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Article ; Online: AF4 and PEG Precipitation as Predictive Assays for Antibody Self-Association.

Condado-Morales, Itzel / Sokolova, Viktoria / Wahlund, Per-Olof / Heding, Kristine E / Auclair, Sarah / Kingsbury, Jonathan S / Arosio, Paolo / Lorenzen, Nikolai

Molecular pharmaceutics

2023 Volume 20, Issue 2, Page(s) 1323–1330

Abstract: Monoclonal antibodies (mAbs) are often formulated as high-protein-concentration solutions, which in some cases can exhibit physical stability issues such as high viscosity and opalescence. To ensure that mAb-based drugs can meet their manufacturing, ... ...

Abstract	Monoclonal antibodies (mAbs) are often formulated as high-protein-concentration solutions, which in some cases can exhibit physical stability issues such as high viscosity and opalescence. To ensure that mAb-based drugs can meet their manufacturing, stability, and delivery requirements, it is advantageous to screen for and select mAbs during discovery that are not prone to such behaviors. It has been recently shown that both these macroscopic properties can be predicted to a certain extent from the diffusion interaction parameter (
MeSH term(s)	Antibodies, Monoclonal ; Polyethylene Glycols/chemistry
Chemical Substances	Antibodies, Monoclonal ; Polyethylene Glycols (3WJQ0SDW1A) ; N-cycloheptyl-1-(p-fluorobenzyl)-1,2-dihydro-2-oxopyridine-3-carboxamide
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.2c00946
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Article ; Online: A Relationship between the Structures and Neurotoxic Effects of Aβ Oligomers Stabilized by Different Metal Ions.

Chia, Sean / Cataldi, Rodrigo Lessa / Ruggeri, Francesco Simone / Limbocker, Ryan / Condado-Morales, Itzel / Pisani, Katarina / Possenti, Andrea / Linse, Sara / Knowles, Tuomas P J / Habchi, Johnny / Mannini, Benedetta / Vendruscolo, Michele

ACS chemical neuroscience

2024 Volume 15, Issue 6, Page(s) 1125–1134

Abstract: Oligomeric assemblies of the amyloid β peptide (Aβ) have been investigated for over two decades as possible neurotoxic agents in Alzheimer's disease. However, due to their heterogeneous and transient nature, it is not yet fully established which of the ... ...

Abstract	Oligomeric assemblies of the amyloid β peptide (Aβ) have been investigated for over two decades as possible neurotoxic agents in Alzheimer's disease. However, due to their heterogeneous and transient nature, it is not yet fully established which of the structural features of these oligomers may generate cellular damage. Here, we study distinct oligomer species formed by Aβ40 (the 40-residue form of Aβ) in the presence of four different metal ions (Al
MeSH term(s)	Humans ; Amyloid beta-Peptides/chemistry ; Alzheimer Disease ; Metals ; Ions ; Peptide Fragments/chemistry
Chemical Substances	Amyloid beta-Peptides ; Metals ; Ions ; Peptide Fragments
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.3c00718
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Article ; Online: Design of Biopharmaceutical Formulations Accelerated by Machine Learning.

Narayanan, Harini / Dingfelder, Fabian / Condado Morales, Itzel / Patel, Bhargav / Heding, Kristine Enemærke / Bjelke, Jais Rose / Egebjerg, Thomas / Butté, Alessandro / Sokolov, Michael / Lorenzen, Nikolai / Arosio, Paolo

Molecular pharmaceutics

2021 Volume 18, Issue 10, Page(s) 3843–3853

Abstract: In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced ... ...

Abstract	In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced algorithms from the domain of machine learning are highly beneficial in complementing analytical screening and rational design. Here, we propose a Bayesian optimization algorithm to accelerate the design of biopharmaceutical formulations. We demonstrate the power of this approach by identifying the formulation that optimizes the thermal stability of three tandem single-chain Fv variants within 25 experiments, a number which is less than one-third of the experiments that would be required by a classical DoE method and several orders of magnitude smaller compared to detailed experimental analysis of full combinatorial space. We further show the advantage of this method over conventional approaches to efficiently transfer historical information as prior knowledge for the development of new biologics or when new buffer agents are available. Moreover, we highlight the benefit of our technique in engineering multiple biophysical properties by simultaneously optimizing both thermal and interface stabilities. This optimization minimizes the amount of surfactant in the formulation, which is important to decrease the risks associated with corresponding degradation processes. Overall, this method can provide high speed of converging to optimal conditions, the ability to transfer prior knowledge, and the identification of new nonlinear combinations of excipients. We envision that these features can lead to a considerable acceleration in formulation design and to parallelization of operations during drug development.
MeSH term(s)	Bayes Theorem ; Biological Products/administration & dosage ; Biological Products/therapeutic use ; Drug Compounding/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Machine Learning ; Nanoparticle Drug Delivery System/administration & dosage
Chemical Substances	Biological Products ; Nanoparticle Drug Delivery System
Language	English
Publishing date	2021-09-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.1c00469
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Article ; Online: Isothermal titration calorimetry determination of individual rate constants of trypsin catalytic activity.

