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Book ; Online ; E-Book: Viruses, pandemics, and immunity

Chakraborty, Arup / Shaw, Andrey S.

2021

Abstract: Informed and accessible overview of viruses and pandemics, how our immune system combats them, and how diagnostic tests, vaccines, and antiviral therapies work to form the foundation of public health"-- ...

Author's details	Arup K. Chakraborty and Andrey S. Shaw
Abstract	"Informed and accessible overview of viruses and pandemics, how our immune system combats them, and how diagnostic tests, vaccines, and antiviral therapies work to form the foundation of public health"--
Keywords	Pandemics ; Viruses / pathogenicity ; Immunity ; Vaccines ; Virus Diseases / drug therapy
Language	English
Size	1 Online-Ressource (xi, 206 Seiten), Illustrationen
Publisher	The MIT Press
Publishing place	Cambridge, Massachusetts
Publishing country	United States
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
HBZ-ID	HT020883482
ISBN	978-0-262-36345-7 ; 9780262542388 ; 0-262-36345-3 ; 0262542382
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Design of immunogens for eliciting antibody responses that may protect against SARS-CoV-2 variants.

Wang, Eric / Chakraborty, Arup K

PLoS computational biology

2022 Volume 18, Issue 9, Page(s) e1010563

Abstract: The rise of SARS-CoV-2 variants and the history of outbreaks caused by zoonotic coronaviruses point to the need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses of diverse sequences and structures of ...

Abstract	The rise of SARS-CoV-2 variants and the history of outbreaks caused by zoonotic coronaviruses point to the need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses of diverse sequences and structures of coronavirus spikes with data from deep mutational scanning to design SARS-CoV-2 variant antigens containing the most significant mutations that may emerge. We trained a neural network to predict RBD expression and ACE2 binding from sequence, which allowed us to determine that these antigens are stable and bind to ACE2. Thus, they represent viable variants. We then used a computational model of affinity maturation (AM) to study the antibody response to immunization with different combinations of the designed antigens. The results suggest that immunization with a cocktail of the antigens is likely to promote evolution of higher titers of antibodies that target SARS-CoV-2 variants than immunization or infection with the wildtype virus alone. Finally, our analysis of 12 coronaviruses from different genera identified the S2' cleavage site and fusion peptide as potential pan-coronavirus vaccine targets.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Antibodies, Neutralizing ; Antibodies, Viral ; Antibody Formation ; COVID-19/prevention & control ; COVID-19 Vaccines ; Humans ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010563
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Article ; Online: A model for cis-regulation of transcriptional condensates and gene expression by proximal lncRNAs.

Natarajan, Pradeep / Shrinivas, Krishna / Chakraborty, Arup K

Biophysical journal

2023 Volume 122, Issue 13, Page(s) 2757–2772

Abstract: Long noncoding RNAs (lncRNAs) perform several important functions in cells including cis-regulation of transcription. Barring a few specific cases, the mechanisms underlying transcriptional regulation by lncRNAs remain poorly understood. Transcriptional ... ...

Abstract	Long noncoding RNAs (lncRNAs) perform several important functions in cells including cis-regulation of transcription. Barring a few specific cases, the mechanisms underlying transcriptional regulation by lncRNAs remain poorly understood. Transcriptional proteins can form condensates via phase separation at protein-binding loci (BL) on the genome (e.g., enhancers and promoters). lncRNA-coding genes are present at loci in close genomic proximity of these BL and these RNAs can interact with transcriptional proteins via attractive heterotypic interactions mediated by their net charge. Motivated by these observations, we propose that lncRNAs can dynamically regulate transcription in cis via charge-based heterotypic interactions with transcriptional proteins in condensates. To study the consequences of this mechanism, we developed and studied a dynamical phase-field model. We find that proximal lncRNAs can promote condensate formation at the BL. Vicinally localized lncRNA can migrate to the BL to attract more protein because of favorable interaction free energies. However, increasing the distance beyond a threshold leads to a sharp decrease in protein recruitment to the BL. This finding could potentially explain why genomic distances between lncRNA-coding genes and protein-coding genes are conserved across metazoans. Finally, our model predicts that lncRNA transcription can fine-tune transcription from neighboring condensate-controlled genes, repressing transcription from highly expressed genes and enhancing transcription of genes expressed at a low level. This nonequilibrium effect can reconcile conflicting reports that lncRNAs can enhance or repress transcription from proximal genes.
MeSH term(s)	RNA, Long Noncoding/genetics ; Gene Expression Regulation ; Proteins/genetics ; Nuclear Bodies ; Gene Expression
Chemical Substances	RNA, Long Noncoding ; Proteins
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2023.05.032
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mechanisms underlying vaccination protocols that may optimally elicit broadly neutralizing antibodies against highly mutable pathogens.

