Multilobular tumor of the zygomatic bone in a dog

Multilobular tumor of bone (MTB) (also known as Multilobular Osteochondrosarcoma) is an uncommon bone tumor frequently located on the skull of dogs, rarely on the ribs or pelvis. These neoplasms are slow growing, locally invasive, and have the potential to compress and invade the brain. A 10-year-old mixed breed dog was presented with a history of approximately 4 months of progressive growth of a left zygomatic mass. Radiographic investigation revealed a finely granular or stippled non homogeneous radiopaque mass involving the zygomatic arch. After surgery, grossly the neoplasm consisted of multiple, variably sized, grayish-white to yellow nodules separated by collagenous septa of different thickness. Histologically, the tumor was characterized by the presence of multiple lobules containing osteoid and cartilage, separated by a net of fibrous septae. This neoplastic pattern was consistent with a typical multilobular tumor of bone and based on clinical, radiographical, gross and light microscopic findings the definitive diagnosis was made. While reviewing veterinary literature only few cases of MTB were found in dogs

the tempio della consolazione in todi integrated geomatictechniques for a monument description including structuraldamage evolution in time

The Tempio della Consolazione in Todi (16th cent.) has always been one of the most significant symbols of the Umbrian landscape. Since the first times after its completion (1606) the structure has exhibited evidences of instability, due to foundation subsiding and/or seismic activity. Structural and geotechnical countermeasures have been undertaken on the Tempio and its surroundings from the 17th century until recent times. Until now a truly satisfactory analysis of the overall deformation and attitude of the building has not been performed, since the existing surveys record the overhangs of the pillars, the crack pattern or the subsidence over limited time spans. Describing the attitude of the whole church is in fact a complex operation due to the architectural character of the building, consisting of four apses (three polygonal and one semicircular) covered with half domes, which surround the central area with the large dome. The present research aims to fill the gap of knowledge with a global study based on geomatic techniques for an accurate 3D reconstruction of geometry and attitude, integrated with a historical research on damage and interventions and a geotechnical analysis. The geomatic survey results from the integration of different techniques: GPS-GNSS for global georeferencing, laser scanning and digital photogrammetry for an accurate 3D reconstruction, high precision total station and geometric leveling for a direct survey of deformations and cracks, and for the alignment of the laser scans. The above analysis allowed to assess the dynamics of the cracks occurred in the last 25 years by a comparison with a previous survey. From the photographic colour associated to the point cloud was also possible to map the damp patches showing on the domes intrados, mapping their evolution over the last years

C. elegans expressing human β2-microglobulin: a novel model for studying the relationship between the molecular assembly and the toxic phenotype.

Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β(2)-microglobulin (β(2)-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β(2)-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β(2)-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β(2)-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β(2)-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β(2)-m

Integrated Geomatic Techniques for Georeferencing and Reconstructing the Position of Underground Archaeological Sites: The Case Study of the Augustus Sundial (Rome)

A large part of the archaeological remains still to be discovered and excavated are not in remote and depopulated areas of the earth but are often beneath urban centres that have buried them with centuries of debris and later constructions. Excavating in these contexts is much more complex than digging in rural or sparsely inhabited areas because of the constraints imposed by existing buildings and infrastructure. It should also be considered that within an urbanised area, any archaeological remains are concentrated in the subsoil of the historic centre, which is, therefore, often surmounted by buildings that are more recent than the remains but historical as well, and thus, of considerable value and vulnerability. For this reason, an archaeological excavation in an urban area must be preceded by a real feasibility study, where the potential risks for the structures above are minimised and accurately quantified. In many situations, as in the case under study, the discovery of a small segment of a structure is the only clue to reconstruct the development of the remaining part still to be excavated, which may stretch tens or hundreds of metres away from the measurable part. As a consequence, an error of a few centimetres in the survey of the excavated part can lead to errors of metres in estimating the positions of the far parts still to be excavated, and this, in many cases, as in the one under study, must absolutely be avoided. In practice, high-precision geomatic surveys, in support of the archaeological and historical interpretation of the observable structures, will help to establish the exact locations to possibly continue the excavations, helping the accurate planning of the excavation itself. Here, we have shown how the various techniques, compared to each other, have made it possible to reconstruct the location of a short stretch (less than 7 metres) of the Emperor Augustus' Sundial, the only currently visible evidence of a scientific instrument of imposing dimensions (tens of metres in length and height) that served to define some of the characteristics of the calendar that we still use today. The portion of the sundial currently observable, according to the most reliable hypotheses, is located approximately at one end of a structure and extends for several tens of metres. The accurate positioning of the observable parts in a geodetic reference system will enable to identify with certainty the possible areas in which excavation may continue and will also allow to accurately reconstruct the principle of operation of the sundial through an approach that could be defined as "reverse engineering" of the scientific instrument itself. The aim of this work is to study and thus define the combination and integration of existing geomatic techniques for this specific field of applicatio

Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses

Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals

The molecular defect of albumin Tagliacozzo: 313 Lys → Asn

AbstractAlbumin Tagliacozzo is a fast-moving genetic variant of human serum albumin found in 19 unrelated families. The protein was isolated from the serum of a heterozygous healthy subject. Analysis of CNBr fragments by isoelectric focusing allowed us to localize the mutation to CNBr fragment IV (residues 299–329). This fragment was isolated on a preparative scale and subjected to tryptic digestion. Sequential analysis of the abnormal tryptic peptide, purified by RP-HPLC, revealed the variant was caused by 313 Lys → Asn substitution, probably due to a point mutation in the structural gene. The lack of a lysine residue accounts for the electrophoretic behavior of albumin Tagliacozzo

Plasminogen activation triggers transthyretin amyloidogenesis in vitro

Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro. In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo. Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro. Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo. Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation

A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β2-microglobulin knock out mice, the D76N β2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis

Disability, anxiety and depression associated with medication-overuse headache can be considerably reduced by detoxification and prophylactic treatment. Results from a multicentre, multinational study (COMOESTAS project)

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