The Experts below are selected from a list of 33978 Experts worldwide ranked by ideXlab platform
Robin T Vollmer - One of the best experts on this subject based on the ideXlab platform.
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blast counts in bone marrow aspirate smears analysis using the Poisson Probability function bayes theorem and information theory
American Journal of Clinical Pathology, 2009Co-Authors: Robin T VollmerAbstract:Counts of cells or other phenomena observed through a microscope are numeric observations and, as such, are subject to mathematical and statistical analyses. For example, the Poisson Probability function provides the Probability of observing a particular number of blasts in a bone marrow aspirate, given an underlying true fraction of blasts present and a particular number of cells evaluated. Furthermore, using the Poisson function, Bayes theorem can provide the probabilities of specific categories of refractory anemia, given a number of observed blasts in a specific total of cells evaluated. Herein, I introduce and demonstrate these mathematical functions for the analysis of counts of blasts in marrow aspirates and explore the uncertainty that naturally arises when counts of blasts are near cut points used to separate the categories of refractory anemia without excess blasts, refractory anemia with excess blasts, and acute leukemia.
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lymph nodes in colorectal carcinoma the Poisson Probability paradigm
American Journal of Clinical Pathology, 2006Co-Authors: John Turner, Robin T VollmerAbstract:This article introduces use of the Poisson Probability density function and Bayes Probability rule to understand and analyze lymph nodal metastases in colorectal carcinoma. We applied these models to 370 patients who underwent resection of their tumors. In 213 cases with negative lymph nodes, we found that the Bayes-estimated Probability of missed metastases was related significantly to subsequent survival ( P = .0006). In 157 cases with lymph nodal metastases, we found that the estimated value of the Poisson parameter α was associated more closely with subsequent survival than pN stage ( P = 9 × 10–6). Consequently, we believe that the Poisson model provides insight and useful results in colorectal carcinoma.
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analysis of lymph nodal metastases in malignant melanoma using the Poisson Probability paradigm and bayes rule
American Journal of Clinical Pathology, 2005Co-Authors: Robin T VollmerAbstract:This article deals with and formalizes 2 notions common to the practice of pathology. The first is that the number of lymph nodes found positive for metastasis relates directly to the total number of lymph nodes examined. The second is that for any patient, there is a chance that the absence of lymph node metastases is a false-negative result. I introduce the Poisson Probability density function to deal with the first notion and the Bayes Probability rule to deal with the second. To illustrate the insight these 2 models provide, I apply them to data regarding lymph nodal metastases in malignant melanoma. In this preliminary study, the results of these 2 models correlate well with observed survival probabilities in patients with stage N0 melanoma and with observed rates of false-negative results in sentinel lymph node biopsy technology. With further development, the combination of these models should provide a way to estimate the Probability of nodal metastasis when, in fact, none have been observed. Thus, these models might provide useful tools for evaluating patients with stage N0 malignant neoplasms.
P R Donald - One of the best experts on this subject based on the ideXlab platform.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in patients with drug resistant pulmonary tuberculosis
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:ABSTRACT The aim of this study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para -aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in drug resistant pulmonary tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:The aim of the study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release (GSR) para- aminosalicylic acid (PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, cross-over design wherein each patient received GSR-PAS 4 g twice daily or GSR-PAS 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender and genotypes were evaluated by linear mixed effects model. The covariate effects associated with efavirenz, gender, NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25%, 37%, -17%, -48% and -27% change, respectively, in oral clearance of PAS. NAT1*10 allele did not influence drug clearance. The time above the minimum inhibitory concentration (MIC) of 1 mg/L was significantly different between the two regimens but not influenced by NAT1 or NAT2 genotypes. Occurrence and intensity of intolerance differed little between regimens. Twice daily 4 g GSR-PAS, but not 8 g once daily ensures concentrations exceeding the MIC (1 mg/L) throughout the dosing interval; PAS intolerance is not related to maximum PAS concentrations over doses studied and was not more frequent after once daily dosing. We confirm that the slow phenotype conferred by NAT1*14 and NAT1* 3 alleles resulted in higher PAS exposure, but found no evidence of increased activity of the NAT1*10 allele.
