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Thesis ; Online: Multiscale Approaches to Complex Human Diseases

Beckmann, Noam D.

2018

Abstract: Elucidating the fundamental biological mechanisms underlying complex diseases remains, to date, a challenging task. Genetic approaches have been used to implicate genes and pathways in disease, but classical (reverse) and population (forward) genetic ... ...

Abstract	Elucidating the fundamental biological mechanisms underlying complex diseases remains, to date, a challenging task. Genetic approaches have been used to implicate genes and pathways in disease, but classical (reverse) and population (forward) genetic approaches have fallen short of bringing new understanding to multi-factorial disorders. With the emergence of rapidly advancing, new technologies and the dramatic reduction of their costs, new algorithms and analytical models that maximally leverage the data these technologies generate, are being developed to uncover novel biological insights for complex traits. Furthermore, the integration of multiple strata of biological information permits the creation of better representations of disease. This thesis aims to leverage some of these models on novel multi-scale datasets to explore the mechanisms of Alzheimer’s disease and the variability of induced pluripotent stem cells.
Keywords	Genetics\|Systematic biology\|Bioinformatics
Language	ENG
Publishing date	2018-01-01 00:00:01.0
Publisher	Icahn School of Medicine at Mount Sinai
Publishing country	us
Document type	Thesis ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.

Pan, Allen L / Audrain, Mickael / Sakakibara, Emmy / Joshi, Rajeev / Zhu, Xiaodong / Wang, Qian / Wang, Minghui / Beckmann, Noam D / Schadt, Eric E / Gandy, Sam / Zhang, Bin / Ehrlich, Michelle E / Salton, Stephen R

bioRxiv : the preprint server for biology

2023

Abstract: Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical ... ...

Abstract	Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. Methods: AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis. Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß Conclusions: In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.24.554335
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Article ; Online: Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

Cells

2022 Volume 11, Issue 23

Abstract: Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged ... ...

Abstract	Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on
MeSH term(s)	Animals ; Female ; Male ; Mice ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hippocampus/metabolism ; Protein Tyrosine Phosphatases/genetics ; Learning
Chemical Substances	Amyloid beta-Peptides ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MKP2 protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2022-12-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11233880
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.

Cervia-Hasler, Carlo / Brüningk, Sarah C / Hoch, Tobias / Fan, Bowen / Muzio, Giulia / Thompson, Ryan C / Ceglarek, Laura / Meledin, Roman / Westermann, Patrick / Emmenegger, Marc / Taeschler, Patrick / Zurbuchen, Yves / Pons, Michele / Menges, Dominik / Ballouz, Tala / Cervia-Hasler, Sara / Adamo, Sarah / Merad, Miriam / Charney, Alexander W /

Puhan, Milo / Brodin, Petter / Nilsson, Jakob / Aguzzi, Adriano / Raeber, Miro E / Messner, Christoph B / Beckmann, Noam D / Borgwardt, Karsten / Boyman, Onur

Science (New York, N.Y.)

2024 Volume 383, Issue 6680, Page(s) eadg7942

Abstract: Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of > ...

Abstract	Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.
MeSH term(s)	Humans ; Complement Activation ; Complement System Proteins/analysis ; Complement System Proteins/metabolism ; Post-Acute COVID-19 Syndrome/blood ; Post-Acute COVID-19 Syndrome/complications ; Post-Acute COVID-19 Syndrome/immunology ; Thromboinflammation/blood ; Thromboinflammation/immunology ; Biomarkers/blood ; Proteome ; Proteomics ; Male ; Female ; Young Adult ; Adult ; Middle Aged ; Aged
Chemical Substances	Complement System Proteins (9007-36-7) ; Biomarkers ; Proteome
Language	English
Publishing date	2024-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.adg7942
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Article ; Online: Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity.

Cell stem cell

2022 Volume 29, Issue 10, Page(s) 1505

Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2022.08.011
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Article ; Online: Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Gruber, Conor N / Patel, Roosheel S / Trachtman, Rebecca / Lepow, Lauren / Amanat, Fatima / Krammer, Florian / Wilson, Karen M / Onel, Kenan / Geanon, Daniel / Tuballes, Kevin / Patel, Manishkumar / Mouskas, Konstantinos / O'Donnell, Timothy / Merritt, Elliot / Simons, Nicole W / Barcessat, Vanessa / Del Valle, Diane M / Udondem, Samantha / Kang, Gurpawan /

Agashe, Charuta / Karekar, Neha / Grabowska, Joanna / Nie, Kai / Le Berichel, Jessica / Xie, Hui / Beckmann, Noam / Gangadharan, Sandeep / Ofori-Amanfo, George / Laserson, Uri / Rahman, Adeeb / Kim-Schulze, Seunghee / Charney, Alexander W / Gnjatic, Sacha / Gelb, Bruce D / Merad, Miriam / Bogunovic, Dusan

Cell

2023 Volume 186, Issue 15, Page(s) 3325

Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Published Erratum
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.06.012
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Article ; Online: Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females

Allen L. Pan / Mickael Audrain / Emmy Sakakibara / Rajeev Joshi / Xiaodong Zhu / Qian Wang / Minghui Wang / Noam D. Beckmann / Eric E. Schadt / Sam Gandy / Bin Zhang / Michelle E. Ehrlich / Stephen R. Salton

Cells, Vol 11, Iss 3880, p

2022 Volume 3880

Abstract: Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity ... ...

