Meta-modelling and graph grammars for multi-paradigm modelling in AToM<Superscript>3</Superscript>

This paper presents the combined use of meta-modelling and graph grammars for the generation of visual modelling tools for simulation formalisms. In meta-modelling, formalisms are described at a meta-level. This information is used by a meta-model processor to generate modelling tools for the described formalisms. We combine meta-modelling with graph grammars to extend the model manipulation capabilities of the generated modelling tools: edit, simulate, transform into another formalism, optimize and generate code. We store all (meta-)models as graphs, and thus, express model manipulations as graph grammars.We present the design and implementation of these concepts in AToM³ (A_To_ol for M_ulti-formalism, M_eta-M_odelling). AToM³ supports modelling of complex systems using different formalisms, all meta-modelled in their own right. Models in different formalisms may be transformed into a single common formalism for further processing. These transformations are specified by graph grammars. Mosterman and Vangheluwe [18] introduced the term multi-paradigm modelling to denote the combination of multiple formalisms, multiple abstraction levels, and meta-modelling. As an example of multi-paradigm modelling we present a meta-model for the Object-Oriented Continuous Simulation Language OOCSMP, in which we combine ideas from UML class diagrams (to express the OOCSMP model structure), Causal Block Diagrams (CBDs), and Statecharts (to specify the methods of the OOCSMP classes). A graph grammar is able to generate OOCSMP code, and then a compiler for this language (C-OOL) generates Java applets for the simulation execution.     

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca²⁺ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.     

SIMULATING STRUCTURAL CHANGE IN ADAPTIVE ORGANIZATIONS

This paper presents an agent-based model of an organization. The model is made of a social network—composed of the different organization workers—and a knowledge network. Workers are assigned tasks, for which they have to use information in the knowledge network. We have modeled the quality of the information by assigning each information item a probability of being wrong. Agents can interact with other agents, who can recommend to them new information items in the knowledge network for the task to be performed. Workers are assigned different information-seeking behavior (passive, active, and learning), governing the way in which they interact with each other. Moreover, indirect interaction is also possible, as a publicly accessible knowledge base contains each agent's preferred information items.

The model was implemented in SDML, and its simulation shows that agents quickly learn to discern the better information items for the given task. However, group formation (agents' collaborating by exchanging information) takes longer to stabilize. Additionally, when the quality of items is changed, agents can quickly select the better new knowledge items, and organization performance improves again to a maximum that is only randomly disturbed.     

Calcite Prisms from Mollusk Shells (Atrina Rigida): Swiss‐cheese‐like Organic–Inorganic Single‐crystal Composites

Biogenic single‐crystal composites, such as sea urchin spines and calcitic prisms from mollusk shells, contain organic macromolecules inside of inorganic single‐crystal matrices. The nanoscale internal structure of these materials, however, is poorly understood, especially how the biomacromolecules are distributed within the crystals without significantly disrupting the crystalline lattice. Here, annular dark‐field scanning transmission electron microscopy and electron tomography reveal, in three dimensions, how biomacromolecules are distributed within the calcitic prisms from Atrina rigida shells. Disk‐like nanopatches, whose scattering intensity is consistent with organic inclusions, are observed to be anisotropically arranged within a continuous, single‐crystalline calcite matrix. These nanopatches are preferentially aligned with the (000l) planes of calcite. Along the crystallographic c‐axis, there are alternating organic‐rich and ‐poor regions on a length scale of tens of nanometers, while, in the ab plane, the distribution of nanopatches is more random and uniform. The structural features elucidated in this work have relevance to understanding the structure–property relationships and formation mechanisms of biominerals, as well as to the development of bio‐inspired strategies to extrinsically tune the properties of single‐crystals.     

A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers.

Topiramate, an anticonvulsant medication, is an efficacious treatment for alcohol dependence. To date, little is known about genetic moderators of side effects from topiramate. The objective of this study was to examine 3 single nucleotide polymorphisms (SNPs) of the glutamate receptor GluR5 gene (GRIK1) as predictors of topiramate-induced side effects in the context of a laboratory study of topiramate. Heavy drinkers (n = 51, 19 women and 32 men), 75% of whom met criteria for an alcohol use disorder, completed a 5-week dose escalation schedule to a target dose of either 200 or 300 mg or matched placebo. The combined medication groups were compared with placebo-treated individuals for side effects at target dose. Analyses revealed that an SNP in intron 9 of the GRIK1 gene (rs2832407) was associated with the severity of topiramate-induced side effects and with serum levels of topiramate. Genes underlying glutamatergic neurotransmission, such as the GRIK1 gene, may help predict heterogeneity in topiramate-induced side effects. Future studies in larger samples are needed to more fully establish these preliminary findings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Surface and interfacial fourier transform infrared spectroscopic studies of latexes. XIV. Surface phase separation in polystyrene/poly-n-butyl acrylate latex films

This study focuses on the behavior of sodium dioctylsulfosuccinate (SDOSS) in 50/50 w/w % polystyrene/poly(butyl acrylate) (p-Sty/p-BA) latex films. Specifically, mobility and orientation are examined in the context of the film formation by the use of dynamic mechanical thermal analysis and attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) spectroscopy. While for the homopolymer blends of p-Sty and p-BA, two T_g values resulting from a phase separation of p-Sty and p-BA phases are observed, only a single T_g is detected for a copolymer of the same mixture, indicating a single phase within the film. ATR FTIR spectroscopic data indicate that the phase separation of p-Sty and p-BA blends does not occur uniformly across the film. After coalescence, p-Sty particles produce a significant degree of stratification at approximately 1.6 μm from the film surface. At this depth, the polystyrene rings assume preferentially parallel orientation to the film surface. At the same time, the hydrophilic groups of SDOSS surfactant (SO⁻₃Na⁺) are oriented preferentiallyparallel to the surface. Under high relative humidity conditions, water is able to diffuse into the film and swells the surface layers, thus causing them to expand. As a result, the top, predominately poly-n-BA surface becomes “thicker», and p-Sty phase appears to be near 2.3 μm from the surface. The polystyrene rings maintain their preferential parallel orientation to the surface, but the hydrophilic groups of SDOSS are able to diffuse into the film with the water uptake and are thus not present at the filmair interface. © 1996 John Wiley & Sons, Inc.     

OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions

The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.     

Strain-specific polyketide synthase genes of Aspergillus niger

In silico comparison of 34 putative pks genes in Aspergillus niger strain CBS 513.88 versus A. niger strain ATCC 1015 genome revealed significant nucleotide identity (>95% covering a minimum of 99% of the gene sequence) for 31 of these genes (approximately 91%). A. niger CBS 513.88 harbors three putative pks genes (An01g01130, An11g05940, and An15g07920), for which nucleotide identity was not found in A. niger ATCC 1015. To compare the results of the in silico analysis with the in vivo situation, experimental data were obtained for a large number of A. niger strains obtained from different substrates and geographical regions. Three putative pks genes that were found to be variable between the two A. niger strains using bioinformatics tools were in fact strain-specific genes based on experimental data. The PCR amplification signals for the An01g01130, An11g05940, and An15g07920 pks genes were detected in only 97%, 71%, and 26% of the strains, respectively. Southern blot analyses confirmed the PCR data. Because one of the strain-specific pks genes (An15g07920) is located in a putative ochratoxin cluster, we focused our investigation on that region. We assessed the ochratoxin production capability of the 119 A. niger strains and found a positive association between the presence of this pks gene and the capability of the respective strain to produce ochratoxin.