Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.     

Empty-State Band Mapping Using Momentum-Resolved Secondary Electron Emission

Material band structures of occupied electronic states are obtainable using conventional angle-resolved photoemission experiments, leaving the unoccupied states far less explored. Here, an alternative approach is built on and expanded to investigate thermalized photoelectrons emitted from crystal surfaces. A model for electron emission is constructed and reveals the material unoccupied state band structure. Potentially applicable to any material and independent from the secondary electron generation mechanism, it is demonstrated on diamond and copper using different light sources. Moreover, the diamond indirect band gap is directly observed and the transverse effective mass at the conduction band minimum can be experimentally obtained, m_t = (0.21 ± 0.015) m_e. This offers a convenient path for angle-resolved photoemission data interpretation and empty-state information extraction.     

Potency and Selectivity Optimization of Tryptophanol-Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer

To search for novel p53 activators, four series of novel (S)- and (R)-tryptophanol-derived oxazoloisoindolinones were synthesized in a straightforward manner and their antiproliferative activity was evaluated in the human colorectal cancer HCT116 cell line. Structural optimization of the hit compound SLMP53-1 led to the identification of a (R)-tryptophanol-derived isoindolinone that was found to be six-fold more active, with increased selectivity for HCT116 cells with p53 and with low toxicity in normal cells. Binding studies with MDM2 showed that the antiproliferative activity of tryptophanol-derived isoindolinones does not involve inhibition of the main negative regulator of the p53 protein. Molecular docking simulations showed that although these molecules establish hydrophobic interactions with MDM2, they do not possess the required features to bind MDM2.     

Milk kefir enriched with inulin-grafted seed extract from white wine pomace: chemical characterisation,antioxidant profile and in vitro gastrointestinal digestion

An innovative functional food with symbiotic and functional potential was produced by combining probiotic milk kefir, and white grape-seed pomace obtained by UAE (ultrasound-assisted extraction) rich in catechin and glycosylated flavonoids. The milk kefir was fortified by adding, after 24 h of fermentation, a polymer of inulin grafted with seed extract. The inulin/grape extract-enriched polymer showed a higher antioxidant profile (P < 0.05). Simulated in vitro digestion demonstrated that 50 g of the kefir product would result in the delivery of antioxidants equivalent to 300 mg of ascorbic acid. The integrity of the intestinal barrier functions was not compromised by kefir treatments (at 10 μg mL^-1).     

Heavy metal uptake in the enological food chain

The research presented here describes the assessment of a number of physiological and xenobiotic metal concentrations occurring throughout the enological production processes of two native wines from Irpinia, Aglianico and Fiano of Avellino. In order to evaluate the wines’ metal content throughout the entire wine-making process, samples of grapes and musts from both wines were taken at time intervals during the fermentation and maturation phases. Copper, chromium, nickel, iron, zinc, lead and cadmium levels were analysed by atomic absorption spectrophotometry. The concentration of metals obtained were compared to the limits fixed by the Organization Internationale de la Vigne et du Vin (O.I.V.) and in the Italian ad European legislation.     

Tracking the time-varying cortical connectivity patterns by adaptive multivariate estimators

The directed transfer function (DTF) and the partial directed coherence (PDC) are frequency-domain estimators that are able to describe interactions between cortical areas in terms of the concept of Granger causality. However, the classical estimation of these methods is based on the multivariate autoregressive modelling (MVAR) of time series, which requires the stationarity of the signals. In this way, transient pathways of information transfer remains hidden. The objective of this study is to test a time-varying multivariate method for the estimation of rapidly changing connectivity relationships between cortical areas of the human brain, based on DTF/PDC and on the use of adaptive MVAR modelling (AMVAR) and to apply it to a set of real high resolution EEG data. This approach will allow the observation of rapidly changing influences between the cortical areas during the execution of a task. The simulation results indicated that time-varying DTF and PDC are able to estimate correctly the imposed connectivity patterns under reasonable operative conditions of signal-to-noise ratio (SNR) ad number of trials. An SNR of five and a number of trials of at least 20 provide a good accuracy in the estimation. After testing the method by the simulation study, we provide an application to the cortical estimations obtained from high resolution EEG data recorded from a group of healthy subject during a combined foot-lips movement and present the time-varying connectivity patterns resulting from the application of both DTF and PDC. Two different cortical networks were detected with the proposed methods, one constant across the task and the other evolving during the preparation of the joint movement.     

A comparative study on the effects of three commercial Ti–B-based grain refiners on the impact properties of A356 cast aluminium alloy

The effect of three commercial Ti–B-based grain refiners on the impact properties of the A356 cast aluminium alloy was assessed. The impact tests were performed by means of an instrumented Charpy pendulum. During impact testing, the maximum load and the total impact energy, as well as its complementary contributions, the energy at maximum load and the crack propagation energy, were measured. Impact properties were studied as a function of size and shape of the main microstructural features, which were analysed by means of optical microscopy and scanning electron microscopy. The results show that the influence of grain refinement on microstructure involves beneficial and detrimental concurrent effects which strongly affect impact properties. The total impact energy decreases with the addition of all the grain refiners due to a shift from a mixed transgranular–intergranular fracture mode to a more severe transgranular mode. Crack initiation and propagation occur mainly through the fracture of Fe-intermetallics and brittle Si particles, and the mechanism of void coalescence. No direct correlation between grain size and impact properties is found. Moreover, the aspect ratio of eutectic Si particles does not change with grain refinement, implying that there are no mutual poisoning effects between Sr and B. Total impact energy is found to depend on both SDAS and β-platelets size. The concurrent effects of SDAS and β-platelets average maximum length on total impact energy can be taken into account by the multiple regression analysis technique.     

Fluorination of suspended graphene

Nano Research - Suspended graphene is exposed to different fluorine-containing species produced by a plasma source fed with CF4 precursor gas. We investigate the fluorination process by selecting...