Amy R. Wyatt

Practice pointsMany medical students incorporate music in their daily lives, however opportunities to engage with music within the medical curriculum are rare.Through participation in a semester-lo...

Introduction: While many have championed the value of music in medical education, research specific to how and why music has been offered in medical education is sparse and there have been few attempts to synthesise the literature. Methods: A Critical Interpretive Synthesis (CIS) of 56 texts including published articles, correspondence, abstracts and one thesis published between 1977 and 2022 was undertaken to explore the evidence basis for offering music in medical education. Results: A total of 52 music‐focused programmes/activities were described, encompassing both curricular and extra‐curricular, receptive and participatory music activities and a wide range of musical genres. Inductive analysis of data extracted from texts revealed a variety of rationales for the use of music in medical education, which could be grouped within seven interrelated themes: well‐being; supportive learning environment; affective engagement; teaching and learning; developing skills for clinical practice; humanism in medicine; and creative expression (identity). Discussion: The results of this synthesis demonstrate that there remains a gap between what is claimed about the affordances of music and what has been explicitly addressed in medical education research. Despite a paucity of research in this area, the available data support that the affordances of music are ‘multiple’ and may not be well represented by linear models. Evidence that engagement with music is beneficial for medical students is strongest in relation to the affordances of music for well‐being, facilitating a supportive learning environment, affective engagement, memorisation and creative expression (identity). That engagement with music might enhance humanism, including developing skills for clinical practice, requires further investigation. Accounting for student agency and the ‘multiple’ affordances of music will ensure that future teaching and research are best positioned to benefit medical students' well‐being and personal and professional development.

Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α₂M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid).α₂M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example,α₂M can stabilise and facilitate the clearance of the Alzheimer’s disease-associated amyloid beta (Aβ) peptide. Additionally,α₂M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions ofα₂M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the nativeα₂M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation ofα₂M and the possible implications of this in neuroinflammation and neurodegeneration.

Protein misfolding underlies the pathology of a large number of human disorders, many of which are age-related. An exception to this is preeclampsia, a leading cause of pregnancy-associated morbidity and mortality in which misfolded proteins accumulate in body fluids and the placenta. We demonstrate that pregnancy zone protein (PZP), which is dramatically elevated in maternal plasma during pregnancy, efficiently inhibits in vitro the aggregation of misfolded proteins, including the amyloid beta peptide (Aβ) that is implicated in preeclampsia as well as with Alzheimer’s disease. The mechanism by which this inhibition occurs involves the formation of stable complexes between PZP and monomeric Aβ or small soluble Aβ oligomers formed early in the aggregation pathway. The chaperone activity of PZP is more efficient than that of the closely related protein alpha-2-macroglobulin (α₂M), although the chaperone activity of α₂M is enhanced by inducing its dissociation into PZP-like dimers. By immunohistochemistry analysis, PZP is found primarily in extravillous trophoblasts in the placenta. In severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent to extracellular plaques containing Aβ, but PZP is not abundant within extracellular plaques. Our data support the conclusion that the up-regulation of PZP during pregnancy represents a major maternal adaptation that helps to maintain extracellular proteostasis during gestation in humans. We propose that overwhelming or disrupting the chaperone function of PZP could underlie the accumulation of misfolded proteins in vivo. Attempts to characterize extracellular proteostasis in pregnancy will potentially have broad-reaching significance for understanding disease-related protein misfolding. Significance Pregnancy is a unique physiological state involving biological stresses that promote protein damage (misfolding) within the maternal body. Currently, little is known regarding how the maternal body copes with elevated protein misfolding in pregnancy. This is important, because the accumulation of misfolded proteins underlies many human disorders, including preeclampsia, a serious complication of pregnancy. In this study, we show that pregnancy zone protein (PZP) efficiently inhibits the aggregation of misfolded proteins, including the amyloid beta peptide, which forms plaques in preeclampsia and in Alzheimer’s disease. We propose that up-regulation of PZP is a major maternal adaptation that helps to maintain protein homeostasis during pregnancy. Moreover, pregnancy-independent up-regulation of PZP indicates that its chaperone function could be broadly important in humans.

Alpha-2-macroglobulin is an abundant secreted protein that is of particular interest because of its diverse ligand binding profile and multifunctional nature, which includes roles as a protease inhibitor and as a molecular chaperone. The activities of alpha-2-macroglobulin are typically dependent on whether its conformation is native or transformed (i.e. adopts a more compact conformation after interactions with proteases or small nucleophiles), and are also influenced by dissociation of the native alpha-2-macroglobulin tetramer into stable dimers. Alpha-2-macroglobulin is predominately present as the native tetramer in vivo; once purified from human blood plasma, however, alpha-2-macroglobulin can undergo a number of conformational changes during storage, including transformation, aggregation or dissociation. We demonstrate that, particularly in the presence of sodium chloride or amine containing compounds, freezing and/or lyophilization of alpha-2-macroglobulin induces conformational changes with functional consequences. These conformational changes in alpha-2-macroglobulin are not always detected by standard native polyacrylamide gel electrophoresis, but can be measured using bisANS fluorescence assays. Increased surface hydrophobicity of alpha-2-macroglobulin, as assessed by bisANS fluorescence measurements, is accompanied by (i) reduced trypsin binding activity, (ii) increased chaperone activity, and (iii) increased binding to the surfaces of SH-SY5Y neurons, in part, via lipoprotein receptors. We show that sucrose (but not glycine) effectively protects native alpha-2-macroglobulin from denaturation during freezing and/or lyophilization, thereby providing a reproducible method for the handling and long-term storage of this protein.