RESUMEN

The four-skills model of decisional capacity for providing informed consent for medical treatment developed by Appelbaum and Grisso is codified into most state statutes in articulating the legal criteria for establishing capacity. Decisional capacity is traditionally determined at a point in time based on a narrow clinical question; however, there are clinical scenarios in which patients may currently have decisional capacity but their recurrent nonadherence to care places them at foreseeable risk of being acutely incapacitated, both decisionally and functionally, in the near future. There is a gap in terms of how these four skills ought to be adapted when applied to a patient with recurrent altered mental status, especially delirium, because of nonadherence. To describe this clinical situation, we introduce a new risk factor, "foreseeable risk of losing decisional and functional capacity," and discuss the clinical evaluation of a patient who currently has capacity but for whom this risk factor applies. We consider the implications of being at foreseeable risk of losing capacity and how foreseeable risk can be translated into a capacity determination in the present. We also describe interventions that can serve to protect the patient's rights and safety.

RESUMEN

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates the degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA, and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and the relationship between the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

RESUMEN

Forensic psychiatry fellowship programs recruit applicants through a nonstandardized process that differs by program. Although there are deadlines, informal guidance, and more recent communication guidelines, perceived differences in recruitment practices persist between geographic regions, small and large programs, and newer and more well-established programs. In the wake of a survey of fellowship applicants that found mixed opinions surrounding the application process, U.S. forensic fellowship directors undertook a mixed method quantitative-qualitative survey of their colleagues to assess interest in a match as a potential improvement and factors influencing that interest (e.g., program size, age, and unfilled positions). With responses from all 46 active U.S. programs, results indicated broad support for principles of fairness, transparency, and minimizing pressure on applicants, with an almost perfectly divided interest in a match. Respondents supported the use of a centralized database to standardize the application process and favored certain exceptions for internal applicants. Hypotheses about the reasons underlying program directors' attitudes toward a match did not yield significant results, with only the size of a program approaching significance. This novel comprehensive survey of forensic fellowship directors offers a model for assessing and monitoring the evolution of application processes for medical subspecialties interested in expanding and improving their recruitment.

Asunto(s)

Becas , Psiquiatría Forense , Humanos , Psiquiatría Forense/educación , Estados Unidos , Encuestas y Cuestionarios , Selección de Personal , Actitud del Personal de Salud , Femenino , Ejecutivos Médicos , Masculino , Adulto

RESUMEN

Multisystemic therapy (MST) is an intense, family-focused, community-based treatment designed for youth with criminal behaviors. Literature on its usefulness among juvenile sexual offenders (JSOs) remains limited. We conducted a systematic review of published studies assessing effectiveness of MST among JSOs. A comprehensive search of published studies, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was undertaken using multiple databases. Search terms included "multisystemic therapy" or "multisystemic family therapy." A total of 542 articles were obtained on initial search. After excluding duplicates, 297 articles were included in further analysis that yielded 48 articles for full-text analysis. Six randomized controlled trials of MST, comprising 231 juvenile sex-offenders, were assessed for final review. MST performed favorably relative to alternative treatments among juvenile sex offenders while also demonstrating lasting treatment effect on sustained follow-up.

Asunto(s)

Terapia Familiar , Delincuencia Juvenil , Delitos Sexuales , Humanos , Delitos Sexuales/psicología , Adolescente , Terapia Familiar/métodos , Delincuencia Juvenil/rehabilitación , Criminales/psicología , Masculino

RESUMEN

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and of the relationship of the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

RESUMEN

Jail-based competency restoration largely emerged as a method to address the backlog at forensic hospitals around the United States, as the number of justice-involved persons in need of restoration outgrew available beds. Jail-based competency restoration units (JBCRUs) appear to be highly effective and cost-saving. However, after the COVID-19 outbreak, services at some JBCRUs were stalled, as providers were forced to either quickly initiate or ramp up technology use to maintain services. The present study describes the course of programming for a JBCRU in Fulton County, Georgia, prior to and after the onset of COVID-19, during which time all treatment shifted to telehealth. A matched comparison group of prepandemic defendants was used to compare in-person versus telehealth services and findings indicated that while defendants' length of stay remained effectively the same, the restoration rate for telehealth increased remarkably over prepandemic levels (χ2 = 10.1, p = .001). Such findings suggest that telehealth services are an effective mode of delivery for competency restoration.

