Contributors:Miguel A. Campodonico, Daniela Vaisman, Jean F. Castro, Valeria Razmilic, Francesca Mercado, Barbara A. Andrews, Adam M. Feist, Juan A. Asenjo
Acidithiobacillus ferrooxidans is a gram-negative chemolithoautotrophic γ-proteobacterium. It typically grows at an external pH of 2 using the oxidation of ferrous ions by oxygen, producing ferric ions and water, while fixing carbon dioxide from the environment. A. ferrooxidans is of great interest for biomining and environmental applications, as it can process mineral ores and alleviate the negative environmental consequences derived from the mining processes. In this study, the first genome-scale metabolic reconstruction of A. ferrooxidans ATCC 23270 was generated (iMC507). A total of 587 metabolic and transport/exchange reactions, 507 genes and 573 metabolites organized in over 42 subsystems were incorporated into the model. Based on a new genetic algorithm approach, that integrates flux balance analysis, chemiosmotic theory, and physiological data, the proton translocation stoichiometry for a number of enzymes and maintenance parameters under aerobic chemolithoautotrophic conditions using three different electron donors were estimated. Furthermore, a detailed electron transfer and carbon flux distributions during chemolithoautotrophic growth using ferrous ion, tetrathionate and thiosulfate were determined and reported. Finally, 134 growth-coupled designs were calculated that enables Extracellular Polysaccharide production. iMC507 serves as a knowledgebase for summarizing and categorizing the information currently available for A. ferrooxidans and enables the understanding and engineering of Acidithiobacillus and similar species from a comprehensive model-driven perspective for biomining applications.
Contributors:Wei Xie, Nai Wang, Zhiyu Qiao, Zhanmin Cao
Based on the experimental phase equilibria and thermodynamic data, a critical evaluation and thermodynamic assessment of the PbO–V2O5 system has been performed. The liquid phase is described by the modified quasichemical model, which takes short-range ordering in liquid solution into account. All intermediate phases are treated as stoichiometric compounds. A set of self-consistent thermodynamic functions for all phases in the PbO–V2O5 system is obtained. The available phase equilibria and thermodynamic data are reproduced well within experimental error limits.
Contributors:Tina Jafari, Aziz A. Fallah, Afshin Barani
The effect of vitamin D on lipid profile in type 2 diabetic patients is controversial. This meta-analysis aimed to assess the effect of vitamin D on serum total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) of these patients to elucidate the subject.
Contributors:Gregory Króliczak, Brian J. Piper, Scott H. Frey
Data from focal brain injury and functional neuroimaging studies implicate a distributed network of parieto-fronto-temporal areas in the human left cerebral hemisphere as playing distinct roles in the representation of meaningful actions (praxis). Because these data come primarily from right-handed individuals, the relationship between left cerebral specialization for praxis representation and hand dominance remains unclear. We used functional magnetic resonance imaging (fMRI) to evaluate the hypothesis that strongly left-handed (right hemisphere motor dominant) adults also exhibit this left cerebral specialization. Participants planned familiar actions for subsequent performance with the left or right hand in response to transitive (e.g., “pounding”) or intransitive (e.g. “waving”) action words. In linguistic control trials, cues denoted non-physical actions (e.g., “believing”). Action planning was associated with significant, exclusively left-lateralized and extensive increases of activity in the supramarginal gyrus (SMg), and more focal modulations in the left caudal middle temporal gyrus (cMTg). This activity was hand- and gesture-independent, i.e., unaffected by the hand involved in subsequent action performance, and the type of gesture (i.e., transitive or intransitive). Compared directly with right-handers, left-handers exhibited greater involvement of the right angular gyrus (ANg) and dorsal premotor cortex (dPMC), which is indicative of a less asymmetric functional architecture for praxis representation. We therefore conclude that the organization of mechanisms involved in planning familiar actions is influenced by one's motor dominance. However, independent of hand dominance, the left SMg and cMTg are specialized for ideomotor transformations—the integration of conceptual knowledge and motor representations into meaningful actions. These findings support the view that higher-order praxis representation and lower-level motor dominance rely on dissociable mechanisms.
