Modeling Metal Flow Systems

Substance flow analysis (SFA) is a frequently used industrial ecology technique for studying societal metal flows, but it is limited in its ability to inform us about future developments in metal flow patterns and how we can affect them. Equation‐based simulation modeling techniques, such as dynamic SFA and system dynamics, can usefully complement static SFA studies in this respect, but they are also restricted in several ways. The objective of this article is to demonstrate the ability of agent‐based modeling to overcome these limitations and its usefulness as a tool for studying societal metal flow systems. The body of the article summarizes the parallel implementation of two models—an agent‐based model and a system dynamics model—both addressing the following research question: What conditions foster the development of a closed‐loop flow network for metals in mobile phones? The results from in silico experimentation with these models highlight three important differences between agent‐based modeling (ABM) and equation‐based modeling (EBM) techniques. An analysis of how these differences affected the insights that could be extracted from the constructed models points to several key advantages of ABM in the study of metal flow systems. In particular, this analysis suggests that a key advantage of the ABM technique is its flexibility to enable the representation of societal metal flow systems in a more native manner. This added flexibility endows modelers with enhanced leverage to identify options for steering metal flows and opens new opportunities for using the metaphor of an ecosystem to understand metal flow systems more fully.     

胜红蓟化感作用研究Ⅶ.胜红蓟素类似物的合成及其对植物与微生物的抑制作用

合成了5种胜红蓟素的结构类似物,将它们与胜红蓟素在对植物和微生物的抑制活性上进行了比较。结果表明,在100mg/l浓度时,对于萝卜和黑麦草两种受体,类似物6－甲酰基－7－甲氧基2,2－二甲基－2H－苯并吡喃和7－羟基－6－甲酰基－3,4－二氢－2,2－二甲基－2H－苯并吡喃较胜红蓟素有更强的抑制作用,尤其是对受体 根长的抑制作用达到显著,这两种类似物同时也具有较强的抗菌活性,在400mg/l浓度下,它们对两种真菌：水稻纹枯病菌和辣椒疫霉病菌的抑制率达到100％;在2000mg/l浓度下,7－羟基－6－甲酰基－3,4－二氢－2,2－二甲基－2H－苯并吡喃还对两种细菌：水稻白叶枯病菌和水稻基腐病菌有较强的抑制作用。研究揭示了构成胜红蓟素基本结构的2,2－二甲基－2H－苯并吡喃对植物无明显抑制作用,对微生物的抑制作用也不强,但当其6位或7位带有活性取代基后,对植物和微生物抑制作用都显著增强。     

The human male reproductive tract antimicrobial peptides of the HE2 family exhibit potent synergy with standard antibiotics

Reproductive tract infections pose a serious threat to health and fertility. Due to the emergence of antibiotic resistant pathogens, antimicrobial proteins and peptides of the reproductive tract are extensively characterized in recent years toward developing newer strategies to treat genital tract infections. Pathogen growth inhibition using a combination of naturally occurring male reproductive tract antimicrobial peptides and commonly used antibiotics has not been reported. Checker board analyses were carried out to determine the nature of interaction (synergistic, additive and antagonistic) between HE2α and HE2β2 peptides and the commonly used antibiotics. Using Escherichia coli as the target organism, the minimal inhibitory concentration and fractional inhibitory concentration indices were determined. We demonstrate for the first time that the human male reproductive tract antimicrobial peptides HE2α and HE2β2 act synergistically with the commonly used antibiotics to inhibit E. coli growth. A combination of HE2α and HE2β2 peptides resulted in an additive effect. Interestingly, the synergistic effects of HE2 peptides were highest with doxycycline and ciprofloxacin, antibiotics generally used to treat epididymitis. Results of this study demonstrate the potential of endogenous HE2 peptides to be pharmacologically important in designing novel strategies to treat reproductive tract infections. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Artificial peptides to induce membrane denaturation and disruption and modulate membrane composition and fusion

