Scatology, the Last Taboo: Introduction to \u3ci\u3eFecal Matters in Early Modern Literature and Art\u3c/i\u3e

This collection of essays was provoked by what its editors considered to be a curious lacuna: the relative academic neglect of the copious and ubiquitous scatological rhetoric of Early Modem Europe, here broadly defined as the representation of the process and product of elimination of the body’s waste products (feces, urine, flatus, phlegm, vomitus). Our most educated forebears, different from ourselves, did not disdain it — if such proof may be found in the mere proliferation of examples — and, further, employed it in all manner of works, not just in the crude jokes of comic ephemera. This neglect led to the idea of an anthology that would invite reconsideration of the many forms and functions of scatology as literary and artistic trope. The results emphasize that while the Rabelaisian corpus may yet serve as the standard referent, hallmark or even touchstone of the scatological in Early Modem European works, critical inquiry must move beyond this so that readers may extend and deepen their understanding of what the Oxford English Dictionary dismisses simply as ‘dirty literature.’Achieving a new respect for, contributing knowledge to and fostering interest in Early Modern scatology within the realm of literary and art history studies would mean, without blush or shame, that this collection has been ‘well shat’ (bien chié). To each generation its idiom; for discerning readers and spectators to gauge its value without prejudice

Scatology, the Last Taboo: Introduction to \u3ci\u3eFecal Matters in Early Modern Literature and Art\u3c/i\u3e

This collection of essays was provoked by what its editors considered to be a curious lacuna: the relative academic neglect of the copious and ubiquitous scatological rhetoric of Early Modem Europe, here broadly defined as the representation of the process and product of elimination of the body’s waste products (feces, urine, flatus, phlegm, vomitus). Our most educated forebears, different from ourselves, did not disdain it — if such proof may be found in the mere proliferation of examples — and, further, employed it in all manner of works, not just in the crude jokes of comic ephemera. This neglect led to the idea of an anthology that would invite reconsideration of the many forms and functions of scatology as literary and artistic trope. The results emphasize that while the Rabelaisian corpus may yet serve as the standard referent, hallmark or even touchstone of the scatological in Early Modem European works, critical inquiry must move beyond this so that readers may extend and deepen their understanding of what the Oxford English Dictionary dismisses simply as ‘dirty literature.’Achieving a new respect for, contributing knowledge to and fostering interest in Early Modern scatology within the realm of literary and art history studies would mean, without blush or shame, that this collection has been ‘well shat’ (bien chié). To each generation its idiom; for discerning readers and spectators to gauge its value without prejudice

Pharmacotherapy for treatment-resistant schizophrenia

Schizophrenia is a disabling mental illness with a lifetime prevalence of 0.7% worldwide and significant, often devastating, consequences on social and occupational functioning. A range of antipsychotic medications are available; however, suboptimal therapeutic response in terms of psychotic symptoms is common and affects up to one-third of people with schizophrenia. Negative symptoms are generally less amenable to treatment. Because of the consequences of inadequate symptom control, effective treatment strategies are required for people with treatment-resistant schizophrenia. Clozapine has been shown to be more effective than other antipsychotics in treatment-resistant populations in several studies; however, the occurrence of adverse effects, some of which are potentially life-threatening, are important limitations. In addition to those who are intolerant to clozapine, only 30% to 50% experience clinically significant symptom improvement. This review describes the recent evidence for treatment strategies for people not responding to nonclozapine antipsychotic agents and people not responding or only partially responding to clozapine

A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer.

Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity

Propionibacterium acnes bacteriophages display limited genetic diversity and broad killing activity against bacterial skin isolates.

UnlabelledInvestigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human disease acne. To explore the diversity of the bacteriophages that infect P. acnes, 11 P. acnes phages were isolated from the sebaceous follicles of donors with healthy skin or acne and their genomes were sequenced. Comparative genomic analysis of the P. acnes phage population, which spans a 30-year temporal period and a broad geographic range, reveals striking similarity in terms of genome length, percent GC content, nucleotide identity (>85%), and gene content. This was unexpected, given the far-ranging diversity observed in virtually all other phage populations. Although the P. acnes phages display a broad host range against clinical isolates of P. acnes, two bacterial isolates were resistant to many of these phages. Moreover, the patterns of phage resistance correlate closely with the presence of clustered regularly interspaced short palindromic repeat elements in the bacteria that target a specific subset of phages, conferring a system of prokaryotic innate immunity. The limited diversity of the P. acnes bacteriophages, which may relate to the unique evolutionary constraints imposed by the lipid-rich anaerobic environment in which their bacterial hosts reside, points to the potential utility of phage-based antimicrobial therapy for acne.ImportancePropionibacterium acnes is a dominant member of the skin microflora and has also been implicated in the pathogenesis of acne; however, little is known about the bacteriophages that coexist with and infect this bacterium. Here we present the novel genome sequences of 11 P. acnes phages, thereby substantially increasing the amount of available genomic information about this phage population. Surprisingly, we find that, unlike other well-studied bacteriophages, P. acnes phages are highly homogeneous and show a striking lack of genetic diversity, which is perhaps related to their unique and restricted habitat. They also share a broad ability to kill clinical isolates of P. acnes; phage resistance is not prevalent, but when detected, it appears to be conferred by chromosomally encoded immunity elements within the host genome. We believe that these phages display numerous features that would make them ideal candidates for the development of a phage-based therapy for acne

