Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome.

Prader-Willi Syndrome (PWS) is caused by loss of expression of paternally expressed genes in the human 15q11.2-q13 imprinting domain. A set of imprinted genes that are active on the paternal but silenced on the maternal chromosome are intricately regulated by a bipartite imprinting center (PWS-IC) located in the PWS imprinting domain. In past work, we discovered that euchromatic histone lysine N-methyltransferase-2 (EHMT2/G9a) inhibitors were capable of un-silencing PWS-associated genes by restoring their expression from the maternal chromosome. Here, in mice lacking the Ehmt2 gene, we document unsilencing of the imprinted Snrpn/Snhg14 gene on the maternal chromosome in the late embryonic and postnatal brain. Using PWS and Angelman syndrome patient derived cells with either paternal or maternal deletion of 15q11-q13, we have found that chromatin of maternal PWS-IC is closed and has compact 3D folding confirmation. We further show that a new and distinct noncoding RNA preferentially transcribed from upstream of the PWS-IC interacts with EHMT2 and forms a heterochromatin complex to silence gene expression of SNRPN in CIS on maternal chromosome. Taken together, these findings demonstrate that allele-specific recruitment of EHMT2 is required to maintain the maternal imprints. Our findings provide novel mechanistic insights and support a new model for imprinting maintenance of the PWS imprinted domain.

Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes.

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3-mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes.

Transcriptional Determinism and Stochasticity Contribute to the Complexity of Autism Associated SHANK Family Genes.

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3 mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We applied an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in human and mice. We unexpectedly discovered an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts were altered in Shank3 mutant mice and postmortem brains tissues from individuals with ASD. The enhanced SHANK3 transcriptome significantly improved the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest the stochastic transcription of genome associated with SHANK family genes.

Assessment of Key Health and Wellness Indicators Among North Carolina Emergency Medical Service Providers.

OBJECTIVE: The objective of this study was to characterize key health indicators in Emergency Medical Services (EMS) personnel and identify areas for intervention in order to ensure a strong and capable emergency health workforce. METHODS: Participants were EMS personnel delivering patients to 4 regional tertiary care emergency departments within North Carolina (NC). After transferring patient care and agreeing to participate, height, weight, and blood pressure (BP) measurements were recorded and each participant completed a questionnaire regarding demographics, activity levels, alcohol consumption, smoking, and medical history. Data were analyzed descriptively. RESULTS: A sample of 452 EMS personnel from across NC was enrolled. The cohort was predominantly male (74.1%) and employed full-time (85.5%). The prevalence of overweight and obesity (80.3%) among EMS personnel was higher than the NC population (65.6%) and the general United States (US) population (70.8%). A previous diagnosis of high BP was reported by only 18.3% of participants, but 65.1% had elevated BP at the time of measurement. Alcohol consumption in the past 30 days among participants (55.4%) was slightly higher than state estimates (48.0%) and similar to national estimates (57.1%). However, heavy drinking (22.2%) and binge drinking (28.8%) were reported at much higher rates than state (5.6% and 15.2%, respectively) and national (6.6% and 18.3%, respectively) estimates. The prevalence of current smoking (21.5%) and quit attempts (48.8%) in the cohort was similar to state (21.8% and 55.0%, respectively) and national (21.2% and 55.7%, respectively) estimates. Likewise, the proportion of EMS providers meeting the Center for Disease Control's activity guidelines (49.6%) was similar to that found in the NC (46.8%) and the general US (48.0%) populations. CONCLUSIONS: These findings suggest a high prevalence of overweight and obesity, heavy drinking, binge drinking, and high BP among NC EMS personnel. Similar to fire service personnel, these rates are higher than the general US population. As such, they suggest areas where intervention would have the greatest positive impact on the health and performance of the EMS workforce.

Accuracy of Reported Community Diagnosis of Autism Spectrum Disorder.

To compare community diagnoses of Autism Spectrum Disorder (ASD) reported by parents to consensus diagnoses made using standardized tools plus clinical observation. 87 participants (85% male, average age 7.4 years), with reported community diagnosis of ASD were evaluated using the Autism Diagnostic Observation Schedule) (ADOS-2), Differential Ability Scale (DAS-II), and Vineland Adaptive Behavior Scales (VABS-II). Detailed developmental and medical history was obtained from all participants. Diagnosis was based on clinical consensus of at least two expert clinicians, using test results, clinical observations, and parent report. 23% of participants with a reported community diagnosis of ASD were classified as non-spectrum based on our consensus diagnosis. ASD and non-spectrum participants did not differ on age at evaluation and age of first community diagnosis. Non-verbal IQ scores and Adaptive Behavior Composite scores were significantly higher in the non-spectrum group compared to the ASD group (104.5 ± 21.7 vs. 80.1 ± 21.6, p < .01; 71.1 ± 15 versus 79.5 ± 17.6, p < .05, respectively). Participants enrolled with community diagnosis of PDD-NOS were significantly more likely to be classified as non-spectrum on the study consensus diagnosis than Participants with Autism or Asperger (36% versus 9.5%, Odds Ratio = 5.4, p < .05). This study shows suboptimal agreement between community diagnoses of ASD and consensus diagnosis using standardized instruments. These findings are based on limited data, and should be further studied, taking into consideration the influence of DSM 5 diagnostic criteria on ASD prevalence.

The changing roles of registered nurses in Pioneer Accountable Care Organizations.

OBJECTIVES: This study focuses on whether and how Pioneer Accountable Care Organization (ACO) leaders believe the deployment of the registered nurse workforce is changing in response to the shared savings incentives. METHODS: Semistructured phone interviews with leaders from 18 of the original 32 Pioneer ACOs were conducted. RESULTS: Narrative analysis suggests that all of the organizations are developing new and enhanced roles for registered nurses across the continuum of care. Overall, eight types of changes were reported: enhancement of roles, substitution, delegation, increased numbers of nurses, relocation of services, transfer of nurses from one setting to another, the use of liaison nurses across settings, and partnerships between nurses coordinating care in primary and acute care settings. CONCLUSIONS: This exploratory study suggests that Pioneer ACO leaders believe that payment models are affecting the deployment of the health workforce and that these changes are, in turn, driving outcomes.