Brief of Amici Curiae Erika R. George and Kali N. Murray in Support of the Association for Molecular Pathology, et al

Amicus ("friend of the court") brief written by Erika George and Kali Murray in support of plaintiffs-appellees, Association for Molecular Pathology, et al (No. 2010-1406)

Translation inhibition by rocaglates activates a species-specific cell death program in the emerging fungal pathogen Candida auris

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.Published versio

Safe from “harm”: The Governance of Violence by Platforms

A number of issues have emerged related to how platforms moderate and mitigate “harm.” Although platforms have recently developed more explicit policies in regard to what constitutes “hate speech” and “harmful content,” it appears that platforms often use subjective judgments of harm that specifically pertains to spectacular, physical violence—but harm takes on many shapes and complex forms. The politics of defining “harm” and “violence” within these platforms are complex and dynamic, and represent entrenched histories of how control over these definitions extends to people\u27s perceptions of them. Via a critical discourse analysis of policy documents from three major platforms (Facebook, Twitter, and YouTube), we argue that platforms\u27 narrow definitions of harm and violence are not just insufficient but result in these platforms engaging in a form of symbolic violence. Moreover, the platforms position harm as a floating signifier, imposing conceptions of not just what violence is and how it manifests, but who it impacts. Rather than changing the mechanisms of their design that enable harm, the platforms reconfigure intentionality and causality to try to stop users from being “harmful,” which, ironically, perpetuates harm. We provide a number of suggestions, namely a restorative justice-focused approach, in addressing platform harm

Admicelle-Based Solid Phase Extraction of Phenols Using Dialkylammonium Surfactant in the Hydroxide Form

A technique for admicelle-based solid phase extraction is presented in which a dialkylammonium surfactant in the hydroxide form is immobilized on silica. By converting dihexadecyldimethylammonium bromide to the hydroxide form, the surfactant is allowed to have the property of a strong base, aiding in the extraction of acidic phenols which are difficult to extract because of their differing polarities. The surfactant-silica admicelle parameters were optimized for the efficient extraction of eight phenols. Adsorbed phenols were eluted from the sorbent using small volumes of methanol. The phenols were preconcentrated from drinking water samples and were determined using high performance liquid chromatography (HPLC) coupled with a photo diode-array detector

It’s the Methodology For Me: A Systematic Review of Early Approaches to Studying TikTok

Research on TikTok has grown along with the app’s rapidly rising global popularity. In this systematic review, we investigate 58 articles examining TikTok, its users, and its content. Focusing on articles published in journals and proceedings across the domains of human-computer interaction, communication, and other related disciplines, we analyze the methods being used to study TikTok, as well as ethical considerations. Based on our analysis, we found that research on TikTok tends to use content analysis as their primary method and mainly focus on user behavior and culture, effects of use, the platform’s policies and governance, and very few articles discuss the ethical implications of collecting and analyzing such data. Additionally, most studies employ traditional forms of data collection when the affordances of TikTok tend to differ from other social media platforms. We conclude with a discussion about possible future directions and contribute to ongoing conversations about ethics and social media data

Effects of dietary supplementation with krill meal on serum pro-inflammatory markers after the iditarod sled dog race

A seafood-based supplement from krill, rich in omega-3 phospholipids and proteins was tested on a group of dogs competing in the 2016 Iditarod dog sled race to investigate the effects of krill meal on exercise-induced inflammation and muscle damage in comparison to a control group. A single team of 16 dogs received 8% krill meal for 5 weeks prior to the start of race, while another team of 16 dogs received no supplementation. Ten dogs of the treatment and 11 dogs of the control group finished the race and their blood was analyzed for omega-3 index, inflammation (CRP) and muscle damage (CK). The omega-3 index of the krill meal-fed dogs was significantly higher at the beginning of the race (mean 6.2% in the supplemented vs 5.2% in the control group, p < .001). CRP concentrations increased from 7.05 ± 2.27 to 37.04 ± 9.16 μg/ml in the control and from 4.26 ± 0.69 to 16.56 ± 3.03 μg/ml in the treatment group, with a significant difference between the groups (p < .001). CK activity was increased from 90.75 ± 8.15 IU/l to 715.90 ± 218.9 IU/l in the control group and from 99.55 ± 12.15 to 515.69 ± 98.98 in the supplemented group, but there were no differences between groups (p = .266). The results showed that krill meal supplementation led to significantly higher omega-3 index, which correlated with lower inflammation and a tendency for reduced muscle damage after this long-distance sled dog competition. However, these results need to be confirmed by more controlled studies, since it was a field study and effects of race speed or other performance-related factors such as fitness and musher skill on the results cannot be excluded

