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Int. J. Mol. Sci., Volume 10, Issue 4 (April 2009) – 32 articles , Pages 1419-1941

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394 KiB  
Article
Fluorescence Lifetime Imaging of Quantum Dot Labeled DNA Microarrays
by Gerard Giraud, Holger Schulze, Till T. Bachmann, Colin J. Campbell, Andrew R. Mount, Peter Ghazal, Mizanur R. Khondoker, Alan J. Ross, Stuart W. J. Ember, Ilenia Ciani, Chaker Tlili, Anthony J. Walton, Jonathan G. Terry and Jason Crain
Int. J. Mol. Sci. 2009, 10(4), 1930-1941; https://doi.org/10.3390/ijms10041930 - 24 Apr 2009
Cited by 42 | Viewed by 15298
Abstract
Quantum dot (QD) labeling combined with fluorescence lifetime imaging microscopy is proposed as a powerful transduction technique for the detection of DNA hybridization events. Fluorescence lifetime analysis of DNA microarray spots of hybridized QD labeled target indicated a characteristic lifetime value of 18.8 [...] Read more.
Quantum dot (QD) labeling combined with fluorescence lifetime imaging microscopy is proposed as a powerful transduction technique for the detection of DNA hybridization events. Fluorescence lifetime analysis of DNA microarray spots of hybridized QD labeled target indicated a characteristic lifetime value of 18.8 ns, compared to 13.3 ns obtained for spots of free QD solution, revealing that QD labels are sensitive to the spot microenvironment. Additionally, time gated detection was shown to improve the microarray image contrast ratio by 1.8, achieving femtomolar target sensitivity. Finally, lifetime multiplexing based on Qdot525 and Alexa430 was demonstrated using a single excitation-detection readout channel. Full article
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1605 KiB  
Review
Heterogeneity of Mitochondria and Mitochondrial Function within Cells as Another Level of Mitochondrial Complexity
by Andrey V. Kuznetsov and Raimund Margreiter
Int. J. Mol. Sci. 2009, 10(4), 1911-1929; https://doi.org/10.3390/ijms10041911 - 24 Apr 2009
Cited by 169 | Viewed by 18944
Abstract
Beyond their fundamental role in energy metabolism, mitochondria perform a great variety of other important cellular functions. However, the interplayamong these various roles of mitochondria is still poorly understood, and the underlying mechanisms can be related to system level properties. Importantly, mitochondria localized [...] Read more.
Beyond their fundamental role in energy metabolism, mitochondria perform a great variety of other important cellular functions. However, the interplayamong these various roles of mitochondria is still poorly understood, and the underlying mechanisms can be related to system level properties. Importantly, mitochondria localized in different regions of a cell may display different morphology, dissimilar biochemical properties, or may differently interact with other intracellular structures. Recent advances in live imaging techniques have also revealed a functional heterogeneity of mitochondria with respect to mitochondrial redox state, membrane potential, respiratory activity, uncoupling proteins, mitochondrial ROS and calcium. An important and still unresolved question is how the heterogeneity of mitochondrial function and the regional specializations of mitochondria are mechanistically realized in the cell and to what extent this could be dependent on environmental aspects. Distinct mitochondrial subsets may also exhibit different responses to substrates and inhibitors and may vary in their sensitivity to pathology, resistance to apoptosis, oxidative stress, thus also demonstrating heterogeneous behavior. All these observations strongly suggest that the intracellular position, organization and the specific surroundings of mitochondria within the cell define their functional features, while also implying that different mitochondrial subpopulations, clusters or even single mitochondrion may execute diverse processes in a cell. The heterogeneity of mitochondrial function demonstrates an additional level of mitochondrial complexity and is a new, challenging area in mitochondrial research that potentially leads to the integration of mitochondrial bioenergetics and cell physiology with various physiological and pathophysiological implications. Full article
(This article belongs to the Special Issue Molecular System Bioenergetics)
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Article
Overexpression of a Weed (Solanum americanum) Proteinase Inhibitor in Transgenic Tobacco Results in Increased Glandular Trichome Density and Enhanced Resistance to Helicoverpa armigera and Spodoptera litura
by Ming Luo, Zhaoyu Wang, Huapeng Li, Kuai-Fei Xia, Yinpeng Cai and Zeng-Fu Xu
Int. J. Mol. Sci. 2009, 10(4), 1896-1910; https://doi.org/10.3390/ijms10041896 - 23 Apr 2009
Cited by 32 | Viewed by 15163
Abstract
In this study we produced transgenic tobacco plants by overexpressing a serine proteinase inhibitor gene, SaPIN2a, from the American black nightshade Solanum americanum under the control of the CaMV 35S promoter using Agrobacterium tumefaciens-mediated transformation. SaPIN2a was properly transcribed and translated as [...] Read more.
In this study we produced transgenic tobacco plants by overexpressing a serine proteinase inhibitor gene, SaPIN2a, from the American black nightshade Solanum americanum under the control of the CaMV 35S promoter using Agrobacterium tumefaciens-mediated transformation. SaPIN2a was properly transcribed and translated as indicated by Northern blot and Western blot analyses. Functional integrity of SaPIN2a in transgenic plants was confirmed by proteinase inhibitory activity assay. Bioassays for insect resistance showed that SaPIN2a-overexpressing transgenic tobacco plants were more resistant to cotton bollworm(Helicoverpa armigera) and tobacco cutworm(Spodoptera litura) larvae, two devastating pests of important crop plants, than the control plants. Interestingly, overexpression of SaPIN2a in transgenic tobacco plants resulted in a significant increase in glandular trichome density and a promotion of trichome branching, which could also provide an additional resistance mechanism in transgenic plants against insect pests. Therefore, SaPIN2a could be used as an alternative proteinase inhibitor for the production of insect-resistant transgenic plants. Full article
(This article belongs to the Special Issue Biotic and Abiotic Stress)
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437 KiB  
Article
Hereditary and Sporadic Forms of Aβ-Cerebrovascular Amyloidosis and Relevant Transgenic Mouse Models
by Samir Kumar-Singh
Int. J. Mol. Sci. 2009, 10(4), 1872-1895; https://doi.org/10.3390/ijms10041872 - 23 Apr 2009
Cited by 28 | Viewed by 15191
Abstract
Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ)-CAA is the [...] Read more.
Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ)-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer’s disease (AD) and Down’s syndrome. Moreover, Aβ-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Aβ domain of the amyloid precursor protein (APP) such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Aβ variants or an unaltered Aβ42/Aβ40 ratio favor vascular Aβ deposition over parenchymal plaques, but higher than critical levels of Aβ40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels. Full article
(This article belongs to the Special Issue Advances in Molecular Neuropathology)
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Review
On the Free Energy That Drove Primordial Anabolism
by Michael Kaufmann
Int. J. Mol. Sci. 2009, 10(4), 1853-1871; https://doi.org/10.3390/ijms10041853 - 22 Apr 2009
Cited by 14 | Viewed by 13180
Abstract
A key problem in understanding the origin of life is to explain the mechanism(s) that led to the spontaneous assembly of molecular building blocks that ultimately resulted in the appearance of macromolecular structures as they are known in modern biochemistry today. An indispensable [...] Read more.
A key problem in understanding the origin of life is to explain the mechanism(s) that led to the spontaneous assembly of molecular building blocks that ultimately resulted in the appearance of macromolecular structures as they are known in modern biochemistry today. An indispensable thermodynamic prerequisite for such a primordial anabolism is the mechanistic coupling to processes that supplied the free energy required. Here I review different sources of free energy and discuss the potential of each form having been involved in the very first anabolic reactions that were fundamental to increase molecular complexity and thus were essential for life. Full article
(This article belongs to the Special Issue Origin of Life)
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Article
Coenzyme Autocatalytic Network on the Surface of Oil Microspheres as a Model for the Origin of Life
by Alexei A. Sharov
Int. J. Mol. Sci. 2009, 10(4), 1838-1852; https://doi.org/10.3390/ijms10041838 - 22 Apr 2009
Cited by 19 | Viewed by 10705
Abstract
Coenzymes are often considered as remnants of primordial metabolism, but not as hereditary molecules. I suggest that coenzyme-like molecules (CLMs) performed hereditary functions before the emergence of nucleic acids. Autocatalytic CLMs modified (encoded) surface properties of hydrocarbon microspheres, to which they were anchored, [...] Read more.
Coenzymes are often considered as remnants of primordial metabolism, but not as hereditary molecules. I suggest that coenzyme-like molecules (CLMs) performed hereditary functions before the emergence of nucleic acids. Autocatalytic CLMs modified (encoded) surface properties of hydrocarbon microspheres, to which they were anchored, and these changes enhanced autocatalysis and propagation of CLMs. Heredity started from a single kind of self-reproducing CLM, and then evolved into more complex coenzyme autocatalytic networks containing multiple kinds of CLMs. Polymerization of CLMs on the surface of microspheres and development of template-based synthesis is a potential evolutionary path towards the emergence of nucleic acids. Full article
(This article belongs to the Special Issue Origin of Life)
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Article
In Vitro Cytochrome P450 Formation of a Mono-Hydroxylated Metabolite of Zearalenone Exhibiting Estrogenic Activities: Possible Occurrence of This Metabolite in Vivo
by Frederique Bravin, Radu C. Duca, Patrick Balaguer and Marcel Delaforge
Int. J. Mol. Sci. 2009, 10(4), 1824-1837; https://doi.org/10.3390/ijms10041824 - 21 Apr 2009
Cited by 50 | Viewed by 13353
Abstract
The mycoestrogen zearalenone (ZEN), as well as its reduced metabolites, which belong to the endocrine disruptor bio-molecule family, are substrates for various enzymes involved in steroid metabolism. In addition to its reduction by the steroid dehydrogenase pathway, ZEN also interacts with hepatic detoxification [...] Read more.
The mycoestrogen zearalenone (ZEN), as well as its reduced metabolites, which belong to the endocrine disruptor bio-molecule family, are substrates for various enzymes involved in steroid metabolism. In addition to its reduction by the steroid dehydrogenase pathway, ZEN also interacts with hepatic detoxification enzymes, which convert it into hydroxylated metabolites (OH-ZEN). Due to their structures to that of estradiol, ZEN and its derived metabolites bind to the estrogen receptors and are involved in endocrinal perturbations and are possibly associated with estrogen-dependent cancers. The primary aim of this present study was to identify the enzymatic cytochrome P450 isoforms responsible for the formation of the most abundant OH-ZEN. We thus studied its in vitro formation using hepatic microsomes in a range of animal model systems including man. OH-ZEN was also recovered in liver and urine of rats treated orally with ZEN. Finally we compared the activity of ZEN and its active metabolites (α-ZAL and OH-ZEN) on estrogen receptors using HeLa ER-α and ER-β reporter cell lines as reporters. OH-ZEN estrogenic activities were revealed to be limited and not as significant as those of ZEN or α-ZAL. Full article
(This article belongs to the Section Biochemistry)
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Article
Uncovering the Properties of Energy-Weighted Conformation Space Networks with a Hydrophobic-Hydrophilic Model
by Zaizhi Lai, Jiguo Su, Weizu Chen and Cunxin Wang
Int. J. Mol. Sci. 2009, 10(4), 1808-1823; https://doi.org/10.3390/ijms10041808 - 21 Apr 2009
Cited by 12 | Viewed by 10049
Abstract
The conformation spaces generated by short hydrophobic-hydrophilic (HP) lattice chains are mapped to conformation space networks (CSNs). The vertices (nodes) of the network are the conformations and the links are the transitions between them. It has been found that these networks have “small-world” [...] Read more.
