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Article ; Online: State-of-the-art genome inference in the human MHC.

Dilthey, Alexander T

The international journal of biochemistry & cell biology

2020 Volume 131, Page(s) 105882

Abstract: The Major Histocompatibility Complex (MHC) on the short arm of chromosome 6 is associated with more diseases than any other region of the genome; it encodes the antigen-presenting Human Leukocyte Antigen (HLA) proteins and is one of the key immunogenetic ...

Abstract	The Major Histocompatibility Complex (MHC) on the short arm of chromosome 6 is associated with more diseases than any other region of the genome; it encodes the antigen-presenting Human Leukocyte Antigen (HLA) proteins and is one of the key immunogenetic regions of the genome. Accurate genome inference and interpretation of MHC association signals have traditionally been hampered by the region's uniquely complex features, such as high levels of polymorphism; inter-gene sequence homologies; structural variation; and long-range haplotype structures. Recent algorithmic and technological advances have, however, significantly increased the accessibility of genetic variation in the MHC; these developments include (i) accurate SNP-based HLA type imputation; (ii) genome graph approaches for variation-aware genome inference from next-generation sequencing data; (iii) long-read-based diploid de novo assembly of the MHC; (iv) cost-effective targeted MHC sequencing methods. Applied to hundreds of thousands of samples over the last years, these technologies have already enabled significant biological discoveries, for example in the field of autoimmune disease genetics. Remaining challenges concern the development of integrated methods that leverage haplotype-resolved de novo assembly of the MHC for the development of improved MHC genotyping methods for short reads and the construction of improved reference panels for SNP-based imputation. Improved genome inference in the MHC can crucially contribute to an improved genetic and functional understanding of many immune-related phenotypes and diseases.
MeSH term(s)	Algorithms ; Alleles ; Base Sequence ; Chromosome Mapping/methods ; Computational Biology/methods ; Genetic Heterogeneity ; Genome, Human/immunology ; HLA Antigens/classification ; HLA Antigens/genetics ; HLA Antigens/immunology ; Haplotypes ; High-Throughput Nucleotide Sequencing/statistics & numerical data ; Histocompatibility Testing/methods ; Humans ; Linkage Disequilibrium ; Major Histocompatibility Complex/genetics ; Polymorphism, Single Nucleotide
Chemical Substances	HLA Antigens
Language	English
Publishing date	2020-11-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2020.105882
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Article: State-of-the-art genome inference in the human MHC

Dilthey, Alexander T

international journal of biochemistry & cell biology. 2021 Feb., v. 131

2021

Abstract	The Major Histocompatibility Complex (MHC) on the short arm of chromosome 6 is associated with more diseases than any other region of the genome; it encodes the antigen-presenting Human Leukocyte Antigen (HLA) proteins and is one of the key immunogenetic regions of the genome. Accurate genome inference and interpretation of MHC association signals have traditionally been hampered by the region’s uniquely complex features, such as high levels of polymorphism; inter-gene sequence homologies; structural variation; and long-range haplotype structures. Recent algorithmic and technological advances have, however, significantly increased the accessibility of genetic variation in the MHC; these developments include (i) accurate SNP-based HLA type imputation; (ii) genome graph approaches for variation-aware genome inference from next-generation sequencing data; (iii) long-read-based diploid de novo assembly of the MHC; (iv) cost-effective targeted MHC sequencing methods. Applied to hundreds of thousands of samples over the last years, these technologies have already enabled significant biological discoveries, for example in the field of autoimmune disease genetics. Remaining challenges concern the development of integrated methods that leverage haplotype-resolved de novo assembly of the MHC for the development of improved MHC genotyping methods for short reads and the construction of improved reference panels for SNP-based imputation. Improved genome inference in the MHC can crucially contribute to an improved genetic and functional understanding of many immune-related phenotypes and diseases.
Keywords	HLA antigens ; autoimmune diseases ; chromosomes ; cost effectiveness ; diploidy ; genetic variation ; genotyping ; haplotypes ; humans ; major histocompatibility complex
Language	English
Dates of publication	2021-02
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2020.105882
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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: The role of microbiome-host interactions in the development of Alzheimer´s disease.

Weber, Christian / Dilthey, Alexander / Finzer, Patrick

Frontiers in cellular and infection microbiology

2023 Volume 13, Page(s) 1151021

Abstract: Alzheimer`s disease (AD) is the most prevalent cause of dementia. It is often assumed that AD is caused by an aggregation of extracellular beta-amyloid and intracellular tau-protein, supported by a recent study showing reduced brain amyloid levels and ... ...

