Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D₁-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.     

The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, with a 5-year survival rate of 7% and 80% of patients diagnosed with advanced or metastatic malignancies. Despite recent advances in diagnostic testing, surgical techniques, and systemic therapies, there remain limited options for the effective treatment of PDAC. There is an urgent need to develop targeted therapies that are able to differentiate between cancerous and non-cancerous cells to reduce side effects and better inhibit tumor growth. Antibody-targeted strategies are a potentially effective option for introducing innovative therapies. Antibody-based immunotherapies and antibody-conjugated nanoparticle-based targeted therapies with antibodies targeting specific tumor-associated antigens (TAA) can be proposed. In this context, glypican-1 (GPC1), which is highly expressed in PDAC and not expressed or expressed at very low levels in non-malignant lesions and healthy pancreatic tissues, is a useful TAA that can be achieved by a specific antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy. In this review, we describe the main clinical features of PDAC. We propose the proteoglycan GPC1 as a useful TAA for PDAC-targeted therapies. We also provide a digression on the main developed approaches of antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy, which can be used to target GPC1.     

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

Industrial Requirements for Distributed SCM Tool

As software development comes to be viewed more and more as an engineering discipline, Software Configuration Management is increasingly recognised as a key technology in the development of software. The Esprit VISCOUNT project¹ aim is to implement an innovative Software Configuration Management (SCM) tool to use in a geographically distributed software development environment, a Virtual Software Corporation (VSC). The features implemented by the tool will be the following: ·Configurable process modelling ·Inter-working capabilities with COTS SCM tools ·Selective replication of archives ·Open to include plug-in applications (security mechanism, encryption, etc) This paper is based on the work undertaken as part of the VISCOUNT project, partially funded by European Union's Esprit Programme, and it describes the SIA (Societa' Italiana Avionica) requirements defined in the framework of VISCOUNT. This revised version was published online in August 2006 with corrections to the Cover Date.     

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).     

A theory of ultimately periodic languages and automata with an application to time granularity

In this paper, we develop a theory of regular ω-languages that consist of ultimately periodic words only and we provide it with an automaton-based characterization. The resulting class of automata, called ultimately periodic automata (UPA), is a subclass of the class of Büchi automata and inherits some properties of automata over finite words (NFA). Taking advantage of the similarities among UPA, Büchi automata, and NFA, we devise efficient solutions to a number of basic problems for UPA, such as the inclusion, the equivalence, and the size optimization problems. The original motivation for developing a theory of ultimately periodic languages and automata was to represent and to reason about sets of time granularities in knowledge-based and database systems. In the last part of the paper, we show that UPA actually allow one to represent (possibly infinite) sets of granularities, instead of single ones, in a compact and suitable to algorithmic manipulation way. In particular, we describe an application of UPA to a concrete time granularity scenario taken from clinical medicine.     

AZ31 magnesium alloy recycling through friction stir extrusion process

Friction Stir Extrusion is a novel technique for direct recycling of metal scrap. In the process, a dedicated tool produces both the heat and the pressure to compact and extrude the original raw material, i.e., machining chip, as a consolidated component. A proper fixture was used to carry out an experimental campaign on Friction Stir Extrusion of AZ31 magnesium alloy. Variable tool rotation and extrusion ratio were considered. Appearance of defects and fractures was related to either too high or too low power input. The extruded rods were investigated both from the metallurgical and mechanical points of view. Tensile strength up to 80 % of the parent material was found for the best combination of process parameters. A peculiar 3D helical material flow was highlighted through metallurgical observation of the specimens.     

Effect of crystal habit and superstructure on modulus of elasticity of isotactic polypropylene by AFM nanoindentation

In this study the effects of crystal habit, crystallinity and superstructure on the modulus of elasticity of isotactic polypropylene films were analyzed by atomic force microscope (AFM) nanoindentation. The modulus of elasticity, evaluated on the nanometer scale by AFM, showed a qualitatively similar dependence on the crystal habit, crystallinity and superstructure as the modulus of elasticity measured by dynamic-mechanical analysis and tensile testing. The observed values of both the surface stiffness measured by AFM and the macroscopic/bulk stiffness were distinctly larger in the presence of non-isometric lamellae organized in spherulite than in the presence of isometric nodular crystals, not organized in a spherulitic superstructure. The experimental data showed that the modulus of elasticity is not primarily influenced by the presence or absence of spherulite but by the molecular-deformation constraint associated to the crystal habit.