The conformation spaces generated by short hydrophobic-hydrophilic (HP) lattice chains are mapped to conformation space networks (CSNs). The vertices (nodes) of the network are the conformations and the links are the transitions between them. It has been found that these networks have “small-world” properties without considering the interaction energy of the monomers in the chain, i. e. the hydrophobic or hydrophilic amino acids inside the chain. When the weight based on the interaction energy of the monomers in the chain is added to the CSNs, it is found that the weighted networks show the “scale-free” characteristic. In addition, it reveals that there is a connection between the scale-free property of the weighted CSN and the folding dynamics of the chain by investigating the relationship between the scale-free structure of the weighted CSN and the noted parameter Z score. Moreover, the modular (community) structure of weighted CSNs is also studied. These results are helpful to understand the topological properties of the CSN and the underlying free-energy landscapes. Full article
(This article belongs to the Special Issue Protein Folding 2009)
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Article
Non-Enzymatic Template-Directed Recombination of RNAs
by Sergey Y. Nechaev, Alexei V. Lutay, Valentin V. Vlassov and Marina A. Zenkova
Int. J. Mol. Sci. 2009, 10(4), 1788-1807; https://doi.org/10.3390/ijms10041788 - 21 Apr 2009
Cited by 11 | Viewed by 11770
Abstract
RNA non-enzymatic recombination reactions are of great interest within the hypothesis of the "RNA world", which argues that at some stage of prebiotic life development proteins were not yet engaged in biochemical reactions and RNA carried out both the information storage task and [...] Read more.
RNA non-enzymatic recombination reactions are of great interest within the hypothesis of the "RNA world", which argues that at some stage of prebiotic life development proteins were not yet engaged in biochemical reactions and RNA carried out both the information storage task and the full range of catalytic roles necessary in primitive self-replicating systems. Here we report on the study of recombination reaction occuring between two 96 nucleotides (nts) fragments of RNAs under physiological conditions and governed by a short oligodeoxyribonucleotide template, partially complementary to sequences within each of the RNAs. Analysis of recombination products shows that ligation is predominantly template-directed, and occurs within the complementary complex with the template in "butt-to-butt" manner, in 1- or 3- nts bulges or in 2-3 nts internal loops. Minor recombination products formed in the template-independent manner are detected as well. Full article
(This article belongs to the Special Issue Origin of Life)
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191 KiB  
Article
Phenolic Compounds Protect Cultured Hippocampal Neurons against Ethanol-Withdrawal Induced Oxidative Stress
by Katalin Prokai-Tatrai, Laszlo Prokai, James W. Simpkins and Marianna E. Jung
Int. J. Mol. Sci. 2009, 10(4), 1773-1787; https://doi.org/10.3390/ijms10041773 - 20 Apr 2009
Cited by 13 | Viewed by 11365
Abstract
Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that [...] Read more.
Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that ethanol withdrawal for 4 h after 24-h ethanol treatment provoked greater levels of oxidative damage than the preceding ethanol exposure. Phenolic antioxidant treatment either during ethanol exposure or ethanol withdrawal only, however, dose-dependently reversed cellular oxidative damage, as demonstrated by the significantly enhanced cell viability, reduced malondialdehyde production and protein carbonylation, compared to untreated cells. Interestingly, the antioxidant treatment schedule had no significant impact on the observed neuroprotection. In addition, the efficacy of the three phenolic compounds was practically equipotent in protecting HT-22 cells in spite of predictions based on an in silico study and a cell free assay of lipid peroxidation. This finding implies that free-radical scavenging may not be the sole factor responsible for the observed neuroprotection and warrants further studies to establish, whether the HT-22 line is indeed a suitable model for in vitro screening of antioxidants against EW-related neuronal damage. Full article
(This article belongs to the Special Issue Phenolics and Polyphenolics)
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671 KiB  
Review
Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing
by Petras Dzeja and Andre Terzic
Int. J. Mol. Sci. 2009, 10(4), 1729-1772; https://doi.org/10.3390/ijms10041729 - 17 Apr 2009
Cited by 313 | Viewed by 28798
Abstract
Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors. A network of adenylate kinase isoforms (AK1-AK7) are distributed throughout intracellular compartments, interstitial space and [...] Read more.
Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors. A network of adenylate kinase isoforms (AK1-AK7) are distributed throughout intracellular compartments, interstitial space and body fluids to regulate energetic and metabolic signaling circuits, securing efficient cell energy economy, signal communication and stress response. The dynamics of adenylate kinase-catalyzed phosphotransfer regulates multiple intracellular and extracellular energy-dependent and nucleotide signaling processes, including excitation-contraction coupling, hormone secretion, cell and ciliary motility, nuclear transport, energetics of cell cycle, DNA synthesis and repair, and developmental programming. Metabolomic analyses indicate that cellular, interstitial and blood AMP levels are potential metabolic signals associated with vital functions including body energy sensing, sleep, hibernation and food intake. Either low or excess AMP signaling has been linked to human disease such as diabetes, obesity and hypertrophic cardiomyopathy. Recent studies indicate that derangements in adenylate kinase-mediated energetic signaling due to mutations in AK1, AK2 or AK7 isoforms are associated with hemolytic anemia, reticular dysgenesis and ciliary dyskinesia. Moreover, hormonal, food and antidiabetic drug actions are frequently coupled to alterations of cellular AMP levels and associated signaling. Thus, by monitoring energy state and generating and distributing AMP metabolic signals adenylate kinase represents a unique hub within the cellular homeostatic network. Full article
(This article belongs to the Special Issue Molecular System Bioenergetics)
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29 KiB  
Correction
Correction: Goldbeck, R.A., et al. Early Events, Kinetic Intermediates and the Mechanism of Protein Folding in Cytochrome c. Int. J. Mol. Sci. 2009, 10, 1476-1499.
by Robert A. Goldbeck, Eefei Chen and David S. Kliger
Int. J. Mol. Sci. 2009, 10(4), 1728; https://doi.org/10.3390/ijms10041728 - 17 Apr 2009
Cited by 6 | Viewed by 8986
Abstract
By mistake, we omitted the support from the National Institutes of Health (U.S.A.) in the Acknowledgements section in our paper recently published in Int. J. Mol. Sci. [1]. Therefore, the Acknowledgements section is revised as follows: [...] Full article
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Article
A Molecular Dynamics Simulation of the Human Lysozyme –Camelid VHH HL6 Antibody System
by Zhi-Yuan Su and Yeng-Tseng Wang
Int. J. Mol. Sci. 2009, 10(4), 1719-1727; https://doi.org/10.3390/ijms10041719 - 17 Apr 2009
Cited by 7 | Viewed by 9668
Abstract
Amyloid diseases such as Alzheimer’s and thrombosis are characterized by an aberrant assembly of specific proteins or protein fragments into fibrils and plaques that are deposited in various tissues and organs. The single-domain fragment of a camelid antibody was reported to be able [...] Read more.
Amyloid diseases such as Alzheimer’s and thrombosis are characterized by an aberrant assembly of specific proteins or protein fragments into fibrils and plaques that are deposited in various tissues and organs. The single-domain fragment of a camelid antibody was reported to be able to combat against wild-type human lysozyme for inhibiting in-vitro aggregations of the amyloidogenic variant (D67H). The present study is aimed at elucidating the unbinding mechanics between the D67H lysozyme and VHH HL6 antibody fragment by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different pulling velocities. The results of the simulation indicated that stretching forces of more than two nano Newton (nN) were required to dissociate the protein-antibody system, and the hydrogen bond dissociation pathways were computed. Full article
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
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532 KiB  
Review
Bidirectionality and Compartmentation of Metabolic Fluxes Are Revealed in the Dynamics of Isotopomer Networks
by David W. Schryer, Pearu Peterson, Toomas Paalme and Marko Vendelin
Int. J. Mol. Sci. 2009, 10(4), 1697-1718; https://doi.org/10.3390/ijms10041697 - 17 Apr 2009
Cited by 14 | Viewed by 12227
Abstract
Isotope labeling is one of the few methods of revealing the in vivo bidirectionality and compartmentalization of metabolic fluxes within metabolic networks. We argue that a shift from steady state to dynamic isotopomer analysis is required to deal with these cellular complexities and [...] Read more.
Isotope labeling is one of the few methods of revealing the in vivo bidirectionality and compartmentalization of metabolic fluxes within metabolic networks. We argue that a shift from steady state to dynamic isotopomer analysis is required to deal with these cellular complexities and provide a review of dynamic studies of compartmentalized energy fluxes in eukaryotic cells including cardiac muscle, plants, and astrocytes. Knowledge of complex metabolic behaviour on a molecular level is prerequisite for the intelligent design of genetically modified organisms able to realize their potential of revolutionizing food, energy, and pharmaceutical production. We describe techniques to explore the bidirectionality and compartmentalization of metabolic fluxes using information contained in the isotopic transient, and discuss the integration of kinetic models with MFA. The flux parameters of an example metabolic network were optimized to examine the compartmentalization of metabolites and and the bidirectionality of fluxes in the TCA cycle of Saccharomyces uvarum for steady-state respiratory growth. Full article
(This article belongs to the Special Issue Molecular System Bioenergetics)
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Communication
Rupture Pathway of Phosphatidylcholine Liposomes on Silicon Dioxide
by Erik Reimhult, Bengt Kasemo and Fredrik Höök
Int. J. Mol. Sci. 2009, 10(4), 1683-1696; https://doi.org/10.3390/ijms10041683 - 17 Apr 2009
Cited by 52 | Viewed by 10271
Abstract
We have investigated the pathway by which unilamellar POPC liposomes upon adsorption undergo rupture and form a supported lipid bilayer (SLB) on a SiO2 surface. Biotinylated lipids were selectively incorporated in the outer monolayer of POPC liposomes to create liposomes with asymmetric [...] Read more.