Ganti, Raman S / Chakraborty, Arup K

Physical review. E

2021 Volume 103, Issue 5-1, Page(s) 52408

Abstract: Effective prophylactic vaccines usually induce the immune system to generate potent antibodies that can bind to an antigen and thus prevent it from infecting host cells. B cells produce antibodies by a Darwinian evolutionary process called affinity ... ...

Abstract	Effective prophylactic vaccines usually induce the immune system to generate potent antibodies that can bind to an antigen and thus prevent it from infecting host cells. B cells produce antibodies by a Darwinian evolutionary process called affinity maturation (AM). During AM, the B cell population evolves in response to the antigen to produce antibodies that bind specifically and strongly to the antigen. Highly mutable pathogens pose a major challenge to the development of effective vaccines because antibodies that are effective against one strain of the virus may not protect against a mutant strain. Antibodies that can protect against diverse strains of a mutable pathogen have high "breadth" and are called broadly neutralizing antibodies (bnAbs). In spite of extensive studies, an effective vaccination strategy that can generate bnAbs in humans does not exist for any highly mutable pathogen. Here we study a minimal model to explore the mechanisms underlying how the selection forces imposed by antigens can be optimally chosen to guide AM to maximize the evolution of bnAbs. For logistical reasons, only a finite number of antigens can be administered in a finite number of vaccinations; that is, guiding the nonequilibrium dynamics of AM to produce bnAbs must be accomplished nonadiabatically. The time-varying Kullback-Leibler divergence (KLD) between the existing B cell population distribution and the fitness landscape imposed by antigens is a quantitative metric of the thermodynamic force acting on B cells. If this force is too small, adaptation is minimal. If the force is too large, contrary to expectations, adaptation is not faster; rather, the B cell population is extinguished for reasons that we describe. We define the conditions necessary for the force to be set optimally such that the flux of B cells from low to high breadth states is maximized. Even in this case we show why the dynamics of AM prevent perfect adaptation. If two shots of vaccination are allowed, the optimal protocol is characterized by a relatively low optimal KLD during the first shot that appropriately increases the diversity of the B cell population so that the surviving B cells have a high chance of evolving into bnAbs upon subsequently increasing the KLD during the second shot. Phylogenetic tree analysis further reveals the evolutionary pathways that lead to bnAbs. The connections between the mechanisms revealed by our analyses and recent simulation studies of bnAb evolution, the problem of generalist versus specialist evolution, and learning theory are discussed.
MeSH term(s)	B-Lymphocytes/immunology ; Broadly Neutralizing Antibodies ; Phylogeny ; Vaccination
Chemical Substances	Broadly Neutralizing Antibodies
Language	English
Publishing date	2021-07-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2844562-4
ISSN	2470-0053 ; 2470-0045
ISSN (online)	2470-0053
ISSN	2470-0045
DOI	10.1103/PhysRevE.103.052408
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Article ; Online: How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

Yin, Rose / Melton, Samuel / Huseby, Eric S / Kardar, Mehran / Chakraborty, Arup K

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 11, Page(s) e2318599121

Abstract: T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. ... ...

Abstract	T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.
MeSH term(s)	Animals ; Mice ; Persistent Infection ; Peripheral Tolerance ; T-Lymphocytes ; Autoantigens ; Peptides ; Autoimmune Diseases
Chemical Substances	Autoantigens ; Peptides
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2318599121
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Article: Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses.

Deng, Yixiang / Tang, Melbourne / Ross, Ted M / Schmidt, Aaron G / Chakraborty, Arup K / Lingwood, Daniel

medRxiv : the preprint server for health sciences

2024

Abstract: The on-going diversification of influenza virus necessicates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the ...

Abstract	The on-going diversification of influenza virus necessicates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the same HA strain will boost antibodies with narrow coverage. However, repeated vaccination with homologous SARS-CoV-2 vaccine eventually elicits neutralizing activity against highly unmatched variants, questioning this immunological premise. We evaluated a longitudinal influenza vaccine cohort, where each year the subjects received the same, novel H1N1 2009 pandemic vaccine strain. Repeated vaccination gradually enhanced receptor-blocking antibodies (HAI) to highly unmatched H1N1 strains within individuals with no initial memory recall against these historical viruses. An
Language	English
Publishing date	2024-03-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.27.24303943
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Article ; Online: A model for organization and regulation of nuclear condensates by gene activity.

Schede, Halima H / Natarajan, Pradeep / Chakraborty, Arup K / Shrinivas, Krishna

Nature communications

2023 Volume 14, Issue 1, Page(s) 4152

Abstract: Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote ... ...

