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Article ; Online: Improved detection of measurable residual disease in acute myeloid leukemia.

Zhang, Xuan / Grimes, H Leighton

2023 Volume 9, Issue 38, Page(s) eadk2533

Abstract: A novel multiplex single-cell genomic and immunophenotypic strategy leverages the sensitivity of MRD detection and distinguishes leukemic and preleukemic subpopulations. ...

Abstract	A novel multiplex single-cell genomic and immunophenotypic strategy leverages the sensitivity of MRD detection and distinguishes leukemic and preleukemic subpopulations.
MeSH term(s)	Humans ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/genetics ; Genomics ; Immunophenotyping
Language	English
Publishing date	2023-09-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adk2533
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Article ; Online: pyInfinityFlow: optimized imputation and analysis of high-dimensional flow cytometry data for millions of cells.

Ferchen, Kyle / Salomonis, Nathan / Grimes, H Leighton

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 5

Abstract: Motivation: While conventional flow cytometry is limited to dozens of markers, new experimental and computational strategies, such as Infinity Flow, allow for the generation and imputation of hundreds of cell surface protein markers in millions of cells. ...

Abstract	Motivation: While conventional flow cytometry is limited to dozens of markers, new experimental and computational strategies, such as Infinity Flow, allow for the generation and imputation of hundreds of cell surface protein markers in millions of cells. Here, we describe an end-to-end analysis workflow for Infinity Flow data in Python. Results: pyInfinityFlow enables the efficient analysis of millions of cells, without down-sampling, through direct integration with well-established Python packages for single-cell genomics analysis. pyInfinityFlow accurately identifies both common and extremely rare cell populations which are challenging to define from single-cell genomics studies alone. We demonstrate that this workflow can nominate novel markers to design new flow cytometry gating strategies for predicted cell populations. pyInfinityFlow can be extended to diverse cell discovery analyses with flexibility to adapt to diverse Infinity Flow experimental designs. Availability and implementation: pyInfinityFlow is freely available in GitHub (https://github.com/KyleFerchen/pyInfinityFlow) and on PyPI (https://pypi.org/project/pyInfinityFlow/). Package documentation with tutorials on a test dataset is available by Read the Docs (pyinfinityflow.readthedocs.io). The scripts and data for reproducing the results are available at https://github.com/KyleFerchen/pyInfinityFlow/tree/main/analysis_scripts, along with the raw flow cytometry input data.
MeSH term(s)	Software ; Flow Cytometry ; Genomics ; Documentation
Language	English
Publishing date	2023-04-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad287
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Zs.A 2374: Show issues

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Article ; Online: A primer on single-cell genomics in myeloid biology.

Ferchen, Kyle / Song, Baobao / Leighton Grimes, H

Current opinion in hematology

2020 Volume 28, Issue 1, Page(s) 11–17

Abstract: Purpose of review: Understanding the fast-moving field of single-cell technologies, as applied to myeloid biology, requires an appreciation of basic molecular, informatics, and biological concepts. Here, we highlight both key and recent articles to ... ...

Abstract	Purpose of review: Understanding the fast-moving field of single-cell technologies, as applied to myeloid biology, requires an appreciation of basic molecular, informatics, and biological concepts. Here, we highlight both key and recent articles to illustrate basic concepts for those new to molecular single-cell analyses in myeloid hematology. Recent findings: Recent studies apply single-cell omics to discover novel cell populations, construct relationships between cell populations, reconfigure the organization of hematopoiesis, and study hematopoietic lineage tree and fate choices. Accompanying development of technologies, new informatic tools have emerged, providing exciting new insights. Summary: Hematopoietic stem and progenitor cells are regulated by complex intrinsic and extrinsic factors to produce blood cell types. In this review, we discuss recent advances in single-cell omics to profile these cells, methods to infer cell type identify, and trajectories from molecular omics data to ultimately derive new insights into hematopoietic stem and progenitor cell biology. We further discuss future applications of these technologies to understand hematopoietic cell interactions, function, and development. The goal is to offer a comprehensive overview of current single-cell technologies and their impact on our understanding of myeloid cell development for those new to single-cell analyses.
MeSH term(s)	Animals ; Cell Communication ; Genomics/methods ; Hematopoiesis ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Myeloid Cells/cytology ; Myeloid Cells/metabolism ; Single-Cell Analysis/methods
Language	English
Publishing date	2020-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000623
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Zs.A 3703: Show issues

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Article: Why Single-Cell Sequencing Has Promise in MDS.

Zhang, Xuan / Grimes, H Leighton

Frontiers in oncology

2021 Volume 11, Page(s) 769753

Abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis. The risk of MDS is associated with aging and the accumulation of somatic mutations in hematopoietic stem cells and progenitors (HSPC). While ...