We have investigated the pathway by which unilamellar POPC liposomes upon adsorption undergo rupture and form a supported lipid bilayer (SLB) on a SiO2 surface. Biotinylated lipids were selectively incorporated in the outer monolayer of POPC liposomes to create liposomes with asymmetric lipid compositions in the outer and inner leaflets. The specific binding of neutravidin and anti-biotin to SLBs formed by liposome fusion, prior to and after equilibrated flip-flop between the upper and lower monolayers in the SLB, were then investigated. It was concluded that the lipids in the outer monolayer of the vesicle predominantly end up on the SLB side facing the SiO2 substrate, as demonstrated by having maximum 30-40% of lipids in the liposome outer monolayer orienting towards the bulk after forming the SLB. Full article
(This article belongs to the Special Issue Molecular Self-Assembly)
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Article
QSAR Analysis of 2-Amino or 2-Methyl-1-Substituted Benzimidazoles Against Pseudomonas aeruginosa
by Sanja O. Podunavac-Kuzmanović, Dragoljub D. Cvetković and Dijana J. Barna
Int. J. Mol. Sci. 2009, 10(4), 1670-1682; https://doi.org/10.3390/ijms10041670 - 17 Apr 2009
Cited by 46 | Viewed by 13117
Abstract
A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a [...] Read more.
A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a combination of various physicochemical, steric, electronic, and structural molecular descriptors. A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the antibacterial activity of the benzimidazole derivatives. The stepwise regression method was used to derive the most significant models as a calibration model for predicting the inhibitory activity of this class of molecules. The best QSAR models were further validated by a leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. To confirm the predictive power of the models, an external set of molecules was used. High agreement between experimental and predicted inhibitory values, obtained in the validation procedure, indicated the good quality of the derived QSAR models. Full article
(This article belongs to the Special Issue Recent Advances in QSAR/QSPR Theory)
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Communication
Origins of Systems Biology in William Harvey’s Masterpiece on the Movement of the Heart and the Blood in Animals
by Charles Auffray and Denis Noble
Int. J. Mol. Sci. 2009, 10(4), 1658-1669; https://doi.org/10.3390/ijms10041658 - 17 Apr 2009
Cited by 26 | Viewed by 15681
Abstract
In this article we continue our exploration of the historical roots of systems biology by considering the work of William Harvey. Central arguments in his work on the movement of the heart and the circulation of the blood can be shown to presage [...] Read more.
In this article we continue our exploration of the historical roots of systems biology by considering the work of William Harvey. Central arguments in his work on the movement of the heart and the circulation of the blood can be shown to presage the concepts and methods of integrative systems biology. These include: (a) the analysis of the level of biological organization at which a function (e.g. cardiac rhythm) can be said to occur; (b) the use of quantitative mathematical modelling to generate testable hypotheses and deduce a fundamental physiological principle (the circulation of the blood) and (c) the iterative submission of his predictions to an experimental test. This article is the result of a tri-lingual study: as Harvey’s masterpiece was published in Latin in 1628, we have checked the original edition and compared it with and between the English and French translations, some of which are given as notes to inform the reader of differences in interpretation. Full article
(This article belongs to the Special Issue Molecular System Bioenergetics)
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348 KiB  
Review
The Interplay between QSAR/QSPR Studiesand Partial Order Ranking and Formal Concept Analyses
by Lars Carlsen
Int. J. Mol. Sci. 2009, 10(4), 1628-1657; https://doi.org/10.3390/ijms10041628 - 17 Apr 2009
Cited by 12 | Viewed by 15130
Abstract
The often observed scarcity of physical-chemical and well as toxicological data hampers the assessment of potentially hazardous chemicals released to the environment. In such cases Quantitative Structure-Activity Relationships/Quantitative Structure-Property Relationships (QSAR/QSPR) constitute an obvious alternative for rapidly, effectively and inexpensively generatng missing experimental [...] Read more.
The often observed scarcity of physical-chemical and well as toxicological data hampers the assessment of potentially hazardous chemicals released to the environment. In such cases Quantitative Structure-Activity Relationships/Quantitative Structure-Property Relationships (QSAR/QSPR) constitute an obvious alternative for rapidly, effectively and inexpensively generatng missing experimental values. However, typically further treatment of the data appears necessary, e.g., to elucidate the possible relations between the single compounds as well as implications and associations between the various parameters used for the combined characterization of the compounds under investigation. In the present paper the application of QSAR/QSPR in combination with Partial Order Ranking (POR) methodologies will be reviewed and new aspects using Formal Concept Analysis (FCA) will be introduced. Where POR constitutes an attractive method for, e.g., prioritizing a series of chemical substances based on a simultaneous inclusion of a range of parameters, FCA gives important information on the implications associations between the parameters. The combined approach thus constitutes an attractive method to a preliminary assessment of the impact on environmental and human health by primary pollutants or possibly by a primary pollutant well as a possible suite of transformation subsequent products that may be both persistent in and bioaccumulating and toxic.The present review focus on the environmental – and human health impact by residuals of the rocket fuel 1,1-dimethyl- hydrazine (heptyl) and its transformation products as an illustrative example. Full article
(This article belongs to the Special Issue Recent Advances in QSAR/QSPR Theory)
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Article
Probing the Structure, Stability and Hydrogen Adsorption of Lithium Functionalized Isoreticular MOF-5 (Fe, Cu, Co, Ni and Zn) by Density Functional Theory
by Natarajan Sathiyamoorthy Venkataramanan, Ryoji Sahara, Hiroshi Mizuseki and Yoshiyuki Kawazoe
Int. J. Mol. Sci. 2009, 10(4), 1601-1608; https://doi.org/10.3390/ijms10041601 - 14 Apr 2009
Cited by 26 | Viewed by 14563
Abstract
Li adsorption on isoreticular MOFs with metal Fe, Cu, Co, Ni and Zn was studied using density function theory. Li functionalization shows a considerable structural change associated with a volume change in isoreticular MOF-5 except for the Zn metal center. Hydrogen binding energies [...] Read more.
