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2.
PLoS Med ; 17(7): e1003172, 2020 07.
Article in English | MEDLINE | ID: mdl-32628679

ABSTRACT

BACKGROUND: The "trimorbidity" of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of psychosis and both contribute to mortality needs investigation in longitudinal studies. METHODS AND FINDINGS: A community-based sample of 437 adults (330 men, mean [SD] age 40.6 [11.2] years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1-8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner's reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.05-1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01-1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02-1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19-2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio [aHR] 1.83, 95% CI 1.09-3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08-3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03-5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus [HIV], and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable. CONCLUSIONS: In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants <55 years of age, history of a psychotic disorder were associated with greater risk for mortality. Modifiable risk factors in people living in precarious housing or homelessness can be a focus for interventions.


Subject(s)
Ill-Housed Persons/statistics & numerical data , Psychotic Disorders/mortality , Substance-Related Disorders/mortality , Adult , Alcoholism/mortality , British Columbia/epidemiology , Female , Housing , Humans , Kaplan-Meier Estimate , Male , Methamphetamine , Middle Aged , Psychotic Disorders/epidemiology , Psychotic Disorders/etiology , Residence Characteristics , Risk Factors , Time Factors
3.
ACS Chem Biol ; 15(2): 562-574, 2020 02 21.
Article in English | MEDLINE | ID: mdl-31994864

ABSTRACT

Post-translational modifications (PTMs) of protein tyrosine (Tyr) residues can serve as a molecular fingerprint of exposure to distinct oxidative pathways and are observed in abnormally high abundance in the majority of human inflammatory pathologies. Reactive oxidants generated during inflammation include hypohalous acids and nitric oxide-derived oxidants, which oxidatively modify protein Tyr residues via halogenation and nitration, respectively, forming 3-chloroTyr, 3-bromoTyr, and 3-nitroTyr. Traditional methods for generating oxidized or halogenated proteins involve nonspecific chemical reactions that result in complex protein mixtures, making it difficult to ascribe observed functional changes to a site-specific PTM or to generate antibodies sensitive to site-specific oxidative PTMs. To overcome these challenges, we generated a system to efficiently and site-specifically incorporate chloroTyr, bromoTyr, and iodoTyr, and to a lesser extent nitroTyr, into proteins in both bacterial and eukaryotic expression systems, relying on a novel amber stop codon-suppressing mutant synthetase (haloTyrRS)/tRNA pair derived from the Methanosarcina barkeri pyrrolysine synthetase system. We used this system to study the effects of oxidation on HDL-associated protein paraoxonase 1 (PON1), an enzyme with important antiatherosclerosis and antioxidant functions. PON1 forms a ternary complex with HDL and myeloperoxidase (MPO) in vivo. MPO oxidizes PON1 at tyrosine 71 (Tyr71), resulting in a loss of PON1 enzymatic function, but the extent to which chlorination or nitration of Tyr71 contributes to this loss of activity is unclear. To better understand this biological process and to demonstrate the utility of our GCE system, we generated PON1 site-specifically modified at Tyr71 with chloroTyr and nitroTyr in Escherichia coli and mammalian cells. We demonstrate that either chlorination or nitration of Tyr71 significantly reduces PON1 enzymatic activity. This tool for site-specific incorporation of halotyrosine will be critical to understanding how exposure of proteins to hypohalous acids at sites of inflammation alters protein function and cellular physiology. In addition, it will serve as a powerful tool for generating antibodies that can recognize site-specific oxidative PTMs.