RESUMEN

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.

Asunto(s)

Adenosina/análogos & derivados , Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Procesamiento Postranscripcional del ARN , ARN/metabolismo , Proteínas tau/metabolismo , Adenosina/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Células HEK293 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Humanos , Masculino , Metilación , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Agregado de Proteínas , Agregación Patológica de Proteínas , ARN/genética , Índice de Severidad de la Enfermedad , Proteínas tau/genética

RESUMEN

Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.

Asunto(s)

Agregado de Proteínas , Agregación Patológica de Proteínas , Multimerización de Proteína , Antígeno Intracelular 1 de las Células T/metabolismo , Proteínas tau/metabolismo , Amiloide/química , Amiloide/metabolismo , Humanos , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas con Motivos de Reconocimiento de ARN/química , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Proteínas Recombinantes , Proteínas tau/química

RESUMEN

Mapping the intricate networks of cellular proteins in the human brain has the potential to address unsolved questions in molecular neuroscience, including the molecular basis of cognition, synaptic plasticity, long-term potentiation, learning, and memory. Perturbations to the protein-protein interaction networks (PPIN) present in neurons, glia, and other cell-types have been linked to multifactorial neurological disorders. Yet while knowledge of brain PPINs is steadily improving, the complexity and dynamic nature of the heterogeneous central nervous system in normal and disease contexts poses a formidable experimental challenge. In this review, the recent applications of functional proteomics and systems biology approaches to study PPINs central to normal neuronal function, during neurodevelopment, and in neurodegenerative disorders are summarized. How systematic PPIN analysis offers a unique mechanistic framework to explore intra- and inter-cellular functional modules governing neuronal activity and brain function is also discussed. Finally, future technological advancements needed to address outstanding questions facing neuroscience are outlined.

Asunto(s)

Mapas de Interacción de Proteínas , Humanos , Neuroglía , Plasticidad Neuronal , Neuronas , Biología de Sistemas

RESUMEN

BACKGROUND: The Toronto Academic Health Sciences Network Health Professions Innovation Fellowship Program began in 2014 as a pilot initiative among 4 academic teaching hospitals in Toronto, Ontario. The purpose of the Program was to cultivate applied leadership, interprofessional collaboration, and quality improvement capacity among health professionals. PURPOSE: This article reports on the evaluation findings from the initial year as well as an update on current program status and sustainability. METHODS: A formative evaluation was conducted focused on the impact on clinical practice, participant skill development, participant experience, and cross-organizational partnerships. Data were collected through a focus group, interviews, and pre- and postsurveys. RESULTS: Data from the initial pilot showed increases in leadership practices, project management, and quality improvement knowledge, with changes in leadership practices being significant. Positive changes in clinical practice at both the individual and unit/team levels and capacity for building relationships were also reported. Since the pilot, more than 160 participants from 15 health professions and 9 organizations have participated. Several graduates have taken on leadership roles since their participation in the Program. CONCLUSIONS: Health care organizations wishing to advance academic practice may benefit from implementing a similar collaborative program to reap benefits beyond organizational silos.

Asunto(s)

Creación de Capacidad , Mejoramiento de la Calidad , Personal de Salud , Humanos , Liderazgo , Ontario , Evaluación de Programas y Proyectos de Salud

RESUMEN

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.

