Metabolic Engineering of Corynebacterium glutamicum for the Production of Flavonoids and Stilbenoids.

Flavonoids and stilbenoids, crucial secondary metabolites abundant in plants and fungi, display diverse biological and pharmaceutical activities, including potent antioxidant, anti-inflammatory, and antimicrobial effects. However, conventional production methods, such as chemical synthesis and plant extraction, face challenges in sustainability and yield. Hence, there is a notable shift towards biological production using microorganisms like Escherichia coli and yeast. Yet, the drawbacks of using E. coli and yeast as hosts for these compounds persist. For instance, yeast's complex glycosylation profile can lead to intricate protein production scenarios, including hyperglycosylation issues. Consequently, Corynebacterium glutamicum emerges as a promising alternative, given its adaptability and recent advances in metabolic engineering. Although extensively used in biotechnological applications, the potential production of flavonoid and stilbenoid in engineered C. glutamicum remains largely untapped compared to E. coli. This review explores the potential of metabolic engineering in C. glutamicum for biosynthesis, highlighting its versatility as a cell factory and assessing optimization strategies for these pathways. Additionally, various metabolic engineering methods, including genomic editing and biosensors, and cofactor regeneration are evaluated, with a focus on C. glutamicum. Through comprehensive discussion, the review offers insights into future perspectives in production, aiding researchers and industry professionals in the field.

Human Platelet Derived Mitochondrial OPA-1 Isoforms and Interaction With TDP-43 in Neurodegenerative Diseases.

Optic atrophy 1(OPA1) is a GTPase protein that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), the mitochondrial network morphology is compromised. Studies on TAR-DNA binding protein 43 (TDP-43) has been the focus in our lab. OPA1 and TDP-43 interaction may shed a light on how aberrant TDP-43 interacts with OPA1, which will lead to mitochondrial dysfunction. The preliminary study tested the idea of whether OPA1 and TDP-43 are physically interacting in human platelet derived mitochondria obtained from healthy human subjects.

Genetic Survey of Psilocybe Natural Products.

Psilocybe magic mushrooms are best known for their main natural product, psilocybin, and its dephosphorylated congener, the psychedelic metabolite psilocin. Beyond tryptamines, the secondary metabolome of these fungi is poorly understood. The genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) were browsed to understand more profoundly common and species-specific metabolic capacities. The genomic analyses revealed a much greater and yet unexplored metabolic diversity than evident from parallel chemical analyses. P. cyanescens and P. mexicana were identified as aeruginascin producers. Lumichrome and verpacamide A were also detected as Psilocybe metabolites. The observations concerning the potential secondary metabolome of this fungal genus support pharmacological and toxicological efforts to find a rational basis for yet elusive phenomena, such as paralytic effects, attributed to consumption of some magic mushrooms.

Humin-promoted microbial electrosynthesis of acetate from CO2 by Moorella thermoacetica.

Humin, an insoluble fraction of humic substances at any pH, has been reported to be an extracellular electron mediator (EEM) that functions in carbon dioxide (CO2 )-fixing acetogenesis. Here, we show that humin promotes the microbial electrosynthesis (MES) of acetate from CO2 using Moorella thermoacetica. Yeast extract, essential for the reaction of M. thermoacetica, resulted in the heterotrophic production of organic acids including acetate, hydrogen, and methane. Excluding the effect of yeast extract, MES with 13 g/L of suspended humin poised at -510 mV (vs. Ag/AgCl) achieved a CO2 -fixing acetate production of 24.2 mg-acetate/L/day (1.9 mg-acetate/day/g-humin); this is 10-folds higher than the humin-free MES, with 90.3% of the coulombic efficiency. Although M. thermoacetica is an electroactive bacterium, it obtains electrons for acetogenesis mostly via humin. The suspended humin-assisted MES poised at -810 mV (vs. Ag/AgCl) increased the acetate production rate to 39.3 mg-acetate/L/day using electrons mainly from electrolyzed hydrogen and humin. Immobilization increased the humin's EEM efficiency, as indicated by the acetate production rate of 20.8 mg-acetate/L/day (6.9 mg-acetate/day/g-humin) with a 98.7% coulombic efficiency in MES with 3 g/L of immobilized humin poised at -510 mV (vs. Ag/AgCl). These results suggest that humin-assisted MES has high potential for microbial CO2 fixation.

Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants.

PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.

A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity.

Epilepsy and Mental Retardation Limited to Females (EFMR) is an infantile onset disorder characterized by clusters of seizures. EFMR is due to mutations in the X-chromosome gene PCDH19, and is underpinned by cellular mosaicism due to X-chromosome inactivation in females or somatic mutation in males. This review characterizes the neuropsychiatric profile of this disorder and examines the association of clinical and molecular factors with neuropsychiatric outcomes. Data were extracted from 38 peer-reviewed original articles including 271 individual cases. We found that seizure onset ≤12 months was significantly associated (p = 4.127 × 10-7) with more severe intellectual disability, compared with onset >12 months. We identified two recurrent variants p.Asn340Ser and p.Tyr366Leufs*10 occurring in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. PCDH19 mutations were associated with psychiatric comorbidities in approximately 60% of females, 80% of affected mosaic males, and reported in nine hemizygous males. Hyperactive, autistic, and obsessive-compulsive features were most frequently reported. There were no genotype-phenotype associations in the individuals with recurrent variants or the group overall. Age at seizure onset can be used to provide more informative prognostic counseling.

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα).

De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.

Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency.

Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression; enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.

Evaluation of popular drug information resources on clinically useful and actionable pharmacogenomic information.

BACKGROUND: Pharmacogenomics is the study of how genes affect a person's response to drugs. This descriptive study assessed whether popular drug information resources provide clinically useful pharmacogenomic (PGx) information. METHODS: Four resources (package inserts, Lexicomp, Micromedex 2.0, and Epocrates) were evaluated for information about twenty-seven drugs. RESULTS: There was wide variability of PGx information. Whereas Lexicomp included relevant PGx biomarker information for all 27 drugs, Epocrates did in less than 50% of the drugs. None of the resources had monographs that fully incorporated Clinical Pharmacogenomics Implementation Consortium (CPIC) recommendations in more than 30% of the drugs. CONCLUSION: Lexicomp appears to be most useful PGx drug information resource, but none of the resources are sufficient.

Wide distribution of extracellular electron transfer functionality in natural proteinaceous organic materials for microbial reductive dehalogenation.

Extracellular electron transfer materials (EETMs) in the environment, such as humic substances and biochar, are formed from the humification/heating of natural organic materials. However, the distribution of extracellular electron transfer (EET) functionality in fresh natural organic materials has not yet been explored. In the present study, we reveal the wide distribution of EET functionality in proteinaceous materials for the first time using an anaerobic pentachlorophenol dechlorinating consortium, whose activity depends on EETM. Out of 11 natural organic materials and 13 reference compounds, seven proteinaceous organic materials (albumin, beef, milk, pork, soybean, yolk, and bovine serum albumin) functioned as EETMs. Carbohydrates and lipids did not function as EETMs. Comparative spectroscopic analyses suggested that a ß-sheet secondary structure was essential for proteins to function as EETMs, regardless of water solubility. A high content of reduced sulfur was potentially involved in EET functionality. Although proteinaceous materials have thus far been considered simply as nutrients, the wide distribution of EET functionality in these materials provides new insights into their impact on biogeochemical cycles. In addition, structural information on EET functionality can provide a scientific basis for the development of eco-friendly EETMs.

Bis(4-acetoxy-N-ethyl-N-n-propyl-tryptammonium) fumarate-fumaric acid (1/1).

The solid-state structure of the title salt/adduct (systemic name: bis-{[2-(4-acet-yloxy-1H-indol-3-yl)eth-yl](eth-yl)propyl-aza-nium} but-2-enedioate-(E)-butenedioic acid (1/1)), 2C17H25N2O2 +·C4H2O4 2-·C4H4O4, was determined by single-crystal X-ray diffraction. The asymmetric unit consists of a singly protonated tryptammonium cation, one half of a fumarate dianion and one half of a fumaric acid mol-ecule. In the crystal, the ions and mol-ecules are linked together in infinite chains propagating along [001] through a series of N-H⋯O and O-H⋯O hydrogen bonds.

Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice.

Analogues of 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) are being sold on recreational drug markets and developed as potential medications for psychedelic-assisted therapies. Many of these tryptamine-based psilocybin analogues produce psychedelic-like effects in rodents and humans primarily by agonist activity at serotonin 2A receptors (5-HT2A). However, the comprehensive pharmacological target profiles for these compounds compared to psilocybin and its active metabolite 4-hydroxy-N,N-dimethyltryptamine (psilocin) are unknown. The present study determined the receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin across a broad range of potential targets. Specifically, we examined tryptamine psychedelics with different 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl (dimethyl, methyl-ethyl, diethyl, methyl-propyl, ethyl-propyl, diisopropyl, methyl-allyl, diallyl) substitutions. Further, the psilocybin analogue 4-propionoxy-N,N-dimethyltryptamine (4-PrO-DMT) was administered to mice in experiments measuring head twitch response (HTR), locomotor activity, and body temperature. Overall, the present pharmacological profile screening data show that the tryptamine psychedelics target multiple serotonin receptors, including serotonin 1A receptors (5-HT1A). 4-Acetoxy and 4-propionoxy analogues of 4-hydroxy compounds displayed somewhat weaker binding affinities but similar target profiles across 5-HT receptors and other identified targets. Additionally, differential binding screen profiles were observed with N,N-dialkyl position variations across several non-5-HT receptor targets (i.e., alpha receptors, dopamine receptors, histamine receptors, and serotonin transporters), which could impact in vivo pharmacological effects of the compounds. In mouse experiments, 4-PrO-DMT displayed dose-related psilocybin-like effects to produce 5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) as well as 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.). Lastly, our data support a growing body of evidence that the 5-HT2A-mediated HTR induced by tryptamine psychedelics is attenuated by 5-HT1A receptor agonist activity at high doses in mice.

Pandemic-Related Stress and Resilience Among Latinx Mothers with a History of Depression: Differences by Immigration Status.

This study explores the impact of the COVID-19 pandemic on low-income, Latinx mothers in Southern California with a history of depression, including undocumented mothers and members of mixed status families. Drawing participants from a parent study that provided a maternal depression intervention to Head Start mothers (n = 119), this mixed method study integrates qualitative and quantitative data in a convergent design. Thirty-four mothers completed semi-structured qualitative interviews and standardized questionnaires in the fall of 2020. Mothers shared overwhelming economic difficulties, with the majority reporting that their family income decreased and half reporting that they were unable to pay for housing. Stressors were compounded for undocumented mothers and members of mixed-status families who were excluded from major relief programs. Stress affected maternal mental health, and mothers with precarious status reported differences in functioning. Mothers also identified positive ways that they coped with adversity. Results show that Latinx mothers with a history of depression, particularly mothers with precarious immigration status, continue to suffer considerable economic, social, and emotional impacts of the COVID-19 pandemic. Social workers can support the human rights of this population by advocating for financial relief, food assistance, and the expansion of medical-legal partnerships and physical and mental health services.

Aicardi Syndrome Is a Genetically Heterogeneous Disorder.

Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.

Activation of extracellular electron network in non-electroactive bacteria by Bombyx mori silk.

Extracellular electron transfer material (EETM) has increasingly attracted attentions for the enhancing effect on multiple microbial reactions. Especially, EETM is known to be essential to activate the energy network in non-electroactive bacteria. It is motivated to find out an EETM which is natural-based, environmentally friendly, and easily produced at large-scale. In this study, Bombyx mori silk is found, for the first time, to function as an EETM by using an EETM-dependent pentachlorophenol (PCP) dechlorinating anaerobic microbial culture. Subsequently, by dividing fibroin fiber into different soluble/insoluble fractions and correlating their EET functions with their structural properties based on various spectroscopic analyses, the ß-sheet configuration is suggested as an essential structure supporting the EET function of silk materials. The analyses also suggested the involvement of sulfur-containing amino acids in this function. The EET function is not degraded by boiling or acid/alkaline treatments and the material can be utilized multiple times, although it is susceptible to UV irradiation. Bombyx mori silk also enhance other microbial reactions, including Fe(III)OOH reduction, CO2 reduction to acetate, and nitrogen fixation. This discovery provides a basis for developing biotechnology for environmental remediation, global warming reduction, and biofertilizer production using Bombyx mori silk and its wastes.

The Emergence of Extracellular Electron Mediating Functionality in Rice Straw-Artificial Soil Mixture during Humification.

This study aimed to elucidate the origin of extracellular electron mediating (EEM) functionality and redox-active center(s) in humic substances, where they are ubiquitously distributed. Here, we show the emergence of EEM functionality during the humification of rice straw in artificial soil (kaolin and sand) with a matric potential of -100 cm at 20 °C for one year. We used the dechlorination activity of an EEM material-dependent pentachlorophenol-dechlorinating anaerobic microbial consortium as an index of the EEM functionality. Although rice straw and its mixture with artificial soil did not initially have EEM functionality, it emerged after one month of humification and increased until six months after which the functionality was maintained for one year. Chemical and electrochemical characterizations demonstrated that the emergence and increase in EEM functionality were correlated with the degradation of rice straw, formation of quinone structures, a decrease in aromatic structures, an increase in nitrogenous and aliphatic structures, and specific electric capacitance during humification. The newly formed quinone structure was suggested as a potential redox-active center for the EEM functionality. These findings provide novel insights into the dynamic changes in EEM functionality during the humification of organic materials.

Effect of Humin and Chemical Factors on CO2-Fixing Acetogenesis and Methanogenesis.

Acetogenesis and methanogenesis have attracted attention as CO2-fixing reactions. Humin, a humic substance insoluble at any pH, has been found to assist CO2-fixing acetogenesis as the sole electron donor. Here, using two CO2-fixing consortia with acetogenic and methanogenic activities, the effect of various parameters on these activities was examined. One consortium utilized humin and hydrogen (H2) as electron donors for acetogenesis, either separately or simultaneously, but with a preference for the electron use from humin. The acetogenic activity was accelerated 14 times by FeS at 0.2 g/L as the optimal concentration, while being inhibited by MgSO4 at concentration above 0.02 g/L and by NaCl at concentrations higher than 6 g/L. Another consortium did not utilize humin but H2 as electron donor, suggesting that humin was not a universal electron donor for acetogenesis. For methanogenesis, both consortia did not utilize extracellular electrons from humin unless H2 was present. The methanogenesis was promoted by FeS at 0.2 g/L or higher concentrations, especially without humin, and with NaCl at 2 g/L or higher concentrations regardless of the presence of humin, while no significant effect was observed with MgSO4. Comparative sequence analysis of partial 16S rRNA genes suggested that minor groups were the humin-utilizing acetogens in the consortium dominated by Clostridia, while Methanobacterium was the methanogen utilizing humin with H2.

Multiple Minority Stress and Behavioral Health Among Young Black and Latino Sexual Minority Men.

Purpose: Young Black and Latino sexual minority men may experience multiple minority stressors, which may negatively impact behavioral health. To investigate this, longitudinal associations between multiple minority stressors and behavioral health outcomes were examined over a 2-year period. Methods: Data were from the Healthy Young Men's Cohort Study. The present study used five waves of data collected every 6 months from 2016 to 2019. Participants were young Black and/or Latino sexual minority men in Los Angeles, California (n = 448; aged 16-24). Participants self-reported their experiences of racial and homonegative discrimination, internalized homonegativity, alcohol use, and depressive symptoms. Latent growth curve models with time-varying covariates examined contemporaneous associations between minority stressors as well as general life stress and behavioral health measures. Results: After accounting for general life stress and demographic characteristics, racial discrimination was persistently associated with unhealthy alcohol use. Internalized homonegativity was associated with unhealthy alcohol use initially, but this association became non-significant over time. In models predicting depressive symptoms, racial discrimination was a significant predictor at early waves, and homonegative discrimination and internalized homonegativity emerged as significant predictors at later waves. Conclusion: These results help clarify which multiple minority stressors are more prominent in their relationship to young Black and Latino sexual minority men's unhealthy alcohol use and depressive symptoms. Interventions targeting multiple minority stressors may be needed at different times during young adulthood.