Subject(s)
Aryldialkylphosphatase/metabolism , Green Fluorescent Proteins/metabolism , RNA, Transfer, Tyr/genetics , Tyrosine-tRNA Ligase/genetics , Tyrosine/analogs & derivatives , Archaeal Proteins/genetics , Aryldialkylphosphatase/chemistry , Aryldialkylphosphatase/genetics , Catalysis , Escherichia coli/genetics , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/genetics , HEK293 Cells , Humans , Methanosarcina barkeri/enzymology , Oxidation-Reduction , Protein Engineering , Protein Processing, Post-Translational , Tyrosine/genetics
4.
ACS Chem Biol ; 14(6): 1328-1336, 2019 06 21.
Article in English | MEDLINE | ID: mdl-31117397

ABSTRACT

Tyrosine nitration has served as a major biomarker for oxidative stress and is present in high abundance in over 50 disease pathologies in humans. While data mounts on specific disease pathways from specific sites of tyrosine nitration, the role of these modifications is still largely unclear. Strategies for installing site-specific tyrosine nitration in target proteins in eukaryotic cells, through routes not dependent on oxidative stress, would provide a powerful method to address the consequences of tyrosine nitration. Developed here is a Methanosarcina barkeri aminoacyl-tRNA synthetase/tRNA pair that efficiently incorporates nitrotyrosine site-specifically into proteins in mammalian cells. We demonstrate the utility of this approach to produce nitrated proteins identified in disease conditions by producing site-specific nitroTyr-containing manganese superoxide dismutase and 14-3-3 proteins in eukaryotic cells.


Subject(s)
Nitrates/metabolism , Proteins/metabolism , Tyrosine/metabolism , 14-3-3 Proteins/metabolism , Amino Acyl-tRNA Synthetases/metabolism , Animals , HEK293 Cells , Humans , Methanosarcina barkeri/enzymology , Oxidative Stress , Superoxide Dismutase/metabolism
5.
Brain Behav ; 9(3): e01233, 2019 03.
Article in English | MEDLINE | ID: mdl-30724486

ABSTRACT

OBJECTIVE: We investigated white matter differences associated with distinct neurocognitive profiles derived from a large cohort of marginally housed persons with comorbid physical and mental illnesses. Our prior work identified three profile cluster groups: a high functioning group (Cluster 1), a low functioning group with relative strength in decision-making (Cluster 3), and an intermediary group with a relative decision-making weakness (Cluster 2). This study extends previous findings of cortical gray matter differences between these groups with evidence for putative neurodevelopmental abnormalities in the low cognitive functioning group (i.e., Cluster 3). We hypothesized that altered white matter diffusion would be associated with the lowest functioning neurocognitive profile and would be associated with previously observed gray matter differences. METHOD: Participants from a socially impoverished neighborhood in Vancouver, Canada underwent neurocognitive evaluation and neuroimaging. We performed Tract-Based Spatial Statistics using diffusion tensor imaging data from 184 participants to examine whole-brain differences in white matter microstructure between cluster analytically derived neurocognitive profiles, as well as unitary neurocognitive measures. Correlations between frontal gray and white matter were also examined. RESULTS: Cluster 3 showed increased diffusion in predominately bilateral frontal and interhemisphere tracts (vs. Clusters 1 and 2), with relatively greater diffusion in the left hemisphere (vs. Cluster 1). Differences in radial diffusivity were more prominent compared with axial diffusivity. A weak association between regional frontal fractional anisotropy and previously defined abnormalities in gyrification was observed. CONCLUSIONS: In a socially marginalized sample, we established several patterns in the covariation of white matter diffusion and neurocognitive functioning. These patterns elucidate the neurobiological substrates and vulnerabilities that are apt to underlie functional impairments inherent to this complex and heterogeneous population.


Subject(s)
Diffusion Tensor Imaging/methods , Gray Matter , Neurocognitive Disorders , White Matter , Adult , Almshouses , Canada/epidemiology , Cognition/physiology , Cohort Studies , Female , Gray Matter/diagnostic imaging , Gray Matter/physiopathology , Humans , Male , Mental Status and Dementia Tests , Multiple Chronic Conditions/epidemiology , Neurocognitive Disorders/diagnosis , Neurocognitive Disorders/epidemiology , Neurocognitive Disorders/physiopathology , Vulnerable Populations , White Matter/diagnostic imaging , White Matter/physiopathology
6.
Psychopharmacology (Berl) ; 234(9-10): 1535-1547, 2017 05.
Article in English | MEDLINE | ID: mdl-28190084