Lize Van Der Merwe - One of the best experts on this subject based on the ideXlab platform.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in patients with drug resistant pulmonary tuberculosis
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:ABSTRACT The aim of this study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para -aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in drug resistant pulmonary tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:The aim of the study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release (GSR) para- aminosalicylic acid (PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, cross-over design wherein each patient received GSR-PAS 4 g twice daily or GSR-PAS 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender and genotypes were evaluated by linear mixed effects model. The covariate effects associated with efavirenz, gender, NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25%, 37%, -17%, -48% and -27% change, respectively, in oral clearance of PAS. NAT1*10 allele did not influence drug clearance. The time above the minimum inhibitory concentration (MIC) of 1 mg/L was significantly different between the two regimens but not influenced by NAT1 or NAT2 genotypes. Occurrence and intensity of intolerance differed little between regimens. Twice daily 4 g GSR-PAS, but not 8 g once daily ensures concentrations exceeding the MIC (1 mg/L) throughout the dosing interval; PAS intolerance is not related to maximum PAS concentrations over doses studied and was not more frequent after once daily dosing. We confirm that the slow phenotype conferred by NAT1*14 and NAT1* 3 alleles resulted in higher PAS exposure, but found no evidence of increased activity of the NAT1*10 allele.
Lizanne De Kock - One of the best experts on this subject based on the ideXlab platform.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in patients with drug resistant pulmonary tuberculosis
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:ABSTRACT The aim of this study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para -aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele.
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n acetyltransferase genotypes and the pharmacokinetics and tolerability of para aminosalicylic acid in drug resistant pulmonary tuberculosis patients
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Lizanne De Kock, Andreas H Diacon, Cedric J Werely, Huiming Xia, Bernd Rosenkranz, Lize Van Der Merwe, P R DonaldAbstract:The aim of the study was to examine the relationships between N -acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release (GSR) para- aminosalicylic acid (PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, cross-over design wherein each patient received GSR-PAS 4 g twice daily or GSR-PAS 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients9 NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson Probability mass function. Comparisons of other tolerability measures by regimens, gender and genotypes were evaluated by linear mixed effects model. The covariate effects associated with efavirenz, gender, NAT1*3 , NAT1*14 , and NAT2*5 alleles corresponded to 25%, 37%, -17%, -48% and -27% change, respectively, in oral clearance of PAS. NAT1*10 allele did not influence drug clearance. The time above the minimum inhibitory concentration (MIC) of 1 mg/L was significantly different between the two regimens but not influenced by NAT1 or NAT2 genotypes. Occurrence and intensity of intolerance differed little between regimens. Twice daily 4 g GSR-PAS, but not 8 g once daily ensures concentrations exceeding the MIC (1 mg/L) throughout the dosing interval; PAS intolerance is not related to maximum PAS concentrations over doses studied and was not more frequent after once daily dosing. We confirm that the slow phenotype conferred by NAT1*14 and NAT1* 3 alleles resulted in higher PAS exposure, but found no evidence of increased activity of the NAT1*10 allele.
Pasquale Stano - One of the best experts on this subject based on the ideXlab platform.
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spontaneous protein crowding in liposomes a new vista for the origin of cellular metabolism
ChemBioChem, 2010Co-Authors: Pier Luigi Luisi, Matteo Allegretti, Tereza Pereira De Souza, Frank Steiniger, Alfred Fahr, Pasquale StanoAbstract:One question in the origin of life is the time at which membrane compartments came into the picture as hosts for the first forms of metabolism. If we assume the proteins and nucleic acids came first, then it is difficult to conceive how all the macromolecular components could have been entrapped at a later time in a single compartment. On the other hand, the hypothesis that metabolism originated from inside the compartment means that we would then have to conceive semipermeable, sophisticated membranes in prebiotic times, which does not appear plausible. With this study, we believe that we can offer a