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Biomedical subjects

Y Gu

Publications and source records attributed to Y Gu.

At least 19 recordsLinked to original sources
PubMed2026

Genomic basis of developmental defects of enamel and sex-specific effects.

We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3-5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5&#xd7;10 ), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25&#xd7;10 9), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2x10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.

developmental defects of enamel↗
PubMed1992

The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.

The ALL-1 gene located at human chromosome 11 band q23 is rearranged in acute leukemias with interstitial deletions or reciprocal translocations between this region and chromosomes 1, 4, 6, 9, 10, or 19. The gene spans approximately 100 kb of DNA and contains at least 21 exons. It encodes a protein of more than 3910 amino acids containing three regions with homology to sequences within the Drosophila trithorax gene, including cysteine-rich regions that can be folded into six zinc finger-like domains. The breakpoint cluster region within ALL-1 spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame. The t(4;11) chromosome translocation results in two reciprocal fusion products coding for chimeric proteins derived from ALL-1 and from a gene on chromosome 4. This suggests that each 11q23 abnormality gives rise to a specific oncogenic fusion protein.

Amino Acid Sequence↗
PubMed1992

The (4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase.

Chromosomal region 11q23 is frequently rearranged in acute lymphocytic leukemias (ALLs) and in acute myeloid leukemias (AMLs), mostly in reciprocal exchanges with various translocation partners. The most common of these translocations is t(4;11)(q21;q23). It is present in approximately 10% of ALL patients, most frequently in very young children. We have recently cloned a region of chromosome 11, the ALL-1 locus, found to be rearranged in malignant cells from patients with the t(4;11), t(9;11), t(11;19), t(1;11), t(6;11), t(10;11), and del(11q23) chromosomal abnormalities. Here we report the cloning and characterization of chromosomal breakpoints from leukemic cells with t(4;11) aberrations. The breakpoints cluster in regions of 7-8 kilobases on both chromosomes 4 and 11. The presence of heptamer- and nonamer-like sequences at the sites of breakage suggests that the VDJ recombinase utilized for immunoglobulin gene rearrangement is also directly involved in these translocations. We also show that leukemic cells with t(4;11) express altered RNAs transcribed from the derivative chromosomes 11 and 4.

Acute Disease↗
PubMed1992

Nerve growth factor promotes collateral sprouting of cholinergic fibers in the septohippocampal cholinergic system of aged rats with fimbria transection.

Nerve growth factor (NGF) was injected intraventricularly into aged (24 months) rats with unilateral fimbria transection. Controls received intraventricular injections of cytochrome c. A quantitative analysis of acetylcholinesterase (AChE)-positive fibers was used to evaluate whether the NGF treatment can stimulate regeneration and reinnervation of the cholinergic axons in the septohippocampal system of aged rats with fimbria transection. A marked increase in the density of AChE-positive fibers was observed in the lateral septum, the dorsal fornix and the dorsal hippocampus of the NGF-treated animals, as compared to the controls. In the lateral septum, the increase was observed in the 2-month NGF-treated animals but not in the 15-day NGF-treated animals. In the dorsal fornix at the level of the dorsal hippocampus, the increase was observed on both the lesioned and unlesioned sides of both the 15-day and 2-month NGF-treated animals. In the denervated (lesioned side) hippocampus, the increase took place in the dorsal hippocampus but not in the ventral hippocampus of both the 15-day and 2-month NGF-treated animals. There was no recovery of AChE-positive fibers on the lesioned side of the fimbria distal to the lesion site even in the 2-month NGF-treated animals. These results demonstrate that intraventricular injections of NGF can stimulate collateral sprouting of intact cholinergic axons in the septohippocampal system and promote cholinergic reinnervation of the denervated hippocampus of aged rats with fimbria transection.

Acetylcholinesterase↗
PubMed1992

An altered 11-kilobase transcript in leukemic cell lines with the t(4;11)(q21;q23) chromosome translocation.

