Modulation of ribosomal subunit associations by eIF6 is critical for mitotic exit and cancer progression.

Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A factor crucial for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3'UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression.

The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration.

The eIF4E family of translation initiation factors bind 5' methylated caps and act as the limiting step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c, for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting that Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation.

Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.

Diagnoses and Treatment in Juvenile Detention Before and After Evaluation by Facility-Based Mental Health Service.

As of 2018, more than 37,000 American youth were residing in juvenile detention or residential placement facilities.1 Prevalence studies have demonstrated high rates of psychiatric illness in this population, with estimates ranging from 50% to 75%.2,3 Comorbidity is common: Abram et al. found that 75% of juvenile detainees meeting criteria for one disorder met criteria for two or more disorders.4 Compared to psychiatric morbidity in justice-involved youth, there is a paucity of data describing mental health services within juvenile justice settings, treatments delivered by these services, or outcomes following treatment. We performed a retrospective study to compare diagnoses and medications prescribed to youth in the community prior to detention with those received after evaluation by the facility-based juvenile justice mental health service (JJMHS) staffing secure detention facilities in New York, NY.

Impact of a Trauma-Informed Intervention for Youth and Staff on Rates of Violence in Juvenile Detention Settings.

The majority of youth in the juvenile justice system have experienced multiple traumatic events in their lives, including community violence, physical abuse, neglect, and traumatic loss. These high prevalence rates, coupled with the known negative consequences of trauma in childhood and adolescence, have led to a greater emphasis on implementing trauma-informed services and practices within juvenile justice settings. However, although many stakeholders and government entities have expressed support for creating more trauma-informed juvenile justice systems, there is still limited empirical knowledge about which interventions are most effective at improving outcomes, particularly at the organizational or facility level. In an effort to fill this gap, the current study evaluated the impact of a trauma-informed milieu intervention, including skills training for youth and training for staff, on rates of violence at two secure juvenile detention facilities (N = 14,856) located in a large Northeastern city. The analyses revealed that the intervention was significantly related to a reduction of violent incidents in Facility A, with no impact on incidents in Facility B. Follow-up analyses revealed that a larger proportion of eligible youth in Facility A completed the skills group program as compared with eligible youth in Facility B (16% vs. 9%). This finding has important implications for the implementation of trauma-informed interventions for youth in juvenile detention settings, as it suggests that to impact outcomes at the facility level, a minimum threshold of youth may need to be exposed to the intervention. In addition, reductions in violence at Facility A were only realized after both staff training and youth skills components were implemented, suggesting that both components are necessary to create change at the facility level. Future research is needed to further explore the impact of organizational and implementation-level factors on trauma-informed care outcomes in juvenile justice settings.

Intellectual Disabilities in Juvenile Justice: The Case for Screening.

Recent efforts to reform and improve the juvenile justice system have overlooked one critically important issue-the widespread failure to routinely screen for intellectual and developmental disabilities (I/DD) in young offenders. Pursuant to the Americans with Disabilities Act and Individuals with Disabilities Education Act, offenders with I/DD must receive appropriate accommodations. Yet across the country, adolescents and adults with I/DD must engage with the juvenile justice system without appropriate supports and often with their disabilities unknown to corrections staff, lawyers, judges, and other personnel.

The DEAD-box protein Dbp2p is linked to noncoding RNAs, the helicase Sen1p, and R-loops.

The DEAD-box RNA helicase Dbp2p is highly conserved in eukaryotes and has been implicated in transcription, ribosome biogenesis, mRNP assembly, nuclear export, and long noncoding RNA (lncRNA) function. It is not understood how Dbp2p performs these seemingly unrelated biological roles. An important step toward addressing this question is the determination of cellular RNA binding sites of Dbp2p. Here, we identify transcriptome-wide RNA binding sites of Dbp2p from Saccharomyces cerevisiae using UV-crosslinking, denaturing tandem affinity purification, and next generation sequencing. We find that Dbp2p crosslinks to mRNAs and ribosomal RNAs, and markedly to noncoding RNAs, including snoRNA, snRNAs, and tRNAs. In snoRNAs, Dbp2p preferentially crosslinks at sites near the 3' ends. These sites coincide with regions where RNA-DNA hybrids (R-loops) form and with binding sites of Sen1p, another RNA helicase that functions in transcription termination and 3' processing of noncoding RNAs. We show that Dbp2p interacts in an RNA-independent manner with Sen1p in vivo. Dbp2p crosslinks to tRNAs and other RNAs also at sites where R-loops form. Collectively, our data link Dbp2p to noncoding RNAs, Sen1p, and R-loops. The transcriptome-wide connection to R-loops provides a unifying theme for diverse cellular roles of Dbp2p.

The helicase Ded1p controls use of near-cognate translation initiation codons in 5' UTRs.

