Chemoinformatic-Guided Engineering of Polyketide Synthases.

Polyketide synthase (PKS) engineering is an attractive method to generate new molecules such as commodity, fine and specialty chemicals. A significant challenge is re-engineering a partially reductive PKS module to produce a saturated β-carbon through a reductive loop (RL) exchange. In this work, we sought to establish that chemoinformatics, a field traditionally used in drug discovery, offers a viable strategy for RL exchanges. We first introduced a set of donor RLs of diverse genetic origin and chemical substrates  into the first extension module of the lipomycin PKS (LipPKS1). Product titers of these engineered unimodular PKSs correlated with chemical structure similarity between the substrate of the donor RLs and recipient LipPKS1, reaching a titer of 165 mg/L of short-chain fatty acids produced by the host Streptomyces albus J1074. Expanding this method to larger intermediates that require bimodular communication, we introduced RLs of divergent chemosimilarity into LipPKS2 and determined triketide lactone production. Collectively, we observed a statistically significant correlation between atom pair chemosimilarity and production, establishing a new chemoinformatic method that may aid in the engineering of PKSs to produce desired, unnatural products

Functionalized Mesoporous SBA-15 with CeF3: Eu3+ Nanoparticle by Three Different Methods: Synthesis, Characterization, and Photoluminescence

Luminescence functionalization of the ordered mesoporous SBA-15 silica is realized by depositing a CeF3: Eu3+ phosphor layer on its surface (denoted as CeF3: Eu3+/SBA-15/IS, CeF3: Eu3+/SBA-15/SI and CeF3: Eu3+/SBA-15/SS) using three different methods, which are reaction in situ (I-S), solution impregnation (S-I) and solid phase grinding synthesis (S-S), respectively. The structure, morphology, porosity, and optical properties of the materials are well characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, N2 adsorption, and photoluminescence spectra. These materials all have high surface area, uniformity in the mesostructure and crystallinity. As expected, the pore volume, surface area, and pore size of SBA-15 decrease in sequence after deposition of the CeF3: Eu3+ nanophosphors. Furthermore, the efficient energy transfer in mesoporous material mainly occurs between the Ce3+ and the central Eu3+ ion. They show the characteristic emission of Ce3+ 5d → 4f (200–320 nm) and Eu3+5D0 → 7FJ(J = 1–4, with 5D0 → 7F1 orange emission at 588 nm as the strongest one) transitions, respectively. In addition, for comparison, the mesoporous material CeF3: Eu3+/SBA-15/SS exhibits the characteristic emission of Eu3+ ion under UV irradiation with higher luminescence intensity than the other materials

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Flavored Cannabis Product Use Among Adolescents in California.

Given the well-documented role of flavors in encouraging tobacco use among adolescents and diversity of the cannabis market, we describe flavored cannabis product use, both smoked and aerosolized ("vaped"), among a sample of adolescents. We surveyed 1,423 students in 8 Northern and Central California public high schools (2019-2020) to record flavored tobacco and cannabis use. Among past 30-day cannabis users, use of flavored cannabis, most often fruit-flavored, was common for smoked (48.1%) and vaped (58.0%) products. Given that youth-appealing flavors may contribute to underage cannabis use, emerging cannabis control policies should consider lessons from tobacco control to prevent youth cannabis use

Cannabis use among adolescents and emerging adults who use e-cigarettes: Findings from an online, national U.S. Sample

Concurrent use of e-cigarettes and cannabis among adolescents and emerging adults is a growing public health concern. More research is needed describing cannabis use among adolescents and emerging adults who vape. The objective of this study was to characterize cannabis use among adolescents and emerging adults (age 14-20) who reported e-cigarette ever-use, particularly their use of blunts and liquid cannabis vape (LCV) products. Using cross-sectional data from a national online survey, we describe their patterns of cannabis use, detail their use of flavored cannabis and tobacco products, and estimate associations of demographic factors and other current substance use behaviors with levels of blunt and LCV use. Of the 2253 respondents in the sample, 1379 (61 %) reported some form of cannabis use in the past 30 days, among whom 80 % used flavored cannabis (including edibles). Significant associations with current cannabis use were observed on several demographic measures, with current cannabis blunt use more frequent among participants not in school, non-Hispanic Blacks, multiracial respondents, and those whose incomes do not meet their expenses. Other than income, demographic characteristics were generally not associated with LCV use frequency. Use of other substances was associated with more frequent use of both blunts and LCV in the past 30 days, and enrollment in college or the military seems somewhat protective for emerging adults. These findings suggest a need for tailored prevention efforts among high-risk adolescents and emerging adults, potential regulation of added flavors in commercialized cannabis products, and stronger enforcement of retail restrictions for individuals under age 21 more broadly

Dental Therapists in the United States: Health Equity, Advancing.

BACKGROUND: Dental therapists (DTs) are primary care dental providers, used globally, and were introduced in the United States (US) in 2005. DTs have now been adopted in 13 states and several Tribal nations. OBJECTIVES: The objective of this study is to qualitatively examine the drivers and outcomes of the US dental therapy movement through a health equity lens, including community engagement, implementation and dissemination, and access to oral health care. METHODS: The study compiled a comprehensive document library on the dental therapy movement including literature, grant documents, media and press, and gray literature. Key stakeholder interviews were conducted across the spectrum of engagement in the movement. Dedoose software was used for qualitative coding. Themes were assessed within a holistic model of oral health equity. FINDINGS: Health equity is a driving force for dental therapy adoption. Community engagement has been evident in diverse statewide coalitions. National accreditation standards for education programs that can be deployed in 3 years without an advanced degree reduces educational barriers for improving workforce diversity. Safe, high-quality care, improvements in access, and patient acceptability have been well documented for DTs in practice. CONCLUSION: Having firmly taken root politically, the impact of the dental therapy movement in the US, and the long-term health impacts, will depend on the path of implementation and a sustained commitment to the health equity principle