Synthesis, Structural Characterization, and Pharmacological Activity of Novel Quaternary Salts of 4-Substituted Tryptamines.

Aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium) is an analogue of psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) that has been identified in several species of psilocybin-containing mushrooms. Our team previously reported the synthesis, structural characterization, and biological activity of the putative metabolite of aeruginascin (4-hydroxy-N,N,N-trimethyltryptammonium; 4-HO-TMT) and its potential prodrug (4-acetoxy-N,N,N-trimethyltryptammonium; 4-AcO-TMT). Here, we report the synthesis, structural characterization, and pharmacological activity of several quaternary tryptammonium analogues of 4-HO-TMT and 4-AcO-TMT, namely, 4-hydroxy-N,N-dimethyl-N-ethyltryptammonium (4-HO-DMET), 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium (4-HO-DMPT), and 4-hydroxy-N,N-dimethyl-N-isopropyltryptammonium (4-HO-DMiPT), as well as their hypothesized prodrugs 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-AcO-DMET), 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT), and 4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium (4-AcO-DMiPT). Compounds were synthesized using established methods, and structures were characterized by single-crystal X-ray diffraction. Test compounds were screened for in vitro pharmacological activity at a variety of receptors and transporters to determine potential targets of action. None of the compounds exhibited measurable affinity for the serotonin 2A receptor (5-HT2A), but several analogues had low micromolar affinity (K i) for the serotonin 1D receptor (5-HT1D) and serotonin 2B receptor (5-HT2B), where they appeared to be weak partial agonists with low micromolar potencies. Importantly, 4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM). The same 4-hydroxy analogues had low to sub-micromolar potencies (IC50) for inhibition of 5-HT uptake at SERT in transfected cells (3.3-12.3 µM) and rat brain tissue (0.31-3.5 µM). Overall, our results show that quaternary tryptammonium analogues do not target 5-HT2A sites, suggesting the compounds lack psychedelic-like subjective effects. However, certain 4-hydroxy quaternary tryptammonium analogues may provide novel templates for exploring structure-activity relationships for selective actions at SERT.

Influences of poly-victimization on adolescents' pre-treatment cognitive motivations and post-treatment outcomes.

INTRODUCTION: Substance use treatment outcomes are challenging to predict: myriad potentially relevant factors influence outcomes, including age, sex, motivations, and history of victimization. METHODS: The current study seeks to assess these factors in adolescents through an evaluation of the relationship between distinct victimization profiles, sex, and cognitive factors related to substance use treatment outcomes-specifically motivation, self-efficacy, and reasons for quitting-and the relationship between these factors and posttreatment outcomes. We report sex differences in the prevalence of specific types of victimization; females are more likely than males to report poly-victimization alongside higher levels of traumagenic characteristics such as fearing for your life, chronic abuse, abuse by a trusted individual, or negative reactions to disclosure. RESULTS: Adolescents who endorsed high levels of poly-victimization and high traumagenic characteristics reported a) higher motivation for treatment, b) more reasons for quitting substance use, c) lower self-efficacy, and d) fewer adjusted days abstinent posttreatment relative to their peers. We report several sex differences: emergent poly-victimization profiles are different for males and females, class membership has a differential proportion, and, last, associations between class membership and pre-treatment cognitive motivations and posttreatment outcomes vary by sex. CONCLUSION: Clinicians working with adolescents who report poly-victimization should aim to leverage their motivation and reasons for quitting, as these factors are traditionally associated with positive outcomes. Last, interventions aimed at fostering self-efficacy may also be particularly important to improve long-term outcomes, specifically among adolescents with a history of poly-victimization.