Resequencing of the TMF-1 (TATA Element Modulatory Factor) regulated protein (TRNP1) gene in domestic and wild canids.

BACKGROUND: Cortical folding is related to the functional organization of the brain. The TMF-1 regulated protein (TRNP1) regulates the expansion and folding of the mammalian cerebral cortex, a process that may have been accelerated by the domestication of dogs. The objectives of this study were to sequence the TRNP1 gene in dogs and related canid species, provide evidence of its expression in dog brain and compare the genetic variation within dogs and across the Canidae. The gene was located in silico to dog chromosome 2. The sequence was experimentally confirmed by amplifying and sequencing the TRNP1 exonic and promoter regions in 72 canids (36 purebred dogs, 20 Gy wolves and wolf-dog hybrids, 10 coyotes, 5 red foxes and 1 Gy fox). RESULTS: A partial TRNP1 transcript was isolated from several regions in the dog brain. Thirty genetic polymorphisms were found in the Canis sp. with 17 common to both dogs and wolves, and only one unique to dogs. Seven polymorphisms were observed only in coyotes. An additional 9 variants were seen in red foxes. Dogs were the least genetically diverse. Several polymorphisms in the promoter and 3'untranslated region were predicted to alter TRNP1 function by interfering with the binding of transcriptional repressors and miRNAs expressed in neural precursors. A c.259_264 deletion variant that encodes a polyalanine expansion was polymorphic in all species studied except for dogs. A stretch of 15 nucleotides that is found in other mammalian sequences (corresponding to 5 amino acids located between Pro58 and Ala59 in the putative dog protein) was absent from the TRNP1 sequences of all 5 canid species sequenced. Both of these aforementioned coding sequence variations were predicted to affect the formation of alpha helices in the disordered region of the TRNP1 protein. CONCLUSIONS: Potentially functionally important polymorphisms in the TRNP1 gene are found within and across various Canis species as well as the red fox, and unique differences in protein structure have evolved and been conserved in the Canidae compared to all other mammalian species.

The folded shape of mammalian brains allows the cerebral cortex and other structures to attain a large surface area to fit into the skull. Over the past several thousand years, the domestication of dogs has led to increased folding as well as a great variety of skull size and shape amongst various breeds. Cortical folding, also known as gyrification, is regulated by numerous genes, including one that encodes the TMF-1 regulated protein (TRNP1). The TRNP1 protein in the brain affects the development of specialized cells in the brain that are involved in gyrification. It is not known whether a functionally distinct TRNP1 protein in dogs is responsible for the increased folding. Variations in the DNA sequence of the gene that encodes TRNP1 may be responsible for these dramatic changes in brain structure in dogs. This study sought to discover the differences in the TRNP1 DNA sequence in seventy-two canids, represented by thirty-six dogs of various breeds, twenty gray wolves and wolf-dog hybrids, ten coyotes, five red foxes and one gray fox.After finding evidence of the expression of this gene in dog brain, we located thirty genetic changes or variants in the canids, with seventeen common to both dogs and wolves, and only one unique to dogs. Another seven of these genetic variants were observed only in coyotes. An additional nine variants were seen in red foxes. Dogs were the least genetically diverse species, an expected result of the inbreeding that characterizes domestication. Several of these changes may affect the function of the TRNP1 gene by affecting the binding of other biomolecules to regions in the DNA which regulate this gene. This study also found two other changes, one only found in dogs, and the other one only found in canids (compared to all other mammalian TRNP1 proteins) may change the length and three-dimensional structure and hence the function of the TRNP1 protein. This study concluded that numerous, potentially functionally significant dissimilarities in the TRNP1 gene exist between dogs and their wild relatives, as well as between canid and all other mammalian species.

Policy dialogue as a collaborative tool for multistakeholder health governance: a scoping study.

INTRODUCTION: Health system governance is the cornerstone of performant, equitable and sustainable health systems aiming towards universal health coverage. Global health actors have increasingly been using policy dialogue (PD) as a governance tool to engage with both state and non-state stakeholders. Despite attempts to frame PD practices, it remains a catch-all term for both health systems professionals and researchers. METHOD: We conducted a scoping study on PD. We identified 25 articles published in English between 1985 and 2017 and 10 grey literature publications. The analysis was guided by the following questions: (1) How do the authors define PD? (2) What do we learn about PD practices and implementation factors? (3) What are the specificities of PD in low-income and middle-income countries? RESULTS: The analysis highlighted three definitions of policy dialogue: a knowledge exchange and translation platform, a mode of governance and an instrument for negotiating international development aid. Success factors include the participants' continued and sustained engagement throughout all the relevant stages, their ability to make a constructive contribution to the discussions while being truly representative of their organisation and their high interest and stake in the subject. Prerequisites to ensuring that participants remained engaged were a clear process, a shared understanding of the goals at all levels of the PD and a PD approach consistent with the PD objective. In the context of development aid, the main challenges lie in the balance of power between stakeholders, the organisational or technical capacity of recipient country stakeholders to drive or contribute effectively to the PD processes and the increasingly technocratic nature of PD. CONCLUSION: PD requires a high level of collaborative governance expertise and needs constant, although not necessarily high, financial support. These conditions are crucial to make it a real driver of health system reform in countries' paths towards universal health coverage.

Metabolic Responses to the Yukon Arctic Ultra: Longest and Coldest in the World.

PURPOSE: The Yukon Arctic Ultra is considered the longest and coldest ultraendurance event in the world. Cold exposure and exercise has been reported to influence circulating levels of myokines, adipokines, and hepatokines that may influence considerable alterations in the regulation of metabolism. The purpose of the study was to evaluate the influence of the Yukon Arctic Ultra (430-mile event) on potential activators of brown fat, metabolites, and body composition in healthy individuals. METHODS: Eight male and female participants (mean ± SEM: age, 44 ± 3 yr; body mass index, 23.4 ± 0.9) were recruited for participation. Blood samples were collected at pre-event, mid-event, and post-event checkpoints. RESULTS: The temperature during the event ranged from -45°C to -8°C. Because of these extremely challenging conditions, 50% of the participants withdrew from competition by the 300-mile mark, and those that surpassed 300 miles lost a significant (P = 0.002; P = 0.01) amount of body weight (76 ± 5 kg to 73 ± 4 kg) and fat mass (13 ± 1 kg to 12 ± 3 kg), respectively. With respect to serum irisin, there was a trend (P = 0.06) toward significance from pre-event (1033 ± 88 ng·mL), mid-event (1265 ± 23 ng·mL) to post-event (1289 ± 24 ng·mL). Serum meteorin-like and fibroblast growth factor-21 remained stable throughout the event. There were no changes in creatinine, acetoacetate, acetate, and valine. Serum lactate decreased (P = 0.04) during the event. CONCLUSIONS: The influence of cold exposure and extreme physical exertion may promote substantial increases in serum irisin, and specific alterations in substrate metabolism that largely preserve skeletal muscle and physiological resilience.