The 11q23 chromosome band is frequently associated with chromosomal aberrations in human leukemias. We have previously cloned a DNA fragment derived from chromosome 11 which could be used as a probe to detect rearrangements in DNAs from the leukemic cells of patients with the t(4;11), t(9;11), and t(11;19) translocations. In this study we now show that the same probe detects DNA rearrangements in malignant cells from patients with the t(1;11), t(6;11), t(10;11), and del (11q23) chromosomal abnormalities. A second probe obtained from a region located centrometric to the breakpoint cluster detects major and minor transcripts of 12.5 and 11.5 kilobases, respectively, in all cell lines examined. The same probe identifies an altered 11-kilobase RNA in all three independent cell lines with the t(4;11)(q21;q23) chromosome translocation.

Chromosomes, Human, Pair 11↗
PubMed1992

Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A.

We have analyzed the cell cycle regulation of human cyclin-dependent kinase 2 (CDK2), a protein closely related to the cell cycle-regulatory protein kinase CDC2. We find that CDK2 activity, like that of CDC2, oscillates during the cell cycle in cultured mammalian fibroblasts. Unlike CDC2 activity (which peaks during mitosis), CDK2 activity rises in late G1 or early S phase and declines during mitosis. Active S-phase CDK2 migrates in multiple large complexes on gel filtration, and CDK2 in one of these complexes is associated with cyclin A. These findings suggest that CDK2 and CDC2, in association with distinct cyclins, regulate separate functions in the mammalian cell cycle.

Amino Acid Sequence↗
PubMed1992

Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15.

We have examined the role of phosphorylation in the regulation of human cyclin-dependent kinase-2 (CDK2), a protein closely related to the cell cycle regulatory kinase CDC2. We find that CDK2 from HeLa cells contains three major tryptic phosphopeptides. Analysis of site-directed mutant proteins, expressed by transient transfection of COS cells, demonstrates that the two major phosphorylation sites are Tyr15 (Y15) and Thr160 (T160). Additional phosphorylation probably occurs on Thr14 (T14). Replacement of T160 with alanine abolishes the kinase activity of CDK2, indicating that phosphorylation at this site (as in CDC2) is required for kinase activity. Mutation of Y15 and T14 stimulates kinase activity, demonstrating that phosphorylation at these sites (as in CDC2) is inhibitory. Similarly, CDK2 is activated in vitro by dephosphorylation of Y15 and T14 by the phosphatase CDC25. Analysis of HeLa cells synchronized at various cell cycle stages indicates that CDK2 phosphorylation on T160 increases during S phase and G2, when CDK2 is most active. Phosphorylation on the inhibitory sites T14 and Y15 is also maximal during S phase and G2. Thus, the activity of a subpopulation of CDK2 molecules is inhibited at a time in the cell cycle when overall CDK2 activity is increased.

Amino Acid Sequence↗
PubMed1992

Binding of 3H-gossypol in organelles of cultured bovine luteal cells.

Gossypol is an antifertility agent which inhibits steroidogenesis in both sexes. The present study investigated the binding of gossypol in organelles of cultured bovine luteal cell to elucidate its inhibitory site of action in steroid biosynthesis. Cultured bovine luteal cells were incubated with 3H-gossypol (4.3 or 2.15 microM) for 3 hours. At the end of treatment, cultured bovine luteal cells were harvested, homogenized and centrifuged for organelle preparation. The radioactivity of gossypol was measured in each subcellular fraction. The cell membrane fraction has the highest binding capacity for gossypol, and the majority of gossypol was located in the particulate fractions. Results of the present study provide information in understanding the regulatory mechanism of gossypol on antisteroidogenic and/or toxic effects in cultured bovine luteal cells.