Asunto(s)

Células Epiteliales Alveolares/metabolismo , COVID-19/metabolismo , Fosfoproteínas/metabolismo , Proteoma/metabolismo , SARS-CoV-2/metabolismo , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Animales , Antivirales , COVID-19/genética , COVID-19/patología , Chlorocebus aethiops , Efecto Citopatogénico Viral , Citoesqueleto , Evaluación Preclínica de Medicamentos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Células Madre Pluripotentes Inducidas/virología , Fosfoproteínas/genética , Transporte de Proteínas , Proteoma/genética , SARS-CoV-2/genética , Transducción de Señal , Células Vero , Tratamiento Farmacológico de COVID-19

RESUMEN

We previously identified a 210 kb region on chromosome 11 (50.37-50.58 Mb, mm10) containing two protein-coding genes (Hnrnph1, Rufy1) that was necessary for reduced methamphetamine-induced locomotor activity in C57BL/6J congenic mice harboring DBA/2J polymorphisms. Gene editing of a small deletion in the first coding exon supported Hnrnph1 as a quantitative trait gene. We have since shown that Hnrnph1 mutants also exhibit reduced methamphetamine-induced reward, reinforcement, and dopamine release. However, the quantitative trait variants (QTVs) that modulate Hnrnph1 function at the molecular level are not known. Nine single nucleotide polymorphisms and seven indels distinguish C57BL/6J from DBA/2J within Hnrnph1, including four variants within the 5' untranslated region (UTR). Here, we show that a 114 kb introgressed region containing Hnrnph1 and Rufy1 was sufficient to cause a decrease in MA-induced locomotor activity. Gene-level transcriptome analysis of striatal tissue from 114 kb congenics vs Hnrnph1 mutants identified a nearly perfect correlation of fold-change in expression for those differentially expressed genes that were common to both mouse lines, indicating functionally similar effects on the transcriptome and behavior. Exon-level analysis (including noncoding exons) revealed decreased 5' UTR usage of Hnrnph1 and immunoblot analysis identified a corresponding decrease in hnRNP H protein in 114 kb congenic mice. Molecular cloning of the Hnrnph1 5' UTR containing all four variants (but none of them individually) upstream of a reporter induced a decrease in reporter signal in both HEK293 and N2a cells, thus, identifying a set of QTVs underlying molecular regulation of Hnrnph1.

Asunto(s)

Regiones no Traducidas 5' , Resistencia a Medicamentos/genética , Exones , Ribonucleoproteínas Nucleares Heterogéneas/genética , Metanfetamina/farmacología , Actividad Motora , Polimorfismo Genético , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , ARN Mensajero

RESUMEN

Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. We defined a global "interactome" comprising over one thousand multi-protein complexes. These include hundreds of brain-selective assemblies that have distinct physical and functional attributes, show regional and cell-type specificity, and have links to core neurological processes and disorders. Using reciprocal pull-downs and a transgenic model, we validated a putative 28-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, suggesting a coordinated function in alternative splicing in disease progression. This brain interaction map (BraInMap) resource facilitates mechanistic exploration of the unique molecular machinery driving core cellular processes of the central nervous system. It is publicly available and can be explored here https://www.bu.edu/dbin/cnsb/mousebrain/.

Asunto(s)

Mapeo Encefálico/métodos , Encéfalo/metabolismo , Conectoma/métodos , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteínas de Unión al ADN/genética , Aprendizaje Automático , Mamíferos/fisiología , Espectrometría de Masas/métodos , Ratones , Mutación/genética

