In hot pursuit: Gothic virgins and villains in nineteenth-century American fiction

This dissertation investigates how three significant nineteenth-century American female writers strategically transform a central Gothic motif – the virtuous heroine pursued by a villain who lusts for sexual and socioeconomic power – to tell new stories about gendered bodies and the erotic relations between them. Established in the genre-defining British Gothic novels of the late eighteenth century, this popular motif endured throughout the nineteenth century in texts written and read on both sides of the Atlantic. This project examines understudied texts by E.D.E.N. Southworth, Louisa May Alcott, and Julia Ward Howe that exhibit a striking intertextual awareness of the motif, reformulating it to critique the era’s marital and inheritance practices that enable and reinforce persistent gender inequities. These texts presciently recognize the performative nature of gender, centering on protagonists that move fluidly between genders with strategic choices about dress, speech, and social roles. By examining these texts together, this project shows that they anticipate the insights of contemporary feminist and queer theory as their protagonists deliberately calculate how to blend traditionally gendered behaviors and transform sexual threats into situations in which they can either consensually participate or cleverly elude. Chapter One argues that E. D. E. N. Southworth’s popular serial novel The Hidden Hand (1859) rewrites the narrative pattern that situates Gothic heroines as vulnerable to rape by positioning its heroine as aware of her fictional status and therefore capable of using her metafictional knowledge to reconfigure sexually threatening situations. Chapter Two examines how Louisa May Alcott’s sensation tale A Long, Fatal Love Chase (1866) blends traditionally male and female Gothic narratives to cast its heroine as a female Faust figure whose desperate desire for freedom leads her to enter naively into a bigamous partnership with a Mephistophelean man whose relentless pursuit ultimately causes her death. Chapter Three contends that Julia Ward Howe’s recently recovered manuscript The Hermaphrodite (1848) situates its ambiguously sexed but male-identifying protagonist as a Gothic “heroine” who employs unconventional strategies to cope with conventional threats to his physical and financial autonomy and rejects all interpersonal bonds because of the gendered restrictions they impose upon him.2019-07-31T00:00:00

The Energetic Cost of Anthropogenic Disturbance on the Southern Sea Otter (Enhydra lutris nereis)

With increased human populations and tourism in coastal areas, there is greater potential for disturbance of marine wildlife. Having high metabolic rates, sea otters (Enhydra lutris nereis) are at risk of increased energetic costs due to disturbance. To investigate these effects, sea otter activity in response to potential disturbance stimuli was recorded over three years, at three California locations: Monterey, Moss Landing, and Morro Bay. A hidden Markov Model was developed to examine how activity varies as a function of location, group size, pup to adult ratio, kelp canopy, and occurrence of and proximity to disturbance stimuli. Results were combined with published estimates of activity-specific metabolic rates, translating activity change into energetic costs. The effects of disturbance stimuli on sea otter behavior appear location specific, and vary non-linearly with distance from disturbance stimuli. The model quantifies the distance-disturbance relationship, calculating distance at which the likelihood of disturbance is low (i.e. averaged across locations, there is \u3c10% potential for disturbance when stimuli are \u3e54 m away). Energetic costs (kJ) for Monterey, Moss Landing, and Morro Bay (given six small-craft approaches of 20 m for a 27.7 kg male otter in kelp, group size 10, and pup ratio 0.5) are expected to increase by 210.1 kJ ± 80.76, 160.07 kJ ± 65.24 and 58.44 kJ ± 23.66, respectively. Our analyses represent a novel approach for estimating behavioral responses and energetic costs of disturbance, furthering understanding of how human activities impact sea otters and providing a sound scientific basis for management

Responding to stakeholder needs to engage rehabilitation professionals in the delivery of evidence-based health programming for adults with osteoarthritis

Although there are many evidence-based programs that promote healthy lifestyles and symptom modification for people with osteoarthritis, their delivery in rehabilitation clinical settings in the United States is limited. These programs can be a primary component of treatment or a discharge option to facilitate long-term mobility and pain management. The purpose of this perspective article is to describe a delivery model that brings one arthritis-appropriate, evidence-based intervention, the Arthritis Foundation's Walk With Ease program, to older adults seeking physical therapy related to their osteoarthritis. We embedded program delivery into a Doctor of Physical Therapy curriculum using a student health coaching approach and partnering with physical therapy clinics and other community agencies for participant referrals. This model of delivery is cost-effective, sustainable, and provides outcomes that meet goals of the national agenda for osteoarthritis. The model provides benefits for students in health professions education programs, community organizations and rehabilitation clinics, and adults living with osteoarthritis

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease

Introduction: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. // Methods and analysis: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). Eligibility criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18–49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. // Ethics and dissemination: Ethical approval granted by South Central–Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. // Trial registration number: ISRCTN30448031; EudraCT number: 2021-005748-31

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Examining the Latent Structure and Correlates of Sensory Reactivity in Autism: A Multi-Site Integrative Data Analysis by the Autism Sensory Research Consortium

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these supra-modal traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a general response pattern factor for each supra-modal construct and determine the added value of modality-specific response pattern scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ω LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many real-world sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations