Fibroblast Growth Factor-2 Antagonist Activity and Angiostatic Capacity of Sulfated Escherichia coli K5 Polysaccharide Derivatives *

The angiogenic basic fibroblast growth factor (FGF2) interacts with tyrosine kinase receptors (FGFRs) and heparan sulfate proteoglycans (HSPGs) in endothelial cells. Here, we report the FGF2 antagonist and antiangiogenic activity of novel sulfated derivatives of the Escherichia coli K5 polysaccharide. K5 polysaccharide was chemically sulfated in N- and/or O-position after N-deacetylation. O-Sulfated and N,O-sulfated K5 derivatives with a low degree and a high degree of sulfation compete with heparin for binding to 125I-FGF2 with different potency. Accordingly, they abrogate the formation of the HSPG.FGF2.FGFR ternary complex, as evidenced by their capacity to prevent FGF2-mediated cell-cell attachment of FGFR1-overexpressing HSPG-deficient Chinese hamster ovary (CHO) cells to wild-type CHO cells. They also inhibited 125I-FGF2 binding to FGFR1-overexpressing HSPG-bearing CHO cells and adult bovine aortic endothelial cells. K5 derivatives also inhibited FGF2-mediated cell proliferation in endothelial GM 7373 cells and in human umbilical vein endothelial (HUVE) cells. In all these assays, the N-sulfated K5 derivative and unmodified K5 were poorly effective. Also, highly O-sulfated and N,O-sulfated K5 derivatives prevented the sprouting of FGF2-transfected endothelial FGF2-T-MAE cells in fibrin gel and spontaneous angiogenesis in vitro on Matrigel of FGF2-T-MAE and HUVE cells. Finally, the highly N,O-sulfated K5 derivative exerted a potent antiangiogenic activity on the chick embryo chorioallantoic membrane. These data demonstrate the possibility of generating FGF2 antagonists endowed with antiangiogenic activity by specific chemical sulfation of bacterial K5 polysaccharide. In particular, the highly N,O-sulfated K5 derivative may provide the basis for the design of novel angiostatic compounds

The upgrade of the ASACUSA scintillating bar detector for antiproton annihilation measurements

Antiproton annihilations on matter nuclei are usually detected by tracking the charged pions emitted in the process. A detector made of plastic scintillating bars have been built and used in the ASACUSA experiment for the last 10 years. Ageing, movements and transports caused stress on the internal mechanical structure and impacted mostly on the optical readout system which was eventually upgraded: the so far used multi-anode photo-multiplier tubes (PMTs) have been replaced by silicon photomultipliers (SiPM) and the front-end electronics had to be adapted to cope with the new signal formation. This work describes the design and operations of the upgrade, as well as the validation tests with cosmic rays

Correction to: Magnetic resonance imaging features of the superior cervical ganglion and expected changes after radiation therapy to the head and neck in a long-term follow-up

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Coinvolgimento cardiaco nella distrofia miotonica di Steinert: uno studio longitudinale dalla diagnostica convenzionale all'imaging avanzato