Membranes consisting of phospholipid bilayers are an essential constituent of eukaryotic cells and their compartments. The alteration of their composition, structure, and morphology plays an important role in modulating physiological processes, such as transport of molecules, cell migration, or signaling, but it can also lead to lethal effects. The three main classes of membrane-active peptides that are responsible for inducing such alterations are cell-penetrating peptides (CPPs), antimicrobial peptides (AMPs), and fusion peptides (FPs). These peptides are able to interact with lipid bilayers in highly specific and tightly regulated manners. They can either penetrate the membrane, inducing nondestructive, transient alterations, or disrupt, permeabilize, or translocate through it, or induce membrane fusion by generating attractive forces between two bilayers. Because of these properties, membrane-active peptides have attracted the attention of the pharmaceutical industry, and naturally occurring bioactive structures have been used as a platform for synthetic modification and the development of artificial analogs with optimized therapeutic properties to transport biologically active cargos or serve as novel antimicrobial agents. In this review, we focus on synthetic membrane interacting peptides with bioactivity comparable with their natural counterparts and describe their mechanism of action.     

Synergistic transmembrane insertion of the heterodimeric PGLa/magainin 2 complex studied by solid-state NMR

The skin secretions of amphibians are a rich source of antimicrobial peptides. The two antimicrobial peptides PGLa and magainin 2, isolated from the African frog Xenopus laevis, have been shown to act synergistically by permeabilizing the membranes of microorganisms. In this report, the literature on PGLa is extensively reviewed, with special focus on its synergistically enhanced activity in the presence of magainin 2. Our recent solid state ²H NMR studies of the orientation of PGLa in lipid membranes alone and in the presence of magainin 2 are described in detail, and some new data from 3,3,3-²H₃-L-alanine labeled PGLa are included in the analysis.     

Phenotypic and genotypic bacterial antimicrobial resistance in liquid pig manure is variously associated with contents of tetracyclines and sulfonamides

Aims: Antibiotic residues as well as antibiotic‐resistant bacteria in environmental samples might pose a risk to human health. This study aimed to investigate the association between antibiotic residues and bacterial antimicrobial resistance in liquid pig manure used as fertilizer. Methods and Results: Concentrations of tetracyclines (TETs) and sulfonamides (SULs) were determined by liquid chromatography‐mass spectrometry in 305 pig manure samples; antibiotic contents were correlated to the phenotypic resistance of Escherichia coli (n = 613) and enterococci (n = 564) towards up to 24 antibiotics. In 121 samples, the concentration of the TET resistance genes tet(M), tet(O) and tet(B) was quantified by real‐time‐PCR. TETs were found in 54% of the samples. The median sum concentration of all investigated TETs in the positive samples was 0·73 mg kg^?1. SULs were found with a similar frequency (51%) and a median sum concentration of 0·15 mg kg^?1 in the positive samples. Associated with the detection of TETs and/or SULs, resistance rates were significantly elevated for several substances – some of them not used in farm animals, e.g. chloramphenicol and synercid. In addition, multiresistant isolates were found more often in samples containing antibiotics. Analysis of the resistance genes tet(M) and tet(O) already showed a significant increase in their concentrations – but not in tet(B) – in the lowest range of total TET concentration. Mean tet(M) concentrations increased by the factor of 4·5 in the TET concentration range of 0·1–1 mg kg^?1, compared to negative manure samples. Conclusions: Antibiotic contamination of manure seems to be associated with a variety of changes in bacterial resistance, calling for a prudent use of antibiotics in farm animals. Significance and Impact of the Study: This study provides an interdisciplinary approach to assess antimicrobial resistance by combining the microbiological analysis of bacterial resistance with high quality chemical analysis of antibiotic residues in a representative number of environmental samples.     

