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Article ; Online: Sutton's Law.

Kleinman, Joel E / Hyde, Thomas M

2023 Volume 180, Issue 7, Page(s) 465–466

Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Editorial
ZDB-ID	280045-7
ISSN	1535-7228 ; 0002-953X
ISSN (online)	1535-7228
ISSN	0002-953X
DOI	10.1176/appi.ajp.20230403
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Article: Brain donation at autopsy: clinical characterization and toxicologic analyses.

Mighdoll, Michelle I / Hyde, Thomas M

Handbook of clinical neurology

2018 Volume 150, Page(s) 143–154

Abstract: The study of postmortem human brain tissue is central to the advancement of neurobiologic studies of psychiatric and neurologic illnesses, particularly the study of brain-specific isoforms and molecules. Due to tissue demands, especially pertaining to ... ...

Abstract	The study of postmortem human brain tissue is central to the advancement of neurobiologic studies of psychiatric and neurologic illnesses, particularly the study of brain-specific isoforms and molecules. Due to tissue demands, especially pertaining to brain regions strongly implicated in the pathophysiology of neuropsychiatric disorders, the success and future of this research depend on the availability of high-quality brain specimens from large numbers of subjects, including nonpsychiatric controls, both of which may be obtained from brain banks. In this chapter, we elaborate on the need for and acquisition of well-curated and properly diagnosed postmortem human brains, relying upon our experience with the Human Brain and Tissue Repository located at the Lieber Institute for Brain Development in Baltimore, MD. We explain the advantages of sourcing postmortem human tissue from medical examiner offices, which provide access to cases of all ages, both with and without central nervous system disorders. Neuropathology analyses and toxicologic screenings, along with autopsy reports and extensive interviews with family members and treating physicians, are invaluable to the diagnoses of postmortem cases. Ultimately, the study of psychiatric and neurologic disorders is the study of brain disease, and accordingly, there is no substitution for human brain tissue.
MeSH term(s)	Autopsy/methods ; Brain/pathology ; Brain Diseases/diagnosis ; Humans ; Tissue Banks ; Tissue Donors
Language	English
Publishing date	2018
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-444-63639-3.00011-6
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Article ; Online: Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue.

Türker, Fulya / Bharadwaj, Rahul A / Kleinman, Joel E / Weinberger, Daniel R / Hyde, Thomas M / White, Cory J / Williams, Dionna W / Margolis, Seth S

The Journal of biological chemistry

2023 Volume 299, Issue 6, Page(s) 104811

Abstract: Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally ... ...

Abstract	Proteasomes are large macromolecular complexes with multiple distinct catalytic activities that are each vital to human brain health and disease. Despite their importance, standardized approaches to investigate proteasomes have not been universally adapted. Here, we describe pitfalls and define straightforward orthogonal biochemical approaches essential to measure and understand changes in proteasome composition and activity in the mammalian central nervous system. Through our experimentation in the mammalian brain, we determined an abundance of catalytically active proteasomes exist with and without a 19S cap(s), the regulatory particle essential for ubiquitin-dependent degradation. Moreover, we learned that in-cell measurements using activity-based probes (ABPs) are more sensitive in determining the available activity of the 20S proteasome without the 19S cap and in measuring individual catalytic subunit activities of each β subunit within all neuronal proteasomes. Subsequently, applying these tools to human brain samples, we were surprised to find that post-mortem tissue retained little to no 19S-capped proteasome, regardless of age, sex, or disease state. In comparing brain tissues (parahippocampal gyrus) from patients with Alzheimer's disease (AD) and unaffected individuals, the available 20S proteasome activity was significantly elevated in severe cases of AD, an observation not previously noted. Taken together, our study establishes standardized approaches for the comprehensive investigation of proteasomes in mammalian brain tissue, and we reveal new insight into brain proteasome biology.
MeSH term(s)	Animals ; Humans ; Brain/metabolism ; Cytoplasm/metabolism ; Mammals/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis
Chemical Substances	Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2023-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104811
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Article: Benchmark of cellular deconvolution methods using a multi-assay reference dataset from postmortem human prefrontal cortex.

Huuki-Myers, Louise A / Montgomery, Kelsey D / Kwon, Sang Ho / Cinquemani, Sophia / Eagles, Nicholas J / Gonzalez-Padilla, Daianna / Maden, Sean K / Kleinman, Joel E / Hyde, Thomas M / Hicks, Stephanie C / Maynard, Kristen R / Collado-Torres, Leonardo

bioRxiv : the preprint server for biology

2024

Abstract: Background: Cellular deconvolution of bulk RNA-sequencing (RNA-seq) data using single cell or nuclei RNA-seq (sc/snRNA-seq) reference data is an important strategy for estimating cell type composition in heterogeneous tissues, such as human brain. ... ...