partial solution to this riddle, at the same time opening a new vista on the principles of the entrapment of solute in vesicles. We used cryo-TEM to study the entrapment of the protein ferritin in liposomes. The novel, surprising principle that appears is that when lipid surfaces close up in a proteincontaining solution to form vesicles, the entrapment frequency does not follow the expected Poisson distribution, but tends to assume a power-law behaviour, characterized by many “empty” vesicles (no or very little entrapped solute), and a long decreasing tail with extremely crowded vesicles. CryoTEM analysis shows indeed some extremely crowded liposomes adjacent to empty ones. The conclusion is that membrane closure can accumulate a remarkable number of solutes inside some compartments. The possible mechanism and relevance of this extreme local super-concentration effect for the origin of life are discussed. The spontaneous formation of lipid vesicles (liposomes) in an aqueous phase containing one or more solutes produces a heterogeneous population of liposomes in terms of solute content. Such entrapments have generally been studied by averaging techniques, such as batch absorbance or fluorescence, whereas little attention has been devoted to studying individual encapsulation. This is partly due to the technical difficulty of directly counting molecules inside liposomes. The encapsulation of biomacromolecules inside liposomes, on the other hand, is an important issue in origins of life research (protocell models) as well as in recent studies on synthetic cells. A series of recent experiments within our project on the construction of minimal living cells revealed possible deviations from the number of macromolecules expected to be entrapped inside liposomes of diameter d<200 nm. In particular, with the aim of producing green fluorescent protein (GFP) inside liposomes, we prepared liposomes in the presence of the transcription–translation macromolecular machinery, namely E. coli extracts as well as PURESYSTEM (a cell-free protein synthesis kit containing 36 purified components, t-RNAs, ribosomes, for a total of about 80 different macromolecules). We showed that GFP was synthesised inside liposomes, despite of the fact that the Poisson Probability of liposome co-entrapment of about 80 different macromolecules (each at a concentration of 0.1–1 mm) is vanishingly small (~10!26). In order to explain the observed positive results, it was suggested that the local (inside vesicles) concentrations of the proteins and nucleic acids required for GFP expression exceeded the expected value by a factor 20 or more. The hypothesis of the spontaneous emergence of a small, yet measurable, fraction of synthetic cells with exceptionally high solute content implies that, in origins-of-life scenarios, functional solutes like RNAs and peptides even if present in dilute solutions could have become entrapped inside vesicles to give rise to functional protocells. How would it be possible to entrap such a large number of molecules inside one single vesicle against the expected Poisson statistics? Here we present evidence that shows that the entrapment frequency does not follow the expected Poisson behaviour. As shown in our previous reports, it is possible to directly visualize and count ferritin molecules inside liposomes by cryoTEM. Being an iron-storage protein, ferritin consists of a nucleus of about 4500 iron ions, spherically enclosed by 24 protein subunits; it is endowed with a large scattering power so that it is classically used as a probe for electron microscopy. Ferritin-containing liposomes are therefore suitable for direct investigation of macromolecular entrapment in cell-like compartments. When liposomes are prepared in a ferritin solution, ferritin is entrapped spontaneously. It is expected that the average number (N0) of ferritin molecules per vesicle is proportional to the ferritin concentration in the bulk (C0) and to the vesicle volume V (i.e. , N0=C0V). At low N0 values, the occupancy frequency of water-soluble molecules in liposomes is classically described by a Poisson distribution, which also accounts for deviations around the average value, as shown in Figure S1. We explored the pattern of ferritin entrapment inside liposomes under different conditions by using ferritin solutions at concentrations of 4, 8, 16 and 32 mm. The liposome composition and concentration were first optimised in order to obtain [a] Prof. P. L. Luisi, M. Allegretti, Dr. P. Stano Dipartimento di Biologia, Universit! degli Studi RomaTre Viale G. Marconi 446, 00146 Rome (Italy) Fax: (+39)0657336321 E-mail : luisi@mat.ethz.ch [b] Dr. T. Pereira de Souza, Prof. Dr. A. Fahr Institut f"r Pharmazie, Friedrich Schiller Universit#t Jena Lessingstrasse 8, 07743 Jena (Germany) [c] Dr. F. Steiniger Elektronenmikroskopisches Zentrum, Friedrich Schiller Universit#t Jena Ziegelm"hlenweg 1, 07743 Jena (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cbic.201000381.