Synthesis,biological activity and solution structure of new analogues of the antimicrobial Gramicidin S

Gramicidin S (GS) is a cyclo‐decapeptide antibiotic isolated from Bacillus brevis. The structural studies have shown that GS forms a two‐stranded antiparallel β‐sheet imposed by two II′ β‐turns. Despite its wide Gram+ and Gram? antimicrobial spectrum, GS is useless in therapy because of its high hemotoxicity in humans. It was found, however, that the analogues of GS‐14 (GS with 14 amino acid residues) attained a better antimicrobial selectivity when their amphipatic moments were perturbed. In this study, we report effects of similar perturbations imposed on GS cyclo‐decapeptide analogues. Having solved their structures by NMR/molecular dynamics and having tested their activities/selectivities, we have concluded that the idea of perturbation of the amphipatic moment does not work for GS‐10_0 analogues. An innovative approach to the synthesis of head‐to‐tail cyclopeptides was used. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Structure‐activity relationship studies of shortened analogues of the antimicrobial peptide EeCentrocin 1 from the sea urchin Echinus esculentus

EeCentrocin 1 is a potent antimicrobial peptide isolated from the marine sea urchin Echinus esculentus. The peptide has a hetero‐dimeric structure with the antimicrobial activity confined in its largest monomer, the heavy chain (HC), encompassing 30 amino acid residues. The aim of the present study was to develop a shorter drug lead peptide using the heavy chain of EeCentrocin 1 as a starting scaffold and to perform a structure‐activity relationship study with sequence modifications to optimize antimicrobial activity. The experiments consisted of 1) truncation of the heavy chain, 2) replacement of amino acids unfavourable for in vitro antimicrobial activity, and 3) an alanine scan experiment on the truncated and modified heavy chain sequence to identify essential residues for antimicrobial activity. The heavy chain of EeCentrocin 1 was truncated to less than half its initial size, retaining most of its original antimicrobial activity. The truncated and optimized lead peptide ( P6 ) consisted of the 12 N‐terminal amino acid residues from the original EeCentrocin 1 HC sequence and was modified by two amino acid replacements and a C‐terminal amidation. Results from the alanine scan indicated that the generated lead peptide ( P6 ) contained the optimal sequence for antibacterial activity, in which none of the alanine scan peptides could surpass its antimicrobial activity. The lead peptide ( P6 ) was also superior in antifungal activity compared to the other peptides prepared and showed minimal inhibitory concentrations (MICs) in the low micromolar range. In addition, the lead peptide ( P6 ) displayed minor haemolytic and no cytotoxic activity, making it a promising lead for further antimicrobial drug development.     

Antibacterial and anti-inflammatory effects of genistein in Staphylococcus aureus induced osteomyelitis in rats

Methicillin-resistant Staphylococcus aureus (MRSA) is a highly infectious Gram-positive pathogen known to cause severe diseases such as endocarditis, food poisoning, pneumonia, osteomyelitis, and septicemia. MRSA is a major public health issue. Among these, osteomyelitis is inflammation of the bone caused by the invasion of the bacterial pathogen in the bones. Its prominent symptoms include fever, pain, and redness of bones. In the case of children, it affects the long bones of arms and legs, whereas in the case of adults it affects the hip, feet, and spine. Bacterial osteomyelitis can trigger pathological remodeling of bones and hence causes substantial morbidity and mortality. The present study aims to evaluate the isoflavone genistein's (5,7-dihydroxy-3-(4-hydroxyphenyl)−4H-1-benzopyran-4-one,4′,5,7 trihydroxyisoflavone) antimicrobial and anti-inflammatory effects against osteomyelitis induced by MRSA in male Wistar rats. Classification of the animals was into the following: sham (Group I), osteomyelitis (Group II, control), genistein (25 mg/kg body weight, Group III), and genistein (50 mg/kg body weight, Group IV). The rats did not receive any treatment for 4 weeks after bacterial inoculation. Genistein was then administered twice daily for 2 weeks. Bacterial growth, mean body weight bone infection status, and side effects of genistein treatment were assessed. Furthermore, lipid peroxidation, superoxide dismutase, glutathione (GSH) peroxidase, catalase, reduced GSH, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 were also determined. Two days after treatment, it was found that genistein significantly suppressed bacterial growth and reduced serum pro-inflammatory cytokines TNF-α and IL-6. Therefore, the study suggests that genistein could be a promising lead against MRSA-induced osteomyelitis.