The complete genome sequence of Corynebacterium pseudotuberculosis FRC41 isolated from a 12-year-old girl with necrotizing lymphadenitis reveals insights into gene-regulatory networks contributing to virulence

Trost E, Ott L, Schneider J, et al. The complete genome sequence of Corynebacterium pseudotuberculosis FRC41 isolated from a 12-year-old girl with necrotizing lymphadenitis reveals insights into gene-regulatory networks contributing to virulence. BMC Genomics. 2010;11(1): 728

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication

The extent to which transcriptional and posttranscriptional regulation contributes to the coupling of histone gene expression and DNA replication was examined during the cell cycle in synchronized HeLa S3 cells. Rates of transcription were determined in vitro in isolated nuclei. A 3-5-fold increase in cell cycle dependent histone gene transcription was observed in early S phase, prior to the peak of DNA synthesis. This result is consistent with a previous determination of histone mRNA synthesis in intact cells [Plumb, M., Stein, J., and Stein, G. (1983) Nucleic Acids Res. 11, 2391]. The transcription of these genes did not change appreciably after inhibition of DNA replication by hydroxyurea treatment, although Northern blot analysis indicated that cellular levels of histone mRNA decreased rapidly in the presence of the drug. Total cellular levels of histone mRNA closely parallel the rate of DNA synthesis as a function of cell cycle progression, reaching a maximal 20-fold increase as compared with non S phase levels. This DNA synthesis dependent accumulation of histone mRNA occurs predominantly in the cytoplasm and appears to be mediated primarily by control of histone mRNA stability. Changes in nuclear histone mRNA levels were less pronounced. These combined observations suggest that both transcriptional regulation and posttranscriptional regulation contribute toward control of the cell cycle dependent accumulation of histone mRNA during S phase, while the stability of histone mRNA throughout S phase and the selective turnover of histone mRNAs, either at the natural termination of S phase or following inhibition of DNA synthesis, are posttranscriptionally regulated.(ABSTRACT TRUNCATED AT 250 WORDS

Histone proteins in HeLa S3 cells are synthesized in a cell cycle stage specific manner

The synthesis of histone proteins in G1 and S phase HeLa S3 cells was examined by two-dimensional electrophoretic fractionation of nuclear and total cellular proteins. Newly synthesized histones were detected only in S phase cells. Histone messenger RNA sequences, as detected by hybridization with cloned human histone genes, were present in the cytoplasm of S phase but not G1 cells

Abstract 5602: Identification of ethnic specific differences in breast cancer and normal breast tissue

Abstract Disparities in breast cancer stage of presentation and survival rates exist in patients of different ethnicities. These differences are undoubtedly a result of a combination of factors, including socio-economic, lifestyle, tumor characteristics and inherent factors, such as genetic composition. Our group is analyzing the genetic contributions to these disparities, with the goal to increase understanding of the underlying biology, leading ultimately to individualized, ethnic-specific diagnostic and therapeutic approaches. Here we report our results of a recently completed study focusing on gene expression profiling in a multi-ethnic cohort of triple negative breast cancer patients. We analyzed breast cancer and self-matched normal tissue samples from 10 African-American (AA), 10 Hispanic (His), and 10 non-Hispanic white (Caucasian) patients from south Florida. Study samples were cut from FFPE (Formalin Fixed Paraffin-embedded tissue) blocks marked by pathology as normal vs. tumor tissue, and sent to Almac Diagnostics for RNA isolation, cDNA preparation, and hybridization of tumor/normal cDNAs to a breast cancer focused gene expression array (Breast Cancer DSA Research Tool). From the Breast Cancer DSA arrays data, a two-way ANOVA (disease state and ethnicity) was used to identify transcripts with a p-value less than 0.01. Data QC indicated that samples clustered well with respect to ethnicity and adjacent normal vs. tumor tissue. We have identified ethnic-specific expression patterns in the matched normal and tumor samples. Initial pathway analysis using MetaCore Program shows that a number of genes related to the DNA repair pathway are differentially expressed across the ethnicities. In a set of ten DNA repair/cell cycle genes, the direction of change (increased or decreased expression) was the same for all three ethnic groups, however, the level of change differed greatly between ethnic groups. Fold change in this set of ten genes ranged from -6.54 to +5.53 with all being greater than 2 fold change in at least one ethnic group. Additional pathway analysis and validation of these results is ongoing. In follow up to this study, we have initiated parallel analysis in normal tissue samples (reduction mammoplasty) samples from AA and Cau non-cancer patients. Combined analysis of tumor and normal expression data will help to better understand the possible significance of gene expression differences in breast tissue between ethnic groups. These studies have important implications for addressing BC health disparities, as well as tailored approaches to prediction, prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5602. doi:10.1158/1538-7445.AM2011-560

