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Article ; Online: The National PTSD Brain Bank: Progress, Promise, and Vision.

Labadorf, Adam

2022 Volume 85, Issue 2, Page(s) 196–200

MeSH term(s)	Brain ; Humans ; Stress Disorders, Post-Traumatic
Language	English
Publishing date	2022-05-19
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	209433-2
ISSN	1943-281X ; 0033-2747
ISSN (online)	1943-281X
ISSN	0033-2747
DOI	10.1080/00332747.2022.2068936
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Article ; Online: Single molecule, long-read Apoer2 sequencing identifies conserved and species-specific splicing patterns.

Gallo, Christina M / Labadorf, Adam T / Ho, Angela / Beffert, Uwe

Genomics

2022 Volume 114, Issue 2, Page(s) 110318

Abstract: Apolipoprotein E receptor 2 (Apoer2) is a synaptic receptor in the brain that binds disease-relevant ligand Apolipoprotein E (Apoe) and is highly alternatively spliced. We examined alternative splicing (AS) of conserved Apoer2 exons across vertebrate ... ...

Abstract	Apolipoprotein E receptor 2 (Apoer2) is a synaptic receptor in the brain that binds disease-relevant ligand Apolipoprotein E (Apoe) and is highly alternatively spliced. We examined alternative splicing (AS) of conserved Apoer2 exons across vertebrate species and identified gain of exons in mammals encoding functional domains such as the cytoplasmic and furin inserts, and loss of an exon in primates encoding the eighth LDLa repeat, likely altering receptor surface levels and ligand-binding specificity. We utilized single molecule, long-read RNA sequencing to profile full-length Apoer2 isoforms and identified 68 and 48 unique full-length Apoer2 transcripts in the mouse and human cerebral cortex, respectively. Furthermore, we identified two exons encoding protein functional domains, the third EGF-precursor like repeat and glycosylation domain, that are tandemly skipped specifically in mouse. Our study provides new insight into Apoer2 isoform complexity in the vertebrate brain and highlights species-specific differences in splicing decisions that support functional diversity.
MeSH term(s)	Alternative Splicing ; Animals ; Humans ; LDL-Receptor Related Proteins/genetics ; Mammals ; Mice ; Protein Structure, Tertiary ; RNA Splicing
Chemical Substances	LDL-Receptor Related Proteins ; low density lipoprotein receptor-related protein 8
Language	English
Publishing date	2022-02-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2022.110318
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Article: Single molecule, long-read Apoer2 sequencing identifies conserved and species-specific splicing patterns

Gallo, Christina M. / Labadorf, Adam T. / Ho, Angela / Beffert, Uwe

Genomics. 2022 Mar., v. 114, no. 2

2022

Abstract	Apolipoprotein E receptor 2 (Apoer2) is a synaptic receptor in the brain that binds disease-relevant ligand Apolipoprotein E (Apoe) and is highly alternatively spliced. We examined alternative splicing (AS) of conserved Apoer2 exons across vertebrate species and identified gain of exons in mammals encoding functional domains such as the cytoplasmic and furin inserts, and loss of an exon in primates encoding the eighth LDLa repeat, likely altering receptor surface levels and ligand-binding specificity. We utilized single molecule, long-read RNA sequencing to profile full-length Apoer2 isoforms and identified 68 and 48 unique full-length Apoer2 transcripts in the mouse and human cerebral cortex, respectively. Furthermore, we identified two exons encoding protein functional domains, the third EGF-precursor like repeat and glycosylation domain, that are tandemly skipped specifically in mouse. Our study provides new insight into Apoer2 isoform complexity in the vertebrate brain and highlights species-specific differences in splicing decisions that support functional diversity.
Keywords	apolipoprotein E ; cerebral cortex ; exons ; functional diversity ; genomics ; glycosylation ; humans ; ligands ; mice ; neurotransmitter receptors
Language	English
Dates of publication	2022-03
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1016/j.ygeno.2022.110318
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Article ; Online: Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain.

Labadorf, Adam / Agus, Filisia / Aytan, Nurgul / Cherry, Jonathan / Mez, Jesse / McKee, Ann / Stein, Thor D

BMC medical genomics

2023 Volume 16, Issue 1, Page(s) 49

Abstract: Background: Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau ...