Li adsorption on isoreticular MOFs with metal Fe, Cu, Co, Ni and Zn was studied using density function theory. Li functionalization shows a considerable structural change associated with a volume change in isoreticular MOF-5 except for the Zn metal center. Hydrogen binding energies on Li functionalized MOFs are seen to be in the range of 0.2 eV, which is the desired value for an ideal reversible storage system. This study has clearly shown that Li doping is possible only in Zn-based MOF-5, which would be better candidate to reversibly store hydrogen. Full article
(This article belongs to the Special Issue Applications of Density Functional Theory)
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Article
Composition-Dependent Dielectric Properties of DMF-Water Mixtures by Molecular Dynamics Simulations
by Guo-Zhu Jia, Ka-Ma Huang, Li-Jun Yang and Xiao-Qing Yang
Int. J. Mol. Sci. 2009, 10(4), 1590-1600; https://doi.org/10.3390/ijms10041590 - 14 Apr 2009
Cited by 36 | Viewed by 13988
Abstract
In this paper, we study the dielectric properties of water-N,N dimethylformamide (DMF) mixtures over the whole composition range using a molecular dynamics (MD) simulation. The static and microwave frequency-dependent dielectric properties of the mixtures are calculated from MD trajectories of at least [...] Read more.
In this paper, we study the dielectric properties of water-N,N dimethylformamide (DMF) mixtures over the whole composition range using a molecular dynamics (MD) simulation. The static and microwave frequency-dependent dielectric properties of the mixtures are calculated from MD trajectories of at least 2 ns length and compared to those of available measurements. We find that the short-ranged structural correlation between neighboring water and DMF molecules strongly influences the static dielectric properties of mixtures. In terms of the dynamics, we report time correlation functions for the dipole densities of mixtures and find that their long-time behavior can be reasonably described by biexponential decays, which means the dielectric relaxations of these mixtures are governed by complex multitimescale mechanisms of rotational diffusion. The dipole density relaxation time is a non-monotonic function of composition passing through a maximum around 0.5 mole fraction DMF, in agreement with the measured main dielectric relaxation time of mixtures. Full article
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
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204 KiB  
Review
Folding by Numbers: Primary Sequence Statistics and Their Use in Studying Protein Folding
by Brent Wathen and Zongchao Jia
Int. J. Mol. Sci. 2009, 10(4), 1567-1589; https://doi.org/10.3390/ijms10041567 - 08 Apr 2009
Cited by 17 | Viewed by 11441
Abstract
The exponential growth over the past several decades in the quantity of both primary sequence data available and the number of protein structures determined has provided a wealth of information describing the relationship between protein primary sequence and tertiary structure. This growing repository [...] Read more.
The exponential growth over the past several decades in the quantity of both primary sequence data available and the number of protein structures determined has provided a wealth of information describing the relationship between protein primary sequence and tertiary structure. This growing repository of data has served as a prime source for statistical analysis, where underlying relationships between patterns of amino acids and protein structure can be uncovered. Here, we survey the main statistical approaches that have been used for identifying patterns within protein sequences, and discuss sequence pattern research as it relates to both secondary and tertiary protein structure. Limitations to statistical analyses are discussed, and a context for their role within the field of protein folding is given. We conclude by describing a novel statistical study of residue patterning in β-strands, which finds that hydrophobic (i,i+2) pairing in β-strands occurs more often than expected at locations near strand termini. Interpretations involving β-sheet nucleation and growth are discussed. Full article
(This article belongs to the Special Issue Protein Folding 2009)
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919 KiB  
Article
Protein GB1 Folding and Assembly from Structural Elements
by Mikael C. Bauer, Wei-Feng Xue and Sara Linse
Int. J. Mol. Sci. 2009, 10(4), 1552-1566; https://doi.org/10.3390/ijms10041552 - 08 Apr 2009
Cited by 14 | Viewed by 13803
Abstract
Folding of the Protein G B1 domain (PGB1) shifts with increasing salt concentration from a cooperative assembly of inherently unstructured subdomains to an assembly of partly pre-folded structures. The salt-dependence of pre-folding contributes to the stability minimum observed at physiological salt conditions. Our [...] Read more.
Folding of the Protein G B1 domain (PGB1) shifts with increasing salt concentration from a cooperative assembly of inherently unstructured subdomains to an assembly of partly pre-folded structures. The salt-dependence of pre-folding contributes to the stability minimum observed at physiological salt conditions. Our conclusions are based on a study in which the reconstitution of PGB1 from two fragments was studied as a function of salt concentrations and temperature using circular dichroism spectroscopy. Salt was found to induce an increase in β-hairpin structure for the C-terminal fragment (residues 41 – 56), whereas no major salt effect on structure was observed for the isolated N-terminal fragment (residues 1 – 41). In line with the increasing evidence on the interrelation between fragment complementation and stability of the corresponding intact protein, we also find that salt effects on reconstitution can be predicted from salt dependence of the stability of the intact protein. Our data show that our variant (which has the mutations T2Q, N8D, N37D and reconstitutes in a manner similar to the wild type) displays the lowest equilibrium association constant around physiological salt concentration, with higher affinity observed both at lower and higher salt concentration. This corroborates the salt effects on the stability towards denaturation of the intact protein, for which the stability at physiological salt is lower compared to both lower and higher salt concentrations. Hence we conclude that reconstitution reports on molecular factors that govern the native states of proteins. Full article
(This article belongs to the Special Issue Protein Folding 2009)
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226 KiB  
Article
Resistance to β-lactams in Bacteria Isolated from Different Types of Portuguese Cheese
by Paula Amador, Ruben Fernandes, Cristina Prudêncio and Luísa Brito
Int. J. Mol. Sci. 2009, 10(4), 1538-1551; https://doi.org/10.3390/ijms10041538 - 07 Apr 2009
Cited by 27 | Viewed by 11448
Abstract
The purpose of this study was to investigate the presence of β-lactam-resistant bacteria in six different types of Portuguese cheese. The numbers of ampicillin resistant (AMPr) bacteria varied from 4.7 x 102 to 1.5 x 107 CFU/g. Within 172 [...] Read more.
