Proteomics and Extracellular Vesicles as Novel Biomarker Sources in Peritoneal Dialysis in Children

Peritoneal dialysis (PD) represents the dialysis modality of choice for pediatric patients with end-stage kidney disease. Indeed, compared with hemodialysis (HD), it offers many advantages, including more flexibility, reduction of the risk of hospital-acquired infections, preservation of residual kidney function, and a better quality of life. However, despite these positive aspects, PD may be associated with several long-term complications that may impair both patient’s general health and PD adequacy. In this view, chronic inflammation, caused by different factors, has a detrimental impact on the structure and function of the peritoneal membrane, leading to sclerosis and consequent PD failure both in adults and children. Although several studies investigated the complex pathogenic pathways underlying peritoneal membrane alterations, these processes remain still to explore. Understanding these mechanisms may provide novel approaches to improve the clinical outcome of pediatric PD patients through the identification of subjects at high risk of complications and the implementation of personalized interventions. In this review, we discuss the main experimental and clinical experiences exploring the potentiality of the proteomic analysis of peritoneal fluids and extracellular vesicles as a source of novel biomarkers in pediatric peritoneal dialysis.     

Efficient breadth first search on multi-GPU systems

Simple algorithms for the execution of a Breadth First Search on large graphs lead, running on clusters of GPUs, to a situation of load unbalance among threads and un-coalesced memory accesses, resulting in pretty low performances. To obtain a significant improvement on a single GPU and to scale by using multiple GPUs, we resort to a suitable combination of operations to rearrange data before processing them. We propose a novel technique for mapping threads to data that achieves a perfect load balance by leveraging prefix-sum and binary search operations. To reduce the communication overhead, we perform a pruning operation on the set of edges that needs to be exchanged at each BFS level. The result is an algorithm that exploits at its best the parallelism available on a single GPU and minimizes communication among GPUs. We show that a cluster of GPUs can efficiently perform a distributed BFS on graphs with billions of nodes.     

Direct Cell-Cell Communication via Membrane Pores,Gap Junction Channels,and Tunneling Nanotubes: Medical Relevance of Mitochondrial Exchange

The history of direct cell-cell communication has evolved in several small steps. First discovered in the 1930s in invertebrate nervous systems, it was thought at first to be an exception to the “cell theory”, restricted to invertebrates. Surprisingly, however, in the 1950s, electrical cell-cell communication was also reported in vertebrates. Once more, it was thought to be an exception restricted to excitable cells. In contrast, in the mid-1960s, two startling publications proved that virtually all cells freely exchange small neutral and charged molecules. Soon after, cell-cell communication by gap junction channels was reported. While gap junctions are the major means of cell-cell communication, in the early 1980s, evidence surfaced that some cells might also communicate via membrane pores. Questions were raised about the possible artifactual nature of the pores. However, early in this century, we learned that communication via membrane pores exists and plays a major role in medicine, as the structures involved, “tunneling nanotubes”, can rescue diseased cells by directly transferring healthy mitochondria into compromised cells and tissues. On the other hand, pathogens/cancer could also use these communication systems to amplify pathogenesis. Here, we describe the evolution of the discovery of these new communication systems and the potential therapeutic impact on several uncurable diseases.     

Superior Cerebellar Atrophy: An Imaging Clue to Diagnose ITPR1-Related Disorders

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP₃-gated calcium channel that modulates intracellular Ca²⁺ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of ITPR1-related conditions, the ITPR1 gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.     

Morphological and Biological Evaluations of Human Periodontal Ligament Fibroblasts in Contact with Different Bovine Bone Grafts Treated with Low-Temperature Deproteinisation Protocol

Several types of deproteinised bovine bone mineral (DBBM) are available on the market, and each one is obtained with a thermic and chemical process that can differ, achieving different results. Currently, several protocols using low temperature are suggested to reduce the possible particle crystallisation during the production process. This study aimed to evaluate the biomorphological reaction of periodontal fibroblast cultures in contact with different DBBM particles treated with a low-temperature protocol (Thermagen^®) and without exposure to sodium hydroxide (NaOH). Morphological evaluation was performed using light, confocal laser, and scanning electron microscopy, and the biological reaction in terms of proliferation was performed using an XTT proliferation assay at 24 h (T1), 72 h (T2), and 7 days (T3). The morphological analysis highlighted how the presence of the materials stimulated a change in the morphology of the cells into a polygonal shape, surface reactions with the thickening of the membrane, and expression of actin. In particular, the morphological changes were appreciable from T1, with a progressive increase in the considered morphological characteristics at T2 and T3 follow-ups. The proliferation assay showed a statistical significance between the different experimental materials and the negative control in T2 and T3 follow-ups. The post hoc analysis did not reveal any differences between the materials. In conclusion, the grafts obtained with the low-temperature extractions protocol and not exposed to NaOH solution showed positive morphological reactions with no differences in the sizes of particles.     

Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity

(1) Background: Disfunctions in autophagy machinery have been identified in various conditions, including neurodegenerative diseases, cancer, and inflammation. Among mammalian autophagy proteins, the Atg8 family member GABARAP has been shown to be greatly involved in the autophagy process of prostate cancer cells, supporting the idea that GABARAP inhibitors could be valuable tools to fight the progression of tumors. (2) Methods: In this paper, starting from the X-ray crystal structure of GABARAP in a complex with an AnkirinB-LIR domain, we identify two new peptides by applying in silico drug design techniques. The two ligands are synthesized, biophysically assayed, and biologically evaluated to ascertain their potential anticancer profile. (3) Results: Two cyclic peptides (WC8 and WC10) displayed promising biological activity, high conformational stability (due to the presence of disulfide bridges), and K_d values in the low micromolar range. The anticancer assays, performed on PC-3 cells, proved that both peptides exhibit antiproliferative effects comparable to those of peptide K1, a known GABARAP inhibitor. (4) Conclusions: WC8 and WC10 can be considered new GABARAP inhibitors to be employed as pharmacological tools or even templates for the rational design of new small molecules.     

A 2D Full-Band Monte Carlo Study of HgCdTe-Based Avalanche Photodiodes

This work presents a numerical simulation study of HgCdTe-based avalanche photodetectors (APDs). The two-dimensional model used is based on a full-band Monte Carlo approach in which the electronic structure is computed using a nonlocal empirical pseudopotential model with spin–orbit corrections. The carrier–phonon scattering rates have been computed from first principles using a rigid pseudo-ion model. The most attractive feature of these devices is the potential for single-carrier ionization when electrons are used as the primary injection carrier. For this reason, this work focuses on two front-illuminated (electron-injection) device structures: a planar diffused PIN structure and a planar diffused PN photodiode with guard rings. To predict the performance of these APDs, the electron multiplication gain has been studied as a function of the position where photogenerated carriers are injected and as a function of the curvature of the p-type diffusion region. We find that, in the diffused PIN structure, the limited lateral spatial extent of the high-electric-field region leads to a reduction of the multiplication gain from the center of the device to the periphery. Furthermore, the higher the curvature, the more abruptly the gain decreases. For the simple PN structure, we find that the presence of the guard rings removes the high electric field from the surface and induces a more gradual roll-off of the gain from the center of the device to the periphery.     

ESD sensitivity of a GaAs MMIC microwave power amplifier

The EOS/ESD sensitivity of the main circuit blocks of a complete GaAs multi-stage power amplifier for microwave applications was investigated under HBM, MM and TLP regimes. Hard breakdown failure modes were identified due to passive components failure. The high current injection state of active components was also analyzed.