitro reaction with acetaldehyde revealed that most acetaldehyde resides in the hemoglobin A0 fraction. The reaction with acetaldehyde in vitro resulted in a significant increase in fast-eluting minor hemoglobin species on cation exchange chromatography concomitant with increased acetaldehyde in the HbA1a+b, HbA1c, and HbA1-AcH fractions. We report three new cation exchange chromatographic peaks after reaction with acetaldehyde: HbA1-AcH-3, HbA1c-1, and HbA0-1. Each new peak was found to associate with a significant quantity of CHD-reactive acetaldehyde. These experiments provide additional evidence that stable adducts form between acetaldehyde and hemoglobin and that these adducts occur in multiple hemoglobin species separated by cation exchange chromatography. Further characterization and structural assignment of these species are warranted in view of their potential utility as markers for ethanol intake.
Acetaldehyde↗
Decreased activity of erythromycin against Streptococcus pyogenes in Taiwan.
A total of 78 clinical isolates of Streptococcus pyogenes were collected from January 1992 through December 1993 from patients in southern Taiwan. The in vitro activities of 10 antimicrobial agents were determined by the agar dilution method. Penicillin, cephalothin, cefotaxime, vancomycin, and ofloxacin were shown to be active against S. pyogenes isolates, with MICs at which 90% of isolates are inhibited (MIC90s) being < or = 0.03, < or = 0.13, < or = 0.13, < or = 0.13, and < or = 0.25 microgram/ml, respectively. Erythromycin and azithromycin both had poor activities (MIC50s, 16 and >128 micrograms/ml, respectively; MIC90s, >128 and >128 micrograms/ml, respectively). The activities of tetracycline, clindamycin, and chloramphenicol against a significant number of these isolates were also limited. As the MICs of clindamycin and chloramphenicol for the isolates increased, the MICs of the two macrolides also increased. Clindamycin, chloramphenicol, and the two macrolides were less potent against isolates recovered form throat swab samples than against those from blood or other sources. Isolates of the T12 and T1 serotypes accounted for 53.8% of all isolates. The majority (87.5%) of the isolates recovered from throat swab samples were of the T12 serotype, whereas 19.2% of the isolates recovered from blood were of the T12 serotype. In contrast, 66.7% of the isolates of the T1 serotype were derived from blood but none were derived from throat swab samples. Of the 33 T12 serotype isolates, erythromycin MICs for 78.8% of the isolates were >128 micrograms/ml. Because of the poor activities of erythromycin and azithromycin against S. pyogenes isolates from patients in southern Taiwan, these drugs should no longer be considered the drugs of choice for the management of group A streptococcal infections among patients who live in this area.
Anti-Bacterial Agents↗
Pi 1 binding sites are negative regulators of bcl-2 expression in pre-B cells.
The bcl-2 gene is differentially regulated during B-cell development, with low-level expression in pre-B cells and higher-level expression in mature B cells. These changes correlate with susceptibility to cell death by apoptosis and suggest that the Bcl-2 protein may play a role in the control of cell death during B-cell development. We have identified two negative regulatory regions in the human bcl-2 5' flanking and 5' untranslated regions in pre-B cells; these regions have no significant function in mature B cells. Further investigation of these regions revealed two pre-B-cell-specific enhancer elements (pi 1 sites) in the 5' negative regulatory region and one in the 3' negative regulatory region. Mutational analysis confirmed that these three sites functioned as negative regulators of the bcl-2 promoter in the pre-B-cell line Nalm-6. Electrophoretic mobility shift assays with each of the three sites demonstrated a complex of identical mobility to that formed with the immunoglobulin heavy-chain enhancer pi 1 site. UV cross-linking experiments revealed that a protein with a molecular mass of 58 kDa bound to the three bcl-2 sites and to the immunoglobulin enhancer site. This protein reacted with an antibody against Ets family proteins. Constructs with the isolated pi 1 sites linked to the simian virus 40 promoter were used in transient transfection experiments in the pre-B-cell line. The bcl-2 sites decreased expression of the simian virus 40 promoter, while the immunoglobulin enhancer site increased its expression. The pi 1 sites in the bcl-2 gene may play a role in the developmental regulation of bcl-2 expression during B-cell differentiation.
B-Lymphocytes↗
Collagen biosynthesis in human oral submucous fibrosis fibroblast cultures.
To investigate the mechanism of collagen accumulation in oral submucous fibrosis (OSF) tissues, we examined the biosynthesis of collagen in fibroblast cultures established from OSF lesions. Fibroblasts obtained from four of ten OSF specimens showed more than a 1.5-fold increase in the production of collagens compared with fibroblasts from age-, sex-, and passage-matched normal controls (p < 0.05). When the relative amounts of collagen synthesis were estimated by SDS polyacrylamide gel electrophoresis, it was found that both OSF and control cells produced about 85% type I collagen and 15% type III collagen. The ratio of alpha 1(I) to alpha 2(I) chains was about 3:1 in OSF cells instead of the 2:1 expected for type I collagen. The excess alpha 1(I) chains could mean that collagen type I trimer was synthesized by the fibroblasts. These findings suggest that collagen overproduction and a reduced degradation of the structure-stable collagen type I trimer synthesized by OSF fibroblasts might contribute to the accumulation of collagen in OSF lesions in vivo. The mechanism(s) of increased procollagen production were analyzed by Northern blot, slot blot, and Southern blot. The OSF fibroblast strains with elevated collagen production also contained higher-than-normal levels of procollagen mRNA, and the ratios of alpha 1(I), alpha 2(I), and alpha 1(III) procollagen mRNAs were compatible with the results of corresponding procollagen alpha chains. The gene copy number of pro alpha 2(I) collagen gene in OSF fibroblasts was about 1.05. No gene amplification was found. These results indicate that expression of these procollagen genes in cultured fibroblasts is regulated at the transcriptional level.
Case-Control Studies↗