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\"Being a superhero is tough enough, but the team must face some everyday chores and obstacles that may prove to be too much, even for them. The Titans tackle the single most terrifying word in the English language: 'dentist.' Will Robin's dental routine save him from making a dreaded trip? Then, the heroes get crafty when Raven and Cyborg create a pair of spooky-looking leggings from a pattern in one of Raven's arcane books\"-- Provided by publisher.

Background: ER+/HER2− breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. Methods: A total of 1702 postmenopausal ER+/HER2− breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (>5 years post diagnosis). Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

Manipulation of the fungal epigenome is hypothesized to be an effective method for accessing natural products from silent biosynthetic pathways. A library of epigenetic modifiers was tested using the fungus Aspergillus niger to determine the impact of small-molecule inhibitors on reversing the transcriptional suppression of biosynthetic genes involved in polyketide (PKS), non-ribosomal peptide (NRPS), and hybrid PKS-NRPS (HPN) production. Examination of expressed sequence tag libraries from A. niger demonstrated that >70% of its PKS-, NRPS-, and HPN-encoding gene clusters were transcriptionally suppressed under standard laboratory culture conditions. Using a chemical epigenetic methodology, we showed that treatment of A. niger with suberoylanilide hydroxamic acid and 5-azacytidine led to the transcriptional upregulation of many secondary-metabolite-encoding biosynthetic gene clusters. Chemical epigenetic modifiers exhibited positional biases for upregulating chromosomally distal gene clusters. In addition, a phylogenetic-based preference was noted in the upregulation of reducing clade I PKS gene clusters, while reducing clade IV PKS gene clusters were largely unaffected. Manipulating epigenetic features in fungi is a powerful method for accessing the products of silent biosynthetic pathways. Moreover, this approach can be readily incorporated into modern microbial screening operations.

Late detection and tumor recurrence are major factors driving the lethality of high-grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) have achieved significant clinical efficacy by selectively targeting DNA repair deficiencies in HGSOC patients with BRCA mutations and homologous recombination deficiency (HRD). However, a subset of patients ultimately develops resistance to PARPi, necessitating alternative effective treatment options. The mutational signatures of APOBEC3 family of DNA deaminases are widespread across a broad array of cancer types. Here, we report that cancer stem cell (CSC)-like tumorspheres exhibit reduced A3B expression compared to non-CSC adherent counterparts. Importantly, inhibition of A3B leads to PARPi resistance, elevated frequency of CSCs, and enhanced expression of stemness factors. In addition, we found that high A3B-expressing cells are under strong replication stress and thus synergize efficiently with PARPi. These studies reveal the important role A3B plays in regulating PARPi response.

Abstract Introduction Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD) and liver fibrosis. This association is related to the hypoxic burden of OSA, although mechanisms are unclear. We have shown that hepatocyte HIF-1 promotes liver fibrosis in mice with diet-induced obesity. Since HIF-1 primarily functions as a transcription factor to regulate the cellular response to hypoxia, we hypothesized that hepatocyte knockout of HIF-1 would cause gene expression differences yielding observed phenotypic variations. Methods Eight-week-old mice with hepatocyte-specific HIF-1α knockout (Hif1aF/FAlb-Cre+/+), and Hif1aF/FAlb-Cre-/- mice serving as wild-type controls, were all fed a high trans-fat diet for six months to mimic human NAFLD, inducing profound steatohepatitis. Upon sacrifice, livers were assessed for fibrosis by Sirius red staining and hydroxyproline assay. RNA was extracted from liver tissue; highest quality samples were used to generate RNA sequencing libraries. Libraries were sequenced with 50 bp single end reads to a depth of approximately 50 million reads/sample. The edgeR and limma packages were used to direct differential expression analysis. Functional enrichment of the differentially expressed genes was performed using the ToppGene Suite. Results Knockout mice had a 56% reduction in liver fibrosis as measured by hydroxyproline content (liver collagen in knockout: 2.67 ± 0.40 μg/mg, versus wild-type: 1.17 ± 0.21 μg/mg, p=0.028). Samples had a sufficient number of unique aligned reads (44.0–49.7 million). Based on 12,530 gene expression comparisons, 17 genes were differentially expressed with statistical significance (p<0.05 adjusted for multiple comparisons). Genes with differential expression at an adjusted significance of p<0.2 (150 individual genes) were included in Toppgene enrichment analysis. “Liver fibrosis, experimental” was the most significantly altered gene expression pathway, with 45 of the 150 genes differentially expressed, of 767 in the described pathway (p<10–29). Conclusion Hepatocyte HIF-1 mediates liver fibrosis in mice with diet-induced obesity, suggesting a mechanistic role for hypoxia in OSA-induced NAFLD progression. Gene expression changes may explain the observed phenotype. Additional mechanistic studies are needed to identify HIF-1 targets in this paradigm. Support (If Any) This work is supported by a grant from the American Sleep Medicine Foundation.

