Biopsy of Canada's family physician shortage.

Family physicians provide comprehensive care for the community and are an integral part of the healthcare system. Canada is experiencing a shortage of family physicians, driven in part by overbearing expectations of family physicians, limited support and resources, antiquated physician compensation, and high clinic operating costs. An additional factor contributing to this scarcity is the shortage of medical school and family medicine residency spots, which have not kept pace with population demand. We analysed and compared data on provincial populations and numbers of physicians, residency spots and medical school seats across Canada. Family physician shortages are the highest in the territories (>55%), Quebec (21.5%) and British Columbia (17.7%). Among the provinces, Ontario, Manitoba, Saskatchewan and British Columbia have the fewest family physicians per 100 000 persons in the population. Among the provinces that offer medical education, British Columbia and Ontario have the fewest medical school seats per population, while Quebec has the most. British Columbia has the smallest medical class size and the least number of family medicine residency spots as a function of population, and one of the highest percentages of provincial residents without family doctors. Paradoxically, Quebec has a relatively large medical class size and a high number of family medicine residency spots as a function of population, but also one of the highest percentages of provincial residents without family doctors. Possible strategies to improve the current shortage include encouraging Canadian medical students and international medical graduates to consider family medicine, and reducing administrative burdens for current physicians. Other steps include creating a national data framework, understanding physician needs to guide effective policy changes, increasing seats in medical schools and family residency programmes, providing financial incentives and facilitating entry into family medicine for international medical graduates.

Challenging muscle homeostasis uncovers novel chaperone interactions in Caenorhabditis elegans.

Proteome stability is central to cellular function and the lifespan of an organism. This is apparent in muscle cells, where incorrect folding and assembly of the sarcomere contributes to disease and aging. Apart from the myosin-assembly factor UNC-45, the complete network of chaperones involved in assembly and maintenance of muscle tissue is currently unknown. To identify additional factors required for sarcomere quality control, we performed genetic screens based on suppressed or synthetic motility defects in Caenorhabditis elegans. In addition to ethyl methyl sulfonate-based mutagenesis, we employed RNAi-mediated knockdown of candidate chaperones in unc-45 temperature-sensitive mutants and screened for impaired movement at permissive conditions. This approach confirmed the cooperation between UNC-45 and Hsp90. Moreover, the screens identified three novel co-chaperones, CeHop (STI-1), CeAha1 (C01G10.8) and Cep23 (ZC395.10), required for muscle integrity. The specific identification of Hsp90 and Hsp90 co-chaperones highlights the physiological role of Hsp90 in myosin folding. Our work thus provides a clear example of how a combination of mild perturbations to the proteostasis network can uncover specific quality control modules.

Using Caenorhabditis elegans as a model system to study protein homeostasis in a multicellular organism.

The folding and assembly of proteins is essential for protein function, the long-term health of the cell, and longevity of the organism. Historically, the function and regulation of protein folding was studied in vitro, in isolated tissue culture cells and in unicellular organisms. Recent studies have uncovered links between protein homeostasis (proteostasis), metabolism, development, aging, and temperature-sensing. These findings have led to the development of new tools for monitoring protein folding in the model metazoan organism Caenorhabditis elegans. In our laboratory, we combine behavioral assays, imaging and biochemical approaches using temperature-sensitive or naturally occurring metastable proteins as sensors of the folding environment to monitor protein misfolding. Behavioral assays that are associated with the misfolding of a specific protein provide a simple and powerful readout for protein folding, allowing for the fast screening of genes and conditions that modulate folding. Likewise, such misfolding can be associated with protein mislocalization in the cell. Monitoring protein localization can, therefore, highlight changes in cellular folding capacity occurring in different tissues, at various stages of development and in the face of changing conditions. Finally, using biochemical tools ex vivo, we can directly monitor protein stability and conformation. Thus, by combining behavioral assays, imaging and biochemical techniques, we are able to monitor protein misfolding at the resolution of the organism, the cell, and the protein, respectively.

Regulation of cellular protein quality control networks in a multicellular organism.

The long-term health of all metazoan cells is linked to protein quality control, which is achieved by proteostasis, a complex network of molecular interactions that determines the health of the proteome under physiological or stress conditions. Studying the regulation of cellular proteostasis in the context of the whole organism has unraveled multiple layers of cell-nonautonomous regulation, including neuronal regulation, cell-to-cell stress signals and endocrine signaling that affect growth, development and aging. Here, we discuss emerging concepts in cell-nonautonomous regulation of protein quality control networks. The identification of organismal modulators of cellular proteostasis may present novel, yet general targets for misfolding disease intervention.