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The CREB-binding protein (CBP) exerts tight control of developmental processes. Here, we investigated the consequences of its selective ablation in newborn neurons. Mice in which CBP was eliminated during neuronal differentiation showed perinatal death and defective diaphragm innervation. Adult-born neurons also showed impaired growth and maturation after inducible and restricted CBP loss in dentate gyrus neuroprogenitors. Consistent with these in vivo findings, cultured neurons displayed impaired outgrowth, immature spines, and deficient activity-dependent synaptic remodeling after CBP ablation. These deficits coincided with broad transcriptional changes affecting genes involved in neuronal growth and plasticity. The affected gene set included many predicted targets of both CBP and the serum response factor (SRF), an activity-regulated transcription factor involved in structural plasticity. Notably, increasing SRF activity in a CBP-independent manner ameliorated the transcriptional, synaptic, and growth defects. These results underscore the relevance of CBP–SRF interactions during neuronal outgrowth and synaptic maturation, and demonstrate that CBP plays an essential role in supporting the gene program underlying the last steps of neuronal differentiation, both during development and in the adult brain.

Activity-driven transcription plays an important role in many brain processes, including those underlying memory and epilepsy. Here we combine genetic tagging of nuclei and ribosomes with RNA sequencing, chromatin immunoprecipitation with sequencing, assay for transposase-accessible chromatin using sequencing and Hi-C to investigate transcriptional and chromatin changes occurring in mouse hippocampal excitatory neurons at different time points after synchronous activation during seizure and sparse activation by novel context exploration. The transcriptional burst is associated with an increase in chromatin accessibility of activity-regulated genes and enhancers, de novo binding of activity-regulated transcription factors, augmented promoter–enhancer interactions and the formation of gene loops that bring together the transcription start site and transcription termination site of induced genes and may sustain the fast reloading of RNA polymerase complexes. Some chromatin occupancy changes and interactions, particularly those driven by AP1, remain long after neuronal activation and could underlie the changes in neuronal responsiveness and circuit connectivity observed in these neuroplasticity paradigms, perhaps thereby contributing to metaplasticity in the adult brain.

Introduction:

Idealmente, la simulación clínica debería ser aplicada a todos los ámbitos para la formación de los profesionales antes de proceder sobre el paciente, pero su uso se ve limitado porque muchas de las herramientas didácticas disponibles precisan simuladores sofisticados y experiencia previa, ya que se centran en aspectos específicos del diseño de escenarios pero no muestran una visión global del proceso. Por este motivo es acuciante simplificarlas, especialmente pensando en instructores noveles. Presentamos una plantilla que durante toda la fase de diseño mantiene a la vista los elementos esenciales en un único plano, lo que permite comprender fácilmente las relaciones entre ellos y, consecuentemente, las bases conceptuales del diseño de escenarios. En nuestra experiencia, esta plantilla mejora la comprensión de la metodología de diseño, especialmente en instructores noveles. Además, creemos que es útil para preparar simulaciones clínicas puesto que su estructura permite detectar incoherencias precozmente, aumenta el realismo y mejora el enfoque del escenario hacia los objetivos del debriefing. Por último, es exportable a cualquier nivel tecnológico por no requerir simuladores complejos. No se pretende aportar nuevos conceptos en simulación, sino ofrecer una herramienta que facilite la comprensión de la metodología de diseño de escenarios, especialmente para instructores no expertos.

Due to the relevance of stockouts in the retail sector together with their significantly negative effect both on retail and the whole supply chain, this paper offers a theoretical review of the stockout definition, rates, its main causes and consequences.

During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons.

Psychiatric evaluation presents a significant challenge because it conceptually integrates the input from multiple psychopathological approaches. Recent technological advances in the study of protein structure, function, and interactions have provided a breakthrough in the diagnosis and treatment of mood disorders (MD), and have identified novel biomarkers to be used as indicators of normal and disease states or response to drug treatment. The investigation of biomarkers for psychiatric disorders, such as enzymes (catechol-O-methyl transferase and monoamine oxidases) or neurotransmitters (dopamine, serotonin, norepinephrine) and their receptors, particularly their involvement in neuroendocrine activity, brain structure, and function, and response to psychotropic drugs, should facilitate the diagnosis of MD. In clinical settings, prognostic biomarkers may be revealed by analyzing serum, saliva, and/or the cerebrospinal fluid, which should promote timely diagnosis and personalized treatment. The mechanisms underlying the activity of most currently used drugs are based on the functional regulation of proteins, including receptors, enzymes, and metabolic factors. In this study, we analyzed recent advances in the identification of biomarkers for MD, which could be used for the timely diagnosis, treatment stratification, and prediction of clinical outcomes.

• Nine patients with the Prader-Willi syndrome, ranging in age from 3 to 21 years, were examined clinically as well as studied in the sleep laboratory. They had striking disturbances of sleep-wakefulness patterns. All patients except one had the symptom of excessive daytime sleepiness. The most striking finding was the presence in five patients of rapid-eye-movement (REM) sleep occurring at sleep onset (SOREM). None of the patients had the condition of sleep apnea. One patient, however, demonstrated severe hypoventilation during REM sleep; the lowest value recorded for O2 saturation was 40%, with a consistent value below 50% for as long as ten to 15 minutes. Previous findings have indicated that the Prader-Willi syndrome is of hypothalamic origin. We hypothesize that both the SOREM and O2 desaturation findings in our patients with the Prader-Willi syndrome are also a result of hypothalamic changes.