Abstract	Alzheimer`s disease (AD) is the most prevalent cause of dementia. It is often assumed that AD is caused by an aggregation of extracellular beta-amyloid and intracellular tau-protein, supported by a recent study showing reduced brain amyloid levels and reduced cognitive decline under treatment with a beta-amyloid-binding antibody. Confirmation of the importance of amyloid as a therapeutic target notwithstanding, the underlying causes of beta-amyloid aggregation in the human brain, however, remain to be elucidated. Multiple lines of evidence point towards an important role of infectious agents and/or inflammatory conditions in the etiology of AD. Various microorganisms have been detected in the cerebrospinal fluid and brains of AD-patients and have thus been hypothesized to be linked to the development of AD, including
MeSH term(s)	Host Microbial Interactions ; Microbiota ; Alzheimer Disease/diagnosis ; Alzheimer Disease/microbiology ; Humans ; Porphyromonas gingivalis/isolation & purification ; Treponema/isolation & purification ; Dysbiosis/complications ; Dysbiosis/microbiology ; Mouth/microbiology ; Oral Health ; Lactoferrin/analysis ; Lactoferrin/metabolism
Chemical Substances	Lactoferrin (EC 3.4.21.-)
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2023.1151021
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Article ; Online: HOGVAX: Exploiting epitope overlaps to maximize population coverage in vaccine design with application to SARS-CoV-2.

Schulte, Sara C / Dilthey, Alexander T / Klau, Gunnar W

Cell systems

2023 Volume 14, Issue 12, Page(s) 1122–1130.e3

Abstract: The efficacy of epitope vaccines depends on the included epitopes as well as the probability that the selected epitopes are presented by the major histocompatibility complex (MHC) proteins of a vaccinated individual. Designing vaccines that effectively ... ...

Abstract	The efficacy of epitope vaccines depends on the included epitopes as well as the probability that the selected epitopes are presented by the major histocompatibility complex (MHC) proteins of a vaccinated individual. Designing vaccines that effectively immunize a high proportion of the population is challenging because of high MHC polymorphism, diverging MHC-peptide binding affinities, and physical constraints on epitope vaccine constructs. Here, we present HOGVAX, a combinatorial optimization approach for epitope vaccine design. To optimize population coverage within the constraint of limited vaccine construct space, HOGVAX employs a hierarchical overlap graph (HOG) to identify and exploit overlaps between selected peptides and explicitly models the structure of linkage disequilibrium in the MHC. In a SARS-CoV-2 case study, we demonstrate that HOGVAX-designed vaccines contain substantially more epitopes than vaccines built from concatenated peptides and predict vaccine efficacy in over 98% of the population with high numbers of presented peptides in vaccinated individuals.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19/prevention & control ; Epitopes, T-Lymphocyte ; Vaccines ; Peptides
Chemical Substances	Epitopes, T-Lymphocyte ; Vaccines ; Peptides
Language	English
Publishing date	2023-12-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2023.11.001
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Article ; Online: Microbial Community Profiling Protocol with Full-length 16S rRNA Sequences and Emu.

Curry, Kristen D / Soriano, Sirena / Nute, Michael G / Villapol, Sonia / Dilthey, Alexander / Treangen, Todd J

Current protocols

2024 Volume 4, Issue 3, Page(s) e978

Abstract: 16S rRNA targeted amplicon sequencing is an established standard for elucidating microbial community composition. While high-throughput short-read sequencing can elicit only a portion of the 16S rRNA gene due to their limited read length, third ... ...

Abstract	16S rRNA targeted amplicon sequencing is an established standard for elucidating microbial community composition. While high-throughput short-read sequencing can elicit only a portion of the 16S rRNA gene due to their limited read length, third generation sequencing can read the 16S rRNA gene in its entirety and thus provide more precise taxonomic classification. Here, we present a protocol for generating full-length 16S rRNA sequences with Oxford Nanopore Technologies (ONT) and a microbial community profile with Emu. We select Emu for analyzing ONT sequences as it leverages information from the entire community to overcome errors due to incomplete reference databases and hardware limitations to ultimately obtain species-level resolution. This pipeline provides a low-cost solution for characterizing microbiome composition by exploiting real-time, long-read ONT sequencing and tailored software for accurate characterization of microbial communities. © 2024 Wiley Periodicals LLC. Basic Protocol: Microbial community profiling with Emu Support Protocol 1: Full-length 16S rRNA microbial sequences with Oxford Nanopore Technologies sequencing platform Support Protocol 2: Building a custom reference database for Emu.
MeSH term(s)	Animals ; RNA, Ribosomal, 16S/genetics ; Dromaiidae/genetics ; Bacteria/genetics ; Sequence Analysis, DNA/methods ; Microbiota/genetics
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.978
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Article ; Online: HOGVAX: Exploiting Peptide Overlaps to Maximize Population Coverage in Vaccine Design with Application to SARS-CoV-2

