Vehicle Trajectories from Unlabeled Data through Iterative Plane Registration

One of the most complex aspects of autonomous driving concerns understanding the surrounding environment. In particular, the interest falls on detecting which agents are populating it and how they are moving. The capacity to predict how these may act in the near future would allow an autonomous vehicle to safely plan its trajectory, minimizing the risks for itself and others. In this work we propose an automatic trajectory annotation method exploiting an Iterative Plane Registration algorithm based on homographies and semantic segmentations. The output of our technique is a set of holistic trajectories (past-present-future) paired with a single image context, useful to train a predictive model

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Constraining Absolute Plate Motions Since the Triassic

The absolute motion of tectonic plates since Pangea can be derived from observations of hotspot trails, paleomagnetism, or seismic tomography. However, fitting observations is typically carried out in isolation without consideration for the fit to unused data or whether the resulting plate motions are geodynamically plausible. Through the joint evaluation of global hotspot track observations (for times <80 Ma), first‐order estimates of net lithospheric rotation (NLR), and parameter estimation for paleo–trench migration (TM), we present a suite of geodynamically consistent, data‐optimized global absolute reference frames from 220 Ma to the present. Each absolute plate motion (APM) model was evaluated against six published APM models, together incorporating the full range of primary data constraints. Model performance for published and new models was quantified through a standard statistical analyses using three key diagnostic global metrics: root‐mean square plate velocities, NLR characteristics, and TM behavior. Additionally, models were assessed for consistency with published global paleomagnetic data and for ages <80 Ma for predicted relative hotspot motion, track geometry, and time dependence. Optimized APM models demonstrated significantly improved global fit with geological and geophysical observations while performing consistently with geodynamic constraints. Critically, APM models derived by limiting average rates of NLR to ~0.05°/Myr and absolute TM velocities to ~27‐mm/year fit geological observations including hotspot tracks. This suggests that this range of NLR and TM estimates may be appropriate for Earth over the last 220 Myr, providing a key step toward the practical integration of numerical geodynamics into plate tectonic reconstructions

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA

Development of a fluorogenic ADAMTS-7 substrate

The extracellular protease ADAMTS-7 has been identified as a potential therapeutic target in atherosclerosis and associated diseases such as coronary artery disease (CAD). However, ADAMTS-7 inhibitors have not been reported so far. Screening of inhibitors has been hindered by the lack of a suitable peptide substrate and, consequently, a convenient activity assay. Here we describe the first fluorescence resonance energy transfer (FRET) substrate for ADAMTS-7, ATS7FP7. ATS7FP7 was used to measure inhibition constants for the endogenous ADAMTS-7 inhibitor, TIMP-4, as well as two hydroxamate-based zinc chelating inhibitors. These inhibition constants match well with IC50 values obtained with our SDS-PAGE assay that uses the N-terminal fragment of latent TGF-β–binding protein 4 (LTBP4S-A) as a substrate. Our novel fluorogenic substrate ATS7FP7 is suitable for high throughput screening of ADAMTS-7 inhibitors, thus accelerating translational studies aiming at inhibition of ADAMTS-7 as a novel treatment for cardiovascular diseases such as atherosclerosis and CAD

Sialendoscopy for salivary stones: principles, technical skills and therapeutic experience

La scialoadenite cronica ostruttiva rappresenta una delle più frequenti patologie non-neoplastiche delle ghiandole salivari e la scialoendoscopia è sempre più utilizzata nella sua diagnosi e nel suo trattamento, associata o meno con la litotripsia laser. La scialoendoscopia può essere inoltre associata ad approcci esterni mini-invasivi nelle litiasi troppo voluminose per essere rimosse con un approccio unicamente endoscopico. Il presente articolo riporta lesperienza delle Cliniche Otorinolaringoiatriche dellOspedale SantOrsola-Malpighi di Bologna e dellAzienda Ospedaliero Universitaria di Cagliari, Italia. È stata eseguita unanalisi retrospettiva su 48 pazienti (26 femmine, 22 maschi; età media di 45,3 anni; range 8-83 anni) trattati per patologia cronica ostruttiva delle ghiandole salivari maggiori mediante procedure chirurgiche endoscopiche o combinate da novembre 2010 ad aprile 2016 presso lAzienda-Ospedaliero-Universitaria di Cagliari. I risultati dellOspedale SantOrsola-Malpighi di Bologna erano stati precedentemente pubblicati. Gli aspetti tecnici della scialoendoscopia sono stati accuratamente descritti. I pazienti trattati presso lAzienda Ospedaliero Universitaria di Cagliari presentavano una patologia unilaterale in 40 casi e bilaterale in 8 casi; sono state trattate 56 ghiandole salivari maggiori (22 sottomandibolari e 34 parotidi). 5 pazienti sono stati sottoposti a scialoendoscopia bilaterale per parotite ricorrente giovanile, 10 per patologia ostruttiva non litiasica e 33 (68,75%) presentavano calcoli salivari (1 paziente presentava una litiasi parotidea bilaterale). Solo 8 pazienti sono stati sottoposti a scialectomia radicale per via esterna (5 scialectomie sottomandibolare e 3 parotidectomie). La chirurgia conservativa nei pazienti con scialoadenite cronica ostruttiva appare efficace e può essere realizzata mediante un approccio puramente endoscopico o combinato, con unalta percentuale di successo. La procedura richiede una strumentazione adeguata e deve essere eseguita da un chirurgo esperto, che abbia svolto un training specifico scialoendoscopico, in modo da evitare le possibili complicanze maggiori e minori. La scialectomia tradizionale rappresenta la extrema ratio, limitata nei casi in cui un approccio conservativo sia risultato inefficace o controindicato