Aguirre, César / Condado-Morales, Itzel / Olguin, Luis F / Costas, Miguel

Analytical biochemistry

2015 Volume 479, Page(s) 18–27

Abstract: Determination of individual rate constants for enzyme-catalyzed reactions is central to the understanding of their mechanism of action and is commonly obtained by stopped-flow kinetic experiments. However, most natural substrates either do not fluoresce/ ... ...

Abstract	Determination of individual rate constants for enzyme-catalyzed reactions is central to the understanding of their mechanism of action and is commonly obtained by stopped-flow kinetic experiments. However, most natural substrates either do not fluoresce/absorb or lack a significant change in their spectra while reacting and, therefore, are frequently chemically modified to render adequate molecules for their spectroscopic detection. Here, isothermal titration calorimetry (ITC) was used to obtain Michaelis-Menten plots for the trypsin-catalyzed hydrolysis of several substrates at different temperatures (278-318K): four spectrophotometrically blind lysine and arginine N-free esters, one N-substituted arginine ester, and one amide. A global fitting of these data provided the individual rate constants and activation energies for the acylation and deacylation reactions, and the ratio of the formation and dissociation rates of the enzyme-substrate complex, leading also to the corresponding free energies of activation. The results indicate that for lysine and arginine N-free esters deacylation is the rate-limiting step, but for the N-substituted ester and the amide acylation is the slowest step. It is shown that ITC is able to produce quality kinetic data and is particularly well suited for those enzymatic reactions that cannot be measured by absorption or fluorescence spectroscopy.
MeSH term(s)	Acylation ; Amides/chemistry ; Amides/metabolism ; Animals ; Arginine/chemistry ; Arginine/metabolism ; Calorimetry ; Cattle ; Esters/chemistry ; Esters/metabolism ; Hydrolysis ; Kinetics ; Lysine/chemistry ; Lysine/metabolism ; Substrate Specificity ; Thermodynamics ; Trypsin/metabolism
Chemical Substances	Amides ; Esters ; Arginine (94ZLA3W45F) ; Trypsin (EC 3.4.21.4) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2015-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2015.03.014
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Article ; Online: Scaling analysis reveals the mechanism and rates of prion replication in vivo.

Meisl, Georg / Kurt, Timothy / Condado-Morales, Itzel / Bett, Cyrus / Sorce, Silvia / Nuvolone, Mario / Michaels, Thomas C T / Heinzer, Daniel / Avar, Merve / Cohen, Samuel I A / Hornemann, Simone / Aguzzi, Adriano / Dobson, Christopher M / Sigurdson, Christina J / Knowles, Tuomas P J

Nature structural & molecular biology

2021 Volume 28, Issue 4, Page(s) 365–372

Abstract: Prions consist of pathological aggregates of cellular prion protein and have the ability to replicate, causing neurodegenerative diseases, a phenomenon mirrored in many other diseases connected to protein aggregation, including Alzheimer's and Parkinson' ... ...

Abstract	Prions consist of pathological aggregates of cellular prion protein and have the ability to replicate, causing neurodegenerative diseases, a phenomenon mirrored in many other diseases connected to protein aggregation, including Alzheimer's and Parkinson's diseases. However, despite their key importance in disease, the individual processes governing this formation of pathogenic aggregates, as well as their rates, have remained challenging to elucidate in vivo. Here we bring together a mathematical framework with kinetics of the accumulation of prions in mice and microfluidic measurements of aggregate size to dissect the overall aggregation reaction into its constituent processes and quantify the reaction rates in mice. Taken together, the data show that multiplication of prions in vivo is slower than in in vitro experiments, but efficient when compared with other amyloid systems, and displays scaling behavior characteristic of aggregate fragmentation. These results provide a framework for the determination of the mechanisms of disease-associated aggregation processes within living organisms.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid/genetics ; Animals ; Humans ; Mice ; Models, Theoretical ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Prions/genetics ; Protein Aggregation, Pathological/genetics
Chemical Substances	Amyloid ; Prions
Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-021-00565-x
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Article ; Online: Microfluidic characterisation reveals broad range of SARS-CoV-2 antibody affinity in human plasma.

Schneider, Matthias M / Emmenegger, Marc / Xu, Catherine K / Condado Morales, Itzel / Meisl, Georg / Turelli, Priscilla / Zografou, Chryssa / Zimmermann, Manuela R / Frey, Beat M / Fiedler, Sebastian / Denninger, Viola / Jacquat, Raphaël Pb / Madrigal, Lidia / Ilsley, Alison / Kosmoliaptsis, Vasilis / Fiegler, Heike / Trono, Didier / Knowles, Tuomas Pj / Aguzzi, Adriano

Life science alliance

2021 Volume 5, Issue 2

Abstract: The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in ...

Abstract	The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants,
MeSH term(s)	Adult ; Aged ; Angiotensin-Converting Enzyme 2/blood ; Angiotensin-Converting Enzyme 2/immunology ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Antibody Affinity ; B-Lymphocytes/immunology ; B-Lymphocytes/virology ; COVID-19/blood ; COVID-19/etiology ; COVID-19/immunology ; Cross Reactions ; Female ; Humans ; Male ; Microfluidics/methods ; Middle Aged ; SARS-CoV-2/immunology ; Severity of Illness Index ; Spike Glycoprotein, Coronavirus/blood ; Spike Glycoprotein, Coronavirus/immunology ; Surface Plasmon Resonance
Chemical Substances	Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202101270
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Article ; Online: Resolving protein mixtures using microfluidic diffusional sizing combined with synchrotron radiation circular dichroism.

Bortolini, Christian / Kartanas, Tadas / Copic, Davor / Condado Morales, Itzel / Zhang, Yuewen / Challa, Pavan K / Peter, Quentin / Jávorfi, Tamás / Hussain, Rohanah / Dong, Mingdong / Siligardi, Giuliano / Knowles, Tuomas P J / Charmet, Jérôme

Lab on a chip

2018 Volume 19, Issue 1, Page(s) 50–58

Abstract: Circular dichroism spectroscopy has become a powerful tool to characterise proteins and other biomolecules. For heterogeneous samples such as those present for interacting proteins, typically only average spectroscopic features can be resolved. Here we ... ...

Abstract	Circular dichroism spectroscopy has become a powerful tool to characterise proteins and other biomolecules. For heterogeneous samples such as those present for interacting proteins, typically only average spectroscopic features can be resolved. Here we overcome this limitation by using free-flow microfluidic size separation in-line with synchrotron radiation circular dichroism to resolve the secondary structure of each component of a model protein mixture containing monomers and fibrils. To enable this objective, we have integrated far-UV compatible measurement chambers into PDMS-based microfluidic devices. Two architectures are proposed so as to accommodate for a wide range of concentrations. The approach, which can be used in combination with other bulk measurement techniques, paves the way to the study of complex mixtures such as the ones associated with protein misfolding and aggregation diseases including Alzheimer's and Parkinson's diseases.
MeSH term(s)	Animals ; Cattle ; Circular Dichroism/instrumentation ; Circular Dichroism/methods ; Diffusion ; Equipment Design ; Insulin/chemistry ; Lab-On-A-Chip Devices ; Particle Size ; Protein Structure, Secondary ; Proteins/analysis ; Proteins/chemistry ; Proteins/isolation & purification ; Reproducibility of Results ; Synchrotrons
Chemical Substances	Insulin ; Proteins
Language	English
Publishing date	2018-12-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2056646-3
ISSN	1473-0189 ; 1473-0197
ISSN (online)	1473-0189
ISSN	1473-0197
DOI	10.1039/c8lc00757h
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Article ; Online: Microfluidic Affinity Profiling reveals a Broad Range of Target Affinities for Anti-SARS-CoV-2 Antibodies in Plasma of Covid Survivors

Schneider, Matthias M. / Emmenegger, Marc / Xu, Catherine K. / Condado Morales, Itzel / Turelli, Priscilla / Zimmermann, Manuela R. / Frey, Beat M. / Fiedler, Sebastian / Denninger, Viola / Meisl, Georg / Kosmoliaptsis, Vasilis / Fiegler, Heike / Trono, Didier / Knowles, Tuomas P. J. / Aguzzi, Adriano AA

medRxiv

Abstract: The clinical outcome of SARS-CoV-2 infections can range from asymptomatic to lethal, and is thought to be crucially shaped by the quality of the immune response which includes antibody titres and affinity for their targets. Using Microfluidic Antibody ... ...