Contributors:Brock Humphries, Zhishan Wang, Chengfeng Yang
MicroRNAs (miRNAs), an important component of epigenetic mechanisms of carcinogenesis, have been shown to play crucial roles in cancer initiation, metastasis, prognosis and responses to drug treatment and may serve as biomarkers for early diagnosis of cancer and tools for cancer therapy. Metal carcinogens, such as arsenic, cadmium, hexavalent chromium and nickel, are well-established human carcinogens causing various cancers upon long term exposure. However, the mechanism of metal carcinogenesis has not been well understood, which limits our capability to effectively diagnose and treat human cancers resulting from chronic metal carcinogen exposure. Over recent years, the role of miRNAs in metal carcinogenesis has been actively explored and a growing body of evidence indicates the critical involvement of miRNAs in metal carcinogenesis. This review aims to discuss recent studies showing that miRNAs play important roles in metal carcinogen-induced cell malignant transformation and tumorigenesis. Some thoughts for future further studies in this field are also presented.
2-Propoxy-1-naphthamide possessing a chiral 2-methylpyrrolidine group exists as a mixture of four diastereomers owing to the rotation of the Ar(CO) and C(O)N bonds. The diastereomers existed in the ratio of 32:32:14:22 in CD3OD. When the MeOH solution of the mixture of diastereomers was irradiated with Pyrex filtered UV light (>290nm) from a high-pressure mercury lamp, the ratio changed to 27:4:43:26. The diastereomeric ratio was reversibly controlled by irradiation and heat. The change was accurately reflected in the intensity of the CD spectra. Furthermore, the reversible axial chirality was transferred to the optical activity of asymmetric reaction products via the photochemical cycloaddition reaction with 9-cyanoanthracene.
Contributors:Sofya Lushchekina, Alexander Nemukhin, Sergei Varfolomeev, Patrick Masson
Conformational dynamics of wild-type human butyrylcholinesterase (BChE), two mutants of residue Ala328, the catalytically active Ala328Cys, and the catalytically inactive (silent) Ala328Asp, and their interactions with butyrylcholine were studied. The aim was to understand the molecular mechanisms by which point mutations may lead to silent BChE variant or alter catalytic activity. Importance of BChE natural variants is due to medical consequences, i.e. prolonged apnea, following administration of the myorelaxant esters, succinylcholine and mivacurium.
Contributors:Muslum Gok, N. Dilara Zeybek, Ebru Bodur
Butyrylcholinesterase (BChE) is mostly associated with the detoxification of xenobiotics. In this study to analyze the involvement of BChE in lipid metabolism, linoleic acid (LA) and α-linolenic acid (ALA) were applied to HepG2 cells along with expression of wild type human BChE. After 48 h of these treatments WST-1 cell proliferation assay, FACS analysis, RT-PCR, Oil Red O staining and activity assays were performed. Application of high concentrations of LA to HepG2 cells without BChE transfection lead to detachment of the cells. The IC50 value LA was found as 149.3 μM whereas the IC50 value for ALA could not be calculated. Hence, in order to display minimal effects on cell viability, 5 μM was chosen as appropriate concentration for LA and ALA application to HepG2 cells. Transfection of wild-type BChE plasmid to HepG2 cells yielded increased BChE expression. Application of 5 μM ALA after BChE transfection to HepG2 cells resulted in increased expression of BChE. Although with this low concentration the number of apoptotic cells was decreased with ALA treatments, LA application did not cause a similar result with the same dose. Moreover ghost cell like property was observed in LA-treated cells. Application of ALA, on the other hand, led to an overall increase in cell numbers, BChE expression and activity. Our results indicate that BChE expression might be regulated by ALA in HepG2 cells.
Bioscavengers are an effective alternative approach for pre- and post-exposure treatments of nerve agent (NA) poisoning. Bioscavengers are natural or recombinant enzymes, reactive proteins, and antibodies that neutralize NAs before they reach their physiological targets. They are administered by injection (protein or gene delivery vector) and react with NAs in the bloodstream. Other ways of delivery can be used: inhalation for pulmonary delivery, topical creams for skin protection, etc. Operational bioscavengers must be producible at low cost, not susceptible to induce immune response and adverse effects, and stable in the bloodstream, upon storage, and under field conditions.
The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3–10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 × 102 vs. 0.2 × 102 M−1min−1, respectively, 37 °C). These hybrids inhibited AChE reversibly, IC50 = 16–48 μM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 μmol/kg in rats and 144, 203 and >506 μmol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.