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  • 1
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Cell and Developmental Biology Vol. 9 ( 2021-10-15)
    In: Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2021-10-15)
    Abstract: During oocyte maturation and the oocyte-to-embryo transition, key developmental regulators such as RNA-binding proteins coordinate translation of particular messenger RNA (mRNAs) and related developmental processes by binding to their cognate maternal mRNAs. In the nematode Caenorhabditis elegans , these processes are regulated by a set of CCCH zinc finger proteins. Oocyte maturation defective-1 (OMA-1) and OMA-2 are two functionally redundant CCCH zinc finger proteins that turnover rapidly during the first embryonic cell division. These turnovers are required for proper transition from oogenesis to embryogenesis. A gain-of-function mutant of OMA-1, oma-1(zu405) , stabilizes and delays degradation of OMA-1, resulting in delayed turnover and mis-segregation of other cell fate determinants, which eventually causes embryonic lethality. We performed a large-scale forward genetic screen to identify suppressors of the oma-1(zu405) mutant. We show here that multiple alleles affecting functions of various anaphase promoting complex/cyclosome (APC/C) subunits, including MAT-1, MAT-2, MAT-3, EMB-30, and FZY-1, suppress the gain-of-function mutant of OMA-1. Transcriptome analysis suggested that overall transcription in early embryos occurred after introducing mutations in APC/C genes into the oma-1(zu405) mutant. Mutations in APC/C genes prevent OMA-1 enrichment in P granules and correct delayed degradation of downstream cell fate determinants including pharynx and intestine in excess-1 (PIE-1), posterior segregation-1 (POS-1), muscle excess-3 (MEX-3), and maternal effect germ-cell defective-1 (MEG-1). We demonstrated that only the activator FZY-1, but not FZR-1, is incorporated in the APC/C complex to regulate the oocyte-to-embryo transition. Our findings suggested a genetic relationship linking the APC/C complex and OMA-1, and support a model in which the APC/C complex promotes P granule accumulation and modifies RNA binding of OMA-1 to regulate the oocyte-to-embryo transition process.
    Type of Medium: Online Resource
    ISSN: 2296-634X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2737824-X
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  • 2
    In: Journal of Animal Science and Biotechnology, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-12)
    Abstract: B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that represses more than 1200 potential target genes. Our previous study showed that a decline in blood production in runting and stunting syndrome (RSS) affected sex-linked dwarf (SLD) chickens compared to SLD chickens. However, the association between BCL6 gene and hematopoietic function remains unknown in chickens. Methods In this study, we used RSS affected SLD (RSS-SLD) chickens, SLD chickens and normal chickens as research object and overexpression of BCL6 in hematopoietic stem cells (HSCs), to investigate the effect of the BCL6 on differentiation and development of HSCs. Results The results showed that comparison of RSS-SLD chickens with SLD chickens, the BCL6 was highly expressed in RSS-SLD chickens bone marrow. The bone marrow of RSS-SLD chickens was exhausted and red bone marrow was largely replaced by yellow bone marrow, bone density was reduced, and the levels of immature erythrocytes in peripheral blood were increased. At the same time, the hematopoietic function of HSCs decreased in RSS-SLD chickens, which was manifested by a decrease in the hematopoietic growth factors (HGFs) EPO, SCF, TPO, and IL-3, as well as hemoglobin α 1 and hemoglobin β expression. Moreover, mitochondrial function in the HSCs of RSS-SLD chickens was damaged, including an increase in ROS production, decrease in ATP concentration, and decrease in mitochondrial membrane potential (ΔΨm). The same results were also observed in SLD chickens compared with normal chickens; however, the symptoms were more serious in RSS-SLD chickens. Additionally, after overexpression of the BCL6 in primary HSCs, the secretion of HGFs (EPO, SCF, TPO and IL-3) was inhibited and the expression of hemoglobin α 1 and hemoglobin β was decreased. However, cell proliferation was accelerated, apoptosis was inhibited, and the HSCs entered a cancerous state. The function of mitochondria was also abnormal, ROS production was decreased, and ATP concentration and ΔΨm were increased, which was related to the inhibition of apoptosis of stem cells. Conclusions Taken together, we conclude that the high expression of BCL6 inhibits the differentiation and development of HSCs by affecting mitochondrial function, resulting in impaired growth and development of chickens. Moreover, the abnormal expression of BCL6 might be a cause of the clinical manifestations of chicken comb, pale skin, stunted growth and development, and the tendency to appear RSS in SLD chickens.
    Type of Medium: Online Resource
    ISSN: 2049-1891
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2630162-3
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  • 3
    In: Ethnicity & Disease, Ethnicity and Disease Inc, Vol. 31, No. 1 ( 2021-01-21), p. 77-88
    Abstract: Objective: Asthma is the most common chronic disease in children. Short-acting bronchodilator medications are the most commonly prescribed asthma treatment worldwide, regardless of disease severity. Puerto Rican children display the high­est asthma morbidity and mortality of any US population. Alarmingly, Puerto Rican children with asthma display poor broncho­dilator drug response (BDR). Reduced BDR may explain, in part, the increased asthma morbidity and mortality observed in Puerto Rican children with asthma. Gene-environ­ment interactions may explain a portion of the heritability of BDR. We aimed to identify gene-environment interactions as­sociated with BDR in Puerto Rican children with asthma.Setting: Genetic, environmental, and psycho-social data from the Genes-environ­ments and Admixture in Latino Americans (GALA II) case-control study.Participants: Our discovery dataset con­sisted of 658 Puerto Rican children with asthma; our replication dataset consisted of 514 Mexican American children with asthma.Main Outcomes Measures: We assessed the association of pairwise interaction mod­els with BDR using ViSEN (Visualization of Statistical Epistasis Networks).Results: We identified a non-linear interac­tion between Native American genetic ancestry and air pollution significantly as­sociated with BDR in Puerto Rican children with asthma. This interaction was robust to adjustment for age and sex but was not significantly associated with BDR in our replication population.Conclusions: Decreased Native American ancestry coupled with increased air pollu­tion exposure was associated with increased BDR in Puerto Rican children with asthma. Our study acknowledges BDR’s phenotypic complexity, and emphasizes the importance of integrating social, environmental, and bi­ological data to further our understanding of complex disease.Ethn Dis. 2021;31(1):77- 88; doi:10.18865/ed.31.1.77
    Type of Medium: Online Resource
    ISSN: 1945-0826 , 1049-510X
    Language: Unknown
    Publisher: Ethnicity and Disease Inc
    Publication Date: 2021
    detail.hit.zdb_id: 2193738-2
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  • 4
    In: Chemical Science, Royal Society of Chemistry (RSC), Vol. 11, No. 28 ( 2020), p. 7292-7301
    Type of Medium: Online Resource
    ISSN: 2041-6520 , 2041-6539
    Language: English
    Publisher: Royal Society of Chemistry (RSC)
    Publication Date: 2020
    detail.hit.zdb_id: 2559110-1
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  • 5
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 12 ( 2016-12-01), p. 1609-1618
    Abstract: Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P & lt; 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry–European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10−7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 6
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2014
    In:  Environmental Science and Pollution Research Vol. 21, No. 13 ( 2014-7), p. 8025-8035
    In: Environmental Science and Pollution Research, Springer Science and Business Media LLC, Vol. 21, No. 13 ( 2014-7), p. 8025-8035
    Type of Medium: Online Resource
    ISSN: 0944-1344 , 1614-7499
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2014192-0
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  • 7
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-07-07)
    Abstract: Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P  〈  0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes ( KCNK2 , C5orf56 , SCAMP2 , and SIN3A ) and the other index SNPs are located close to GSTM4 , AMPD2 , CASTOR2 , and RP11-168G16.2 . Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 8
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4397-4397