Animals↗
PubMed1992

Electron microscopical demonstration of horseradish peroxidase by use of tetramethylbenzidine as chromogen and sodium tungstate as stabilizer (TMB-ST method): a tracing method with high sensitivity and well preserved ultrastructural tissue.

Until now methods using tetramethylbenzidine (TMB) for electron microscopy (TMB-EM methods) are all unable to provide a maximum demonstration of transported horseradish peroxidase (HRP) while maintaining good ultrastructural tissue preservation. In order to solve this problem, we have attempted to adapt a newly developed, highly sensitive TMB method using sodium tungstate (ST) as the stabilizer (TMB-ST method) for HRP electron microscopic retrograde and anterograde fiber tracing. The present study shows that the TMB-ST method combined with diaminobenzidine-cobalt (DAB-Co) is more sensitive than existing TMB-EM methods and that ultrastructural details are well preserved with this combined method. The resultant reaction product complex after osmication is stable and is observed as characteristic crystal-like structures which are extremely electron dense and often aggregated into clumps. In contrast, the TMB-ST method without the DAB-Co step frequently produces a moderate electron-dense reaction product. Therefore, we recommend the TMB-ST method combined with DAB-Co for HRP electron microscopy.

3,3'-Diaminobenzidine↗
PubMed1992

BiP forms stable complexes with unassembled subunits of the acetylcholine receptor in transfected COS cells and in C2 muscle cells.

We have investigated the role of the immunoglobulin-binding protein (BiP) in the folding and assembly of subunits of the acetylcholine receptor (AChR) in COS cells and in C2 muscle cells. Immunoprecipitation in COS cells showed that alpha, beta, and delta subunits are associated with BiP. In the case of the alpha subunit, which first folds to acquire toxin-binding activity and is then assembled with the other subunits to form the AChR, BiP was associated only with a form that is unassembled and does not bind alpha-bungarotoxin. Similar results were found in C2 cells. Although the alpha and beta subunits of the AChR are minor membrane proteins in C2 cells, they were prominent among the proteins immunoprecipitated by antibodies to BiP, suggesting that BiP could play a role in their maturation or folding. In pulse-chase experiments in C2 cells, however, labeled alpha subunit formed a stable complex with BiP that was first detected after most of the alpha subunit had acquired toxin-binding activity and whose amount continued to increase for several hours. These kinetics are not compatible with a role for the BiP complex in the folding or assembly pathway of the AChR, and suggest that BiP is associated with a misfolded form of the subunit that is slowly degraded.

Adenosine Triphosphate↗
PubMed1992

Activation of human cyclin-dependent kinases in vitro.

We have analyzed the activation of human cyclin-dependent kinases in a cell-free system. Human CDC2, cyclin-dependent kinase 2 (CDK2), cyclin A, and cyclin B1 were produced in insect cells by infection with recombinant baculoviruses. CDC2 or CDK2 monomers in lysates of infected cells could be activated by the addition of lysates containing cyclin A or B1. CDC2 activation by cyclin B1, as well as CDK2 activation by cyclins A and B1, was accompanied by the formation of high molecular weight complexes. In contrast, CDC2 did not bind effectively to cyclin A. CDC2 activation by cyclin B1 was studied in detail and was found to be accompanied by phosphorylation of CDC2 on Threonine 161. The binding of CDC2 to cyclin B1 also occurred under conditions where CDC2 phosphorylation was prevented, resulting in an inactive complex that could then be phosphorylated and activated on addition of cell extract. Highly purified CDC2 and cyclin B1 also formed inactive complexes that could be activated in an ATP-dependent fashion by unidentified components in crude cell extracts. These data suggest that the CDC2 activation process begins with cyclin binding, after which CDC2 phosphorylation, catalyzed by a separate enzyme, leads to activation.

Amino Acid Sequence↗
PubMed1992

Localization of a novel integrin of the beta 1 subfamily in human tissues.

