Perspective: Resident physician wellness: a new hope.

Residency training is a challenging period in a physician's career owing to a multitude of stressors perhaps not previously encountered. In some cases, these stressors may culminate in a state of burnout. In response, much has been written about the issues of personal wellness during residency training. Recently, duty hours reform has been the major focus of addressing resident wellness; however, this intervention has established little benefit and has created unintended negative consequences. Alternatively, an emerging solution may be the implementation of resident wellness programs into residency training. Such programs are defined by a combination of active and passive initiatives targeting the various domains of physical, mental, social, and intellectual wellness. In contrast to duty hours reform, resident wellness programs are generally free from controversy and have been shown to improve resident wellness and enhance empathy.This article highlights the salient causes of burnout as it applies to present-day resident physicians and the patient care they provide. Moreover, in the wake of the controversy surrounding duty hours reform, a novel approach to resident wellness involving structured resident wellness programs is discussed. Specifically included are the fundamental components of a wellness program, the advantages held over duty hours reform, methods to evaluate program efficacy, and the current evidence to support these initiatives. Formal wellness curricula, including an evaluative process, should be an integral component of physician training. These programs represent a new hope in the solution to the long-debated issue of burnout and wellness during residency training.

CD44 interacts directly with Lck in a zinc-dependent manner.

CD44 is a widely expressed cell adhesion molecule with functional similarities to the selectin and integrin adhesion molecules. CD44 has a lectin domain that binds hyaluronan, a component of the extracellular matrix. Interactions between CD44 and hyaluronan promote lymphocyte rolling under flow and cell-cell and cell-matrix adhesion. Attachment of lymphocytes to immobilized CD44 antibodies induces cell adhesion and spreading, which is dependent on Src family kinase activity. Both Lck and Fyn associate with CD44 in T cells. CD4 and CD8 associate with Lck via a zinc-dependent interaction that is inhibited by the divalent metal cation chelator, 1,10-phenanthroline. Here we show that both CD4 and CD44-mediated T cell spreading is abolished in the presence of 1,10-phenanthroline and their association with Lck is significantly reduced. In contrast, the co-immunoprecipitation of Fyn by CD44 was unaffected. The cytoplasmic domain of CD44 was required for divalent cation-dependent association of Lck, but not for its association with Fyn. Mutational analysis of CD44 revealed that cysteine residues were not essential for the interaction nor were the carboxy-terminal 41 amino acids. Progressive deletion of the remaining 31 amino acids of the CD44 cytoplasmic domain revealed the importance of this membrane proximal region for its association with Lck. Using purified recombinant proteins, we demonstrated a direct, zinc-inducible interaction between the cytoplasmic domain of CD44 and Lck but not Fyn. The zinc-inducible interaction required the first 13 amino acids of the cytoplasmic domain of CD44 and the non-catalytic regions of Lck. Taken together, we conclude that CD44 directly associates with Lck in a zinc-inducible manner and this is important for the transmission of CD44-mediated signaling events leading to T cell spreading.

Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation.

CD45 is a transmembrane, two-domain protein-tyrosine phosphatase expressed exclusively in nucleated hematopoietic cells. The Src family kinase, Lck, is a major CD45 substrate in T cells and CD45 dephosphorylation of Lck is important for both T cell development and activation. However, how the substrate specificity of phosphatases such as CD45 is achieved is not well understood. Analysis of the interaction between the cytoplasmic domain of CD45 and its substrate, Lck, revealed that the active, membrane-proximal phosphatase domain of CD45 (CD45-D1) bound to the phosphorylated Lck kinase domain, the SH2 domain, and the unique N-terminal region of Lck. The second, inactive phosphatase domain (CD45-D2) bound only to the kinase domain of Lck. CD45-D2 was unable to bind phosphotyrosine, and its interaction with the kinase domain of Lck was independent of tyrosine phosphorylation. The binding of CD45-D2 was localized to subdomain X (SD10) of Lck. CD45-D2 bound similarly to Src family kinases but bound Csk to a lesser extent and did not bind significantly to the less related kinase, Erk1. CD45 dephosphorylated Lck and Src at similar rates but dephosphorylated Csk and Erk1 at lower rates. Replacement of Erk1 SD10 with that of Lck resulted in the binding of CD45-D2 and the conversion of Erk1 to a more efficient CD45 substrate. This demonstrates a role for CD45-D2 in binding substrate and identifies the SD10 region in Lck as a novel site involved in substrate recognition.

The noncatalytic domains of Lck regulate its dephosphorylation by CD45.

The Src-family tyrosine kinase, Lck, contains two key regulatory phosphotyrosine residues, tyrosine 394 (Tyr-394) and tyrosine 505 (Tyr-505), both of which can be dephosphorylated by CD45. Here, the interaction of CD45 with its substrate, Lck, was determined to be complex, involving multiple interactions with both the catalytic and noncatalytic regions of Lck. CD45 preferentially dephosphorylated Tyr-394 over Tyr-505 in Lck. This was not due to sequence specificity surrounding the phosphotyrosine, but was due to the noncatalytic domains of Lck. The interactions with the noncatalytic domains of Lck and CD45 enhanced the dephosphorylation of Tyr-394 whereas intramolecular interactions within Lck reduced, but did not abolish, the dephosphorylation of Tyr-505. This demonstrates that the noncatalytic domains of Lck regulate the dephosphorylation of both Tyr-394 and Tyr-505 by CD45.