Recovery of Forest Floor Diversity After Removal of the Nonnative, Invasive Plant Euonymus fortunei

The vine Euonymus fortunei (Turcz.) Hand.-Mazz. is invading forests of the eastern United States; as a result, removal of E. fortunei has become a priority of resource managers. This study examined the effectiveness of five techniques for eliminating E. fortunei, restoring plant species richness, and enhancing recolonization by woody species. In 2003, the following five treatments were applied: burn with a propane torch, light exclusion by plastic tarp, burn and glyphosate application, cut (simulated grazing) and glyphosate application, mow and glyphosate application, plus an untreated control. Each treatment was replicated four times in a randomized block design located in a heavily E. fortunei–invaded forest remnant in Lexington, KY. Vegetation was surveyed in 2004, 2005, 2006, 2007, and 2013. Across years, most treatments were associated with reduced E. fortunei cover and increased total species richness. Over time, E. fortunei cover increased across treatments, such that by 2013, no difference in E. fortunei cover was detectible among treatments. Some differences in total and native species richness among treatments were still perceptible by 2013. Increased E. fortunei cover was correlated with decreased ground-layer species richness, native species richness, sapling richness, and sapling density. Light exclusion by plastic tarp, a method absent from many management recommendations, was unique in its long-term reduction of E. fortunei cover and its association with increased total species richness, but use of plastic tarps may have drawbacks. This study quantified the long-term community effects of removing an established invasive species from a mature, urban forest. Removal allowed native plants, notably woody species, to reestablish. Because richness continues to decline as E. fortunei reinhabits plots, land managers seeking to conserve biodiversity under conditions similar to those within our study site should maintain proactive E. fortunei removal plans

Parathyroid hormone receptor signaling induces bone resorption in the adult skeleton by directly regulating the RANKL gene in osteocytes

PTH upregulates the expression of the receptor activator of nuclear factor κB ligand (Rankl) in cells of the osteoblastic lineage, but the precise differentiation stage of the PTH target cell responsible for RANKL-mediated stimulation of bone resorption remains undefined. We report that constitutive activation of PTH receptor signaling only in osteocytes in transgenic mice (DMP1-caPTHR1) was sufficient to increase Rankl expression and bone resorption. Resorption in DMP1-caPTHR1 mice crossed with mice lacking the distal control region regulated by PTH in the Rankl gene (DCR(-/-)) was similar to DMP1-caPTHR1 mice at 1 month of age, but progressively declined to reach values undistinguishable from wild-type (WT) mice at 5 months of age. Moreover, DMP1-caPTHR1 mice exhibited low tissue material density and increased serum alkaline phosphatase activity at 5 month of age, and these indices of high remodeling were partially and totally corrected in compound DMP1-caPTHR1;DCR(-/-) male mice, and less affected in female mice. Rankl expression in bones from DMP1-caPTHR1 mice was elevated at both 1 and 5 months of age, whereas it was high, similar to DMP1-caPTHR1 mice at 1 month, but low, similar to WT levels at 5 months in compound mice. Moreover, PTH increased Rankl and decreased Sost and Opg expression in ex vivo bone organ cultures established from WT mice, but only regulated Sost and Opg expression in cultures from DCR(-/-) mice. PTH also increased RANKL expression in osteocyte-containing primary cultures of calvarial cells, in isolated murine osteocytes, and in WT but not in DCR(-/-) osteocyte-enriched bones. Thus, PTH upregulates Rankl expression in osteocytes in vitro, ex vivo and in vivo, and resorption induced by PTH receptor signaling in the adult skeleton requires direct regulation of the Rankl gene in osteocytes.We thank Dr. Keith Condon and Ms. Naomie Olivos for technical assistance and Dr Munro Peacock for measurement of alkaline phosphatase. This research was supported by the National Institutes of Health (R01DK076007 and American Recovery and Reinvestment Act supplement S10-RR023710 to T.B.) and the Veterans Administration (Merit Review I01BX002104 to T.B.). Disclosure Summary: The authors declare that no conflict of interest exists

The International-Trade Network: Gravity Equations and Topological Properties

This paper begins to explore the determinants of the topological properties of the international - trade network (ITN). We fit bilateral-trade flows using a standard gravity equation to build a "residual" ITN where trade-link weights are depurated from geographical distance, size, border effects, trade agreements, and so on. We then compare the topological properties of the original and residual ITNs. We find that the residual ITN displays, unlike the original one, marked signatures of a complex system, and is characterized by a very different topological architecture. Whereas the original ITN is geographically clustered and organized around a few large-sized hubs, the residual ITN displays many small-sized but trade-oriented countries that, independently of their geographical position, either play the role of local hubs or attract large and rich countries in relatively complex trade-interaction patterns