Abstract 2368: Differential gene expression in key oncolytic pathways between node-matched Caucasian-American, African-American and East African triple-negative breast cancer patients

Abstract African-American (AA) women have a 20% greater mortality rate from breast cancer (BC) than that observed in Caucasian-American women (CA). Additional BC disparities in AA women include later stage presentation with higher tumor grade, and increased occurrence of Triple-negative breast cancer (TNBC). In this study, we performed a series of gene expression array analyses on archived formalin fixed paraffin embedded (FFPE) blocks from a multi-ethnic U.S. cohort of node-negative (N0) TNBC samples, in addition to a cohort of (N0) TNBC samples from East African patients (Kijabe,Kenya). Using 10 μm scrolls from each FFPE block, total RNA was isolated, cDNA prepared, and hybridized to a breast-enriched gene expression array (Affymetrix, BC DSA Research Tool®). Expression analysis was conducted using GeneSpring 12.1® analytical software. After QC analyses, the final study cohort consisted of 10-AA, 13-CA and 21-Kenyan samples. PCA analysis revealed that the samples clustered well with respect to ethnicity. Unsupervised cluster analysis, based on ethnicity and genes (p value 2.5), was performed. The resulting dendogram clearly segregated into distinct subgroups based on ethnicity, revealing a pattern of differential gene expression between the cohorts. A list of differentially expressed genes from each cohort (DEG) were selected using ANOVA analysis (fold change > 3.0, p value <.05) followed by the Benjamin/Hochberg method for multiple-testing correction. Finally, the lists of DEG were uploaded into GeneGo MetaCore to identify functionally enriched pathways. These analyses revealed differentially expressed genes pathways enriched for cytoskeletal remodeling, cell adhesion and EMT pathways. In particular, significantly deregulated genes associated with the Wnt/β-catenin pathway were observed in the AA cohort as compared to the CA, suggesting that this pathway may contribute to the more aggressive phenotype in AA women diagnosed with TNBC. Additionally, significantly deregulated genes associated with the Oncostatin M pathway were discovered in the Kenyan cohort, as compared to the AA and CA tumors. In particular, STAT1 was significantly downregulated in the Kenyan cohort compared to the CA and AA. Thus, our results indicate gene expression differences within several key oncolytic pathways across these ethnic groups. These results are being technically and biologically validated through several parallel approaches. Validation study results will be presented. In summary, this study represents the first direct comparison of gene expression in TNBC specimens across U.S. CA and AA BC patients and Kenyan East Africans. These studies have important implications for further understanding BC ethnic disparities, as well as future tailored approaches to prediction, prevention and therapeutic advances. Citation Format: Julie Getz, Mary E. Ahearn, Carmen Gomez, Mark Pegram, Peter Bird, John Carpten, Lisa L. Baumbach-Reardon. Differential gene expression in key oncolytic pathways between node-matched Caucasian-American, African-American and East African triple-negative breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2368. doi:10.1158/1538-7445.AM2014-236

Abstract 4023: Comparison of transcriptional signatures in US African American and Kenyan TNBC samples identifies differential expression in key oncogenic pathways

