On simulations of discrete fracture network flows with an optimization-based extended finite element method

Following the approach introduced in [Berrone,Pieraccini,Scialò,2013], we consider the formulation of the problem of fluid flow in a system of fractures as a PDE constrained optimization problem, with discretization performed using suitable extended finite elements; the method allows independent meshes on each fracture, thus completely circumventing meshing problems usually related to the DFN approach. The application of the method to discrete fracture networks of medium complexity is fully analyzed here, accounting for several issues related to viable and reliable implementations of the method in complex problems

A globally conforming method for solving flow in discrete fracture networks using the Virtual Element Method

A new approach for solving flow in Discrete Fracture Networks (DFN) is developed in this work by means of the Virtual Element Method. Taking advantage of the features of the VEM, we obtain global conformity of all fracture meshes while preserving a fracture-independent meshing process. This new approach is based on a generalization of globally conforming Finite Elements for polygonal meshes that avoids complications arising from the meshing process. The approach is robust enough to treat many DFNs with a large number of fractures with arbitrary positions and orientations, as shown by the simulations. Higher order Virtual Element spaces are also included in the implementation with the corresponding convergence results and accuracy aspects

A hybrid mortar virtual element method for discrete fracture network simulations

The most challenging issue in performing underground flow simulations in Discrete Fracture Networks (DFN), is to effectively tackle the geometrical difficulties of the problem. In this work we put forward a new application of the Virtual Element Method combined with the Mortar method for domain decomposition: we exploit the flexibility of the VEM in handling polygonal meshes in order to easily construct meshes conforming to the traces on each fracture, and we resort to the mortar approach in order to ``weakly'' impose continuity of the solution on intersecting fractures. The resulting method replaces the need for matching grids between fractures, so that the meshing process can be performed independently for each fracture. Numerical results show optimal convergence and robustness in handling very complex geometries

On the role of the cellular prion protein in the uptake and signaling of pathological aggregates in neurodegenerative diseases

Neurodegenerative disorders are associated with intra- or extra-cellular deposition of aggregates of misfolded insoluble proteins. These deposits composed of tau, amyloid-\u3b2 or \u3b1-synuclein spread from cell to cell, in a prion-like manner. Novel evidence suggests that the circulating soluble oligomeric species of these misfolded proteins could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Recent convincing data support the proposition that the cellular prion protein, PrPC, act as a toxicity-inducing receptor for amyloid-\u3b2 oligomers. As a consequence, several studies focused their investigations to the role played by PrPC in binding other protein aggregates, such as tau and \u3b1-synuclein, for its possible common role in mediating toxic signalling. The biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, could lead to relevant therapeutic implications. Here we describe the structure of PrPC and the proposed interplay with its pathological counterpart PrPSc and then we recapitulate the most recent findings regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins

FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade

Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics

EXD2 governs germ stem cell homeostasis and lifespan by promoting mitoribosome integrity and translation

Mitochondria are subcellular organelles critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, as well as their coordinated translation, import and respiratory complex assembly. Here we describe the characterization of exonuclease domain like 2 (EXD2), a nuclear encoded gene that we show is targeted to the mitochondria and prevents the aberrant association of mRNAs with the mitochondrial ribosome. The loss of EXD2 resulted in defective mitochondrial translation, impaired respiration, reduced ATP production, increased reactive oxygen species and widespread metabolic abnormalities. Depletion of EXD2/CG6744 in D.melanogaster caused developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that could be reversed with an anti-oxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and aging

Comparative Analysis of C9orf72 and Sporadic Disease in a Large Multicenter ALS Population: The Effect of Male Sex on Survival of C9orf72 Positive Patients

We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease