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Sickle cell disease (SCD) pain is often acute-on-chronic, likening it to other chronic acute-on-chronic pain conditions. Pain treatment of SCD was already reported as inadequate prior to the current opioid epidemic, but attitudes underlying treatment were understudied. Understanding these attitudes prior to the current epidemic would be revealing. Therefore in 1997, before the current opioid epidemic, we surveyed physicians' attitudes toward pain management and treatment preferences for acute pain exacerbations in the Emergency Department in SCD versus those of chronic pancreatitis and chronic low back pain, two other acute-on-chronic pain diseases. Thirty-nine residency trainees were surveyed in a level one triage hospital. Resident estimates of the rate of opioid addiction in SCD were higher than estimates in both chronic pancreatitis and chronic low back pain. Most residents relied on their personal clinical experience rather than external sources of data or knowledge as the most important driver when they managed chronic pain. This survey research shows that, predating the current opioid epidemic, there was both a backdrop of opioid-phobia and a bias against treating SCD pain compared to other chronic pain conditions among our sample. Repeating this survey research among current training physicians, along with surveys of other attitudes, would provide useful comparisons.

The 70 kD heat shock proteins (Hsp70s) are ubiquitous and highly conserved molecular chaperones essential for cellular protein folding and proteostasis. Each Hsp70 has two functional domains: a nucleotide-binding domain (NBD) that binds and hydrolyzes ATP, and a substrate-binding domain (SBD) that binds extended polypeptides. NBD and SBD interact little when in ADP; however, ATP binding allosterically couples the polypeptide- and ATP-binding sites. ATP binding promotes polypeptide release; polypeptide rebinding stimulates ATP hydrolysis. This allosteric coupling was poorly understood. To explore the molecular mechanism of this essential ATP-induced allosteric coupling, we solved a crystal structure of an intact Hsp70 from E. coli in complex with ATP at 1.96 A resolution. NBD-ATP adopts a unique conformation, forming extensive interfaces with a radically changed SBD that has its α-helical lid displaced and the polypeptide-binding pocket of its β-subdomain flipped open. Our biochemical analysis inspired by this structure provides a long-sought mechanistic explanation of how ATP binding allosterically opens the polypeptide-binding site.

Highly conserved molecular chaperone Hsp70 heat shock proteins play a key role in maintaining protein homeostasis (proteostasis). DnaK, a major Hsp70 in Escherichia coli, has been widely used as a paradigm for studying Hsp70s. In the absence of ATP, purified DnaK forms low-ordered oligomer, whereas ATP binding shifts the equilibrium toward the monomer. Recently, we solved the crystal structure of DnaK in complex with ATP. There are two molecules of DnaK-ATP in the asymmetric unit. Interestingly, the interfaces between the two molecules of DnaK are large with good surface complementarity, suggesting functional importance of this crystallographic dimer. Biochemical analyses of DnaK protein supported the formation of dimer in solution. Furthermore, our cross-linking experiment based on the DnaK-ATP structure confirmed that DnaK forms specific dimer in an ATP-dependent manner. To understand the physiological function of the dimer, we mutated five residues on the dimer interface. Four mutations, R56A, T301A, N537A, and D540A, resulted in loss of chaperone activity and compromised the formation of dimer, indicating the functional importance of the dimer. Surprisingly, neither the intrinsic biochemical activities, the ATP-induced allosteric coupling, nor GrpE co-chaperone interaction is affected appreciably in all of the mutations except for R56A. Unexpectedly, the interaction with co-chaperone Hsp40 is significantly compromised. In summary, this study suggests that DnaK forms a transient dimer upon ATP binding, and this dimer is essential for the efficient interaction of DnaK with Hsp40.

There is burgeoning belief that regional medical campuses (RMCs) are a significant part of the narrative about medical education and the health care workforce in the United States and Canada. Although RMCs are not new, in the recent years of medical education enrollment expansion, they have seen their numbers increase. Class expansion explains the rapid growth of RMCs in the past 10 years, but it does not adequately describe their function. Often, RMCs have missions that differ from their main campus, especially in the areas of rural and community medicine. The absence of an easy-to-use classification system has led to a lack of current research about RMCs as evidenced by the small number of articles in the current literature. The authors describe the process of the Group on Regional Medical Campuses used to develop attributes of a campus separate from the main campus that constitute a "classification" of a campus as an RMC. The system is broken into four models-basic science, clinical, longitudinal, and combined-and is linked to Liaison Committee on Medical Education standards. It is applicable to all schools and can be applied by any medical school dean or medical education researcher. The classification system paves the way for stakeholders to agree on a denominator of RMCs and conduct future research about their impact on medical education.