Abstract Strong epidemiological data supports breast cancer (BC) as the second leading cause of cancer death among US African American (AA) women, with a 20% greater mortality rate than that in Caucasians (Cauc). Collection of similar BC incidence and mortality data for Eastern Africa is limited, however, it is known that BC presents as advanced-stage disease, comprised mainly of poorly differentiated cancers that are less likely to be hormone responsive. Our combined investigative team continues to analyze a cohort of indigenous Kenyan BC patients, in order to begin to understand biological similarities and differences between BC in native African and AA patients. Previous related gene expression studies conducted in a Triple Negative Breast Cancer (TNBC) stage-matched multi-ethnic US cohort suggested differential expression patterns across ethnicities. We are extending this focus to similar studies involving native African samples. Archived BC pathology samples (FFPE) were either obtained from University of Miami or from a native African tumor bank (Kenya). Forty-seven BC samples were contributed from Kenya, and re-analyzed (in Miami) for ER/PR/ Her2Neu status, resulting in confirmation of 29 Kenyan TNBC cases. 10 um sections were cut from each tumor FFPE block, and following RNA isolation and cDNA preparation, hybridized to the Almac breast-enriched gene expression array (Breast Cancer DSA Research Tool). After quality control assessment of array data, a total of 60,856 gene/probes were analyzed by RMA; normalized, log transformed to the median, and compared on GeneSpring® analytical software. Data sets were separated by further analysis based on node status [(N0-Kenyan-7, AA-10); (Mixed Node-Kenyan-16, AA-7)]. Unpaired student's T-test was performed on all subsets and the resulting p-values were corrected for Multiple Testing using Benjamin-Hochberg. Differentially expressed genes/probes were extracted for each subset using p-value 1.5. These probe/gene lists were further analyzed using GeneGo pathway analysis and enriched pathways were identified. Comparisons of transcriptional differences between Kenyan and AA TNBC, regardless of node status, suggest expression alterations in several key pathways, including EMT Transition, Cytoskeleton Remodeling, Immune Response and Epigenetic Control. These preliminary results are being validated by QPCR and other methodologies. In conclusion, we have demonstrated that high quality RNA can be extracted from archived FFPE tumor samples, including samples from East Africa. This observation raises the possibility of future genomic analyses using archived samples. We are intrigued by our study observations, which suggest that inherent gene expression differences exist between Kenyan and AA TNBC samples in previously-recognized pathways important in onocogenesis. Citation Format: Lisa L. Baumbach-Reardon, Julie Getz, Mary Ellen Ahearn, Carmen Gomez, Peter Bird, John Carpten, Mark Pegram. Comparison of transcriptional signatures in US African American and Kenyan TNBC samples identifies differential expression in key oncogenic pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2013-402

Hypothesis of a potential BrainBiota and its relation to CNS autoimmune inflammation

Infectious agents have been long considered to play a role in the pathogenesis of neurological diseases as part of the interaction between genetic susceptibility and the environment. The role of bacteria in CNS autoimmunity has also been highlighted by changes in the diversity of gut microbiota in patients with neurological diseases such as Parkinson's disease, Alzheimer disease and multiple sclerosis, emphasizing the role of the gut-brain axis. We discuss the hypothesis of a brain microbiota, the BrainBiota: bacteria living in symbiosis with brain cells. Existence of various bacteria in the human brain is suggested by morphological evidence, presence of bacterial proteins, metabolites, transcripts and mucosal-associated invariant T cells. Based on our data, we discuss the hypothesis that these bacteria are an integral part of brain development and immune tolerance as well as directly linked to the gut microbiome. We further suggest that changes of the BrainBiota during brain diseases may be the consequence or cause of the chronic inflammation similarly to the gut microbiota.Published versionMLE is grateful for financial support from Lundbeckfonden (no. R347-2020-2454). ZI is grateful for financial support from Independent Research Fund Denmark (DFF 9039-00370B), Lundbeckfonden (R118-A11472), Scleroseforeningen (A25341, A29926, A31829, A33600), University of Southern Denmark (14/24200), Odense University Hospital (5798002573633). JB is grateful for financial support from the Center for Data and Computing in Natural Sciences (CDCS), and by his VILLUM Young Investigator Grant nr.13154. Furthermore, this project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 777111