The purpose of this study was to investigate the presence of β-lactam-resistant bacteria in six different types of Portuguese cheese. The numbers of ampicillin resistant (AMPr) bacteria varied from 4.7 x 102 to 1.5 x 107 CFU/g. Within 172 randomly selected β-lactam-resistant bacteria, 44 resistant phenotypes were found and 31.4% were multidrug resistant. The majority (85%) of the isolates identified belonged to the Enterobacteriaceae family. The presence of the blaTEM gene was detected in 80.9% of the tested isolates. The results suggest that without thermal processing of the milk and good hygienic practices, cheese may act as a vehicle of transfer of β-lactam-resistant bacteria to the gastrointestinaltract of consumers. Full article
(This article belongs to the Section Biochemistry)
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240 KiB  
Review
Pseudo-Replication of [GADV]-Proteins and Origin of Life
by Kenji Ikehara
Int. J. Mol. Sci. 2009, 10(4), 1525-1537; https://doi.org/10.3390/ijms10041525 - 02 Apr 2009
Cited by 27 | Viewed by 15373
Abstract
The RNA world hypothesis on the origin of life is generally considered as the key to solve the “chicken and egg dilemma” concerning the evolution of genes and proteins as observed in the modern organisms. This hypothesis, however, contains several serious weak points. [...] Read more.
The RNA world hypothesis on the origin of life is generally considered as the key to solve the “chicken and egg dilemma” concerning the evolution of genes and proteins as observed in the modern organisms. This hypothesis, however, contains several serious weak points. We have a counterproposal called [GADV]-protein world hypothesis, abbreviated as GADV hypothesis, in which we have suggested that life originated from a [GADV]-protein world, which comprised proteins composed of four amino acids: Gly [G], Ala [A], Asp [D], and Val [V]. A new concept “pseudo-replication” is crucial for the description of the emergence of life. The new hypothesis not only plausibly explains how life originated from the initial chaotic protein world, but also how genes, genetic code, and proteins co-evolved. Full article
(This article belongs to the Special Issue Origin of Life)
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232 KiB  
Review
Control and Regulation of Integrated Mitochondrial Function in Metabolic and Transport Networks
by Sonia Cortassa, Brian O’Rourke, Raimond L. Winslow and Miguel A. Aon
Int. J. Mol. Sci. 2009, 10(4), 1500-1513; https://doi.org/10.3390/ijms10041500 - 01 Apr 2009
Cited by 20 | Viewed by 11825
Abstract
The pattern of flux and concentration control coefficients in an integrated mitochondrial energetics model is examined by applying a generalized matrix method of control analysis to calculate control coefficients, as well as response coefficients The computational model of Cortassa et al. encompasses oxidative [...] Read more.
The pattern of flux and concentration control coefficients in an integrated mitochondrial energetics model is examined by applying a generalized matrix method of control analysis to calculate control coefficients, as well as response coefficients The computational model of Cortassa et al. encompasses oxidative phosphorylation, the TCA cycle, and Ca2+ dynamics. Control of ATP synthesis, TCA cycle, and ANT fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP/ADP production and transport, as well as by Ca2+ dynamics. The calculation also analyzed the control of the concentrations of key regulatory ions and metabolites (Ca2+, NADH, ADP). The approach we have used demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis. Full article
(This article belongs to the Special Issue Molecular System Bioenergetics)
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230 KiB  
Review
Early Events, Kinetic Intermediates and the Mechanism of Protein Folding in Cytochrome c
by Robert A. Goldbeck, Eefei Chen and David S. Kliger
Int. J. Mol. Sci. 2009, 10(4), 1476-1499; https://doi.org/10.3390/ijms10041476 - 01 Apr 2009
Cited by 28 | Viewed by 15210 | Correction
Abstract
Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and [...] Read more.
Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and amide hydrogen exchange studies on the t £ 1 ms timescale reveals a picture of cytochrome c folding that starts with the ~ 1-ms conformational diffusion dynamics of the unfolded chains. A fractional population of the unfolded chains collapses on the 1 – 100 ms timescale to a compact intermediate IC containing some native-like secondary structure. Although the existence and nature of IC as a discrete folding intermediate remains controversial, there is extensive high time-resolution kinetic evidence for the rapid formation of IC as a true intermediate, i.e., a metastable state separated from the unfolded state by a discrete free energy barrier. Final folding to the native state takes place on millisecond and longer timescales, depending on the presence of kinetic traps such as heme misligation and proline mis-isomerization. The high folding rates observed in equilibrium molten globule models suggest that IC may be a productive folding intermediate. Whether it is an obligatory step on the pathway to the high free energy barrier associated with millisecond timescale folding to the native state, however, remains to be determined. Full article
(This article belongs to the Special Issue Protein Folding 2009)
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85 KiB  
Article
Mycotoxin Detection in Human Samples from Patients Exposed to Environmental Molds
by Dennis G. Hooper, Vincent E. Bolton, Frederick T. Guilford and David C. Straus
Int. J. Mol. Sci. 2009, 10(4), 1465-1475; https://doi.org/10.3390/ijms10041465 - 01 Apr 2009
Cited by 63 | Viewed by 17470
Abstract
The goal of this study was to determine if selected mycotoxins (trichothecenes, aflatoxins, and ochratoxins) could be extracted and identified in human tissue and body fluids from patients exposed to toxin producing molds in their environment. Human urine and methanol extracted tissues and [...] Read more.