    Abstract: Background: Multiple myeloma (MM) treatment has advanced considerably with proteasome inhibitors, immunomodulatory drugs (IMiDs), and, most recently, monoclonal antibodies. However, treatment response is quite heterogeneous, and many patients still progress even with novel combination therapies. Thus, understanding the factors that underlie response to treatment is a priority. Several somatic genomic aberrations and mutations predict poor response to therapy. However, germline variation has not previously been investigated as a predictor of treatment response in MM. We used genome-wide association and transcriptome-wide association approaches to identify germline genetic predictors of treatment response in MM. Methods: We included 510 MM patients from Mayo Clinic and 324 MM patients from UCSF diagnosed from 1999-2015. Basic demographics, laboratory values and pathology at diagnosis, type of initial therapy, duration of therapy, and follow-up were ascertained by chart review. Patients were grouped into categories of treatment based on their first line therapy: proteasome inhibitor-based regimen, IMiD based regimen, combination proteasome and IMiD based regimen, or other. Response was assessed using International Myeloma Working Group (IMWG) response criteria after 4-6 cycles of induction. As such, response was categorized into progressive disease (PD), minimal response (MR), partial response (PR), very good partial response (VGPR), or complete response (CR). Germline samples were genotyped using Illumina or Affymetrix arrays and were imputed based on the Haplotype Reference Consortium (HRC). For the genome-wide association study (GWAS), we included all SNPs with minor allele frequency 〉 0.01 and imputation r2 of 〉 0.5. We tested each SNP for association with treatment response using a linear regression model that adjusted for age, gender, and genetic ancestry (from principal components analysis (PCA)). To perform the transcriptome-wide association study (TWAS), we calculated predicted gene expression data using PREDIXCAN software on a reference cohort of 922 individuals with genotype and RNA expression data from peripheral blood. We then tested the association between predicted gene expression and response to therapy using linear regression models. Both the GWAS and TWAS were performed on subgroups of patients who received either proteasome inhibitors or IMiD therapies. The analyses of patients on proteasome inhibitors were adjusted for IMiD use as a covariate and analyses of patients on IMiDs were adjusted for proteasome inhibitor use. The threshold for genome-wide significance loci was set at P = 5 x 10-8 and the threshold for suggestive loci was set at P = 10-6. The threshold for significance for TWAS was set at P = 4 x 10-6 by using a Bonferroni correction for the number of genes for which genetic models of expression could be developed by PREDIXCAN. Results: Overall, 42.7% (59 of 138) of patients on proteasome inhibitors alone, 32.5% (66 of 203) of patients on IMiDs alone, and 58.1% (50 of 86) of patients on combination achieved at least a VGPR. There were no significant differences in response across centers in analyses that adjusted for age, sex and types of therapy. There were no genome wide significant loci to predict for response. We identified 8 suggestive SNPs associated with proteasome inhibitor response and 4 suggestive SNPs associated with IMiD response. TWAS identified ZNF622 as a candidate genetic modifier of proteasome inhibitor effect that was significant after correction for multiple hypothesis testing (P = 1.6 x 10-6). Higher genetically predicted expression was associated with improved response to proteasome inhibitor therapy. Among patients above the median of predicted expression of ZNF622 on proteasome inhibitors, 62.6% achieved at least VGPR; among patients at or below the median of expression, only 37.6% achieved at least VGPR. Conclusions: We identified an association between predicted expression of ZNF622 and clinical response to proteasome inhibitor therapy among MM patients. ZNF622 is a zinc finger binding protein which is known to be co-activator of B Myb activity and to affect apoptosis in response to oxidative stress. Our work highlights the potential importance of pharmacogenetic modifiers of treatment response in MM. Disclosures Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wong:Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 192, No. 5 ( 2015-09-01), p. 634-637
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    RVK:
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2015
    detail.hit.zdb_id: 1468352-0
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  • 10
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 192, No. 1 ( 2015-07-01), p. 47-56
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    RVK:
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2015
    detail.hit.zdb_id: 1468352-0
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