Navy Force Structure Review Strategic Risk Workshop and Technology Review

NPS NRP Project PosterThe study's goal is to comparatively evaluate combat effectiveness of the planned Fleet Design with a novel alternative design against potential global adversaries in the 2040 timeframe. Insights and recommendations from the study will be used in the next Force Structure Assessment and the FY 2024 30-Year Shipbuilding Plan.N8 - Integration of Capabilities & ResourcesThis research is supported by funding from the Naval Postgraduate School, Naval Research Program (PE 0605853N/2098). https://nps.edu/nrpChief of Naval Operations (CNO)Approved for public release. Distribution is unlimited.

Navy Force Structure Review Strategic Risk Workshop and Technology Review

NPS NRP Executive SummaryThe study's goal is to comparatively evaluate combat effectiveness of the planned Fleet Design with a novel alternative design against potential global adversaries in the 2040 timeframe. Insights and recommendations from the study will be used in the next Force Structure Assessment and the FY 2024 30-Year Shipbuilding Plan.N8 - Integration of Capabilities & ResourcesThis research is supported by funding from the Naval Postgraduate School, Naval Research Program (PE 0605853N/2098). https://nps.edu/nrpChief of Naval Operations (CNO)Approved for public release. Distribution is unlimited.

Southern Ocean bottom water characteristics in CMIP5 models

Southern Ocean deep water properties and formation processes in climate models are indicative of their capability to simulate future climate, heat and carbon uptake, and sea level rise. Southern Ocean temperature and density averaged over 1986–2005 from 15 CMIP5 (Coupled Model Intercomparison Project Phase 5) climate models are compared with an observed climatology, focusing on bottom water. Bottom properties are reasonably accurate for half the models. Ten models create dense water on the Antarctic shelf, but it mixes with lighter water and is not exported as bottom water as in reality. Instead, most models create deep water by open ocean deep convection, a process occurring rarely in reality. Models with extensive deep convection are those with strong seasonality in sea ice. Optimum bottom properties occur in models with deep convection in the Weddell and Ross Gyres. Bottom Water formation processes are poorly represented in ocean models and are a key challenge for improving climate predictions

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer

BACKGROUND: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. METHODS: We identified ≥ pT3pN0-3M0 LABC patients in the National Cancer Database diagnosed 2004-2014 who underwent RC ± PORT. OS was calculated using Kaplan-Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. RESULTS: 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2-21.8) for PORT vs 20.8 months (95% CI, 20.3-21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008. A one-to-three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity-matched cohort, median OS was 19.8 months (95% CI, 18.0-21.6) for PORT vs 16.9 months (95% CI, 15.6-18.1) for no PORT (P = 0.030). In the propensity-matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P \u3c 0.01 all). CONCLUSION: In this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted

Restricting sugar or carbohydrate intake does not impact physical activity level or energy intake over 24 h despite changes in substrate use : A randomised crossover study in healthy men and women

Purpose To determine the effects of dietary sugar or carbohydrate restriction on physical activity energy expenditure, energy intake, and physiological outcomes across 24 h. Methods In a randomized, open-label crossover design, twenty-five healthy men (n = 10) and women (n = 15) consumed three diets over a 24-h period: moderate carbohydrate and sugar content (MODSUG = 50% carbohydrate [20% sugars], 15% protein, 35% fat); low sugar content (LOWSUG = 50% carbohydrate [< 5% sugars], 15% protein, 35% fat); and low carbohydrate content (LOWCHO = 8% carbohydrate [< 5% sugars], 15% protein, 77% fat). Postprandial metabolic responses to a prescribed breakfast (20% EI) were monitored under laboratory conditions before an ad libitum test lunch, with subsequent diet and physical activity monitoring under free-living conditions until blood sample collection the following morning. Results The MODSUG, LOWSUG and LOWCHO diets resulted in similar mean [95%CI] rates of both physical activity energy expenditure (771 [624, 919] vs. 677 [565, 789] vs. 802 [614, 991] kcal·d−1; p = 0.29] and energy intake (2071 [1794, 2347] vs. 2195 [1918, 2473] vs. 2194 [1890, 2498] kcal·d−1; P = 0.34), respectively. The LOWCHO condition elicited the lowest glycaemic and insulinaemic responses to breakfast (P < 0.01) but the highest 24-h increase in LDL-cholesterol concentrations (P < 0.001), with no differences between the MODSUG and LOWSUG treatments. Leptin concentrations decreased over 24-h of consuming LOWCHO relative to LOWSUG (p < 0.01). Conclusion When energy density is controlled for, restricting either sugar or total dietary carbohydrate does not modulate physical activity level or energy intake over a 24-h period (~ 19-h free-living) despite substantial metabolic changes. Clinical trials registration ID NCT03509610, https://clinicaltrials.gov/show/NCT0350961