Regioselective Glycosylation Strategies for the Synthesis of Group Ia and Ib Streptococcus Related Glycans Enable Elucidating Unique Conformations of the Capsular Polysaccharides

Group B Streptococcus serotypes Ia and Ib capsular polysaccharides are key targets for vaccine development. In spite of their immunospecifity these polysaccharides share high structural similarity. Both are composed of the same monosaccharide residues and differ only in the connection of the Neu5Acα2-3Gal side chain to the GlcNAc unit, which is a β1-4 linkage in serotype Ia and a β1-3 linkage in serotype Ib. We described development of efficient regioselective routes for GlcNAcβ1-3[Glcβ1-4)]Gal synthons giving access to different GBS Ia and Ib repeating unit frameshifts. These glycans were used to probe the conformation and molecular dynamics of the two polysaccharides, highlighting the different presentation of the protruding Neu5Acα2-3Gal moieties on the polysaccharide backbones and a higher flexibility of Ib polymer compared to Ia which can impact epitope exposure.Bio-organic Synthesi

RAPPORTO SULLE INDAGINI DI SISMICA A RIFLESSIONE, GRAVIMETRICHE, MAGNETOMETRICHE, MORFOBATIMETRICHE E CAMPIONAMENTO FONDO MARE NELL’ ARCO CALABRO (MAR IONIO) CAMPAGNA CALAMARE08

The study of the Calabrian Arc in the Ionian Sea is key to understanding of the geological processes in the Mediterranean Sea. We present the technical details and results of cruise CALAMARE08 with N/O Urania during spring 2008. We acquired a large set of geological and geophysical data, among them Multichannels Seismic and SBP, magnetometry, gravimetry, swath bathymetry and coring of sea bottom

Determinants of the Morning-Evening Home Blood Pressure Difference in Treated Hypertensives: The HIBA-Home Study

Background. The morning home blood pressure (BP) rise is a significant asymptomatic target organ damage predictor in hypertensives. Our aim was to evaluate determinants of home-based morning-evening difference (MEdiff) in Argentine patients. Methods. Treated hypertensive patients aged ≥18 years participated in a cross-sectional study, after performing home morning and evening BP measurement. MEdiff was morning minus evening home average results. Variables identified as relevant predictors were entered into a multivariable linear regression analysis model. Results. Three hundred sixty-seven medicated hypertensives were included. Mean age was 66.2 (14.5), BMI 28.1 (4.5), total cholesterol 4.89 (1.0) mmol/L, 65.9% women, 11.7% smokers, and 10.6% diabetics. Mean MEdiff was 1.1 (12.5) mmHg systolic and 2.3 (6.1) mmHg diastolic, respectively. Mean self-recorded BP was 131.5 (14.1) mmHg systolic and 73.8 (7.6) mmHg diastolic, respectively. Mean morning and evening home BPs were 133.1 (16.5) versus 132 (15.7) systolic and 75.8 (8.4) versus 73.5 (8.2) diastolic, respectively. Significant beta-coefficient values were found in systolic MEdiff for age and smoking and in diastolic MEdiff for age, smoking, total cholesterol, and calcium-channel blockers. Conclusions. In a cohort of Argentine medicated patients, older age, smoking, total cholesterol, and use of calcium channel blockers were independent determinants of home-based MEdiff