We have previously described a novel integrin composed of a beta 1-chain non-covalently linked to an alpha-chain which is biochemically different from those known so far (i.e., alpha 1-alpha 7 and alpha v). This molecule has been identified with a monoclonal antibody (MAb) termed 10.1.2 raised against long-term cultured human thymic epithelial cells (TEC). In this study we analyzed the immunohistochemical distribution of this new integrin in a variety of human tissues. MAb 10.1.2 stains several types of endothelial and epithelial cells. Among the endothelia, a strong reaction was detected in the HEV of lymphoid organs including thymus, lymph node, tonsil, and mucosa-associated lymphoid tissue. Epithelial localizations of note were those in the basal layer of the epidermis and of other stratified squamous epithelia, where the lateral and apical but not the deep surfaces of most cells were stained. A variety of water-electrolyte transporting cells in sweat glands, salivary glands, and kidney were also stained at their deep surface. The latter findings suggest that this molecule may subserve other functions in addition to those related to cell adhesion.

Adult↗
PubMed1992

Alpha 2-macroglobulin expression in the mesometrial decidua and its regulation by decidual luteotropin and prolactin.

During decidualization, cells of the endometrium grow and differentiate giving rise to two different decidual tissues located in either the antimesometrial or mesometrial site of the uterus in the rat. These tissues have different functions in pregnancy. The antimesometrial decidua is an endocrine gland that secretes hormones, whereas the mesometrial decidua appears to play an important role in limiting trophoblast invasion. Since the decidual tissue of the rat produces alpha 2-macroglobulin (alpha 2MG), we examined whether this potent protease inhibitor is specifically expressed by the mesometrial tissue, the site of trophoblast invasion, and whether the alph 2MG gene is regulated by decidual luteotropin (DLt), the PRL-like hormone secreted by the neighboring antimesometrial cells. To determine the secretory proteins of the rat decidua, antimesometrial and mesometrial tissues were dissected out from pseudopregnant rats and cultured with [35S]methionine. The major protein secreted by the antimesometrial cell was the 29-kilodalton decidual luteotropin, whereas a 180-kilodalton protein was predominantly secreted by the mesometrial tissue. Immunoprecipitation studies of 35S-radiolabeled proteins revealed that this high mol wt protein is alpha 2MG and that it is secreted exclusively by the cells forming the mesometrial tissue. To examine whether the alpha 2MG gene was also expressed specifically in the mesometrial decidua, total RNA was isolated from both mesometrial and antimesometrial tissues of day 9-12 pseudopregnant rats and hybridized with alpha 2MG cDNA. Northern blot analysis revealed a 5.4-kilobase message, which was abundantly expressed in the mesometrial decidua. Little, if any, alpha 2MG mRNA was detected in antimesometrial decidua. The ontogeny of the message in the decidua correlated well with the development of the mesometrial tissue. To examine whether alpha 2MG expression is regulated by DLt and/or PRL, a highly specific polyclonal antibody to DLt was generated and decidual tissues were cultured in the presence or absence of DLt antibodies with or without PRL. Neutralization of DLt caused a marked decrease in alpha 2MG mRNA levels. This down-regulation was totally reversed by the addition of PRL and was not affected by alpha 2MG antibodies. In summary, the results of this investigation revealed a compartmentalized gene expression, synthesis and secretion of alpha 2MG in the decidua. The secretion of this protease inhibitor, specifically by the mesometrial tissue which is the site of trophoblast invasion, may be the reason for the minimal amount of tissue damage that occurs during placentation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Genotype and treatment biases in estimation of carcass lean of swine.