ABSTRACT

RATIONALE: The psychostimulant drugs cocaine and methamphetamine are potent indirect dopamine receptor agonists which act through similar but not identical mechanisms. Studies in humans have observed that a large proportion of those who chronically use these drugs experience psychotic symptoms. However, direct comparisons of psychotic symptom severity between cocaine and methamphetamine users are lacking. OBJECTIVES: The goal of the present study was to directly compare severity of psychotic symptoms between cocaine- and methamphetamine-dependent individuals. Additionally, we sought to determine how concurrent cocaine + methamphetamine dependence would influence psychotic symptoms. METHODS: We recruited 153 polysubstance-using subjects meeting DSM-IV-TR criteria for cocaine dependence, 38 with methamphetamine dependence, and 32 with cocaine + methamphetamine dependence. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) and analyzed using a five-factor model. All participants were also assessed for physical and mental illnesses as well as recent substance use. Most subjects completed a comprehensive neurocognitive battery. RESULTS: While all three groups exhibited high total PANSS scores, the positive symptom subscale was significantly higher in the methamphetamine-dependent (17.03 ± 6.3) than the cocaine-dependent group (13.51 ± 4.12) and non-significantly higher (p = 0.08) than the cocaine + methamphetamine group (14.44 ± 5.50). Groups also differed on demographic variables, viral infection, and other indices of substance use, which were unlikely to account for the difference in positive symptoms. There were only modest differences between groups in neurocognitive function. CONCLUSIONS: Methamphetamine dependence was associated with more severe positive symptoms of psychosis than cocaine dependence. Concurrent cocaine + methamphetamine dependence did not increase psychosis severity.


Subject(s)
Amphetamine-Related Disorders/psychology , Cocaine-Related Disorders/psychology , Methamphetamine , Psychoses, Substance-Induced/psychology , Adult , Amphetamine-Related Disorders/diagnosis , Central Nervous System Stimulants , Cocaine-Related Disorders/diagnosis , Cohort Studies , Diagnostic and Statistical Manual of Mental Disorders , Female , Follow-Up Studies , Humans , Male , Middle Aged , Psychoses, Substance-Induced/diagnosis
7.
Addict Biol ; 22(3): 873-881, 2017 May.
Article in English | MEDLINE | ID: mdl-26833821

ABSTRACT

With sufficient drug exposure, some individuals develop transient psychotic symptoms referred to as 'substance-induced psychosis' (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Only a small number of studies have investigated structural alterations in SIP, and all have been limited to volumetric imaging methods, with none controlling for the effects of chronic drug exposure. To investigate white matter abnormalities associated with SIP, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n = 24) and a cocaine-dependent non-psychotic (CDN) group (n = 43). Tract-based spatial statistics was used to investigate group differences in white matter diffusion parameters. The CAP group showed significantly lower fractional anisotropy values than the CDN group (p < 0.05) in voxels within white matter tracts of fronto-temporal, fronto-thalamic and interhemispheric pathways. The greatest differences in white matter integrity were present in the corpus callosum, corona radiata, bilateral superior longitudinal fasciculi and bilateral inferior longitudinal fasciculi. Additionally, the CAP group had voxels of significantly higher radial diffusivity in a subset of the previously mentioned pathways. These results are the first description of white matter integrity abnormalities in a SIP sample and indicate that differences in these pathways may be a shared factor in the expression of different forms of psychosis.


Subject(s)
Cocaine-Related Disorders/complications , Cocaine-Related Disorders/pathology , Psychoses, Substance-Induced/complications , White Matter/pathology , Adult , Brain Mapping/methods , Diffusion Tensor Imaging/methods , Female , Humans , Image Processing, Computer-Assisted/methods , Male , Psychoses, Substance-Induced/pathology , White Matter/diagnostic imaging
8.
Schizophr Res ; 176(2-3): 158-163, 2016 10.
Article in English | MEDLINE | ID: mdl-27499362

