Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors

The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration

Gait impairment and cholinergic dysfunction in early PD: Does vascular risk play a moderating role?

[Poster] Objective: To compare the relationship between short latency afferent inhibition (SAI) and quantitative gait characteristics in Parkinson's (PD) subjects with high and low vascular risk. Background: Cholinergic dysfunction contributes to gait impairment in PD. Recently, cardiovascular risk factors have been implicated in higher level gait disorders in PD. We hypothesised that the relationship between gait and SAI would be moderated by cerebrovascular damage to cholinergic pathways. Methods: Forty one incident PD subjects and 44 age-matched controls were assessed as part of the ongoing ICICLE-GAIT study, a collaborative study with ICICLE-PD. Mean age 69.3 ± 10.1 years in PD, 68.5 ± 8.4 years in controls (p=0.695). Subjects’ past medical history was obtained and relative cardiovascular risk quantified as 10 year risk compared to expected risk for age and sex, using the QRISK2 calculator. This was used as a proxy for risk of cerebrovascular damage. Low risk was defined as a relative risk ratio ≤1 and high risk as a ratio >1, or existing cardiovascular disease. Cholinergic function was quantified by short latency afferent inhibition (SAI). A 7m instrumented walkway (GAITrite) measured 16 gait characteristics, including: gait speed, step length, stance time, gait variability and asymmetry. SPSS 21 was used to perform Pearson's bivariate correlations and linear regression models. Results: SAI was higher (more impaired) in PD than controls (75.53 ± 23.72 vs. 58.67 ± 22.17, p=0.001). Gait was impaired in PD subjects, who showed reduced velocity (p=0.005), step length (p=0.005), increased step length variability (p=0.017) and stance time asymmetry (p=0.027). There was no difference in SAI or gait characteristics between high (n=17) and low risk (n=24) PD groups (p=0.611) . Despite this, SAI explained 45.7% of variance in step length in high risk PD compared to only 2.6% in low risk PD and 0.2% in high risk controls. Conclusions: Our findings suggest that vascular burden may underpin gait impairment associated with cholinergic dysfunction in PD. This relationship was only observed in those with PD and high vascular risk and was not observed in high risk control participants so is unlikely to be related to fitness or cerebrovascular burden alone. Rather, it may represent a cumulative burden of cerebrovascular parenchymal damage, dopaminergic loss, and cholinergic dysfunction, with implications for early gait impairment

Calcium/NFAT signalling promotes early nephrogenesis

A number of Wnt genes are expressed during, and are known to be essential for, early kidney development. It is typically assumed that their products will act through the canonical β-catenin signalling pathway. We have found evidence that suggests canonical Wnt signalling is not active in the early nephrogenic metanephric mesenchyme, but instead provide expressional and functional evidence that implicates the non-canonical Calcium/NFAT Wnt signalling pathway in nephrogenesis. Members of the NFAT (Nuclear Factor Activated in T cells) transcription factor gene family are expressed throughout murine kidney morphogenesis and NFATc3 is localised to the developing nephrons. Treatment of kidney rudiments with Cyclosporin A (CSA), an inhibitor of Calcium/NFAT signalling, decreases nephron formation — a phenotype similar to that in Wnt4−/− embryos. Treatment of Wnt4−/− kidneys with Ionomycin, an activator of the pathway, partially rescues the phenotype. We propose that the non-canonical Calcium/NFAT Wnt signalling pathway plays an important role in early mammalian renal development and is required for complete MET during nephrogenesis, potentially acting downstream of Wnt4

Mechanistic principles and applications of resonance energy transfer

Resonance energy transfer is the primary mechanism for the migration of electronic excitation in the condensed phase. Well-known in the particular context of molecular photochemistry, it is a phenomenon whose much wider prevalence in both natural and synthetic materials has only slowly been appreciated, and for which the fundamental theory and understanding have witnessed major advances in recent years. With the growing to maturity of a robust theoretical foundation, the latest developments have led to a more complete and thorough identification of key principles. The present review first describes the context and general features of energy transfer, then focusing on its electrodynamic, optical, and photophysical characteristics. The particular role the mechanism plays in photosynthetic materials and synthetic analogue polymers is then discussed, followed by a summary of its primarily biological structure determination applications. Lastly, several possible methods are described, by the means of which all-optical switching might be effected through the control and application of resonance energy transfer in suitably fabricated nanostructures.Key words: FRET, Förster energy transfer, photophysics, fluorescence, laser