ABSTRACT

Embryonic stem (ES) cells are pluripotent cells capable of unlimited self-renewal and differentiation into the three embryonic germ layers under appropriate conditions. Mechanisms for control of the early period of differentiation, involving exit from the pluripotent state and lineage commitment, are not well understood. An emerging concept is that epigenetic histone modifications may play a role during this early period. We have found that upon differentiation of mouse ES cells by removal of the cytokine leukemia inhibitory factor, there is a global increase in coupled histone H3 phosphorylation (Ser-10)-acetylation (Lys-14) (H3 phosphoacetylation). We show that this occurs through activation of both the extracellular signal-regulated kinase (ERK) and p38 MAPK signaling pathways. Early ES cell differentiation is delayed using pharmacological inhibitors of the ERK and p38 pathways. One common point of convergence of these pathways is the activation of the mitogen-and stress-activated protein kinase 1 (MSK1). We show here that MSK1 is the critical mediator of differentiation-induced H3 phosphoacetylation using both the chemical inhibitor H89 and RNA interference. Interestingly, inhibition of H3 phosphoacetylation also alters gene expression during early differentiation. These results point to an important role for both epigenetic histone modifications and kinase pathways in modulating early ES differentiation. Embryonic stem (ES)2 cells are pluripotent cells with the capacity for unlimited self-renewal or differentiation into the three germ layers: endoderm, ectoderm, and mesoderm. This ability to form different cell types under appropriate conditions makes them a powerful tool in the study of biological mechanisms and treatment of disease. Mouse ES cells are derived from the inner cell mass of the developing blastocyst (1). In vivo, the inner cell mass becomes organized into a pluripotent epithelial layer, the epiblast, from which embryonic tissues are derived (2). In vitro, mouse ES cells can be maintained in an undifferentiated state with the addition of the cytokine leukemia inhibitory factor (LIF) to culture media. LIF primarily acts via the JAK-STAT signaling pathway to maintain pluripotency (3). Self-renewal also is enhanced by inhibition of mitogen-activated protein kinase (MAPK) pathways (4). Withdrawal of LIF results in spontaneous differentiation of the ES cells into all three lineages, which is marked by changes in gene expression and cell morphology (see Fig. 1A).Although much focus has been placed on factors involved in self-renewal, the mechanisms regulating exit from the pluripotent state followed by commitment to specific lineages remain largely unknown. An emerging concept is that alterations in epigenetic histone modifications may be important during this timeframe (5). The nucleosome, with DNA wrapped around an octamer of core histones (H2A, H2B, H3, and H4), forms the basic building blocks of chromatin. Histone tails are subject to numerous covalent modifications, including acetylation, phosp...

Introduction: Quality improvement (QI) is an increasingly important aspect of health care and residency education. There is relatively little research describing QI curricula for residents in psychiatry. Although QI curricula have been published in MedEdPORTAL, the current resource represents the first such curriculum specific to psychiatry residents. This resource aims to present a QI curriculum for psychiatry residents. Methods: The University of Wisconsin psychiatry residency program implemented a QI curriculum for our PGY 3 psychiatry residents in 2010. The initial version of the curriculum has undergone marked changes over the ensuing years, reflecting feedback received from learners and faculty instructors, as well as ongoing review of the literature, to ascertain best practices in this area of medical education. Steps taken have included faculty training, development of evaluation forms, and implementation of elements to increase accountability for successful, sustainable project development. Results: During the 8 completed years of this curriculum, 77 PGY 3 psychiatry residents have completed it. The Quality Improvement Knowledge Application Tool adapted for psychiatry was completed by PGY 3 residents in advance of and upon completion of the curriculum for the first 2 years of the curriculum; results demonstrated a significant improvement in scores as a measurement of QI knowledge and skills. Thirty-one of 32 resident teams (97%) have implemented a QI project. Discussion: Our QI curriculum for PGY 3 psychiatry residents has been successful in equipping residents with QI knowledge and having them implement QI projects.

Mental health professionals often use structured assessment tools to help detect individuals who are feigning or exaggerating symptoms. Yet estimating the accuracy of these tools is problematic because no "gold standard" establishes whether someone is malingering or not. Several investigators have recommended using mixed group validation (MGV) to estimate the accuracy of malingering measures, but simulation studies show that typical implementations of MGV may yield vague, biased, or logically impossible results. In this article we describe a Bayesian approach to MGV that addresses and avoids these limitations. After explaining the concepts that underlie our approach, we use previously published data on the Test of Memory Malingering (TOMM; Tombaugh, 1996) to illustrate how our method works. Our findings concerning the TOMM's accuracy, which include insights about covariates such as study population and litigation status, are consistent with results that appear in previous publications. Unlike most investigations of the TOMM's accuracy, our findings neither rely on possibly flawed assumptions about subjects' intentions nor assume that experimental simulators can duplicate the behavior of real-world examinees. Our conceptual approach may prove helpful in evaluating the accuracy of many assessment tools used in clinical contexts and psycholegal determinations.

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