Carcasses of 181 barrows, representing five genotypes, 1) H x HD, 2) SYN, 3) HD x L[YD], 4) L x YD, and 5) Y x L (H = Hampshire, D = Duroc, SYN = synthetic terminal sire line, L = Landrace, and Y = Yorkshire), and two levels of ractopamine (RAC) treatment (0 and 20 ppm) were completely dissected and the data were used to examine genotype and treatment (RAC) biases in estimation of fat-standardized lean weight and to evaluate accuracies and precisions realized by use of equations based on variables derived from different technologies. Independent variables used to establish regression equations represented technologies of direct carcass measurements, optical probe data, TOBEC (total body electrical conductivity) readings, and dissected (DHMLN) and fat-standardized (FSHMLN) ham lean. Genotype bias existed when any equation from a single technology was used and was minimized by combining FSHMLN with one TOBEC reading, carcass length, and the probe measurement of 10th rib fat depth. Large RAC biases appeared when equations from direct carcass measurements or optical probe data were used and were minimized by an equation using either DHMLN or FSHMLN. A practical equation with relatively high R2 value and small genotype and RAC biases were developed by combining TOBEC readings with direct carcass measurements of 10th rib fat depth and warm carcass weight.

Adipose Tissue↗
PubMed1992

Growth, development, and carcass composition in five genotypes of swine.

An experiment with 127 barrows representing five genotypes, 1) H x HD, 2) SYN, 3) HD x L[YD], 4) L x YD, and 5) Y x L (H = Hampshire, D = Duroc, SYN = synthetic terminal sire line, L = Landrace, and Y = Yorkshire), was conducted to evaluate growth and development of swine from 59 to 127 kg live weight. Animals were allowed ad libitum access to a pelleted finishing diet containing 18.5% CP, .95% lysine, and 10.5% fat, with an energy density of 3,594 kcal of ME/kg. Pigs were serially slaughtered at either 59, 100, 114, or 127 kg live BW. After slaughter, carcasses were chilled and backfat was measured at four locations. The right side of each carcass was fabricated into primal cuts of ham, loin, Boston Butt, picnic, and belly. Composition of each primal cut was determined by physical dissection into lean, fat, bone, and skin. Estimated allometric growth coefficients for carcass length, carcass weight, and longissimus muscle area relative to BW; carcass lean, fat, bone, and skin relative to both BW and carcass weight; and lean in each of the primal cuts relative to total carcass lean did not differ (P greater than .05) among genotypes. Relative to BW, the pooled growth coefficient(s) for carcass weight was (were) greater (P less than .001) than unity, whereas those for carcass length, longissimus muscle area, and backfat at first rib were smaller (P less than .001) than unity. Those for other backfat measurements were close to 1.00. Relative to either BW or carcass weight, the pooled coefficient(s) for fat was (were) greater (P less than .001) than unity, whereas those for lean, bone, and skin were smaller (P less than .001) than unity. Growth of lean, backfat, bone, and skin in the carcass were nearly linearly associated with increases in BW. The increase in fat weight was curvilinear as the pig grew and was accelerated in later growth stages, indicating that carcass fat percentage increased with increased BW.

Adipose Tissue↗
PubMed1992

Isolation of adult pig islet. In vitro assessment and xenotransplantation.

This study was conducted to develop an isolation method for adult pig islets and to investigate in vivo function after xenotransplantation as well as in vitro function of isolated islets. From the splenic portion of the glands (n = 20), 3277 +/- 645 islets per gram of pancreas were isolated and recovered by a five-step dextran discontinuous density gradient method. Purity of the final preparation obtained from 20 different consecutive pig pancreata was 80-90%. In vitro incubation study revealed a significant insulin release from isolated adult pig islets in response to glucose stimulation. In vitro perifusion study demonstrated a biphasic insulin response to glucose stimulation from isolated islets. Xenotransplantation of approx 2000 isolated adult pig islets into the portal vein of diabetic Wistar rats (n = 8) significantly reduced serum glucose levels from 431 +/- 24 mg/dL to 173 +/- 18 mg/dL 24 h after transplantation. This study provides a development of an isolation method for adult pig islets and demonstrates that isolated islets are viable and functioning both in vitro study and in vivo study of xenotransplantation.

Animals↗