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

A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome

CHIANTI - an Atomic Database for Emission Lines. Paper VI: Proton Rates and Other Improvements

The CHIANTI atomic database contains atomic energy levels, wavelengths, radiative transition probabilities and electron excitation data for a large number of ions of astrophysical interest. Version 4 has been released, and proton excitation data is now included, principally for ground configuration levels that are close in energy. The fitting procedure for excitation data, both electrons and protons, has been extended to allow 9 point spline fits in addition to the previous 5 point spline fits. This allows higher quality fits to data from close-coupling calculations where resonances can lead to significant structure in the Maxwellian-averaged collision strengths. The effects of photoexcitation and stimulated emission by a blackbody radiation field in a spherical geometry on the level balance equations of the CHIANTI ions can now be studied following modifications to the CHIANTI software. With the addition of H I, He I and N I, the first neutral species have been added to CHIANTI. Many updates to existing ion data-sets are described, while several new ions have been added to the database, including Ar IV, Fe VI and Ni XXI. The two-photon continuum is now included in the spectral synthesis routines, and a new code for calculating the relativistic free-free continuum has been added. The treatment of the free-bound continuum has also been updated.Comment: CHIANTI is available at http://wwwsolar.nrl.navy.mil/chianti.htm

The assessment of neuromuscular fatigue during 120 min of simulated soccer exercise

Purpose This investigation examined the development of neuromuscular fatigue during a simulated soccer match incorporating a period of extra time (ET) and the reliability of these responses on repeated test occasions. Methods Ten male amateur football players completed a 120 min soccer match simulation (SMS). Before, at half time (HT), full time (FT), and following a period of ET, twitch responses to supramaximal femoral nerve and transcranial magnetic stimulation (TMS) were obtained from the knee-extensors to measure neuromuscular fatigue. Within 7 days of the first SMS, a second 120 min SMS was performed by eight of the original ten participants to assess the reliability of the fatigue response. Results At HT, FT, and ET, reductions in maximal voluntary force (MVC; −11, −20 and −27%, respectively, P ≤ 0.01), potentiated twitch force (−15, −23 and −23%, respectively, P < 0.05), voluntary activation (FT, −15 and ET, −18%, P ≤ 0.01), and voluntary activation measured with TMS (−11, −15 and −17%, respectively, P ≤ 0.01) were evident. The fatigue response was robust across both trials; the change in MVC at each time point demonstrated a good level of reliability (CV range 6–11%; ICC2,1 0.83–0.94), whilst the responses identified with motor nerve stimulation showed a moderate level of reliability (CV range 5–18%; ICC2,1 0.63–0.89) and the data obtained with motor cortex stimulation showed an excellent level of reliability (CV range 3–6%; ICC2,1 0.90–0.98). Conclusion Simulated soccer exercise induces a significant level of fatigue, which is consistent on repeat tests, and involves both central and peripheral mechanisms

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

Assessing the Quality of Clinical Teachers: A Systematic Review of Content and Quality of Questionnaires for Assessing Clinical Teachers

BACKGROUND: Learning in a clinical environment differs from formal educational settings and provides specific challenges for clinicians who are teachers. Instruments that reflect these challenges are needed to identify the strengths and weaknesses of clinical teachers. OBJECTIVE: To systematically review the content, validity, and aims of questionnaires used to assess clinical teachers. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and ERIC from 1976 up to March 2010. REVIEW METHODS: The searches revealed 54 papers on 32 instruments. Data from these papers were documented by independent researchers, using a structured format that included content of the instrument, validation methods, aims of the instrument, and its setting. Results : Aspects covered by the instruments predominantly concerned the use of teaching strategies (included in 30 instruments), supporter role (29), role modeling (27), and feedback (26). Providing opportunities for clinical learning activities was included in 13 instruments. Most studies referred to literature on good clinical teaching, although they failed to provide a clear description of what constitutes a good clinical teacher. Instrument length varied from 1 to 58 items. Except for two instruments, all had to be completed by clerks/residents. Instruments served to provide formative feedback ( instruments) but were also used for resource allocation, promotion, and annual performance review (14 instruments). All but two studies reported on internal consistency and/or reliability; other aspects of validity were examined less frequently. CONCLUSIONS: No instrument covered all relevant aspects of clinical teaching comprehensively. Validation of the instruments was often limited to assessment of internal consistency and reliability. Available instruments for assessing clinical teachers should be used carefully, especially for consequential decisions. There is a need for more valid comprehensive instruments

Sources of flooding on floodplains of the tidal Thames

The Thames Estuary 2100 (TE2100) project requires an assessment of flood risk for present day and future scenarios for the tidal Thames floodplains, to provide a basis for planning flood risk management over the next 100 years and beyond. To do this it is first necessary to understand the causes of flooding. The main potential sources of flooding include the surge tides on the tidal Thames, and fluvial flooding from the Thames, tributaries, land drainage systems and urban drainage systems. Flooding is affected by the operation of moveable gates including the Thames Barrier and barriers on other tributaries. The paper describes the sources of flooding, the ways in which they interact and the effects that they have on flood levels. The flood management system on the tidal Thames is described, and the impacts of failure of elements of the system are considered. Extreme sea levels and fluvial flows are expected to increase in the future, and the main implications for flood management on the Thames are summarised