ENGLISH: Background – Heart disease is a major cause of death in Steinert’s/type 1 myotonic dystrophy (DM1). Pe-riodic multimodal cardiac evaluation is recommended, but the prognostic potential of cardiac imaging is still poorly characterised. Objective – To study the prognostic value of cardiac imaging in Steinert’s disease. Design - Retrospective-prospective observational cohort study. Setting - A cardiological centre for tertiary care. Records spanned from December 1999 to October 2020. Patients - Seventy-seven patients (46 males) aged 42±10 years with DM1 reported on their charts, whose diagnosis was then confirmed by genetic records. Previous myocardial infarction was excluded. Measurements - Charts were reviewed. Records of 12-lead electrocardiography, 24h-Holter monitoring, echocardiography (standard, Doppler and tissue Doppler imaging - TDI), cardiac magnetic resonance (CMR) and laboratory tests (CK, NT-proBNP, hs-cTnT) were analyzed. Live patients were interviewed for clinical updates at the end of a median 3.26 (1.63 - 4.71) years of follow-up from first imaging. Results - Baseline echocardiography showed left (LVEF<50%) and right (S-wave <9,5 cm/s at TDI) systolic dysfunction in 11% and 14% of patients respectively, grade-I diastolic dysfunction in 18%. CMR was per-formed in 34 (44%) patients: 5 (15%) presented with a LVEF<50%, 5 (15%) with a RVEF<50%, 12 (35%) with a decreased LV end-diastolic volume, 7 (21%) with a decreased LV mass, 29 (85%) with a decreased mass/volume ratio, 9 (26%) with late gadolinium enhancement (LGE), 14 (41%) with fatty infiltration. Native T1 approached the upper reference limit (1041±53 ms), while the extracellular volume was slightly increased (33±2%). By the end of follow-up, 16 (21%) patients died from any cause, 13 (17%) developed atrial flutter/fibrillation, 12 (16%) a LVEF<50%, 16 (21%) were implanted with a PM/ICD. Among cardiac ul-trasound variables, left ventricular mass index predicted the occurrence of LV systolic dysfunction (p=0.024), device implantation (p=0.036) and supraventricular tachycardia (p=0.044). Among CMR param-eters, left ventricular mass index predicted the need for pacemaker implantation (p=0.005), LGE the occur-rence of Lown class≥2 ventricular arrhythmias (p=0.026). Consistent predictors of death lacked: thickening of the posterior wall (p=0,001) at ultrasound, a low E/A ratio (p=0.020) and a high A wave (p<0.001) at transmitral Doppler were all predictors, as well as a high mass/volume ratio at CMR. Limitations - Most data were retrospective. The setting might have produced a referral bias. Conclusions - In keeping with previous reports, we observed various structural and mechanical cardiac abnormalities in DM1. Cardiac imaging likely has prognostic value and magnetic resonance seems to uncover some features better than echocardiography. Further studies are warranted to confirm our findings and to integrate imaging and electrocardiography for risk stratification. ITALIANO: Background - Il coinvolgimento cardiaco è fra le principali cause di morte nella distrofia di Steinert/miotonica di tipo 1 (DM1). È raccomandata una valutazione cardiologica periodica, ma il potenziale prognostico dell’imaging rimane scarsamente definito. Obiettivo - Studiare il valore prognostico dell’imaging cardiaco nella DM1. Disegno dello studio - Di coorte, retrospettivo-prospettico osservazionale. Sede - Un centro per le cure cardiologiche di terzo livello. Sono stati consultati gli archivi dal 1999 al 2020. Pazienti - Settantasette pazienti (46 maschi) di 42±10 anni d’età, con una diagnosi di DM1 riportata nelle loro cartelle e confermata da test genetici. È stata esclusa la presenza di pregresso infarto del miocardio. Misurazioni - Sono state esaminate le cartelle cliniche. Sono stati rivisti ed annotati gli esiti degli esami elettrocardiografici basali (12 derivazioni) e secondo Holter (nelle 24 ore), delle ecocardiografie (standard, Doppler e Doppler tissutale), degli esami di risonanza magnetica cardiaca (CMR) e le determinazioni dei biomarcatori cardiaci (CK, NT-proBNP, hs-cTnT). Risultati - All’inizio del periodo d’osservazione, l’ecocardiografia mostrava una disfunzione sistolica sinistra (LVEF<50%) e destra (onda S<9,5 cm/s) rispettivamente nell’11% e nel 14% dei pazienti e una disfunzione diastolica di primo grado nel 18%. Una risonanza magnetica cardiaca era disponibile in 34 (44%) pazienti: in 5 (15%) è stata osservata una LVEF<50%, in 5 (15%) una RVEF<50%. Confrontando con valori di riferimento specifici per età e sesso, 12 (35%) soggetti presentavano un volume telediastolico ventricolare sinistro indicizzato (LVEDVi) diminuito, 7 (21%) un indice di massa ventricolare sinistra (LVMi) ridotto, 29 (85%) un basso rapporto massa/volume (M/V). In 9 (26%) soggetti sono state osservate aree di late gadolinium enhancement (LGE), in 14 (41%) delle infiltrazioni adipose. Nel setto interventricolare il T1 nativo (1041±53 ms) si avvicinava al limite superiore della norma ed il volume extracellulare è risultato leggermente aumentato (33±2%). Entro la fine del follow-up 16 (21%) soggetti sono deceduti, 13 (17%) hanno manifestato episodi di fibrillazione/flutter atriale, 12 (16%) una LVEF<50%, e in 16 (21%) è stata posta l'indicazione all’impianto di pacemaker o defibrillatore. Fra le variabili ecografiche, un alto LVMi è risultato un predittore dell'insorgenza di disfunzione sistolica (p=0.024) e di episodi di tachicardia sopraventricolare (p=0.044) e dell’indicazione all’impianto di device (p=0.036). Alla risonanza magnetica, un alto LVMi è risultato un predittore dell’indicazione al pacing (p=0.005) e la presenza di LGE dell’insorgenza di aritmie ventricolari con classe di Lown≥2 (p=0.026). Non sono stati identificati fattori prognostici quoad vitam costanti fra le metodiche imaging ed i diversi indici considerati: all'ecocardiografia, l’ispessimento della parete posteriore (p=0,001), un basso rapporto E/A (p=0.020) ed un’aumentata onda A (p<0.001) sono risultati indici in grado di predire il decesso per tutte le cause. Alla risonanza magnetica, un elevato rapporto M/V sembrerebbe associato ad una peggiore prognosi. Limiti - La maggior parte dei dati è retrospettiva. L’istituzione, di terzo livello, potrebbe aver favorito un bias di selezione. Conclusioni - In accordo con quanto precedentemente riportato in letteratura, abbiamo osservato varie anomalie cardiache strutturali e meccaniche nella DM1. L’imaging cardiaco probabilmente ha un valore prognostico in questo contesto e la risonanza magnetica sembra evidenziare dei tratti caratteristici della patologia meglio dell’ecocardiografia. Ulteriori studi sarebbero giustificati, con l’obiettivo di confermare i nostri risultati ed integrare diagnostica per immagini ed elettrocardiografia nella stratificazione prognostica dei soggetti con distrofia di Steinert

