Alterations in long noncoding RNAs in women with and without polycystic ovarian syndrome

Long noncoding RNAs (lncRNAs) are RNA transcripts over 200 nucleotides long that are not translated into protein; however, there is increasing evidence of their regulatory functions. To date, there are few studies measuring lncRNA in control women or women with polycystic ovary syndrome (PCOS). Objective: To determine lncRNA differences between PCOS and control women. Design: Cross sectional study. Patients: Twenty four anovulatory women with all three diagnostic features of PCOS compared to 24 control women in the follicular phase of their menstrual cycle from a PCOS biobank. Results: Women with PCOS were age and weight matched compared to the control women but were significantly insulin resistant and hyperandrogenemic (

Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes

Background: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods: We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results: We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. Conclusion: We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.We would like to thank Weill Cornell Medicine in Qatar (WCM-Q) and the Qatar National Leadership Program (QNLP) for research support. We would also like to thank the WCM-Q Advanced Computing Division for computing time and software support. Finally, we would like to thank colleagues and reviewers for experimental support and critical discussions. This study was made possible by JSREP grant 4-011-1-003 from the Qatar National Research Fund (a member of Qatar Foundation) and the QF Leadership program. The statements made herein are solely the responsibility of the author[s]. The funders had no role in the design of the study or in the collection, analysis, and interpretation of data and in writing the manuscript.Scopu

The complete genome sequence and analysis of the Epsilonproteobacterium \u3cem\u3eArcobacter butzleri\u3c/em\u3e

Arcobacter butzleri is a member of the epsilon subdivision of the Proteobacteria and a close taxonomic relative of established pathogens, such as Campylobacter jejuni and Helicobacter pylori. Here we present the complete genome sequence of the human clinical isolate, A. butzleri strain RM4018. Methodology/Principal Findings: Arcobacter butzleri is a member of the Campylobacteraceae, but the majority of its proteome is most similar to those of Sulfuromonas denitrificans and Wolinella succinogenes, both members of the Helicobacteraceae, and those of the deep-sea vent Epsilonproteobacteria Sulfurovum and Nitratiruptor. In addition, many of the genes and pathways described here, e.g. those involved in signal transduction and sulfur metabolism, have been identified previously within the epsilon subdivision only in S. denitrificans, W. succinogenes, Sulfurovum, and/or Nitratiruptor, or are unique to the subdivision. In addition, the analyses indicated also that a substantial proportion of the A. butzleri genome is devoted to growth and survival under diverse environmental conditions, with a large number of respiration-associated proteins, signal transduction and chemotaxis proteins and proteins involved in DNA repair and adaptation. To investigate the genomic diversity of A. butzleri strains, we constructed an A. butzleri DNA microarray comprising 2238 genes from strain RM4018. Comparative genomic indexing analysis of 12 additional A. butzleri strains identified both the core genes of A. butzleri and intraspecies hypervariable regions, where, 70% of the genes were present in at least two strains. Conclusion/Significance: The presence of pathways and loci associated often with non-hostassociated organisms, as well as genes associated with virulence, suggests that A. butzleri is a free-living, water-borne organism that might be classified rightfully as an emerging pathogen. The genome sequence and analyses presented in this study are an important first step in understanding the physiology and genetics of this organism, which constitutes a bridge between the environment and mammalian hosts

The Complete Genome Sequence and Analysis of the Epsilonproteobacterium Arcobacter butzleri

BACKGROUND: Arcobacter butzleri is a member of the epsilon subdivision of the Proteobacteria and a close taxonomic relative of established pathogens, such as Campylobacter jejuni and Helicobacter pylori. Here we present the complete genome sequence of the human clinical isolate, A. butzleri strain RM4018. METHODOLOGY/PRINCIPAL FINDINGS: Arcobacter butzleri is a member of the Campylobacteraceae, but the majority of its proteome is most similar to those of Sulfuromonas denitrificans and Wolinella succinogenes, both members of the Helicobacteraceae, and those of the deep-sea vent Epsilonproteobacteria Sulfurovum and Nitratiruptor. In addition, many of the genes and pathways described here, e.g. those involved in signal transduction and sulfur metabolism, have been identified previously within the epsilon subdivision only in S. denitrificans, W. succinogenes, Sulfurovum, and/or Nitratiruptor, or are unique to the subdivision. In addition, the analyses indicated also that a substantial proportion of the A. butzleri genome is devoted to growth and survival under diverse environmental conditions, with a large number of respiration-associated proteins, signal transduction and chemotaxis proteins and proteins involved in DNA repair and adaptation. To investigate the genomic diversity of A. butzleri strains, we constructed an A. butzleri DNA microarray comprising 2238 genes from strain RM4018. Comparative genomic indexing analysis of 12 additional A. butzleri strains identified both the core genes of A. butzleri and intraspecies hypervariable regions, where <70% of the genes were present in at least two strains. CONCLUSION/SIGNIFICANCE: The presence of pathways and loci associated often with non-host-associated organisms, as well as genes associated with virulence, suggests that A. butzleri is a free-living, water-borne organism that might be classified rightfully as an emerging pathogen. The genome sequence and analyses presented in this study are an important first step in understanding the physiology and genetics of this organism, which constitutes a bridge between the environment and mammalian hosts

