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Potent 3CLpro inhibitors effective against SARS-CoV-2 and MERS-CoV in animal models by therapeutic treatment
No full textSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, and , in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.IMPORTANCEHuman coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses
Genomic insights into Plasmodium vivax population structure and diversity in central Africa
No full textThese results suggest an endemic P. vivax population is present in central Africa. Intentional sampling of P. vivax across Africa would further contextualize this sample within African P. vivax diversity and shed light on the mechanisms of infection in Duffy negative individuals. These results are limited by the uncertainty of how representative this single sample is of the larger population of P. vivax in central Africa
Place Identity Variation across Ages in a Hyper-Segregated Neighborhood: Wendell Phillips Neighborhood, Kansas City Missouri
No full textThis research was presented on June 21, 2024 at the 55th Environmental Design Research Association conference, held in Portland, Oregon June 19-22nd.This study explores and comprehends the intricacies of place identity within Wendel Phillips, a Kansas City, Missouri neighborhood established in unjust socio-economic conditions and racial segregation. Place identity embodies the subjective and emotive ties individuals or communities forge with a specific geographic location, encompassing personal meanings, emotions, memories, and symbolic affiliations. These elements significantly shape one's sense of belonging, attachment, and identification with a particular environment, intertwining with the construction of a distinct identity closely linked to the attributes of that place. The research methodology involved qualitative methods, including unstructured interviews, and mapping exercises, engaging 20 residents from diverse age groups (above 18 years old), genders, and residency durations within Wendel Phillips. This comprehensive approach aimed to straighten out how demographic variances influence the perception of identity within a shared environment characterized by similar challenges and aspirations. By amplifying the voices of the community, this study seeks to spotlight multifaceted perspectives, diverse familiarities, and future visions, ultimately proposing inclusive changes.
Place identity plays a pivotal role in an individual's self-concept and their connection with the broader world, fostering a profound sense of belonging to a specific place or community. By scrutinizing a spectrum of personal perceptions across different ages and genders within the neighborhood, this research endeavors to reshape the prevailing narrative from suppression to optimism for the future. It emphasizes the profound impact of stories on shaping present perceptions and empowering the potential trajectory of the neighborhood. Recognizing the evolutionary nature of identity with perceptions, this study challenges the subjective essence of place identity. It sheds light on residents proposed future changes, offering a glimpse into transformative pathways within the community. By embracing diverse narratives, this research underlines the dynamic nature of identity within a shared space and the implications for future development.
In essence, this study not only unties the complexities of place identity within a marginalized community but also advocates for a more inclusive and empowered future. By acknowledging and amplifying diverse perspectives, it paves the way for understanding the nuanced interplay between individual identities and the environment, envisioning a neighborhood that thrives on collective narratives and inclusive transformations
Teaching How Official History Is Made: State Standards as Primary Sources
No full textThe supplemental files from the article are included in this record. The accompanying video is available at http://www.kaltura.com/tiny/yfkx6 .This article traces the controversial rise and uses of state history standards for K-12 education and offers teachers a flexible lesson plan that encourages them to draw upon the standards in their own state to help students better understand the complexities of how local constructions of official knowledge are formulated. Jackson provides a quick history of the rise of state history standards in the American context beginning in the 1970s and 1980s; an ensemble of discussion questions about what history standards include, what they leave out, and how they balance critical thinking and content coverage; and a writing assignment that asks students to identify and revise what they see as a problematic single history standard
Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus
No full textFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.
IMPORTANCE
Food-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals
“The Indians Complain, and with Good Cause”: Allotting Standing Rock—U.S. Policy Meets a Tribe’s Assertion of Rights
No full textLand allotment was embraced by the U.S. Government in the late 1800s and early 1900s as part of a solution to the “Indian problem”, the goal of which was assimilation into the Euro-American cultural and economic system. As a progressivist program, it was imposed with enthusiasm and confidence, dividing reservations into rectangular land parcels (allotments) in the belief that the allotment recipients would become yeoman farmers of the Jeffersonian mold. Tribes were unable to thwart the imposition of allotment, despite their best efforts, and its devastating long-term effects are now well known. Much less is understood, however, about the efforts of various tribes, sometimes successful and sometimes not, to obtain modifications to the terms of allotment imposed on them. We describe how the people of the Standing Rock Reservation in North and South Dakota successfully advocated for modifications which worked to their significant advantage. We draw heavily from the outgoing correspondence and allotment records of the Special Allotting Agent, Carl Gunderson, along with contemporaneous records of legislative proceedings and other documents. The successful efforts of the people of Standing Rock resulted not only in equitable access to scarce timber, but in allotments to numerous individuals who otherwise would have been ineligible. The net impact was the additional allotment of nearly 400,000 acres (160,000 ha) to over 1800 individuals who otherwise would have received nothing