The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation1. Mutations in DDX3 are linked to tumorigenesis2-4 and intellectual disability5, and the enzyme is targeted by a range of viruses6. How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5' untranslated regions. Ded1p associates with the translation pre-initiation complex at the mRNA entry channel and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5' untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures and decreased protein synthesis from the corresponding main open reading frames. The data reveal a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed. Our observations indicate that Ded1p affects translation initiation by controlling the use of near-cognate initiation codons that are proximal to mRNA structure in 5' untranslated regions.

Pediatric PTSD: Clinical, Forensic, and Diagnostic Understanding.

Exposure to trauma is a common event in the lives of children and adolescents living in the United States. Although a minority of youth develop full posttraumatic stress disorder (PTSD) after a traumatic event, those who do tend to have an extended course of symptoms in multiple functional domains and higher rates of psychiatric comorbidities. Pediatric PTSD can play an important role in legal settings, and requires that an expert witness be well versed in advances in clinical and conceptual models of this diagnosis and familiar with current research devoted to the posttraumatic response in youth. This review is designed to be a resource for the forensic evaluator and outlines the current understanding of epidemiological and clinical features of pediatric PTSD, as well as the neurobiological, dimensional, and developmental conceptual models that describe it.

Pediatric PTSD in the DSM-5 and the Forensic Interview of Traumatized Youth.

Since the Third Edition, the Diagnostic and Statistical Manual of Mental Disorders (DSM) has increasingly incorporated developmentally informed criteria for posttraumatic stress disorder (PTSD) because of recognition that children and adolescents can manifest PTSD differently from adults. The most recent edition, DSM-5, among other changes, has introduced a developmental subtype for children six years of age or younger. As pediatric PTSD features very prominently in both civil and criminal proceedings, it is vital that the expert witness be familiar with the updated criteria and know how to interview traumatized youth appropriately in the forensic setting. In this review, we discuss the importance of the evolution of PTSD from past DSM editions to the current one, and the implications of using the new diagnostic criteria and current conceptual models in the forensic evaluation of pediatric PTSD.

Outliers in American juvenile justice: the need for statutory reform in North Carolina and New York.

There is a well-established and growing body of evidence from research that adolescents who commit crimes differ in many regards from their adult counterparts and are more susceptible to the negative effects of adjudication and incarceration in adult criminal justice systems. The age of criminal court jurisdiction in the United States has varied throughout history; yet, there are only two remaining states, New York and North Carolina, that continue to automatically charge 16 year olds as adults. This review traces the statutory history of juvenile justice in these two states with an emphasis on political and social factors that have contributed to their outlier status related to the age of criminal court jurisdiction. The neurobiological, psychological, and developmental aspects of the adolescent brain and personality, and how those issues relate both to a greater likelihood of rehabilitation in appropriate settings and to greater vulnerability in adult correctional facilities, are also reviewed. The importance of raising the age in New York and North Carolina not only lies in protecting incarcerated youths but also in preventing the associated stigma following release. Mental health practitioners are vital to the process of local and national juvenile justice reform. They can serve as experts on and advocates for appropriate mental health care and as experts on the adverse effects of the adult criminal justice system on adolescents.

Ziprasidone's effect on metabolic markers in patients with diabetes and chronic schizophrenia.

BACKGROUND: Despite numerous studies of diabetes mellitus type II (DM-II) in schizophrenia and schizoaffective disorder, there have been no studies on the glycemic effects of switching patients with long-standing symptomatic DM-II from their current antipsychotic regimen to ziprasidone. METHODS: An open-label, prospective inpatient study was conducted with 26 suboptimally responding inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and comorbid DM-II who were switched to ziprasidone monotherapy and followed for 8 weeks. Outcome measures were fasting glucose, triglycerides, cholesterol, insulin levels, capillary blood glucose levels and weight. After a 3-week cross-titration period, patients were treated with ziprasidone up to a dose of 320 mg daily. RESULTS: Of the 26 study participants, 16 completed the entire study period of 63 days and 10 (38.46%) discontinued participation, primarily due to psychotic relapse. There was a statistically significant reduction in fasting glucose (F=4.43, p=0.05; 14.68 mg/dL mean reduction), capillary blood glucose levels (F=8.90, p=0.01; 25.36 mg/dL mean reduction), weight (F=4.46, p=0.05; 4.68 lb mean weight loss) and Body Mass Index (F=4.40, p=0.05; 3.62 kg/m(2) mean reduction). There was also a reduction in the use of antidiabetic medications after the switch to ziprasidone. Nine (34.62%) patients met criteria for metabolic syndrome (MetS) at baseline, as compared to 4 (15.38%) at endpoint. No change was observed in positive symptoms (F=0.62, p=0.44), negative symptoms (F=1.47, p=0.24) and in total PANSS score (F=0.12, p=0.74). CONCLUSIONS: This study suggests significant improvement in metabolic side effects and MetS in the subset of the patients who were able to tolerate switching from a polypharmacy regimen to ziprasidone. There was a large discontinuation rate, which limited the sustained beneficial effects of ziprasidone. The decision to switch to ziprasidone in patients with prior suboptimal response has to balance the potential metabolic benefits and the potential relapse risks of the individual patient first and foremost.