Litho-sedimentological and morphodynamic characterization of the Pisa Province coastal area (northern Tuscany, Italy)

In this paper litho-sedimentological and morphodynamic maps of the coastal sector belonging to the Pisa Province are presented as an example of how increasing the accessibility to data on lithology, sedimentology, and morphodynamics may lead to a better approach to coastal management. The database used to build the maps includes an original rendering of remote sensing data (aerial imagery) and new field data (geologic survey), as well as data retrieved from the scientific literature (grain-size and past coastline positions). The maps show that the geometry of beach ridges is an indication of the evolution of the Arno River delta in the last 3000 years, highlighting the relationships between geological aspects and morphodynamic features. The maps represent the synthesis of different data available in the database, and they may be a useful support to coastal management as they are more easily understandable and straightforward than the database from which are created

Wear predictions for reverse total shoulder replacements

Reverse total shoulder arthroplasty (RTSA) has become the gold standard to treat rotator cuff tear arthropathy. RTSA is performed by substituting the humeral head and the glenoid cavity by a plastic cup in UHMWPE and a metallic head, respectively, in a geometrical reversed configuration with respect to the anatomical one. Major complications affect 27% of cases and mainly regard scapular notching due to cup-bone impingement and wear debris. Unfortunately, wear in shoulder prosthesis has not been largely studied as for hip and knee implants. Indeed, no wear test standards or even shoulder simulators exist, also because of a limited knowledge on shoulder/RTSA dynamics. Additionally, only a few numerical wear models for RTSA can be found in the literature, mainly focused on the comparison between anatomical and reverse solutions, and which often simulates simplified conditions, such as planar unloaded motions even neglecting fundamental aspects of wear process, i.e. cross-shearing (CS). The aim of the present study is to numerically investigate wear in RTSAs analysing the effect of: a) wear factor and wear law; a) implant geometry; b) inversion of bearing materials, i.e. plastic head + metallic cup, which should reduce the risks associated to scapular notching

Disseminated phaeohyphomycosis in a beluga sturgeon (Huso huso)

Phaeohyphomycosis is a fungal infection caused by dematiaceous or melanised fungi (Seyedmousavi, Guillot, and de Hoog 2013). Although considered ubiquitous residents of plant material, soil, and wood, melanised fungi are likely adapted to specific niches that facilitate variable opportunistic or true pathogenic potentials. Exposure is typically associated with inoculation by minor trauma or inhalation. In mammals, infections are commonly cutaneous, subcutaneous, upper respiratory or primary cerebral, but in cold-blooded vertebrates are often disseminated and accompanied by severe tissue necrosis (Revankar, Sutton, and Rinaldi 2004; Seyedmousavi, Guillot, and de Hoog 2013)

New synthetic routes to Triazolo-benzodiazepine analogues:expanding the scope of the bump-and-hole approach for selective Bromo and Extra-Terminal (BET) bromodomain inhibition

We describe new synthetic routes developed toward a range of substituted analogues of bromo and extra-terminal (BET) bromodomain inhibitors I-BET762/JQ1 based on the triazolo-benzodiazepine scaffold. These new routes allow for the derivatization of the methoxyphenyl and chlorophenyl rings, in addition to the diazepine ternary center and the side chain methylene moiety. Substitution at the level of the side chain methylene afforded compounds targeting specifically and potently engineered BET bromodomains designed as part of a bump and hole approach. We further demonstrate that marked selectivity for the second over the first bromodomain can be achieved with an indole derivative that exploits differential interaction with an aspartate/histidine conservative substitution on the BC loop of BET bromodomains

Regional Analysis of the Magnetization Transfer Ratio of the Brain in Mild Alzheimer Disease and Amnestic Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. MATERIALS AND METHODS: Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. RESULTS: Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. CONCLUSIONS: Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Interdisciplinary approach for geomorphological study of an high slope instability area in the northern Apennines mountains

Abstract Number: GSM01319

Spatio-temporal ground displacements monitoring of the Corniglio landslide (Parma, Italy)

Abstract Number: GHZ05812

Iterative design and optimization of initially inactive Proteolysis Targeting Chimeras (PROTACs) identify VZ185 as a potent, fast and selective von Hippel-Lindau (VHL)-based dual degrader probe of BRD9 and BRD7

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers, and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown, and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations