Genetic variants that introduce premature termination codons (PTCs) have remained difficult to therapeutically target due to lack of protein product. Nonsense mediated mRNA decay (NMD) targets PTC-bearing transcripts to reduce the potentially damaging effects of truncated proteins. Readthrough compounds have been tested on PTC-generating variants in attempt to permit translation through a premature stop. However, readthrough compounds have not proved efficacious in a clinical setting due to lack of stable mRNA. Here, we investigate N-terminal variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which have been shown to escape NMD, potentially through a mechanism of alternative translation initiation at downstream AUG codons. We hypothesized that N-terminal variants in CFTR that evade NMD will produce stable transcript, allowing CFTR function to be restored by a combination of readthrough and protein modulator therapy. We investigate this using two cell line models expressing CFTR-expression minigenes (EMG; HEK293s and CFBEs) and primary human nasal epithelial (NE) cells, and we test readthrough compounds G418 and ELX-02 in combination with CFTR protein modulators. HEK293 cells expressing the variants E60X and L88X generate CFTR-specific core glycosylated products that are consistent with downstream translation initiation. Mutation of downstream methionines at codons 150 and 152 does not result in changes in CFTR protein processing in cells expressing L88X-CFTR-EMG. However, mutation of methionine at 265 results in loss of detectable CFTR protein in cells expressing E60X, L88X, and Y122X CFTR-EMGs, indicating that downstream translation initiation is occurring at the AUG codon at position M265. In HEK293 stable cells harboring L88X, treatment with readthrough compounds alone allows for formation of full-length, but misfolded CFTR protein. Upon addition of protein modulators in combination with readthrough, we observe formation of mature, complex-glycosylated CFTR. In CFBE and NE cells, addition of readthrough ELX-02 and modulator therapy results in substantial recovery of CFTR function. Our work indicates that N-terminal variants generate stable CFTR transcript due to translation initiation at a downstream AUG codon. Thus, individuals with CF bearing 5′ nonsense variants that evade NMD are ideal candidates for treatment with clinically safe readthrough compounds and modulator therapy.

Prospect theory has been an essential theoretical foundation for behavioral economics, as recognized with the Nobel Prize in economic sciences in 2002. The growing interest in behavioral economics among tourism researchers necessitates a systematic assessment of prospect theory and its application in tourism research to critically examine the current status of tourism decision-making studies. This study therefore clarifies the theoretical background of prospect theory and analyzes 93 published studies to examine how prospect theory has performed in explaining tourism decision-making. The study also evaluates the application of prospect theory in tourism research and provides future research directions with respect to under-researched dimensions, reference points, dynamic decision-making processes, and the logical continuity and systemization of prospect theory.

Purpose This study aims to critically evaluate hospitality and tourism demand research and introduce a behavioral economics approach to solve the problems faced by researchers. Design/methodology/approach Current issues in hospitality and tourism demand analysis are identified through critical reflection, and a behavioral economics approach is adopted to develop a new conceptual framework. Findings Four issues in hospitality and tourism studies are identified from the microeconomic theory and econometric modeling perspectives. The study’s demand framework provides both a theoretical underpinning and quantitative models to resolve the identified issues. With a focus on consumers’ cost–benefit assessments in light of individual differences and environmental factors, the authors’ conceptual framework represents a new effort to quantify hospitality and tourism demand at the disaggregate level with interactive multiple demand curve estimations. Research limitations/implications The study’s analytical framework for hospitality and tourism demand analysis is unique, and it fills the research gap. However, this research is still in the conceptual stage, and the authors leave it to future studies to empirically test the framework. Practical implications The proposed demand framework at the disaggregate level will benefit both private and public sectors involved in hospitality and tourism businesses in terms of pricing, marketing and policymaking. Originality/value The authors offer a new conceptual model that bridges the gap between aggregate and disaggregate hospitality and tourism demand analyses. Specifically, the authors identify research directions for future hospitality and tourism demand research involving individual tourists/consumers at the disaggregate level.