Abstract	Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote gene expression. How diverse properties of nuclear condensates are shaped by gene organization and activity is poorly understood. Here, we develop a physics-based model to interrogate how spatially-varying transcription activity impacts condensate properties and dynamics. Our model predicts that spatial clustering of active genes can enable precise localization and de novo nucleation of condensates. Strong clustering and high activity results in aspherical condensate morphologies. Condensates can flow towards distant gene clusters and competition between multiple clusters lead to stretched morphologies and activity-dependent repositioning. Overall, our model predicts and recapitulates morphological and dynamical features of diverse nuclear condensates and offers a unified mechanistic framework to study the interplay between non-equilibrium processes, spatially-varying transcription, and multicomponent condensates in cell biology.
MeSH term(s)	Multigene Family ; Cluster Analysis ; Genomics ; Nucleic Acids ; Physics
Chemical Substances	Nucleic Acids
Language	English
Publishing date	2023-07-12
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39878-4
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Article ; Online: Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens.

Yang, Leerang / Caradonna, Timothy M / Schmidt, Aaron G / Chakraborty, Arup K

Cell reports

2023 Volume 42, Issue 3, Page(s) 112160

Abstract: Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate ... ...

Abstract	Immunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin may serve as candidates for a universal influenza vaccine. Here, we develop a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a heterotrimeric "chimera" hemagglutinin that is enriched for the RBS epitope relative to other B cell epitopes and a cocktail composed of three non-epitope-enriched homotrimers of the monomers that comprise the chimera. Experiments in mice find that the chimera outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse helper T cells and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed light on antibody evolution and highlight how immunogen design and T cells modulate vaccination outcomes.
MeSH term(s)	Animals ; Mice ; Humans ; Influenza, Human ; Influenza Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing ; Hemagglutinins ; Hemagglutinin Glycoproteins, Influenza Virus ; Vaccination
Chemical Substances	Influenza Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing ; Hemagglutinins ; Hemagglutinin Glycoproteins, Influenza Virus
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112160
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Article ; Online: Polymer folding through active processes recreates features of genome organization.

Goychuk, Andriy / Kannan, Deepti / Chakraborty, Arup K / Kardar, Mehran

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 20, Page(s) e2221726120

Abstract: From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, ...

Abstract	From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate. Moreover, chromatin motion varies with genomic coordinate, pointing toward a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers nonequilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward exploring whether active mechanisms contribute to shaping genome conformations, we discuss a data-driven approach.
MeSH term(s)	Polymers/chemistry ; Chromatin/genetics ; Chromosomes/metabolism ; Genome ; Genomics
Chemical Substances	Polymers ; Chromatin
Language	English
Publishing date	2023-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2221726120
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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: A Perspective on the Role of Computational Models in Immunology.

Chakraborty, Arup K

Annual review of immunology

2017 Volume 35, Page(s) 403–439

Abstract: This is an exciting time for immunology because the future promises to be replete with exciting new discoveries that can be translated to improve health and treat disease in novel ways. Immunologists are attempting to answer increasingly complex ... ...

Abstract	This is an exciting time for immunology because the future promises to be replete with exciting new discoveries that can be translated to improve health and treat disease in novel ways. Immunologists are attempting to answer increasingly complex questions concerning phenomena that range from the genetic, molecular, and cellular scales to that of organs, whole animals or humans, and populations of humans and pathogens. An important goal is to understand how the many different components involved interact with each other within and across these scales for immune responses to emerge, and how aberrant regulation of these processes causes disease. To aid this quest, large amounts of data can be collected using high-throughput instrumentation. The nonlinear, cooperative, and stochastic character of the interactions between components of the immune system as well as the overwhelming amounts of data can make it difficult to intuit patterns in the data or a mechanistic understanding of the phenomena being studied. Computational models are increasingly important in confronting and overcoming these challenges. I first describe an iterative paradigm of research that integrates laboratory experiments, clinical data, computational inference, and mechanistic computational models. I then illustrate this paradigm with a few examples from the recent literature that make vivid the power of bringing together diverse types of computational models with experimental and clinical studies to fruitfully interrogate the immune system.
MeSH term(s)	Animals ; Biomedical Research ; Computational Biology ; Computer Simulation ; High-Throughput Screening Assays ; Humans ; Models, Immunological ; Monitoring, Immunologic/methods ; Receptors, Antigen, T-Cell/genetics ; Signal Transduction ; T-Lymphocytes/immunology ; Vaccines/immunology
Chemical Substances	Receptors, Antigen, T-Cell ; Vaccines
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604953-9
ISSN	1545-3278 ; 0732-0582
ISSN (online)	1545-3278
ISSN	0732-0582
DOI	10.1146/annurev-immunol-041015-055325
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