Abstract	Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis. The risk of MDS is associated with aging and the accumulation of somatic mutations in hematopoietic stem cells and progenitors (HSPC). While advances in DNA sequencing in the past decade unveiled clonal selection driven by mutations in MDS, it is unclear at which stage the HSPCs are trapped or what prevents mature cells output. Single-cell-sequencing techniques in recent years have revolutionized our understanding of normal hematopoiesis by identifying the transitional cell states between classical hematopoietic hierarchy stages, and most importantly the biological activities behind cell differentiation and lineage commitment. Emerging studies have adapted these powerful tools to investigate normal hematopoiesis as well as the clonal heterogeneity in myeloid malignancies and provide a progressive description of disease pathogenesis. This review summarizes the potential of growing single-cell-sequencing techniques, the evolving efforts to elucidate hematopoiesis in physiological conditions and MDS at single-cell resolution, and discuss how they may fill the gaps in our current understanding of MDS biology.
Language	English
Publishing date	2021-12-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.769753
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Article ; Online: Decision level integration of unimodal and multimodal single cell data with scTriangulate.

Li, Guangyuan / Song, Baobao / Singh, Harinder / Surya Prasath, V B / Leighton Grimes, H / Salomonis, Nathan

Nature communications

2023 Volume 14, Issue 1, Page(s) 406

Abstract: Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a computational framework to mix-and-match multiple ... ...

Abstract	Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a computational framework to mix-and-match multiple clustering results, modalities, associated algorithms, and resolutions to achieve an optimal solution. Rather than ensemble approaches which select the "consensus", scTriangulate picks the most stable solution through coalitional iteration. When evaluated on diverse multimodal technologies, scTriangulate outperforms alternative approaches to identify high-confidence cell-populations and modality-specific subtypes. Unlike existing integration strategies that rely on modality-specific joint embedding or geometric graphs, scTriangulate makes no assumption about the distributions of raw underlying values. As a result, this approach can solve unprecedented integration challenges, including the ability to automate reference cell-atlas construction, resolve clonal architecture within molecularly defined cell-populations and subdivide clusters to discover splicing-defined disease subtypes. scTriangulate is a flexible strategy for unified integration of single-cell or multimodal clustering solutions, from nearly unlimited sources.
MeSH term(s)	Cluster Analysis ; Algorithms
Language	English
Publishing date	2023-01-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36016-y
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Article ; Online: Assay optimization for the objective quantification of human multilineage colony-forming units.

Thompson, Evrett N / Carlino, Maximillian J / Scanlon, Vanessa M / Grimes, H Leighton / Krause, Diane S

Experimental hematology

2023 Volume 124, Page(s) 36–44.e3

Abstract: Colony-forming unit (CFU) assays are a powerful tool in hematopoietic research because they allow researchers to functionally test the lineage potential of individual stem and progenitor cells. Assaying for lineage potential is important for determining ... ...

Abstract	Colony-forming unit (CFU) assays are a powerful tool in hematopoietic research because they allow researchers to functionally test the lineage potential of individual stem and progenitor cells. Assaying for lineage potential is important for determining and validating the identity of progenitor populations isolated by methods such as fluorescence-activated cell sorting (FACS). However, current methods for CFU assays are limited in their ability to robustly assay multipotent progenitors with the ability to differentiate down the myeloid, erythroid, and megakaryocytic lineages because of the lack of specific growth factors necessary for certain lineage outputs. In addition, manual counting of colony types is subjective resulting in user to user variability in assessments of cell types based on colony and cell morphologies. We demonstrate that the addition of granulocyte colony-stimulating factor (G-CSF), macrophage (M)-CSF, and granulocyte-macrophage (GM)-CSF into a collagen-based MegaCult medium containing IL-3, IL-6, SCF, EPO, and TPO allows for the differentiation of common myeloid progenitors into expected proportions of colonies containing granulocytic (G), monocytic (M), erythroid (E), and megakaryocytic (Mk) cells. Additionally, we demonstrate an objective method using in situ immunofluorescence (IF) with anti-CD66b, anti-CD14, anti-CD235a, and anti-CD41 to detect G, M, E, and Mk cells, respectively. IF stained colonies can be analyzed individually at a microscope or using high-throughput microscopy. Thus, our improvements to the culture conditions and method for assay readout increase the accuracy, reproducibility, and throughput of the myeloid CFU assay.
MeSH term(s)	Humans ; Interleukin-3 ; Reproducibility of Results ; Granulocyte-Macrophage Colony-Stimulating Factor ; Hematopoietic Stem Cells ; Colony-Forming Units Assay ; Cells, Cultured
Chemical Substances	Interleukin-3 ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2023-06-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2023.05.007
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Zs.A 922: Show issues

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Article ; Online: PUF60-related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants.

Grimes, H / Ansari, M / Ashraf, T / Cueto-González, Anna Mª / Calder, A / Day, M / Fernandez Alvarez, P / Foster, A / Lahiri, N / Repetto, G M / Scurr, I / Varghese, V / Low, Karen J

American journal of medical genetics. Part A

2023 Volume 191, Issue 10, Page(s) 2610–2622

Abstract: PUF60-related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, ...