The institution of a regulatory requirement for patient-oriented labeling in the European Union—the User Package Leaflet (Patient Information Leaflet)—engendered the need to prepare accurate and comprehensible labeling for many marketed products in a number of therapy areas within a short time frame. In order to ensure the quality and consistency of “translation” of the medically-sophisticated Summary of Product Characteristics into the corresponding consumer-oriented leaflets, the authors prepared a “dictionary” of scientific and medical terms and their acceptable lay equivalents. Consistency in the language of the leaflets and reduced preparation time were achieved after implementation of the dictionary at headquarters and in European subsidiary offices.

Aberrant RNA editing by adenosine deaminases is increasingly recognized as a source of transcriptional diversity in adult cancer, yet its role in pediatric leukemia remains poorly understood. Here, we systematically profiled RNA editing events from bulk RNA-seq data of 1,025 pediatric T-cell acute lymphoblastic leukemia (T-ALL) samples, 37 matched B-ALL diagnosis/relapse pairs, and 6 age-matched non-leukemic controls. We uncovered a widespread global increase in A-to-I editing in T-ALL, affecting both non-coding Alu elements and coding sequences. By contrast, B-ALL shows relatively modest increases in RNA editing at both diagnosis and relapse with no differences in ADAR1 levels. ADAR1 expression is strongly associated with double-stranded RNA (dsRNA) sensors and interferon signaling in T-ALL. Genelevel analyses highlight recurrent editing of oncogenic drivers and regulators of immune signaling, chromatin remodeling, and RNA processing. Unexpectedly, increased editing levels in select genes ( , and in T-ALL; in B-ALL) were significantly associated with better patient survival, suggesting a potential prognostic role for editing dysregulation at individual gene levels. Together, these results deepen our understanding of the pediatric ALL transcriptome landscape and provided novel candidate regulators and therapeutic targets for future mechanistic and translational investigation.

Although Frankenstein has now been canonized in the Romantic classroom, less attention than ever has been paid to the considerable corpus of Mary Shelley’s other works—in fact, until now the excitement of the last decade over feminist themes found in Frankenstein has helped to obscure the actual persona of its author. This collection of essays however, written by a pre-eminent assemblage of Romantic scholars, begins to sketch a portrait of the “other Mary Shelley”; the writer and intellectual who recognized the turbulent relationship among the various agendae of family, gender, and society, and whose narratives still resonate strongly in the setting of contemporary politics and culture. By analysing a previously neglected body of reviews, essays, novellas, letters, biographies, sketches, and tales, and in locating Mary Shelley as a shrewd critic of the Romantic zeitgeist, the essays in this volume offer a ground-breaking, complete evaluation of one of the foremost thinkers of the 19th century.

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds, especially those from Africa for which genomic resources are particularly limited, despite their disproportionate importance to the continent’s economies. To mitigate this issue, we have generated assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into a graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1 Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research. Cattle reference genomes are valuable resources but are currently heavily biased towards European breeds. Here the authors integrate assemblies for African breeds into a more representative cattle graph genome capturing global breed diversity.