Vangl2-Regulated Polarisation of Second Heart Field-Derived Cells Is Required for Outflow Tract Lengthening during Cardiac Development.

Planar cell polarity (PCP) is the mechanism by which cells orient themselves in the plane of an epithelium or during directed cell migration, and is regulated by a highly conserved signalling pathway. Mutations in the PCP gene Vangl2, as well as in other key components of the pathway, cause a spectrum of cardiac outflow tract defects. However, it is unclear why cells within the mesodermal heart tissue require PCP signalling. Using a new conditionally floxed allele we show that Vangl2 is required solely within the second heart field (SHF) to direct normal outflow tract lengthening, a process that is required for septation and normal alignment of the aorta and pulmonary trunk with the ventricular chambers. Analysis of a range of markers of polarised epithelial tissues showed that in the normal heart, undifferentiated SHF cells move from the dorsal pericardial wall into the distal outflow tract where they acquire an epithelial phenotype, before moving proximally where they differentiate into cardiomyocytes. Thus there is a transition zone in the distal outflow tract where SHF cells become more polarised, turn off progenitor markers and start to differentiate to cardiomyocytes. Membrane-bound Vangl2 marks the proximal extent of this transition zone and in the absence of Vangl2, the SHF-derived cells are abnormally polarised and disorganised. The consequent thickening, rather than lengthening, of the outflow wall leads to a shortened outflow tract. Premature down regulation of the SHF-progenitor marker Isl1 in the mutants, and accompanied premature differentiation to cardiomyocytes, suggests that the organisation of the cells within the transition zone is important for maintaining the undifferentiated phenotype. Thus, Vangl2-regulated polarisation and subsequent acquisition of an epithelial phenotype is essential to lengthen the tubular outflow vessel, a process that is essential for on-going cardiac morphogenesis

A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion

Heterozygous mutations in $\textit{UMOD}$ encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous $\textit{UMOD}$ mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.J.A.S. is supported by the Kidney Research Fund and the Medical Research Council (MR/M012212/1). S.A.R. is a Kidney Research UK Post-Doctoral Fellow. O.D. is supported by grants from the European Community’s Seventh Framework Programme (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) programme, the Swiss National Science Foundation (31003A_169850) and the Rare Disease Initiative Zu¨rich (Radiz), a clinical research priority program of the University of Zurich, Switzerland. E.O. is supported by the Fonds National de la Recherche Luxembourg (6903109) and the University Research Priority Programme ‘Integrative Human Physiology, ZIHP’ of the University of Zurich

Developing a new curvilinear allometric model to improve the fit and validity of the 20-m shuttle run test as a predictor of cardiorespiratory fitness in adults and youth

This is an accepted manuscript of an article published by Springer in Sports Medicine on 24 September 2020, available online at: https://doi.org/10.1007/s40279-020-01346-0 The accepted version of the publication may differ from the final published version.Background and Objectives: Doubts have been raised concerning the validity of the 20m shuttle run test (20mSRT) as a predictor of cardiorespiratory fitness (CRF) in youth based on Léger’s equation/model. An alternative allometric model has been published recently that is thought to provide, not only a superior fit (criterion validity) but also a more biologically and physiologically interpretable model (construct validity). The purposes of this study were to explore whether allometry can provide a more valid predictor of CRF using 20mSRT compared with Léger’s equation/model. Methods: We fitted and compared Léger’s original model and an alternative allometric model using two cross-sectional datasets (youth, n=306; adult n=105) that contained measurements of CRF (V ̇O2peak /V ̇O2max) and 20mSRT performance. Quality-of-fit was assessed using explained variance (R2) and Bland and Altman’s limits of agreement. Results: The allometric models provided superior fits for the youth (explained variance R2=71.9%) and adult (R2=77.7%) datasets compared with Léger’s equation using their original fixed (R2=35.2%) or re-estimated parameter models (R2=65.9%), confirming that the allometric models demonstrate acceptable criterion validity. However, the allometric models also identified a non-linear “J-shaped” increase in energy cost (V ̇O2peak/V ̇O2max) with faster final shuttle-run speeds, (fitted speed exponent =1.52; 95% CI 1.38 to 1.65). Conclusion: Not only do allometric models provide more accurate predictions of CRF (V ̇O2peak/V ̇O2max; ml.kg-1.min-1) for both youth and adults (evidence of criterion validity), the “J-shaped” rise in energy demand with increasing final shuttle-run speed also provides evidence of construct validity, resulting in a more plausible, physiologically sound and interpretable model

High intensity intermittent games-based activity and adolescents’ cognition: moderating effect of physical fitness

Background: An acute bout of exercise elicits a beneficial effect on subsequent cognitive function in adolescents. The effect of games-based activity, an ecologically valid and attractive exercise model for young people, remains unknown; as does the moderating effect of fitness on the acute exercise-cognition relationship. Therefore, the aim of the present study was to examine the effect of games-based activity on subsequent cognition in adolescents, and the moderating effect of fitness on this relationship. Methods: Following ethical approval, 39 adolescents (12.3 ± 0.7 year) completed an exercise and resting trial in a counterbalanced, randomised crossover design. During familiarisation, participants completed a multi-stage fitness test to predict VO2 peak. The exercise trial consisted of 60-min games-based activity (basketball), during which heart rate was 158 ± 11 beats∙min−1. A battery of cognitive function tests (Stroop test, Sternberg paradigm, trail making and d2 tests) were completed 30-min before, immediately following and 45-min following the basketball. Results: Response times on the complex level of the Stroop test were enhanced both immediately (p = 0.021) and 45-min (p = 0.035) post-exercise, and response times on the five item level of the Sternberg paradigm were enhanced immediately post-exercise (p = 0.023). There were no effects on the time taken to complete the trail making test or any outcome of the d2 test. In particular, response times were enhanced in the fitter adolescents 45-min post-exercise on both levels of the Stroop test (simple, p = 0.005; complex, p = 0.040) and on the three item level of the Sternberg paradigm immediately (p = 0.017) and 45-min (p = 0.008) post-exercise. Conclusions: Games-based activity enhanced executive function and working memory scanning speed in adolescents, an effect particularly evident in fitter adolescents, whilst the high intensity intermittent nature of games-based activity may be too demanding for less fit children