The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to “open” the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system

A robust numerical methodology for fatigue damage evolution simulation in composites

Composite materials, like metals, are subject to fatigue effects, representing one of the main causes for component collapse in carbon fiber‐reinforced polymers. Indeed, when subject to low stress cyclic loading, carbon fiber‐reinforced polymers exhibit gradual degradation of the mechanical properties. The numerical simulation of this phenomenon, which can strongly reduce time and costs to market, can be extremely expensive in terms of computational effort since a very high number of static analyses need to be run to take into account the real damage propagation due the fatigue effects. In this paper, a novel cycle jump strategy, named Smart Cycle strategy, is introduced in the numerical model to avoid the simulation of every single cycle and save computational resources. This cycle jump strategy can be seen as an enhancement of the empirical model proposed by Shokrieh and Lessard for the evaluation of the fatigue‐induced strength and stiffness degradation. Indeed, the Smart Cycle allows quickly obtaining a preliminary assessment of the fatigue behavior of composite structures. It is based on the hypothesis that the stress redistribution, due to the fatigue‐induced gradual degradation of the material properties, can be neglected until sudden fiber and/or matrix damage is verified at element/lamina level. The numerical procedure has been implemented in the commercial finite element code ANSYS MECHANICAL, by means of Ansys Parametric Design Languages (APDL). Briefly, the Smart Cycle routine is able to predict cycles where fatigue failure criteria are likely to be satisfied and to limit the numerical simulation to these cycles where a consistent damage propagation in terms of fiber and matrix breakage is expected. The proposed numerical strategy was preliminarily validated, in the frame of this research study, on 30° fiber‐oriented unidirectional coupons subjected to tensile– tensile fatigue loading conditions. The numerical results were compared with literature experimental data in terms of number of cycles at failure for different percentage of the static strength. Lastly, in order to assess its potential in terms of computational time saving on more complex structures and different loading conditions, the proposed numerical approach was used to investigate the fatigue behavior of a cross‐ply open‐hole composite panel under tension–tension fatigue loading conditions

Therapeutic advances in ADPKD: the future awaits

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies. Graphical abstract: [Figure not available: see fulltext.

Characterization of Propagation Patterns with Omnipolar EGM in Epicardial Multi-Electrode Arrays

Omnipolar Electrogram (OP-EGM) is a recently proposed technique to characterize myocardial propagation in multi-electrode catheters regardless of the angle between propagation direction and catheter bipolar. This work aims to evaluate the accuracy of atrial propagation parameters obtained with OP-EGM in sinus rhythm (SR) and in different patterns of atrial fibrillation (AF).Real and simulated unipolar electrograms (u-EGMs) were used in this study. For both types of data, conduction velocity was obtained for each clique of 4 neighbour electrodes using OP-EGM. As a reference, conduction velocity was also computed from local activation times (LATs) using a linear propagation model.Analysis of simulated data showed that conduction velocity had good concordance with propagation patterns for both estimations, although the LAT-based errors were lower in most of the cases. When conduction velocity magnitude (CV) was 1 mm/ms, its estimation errors (expressed as mean ± std) calculated with OP-EGM and from LATs were 0.053 ± 0.005 mm/ms and 0.003 ±2.1 ×10-5 mm/ms, respectively, when focus was at 30 mm from the bottom of the tissue slice, while propagation direction angular errors were 6.64 ± 4.3°and 4.35 ± 2.8°. In real data, maps obtained with OP-EGM presented smoother and more coherent patterns than those based on LATs

Artificial dermal substitutes for tissue regeneration: comparison of the clinical outcomes and histological findings of two templates

Objective: Artificial dermal substitutes (DSs) are fundamental in physiological wound healing to ensure consistent and enduring wound closure and provide a suitable scaffold to repair tissue. We compared the clinical and histological features of two DSs, Pelnac and Integra, in the treatment of traumatic and iatrogenic skin defects. Methods: This prospective observational study involved 71 randomly selected patients from our hospital. Wound healing was analyzed using the Wound Surface Area Assessment, the Vancouver Scar Scale, and a visual analog scale. Histological and immunohistochemical evaluations were also performed. Results: At 2 weeks, greater regeneration with respect to proliferation of the epidermis and renewal of the dermis was observed with Pelnac than with Integra. At 4 weeks, the dermis had regenerated with both DSs. Both templates induced renewed collagen and revascularization. Differences in the Vancouver Scar Scale score were statistically significant at 4 weeks and 1 year. Pelnac produced a significant increase in contraction at 2 weeks with increasing effectiveness at 4 weeks. Integra produced a higher percentage reduction in the wound surface area and a shorter healing time than Pelnac for wounds >1.5 cm deep. Conclusion: Our observational data indicate that both DSs are effective and applicable in different clinical contexts