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spontaneous protein crowding in liposomes a new vista for the origin of cellular metabolism
ChemBioChem, 2010Co-Authors: Pier Luigi Luisi, Matteo Allegretti, Tereza Pereira De Souza, Frank Steiniger, Alfred Fahr, Pasquale StanoAbstract:One question in the origin of life is the time at which membrane compartments came into the picture as hosts for the first forms of metabolism. If we assume the proteins and nucleic acids came first, then it is difficult to conceive how all the macromolecular components could have been entrapped at a later time in a single compartment. On the other hand, the hypothesis that metabolism originated from inside the compartment means that we would then have to conceive semipermeable, sophisticated membranes in prebiotic times, which does not appear plausible. With this study, we believe that we can offer a partial solution to this riddle, at the same time opening a new vista on the principles of the entrapment of solute in vesicles. We used cryo-TEM to study the entrapment of the protein ferritin in liposomes. The novel, surprising principle that appears is that when lipid surfaces close up in a proteincontaining solution to form vesicles, the entrapment frequency does not follow the expected Poisson distribution, but tends to assume a power-law behaviour, characterized by many “empty” vesicles (no or very little entrapped solute), and a long decreasing tail with extremely crowded vesicles. CryoTEM analysis shows indeed some extremely crowded liposomes adjacent to empty ones. The conclusion is that membrane closure can accumulate a remarkable number of solutes inside some compartments. The possible mechanism and relevance of this extreme local super-concentration effect for the origin of life are discussed. The spontaneous formation of lipid vesicles (liposomes) in an aqueous phase containing one or more solutes produces a heterogeneous population of liposomes in terms of solute content. Such entrapments have generally been studied by averaging techniques, such as batch absorbance or fluorescence, whereas little attention has been devoted to studying individual encapsulation. This is partly due to the technical difficulty of directly counting molecules inside liposomes. The encapsulation of biomacromolecules inside liposomes, on the other hand, is an important issue in origins of life research (protocell models) as well as in recent studies on synthetic cells. A series of recent experiments within our project on the construction of minimal living cells revealed possible deviations from the number of macromolecules expected to be entrapped inside liposomes of diameter d<200 nm. In particular, with the aim of producing green fluorescent protein (GFP) inside liposomes, we prepared liposomes in the presence of the transcription–translation macromolecular machinery, namely E. coli extracts as well as PURESYSTEM (a cell-free protein synthesis kit containing 36 purified components, t-RNAs, ribosomes, for a total of about 80 different macromolecules). We showed that GFP was synthesised inside liposomes, despite of the fact that the Poisson Probability of liposome co-entrapment of about 80 different macromolecules (each at a concentration of 0.1–1 mm) is vanishingly small (~10!26). In order to explain the observed positive results, it was suggested that the local (inside vesicles) concentrations of the proteins and nucleic acids required for GFP expression exceeded the expected value by a factor 20 or more. The hypothesis of the spontaneous emergence of a small, yet measurable, fraction of synthetic cells with exceptionally high solute content implies that, in origins-of-life scenarios, functional solutes like RNAs and peptides even if present in dilute solutions could have become entrapped inside vesicles to give rise to functional protocells. How would it be possible to entrap such a large number of molecules inside one single vesicle against the expected Poisson statistics? Here we present evidence that shows that the entrapment frequency does not follow the expected Poisson behaviour. As shown in our previous reports, it is possible to directly visualize and count ferritin molecules inside liposomes by cryoTEM. Being an iron-storage protein, ferritin consists of a nucleus of about 4500 iron ions, spherically enclosed by 24 protein subunits; it is endowed with a large scattering power so that it is classically used as a probe for electron microscopy. Ferritin-containing liposomes are therefore suitable for direct investigation of macromolecular entrapment in cell-like compartments. When liposomes are prepared in a ferritin solution, ferritin is entrapped spontaneously. It is expected that the average number (N0) of ferritin molecules per vesicle is proportional to the ferritin concentration in the bulk (C0) and to the vesicle volume V (i.e. , N0=C0V). At low N0 values, the occupancy frequency of water-soluble molecules in liposomes is classically described by a Poisson distribution, which also accounts for deviations around the average value, as shown in Figure S1. We explored the pattern of ferritin entrapment inside liposomes under different conditions by using ferritin solutions at concentrations of 4, 8, 16 and 32 mm. The liposome composition and concentration were first optimised in order to obtain [a] Prof. P. L. Luisi, M. Allegretti, Dr. P. Stano Dipartimento di Biologia, Universit! degli Studi RomaTre Viale G. Marconi 446, 00146 Rome (Italy) Fax: (+39)0657336321 E-mail : luisi@mat.ethz.ch [b] Dr. T. Pereira de Souza, Prof. Dr. A. Fahr Institut f"r Pharmazie, Friedrich Schiller Universit#t Jena Lessingstrasse 8, 07743 Jena (Germany) [c] Dr. F. Steiniger Elektronenmikroskopisches Zentrum, Friedrich Schiller Universit#t Jena Ziegelm"hlenweg 1, 07743 Jena (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cbic.201000381.