ABSTRACT

After prolonged psychostimulant abuse, transient psychotic symptoms referred to as "substance-induced psychosis" (SIP) can develop - closely resembling symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and schizophrenias suggests that similar underlying neural deficits may contribute to the expression of psychosis across these disorders. To date, neuroanatomical characterization of grey matter structural alterations in SIP has been limited to methamphetamine associated psychosis, with no studies controlling for potential neurotoxic effects of the psychostimulant that precipitates psychosis. To investigate grey matter subcortical alterations in SIP, a voxel-based analysis of magnetic resonance images (MRI) was performed between a group of 74 cocaine dependent nonpsychotic individuals and a group of 29 individuals with cocaine-associated psychosis. The cocaine-associated psychosis group had significantly smaller volumes of the thalamus and left hippocampus, controlling for age, total brain volume, current methamphetamine dependence, and current marijuana dependence. No differences were present in bilateral caudate structures. The findings of reduced thalamic and hippocampal volumes agree with previous reports in the schizophrenia literature, suggesting alterations of these structures are not specific to schizophrenia, but may be common to multiple forms of psychosis.


Subject(s)
Cocaine-Related Disorders/complications , Cocaine-Related Disorders/diagnostic imaging , Gray Matter/diagnostic imaging , Psychoses, Substance-Induced/diagnostic imaging , Amphetamine-Related Disorders/complications , Amphetamine-Related Disorders/diagnostic imaging , Amphetamine-Related Disorders/psychology , Analysis of Variance , Brain/diagnostic imaging , Cocaine-Related Disorders/psychology , Female , Humans , Interview, Psychological , Magnetic Resonance Imaging , Male , Marijuana Abuse/complications , Marijuana Abuse/diagnostic imaging , Marijuana Abuse/psychology , Middle Aged , Organ Size , Psychiatric Status Rating Scales , Psychoses, Substance-Induced/etiology
9.
Psychiatry Res ; 240: 336-342, 2016 06 30.
Article in English | MEDLINE | ID: mdl-27138828

ABSTRACT

Approximately half of psychostimulant users experience psychotic symptoms, which include both positive and negative symptoms. Prior reports have exclusively used positive symptoms to characterize psychostimulant associated psychosis. Symptoms vary dramatically in severity, though most investigations categorize psychosis as a dichotomous occurrence. To explore the association between different substances of abuse and the severity of psychotic symptoms, we investigated 171 individuals meeting DSM-IV-TR criteria for psychostimulant (cocaine or methamphetamine) dependence in an observational cross-sectional study. Participants were predominantly male (72.5%), recruited from a socially disadvantaged neighborhood in Vancouver, Canada, with a mean age of 45.5(±8.8) years. Of the total sample, 85% were dependent on cocaine, and 28.1% were dependent on methamphetamine. Participants had a median total PANSS score of 63, ranging from 37 to 111. Demographic information, current substance use and early substance exposure were used to predict positive and negative psychotic symptom severity in linear regression models. Increased severity of positive psychotic symptoms was significantly related to greater methamphetamine and marijuana use in the past 28 days, and methadone-abstinence. Negative symptom severity was related to increased opioid use in the past 28 days. There was no overlap between predictors of positive and negative symptom severity.


Subject(s)
Amphetamine-Related Disorders/complications , Central Nervous System Stimulants , Cocaine-Related Disorders/complications , Methamphetamine , Psychoses, Substance-Induced/diagnosis , Adult , Canada , Cross-Sectional Studies , Diagnostic and Statistical Manual of Mental Disorders , Female , Humans , Male , Marijuana Smoking , Middle Aged , Psychoses, Substance-Induced/etiology , Severity of Illness Index
10.
BMC Res Notes ; 8: 515, 2015 Sep 30.
Article in English | MEDLINE | ID: mdl-26423806

ABSTRACT

BACKGROUND: Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function. METHODS: Twenty-one subjects (mean age 37.5 ± 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 ± 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health. RESULTS: The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests. CONCLUSIONS: White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required.