Schulte, Sara C. / Dilthey, Alexander T. / Klau, Gunnar W.

bioRxiv

Abstract: Peptide vaccines present a safe and cost-efficient alternative to traditional vaccines. Their efficacy depends on the peptides included in the vaccine and the ability of major histocompatibility complex (MHC) molecules to bind and present these peptides. ...

Abstract	Peptide vaccines present a safe and cost-efficient alternative to traditional vaccines. Their efficacy depends on the peptides included in the vaccine and the ability of major histocompatibility complex (MHC) molecules to bind and present these peptides. Due to the high diversity of MHC alleles, their diverging peptide binding specificities, and physical constraints on the maximum length of peptide vaccine constructs, choosing a set of peptides that effectively achieve immunization across a large proportion of the population is challenging. Here, we present HOGVAX, a combinatorial optimization approach to select peptides that maximize population coverage. The key idea behind HOGVAX is to exploit overlaps between peptide sequences to include a large number of peptides in limited space and thereby also cover rare MHC alleles. We formalize the vaccine design task as a theoretical problem, which we call the Maximum Scoring k-Superstring Problem (MSKS). We show that MSKS is NP-hard, reformulate it into a graph problem using the hierarchical overlap graph (HOG), and present a haplotype-aware variant of MSKS to take linkage disequilibrium between MHC loci into account. We give an integer linear programming formulation for the graph problem and provide an open source implementation. We demonstrate on a SARS-CoV-2 case study that HOGVAX-designed vaccine formulations contain significantly more peptides than vaccine sequences built from concatenated peptides. We predict over 98% population coverage and high numbers of per-individual presented peptides, leading to robust immunity against new pathogens or viral variants.
Keywords	covid19
Language	English
Publishing date	2023-01-10
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.01.09.523288
Database	COVID19

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Article ; Online: Insights into gut microbiomes in stem cell transplantation by comprehensive shotgun long-read sequencing.

Spohr, Philipp / Scharf, Sebastian / Rommerskirchen, Anna / Henrich, Birgit / Jäger, Paul / Klau, Gunnar W / Haas, Rainer / Dilthey, Alexander / Pfeffer, Klaus

Scientific reports

2024 Volume 14, Issue 1, Page(s) 4068

Abstract: The gut microbiome is a diverse ecosystem, dominated by bacteria; however, fungi, phages/viruses, archaea, and protozoa are also important members of the gut microbiota. Exploration of taxonomic compositions beyond bacteria as well as an understanding of ...

Abstract	The gut microbiome is a diverse ecosystem, dominated by bacteria; however, fungi, phages/viruses, archaea, and protozoa are also important members of the gut microbiota. Exploration of taxonomic compositions beyond bacteria as well as an understanding of the interaction between the bacteriome with the other members is limited using 16S rDNA sequencing. Here, we developed a pipeline enabling the simultaneous interrogation of the gut microbiome (bacteriome, mycobiome, archaeome, eukaryome, DNA virome) and of antibiotic resistance genes based on optimized long-read shotgun metagenomics protocols and custom bioinformatics. Using our pipeline we investigated the longitudinal composition of the gut microbiome in an exploratory clinical study in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT; n = 31). Pre-transplantation microbiomes exhibited a 3-cluster structure, characterized by Bacteroides spp. /Phocaeicola spp., mixed composition and Enterococcus abundances. We revealed substantial inter-individual and temporal variabilities of microbial domain compositions, human DNA, and antibiotic resistance genes during the course of alloHSCT. Interestingly, viruses and fungi accounted for substantial proportions of microbiome content in individual samples. In the course of HSCT, bacterial strains were stable or newly acquired. Our results demonstrate the disruptive potential of alloHSCTon the gut microbiome and pave the way for future comprehensive microbiome studies based on long-read metagenomics.
MeSH term(s)	Humans ; Gastrointestinal Microbiome/genetics ; Microbiota/genetics ; Hematopoietic Stem Cell Transplantation ; Bacteria/genetics ; Anti-Bacterial Agents ; Fungi/genetics ; DNA, Ribosomal ; Metagenomics/methods
Chemical Substances	Anti-Bacterial Agents ; DNA, Ribosomal
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53506-1
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Article ; Online: Ultraplexing: increasing the efficiency of long-read sequencing for hybrid assembly with k-mer-based multiplexing.