Abstract	Background: Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. Methods: To address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. Results: Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. Conclusions: Together, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.
MeSH term(s)	Humans ; Chronic Traumatic Encephalopathy/genetics ; Chronic Traumatic Encephalopathy/metabolism ; Chronic Traumatic Encephalopathy/pathology ; tau Proteins/genetics ; tau Proteins/metabolism ; Brain/metabolism ; Inflammation/metabolism ; Transcriptome ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics
Chemical Substances	tau Proteins ; TMEM106B protein, human ; Membrane Proteins ; Nerve Tissue Proteins
Language	English
Publishing date	2023-03-09
Publishing country	England
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	2411865-5
ISSN	1755-8794 ; 1755-8794
ISSN (online)	1755-8794
ISSN	1755-8794
DOI	10.1186/s12920-023-01471-5
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Article ; Online: Publisher Correction: Prediction of genome-wide effects of single nucleotide variants on transcription factor binding.

Carrasco Pro, Sebastian / Bulekova, Katia / Gregor, Brian / Labadorf, Adam / Fuxman Bass, Juan Ignacio

Scientific reports

2021 Volume 11, Issue 1, Page(s) 3395

Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-83094-3
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Article: Evidence for a Pan-Neurodegenerative Disease Response in Huntington's and Parkinson's Disease Expression Profiles.

Labadorf, Adam / Choi, Seung H / Myers, Richard H

Frontiers in molecular neuroscience

2018 Volume 10, Page(s) 430

Abstract: Huntington's and Parkinson's Diseases (HD and PD) are neurodegenerative disorders that share some pathological features but are disparate in others. For example, while both diseases are marked by aberrant protein aggregation in the brain, the specific ... ...

Abstract	Huntington's and Parkinson's Diseases (HD and PD) are neurodegenerative disorders that share some pathological features but are disparate in others. For example, while both diseases are marked by aberrant protein aggregation in the brain, the specific proteins that aggregate and types of neurons affected differ. A better understanding of the molecular similarities and differences between these two diseases may lead to a more complete mechanistic picture of both the individual diseases and the neurodegenerative process in general. We sought to characterize the common transcriptional signature of HD and PD as well as genes uniquely implicated in each of these diseases using mRNA-Seq data from post mortem human brains in comparison to neuropathologically normal controls. The enriched biological pathways implicated by HD differentially expressed genes show remarkable consistency with those for PD differentially expressed genes and implicate the common biological processes of neuroinflammation, apoptosis, transcriptional dysregulation, and neuron-associated functions. Comparison of the differentially expressed (DE) genes highlights a set of consistently altered genes that span both diseases. In particular, processes involving nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and transcription factor cAMP response element-binding protein (CREB) are the most prominent among the genes common to HD and PD. When the combined HD and PD data are compared to controls, relatively few additional biological processes emerge as significantly enriched, suggesting that most pathways are independently seen within each disorder. Despite showing comparable numbers of DE genes, DE genes unique to HD are enriched in far more coherent biological processes than the DE genes unique to PD, suggesting that PD may represent a more heterogeneous disorder. The complexity of the biological processes implicated by this analysis provides impetus for the development of better experimental models to validate the results.
Language	English
Publishing date	2018-01-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2017.00430
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Article ; Online: Evidence of Extensive Alternative Splicing in Post Mortem Human Brain HTT Transcription by mRNA Sequencing.

Labadorf, Adam T / Myers, Richard H

PloS one

2015 Volume 10, Issue 10, Page(s) e0141298

Abstract: Despite 20 years since its discovery, the gene responsible for Huntington's Disease, HTT, has still not had its function or transcriptional profile completely characterized. In response to a recent report by Ruzo et al. of several novel splice forms of ... ...

Abstract	Despite 20 years since its discovery, the gene responsible for Huntington's Disease, HTT, has still not had its function or transcriptional profile completely characterized. In response to a recent report by Ruzo et al. of several novel splice forms of HTT in human embryonic stem cell lines, we have analyzed a set of mRNA sequencing datasets from post mortem human brain from Huntington's disease, Parkinson's disease, and neurologically normal control subjects to evaluate support for previously observed and to identify novel splice patterns. A custom analysis pipeline produced supporting evidence for some of the results reported by two previous studies of alternative isoforms as well as identifying previously unreported splice patterns. All of the alternative splice patterns were of relatively low abundance compared to the canonical splice form.
MeSH term(s)	Alternative Splicing ; Brain/metabolism ; Case-Control Studies ; Exons ; Humans ; Huntingtin Protein ; Huntington Disease/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Sequence Analysis, RNA ; Transcription, Genetic
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; Protein Isoforms ; RNA, Messenger
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0141298
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Functional genome-wide short hairpin RNA library screening identifies key molecules for extracellular vesicle secretion from microglia.

Ruan, Zhi / Takamatsu-Yukawa, Kayo / Wang, Yuzhi / Ushman, Margaret L / Labadorf, Adam Thomas / Ericsson, Maria / Ikezu, Seiko / Ikezu, Tsuneya

Cell reports

2022 Volume 39, Issue 6, Page(s) 110791

Abstract: Activated microglia release extracellular vesicles (EVs) as modulators of brain homeostasis and innate immunity. However, the molecules critical for regulating EV production from microglia are poorly understood. Here we establish a murine microglial cell ...

