The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of ...product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium‐catalyzed trans‐hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch‐type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron‐catalyzed reductive formation of a non‐terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring‐closing alkyne metathesis catalyzed by a molybdenum alkylidyne.
The focal point: The recently disclosed ruthenium‐catalyzed trans‐hydrogenation of internal alkynes to E‐alkenes is noteworthy for its unorthodox stereochemical course, as well as its compatibility with other reducible or sensitive sites. This favorable profile allowed this emerging methodology to be implemented in a concise total synthesis of brefeldin A at a stage at which a conventional Birch‐type trans‐reduction would no longer be applicable.
Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most ...common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR) has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects.
The Cabin in the Woods (2011) is a highly self-reflexive movie that is aware of its generic roots. In particular, the film struggles with the meaning of “the woods” in the horror genre. Cabin’s ...central twist in this respect is that the titular “woods” are not untamed nature, but rather a place of artifice. Cabin’s woods are not uncanny because they are far removed from “civilization,” but rather exactly because they are part of it. The film’s emphasis on the artificiality of nature suggests that the concept of “nature” is exactly that—a concept, a cultural construct, loaded with meaning. The film’s ending envisions the end of that discursive construct—but for that to happen, humankind must vanish.
This article discusses sports video game story modes in Fight Night Champion (EA Canada, 2011), a boxing game, NBA 2K16 (Visual Concepts, 2015), a basketball game, and the story that stretches across ...Madden NFL 18 (EA Tiburon, 2017) and Madden NFL 19 (EA Tiburon, 2018), EA Sports’ annual football series. Focusing on African American athletes, the stories tap into the utopianism of sports and suggest that anyone, irrespective of skin color, can make it in America. This article explores the racial politics of these games, in particular as experienced by a white player such as the author. Primarily focusing on narrative and gameplay, the article discusses how a white player’s control over black bodies confronts them with their racial normativity.
Editor's Editorial Fuchs, Michael
JAAAS: Journal of the Austrian Association for American Studies,
08/2020, Letnik:
1, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This is the editor's editorial. In lieu of an abstract, here is the editorial's first paragraph: In the first issue of Textual Practice, the late Shakespeare scholar Terence Hawkes claimed, "It is ...never a good time to start a new journal." "The Humanities in particular feel marginalized and underfunded," he continued. "They sense themselves to be hopelessly at odds with a culture which has long abandoned any recognition of the value of their role."1 More than thirty years later, some of these words still ring very true.
This book is available as open access through the Bloomsbury Open Access programme and is available on www.bloomsburycollections.com While all media are part of intermedial networks, video games are ...often at the nexus of that network. They not only employ cinematics, embedded books, and in-world television screens for various purposes, but, in our convergence culture, video games also play a vital role in allowing players to explore transmedia storyworlds. At the same time, video games are frequently thematized and remediated in film, television, and literature. Indeed, the central role video games assume in intermedial networks provides testament to their significance in the contemporary media environment. In this volume, an international group of contributors discuss not only intermedial phenomena in video games, but also the intermedial networks surrounding them. Intermedia Games-Games Inter Media will deepen readers' understanding of the convergence culture of the early twenty-first century and video games' role in it.
Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT ...without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single‐blind, placebo‐controlled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End‐Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide‐binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow‐up with SOC maintenance was performed until 5 months. FMT‐assigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post‐FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post‐FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E‐cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin‐6 (P = 0.02) and serum LBP (P = 0.009) reduced post‐FMT. EncephalApp performance improved post‐FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.
Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve ...dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open‐label, randomized clinical trial with a 5‐month follow‐up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT‐randomized patients received 5 days of broad‐spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow‐up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT‐related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End‐Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post‐FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727–1738)
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