Introduction to the Special Section on “Modeling Sustainable Risk Management”

In recent years, risk management has attracted a great deal of attention from both researchers and practitioners. Risk management practice has required new tools to achieve sustainability when dealing with loss exposure. Sustainable risk management is studied from different silo disciplinary perspectives.     

A minimal model for the mitochondrial rapid mode of Ca²+ uptake mechanism

Mitochondria possess a remarkable ability to rapidly accumulate and sequester Ca²⁺. One of the mechanisms responsible for this ability is believed to be the rapid mode (RaM) of Ca²⁺ uptake. Despite the existence of many models of mitochondrial Ca²⁺ dynamics, very few consider RaM as a potential mechanism that regulates mitochondrial Ca²⁺ dynamics. To fill this gap, a novel mathematical model of the RaM mechanism is developed herein. The model is able to simulate the available experimental data of rapid Ca²⁺ uptake in isolated mitochondria from both chicken heart and rat liver tissues with good fidelity. The mechanism is based on Ca²⁺ binding to an external trigger site(s) and initiating a brief transient of high Ca²⁺ conductivity. It then quickly switches to an inhibited, zero-conductive state until the external Ca²⁺ level is dropped below a critical value (∼100–150 nM). RaM''s Ca²⁺- and time-dependent properties make it a unique Ca²⁺ transporter that may be an important means by which mitochondria take up Ca²⁺ in situ and help enable mitochondria to decode cytosolic Ca²⁺ signals. Integrating the developed RaM model into existing models of mitochondrial Ca²⁺ dynamics will help elucidate the physiological role that this unique mechanism plays in mitochondrial Ca²⁺-homeostasis and bioenergetics.     

Exploration of new scaffolds as potential MAO-A inhibitors using pharmacophore and 3D-QSAR based in silico screening

Monoamine oxidase-A (MAO-A) inhibitors are of particular importance in the treatment of depressive disorders. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported pyrrole based MAO-A inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated consisted of four features DHHR: a hydrogen bond donor (D), two hydrophobic groups (H) and an aromatic ring (R). Based on model generated, a statistically valid 3D-QSAR with good predictability was developed. Derived pharmacophore was used as a query to search Zinc ‘clean drug-like’ database. Hits retrieved were passed progressively through filters like fitness score, predicted activity and docking scores. The survived hits present new scaffolds with a potential for MAO-A inhibition.     

Identification of N-terminal extracellular domain determinants in nicotinic acetylcholine receptor (nAChR) α6 subunits that influence effects of wild-type or mutant β3 subunits on function of α6β2*- or α6β4*-nAChR

Despite the apparent function of naturally expressed mammalian α6*-nicotinic acetylcholine receptors (α6*-nAChR; where * indicates the known or possible presence of additional subunits), their functional and heterologous expression has been difficult. Here, we report that coexpression with wild-type β3 subunits abolishes the small amount of function typically seen for all-human or all-mouse α6β4*-nAChR expressed in Xenopus oocytes. However, levels of function and agonist potencies are markedly increased, and there is atropine-sensitive blockade of spontaneous channel opening upon coexpression of α6 and β4 subunits with mutant β3 subunits harboring valine-to-serine mutations at 9'- or 13'-positions. There is no function when α6 and β2 subunits are expressed alone or in the presence of wild-type or mutant β3 subunits. Interestingly, hybrid nAChR containing mouse α6 and human (h) β4 subunits have function potentiated rather than suppressed by coexpression with wild-type hβ3 subunits and potentiated further upon coexpression with hβ3(V9'S) subunits. Studies using nAChR chimeric mouse/human α6 subunits indicated that residues involved in effects seen with hybrid nAChR are located in the α6 subunit N-terminal domain. More specifically, nAChR hα6 subunit residues Asn-143 and Met-145 are important for dominant-negative effects of nAChR hβ3 subunits on hα6hβ4-nAChR function. Asn-143 and additional residues in the N-terminal domain of nAChR hα6 subunits are involved in the gain-of-function effects of nAChR hβ3(V9'S) subunits on α6β2*-nAChR function. These studies illuminate the structural bases for effects of β3 subunits on α6*-nAChR function and suggest that unique subunit interfaces involving the complementary rather than the primary face of α6 subunits are involved.     

