Medication-assisted treatment for youth with opioid use disorder: Current dilemmas and remaining questions

Chang, Derek C.; Klimas, Jan; Wood, Evan; Fairbairn, Nadia

doi:10.1080/00952990.2017.1399403

Cited by 39 publications

(32 citation statements)

References 19 publications

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“…We anticipate that an optimal translation protocol [48] could be predicted with knowledge of the substructure-specific folding and translation rates, as well as their propensities for forming non-native interactions, including interactions with the surface of the ribosome [49]. In addition, an optimal translation protocol is likely to be affected by the presence of misfolded intermediates, which may be avoided by increasing the local translation rate [50,51].The approach that we have taken in this work improves upon earlier studies of rare-codon usage, which have addressed alternative hypotheses regarding translational pausing but yielded mixed results [35,38,[52][53][54][55][56]. In addition to our distinct focus on co-translational folding pathways, our conclusions are more robust due to our use of a multiple-sequence analysis to detect evolutionary conservation, as well as our formulation of a neutral model that controls for both amino-acid composition and the inherent codon-usage variability across genes.…”

supporting

confidence: 53%

“…The approach that we have taken in this work improves upon earlier studies of rare-codon usage, which have addressed alternative hypotheses regarding translational pausing but yielded mixed results [35,38,[52][53][54][55][56]. In addition to our distinct focus on co-translational folding pathways, our conclusions are more robust due to our use of a multiple-sequence analysis to detect evolutionary conservation, as well as our formulation of a neutral model that controls for both amino-acid composition and the inherent codon-usage variability across genes.…”

Section: Discussionmentioning

confidence: 63%

“…The ribosome exit tunnel is widely believed to conceal between 30 and 40 amino acids [35,43], although a greater number may be accommodated in partially helical conformations [44]. In addition, some tertiary structure formation may commence within the exit-tunnel vestibule [45].…”

Section: Comparison With Predicted Co-translational Folding Pathwaysmentioning

confidence: 99%

“…Consequently, we have excluded N-terminal rare codons from our analysis. In addition to rare-codon usage, various studies have proposed that additional factors, such as interactions between the nascent chain and the ribosome exit tunnel [35] or the presence of internal Shine-Dalgarno motifs [30], can affect translation rates. It is likely that a more complete picture of sequence-dependent translation kinetics will enable further refinements to the co-translational folding model presented here.…”

Section: Cc-by-nc-nd 40 International License Peer-reviewed) Is the mentioning

confidence: 99%

“…codons that are used substantially less often than alternate synonymous codons in highly expressed genes [28]. Despite numerous attempts to predict codon-specific translation rates based on physical factors [29][30][31][32], such as tRNA concentrations, translationspeed estimates based on relative-usage metrics [28,33] remain among the most accurate [34][35][36]. Thus, using codon rarity as a proxy for translation speed, we can look for pauses in synthesis by identifying regions in a mRNA transcript that are locally enriched in rare codons.…”

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confidence: 99%

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Evidence of evolutionary selection for co-translational folding

Jacobs

Shakhnovich

2017

Preprint

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Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from co-translational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for co-translational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with co-translational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of co-translational folding account for the majority of these loci across more than 500 E. coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context. INTRODUCTIONMany proteins can begin folding to their native states before their synthesis is complete [1,2]. As much as one-third of a bacterial proteome is believed to fold cotranslationally [3], with an even higher percentage likely in more slowly translated eukaryotic proteomes. Numerous experiments on both natural and engineered aminoacid sequences have shown that folding during synthesis can have profound effects: compared to denatured and refolded chains, co-translationally folded proteins may be less prone to misfolding [4][5][6][7][8][9][10][11], aggregation [12] and degradation [13], or they may preferentially adopt alternate stable structures [14][15][16]. Because the timescales for protein synthesis and folding are often similar [17,18], it is clear that the rate of translation can be used to tune the self-assembly of peptide chains in vivo [19,20]. To this point, however, there exists little evidence that evolution has selected specifically for efficient co-translational folding kinetics across any substantial fraction of an organism's proteome.In this work, we provide evidence that evolutionary selection has tuned protein-translation rates to optimize co-translational folding pathways. Our approach is motivated by the hypothesis that pauses during protein synthesis may be beneficial for promoting the formation of native structure. By increasing the separation between the timescales for folding and translation, such pauses may promote the assembly of on-pathway intermediates, which, in turn, template the growth of further native structure. Many experimental and computational studies have shown that protein-folding naturally proceeds in a step-wise manner via structurally distinct intermediates [21,22], and that...