The goal of this study was to determine if selected mycotoxins (trichothecenes, aflatoxins, and ochratoxins) could be extracted and identified in human tissue and body fluids from patients exposed to toxin producing molds in their environment. Human urine and methanol extracted tissues and sputum were examined. Trichothecenes were tested using competitive ELISA techniques. Aflatoxins B1, B2, G1, and G2, and ochratoxin A were tested by using immunoaffinity columns and fluorometry. Test sensitivity and specificity were determined. Levels of detection for the various mycotoxins varied from 0.2 ppb for trichothecenes, 1.0 ppb for aflatoxins, and 2.0 ppb for ochratoxins. Trichothecene levels varied in urine, sputum, and tissue biopsies (lung, liver, brain) from undetectable (<0.2 ppb) to levels up to 18 ppb. Aflatoxin levels from the same types of tissues varied from 1.0 to 5.0 ppb. Ochratoxins isolated in the same type of tissues varied from 2.0 ppb to > 10.0 ppb. Negative control patients had no detectable mycotoxins in their tissues or fluids. These data show that mycotoxins can be detected in body fluids and human tissue from patients exposed to mycotoxin producing molds in the environment, and demonstrate which human tissues or fluids are the most likely to yield positive results. Full article
110 KiB  
Review
Biodegradation of Silk Biomaterials
by Yang Cao and Bochu Wang
Int. J. Mol. Sci. 2009, 10(4), 1514-1524; https://doi.org/10.3390/ijms10041514 - 31 Mar 2009
Cited by 513 | Viewed by 23715
Abstract
Silk fibroin from the silkworm, Bombyx mori, has excellent properties such as biocompatibility, biodegradation, non-toxicity, adsorption properties, etc. As a kind of ideal biomaterial, silk fibroin has been widely used since it was first utilized for sutures a long time ago. The [...] Read more.
Silk fibroin from the silkworm, Bombyx mori, has excellent properties such as biocompatibility, biodegradation, non-toxicity, adsorption properties, etc. As a kind of ideal biomaterial, silk fibroin has been widely used since it was first utilized for sutures a long time ago. The degradation behavior of silk biomaterials is obviously important for medical applications. This article will focus on silk-based biomaterials and review the degradation behaviors of silk materials. Full article
(This article belongs to the Special Issue Biodegradability of Materials)
198 KiB  
Article
Impact of Methylglyoxal and High Glucose Co-treatment on Human Mononuclear Cells
by Ming-Shu Hsieh and Wen-Hsiung Chan
Int. J. Mol. Sci. 2009, 10(4), 1445-1464; https://doi.org/10.3390/ijms10041445 - 31 Mar 2009
Cited by 20 | Viewed by 10582
Abstract
Hyperglycemia and elevation of methylglyoxal (MG) are symptoms of diabetes mellitus (DM). In this report, we show that co-treatment of human mononuclear cells (HMNCs) with MG (5 μM) and high glucose (HG; 15 – 30 mM) induces apoptosis or necrosis. HG/MG co-treatment directly [...] Read more.
Hyperglycemia and elevation of methylglyoxal (MG) are symptoms of diabetes mellitus (DM). In this report, we show that co-treatment of human mononuclear cells (HMNCs) with MG (5 μM) and high glucose (HG; 15 – 30 mM) induces apoptosis or necrosis. HG/MG co-treatment directly enhanced the reactive oxygen species (ROS) content in HMNCs, leading to decreased intracellular ATP levels, which control cell death via apoptosis or necrosis. Concentrations of 5 μM MG and 15 mM glucose significantly increased cytoplasmic free calcium and nitric oxide (NO) levels, loss of mitochondrial membrane potential (MMP), activation of caspases-9 and -3, and cell death. In contrast, no apoptotic biochemical changes were detected in HMNCs treated with 5 μM MG and 25 mM glucose, which appeared to undergo necrosis. Pretreatment with nitric oxide (NO) scavengers inhibited apoptotic biochemical changes induced by 5 μM MG/15 mM glucose, and increased the gene expression levels of p53 and p21 involved in apoptotic signaling. The results collectively suggest that the treatment dosage of MG and glucose determines the mode of cell death (apoptosis vs. necrosis) of HMNCs, and that both ROS and NO play important roles in MG/HG-induced apoptosis. Full article
(This article belongs to the Section Biochemistry)
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147 KiB  
Review
Occurence and Bioactivities of Funicone-Related Compounds
by Rosario Nicoletti, Emiliano Manzo and Maria Letizia Ciavatta
Int. J. Mol. Sci. 2009, 10(4), 1430-1444; https://doi.org/10.3390/ijms10041430 - 30 Mar 2009
Cited by 31 | Viewed by 13540
Abstract
Studies on production of secondary metabolites by fungi have received a substantial boost lately, particularly with reference to applications of their biological properties in human medicine. Funicones represent a series of related compounds for which there is accumulating evidence supporting their possible use [...] Read more.
Studies on production of secondary metabolites by fungi have received a substantial boost lately, particularly with reference to applications of their biological properties in human medicine. Funicones represent a series of related compounds for which there is accumulating evidence supporting their possible use as pharmaceuticals. This paper provides a review on the current status of knowledge on these fungal extrolites, with special reference to aspects concerning their molecular structures and biological activities. Full article
(This article belongs to the Special Issue Single Molecules)
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