early in short days 4, a mutation in Arabidopsis that causes early flowering and reduces the mRNA abundance of the floral repressor FLC

The plant shoot is derived from the apical meristem, a group of stem cells formed during embryogenesis. Lateral organs form on the shoot of an adult plant from primordia that arise on the flanks of the shoot apical meristem. Environmental stimuli such as light, temperature and nutrient availability often influence the shape and identity of the organs that develop from these primordia. In particular, the transition from forming vegetative lateral organs to producing flowers often occurs in response to environmental cues. This transition requires increased expression in primordia of genes that confer floral identity, such as the Arabidopsis gene LEAFY. We describe a novel mutant, early in short days 4 (esd4), that dramatically accelerates the transition from vegetative growth to flowering in Arabidopsis: The effect of the mutation is strongest under short photoperiods, which delay flowering of Arabidopsis: The mutant has additional phenotypes, including premature termination of the shoot and an alteration of phyllotaxy along the stem, suggesting that ESD4 has a broader role in plant development. Genetic analysis indicates that ESD4 is most closely associated with the autonomous floral promotion pathway, one of the well-characterized pathways proposed to promote flowering of Arabidopsis: Furthermore, mRNA levels of a floral repressor (FLC), which acts within this pathway, are reduced by esd4, and the expression of flowering-time genes repressed by FLC is increased in the presence of the esd4 mutation. Although the reduction in FLC mRNA abundance is likely to contribute to the esd4 phenotype, our data suggest that esd4 also promotes flowering independently of FLC. The role of ESD4 in the regulation of flowering is discussed with reference to current models on the regulation of flowering in Arabidopsis.     

Comparative analysis of protein unfoldedness in human housekeeping and non-housekeeping proteins

Absence of any regular structure is increasingly being observed in structural studies of proteins. These disordered regions or random coils, which have been observed under physiological conditions, are indicators of protein plasticity. The wide variety of interactions possible due to the flexibility of these 'natively disordered' regions confers functional advantage to the protein and the organism in general. This concept is underscored by the increasing proportion of intrinsically unstructured proteins seen with the ascension in the complexity of the organisms. The 'natively unfolded/disordered' state of the protein can be predicted utilizing Uversky's or Dunker's algorithm. We utilized Uversky's prediction scheme and based on the unique position of a protein in the charge-hydrophobicity plot, a derived net score was used to predict the overall disorder of the human housekeeping and non-housekeeping proteins. Substantial numbers of proteins in both the classes were predicted to be unfolded. However, comparative genomic analysis of predicted unfolded Homo sapiens proteins with homologues in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus revealed significant increase in unfoldedness in non-housekeeping proteins in comparison with housekeeping proteins. Our analysis in the evolutionary context suggests addition or substitution of amino acid residues which favour unfoldedness in non-housekeeping proteins compared to housekeeping proteins.     

Network Environment and Financial Risk Using Machine Learning and Sentiment Analysis

Under the network environment, the trading volume and asset price of a financial commodity or instrument are affected by various complicated factors. Machine learning and sentiment analysis provide powerful tools to collect a great deal of data from the website and retrieve useful information for effectively forecasting financial risk of associated companies. This article studies trading volume and asset price risk when sentimental financial information data are available using both sentiment analysis and popular machine learning approaches: artificial neural network (ANN) and support vector machine (SVM). Nonlinear GARCH-based mining models are developed by integrating GARCH (generalized autoregressive conditional heteroskedasticity) theory and ANN and SVM. Empirical studies in the U.S. stock market show that the proposed approach achieves favorable forecast performances. GARCH-based SVM outperforms GARCH-based ANN for volatility forecast, whereas GARCH-based ANN achieves a better forecast result for the volatility trend. Results also indicate a strong correlation between information sentiment and both trading volume and asset price volatility.     

Acetyl‐ed question in mitochondrial biology?

Lysine acetylation on numerous mitochondrial proteins, targeted by the sirtuin deacylase SIRT3, has been proposed to play a major role in regulating diverse mitochondrial functions, particularly in the liver. A new study by Weinert, Choudhary, and colleagues, in this issue of The EMBO Journal, finds that the absolute levels of hepatic mitochondrial protein acetylation in wild‐type mice are extremely low and may be insufficient to exert regulatory effects.