Abstract	Background: Cellular deconvolution of bulk RNA-sequencing (RNA-seq) data using single cell or nuclei RNA-seq (sc/snRNA-seq) reference data is an important strategy for estimating cell type composition in heterogeneous tissues, such as human brain. Computational methods for deconvolution have been developed and benchmarked against simulated data, pseudobulked sc/snRNA-seq data, or immunohistochemistry reference data. A major limitation in developing improved deconvolution algorithms has been the lack of integrated datasets with orthogonal measurements of gene expression and estimates of cell type proportions on the same tissue sample. Deconvolution algorithm performance has not yet been evaluated across different RNA extraction methods (cytosolic, nuclear, or whole cell RNA), different library preparation types (mRNA enrichment vs. ribosomal RNA depletion), or with matched single cell reference datasets. Results: A rich multi-assay dataset was generated in postmortem human dorsolateral prefrontal cortex (DLPFC) from 22 tissue blocks. Assays included spatially-resolved transcriptomics, snRNA-seq, bulk RNA-seq (across six library/extraction RNA-seq combinations), and RNAScope/Immunofluorescence (RNAScope/IF) for six broad cell types. The Conclusions: Bisque
Language	English
Publishing date	2024-04-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.09.579665
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Article: scMeFormer: a transformer-based deep learning model for imputing DNA methylation states in single cells enhances the detection of epigenetic alterations in schizophrenia.

Zhou, Jiyun / Luo, Chongyuan / Liu, Hanqing / Heffel, Matthew G / Straub, Richard E / Kleinman, Joel E / Hyde, Thomas M / Ecker, Joseph R / Weinberger, Daniel R / Han, Shizhong

bioRxiv : the preprint server for biology

2024

Abstract: DNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual ... ...

Abstract	DNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual cells, but they often suffer from limited coverage of CpG sites. In this study, we introduce scMeFormer, a transformer-based deep learning model designed to impute DNAm states for each CpG site in single cells. Through comprehensive evaluations, we demonstrate the superior performance of scMeFormer compared to alternative models across four single-nucleus DNAm datasets generated by distinct technologies. Remarkably, scMeFormer exhibits high-fidelity imputation, even when dealing with significantly reduced coverage, as low as 10% of the original CpG sites. Furthermore, we applied scMeFormer to a single-nucleus DNAm dataset generated from the prefrontal cortex of four schizophrenia patients and four neurotypical controls. This enabled the identification of thousands of differentially methylated regions associated with schizophrenia that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia within specific cell types. Our study highlights the power of deep learning in imputing DNAm states in single cells, and we expect scMeFormer to be a valuable tool for single-cell DNAm studies.
Language	English
Publishing date	2024-01-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.25.577200
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Article ; Online: Molecular mechanisms and timing of cortical immune activation in schizophrenia.

Hyde, Thomas M / Bharadwaj, Rahul A

The American journal of psychiatry

2015 Volume 172, Issue 11, Page(s) 1052–1053

MeSH term(s)	Animals ; Female ; Humans ; Male ; Prefrontal Cortex/immunology ; Pregnancy ; RNA, Messenger/immunology ; Schizophrenia/immunology
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2015-11-01
Publishing country	United States
Document type	Comment ; Editorial
ZDB-ID	280045-7
ISSN	1535-7228 ; 0002-953X
ISSN (online)	1535-7228
ISSN	0002-953X
DOI	10.1176/appi.ajp.2015.15091187
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Article ; Online: The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics.

Weber, Lukas M / Divecha, Heena R / Tran, Matthew N / Kwon, Sang Ho / Spangler, Abby / Montgomery, Kelsey D / Tippani, Madhavi / Bharadwaj, Rahul / Kleinman, Joel E / Page, Stephanie C / Hyde, Thomas M / Collado-Torres, Leonardo / Maynard, Kristen R / Martinowich, Keri / Hicks, Stephanie C

eLife

2024 Volume 12

Abstract: Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. ... ...

Abstract	Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer's and Parkinson's disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.
MeSH term(s)	Humans ; Locus Coeruleus ; Solitary Nucleus ; Gene Expression Profiling ; Central Nervous System ; Norepinephrine ; Gene Expression
Chemical Substances	Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2024-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.84628
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Article: Comparison of gene expression in living and postmortem human brain.

Collado-Torres, Leonardo / Klei, Lambertus / Liu, Chunyu / Kleinman, Joel E / Hyde, Thomas M / Geschwind, Daniel H / Gandal, Michael J / Devlin, Bernie / Weinberger, Daniel R

medRxiv : the preprint server for health sciences

2023

Abstract: Molecular mechanisms of neuropsychiatric disorders are challenging to study in human brain. For decades, the preferred model has been to study postmortem human brain samples despite the limitations they entail. A recent study generated RNA sequencing ... ...

Abstract	Molecular mechanisms of neuropsychiatric disorders are challenging to study in human brain. For decades, the preferred model has been to study postmortem human brain samples despite the limitations they entail. A recent study generated RNA sequencing data from biopsies of prefrontal cortex from living patients with Parkinson's Disease and compared gene expression to postmortem tissue samples, from which they found vast differences between the two. This led the authors to question the utility of postmortem human brain studies. Through re-analysis of the same data, we unexpectedly found that the living brain tissue samples were of much lower quality than the postmortem samples across multiple standard metrics. We also performed simulations that illustrate the effects of ignoring RNA degradation in differential gene expression analyses, showing the effects can be substantial and of similar magnitude to what the authors find. For these reasons, we believe the authors' conclusions are unjustified. To the contrary, while opportunities to study gene expression in the living brain are welcome, evidence that this eclipses the value of postmortem analyses is not apparent.
Language	English
Publishing date	2023-11-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.08.23298172
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Article ; Online: Investigating trait variability of gene co-expression network architecture in brain by controlling for genomic risk of schizophrenia.