Abstract	Activated microglia release extracellular vesicles (EVs) as modulators of brain homeostasis and innate immunity. However, the molecules critical for regulating EV production from microglia are poorly understood. Here we establish a murine microglial cell model to monitor EV secretion by measuring the fluorescence signal of tdTomato, which is linked to tetraspanin CD63. Stimulation of tdTomato
MeSH term(s)	Adenosine Triphosphate ; Animals ; Extracellular Vesicles ; Lipopolysaccharides/pharmacology ; Mice ; Microglia ; RNA, Small Interfering
Chemical Substances	Lipopolysaccharides ; RNA, Small Interfering ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110791
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Article ; Online: The caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal Huntington's disease brain.

Agus, Filisia / Crespo, Diego / Myers, Richard H / Labadorf, Adam

BMC medical genomics

2019 Volume 12, Issue 1, Page(s) 137

Abstract: Background: The mechanisms underlying neurodegeneration in the striatum of Huntingon's Disease (HD) brain are currently unknown. While the striatum is massively degenerated in symptomatic individuals, which makes cellular characterization difficult, it ... ...

Abstract	Background: The mechanisms underlying neurodegeneration in the striatum of Huntingon's Disease (HD) brain are currently unknown. While the striatum is massively degenerated in symptomatic individuals, which makes cellular characterization difficult, it is largely intact in asymptomatic HD gene positive (HD+) individuals. Unfortunately, as striatal tissue samples from HD+ individuals are exceedingly rare, recent focus has been on the Brodmann Area 9 (BA9), a relatively unaffected region, as a surrogate tissue. In this study, we analyze gene expression in caudate nucleus (CAU) from two HD+ individuals and compare the results with healthy and symptomatic HD brains. Methods: High-throughput mRNA sequencing (mRNA-Seq) datasets were generated from post-mortem CAU of 2 asymptomatic HD+ individuals and compared with 26 HD and 56 neurologically normal controls. Datasets were analyzed using a custom bioinformatic analysis pipeline to identify and interpret differentially expressed (DE) genes. Results were compared to publicly available brain mRNA-Seq datasets from the Genotype-Tissue Expression (GTEx) project. The analysis employed current state of the art bioinformatics tools and tailored statistical and machine learning methods. Results: The transcriptional profiles in HD+ CAU and HD BA9 samples are highly similar. Differentially expressed (DE) genes related to the heat shock response, particularly HSPA6 and HSPA1A, are common between regions. The most perturbed pathways show extensive agreement when comparing disease with control. A random forest classifier predicts that the two HD+ CAU samples strongly resemble HD BA9 and not control BA9. Nonetheless, when genes were prioritized by their specificity to HD+ CAU, pathways spanning many biological processes emerge. Comparison of HD+ BA9 with HD BA9 identified NPAS4 and REST1/2 as potential early responders to disease and reflect the active disease process. Conclusions: The caudate nucleus in HD brain is dramatically affected prior to symptom onset. Gene expression patterns observed in the HD BA9 are also present in the CAU, suggesting a common response to disease. Substantial caudate-specific differences implicate many different biological pathways including metabolism, protein folding, inflammation, and neurogenic processes. While these results are at best trends due to small sample sizes, these results nonetheless provide the most detailed insight to date into the primary HD disease process.
MeSH term(s)	Brain/metabolism ; Case-Control Studies ; Caudate Nucleus/metabolism ; Computational Biology/methods ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Huntington Disease/genetics ; Huntington Disease/pathology ; Sequence Analysis, RNA ; Transcription, Genetic
Language	English
Publishing date	2019-10-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-019-0581-9
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Article ; Online: The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Wu, Muzhou / Hanly, Ailish / Gibson, Frederick / Fisher, Robert / Rogers, Samantha / Park, Kihyun / Zuger, Angelina / Kuang, Kevin / Kalin, Jay H / Nocco, Sarah / Cole, Matthew / Xiao, Amy / Agus, Filisia / Labadorf, Adam / Beck, Samuel / Collard, Marianne / Cole, Philip A / Alani, Rhoda M

The Journal of clinical investigation

2024 Volume 134, Issue 6

Abstract: Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable ... ...

Abstract	Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.
MeSH term(s)	Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Co-Repressor Proteins/genetics ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; Protein Kinase Inhibitors/pharmacology ; Phenotype ; p38 Mitogen-Activated Protein Kinases
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Co-Repressor Proteins ; Protein Kinase Inhibitors ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI171063
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