Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.

In both health and disease, the ubiquitin-proteasome system (UPS) degrades point mutants that retain partial function but have decreased stability compared with their wild-type counterparts. This class of UPS substrate includes routine translational errors and numerous human disease alleles, such as the most common cause of cystic fibrosis, ΔF508-CFTR. Yet, there is no systematic way to discover novel examples of these "minimally misfolded" substrates. To address that shortcoming, we designed a genetic screen to isolate functional-but-degraded point mutants, and we used the screen to study soluble, monomeric proteins with known structures. These simple parent proteins yielded diverse substrates, allowing us to investigate the structural features, cytotoxicity, and small-molecule regulation of minimal misfolding. Our screen can support numerous lines of inquiry, and it provides broad access to a class of poorly understood but biomedically critical quality-control substrates.

Yca1 metacaspase: diverse functions determine how yeast live and let die.

The Yca1 metacaspase was discovered due to its role in the regulation of apoptosis in Saccharomyces cerevisiae. However, the mechanisms that drive apoptosis in yeast remain poorly understood. Additionally, Yca1 and other metacaspase proteins have recently been recognized for their involvement in other cellular processes, including cellular proteostasis and cell cycle regulation. In this minireview, we outline recent findings on Yca1 that will enable the further study of metacaspase multifunctionality and novel apoptosis pathways in yeast and other nonmetazoans. In addition, we discuss advancements in high-throughput screening technologies that can be applied to answer complex questions surrounding the apoptotic and nonapoptotic functions of metacaspase proteins across a diverse range of species.

Evidence for the Use of Ultrasound Imaging in Pediatric Regional Anesthesia: A Systematic Review.

An earlier review to evaluate the quality and outcomes of studies assessing ultrasound imaging in regional anesthesia for the pediatric population considered articles published from 1994 to 2009 and showed some evidence in support of block-related outcomes (block onset, success, duration) and process-related outcomes (performance time, local anesthetic dose, and spread). At that time, strong evidence in the form of randomized controlled trials and well-designed prospective observational studies was limited, leading to a call for additional research. The current systematic review (2009-2014) compares and updates the evidence for ultrasound-guided pediatric regional anesthesia published since our last review. Using the MEDLINE and EMBASE databases, we included in this review studies examining ultrasound imaging for nerve localization in the pediatric population between 2009 and March 2014 (meta-analyses, systematic reviews, randomized controlled trials, controlled studies without randomization, observational studies, comparative studies, and case series involving at least 10 patients). In the current review, we identified 24 and 13 articles evaluating peripheral nerve blocks and neuraxial anesthesia, respectively. WHAT'S NEW: Studies in the current review provide stronger evidence and have addressed a number of outcomes that were previously inconsistent or lacked strength in evidence. In the current systematic review, we identified more studies in a shorter period compared with the previous review, and these studies contain higher levels of evidence compared with what we previously found. Randomized controlled trials and well-designed prospective observational studies have replaced case series. Stronger evidence from the literature suggests that ultrasound-guided peripheral blocks decrease block performance time when compared with nerve stimulation (but take longer than the landmark technique), increase block success, and increase block quality (as measured by analgesic consumption, block duration, and pain scores). Ultrasound guidance in neuraxial blocks improves needling time, predicts epidural depth, allows visualization of the catheter and local anesthetic spread, and improves block quality. Furthermore, we identified 2 large-scale prospective studies describing the incidence of adverse events and complications in pediatric regional anesthesia. The increase in evidence presented in this review reflects the efficacy and prevalent use of ultrasound imaging in pediatric regional anesthesia.