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Site-specific incorporation of unnatural amino acids (Uaas) in living cells relies on engineered aminoacyl-transfer RNA synthetase–tRNA pairs borrowed from a distant domain of life. Such heterologous suppressor tRNAs often have poor intrinsic activity, presumably due to suboptimal interaction with a non-native translation system. This limitation can be addressed in Escherichia coli using directed evolution. However, no suitable selection system is currently available to do the same in mammalian cells. Here we report virus-assisted directed evolution of tRNAs (VADER) in mammalian cells, which uses a double-sieve selection scheme to facilitate single-step enrichment of active yet orthogonal tRNA mutants from naive libraries. Using VADER we developed improved mutants of Methanosarcina mazei pyrrolysyl-tRNA, as well as a bacterial tyrosyl-tRNA. We also show that the higher activity of the most efficient mutant pyrrolysyl-tRNA is specific for mammalian cells, alluding to an improved interaction with the unique mammalian translation apparatus. Virus-assisted directed evolution of tRNAs (VADER) enables selection of improved suppressor tRNAs in mammalian cells. Improved pyrrolysyl- and tyrosyl-tRNA variants enhance unnatural amino acid incorporation in mammalian systems.

We develop a continuum of stochastic dominance rules for expected utility maximizers. The new rules encompass the traditional integer-degree stochastic dominance; between adjacent integer degrees, they formulate the consensus of individuals whose absolute risk aversion at the corresponding integer degree has a negative lower bound. By extending the concept of “uniform risk aversion” previously proposed in the literature to high-order risk preferences, we interpret the fractionalized degree parameter as a benchmark individual relative to whom all considered individuals are uniformly no less risk averse in the lottery choices. The equivalent distribution conditions for the new rules are provided, and the fractional degree “increase in risk” is defined. We generalize the previously defined notion of “risk apportionment” and demonstrate its usefulness in characterizing comparative statics of risk changes in fractional degrees. This paper was accepted by David Simchi-Levi, decision analysis .

Leshno and Levy [Leshno M, Levy H (2002) Preferred by \"all\" and preferred by \"most\" decision makers: Almost stochastic dominance. Management Sci. 48(8):1074-1085] established almost stochastic dominance to reveal preferences for most rather than all decision makers with an increasing and concave utility function. In this paper, we first provide a counterexample to the main theorem of Leshno and Levy related to almost second-degree stochastic dominance. We then redefine this dominance condition and show that the newly defined almost second-degree stochastic dominance is the necessary and sufficient condition to rank distributions for all decision makers excluding the pathological concave preferences. We further extend our results to almost higher-degree stochastic dominance. This paper was accepted by Peter Wakker, decision analysis.

There is a wide variation in the reported prevalence of primary hyperhidrosis in the literature. Further, it is unknown if primary hyperhidrosis is a lifelong condition, or if demographical factors influence hyperhidrosis prevalence. This study aims to examine the prevalence of hyperhidrosis in multiple ethnic groups from two ethnically diverse cities and to determine if the prevalence of primary hyperhidrosis changes according to age, gender, ethnicity, body mass index, and geographical locations. In total, 1010 consecutive subjects attending dermatology outpatient clinics in Shanghai Skin Disease Hospital and 1018 subjects in Skin Care Center of Vancouver General Hospital were invited to fill out a questionnaire on their presenting concerns, demographical information, and sweating symptoms. The subjects were then classified to have primary hyperhidrosis using the criteria of International Hyperhidrosis Society, late-onset hyperhidrosis, or no-hyperhidrosis. The prevalence of primary HH and late-onset HH was calculated for the entire study population and in subgroups stratified according to age of examination, sex, ethnicity, presenting diagnosis, body mass index, and specific study cities. Multivariate logistic regression analyses were performed to assess the impact of these factors on HH prevalence. The prevalence of primary hyperhidrosis is very similar in Shanghai and in Vancouver, at 14.5% and 12.3% respectively. In addition, 4.0% of subjects in Shanghai and 4.4% subjects in Vancouver suffer from late-onset HH. Primary HH has highest prevalence in those younger than 30 years of age, decreasing dramatically in later years. Caucasian subjects are at least 2.5 times more likely to develop axillary hyperhidrosis compared to Chinese subjects. Obesity does not have much influence on primary HH presentation, although it does increase significantly the development of late-onset HH. Finally, there is no major difference of hyperhidrosis between Chinese subjects in Shanghai and Vancouver. The data were gathered according to patients' self-reports only and the sample size was relatively small in some groups after stratification for gender, ethnicity and age. Prevalence of primary HH and late-onset HH is similar in dermatology outpatients independent of geographical locations. However, certain specific HH subtypes can show great variations according to ethnicity, age, body mass index and sex.