Dilthey, Alexander T / Meyer, Sebastian A / Kaasch, Achim J

Genome biology

2020 Volume 21, Issue 1, Page(s) 68

Abstract: Hybrid genome assembly has emerged as an important technique in bacterial genomics, but cost and labor requirements limit large-scale application. We present Ultraplexing, a method to improve per-sample sequencing cost and hands-on time of Nanopore ... ...

Abstract	Hybrid genome assembly has emerged as an important technique in bacterial genomics, but cost and labor requirements limit large-scale application. We present Ultraplexing, a method to improve per-sample sequencing cost and hands-on time of Nanopore sequencing for hybrid assembly by at least 50% compared to molecular barcoding while maintaining high assembly quality. Ultraplexing requires the availability of Illumina data and uses inter-sample genetic variability to assign reads to isolates, which obviates the need for molecular barcoding. Thus, Ultraplexing can enable significant sequencing and labor cost reductions in large-scale bacterial genome projects.
MeSH term(s)	Genome, Bacterial ; High-Throughput Nucleotide Sequencing ; Humans ; Nanopore Sequencing/methods ; Plasmids/genetics ; Staphylococcus aureus/genetics ; Staphylococcus aureus/isolation & purification
Language	English
Publishing date	2020-03-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-020-01974-9
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Article ; Online: RNA transcription and degradation of Alu retrotransposons depends on sequence features and evolutionary history.

Baar, Till / Dümcke, Sebastian / Gressel, Saskia / Schwalb, Björn / Dilthey, Alexander / Cramer, Patrick / Tresch, Achim

G3 (Bethesda, Md.)

2022 Volume 12, Issue 5

Abstract: Alu elements are one of the most successful groups of RNA retrotransposons and make up 11% of the human genome with over 1 million individual loci. They are linked to genetic defects, increases in sequence diversity, and influence transcriptional ... ...

Abstract	Alu elements are one of the most successful groups of RNA retrotransposons and make up 11% of the human genome with over 1 million individual loci. They are linked to genetic defects, increases in sequence diversity, and influence transcriptional activity. Still, their RNA metabolism is poorly understood yet. It is even unclear whether Alu elements are mostly transcribed by RNA Polymerase II or III. We have conducted a transcription shutoff experiment by α-amanitin and metabolic RNA labeling by 4-thiouridine combined with RNA fragmentation (TT-seq) and RNA-seq to shed further light on the origin and life cycle of Alu transcripts. We find that Alu RNAs are more stable than previously thought and seem to originate in part from RNA Polymerase II activity, as previous reports suggest. Their expression however seems to be independent of the transcriptional activity of adjacent genes. Furthermore, we have developed a novel statistical test for detecting the expression of quantitative trait loci in Alu elements that relies on the de Bruijn graph representation of all Alu sequences. It controls for both statistical significance and biological relevance using a tuned k-mer representation, discovering influential sequence features missed by regular motif search. In addition, we discover several point mutations using a generalized linear model, and motifs of interest, which also match transcription factor-binding motifs.
MeSH term(s)	Alu Elements/genetics ; Humans ; RNA/genetics ; RNA Polymerase II/metabolism ; Retroelements/genetics ; Transcription, Genetic
Chemical Substances	Retroelements ; RNA (63231-63-0) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2022-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkac054
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Article: Characterisation of Type II DNA Methyltransferases of

Vogelgsang, Lars / Nisar, Azlan / Scharf, Sebastian Alexander / Rommerskirchen, Anna / Belick, Dana / Dilthey, Alexander / Henrich, Birgit

Microorganisms

2023 Volume 11, Issue 6

Abstract: Bacterial virulence, persistence and defence are affected by epigenetic modifications, including DNA methylation. Solitary DNA methyltransferases modulate a variety of cellular processes and influence bacterial virulence; as part of a restriction- ... ...

Abstract	Bacterial virulence, persistence and defence are affected by epigenetic modifications, including DNA methylation. Solitary DNA methyltransferases modulate a variety of cellular processes and influence bacterial virulence; as part of a restriction-modification (RM) system, they act as a primitive immune system in methylating the own DNA, while unmethylated foreign DNA is restricted. We identified a large family of type II DNA methyltransferases in
Language	English
Publishing date	2023-06-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms11061591
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