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supporting

confidence: 53%

Section: Discussionmentioning

confidence: 63%

Section: Comparison With Predicted Co-translational Folding Pathwaysmentioning

confidence: 99%

Section: Cc-by-nc-nd 40 International License Peer-reviewed) Is the mentioning

confidence: 99%

mentioning

confidence: 99%

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Evidence of evolutionary selection for co-translational folding

Jacobs

Shakhnovich

2017

Preprint

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Access to Medications for Opioid Use Disorder and Associated Factors Among Adolescents and Young Adults

2022

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IMPORTANCEThe ongoing overdose crisis continues to adversely affect adolescents and young adults (AYAs) and has led to numerous preventable deaths. Medications for opioid use disorder (MOUD), such as methadone, buprenorphine, and naltrexone, have the potential to reduce opioid use and associated harms; however, there are concerns that AYAs lack access to these potentially life-saving medications.OBJECTIVE To systematically review peer-reviewed literature on MOUD access and associated factors to synthesize strategies that can improve MOUD access for AYAs who use opioids. EVIDENCE REVIEWThe MEDLINE, Embase, PsycINFO, CINAHL, Sociological Abstracts, Web of Science, and Global Dissertations & Theses databases were searched from database inception until May 3, 2021. English, French, Russian, or Spanish peer-reviewed studies that evaluated the availability, prescription receipt, or initiation of MOUD were eligible for inclusion.FINDINGS This systematic review identified 37 cohort (n = 17), cross-sectional (n = 15), and qualitative (n = 5) studies that accounted for 179 785 AYAs (mean [SD] age, 24.4 [3.9] years; 148 779 [85%] were female; 67 771 [84%] were White) and examined access to methadone (30 studies), buprenorphine (26 studies), and naltrexone (10 studies). Findings reinforce concerns that AYAs were less likely to access MOUD and suggest that adolescents were more likely to receive naltrexone or buprenorphine-naloxone, which have a lower potential for abuse, in comparison with young adults. This review also identified other factors that were associated with MOUD access, including criminal justice involvement, residing in the US South, living in a limited-income area, Black race, and Hispanic or Latino ethnicity, suggesting ways in which treatment services may be improved to increase MOUD access and meet the treatment goals of AYAs.CONCLUSION AND RELEVANCE This systematic review found gaps in MOUD access between AYAs and non-AYA populations in addition to differences in MOUD access between adolescents and young adults. Considering that existing clinical guidelines recommend the use of MOUD among AYAs, and in light of the increasing number of opioid toxicity deaths, there is a need to improve MOUD access among AYAs by reducing barriers to MOUD and providing AYAs with a continuum of health and social supports alongside MOUD. Future research into ways to encourage MOUD uptake among AYAs may improve the treatment and health outcomes for this population.

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Opioid use disorder and youth: Agonists recommended

Knopf¹

2020

Child and Adolescent Update

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Extreme concern about opioid overdoses and overdose deaths among young people is dovetailing with solutions — in particular, expanding treatment with buprenorphine and methadone for this population. Expansion of treatment for adolescents and young adults — ages 15 to 25 — with opioid use disorders (OUDs) is critical, researcher after researcher has written. But there has been a reticence by parents in particular, and even by some clinicians, about prescribing buprenorphine, a Schedule III opioid, to young people, or to sending them to an opioid treatment program (the only kind of facility in the United States where methadone can be dispensed for OUD). Both medications can be given to youth as young as 16.

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Medication-assisted treatment for youth with opioid use disorder: Current dilemmas and remaining questions

Cited by 39 publications

References 19 publications

Evidence of evolutionary selection for co-translational folding

Evidence of evolutionary selection for co-translational folding

Access to Medications for Opioid Use Disorder and Associated Factors Among Adolescents and Young Adults

Opioid use disorder and youth: Agonists recommended

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