Abstract	Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 ( DUSP4 ) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF , is downregulated in postmortem Alzheimer’s disease (AD) brains. We investigated the roles that this VGF / DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12–18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.
Keywords	Alzheimer’s disease ; dual-specificity protein phosphatase 4 ; disease-associated microglia ; mitogen-activated protein kinase ; neuroinflammation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: FLAIRR-Seq: A Method for Single-Molecule Resolution of Near Full-Length Antibody H Chain Repertoires.

Ford, Easton E / Tieri, David / Rodriguez, Oscar L / Francoeur, Nancy J / Soto, Juan / Kos, Justin T / Peres, Ayelet / Gibson, William S / Silver, Catherine A / Deikus, Gintaras / Hudson, Elizabeth / Woolley, Cassandra R / Beckmann, Noam / Charney, Alexander / Mitchell, Thomas C / Yaari, Gur / Sebra, Robert P / Watson, Corey T / Smith, Melissa L

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 210, Issue 10, Page(s) 1607–1619

Abstract: ... transcripts. FLAIRR-seq was benchmarked by comparing H chain V (IGHV), D (IGHD), and J (IGHJ) gene usage ...

Abstract	Current Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using short-read sequencing strategies resolve expressed Ab transcripts with limited resolution of the C region. In this article, we present the near-full-length AIRR-seq (FLAIRR-seq) method that uses targeted amplification by 5' RACE, combined with single-molecule, real-time sequencing to generate highly accurate (99.99%) human Ab H chain transcripts. FLAIRR-seq was benchmarked by comparing H chain V (IGHV), D (IGHD), and J (IGHJ) gene usage, complementarity-determining region 3 length, and somatic hypermutation to matched datasets generated with standard 5' RACE AIRR-seq using short-read sequencing and full-length isoform sequencing. Together, these data demonstrate robust FLAIRR-seq performance using RNA samples derived from PBMCs, purified B cells, and whole blood, which recapitulated results generated by commonly used methods, while additionally resolving H chain gene features not documented in IMGT at the time of submission. FLAIRR-seq data provide, for the first time, to our knowledge, simultaneous single-molecule characterization of IGHV, IGHD, IGHJ, and IGHC region genes and alleles, allele-resolved subisotype definition, and high-resolution identification of class switch recombination within a clonal lineage. In conjunction with genomic sequencing and genotyping of IGHC genes, FLAIRR-seq of the IgM and IgG repertoires from 10 individuals resulted in the identification of 32 unique IGHC alleles, 28 (87%) of which were previously uncharacterized. Together, these data demonstrate the capabilities of FLAIRR-seq to characterize IGHV, IGHD, IGHJ, and IGHC gene diversity for the most comprehensive view of bulk-expressed Ab repertoires to date.
MeSH term(s)	Humans ; Complementarity Determining Regions/genetics ; Base Sequence
Chemical Substances	Complementarity Determining Regions
Language	English
Publishing date	2023-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200825
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Article: A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses.

medRxiv : the preprint server for health sciences

2021

Language	English
Publishing date	2021-02-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.01.29.21250755
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A study of gene expression in the living human brain.

Liharska, Lora E / Park, You Jeong / Ziafat, Kimia / Wilkins, Lillian / Silk, Hannah / Linares, Lisa M / Vornholt, Eric / Sullivan, Brendan / Cohen, Vanessa / Kota, Prashant / Feng, Claudia / Cheng, Esther / Moya, Emily / Thompson, Ryan C / Johnson, Jessica S / Rieder, Marysia-Kolbe / Huang, Jia / Scarpa, Joseph / Hashemi, Alice /

Polanco, Jairo / Levin, Matthew A / Nadkarni, Girish N / Sebra, Robert / Crary, John / Schadt, Eric E / Beckmann, Noam D / Kopell, Brian H / Charney, Alexander W

medRxiv : the preprint server for health sciences

2023

Abstract: A goal of medical research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through observational studies of gene expression in human brain tissue. Due to the unavailability of brain tissue from ... ...

Abstract	A goal of medical research is to determine the molecular basis of human brain health and illness. One way to achieve this goal is through observational studies of gene expression in human brain tissue. Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain donors. An assumption underlying this practice is that gene expression in the postmortem human brain is an accurate representation of gene expression in the living human brain. Here, this assumption - which, until now, had not been adequately tested - is tested by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Expression levels differed significantly for nearly 80% of genes, and a systematic examination of alternative explanations for this observation determined that these differences are not a consequence of cell type composition, RNA quality, postmortem interval, age, medication, morbidity, symptom severity, tissue pathology, sample handling, batch effects, or computational methods utilized. Analyses integrating the data generated for this study with data from earlier landmark studies that used tissue from postmortem brain donors showed that postmortem brain gene expression signatures of neurological and mental illnesses, as well as of normal traits such as aging, may not be accurate representations of these gene expression signatures in the living brain. By using tissue from large cohorts living people, future observational studies of human brain biology have the potential to (1) determine the medical research questions that can be addressed using postmortem tissue as a proxy for living tissue and (2) expand the scope of medical research to include questions about the molecular basis of human brain health and illness that can only be addressed in living people (e.g., "What happens at the molecular level in the brain as a person experiences an emotion?").
Language	English
Publishing date	2023-08-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.21.23288916
Database	MEDical Literature Analysis and Retrieval System OnLINE

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