Genome Diversity and the Origin of the Arabian Horse

The Arabian horse, one of the world\u27s oldest breeds of any domesticated animal, is characterized by natural beauty, graceful movement, athletic endurance, and, as a result of its development in the arid Middle East, the ability to thrive in a hot, dry environment. Here we studied 378 Arabian horses from 12 countries using equine single nucleotide polymorphism (SNP) arrays and whole-genome re-sequencing to examine hypotheses about genomic diversity, population structure, and the relationship of the Arabian to other horse breeds. We identified a high degree of genetic variation and complex ancestry in Arabian horses from the Middle East region. Also, contrary to popular belief, we could detect no significant genomic contribution of the Arabian breed to the Thoroughbred racehorse, including Y chromosome ancestry. However, we found strong evidence for recent interbreeding of Thoroughbreds with Arabians used for flat-racing competitions. Genetic signatures suggestive of selective sweeps across the Arabian breed contain candidate genes for combating oxidative damage during exercise, and within the Straight Egyptian subgroup, for facial morphology. Overall, our data support an origin of the Arabian horse in the Middle East, no evidence for reduced global genetic diversity across the breed, and unique genetic adaptations for both physiology and conformation

Longitudinal Study of Recurrent Metastatic Melanoma Cell Lines Underscores the Individuality of Cancer Biology.

Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.Journal of Investigative Dermatology advance online publication, 2 January 2014; doi:10.1038/jid.2013.495

Two prolonged viremic SARS-CoV-2 infections with conserved viral genome for two months.

We document two cases of viremic and prolonged active infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) where the viral genome was conserved for two months, but infection was with little or no symptoms. The first infection persisted for 80 days and the second for 62 days. Clearance of infection occurred 40 and 41 days, respectively, after development of detectable antibodies. Both cases were identified incidentally in an investigation of reinfection in a cohort of 133,266 laboratory-confirmed infected persons

Assessment of the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reinfection in an Intense Reexposure Setting.

BACKGROUND: Risk of reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. We assessed the risk and incidence rate of documented SARS-CoV-2 reinfection in a cohort of laboratory-confirmed cases in Qatar. METHODS: All SARS-CoV-2 laboratory-confirmed cases with at least 1 polymerase chain reaction-positive swab that was ≥45 days after a first positive swab were individually investigated for evidence of reinfection. Viral genome sequencing of the paired first positive and reinfection viral specimens was conducted to confirm reinfection. RESULTS: Out of 133 266 laboratory-confirmed SARS-CoV-2 cases, 243 persons (0.18%) had at least 1 subsequent positive swab ≥45 days after the first positive swab. Of these, 54 cases (22.2%) had strong or good evidence for reinfection. Median time between the first swab and reinfection swab was 64.5 days (range, 45-129). Twenty-three of the 54 cases (42.6%) were diagnosed at a health facility, suggesting presence of symptoms, while 31 (57.4%) were identified incidentally through random testing campaigns/surveys or contact tracing. Only 1 person was hospitalized at the time of reinfection but was discharged the next day. No deaths were recorded. Viral genome sequencing confirmed 4 reinfections of 12 cases with available genetic evidence. Reinfection risk was estimated at 0.02% (95% confidence interval [CI], .01%-.02%), and reinfection incidence rate was 0.36 (95% CI, .28-.47) per 10 000 person-weeks. CONCLUSIONS: SARS-CoV-2 reinfection can occur but is a rare phenomenon suggestive of protective immunity against reinfection that lasts for at least a few months post primary infection