Inhibitor of Apoptosis Proteins in Eukaryotic Evolution and Development: A Model of Thematic Conservation

The past decade and a half has witnessed the discovery of a large, evolutionarily conserved family of cellular genes bearing homology to the prototype baculovirus Inhibitor of Apoptosis (IAP). The logical decision in the field to also refer to these cellular proteins as IAPs fails to do justice to this versatile group of factors that play a wide range of roles in eukaryotic development and homeostasis which include, but are not limited to, the regulation of programmed cell death. Here we describe the shared functional characteristics of several well-characterized IAPs whose defining motifs place them more in the category of multifunctional modular protein interaction domains

XIAP Regulates Cytosol-Specific Innate Immunity to Listeria Infection

The inhibitor of apoptosis protein (IAP) family has been implicated in immune regulation, but the mechanisms by which IAP proteins contribute to immunity are incompletely understood. We show here that X-linked IAP (XIAP) is required for innate immune control of Listeria monocytogenes infection. Mice deficient in XIAP had a higher bacterial burden 48 h after infection than wild-type littermates, and exhibited substantially decreased survival. XIAP enhanced NF-κB activation upon L. monocytogenes infection of activated macrophages, and prolonged phosphorylation of Jun N-terminal kinase (JNK) specifically in response to cytosolic bacteria. Additionally, XIAP promoted maximal production of pro-inflammatory cytokines upon bacterial infection in vitro or in vivo, or in response to combined treatment with NOD2 and TLR2 ligands. Together, our data suggest that XIAP regulates innate immune responses to L. monocytogenes infection by potentiating synergy between Toll-like receptors (TLRs) and Nod-like receptors (NLRs) through activation of JNK- and NF-κB–dependent signaling

Akt: A Therapeutic Target in Hepatic Ischemia–Reperfusion Injury

Background: Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation. Objective: A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver. Methods: An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of “hepatic ischemia/reperfusion injury”, “Akt/PKB”, “preconditioning” and “postconditioning.” Results: Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect. Conclusion: The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials

Improving departmental psychological safety through a medical school-wide initiative

Abstract Background Psychological safety is a team-based phenomenon whereby group members are empowered to ask questions, take appropriate risks, admit mistakes, propose novel ideas, and candidly voice concerns. Growing research supports the benefits of psychological safety in healthcare and education for patient safety, learning, and innovation. However, there is a paucity of research on how to create psychological safety, especially within academic medicine. To meet this need, the present study describes and evaluates a multi-year, medical school-wide psychological safety initiative. Methods We created, implemented, and assessed a multi-pronged psychological safety initiative including educational training sessions, departmental champions, videos, infographics, and targeted training for medical school leaders. Employees’ perceptions of psychological safety at both the departmental and institutional levels were assessed annually. The impact of educational training sessions was quantified by post-session surveys. Results Deidentified employee surveys revealed a statistically significant increase in departmental psychological safety between the first and second annual surveys. Perceived psychological safety remained lower at the institution-wide level than at the departmental level. No significant differences in psychological safety were observed based on gender, position, or employment length. Post-educational training session surveys showed that the sessions significantly increased knowledge of the topic as well as motivation to create a culture of psychological safety within the medical school. Conclusions This study establishes an evidence-based method for increasing psychological safety within medical school departments and serves as a template for other health professions schools seeking to promote psychological safety. Training leadership, faculty, and staff is an important first step towards creating a culture of psychological safety for everyone, including trainees