Radulescu, Eugenia / Chen, Qiang / Pergola, Giulio / Di Carlo, Pasquale / Han, Shizhong / Shin, Joo Heon / Hyde, Thomas M / Kleinman, Joel E / Weinberger, Daniel R

PLoS genetics

2023 Volume 19, Issue 10, Page(s) e1010989

Abstract: The effect of schizophrenia (SCZ) genetic risk on gene expression in brain remains elusive. A popular approach to this problem has been the application of gene co-expression network algorithms (e.g., WGCNA). To improve reliability with this method it is ... ...

Abstract	The effect of schizophrenia (SCZ) genetic risk on gene expression in brain remains elusive. A popular approach to this problem has been the application of gene co-expression network algorithms (e.g., WGCNA). To improve reliability with this method it is critical to remove unwanted sources of variance while also preserving biological signals of interest. In this WCGNA study of RNA-Seq data from postmortem prefrontal cortex (78 neurotypical donors, EUR ancestry), we tested the effects of SCZ genetic risk on co-expression networks. Specifically, we implemented a novel design in which gene expression was adjusted by linear regression models to preserve or remove variance explained by biological signal of interest (GWAS genomic scores for SCZ risk-(GS-SCZ), and genomic scores- GS of height (GS-Ht) as a negative control), while removing variance explained by covariates of non-interest. We calculated co-expression networks from adjusted expression (GS-SCZ and GS-Ht preserved or removed), and consensus between them (representative of a "background" network free of genomic scores effects). We then tested the overlap between GS-SCZ preserved modules and background networks reasoning that modules with reduced overlap would be most affected by GS-SCZ biology. Additionally, we tested these modules for convergence of SCZ risk (i.e., enrichment in PGC3 SCZ GWAS priority genes, enrichment in SCZ risk heritability and relevant biological ontologies. Our results highlight key aspects of GS-SCZ effects on brain co-expression networks, specifically: 1) preserving/removing SCZ genetic risk alters the co-expression modules; 2) biological pathways enriched in modules affected by GS-SCZ implicate processes of transcription, translation and metabolism that converge to influence synaptic transmission; 3) priority PGC3 SCZ GWAS genes and SCZ risk heritability are enriched in modules associated with GS-SCZ effects. Overall, our results indicate that gene co-expression networks that selectively integrate information about genetic risk can reveal novel combinations of biological pathways involved in schizophrenia.
MeSH term(s)	Humans ; Schizophrenia/genetics ; Reproducibility of Results ; Genetic Predisposition to Disease ; Brain/metabolism ; Genomics ; Genome-Wide Association Study
Language	English
Publishing date	2023-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010989
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Article: Chronic traumatic encephalopathy neuropathologic change is uncommon in men who played amateur American football.

Iverson, Grant L / Jamshidi, Pouya / Fisher-Hubbard, Amanda O / Deep-Soboslay, Amy / Hyde, Thomas M / Kleinman, Joel E / deJong, Joyce L / Shepherd, Claire E / Hazrati, Lili-Naz / Castellani, Rudolph J

Frontiers in neurology

2023 Volume 14, Page(s) 1143882

Abstract: Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football ... ...

Abstract	Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football during their youth would be more likely to have CTE-NC than those who did not play contact or collision sports, and (iii) there would be no association between CTE-NC and suicide as a manner of death. Methods: Brain tissue from 186 men and accompanying clinical information were obtained from the Lieber Institute for Brain Development. Manner of death was determined by a board-certified forensic pathologist. Information was obtained from next of kin telephone interviews, including medical, social, demographic, family, and psychiatric history. The 2016 and 2021 consensus definitions were used for CTE-NC. Two authors screened all cases, using liberal criteria for identifying "possible" CTE-NC, and five authors examined the 15 selected cases. Results: The median age at the time of death was 65 years (interquartile range = 57-75; range = 50-96). There were 25.8% with a history of playing American football and 36.0% who had suicide as their manner of death. No case was rated as definitively having "features" of CTE-NC by all five authors. Ten cases were rated as having features of CTE-NC by three or more authors (5.4% of the sample), including 8.3% of those with a personal history of playing American football and 3.9% of those who did not play contact or collision sports. Of those with mood disorders during life, 5.5% had features of CTE-NC compared to 6.0% of those who did not have a reported mood disorder. Of those with suicide as a manner of death, 6.0% had features of CTE-NC compared to 5.0% of those who did not have suicide as a manner of death. Discussion: We did not identify a single definitive case of CTE-NC, from the perspective of all raters, and only 5.4% of cases were identified as having possible features of CTE-NC by some raters. CTE-NC was very uncommon in men who played amateur American football, those with mood disorders during life, and those with suicide as a manner of death.
Language	English
Publishing date	2023-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2023.1143882
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