Almost stochastic dominance allows small violations of stochastic dominance rules to avoid situations where most decision makers prefer one alternative to another but stochastic dominance cannot rank them. While the idea behind almost stochastic dominance is quite promising, it has not caught on in practice. Implementation issues and inconsistencies between integral conditions and their associated utility classes contribute to this situation. We develop generalized almost second-degree stochastic dominance and almost second-degree risk in terms of the appropriate utility classes and their corresponding integral conditions, and extend these concepts to higher degrees. We address implementation issues and show that generalized almost stochastic dominance inherits the appealing properties of stochastic dominance. Finally, we define convex generalized almost stochastic dominance to deal with risk-prone preferences. Generalized almost stochastic dominance could be useful in decision analysis, empirical research (e.g., in finance), and theoretical analyses of applied situations.

Levy [Levy H (2016) Aging population, retirement, and risk taking. Management Sci. 62(5):1415–1430.] proposes asymptotic first-degree stochastic dominance (AFSD) as a distribution-ranking criterion for all nonsatiable decision makers with infinite investment horizons. By assuming that the terminal wealth follows a log-normal distribution and that the marginal utility is bounded, he offers the necessary and sufficient distributional condition for AFSD. Given Levy’s setting, we provide a counterexample to show that his condition is not necessary and offer the correct equivalent distributional condition for AFSD. This paper was accepted by Karl Diether, finance.

Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference >  + 2, < − 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.

Using data from a Taiwanese finance company, this paper empirically investigates the value of soft information, information that requires the subjective interpretation by the loan officers who collect it and cannot be credibly transmitted to others, for making small business loans. It finds that the use of soft information significantly improves the power of default prediction models. It also identifies the types of soft information that are helpful for predicting loan defaults. In addition, it shows that borrowers with more favorable soft information enjoy lower interest rates. These results imply that soft information is important for small business lending.

Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen organization that was translated into significantly increased wound tensile strength compared to controls. Overall, VTI-1002 gel was well-tolerated in vivo and no adverse events were observed. Topical application of VTI-1002 represents a novel therapeutic approach for the treatment of cutaneous burn wounds. Chronic wounds: Gel encourages healing and reduces scarring A promising, recently developed topical treatment prevents detrimental enzyme activity in burn wounds, accelerates healing and reduces scarring. Chronic wounds that do not heal fully and require ongoing medical attention are common in the elderly, obese, and/or diabetic populations, resulting in enormous costs to healthcare services. Recent research indicates that an enzyme called granzyme. (GzmB) accumulates in chronically inflamed wounds, impairing collagen organization and disrupting tissue remodeling. David Granville at the University of British Columbia, Vancouver, Canada, and co-workers trialed a topical gel designed to inhibit GzmB activity in burn injuries in diabetic mice. When applied to the wounds for 30 days, the gel improved wound closure and remodeling while reducing scarring. The gel targeted wounds directly with no effect on surrounding tissues, and no adverse effects were observed during treatment.

We examine insurance markets with two-dimensional asymmetric information on risk type and on preferences related to regret. In contrast to Rothschild and Stiglitz (1976), the equilibrium can be efficient; that is, it can coincide with the equilibrium under full information. Furthermore, we show that pooling, semipooling, and separating equilibria can exist. Specifically, there exist separating equilibria that predict a positive correlation between the level of insurance coverage and risk type, as in the standard economic models of adverse selection, but there also exist separating equilibria that predict a negative correlation between the level of insurance coverage and risk type. Since optimal choice of regretful customers depends on foregone alternatives, the equilibrium includes a contract that is offered but not purchased.