Optimization of a 3D dynamic culturing system for in vitro modeling of Frontotemporal Neurodegeneration-relevant pathologic features

Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative disorder that is diagnosed with increasing frequency in clinical setting. Currently, no therapy is available and in addition the molecular basis of the disease are far from being elucidated. Consequently, it is of pivotal importance to develop reliable and cost-effective in vitro models for basic research purposes and drug screening. To this respect, recent results in the field of Alzheimer’s disease have suggested that a tridimensional (3D) environment is an added value to better model key pathologic features of the disease. Here, we have tried to add complexity to the 3D cell culturing concept by using a microfluidic bioreactor, where cells are cultured under a continuous flow of medium, thus mimicking the interstitial fluid movement that actually perfuses the body tissues, including the brain. We have implemented this model using a neuronal-like cell line (SH-SY5Y), a widely exploited cell model for neurodegenerative disorders that shows some basic features relevant for FTLD modeling, such as the release of the FTLD-related protein progranulin (PRGN) in specific vesicles (exosomes). We have efficiently seeded the cells on 3D scaffolds, optimized a disease-relevant oxidative stress experiment (by targeting mitochondrial function that is one of the possible FTLD-involved pathological mechanisms) and evaluated cell metabolic activity in dynamic culture in comparison to static conditions, finding that SH-SY5Y cells cultured in 3D scaffold are susceptible to the oxidative damage triggered by a mitochondrial-targeting toxin (6-OHDA) and that the same cells cultured in dynamic conditions kept their basic capacity to secrete PRGN in exosomes once recovered from the bioreactor and plated in standard 2D conditions. We think that a further improvement of our microfluidic system may help in providing a full device where assessing basic FTLD-related features (including PRGN dynamic secretion) that may be useful for monitoring disease progression over time or evaluating therapeutic interventions

Biomechanics of the lumbar spine after dynamic stabilization

Target of the study was to predict the biomechanics of the instrumented and adjacent levels due to the insertion of the DIAM spinal stabilization system (Medtronic Ltd). For this purpose, a 3-dimensional finite element model of the intact L3/ S1 segment was developed and subjected to different loading conditions (flexion, extension, lateral bending, axial rotation). The model was then instrumented at the L4/L5 level and the same loading conditions were reapplied. Within the assumptions of our model, the simulation results suggested that the implant caused a reduction in range of motion of the instrumented level by 17% in flexion and by 43% in extension, whereas at the adjacent levels, no significant changes were predicted. Numerical results in terms of intradiscal pressure, relative to the intact condition, predicted that the intervertebral disc at the instrumented level was unloaded by 27% in flexion, by 51% in extension, and by 6% in axial rotation, while no variations in pressure were caused by the device in lateral bending. At the adjacent levels, a change of relative intradiscal pressure was predicted in extension, both at the L3/L4 level, which resulted unloaded by 26% and at the L5/S1 level, unloaded by 8%. Furthermore, a reduction in terms of principal compressive stress in the annulus fibrosus of the L4/L5 instrumented level was predicted, as compared with the intact condition. These numerical predictions have to be regarded as a theoretical representation of the behavior of the spine, because any finite element model represents only a simplification of the real Structure

Therapeutic effect of neural progenitor cells expanded in the 3D nano-engineered Nichoid substrate in a Parkinson’s disease preclinical model

3D microscaffoldsare becoming more and more relevant in regenerative medicine, as they lead to the creation of a structure similar to a physiologicalniche. An example is the nano-engineered Nichoid, a 3D structure in which the cells are able to proliferate. In this work,we investigated the proliferation and stemness properties of Er-NPCswhen grown inside the Nichoid, and their potential therapeutic application in the treatment of Parkinson\u2019s Disease.3D microscaffolds are becoming more and more relevant in regenerative medicine, as they lead to the creation of a structure similar to a physiological niche. An example is the nano-engineered Nichoid, a 3D structure in which the cells are able to proliferate. In this work, we investigated the proliferation and stemness properties of Er-NPCs when grown inside the Nichoid, and their potential therapeutic application in the treatment of Parkinson\u2019s Disease

Stripes, pseudogaps, and SO(6) in the cuprate superconductors

We briefly summarize two related calculations. First, we demonstrate that the instabilities (either nesting or pairing) associated with the high-T_c cuprates can be described by an SO(6) transformation group. There are two independent 6-dimensional representations (`superspins'). One superspin combines Zhang's 5-component superspin with a flux phase instability; the other involves a charge density wave, s-wave superconductivity, and an exotic spin current. The second calculation is a self-consistent slave boson calculation, which provides a good description of the doping dependence of the photoemission dispersion in terms of dynamic striped phases. The stripes are stabilized by strong electron-phonon coupling, and provide evidence for a doping-dependent crossover between the two superspin groundstates.Comment: 5 pages, 8 figures included as ps files; presented at SNS97 (Spectroscopies in Novel Superconductors), Sept. 14-18, Cape Cod; proceedings to appear in J. Phys. Chem. So

Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods. Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer dev

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Metodo e strumento per la stima geometrica di lesioni di tessuti o organi interni

Viene descritto uno strumento chirurgico ed un metodo per la stima geometrica di un oggetto entro un corpo di un essere umano o animale. Lo strumento comprende un'impugnatura, un dispositivo di riferimento e mezzi per portare detto dispositivo di riferimento in prossimita' di detto oggetto, detto strumento cooperando con un dispositivo di acquisizione diimmagini per acquisire almeno un'immagine di detto dispositivo di riferimento quando si trova in prossimita' di detto oggetto. Tipicamente, l'oggetto e' una lesione di un tessuto interno, ad esempio un tessuto cartilagineo di un'articolazione del ginocchio