72 research outputs found
The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant
Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure
The restorative role of annexin A1 at the blood–brain barrier
Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune
system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the
study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the
peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule
in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective
actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the
possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS
vasculature, and its potential for repairing blood–brain barrier damage in disease and aging
Is the astronomical forcing a reliable and unique pacemaker for climate? A conceptual model study
There is evidence that ice age cycles are paced by astronomical forcing,
suggesting some kind of synchronisation phenomenon. Here, we identify the type
of such synchronisation and explore systematically its uniqueness and
robustness using a simple paleoclimate model akin to the van der Pol relaxation
oscillator and dynamical system theory. As the insolation is quite a complex
quasiperiodic signal involving different frequencies, the traditional concepts
used to define synchronisation to periodic forcing are no longer applicable.
Instead, we explore a different concept of generalised synchronisation in terms
of (coexisting) synchronised solutions for the forced system, their basins of
attraction and instabilities. We propose a clustering technique to compute the
number of synchronised solutions, each of which corresponds to a different
paleoclimate history. In this way, we uncover multistable synchronisation
(reminiscent of phase- or frequency-locking to individual periodic components
of astronomical forcing) at low forcing strength, and monostable or unique
synchronisation at stronger forcing. In the multistable regime, different
initial conditions may lead to different paleoclimate histories. To study their
robustness, we analyse Lyapunov exponents that quantify the rate of convergence
towards each synchronised solution (local stability), and basins of attraction
that indicate critical levels of external perturbations (global stability). We
find that even though synchronised solutions are stable on a long term, there
exist short episodes of desynchronisation where nearby climate trajectories
diverge temporarily (for about 50 kyr). (...)Comment: 22 pages, 18 figure
Good Manufacturing Practices-Grade Preformed Ossicular Prostheses From Banked Bone Via Computer Numerically Controlled Micromilling
Objectives: The aim of this study was the fabrication of ossicular replacement prostheses (ORPs) from decellularized
banked cortical bone via computer numerically controlled (CNC) ultraprecision micromilling, in order to obtain preformed
clinical-grade tissue products, reproducing shape, size, and details perfectly comparable to those of synthetic
devices.
Methods: Banked femoral compact bone was used to fabricate partial and total ORPs via CNC micromilling according
to Good Manufacturing Practices procedures. Drawings of ORPs with different shapes and sizes were uploaded to the
computer interface, and different surface-finish parameters were tested. The obtained products underwent dimensional,
weight, and surface characterizations. A histologic analysis was pursued to compare the bone matrix compactness of the
produced ORPs to that of the ear ossicles.
Results: Banked-bone ORPs were produced with high dimensional accuracy. Partial ORP weights averaged (±SD) 31.2
± 0.6 mg, and total ORP weights averaged 69.3 ± 0.7 mg. The best-finish mode allowed microscale or nanoscale roughness
free from machinery textures to be obtained. Finally, the histologic analysis confirmed that the extracellular matrix compactness
of the produced ORPs was suitable for ossicular chain replacement.
Conclusions: This study assesses the fabrication feasibility of novel banked-bone ORPs of extremely high dimensional
accuracy. Such devices are aimed at combining the most favorable aspects of both synthetic (reproducibility, convenience,
and biosafety) and biological replacements (total biocompatibility)
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