RESUMEN

Individual variation in the addiction liability of amphetamines has a heritable genetic component. We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying decreased methamphetamine-induced locomotor activity in mice. Here, we showed that mice (both females and males) with a heterozygous mutation in the first coding exon of Hnrnph1 (H1+/-) showed reduced methamphetamine reinforcement and intake and dose-dependent changes in methamphetamine reward as measured via conditioned place preference. Furthermore, H1+/- mice showed a robust decrease in methamphetamine-induced dopamine release in the NAc with no change in baseline extracellular dopamine, striatal whole-tissue dopamine, dopamine transporter protein, dopamine uptake, or striatal methamphetamine and amphetamine metabolite levels. Immunohistochemical and immunoblot staining of midbrain dopaminergic neurons and their forebrain projections for TH did not reveal any major changes in staining intensity, cell number, or forebrain puncta counts. Surprisingly, there was a twofold increase in hnRNP H protein in the striatal synaptosome of H1+/- mice with no change in whole-tissue levels. To gain insight into the mechanisms linking increased synaptic hnRNP H with decreased methamphetamine-induced dopamine release and behaviors, synaptosomal proteomic analysis identified an increased baseline abundance of several mitochondrial complex I and V proteins that rapidly decreased at 30 min after methamphetamine administration in H1+/- mice. In contrast, the much lower level of basal synaptosomal mitochondrial proteins in WT mice showed a rapid increase. We conclude that H1+/- decreases methamphetamine-induced dopamine release, reward, and reinforcement and induces dynamic changes in basal and methamphetamine-induced synaptic mitochondrial function.SIGNIFICANCE STATEMENT Methamphetamine dependence is a significant public health concern with no FDA-approved treatment. We discovered a role for the RNA binding protein hnRNP H in methamphetamine reward and reinforcement. Hnrnph1 mutation also blunted methamphetamine-induced dopamine release in the NAc, a key neurochemical event contributing to methamphetamine addiction liability. Finally, Hnrnph1 mutants showed a marked increase in basal level of synaptosomal hnRNP H and mitochondrial proteins that decreased in response to methamphetamine, whereas WT mice showed a methamphetamine-induced increase in synaptosomal mitochondrial proteins. Thus, we identified a potential role for hnRNP H in basal and dynamic mitochondrial function that informs methamphetamine-induced cellular adaptations associated with reduced addiction liability.

Asunto(s)

Dopamina/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Metanfetamina/farmacología , Mitocondrias/efectos de los fármacos , Refuerzo en Psicología , Recompensa , Sinaptosomas/metabolismo , Animales , Ansiedad/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Exones/genética , Conducta Exploratoria/efectos de los fármacos , Femenino , Heterocigoto , Masculino , Mesencéfalo/efectos de los fármacos , Mesencéfalo/metabolismo , Metanfetamina/toxicidad , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Mutación , Reflejo de Sobresalto/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Trastornos Relacionados con Sustancias/fisiopatología

RESUMEN

This study reports on restoration outcomes of a sample of pretrial defendants (n = 877, 69% male) who were found incompetent to stand trial and underwent restoration services in a large urban county. Each male defendant was initially assigned to restoration in one of four settings on a continuum of services of varying intensity (ie, outpatient, jail general population, dedicated jail-based restoration unit, or forensic hospital inpatient unit) based on the defendant's assessed clinical need. Of those who received services on the jail-based restoration unit (n = 398), 40 percent were restored to competency, 31 percent were diverted out of the criminal justice system, and 29 percent were referred for more intensive inpatient services, primarily because of refusal of medication (i.e., the jail would not allow involuntary medication, even if court-ordered). Advantages of restoration on the jail unit compared with inpatient hospitalization included more rapid institution of restoration services and higher rates of diversion out of the criminal justice system at one-third of the cost of inpatient restoration services. A continuum of restoration services that allows the type of restoration service to be matched to the needs of the individual incompetent defendant has significant advantages over routine transfer to a forensic hospital for restoration.

Asunto(s)

Instalaciones Correccionales/organización & administración , Competencia Mental/psicología , Trastornos Mentales/rehabilitación , Servicios de Salud Mental/organización & administración , Adulto , Femenino , Georgia , Hospitalización , Humanos , Masculino , Competencia Mental/legislación & jurisprudencia , Evaluación de Procesos y Resultados en Atención de Salud , Evaluación de Programas y Proyectos de Salud

RESUMEN

While many of the principles of assessing risk to self and others in adults are applicable to risk assessments of children and adolescents, developmental and legal factors regarding youths give rise to some significant differences. This article highlights major differences in assessing and managing risk in working with suicidal and homicidal youths and gives suggestions for reducing clinicians' liability in these challenging cases.