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Most rare disease patients (75–50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.

Writing clear and unambiguous requirements that are conflict-free and complete is no easy task. Incorrect requirements lead to errors being introduced early in the design process. The longer the gap between error introduction and error discovery, the higher the cost associated with the error. To address the growing cost of system development, we introduce a tool called Analysis of Semantic Specifications and Efficient generation of Requirements-based Tests (ASSERT™) for capturing requirements, backed by a formal requirements analysis engine. ASSERT also automatically generates a complete set of requirements-based test cases. The requirements are captured in a structured natural language that is both human- and machine-readable. Formal analysis of these requirements with an automated theorem prover identifies errors as soon as requirements are written. It also addresses the historical problem that analysis engines are hard to use and understand for someone without formal methods expertise and analysis results are often difficult for the end-user to understand and make actionable. ASSERT’s major contribution is to bring powerful requirements capture and analysis capability to the domain of the end-user. We provide explainable and automated formal analysis, something we found important for a tool’s adoptability in industry. Automating test case generation in ASSERT also provides clear and measurable productivity gains in system development.

In “Unsettling Geographies: Primitivist Utopias in Queer American Literature from Walt Whitman to Willa Cather,” I argue that the colonial discourse of primitivism played a central role in the queer literary imaginaries of both canonical and non-canonical U.S. authors. Building on the work of historians of sexuality who trace the complex development of the twentieth-century homo-/hetero- binary, I show how literary works produced in this historical moment—roughly 1860 to 1925—explored and in some instances even advocated alternative queer modes of citizenship and erotic imagination and practice. Focusing on the works of Walt Whitman, Emily Dickinson, Charles Warren Stoddard, and Willa Cather, I demonstrate throughout that while those erotic alternatives have been posited as inherently politically radical in many feminist and queer theoretical traditions, the pervasive primitivization of indigenous bodies and lands in these literatures tells us a more complicated and troubling story about the co-implicated histories of non-heteronormativity and settler colonialism in the U.S. If much recent queer theory has explored the ways in which racial and sexual normativities derive from histories of settler colonialism, my dissertation contributes to this discussion by addressing how queer literary representations of racial and national otherness both challenge those normative discourses and participate in ongoing colonial and imperial projects.

Fort Lauderdale has lost its decidedly unwanted No. 1 ranking as the most crime-infested big city in the nation, a Sun-Sentinel analysis of FBI data shows. Fort Lauderdale, ranked No. 1 in overall crime in 1994, fell to seventh place in 1995, a computer analysis of FBI crime statistics released on Sunday showed. The city's violent-crime rate, which measures the number of reported murders, rapes, robberies and aggravated assaults compared to population, ranked 52nd among cities with populations of 100,000 or more, the Sun-Sentinel analysis showed.

Tom Schmidt of Fort Lauderdale got a late start on Christmas shopping, but didn't feel rushed at all last week. Halle Hutcherson of Fort Lauderdale shopped for herself last week but postponed serious shopping for gifts until this week, when she feels confident there will be good sales. Schmidt and Hutcherson are like a lot of Americans, who seem to put off holiday shopping later each year.

Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis 1 – 4 . They are also implicated in human developmental disorders and cancers 5 – 8 , supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies 9 – 11 . However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A . TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1 , a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2) 8 , 12 , 13 ), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and  NSD1 -mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans -chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth. H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.

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