Left Ventricular Morphology in Patients with Aortic Coarctation and Bicuspid Aortic Valve: Novel Insights from a Statistical Shape Modelling Framework

Background The functional implications of left ventricular (LV) morphological characterization in congenital heart disease (CHD) are not widely explored. This study qualitatively and quantitatively assessed LV shape associations with a) LV function and b) thoracic aortic morphology in patients with aortic coarctation (CoA) with/without bicuspid aortic valve (BAV). Methods A statistical shape modelling (SSM) framework was employed to analyse three-dimensional (3D) LV shapes from cardiac magnetic resonance (CMR) data in isolated CoA (n=25), CoA+BAV (n=30), isolated BAV (n=30), and age-matched healthy controls (n=25). Average 3D templates and deformations were computed. Correlations between shape data and CMR-derived morphometric parameters (i.e. sphericity, conicity) or global and apical strain values were assessed to elucidate possible functional implications. The relationship between LV shape features and arch architecture was also explored. Results The LV template was shorter and more spherical in CoA patient and LV sphericity was associated (p≤0.04) with lower global longitudinal, radial and circumferential strain, irrespective of the presence of aortic stenosis and/or regurgitation. Conversely, LV strain was not associated with arch architecture. Conclusions Differences in LV morphology were observed between CoA and BAV patients. Increasing LV sphericity was associated with reduced strain, independent of aortic arch architecture and functional aortic valve disease.

L-Type Ca2+ Channel Regulation by Calmodulin and CaBP1

L-type voltage-gated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca2+ sensor proteins, calmodulin (CaM) and Ca2+ binding Protein 1 (CaBP1), that oppositely control Ca2+-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca2+ levels (caused by CaV channel opening), Ca2+-bound CaM binding to CaV is essential for promoting rapid Ca2+-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca2+-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca2+-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca2+ binding data suggest that CaM and CaBP1 are both calculated to bind to Ca2+ with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca2+ concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca2+-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca2+-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI.

Parkin beyond Parkinson’s Disease—A Functional Meaning of Parkin Downregulation in TDP-43 Proteinopathies

Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson’s disease (PD) caused by loss-of-function mutations in the PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases—especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.

Anatomy and histomorphology of the flexor digitorum profundus enthesis: functional implications for tissue engineering and surgery

Background The enthesis possesses morphological adaptations across the soft-hard tissue junction which are not fully restored during surgical avulsion repairs. This loss of anatomical structure, highly related to function, contributes to poor clinical outcomes. Investigating the native macro- and micro-structure of a specific enthesis can provide functional and biomechanical insights to develop specialised, novel tissue-engineered therapeutic options and potentially improve current surgical treatments for avulsion injuries. Methods This study examines the anatomy and histomorphology of the flexor digitorum profundus (FDP) enthesis in 96 fresh-frozen human cadaveric fingers, quantitatively and qualitatively analyzing the shape, size, angle of tendon fibres and histological architecture, and explores differences in sex, finger and distance along the enthesis using linear mixed effects models. Results Macroscopically, results showed a consistent trapezoidal insertion shape of 29.29 ± 2.35 mm2 mean surface area, but with significant morphometric size differences influenced primarily by the smaller dimensions of the little finger. Microscopically, a fibrocartilaginous enthesis was apparent with a 30.05 ± 0.72o mean angle of inserting tendon fibres, although regional variation in fibrocartilage and the angle change of tendon fibres before insertion existed. Conclusions The implication of these findings on native and specific FDP enthesis function is discussed whilst providing recommendations for optimal FDP enthesis recreation for interfacial tissue engineers and hand surgeons. The study emphasizes the importance of region-specific knowledge whilst also describing methods applicable to assessing any soft tissue insertion.

Subjective Time in Dementia: A Critical Review

The capacity for subjective time in humans encompasses the perception of time’s unfolding from moment to moment, as well as the ability to traverse larger temporal expanses of past- and future-oriented thought via mental time travel. Disruption in time perception can result in maladaptive outcomes—from the innocuous lapse in timing that leads to a burnt piece of toast, to the grievous miscalculation that produces a traffic accident—while disruption to mental time travel can impact core functions from planning appointments to making long-term decisions. Mounting evidence suggests that disturbances to both time perception and mental time travel are prominent in dementia syndromes. Given that such disruptions can have severe consequences for independent functioning in everyday life, here we aim to provide a comprehensive exposition of subjective timing dysfunction in dementia, with a view to informing the management of such disturbances. We consider the neurocognitive mechanisms underpinning changes to both time perception and mental time travel across different dementia disorders. Moreover, we explicate the functional implications of altered subjective timing by reference to two key and representative adaptive capacities: prospective memory and intertemporal decision-making. Overall, our review sheds light on the transdiagnostic implications of subjective timing disturbances in dementia and highlights the high variability in performance across clinical syndromes and functional domains.