Nanoliter contact angle probes tumor angiogenic ligand-receptor protein interactions

Any molecular recognition reaction supported by a solid-phase drives a specific change of the solid-solution interfacial tension. Sessile Contact Angle (CA) experiments can be readily used to track this thermodynamic parameter, prompting this well-known technique to be reinvented as an alternative, easy-access and label-free way to probe and study molecular recognition events. Here we deploy this technique, renamed for this application CONAMORE (CONtact Angle MOlecular REcognition), to study the interaction of the tumor-derived pro-angiogenic vascular endothelial growth factor-A (VEGF-A) with the extracellular domain of its receptor VEGFR2. We show that CONAMORE recognizes the high affinity binding of VEGF-A at nanomolar concentrations to surface-immobilized VEGFR2 regardless of the presence of a ten folds excess of a non specific interacting protein, and that it further proofs its specificity and reliability on competitive binding experiments involving neutralizing anti-VEGF-A antibodies. Finally, CONAMORE shows the outstanding capability to detect the specific interaction between VEGFR2 and low molecular weight ligands, such as Cyclo-VEGI, a VEGFR2 antagonist cyclo-peptide, that weights about 2 kDa

Experimental evidence of antiproton reflection by a solid surface

We report here experimental evidence of the reflection of a large fraction of a beam of low energy antiprotons by an aluminum wall. This derives from the analysis of a set of annihilations of antiprotons that come to rest in rarefied helium gas after hitting the end wall of the apparatus. A Monte Carlo simulation of the antiproton path in aluminum indicates that the observed reflection occurs primarily via a multiple Rutherford-style scattering on Al nuclei, at least in the energy range 1-10 keV where the phenomenon is most visible in the analyzed data. These results contradict the common belief according to which the interactions between matter and antimatter are dominated by the reciprocally destructive phenomenon of annihilation.Comment: 5 pages with 5 figure

Gremlin is a novel agonist of the major pro-angiogenic receptor VEGFR2

The bone morphogenic protein antagonist gremlin is expressed during embryonic development and under different pathologic conditions, including cancer. Gremlin is a proangiogenic protein belonging to the cystine-knot superfamily that includes transforming growth factor-β proteins and the angiogenic vascular endothelial growth factors (VEGFs). Here, we demonstrate that gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals, in a bone morphogenic protein-independent manner. Similar to VEGF-A, gremlin activates VEGFR2 in endothelial cells, leading to VEGFR2-dependent angiogenic responses in vitro and in vivo. Gremlin thus represents a novel proangiogenic VEGFR2 agonist distinct from the VEGF family ligands with implications in vascular development, angiogenesis-dependent diseases, and tumor neovascularization

Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.

OBJECTIVE: Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives. METHODS AND RESULTS: Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane. CONCLUSIONS: LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds

Fibroblast growth factor 2-antagonist activity of a long-pentraxin 3-derived antiangiogenic pentapeptide.

Fibroblast growth factor-2 (FGF2) plays a major role in angiogenesis. The pattern recognition receptor long-pentraxin 3 (PTX3) inhibits the angiogenic activity of FGF2. To identify novel FGF2-antagonistic peptide(s), four acetylated (Ac) synthetic peptides overlapping the FGF2-binding region PTX3-(97-110) were assessed for their FGF2-binding capacity. Among them, the shortest pentapeptide Ac-ARPCA-NH(2) (PTX3-[100-104]) inhibits the interaction of FGF2 with PTX3 immobilized to a BIAcore sensorchip and suppresses FGF2-dependent proliferation in endothelial cells, without affecting the activity of unrelated mitogens. Also, Ac-ARPCA-NH(2) inhibits angiogenesis triggered by FGF2 or by tumorigenic FGF2-overexpressing murine endothelial cells in chick and zebrafish embryos, respectively. Accordingly, the peptide hampers the binding of FGF2 to Chinese Hamster ovary cells overexpressing the tyrosine-kinase FGF receptor-1 (FGFR1) and to recombinant FGFR1 immobilized to a BIAcore sensorchip without affecting heparin interaction. In all the assays the mutated Ac-ARPSA-NH(2) peptide was ineffective. In keeping with the observation that hydrophobic interactions dominate the interface between FGF2 and the FGF-binding domain of the Ig-like loop D2 of FGFR1, amino acid substitutions in Ac-ARPCA-NH(2) and saturation transfer difference-nuclear magnetic resonance analysis of its mode of interaction with FGF2 implicate the hydrophobic methyl groups of the pentapeptide in FGF2 binding. These results will provide the basis for the design of novel PTX3-derived anti-angiogenic FGF2 antagonists