Abstract	PUF60-related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, and congenital anomalies of the heart, kidney, and musculoskeletal system. Behavioral and intellectual difficulties are also observed. While less common than other features associated with PUF60-related developmental disorder, for instance hearing impairment and short stature, identification of specific anomalies such as ophthalmic coloboma can aid with diagnostic identification given the limited spectrum of genes linked with this feature. We describe 10 patients with PUF60 gene variants, bringing the total number reported in the literature, to varying levels of details, to 56 patients. Patients were recruited both via locally based exome sequencing from international sites and from the DDD study in the United Kingdom. Eight of the variants reported were novel PUF60 variants. The addition of a further patient with a reported c449-457del variant to the existing literature highlights this as a recurrent variant. One variant was inherited from an affected parent. This is the first example in the literature of an inherited variant resulting in PUF60-related developmental disorder. Two patients (20%) were reported to have a renal anomaly consistent with 22% of cases in previously reported literature. Two patients received specialist endocrine treatment. More commonly observed were clinical features such as: cardiac anomalies (40%), ocular abnormalities (70%), intellectual disability (60%), and skeletal abnormalities (80%). Facial features did not demonstrate a recognizable gestalt. Of note, but remaining of unclear causality, we describe a single pediatric patient with pineoblastoma. We recommend that stature and pubertal progress should be monitored in PUF60-related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with PUF60-related developmental disorder which has important genetic counseling implications for families.
MeSH term(s)	Child ; Humans ; Abnormalities, Multiple/diagnosis ; Abnormalities, Multiple/genetics ; Coloboma ; Developmental Disabilities/genetics ; Heart Defects, Congenital/genetics ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics
Chemical Substances	poly-U binding splicing factor 60KDa
Language	English
Publishing date	2023-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.63313
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Book: Coupling single-cell RNA-seq with tracking of regulatory determinants reveals rare hematopoietic transition states

Grimes, H. Leighton

2015

Abstract: CIT): Dr. Grimes received his Ph.D. in Molecular Pathology and Immunology studying gene regulation with Maureen Goodenow at the University of Florida, then joined Philip Tsichlis at Fox Chase Cancer Center, cloning novel genes activated by insertion ... ...

Institution	National Institutes of Health (U.S.). / Immunology Interest Group,
Author's details	H. Leighton Grimes ; Immunology Interest Group
Abstract	(CIT): Dr. Grimes received his Ph.D. in Molecular Pathology and Immunology studying gene regulation with Maureen Goodenow at the University of Florida, then joined Philip Tsichlis at Fox Chase Cancer Center, cloning novel genes activated by insertion mutagenesis (e.g. Akt, Tpl2). He has a broad background in hematopoiesis, molecular biology, and molecular oncology including modeling of hematopoiesis, myelopoiesis and leukemia. His work on the Growth factor independent-1 (Gfi1) transcriptional repressor protein has spanned the initial identification of Gfi1 in a model of leukemia and the role of Gfi1 in normal myeloid biology, to the identification of GFI1 mutations in patients with severe congenital neutropenia (SCN) and non-immune chronic idiopathic neutropenia of adults (NI-CINA). His work bridges normal hematopoietic development and innate immune action with marrow failure and transformation. His lab does it all! Don"t miss this talk by a dynamic speaker!.
MeSH term(s)	Hematopoiesis/genetics ; Cell Differentiation ; Gene Expression Regulation
Language	English
Size	1 online resource (1 streaming video file (53 min.)) :, color, sound
Document type	Book
Note	Closed-captioned.
Database	Catalogue of the US National Library of Medicine (NLM)

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Article ; Online: Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring.

Govindarajah, Vinothini / Sakabe, Masahide / Good, Samantha / Solomon, Michael / Arasu, Ashok / Chen, Nong / Zhang, Xuan / Grimes, H Leighton / Kendler, Ady / Xin, Mei / Reynaud, Damien

The Journal of clinical investigation

2024 Volume 134, Issue 2

Abstract: Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed ... ...

Abstract	Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.
MeSH term(s)	Humans ; Female ; Pregnancy ; Animals ; Mice ; Diabetes, Gestational/genetics ; Placenta/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Inflammasomes/metabolism ; Atherosclerosis ; Hematopoietic System/metabolism
Chemical Substances	NLR Family, Pyrin Domain-Containing 3 Protein ; Inflammasomes
Language	English
Publishing date	2024-01-16
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/JCI169730
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Article ; Online: Unraveling bone marrow architecture.

Lucas, Daniel / Salomonis, Nathan / Grimes, H Leighton

Nature cell biology

2019 Volume 22, Issue 1, Page(s) 5–6

MeSH term(s)	Bone Marrow ; Transcriptome
Language	English
Publishing date	2019-12-22
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-019-0447-6
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