Abstract	The clinical outcome of SARS-CoV-2 infections can range from asymptomatic to lethal, and is thought to be crucially shaped by the quality of the immune response which includes antibody titres and affinity for their targets. Using Microfluidic Antibody Affinity Profiling (MAAP), we determined the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 23 of whom were confirmed to be SARS-CoV-2-positive by PCR testing. We found that dissociation constants (Kd) of anti-RBD antibodies spanned more than two orders of magnitude from 80 pM to 25 nM, despite having similar antibody concentrations. Individual patients showed progressively higher antibody concentrations but constant Kd values, suggesting that affinities did not mature over time. 33 sera showed affinities higher than that of the CoV2 spike for its ACE2 receptor. Accordingly, addition of seropositive plasma to pre-formed spike-ACE2 receptor complexes led to their dissociation. Finally, we observed that the RBD of HKU1, OC43, and SARS-CoV coronaviruses, but not unrelated control proteins, were able to compete substantially with the RBD of SARS-CoV-2 in solution. Therefore, the affinity of total plasma immunoglobulins to SARS-CoV-2 is an indicator of the quality of the immune response to SARS-CoV-2, and may help select the most efficacious samples for therapeutic plasmapheresis.
Keywords	covid19
Language	English
Publishing date	2020-09-23
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.09.20.20196907
Database	COVID19

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Article ; Online: Population-wide evolution of SARS-CoV-2 immunity tracked by a ternary immunoassay

Emmenegger, Marc / De Cecco, Elena / Lamparter, David / Jacquat, Raphael P. B. / Ebner, Daniel / Schneider, Matthias M / Condado Morales, Itzel / Schneider, Dezirae / Dogancay, Berre / Guo, Jingjing / Wiedmer, Anne / Domange, Julie / Imeri, Marigona / Moos, Rita / Zografou, Chryssa / Trevisan, Chiara / Gonzalez-Guerra, Andres / Carrella, Alessandra / Dubach, Irina L. /

Xu, Catherine K. / Meisl, Georg / Kosmoliaptsis, Vasilis / Malinauskas, Tomas / Burgess-Brown, Nicola / Owens, Ray / Mongkolsapaya, Juthathip / Hatch, Stephanie / Screaton, Gavin R. / Schubert, Katharina / Huck, John D. / Liu, Feimei / Pojer, Florence / Lau, Kelvin / Hacker, David / Probst-Mueller, Elsbeth / Cervia, Carlo / Nilsson, Jakob / Boyman, Onur / Saleh, Lanja / Spanaus, Katharina / von Eckardstein, Arnold / Schaer, Dominik J. / Ban, Nenad / Tsai, Ching-Ju / Marino, Jacopo / Schertler, Gebhard F. X. / Gottschalk, Jochen / Frey, Beat M. / Reimann, Regina / Hornemann, Simone / Ring, Aaron M. / Knowles, Tuomas P. J. / Xenarios, Ioannis / Stuart, David I. / Aguzzi, Adriano

medRxiv

Abstract: Serological assays can detect anti-SARS-CoV-2 (SARS2) antibodies, but their sensitivity often comes at the expense of specificity. Here we used a Ternary Automated Blood Im-munoassay (TRABI) to assess the IgG response against SARS2 in 3,815 prepandemic ... ...

Abstract	Serological assays can detect anti-SARS-CoV-2 (SARS2) antibodies, but their sensitivity often comes at the expense of specificity. Here we used a Ternary Automated Blood Im-munoassay (TRABI) to assess the IgG response against SARS2 in 3,815 prepandemic plasma samples and 126 virologically and/or clinically confirmed COVID-19 samples. Posterior probabilities were calculated from 3x8 measurements of logarithmically diluted samples against the ectodomain and the receptor-binding domain of the spike protein and the nucleoprotein. We then performed 429,624 assays on 17,901 blood samples from patients of the University Hospital Zurich and from healthy blood donors. We found se-ropositivity in 44 of 8,591 patients and in 26 of 5,388 blood donors from December 2019 to May 2020. Western blotting confirmed seropositivity in COVID samples but in none of the prepandemic samples. Solution-equilibrium measurements revealed immunodominant antibodies with nanomolar affinity in COVID samples, whereas prepandemic plasma showed lower affinities despite similar titers for individual SARS2 antigens. Hence, TRABI identifies seropositive individuals in large unselected cohorts, discriminates be-tween SARS2 immunity and low-affinity crossreactivity, and is therefore suitable for large-scale nationwide screening campaigns.
Keywords	covid19
Language	English
Publishing date	2020-06-02
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.05.31.20118554
Database	COVID19

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