Subject(s)
Central Nervous System Stimulants/adverse effects , Cognition Disorders/pathology , Cognition/drug effects , HIV Infections/pathology , Substance-Related Disorders/pathology , White Matter/drug effects , Adult , Amphetamines/adverse effects , Anisotropy , Case-Control Studies , Cocaine/adverse effects , Cognition Disorders/complications , Cognition Disorders/physiopathology , Corpus Callosum/drug effects , Corpus Callosum/pathology , Corpus Callosum/physiopathology , Crack Cocaine/adverse effects , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging , Female , HIV Infections/complications , HIV Infections/physiopathology , Humans , Internal Capsule/drug effects , Internal Capsule/pathology , Internal Capsule/physiopathology , Male , Middle Aged , Neuropsychological Tests , Septal Nuclei/drug effects , Septal Nuclei/pathology , Septal Nuclei/physiopathology , Substance-Related Disorders/complications , Substance-Related Disorders/physiopathology , White Matter/pathology , White Matter/physiopathology
11.
J Am Chem Soc ; 135(50): 18806-14, 2013 Dec 18.
Article in English | MEDLINE | ID: mdl-24303933

ABSTRACT

The amino acid acridon-2-ylalanine (Acd) can be a valuable probe of protein conformational change because it is a long lifetime, visible wavelength fluorophore that is small enough to be incorporated during ribosomal biosynthesis. Incorporation of Acd into proteins expressed in Escherichia coli requires efficient chemical synthesis to produce large quantities of the amino acid and the generation of a mutant aminoacyl tRNA synthetase that can selectively charge the amino acid onto a tRNA. Here, we report the synthesis of Acd in 87% yield over five steps from Tyr and the identification of an Acd synthetase by screening candidate enzymes previously evolved from Methanococcus janaschii Tyr synthetase for unnatural amino acid incorporation. Furthermore, we characterize the photophysical properties of Acd, including quenching interactions with select natural amino acids and Förster resonance energy transfer (FRET) interactions with common fluorophores such as methoxycoumarin (Mcm). Finally, we demonstrate the value of incorporation of Acd into proteins, using changes in Acd fluorescence lifetimes, Mcm/Acd FRET, or energy transfer to Eu(3+) to monitor protein folding and binding interactions.


Subject(s)
Acridines/chemistry , Alanine/chemistry , Fluorescence Resonance Energy Transfer/methods , Acridines/chemical synthesis , Alanine/chemical synthesis , Luminescence , Models, Molecular
12.
Biochemistry ; 51(13): 2899-910, 2012 Apr 03.
Article in English | MEDLINE | ID: mdl-22409376

ABSTRACT

Hyperthermophilic archaeal viruses, including Sulfolobus spindle-shaped viruses (SSVs) such as SSV-1 and SSV-Ragged Hills, exhibit remarkable morphology and genetic diversity. However, they remain poorly understood, in part because their genomes exhibit limited or unrecognizable sequence similarity to genes with known function. Here we report structural and functional studies of E73, a 73-residue homodimeric protein encoded within the SSV-Ragged Hills genome. Despite lacking significant sequence similarity, the nuclear magnetic resonance (NMR) structure reveals clear similarity to ribbon-helix-helix (RHH) domains present in numerous proteins involved in transcriptional regulation. In vitro double-stranded DNA (dsDNA) binding experiments confirm the ability of E73 to bind dsDNA in a nonspecific manner with micromolar affinity, and characterization of the K11E variant confirms the location of the predicted DNA binding surface. E73 is distinct, however, from known RHH domains. The RHH motif is elaborated upon by the insertion of a third helix that is tightly integrated into the structural domain, giving rise to the "RH3" fold. Within the homodimer, this helix results in the formation of a conserved, symmetric cleft distal to the DNA binding surface, where it may mediate protein-protein interactions or contribute to the high thermal stability of E73. Analysis of backbone amide dynamics by NMR provides evidence of a rigid core, fast picosecond to nanosecond time scale NH bond vector motions for residues located within the antiparallel ß-sheet region of the proposed DNA-binding surface, and slower microsecond to millisecond time scale motions for residues in the α1-α2 loop. The roles of E73 and its SSV homologues in the viral life cycle are discussed.


Subject(s)
Archaeal Viruses/chemistry , DNA, Viral/genetics , Archaeal Viruses/genetics , Dimerization , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular
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