NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

Structure of saguaro cactus virus 3' translational enhancer mimics 5' cap for eIF4E binding.

The genomes of several plant viruses contain RNA structures at their 3' ends called cap-independent translation enhancers (CITEs) that bind the host protein factors such as mRNA 5' cap-binding protein eIF4E for promoting cap-independent genome translation. However, the structural basis of such 5' cap-binding protein recognition by the uncapped RNA remains largely unknown. Here, we have determined the crystal structure of a 3' CITE, panicum mosaic virus-like translation enhancer (PTE) from the saguaro cactus virus (SCV), using a Fab crystallization chaperone. The PTE RNA folds into a three-way junction architecture with a pseudoknot between the purine-rich R domain and pyrimidine-rich Y domain, which organizes the overall structure to protrude out a specific guanine nucleotide, G18, from the R domain that comprises a major interaction site for the eIF4E binding. The superimposable crystal structures of the wild-type, G18A, G18C, and G18U mutants suggest that the PTE scaffold is preorganized with the flipped-out G18 ready to dock into the eIF4E 5' cap-binding pocket. The binding studies with wheat and human eIF4Es using gel electrophoresis and isothermal titration calorimetry, and molecular docking computation for the PTE-eIF4E complex demonstrated that the PTE structure essentially mimics the mRNA 5' cap for eIF4E binding. Such 5' cap mimicry by the uncapped and structured viral RNA highlights how viruses can exploit RNA structures to mimic the host protein-binding partners and bypass the canonical mechanisms for their genome translation, providing opportunities for a better understanding of virus-host interactions and non-canonical translation mechanisms found in many pathogenic RNA viruses.

What about the Rest of Them? Fatal Injuries Related to Production Agriculture Not Captured by the Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI).

Surveillance of injuries in production agriculture is necessary to inform stakeholders about workplace hazards and risks in order to improve and advance injury prevention policies and practices for this dangerous industry. The most comprehensive fatal injury surveillance effort currently in the United States is the Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI), which covers occupational fatalities in all U.S. industries, including production agriculture. However, this surveillance does not include many categories of fatalities that occur during agricultural work or on production agriculture worksites. To better capture the human cost of production agriculture, the authors of this paper call for the collection of additional data with a broader scope that supplements, not replaces, the current CFOI. This paper describes challenges in surveillance, highlights key procedural gaps, and offers recommendations for advancing national surveillance of fatal traumatic injuries associated with production agriculture.

Coding agricultural injury: Factors affecting coder agreement.

OBJECTIVES: To determine coders' agreement level for the Occupational Injury and Illness Classification System (OIICS) source of injury and injury event codes, and the Farm and Agricultural Injury Classification (FAIC) code in the AgInjuryNews.org and to determine the effects of supplemental information and follow-up discussion in final code assignments. METHODS: Two independent researchers initially coded 1304 injury cases from AgInjurynews.org using the OIICS and the FAIC coding schemes. Code agreement levels for injury source, event, and FAIC and the effect of supplemental information and follow-up discussions on final coding was assessed. RESULTS: Coders' agreement levels were almost perfect for OIICS source and event categories at the 3-digit level, with lower agreement at the 4-digit level. By using supplemental information and follow-up discussion, coders improved the coding accuracy by an average 20% for FAIC. Supplemental information and follow-up discussions had helped finalize the disagreed codes 55% of the time for OIICS source coding assignments and 40% of time for OIICS event coding assignments for most detailed 4-digit levels. Five key themes emerged regarding accurate and consistent coding of the agricultural injuries: inclusion/exclusion based on industry classification system; inconsistent/discrepant reports; incomplete/nonspecific reports; effects of supplemental information on coding; and differing interpretations of code selection rules. Practical applications: Quantifying the level of agreement for agricultural injuries will lead to a better understanding of coding discrepancies and may uncover areas for improvement to coding scheme itself. High level of initial and final agreement with FAIC and OIICS codes suggest that these coding schemes are user-friendly and amenable to widespread use.

Redesigning a Sentinel Surveillance System for Collecting and Disseminating Near Real-Time Agricultural Injury Reports: System Usability Study.

BACKGROUND: Injury data and reports provide valuable information for both public and private organizations to guide programming, policy, and prevention, but in the increasingly complex and dangerous industry of US agriculture, the injury surveillance needed to produce this data is lacking. To address the gap, AgInjuryNews was established in 2015. The system includes fatal and nonfatal injury cases derived from publicly available reports, including occupational and nonoccupational injuries, occurring in the agricultural, forestry, and fishing (AFF) industry. OBJECTIVE: The study aimed to develop a stakeholder-engaged redesign of the interactive, up-to-date, and publicly available dataset of US AFF injury and fatality reports. METHODS: Instructor-led heuristic evaluations within a 15-student undergraduate course, data from 8 student participants of laboratory-based usability testing and 2016 and 2017 AgInjuryNews-registered user surveys, coupled with input from the National Steering Committee informed the development priorities for 2018. An interdisciplinary team employed an agile methodology of 2-week sprints developing in ASP.NET and Structured Query Language to deliver an intuitive frontend and a flexible, yet structured, backend, including a case report input form for capturing more than 50 data points on each injury report. RESULTS: AgInjuryNews produced 17,714 page views from 43 countries in 2018 captured via Google Analytics, whereas 623 injury reports were coded and loaded, totaling more than 31,000 data points. Newly designed features include customizable email alerts, an interactive map, and expanded search and filter options. User groups such as the Bureau of Labor Statistics and the Agricultural Safety and Health Council of America have endorsed the system within their networks. News media have cited or referenced the system in national outlets such as the New York Times, Politico, and the Washington Post. CONCLUSIONS: The new system's features, functions, and improved data granularity have sparked innovative lines of research and increased collaborative interest domestically and abroad. It is anticipated that this nontraditional sentinel surveillance system and its dataset will continue to serve many purposes for public and private agricultural safety and health stakeholders in the years to come. .

Supporting Disabled People's Independence With Digital Skills in the Community.

This presentation discusses research by Good Things Foundation with community organisations supporting disabled people within the national Online Centres network, to explore the barriers to digital inclusion (DI) they face. The research informed a handbook to help similar organisations get disabled people online.