Fixed-Stress Systems
No full textSlavic languages are noted for their historical preservation of elements of a pitch-accent system that was characteristic of Proto-Slavic and is closely related to an analogous system in Baltic, which are characterized by lexically determined paradigmatic-stress patterns, each with distinct distributions of pitch and stress placement. In subsets of the modern Slavic languages, systems with fixed stress have developed, most notably in West Slavic (Czech, Slovak, Polish, Kashubian, and Upper and Lower Sorbian) and South Slavic (Macedonian). The entry treats the synchronic distribution of such systems, variations found in regional varieties, and partially fixed systems. A sketch of views on historical motivations for and processes leading to fixed systems is also presented.Work on this article was supported under the auspices of the Foreign Visitors Fellowship Program, Fall 2022, from the Slavic-Eurasian Research Center, Hokkaido University, Japan. The work benefitted from discussions with hosts and audience members following the author's presentation at the 126th NINJAL Colloquium "The Reduction of Word-Prosody Systems in Slavic Languages and Dialects (with Some Furtive Comparison to Japanese)," Tokyo, Oct. 4, 2022, organized by Dr. Motoki Nomachi / 野町 素己 (SRC, Hokkaido) and Dr. Yosuke Igarashi / 五十嵐陽介 (NINJAL, Tokyo)
Comparing Approximated Heat Stress Measures Across the United States
No full textClimate change is escalating the threat of heat stress to global public health, with the majority of humans today facing increasingly severe and prolonged heat waves. Accurate weather data reflecting the complexity of measuring heat stress is crucial for reducing the impact of extreme heat on health worldwide. Previous studies have employed Heat Index (HI) and Wet Bulb Globe Temperature (WBGT) metrics to understand extreme heat exposure, forming the basis for heat stress guidelines. However, systematic comparisons of meteorological and climate data sets used for these metrics and the related parameters, like air temperature, humidity, wind speed, and solar radiation crucial for human thermoregulation, are lacking. We compared three heat measures (HImax, WBGTBernard, and WBGTLiljegren) approximated from gridded weather data sets (ERA5‐Land, PRISM, Daymet) with ground‐based data, revealing strong agreement from HI and WBGTBernard (R 2 0.76–0.95, RMSE 1.69–6.64°C). Discrepancies varied by Köppen‐Geiger climates (e.g., Adjusted R 2 HImax 0.88–0.95, WBGTBernard 0.79–0.97, and WBGTLiljegren 0.80–0.96), and metrological input variables (Adjusted R 2 T max 0.86–0.94, T min 0.91–0.94, Wind 0.33, Solarmax 0.38, Solaravg 0.38, relative humidity 0.51–0.74). Gridded data sets can offer reliable heat exposure assessment, but further research and local networks are vital to reduce measurement errors to fully enhance our understanding of how heat stress measures link to health outcomes
“This Sea of Upturned Faces”: The Rhetorical Role of Audience in Frederick Douglass’s Constitutional Interpretation at Midcentury
No full textThis is a pre-copyedited, author-produced version of an article accepted for publication in MELUS following peer review. The version of record Laura L Mielke, “This Sea of Upturned Faces”: The Rhetorical Role of Audience in Frederick Douglass’s Constitutional Interpretation at Midcentury, MELUS, Volume 49, Issue 1, Spring 2024, Pages 3–27is available online at:, https://doi.org/10.1093/melus/mlae009Laura L Mielke, “This Sea of Upturned Faces”: The Rhetorical Role of Audience in Frederick Douglass’s Constitutional Interpretation at Midcentury, MELUS, Volume 49, Issue 1, Spring 2024, Pages 3–27, https://doi.org/10.1093/melus/mlae00
Expanding the CRISPR Toolbox for Engineering Lycopene Biosynthesis in Corynebacterium Glutamicum
No full textLycopene represents one of the central compounds in the carotenoid pathway and it exhibits a potent antioxidant ability with wide potential applications in medicine, food, and cosmetics. The microbial production of lycopene has received increasing concern in recent years. () is considered to be a safe and beneficial industrial production platform, naturally endowed with the ability to produce lycopene. However, the scarcity of efficient genetic tools and the challenge of identifying crucial metabolic genes impede further research on for achieving high-yield lycopene production. To address these challenges, a novel genetic editing toolkit, CRISPR/MAD7 system, was established and developed. By optimizing the promoter, ORI and PAM sequences, the CRISPR/MAD7 system facilitated highly efficient gene deletion and exhibited a broad spectrum of PAM sites. Notably, 25 kb of DNA from the genome was successfully deleted. In addition, the CRISPR/MAD7 system was effectively utilized in the metabolic engineering of , allowing for the simultaneous knockout of and genes in one step to enhance the accumulation of lycopene by blocking the branching pathway. Through screening crucial genes such as , , , , , and , an optimal carotenogenic gene combination was obtained. Particularly, , a membrane protein gene, was found to play a vital role in lycopene production. Therefore, the CBIEbR strain was obtained by overexpressing , , and while strategically blocking the by-products of the lycopene pathway. As a result, the final engineered strain produced lycopene at 405.02 mg/L (9.52 mg/g dry cell weight, DCW) in fed-batch fermentation, representing the highest reported lycopene yield in to date. In this study, a powerful and precise genetic tool was used to engineer for lycopene production. Through the modifications between the host cell and the carotenogenic pathway, the lycopene yield was stepwise improved by 102-fold as compared to the starting strain. This study highlights the usefulness of the CRISPR/MAD7 toolbox, demonstrating its practical applications in the metabolic engineering of industrially robust