Computer-Aided Tolerancing Analysis of a High-Performance Car Engine Assembly

This paper proposes the analysis of the tolerances (values, types, datum) and their effects on a mechanical assembly, as a high-performance car engine, by means of a Computer-Aided Tolerancing software. The 3D tolerance stack-ups are investigated to assess the fulfillment of the functional requirements as well as the performance specifications of the assembly. Moreover, after identifying the tolerances that mainly affect the product variability, we finally propose some corrective actions on the tolerances and assess their functional allocation, tightening or relaxing their values, ensuring assemblability and cost reduction

A Keyword, Taxonomy and Cartographic Research Review of Sustainability Concepts for Production Scheduling in Manufacturing Systems

The concept of sustainability is defined as composed of three pillars: social, environmental, and economic. Social sustainability implies a commitment to equity in terms of several “interrelated and mutually supportive” principles of a “sustainable society”; this concept includes attitude change, the Earth’s vitality and diversity conservation, and a global alliance to achieve sustainability. The social and environmental aspects of sustainability are related in the way sustainability indicators are related to “quality of life” and “ecological sustainability”. The increasing interest in green and sustainable products and production has influenced research interests regarding sustainable scheduling problems in manufacturing systems. This study is aimed both at reducing pollutant emissions and increasing production efficiency: this topic is known as Green Scheduling. Existing literature research reviews on Green Scheduling Problems have pointed out both theoretical and practical aspects of this topic. The proposed work is a critical review of the scientific literature with a three-pronged approach based on keywords, taxonomy analysis, and research mapping. Specific research questions have been proposed to highlight the benefits and related objectives of this review: to discover the most widely used methodologies for solving SPGs in manufacturing and identify interesting development models, as well as the least studied domains and algorithms. The literature was analysed in order to define a map of the main research fields on SPG, highlight mainstream SPG research, propose an efficient view of emerging research areas, propose a taxonomy of SPG by collecting multiple keywords into semantic clusters, and analyse the literature according to a semantic knowledge approach. At the same time, GSP researchers are provided with an efficient view of emerging research areas, allowing them to avoid missing key research areas and focus on emerging ones

A design methodology for an innovative racing mini motorcycle frame

Sports equipment design is a young and evolving engineering discipline focused on the best simultaneous optimization of user and product as a system. In motorsports, in particular, the final performance during a race depends on many parameters related to the vehicle, circuit, weather, and tyres and the personal feelings of every single driver. Top teams in high-tech categories can invest huge amounts of money in developing simulators, but such economic commitment is not sustainable for all those teams that operate in minor but very popular categories, such as karts or mini-motorcycles. In these fields, the most common design approach is trial and error on physical prototypes. Such an approach leads to high costs, long optimization times, poor innovation, and inefficient management of the design knowledge. The present paper proposes a driver centred methodology for the design of an innovative mini racing motorcycle frame. It consists of two main phases: the drivers’ feelings translation into engineering requirements and constraints, and the exploration of the design solution space. Expected effects of the application of the proposed methodology are an overall increase in the degree of innovation, time compression, and cost reduction during the development process, with a significant impact on the competitiveness of small racing teams in minor categories

Pathophysiology and Clinical Meaning of Ventilation-Perfusion Mismatch in the Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) remains an important clinical challenge with a mortality rate of 35–45%. It is being increasingly demonstrated that the improvement of outcomes requires a tailored, individualized approach to therapy, guided by a detailed understanding of each patient’s pathophysiology. In patients with ARDS, disturbances in the physiological matching of alveolar ventilation (V) and pulmonary perfusion (Q) (V/Q mismatch) are a hallmark derangement. The perfusion of collapsed or consolidated lung units gives rise to intrapulmonary shunting and arterial hypoxemia, whereas the ventilation of non-perfused lung zones increases physiological dead-space, which potentially necessitates increased ventilation to avoid hypercapnia. Beyond its impact on gas exchange, V/Q mismatch is a predictor of adverse outcomes in patients with ARDS; more recently, its role in ventilation-induced lung injury and worsening lung edema has been described. Innovations in bedside imaging technologies such as electrical impedance tomography readily allow clinicians to determine the regional distributions of V and Q, as well as the adequacy of their matching, providing new insights into the phenotyping, prognostication, and clinical management of patients with ARDS. The purpose of this review is to discuss the pathophysiology, identification, consequences, and treatment of V/Q mismatch in the setting of ARDS, employing experimental data from clinical and preclinical studies as support

ASACUSA Status Report

ASACUSA progress during 2009 and plans for 201