A review on artificial intelligence applications to the optimal design of dedicated and reconfigurable manufacturing systems

Reconfigurable manufacturing systems (RMS) are considered the future of manufacturing, being able to overcome both dedicated (DMS) and flexible manufacturing systems (FMS). In fact, they provide significant cost and time reductions in the launch of new products, and in the integration of new manufacturing processes into existing systems. The goals of RMS design are the extension of the production variety, the adaption to rapid changes in the market demand, and the minimization of the investment costs. Despite the interest of many authors, the debate on RMS is still open due to the lack of practical applications. This work is a review of the state-of-the-art on the design of cellular RMS, compared to DMS, by means of optimization. The problem addressed belongs to the NP-Hard family of combinatorial problem. The focus is on non-exact meta-heuristic and artificial intelligence methods, since these have been proven to be effective and robust in solving complex manufacturing design problems. A wide investigation on the most recurrent techniques in DMS and RMS literature is performed at first. A critical analysis over these techniques is given in the end

Age related changes of monoaminoxidases in rat cerebellar cortex.

Age-related changes of the monoaminoxidases, evaluated by enzymatic staining, quantitative analysis of images, biochemical assay and statistical analysis of data were studied in cerebellar cortex of young (3-month-old) and aged (26- month-old) male Sprague-Dawley rats. The enzymatic staining shows the presence of monoamino-oxidases within the molecular and granular layers as well as within the Purkinje neurons of the cerebellum of young and aged animals. In molecular layer, and in Purkinje neurons the levels of monoaminooxidases were strongly increased in old rats. The granular layer showed, on the contrary, an age-dependent loss of enzymatic staining. These morphological findings were confirmed by biochemical results. The possibility that age-related changes in monoaminooxidase levels may be due to impaired energy production mechanisms and/or represent the consequence of reduced energetic needs is discussed