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Article ; Online: Molecular mechanisms insulating proliferation from genotoxic stress in B lymphocytes.

Wright, Nathaniel E / Mandal, Malay / Clark, Marcus R

2023 Volume 44, Issue 9, Page(s) 668–677

Abstract: In mammals, B cells strictly segregate proliferation from somatic mutation as they develop within the bone marrow and then mature through germinal centers (GCs) in the periphery. Failure to do so risks autoimmunity and neoplastic transformation. Recent ... ...

Abstract	In mammals, B cells strictly segregate proliferation from somatic mutation as they develop within the bone marrow and then mature through germinal centers (GCs) in the periphery. Failure to do so risks autoimmunity and neoplastic transformation. Recent work has described how B cell progenitors transition between proliferation and mutation via cytokine signaling pathways, epigenetic chromatin regulation, and remodeling of 3D chromatin conformation. We propose a three-zone model of the GC that describes how proliferation and mutation are regulated. Using this model, we consider how recent mechanistic discoveries in B cell progenitors inform models of GC B cell function and reveal fundamental mechanisms underpinning humoral immunity, autoimmunity, and lymphomagenesis.
MeSH term(s)	Humans ; Animals ; B-Lymphocytes ; Germinal Center ; DNA Damage ; Chromatin ; Cell Proliferation ; Mammals
Chemical Substances	Chromatin
Language	English
Publishing date	2023-08-10
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.06.010
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Compartments and Connections Within the Germinal Center.

Kennedy, Domenick E / Clark, Marcus R

Frontiers in immunology

2021 Volume 12, Page(s) 659151

Abstract: Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and ... ...

Abstract	Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.
MeSH term(s)	Animals ; Antibody Formation ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cell Plasticity/genetics ; Cell Plasticity/immunology ; Germinal Center/cytology ; Germinal Center/physiology ; Humans ; Immunity, Humoral ; Immunoglobulin Class Switching/genetics ; Immunoglobulin Class Switching/immunology
Language	English
Publishing date	2021-03-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.659151
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Article ; Online: PI3Kδ: Too much of a good thing.

Kennedy, Domenick E / Clark, Marcus R

Nature immunology

2018 Volume 19, Issue 9, Page(s) 910–911

MeSH term(s)	Immunity, Humoral
Language	English
Publishing date	2018-08-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-018-0183-2
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Comparing Cognitive Disengagement Syndrome Growth in Youth With and Without Spina Bifida.

Darow, Eva L / Flax, Marcus A / Clark, Olivia E / Holmbeck, Grayson N / Smith, Zoe R

Journal of pediatric psychology

2023 Volume 48, Issue 8, Page(s) 720–730

Abstract: Objective: Cognitive disengagement syndrome (CDS; formally known as sluggish cognitive tempo), difficulties with social engagement, and lower levels of autonomy have been identified as maladaptive comorbidities in youth with spina bifida (SB). This ... ...

Abstract	Objective: Cognitive disengagement syndrome (CDS; formally known as sluggish cognitive tempo), difficulties with social engagement, and lower levels of autonomy have been identified as maladaptive comorbidities in youth with spina bifida (SB). This study compared growth curves of CDS for youth with and without SB and examined whether these trajectories were associated with later functioning. Methods: Longitudinal data spanning 8 years included youth with SB (n = 68, Mage = 8.34) and a demographically matched sample of typically developing (TD) peers (n = 68, Mage = 8.49). Adolescents, along with their caregivers and teachers, reported on youth social skills, behavioral functioning, and CDS. Growth curve models were examined by comparing CDS trajectories by SB status. Results: Growth curves indicated that youth with SB had higher levels of teacher-reported CDS at ages 8 and 9, but growth curves were relatively stable for both groups. When predicting social skills, higher levels of teacher-reported (but not mother-reported) CDS at baseline predicted worse social functioning for both youth with and without SB in adolescence. For the slope findings, higher rates of mother-reported CDS over time predicted worse social skills (β = -0.43) and lower levels of youth decision-making (β = -0.43) for the SB group, while higher rates of teacher-reported CDS predicted worse social skills for the TD group. Conclusion: Next steps include understanding the impact that impaired social functioning and restricted autonomy have on youth with and without SB due to CDS to inform interventions. Additionally, advocacy for increased awareness of CDS-related impairment is needed, particularly for youth with chronic health conditions.
MeSH term(s)	Female ; Humans ; Adolescent ; Social Skills ; Social Adjustment ; Peer Group ; Spinal Dysraphism/complications ; Spinal Dysraphism/psychology ; Cognition
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	625329-5
ISSN	1465-735X ; 0146-8693
ISSN (online)	1465-735X
ISSN	0146-8693
DOI	10.1093/jpepsy/jsad038
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Article ; Online: Cellular aspects of the pathogenesis of lupus nephritis.

Chang, Anthony / Clark, Marcus R / Ko, Kichul

Current opinion in rheumatology

2021 Volume 33, Issue 2, Page(s) 197–204

Abstract: Purpose of review: Lupus nephritis is a common severe manifestation of systemic lupus erythematosus. Despite recent advances in therapeutics and understanding of its pathogenesis, there are still substantial unmet needs. This review discusses recent ... ...

Abstract	Purpose of review: Lupus nephritis is a common severe manifestation of systemic lupus erythematosus. Despite recent advances in therapeutics and understanding of its pathogenesis, there are still substantial unmet needs. This review discusses recent discoveries in these areas, especially the role of tubulointerstitial inflammation (TII) in lupus nephritis. Recent findings: Non-white ethnicity is still a major risk and poor prognostic factor in lupus nephritis. TII and fibrosis have been found to be associated with worse renal outcome but the current lupus nephritis treatment guidelines and trials are based on the degree of glomerular inflammation. In combination with mycophenolate mofetil, a B-cell-targeted therapy (belimumab) and a calcineurin inhibitor (voclosporin) have shown efficacy in recent lupus nephritis trials. However, response rates have been modest. While lupus glomerulonephritis results from immune complex deposition derived from systemic autoantibodies, TII arises from complex processes associated with in situ adaptive cell networks. These include local antibody production, and cognate or antigen-induced interactions between T follicular helper cells, and likely other T-cell populations, with antigen presenting cells including B cells, myeloid dendritic cells and plasmacytoid dendritic cells. Summary: Better understanding of the pathogenesis of TII will identify novel therapeutic targets predicted to improve outcomes in our patients with lupus nephritis.
MeSH term(s)	Autoantibodies ; Humans ; Inflammation ; Kidney ; Lupus Erythematosus, Systemic ; Lupus Nephritis/etiology ; Lupus Nephritis/therapy
Chemical Substances	Autoantibodies
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1045317-9
ISSN	1531-6963 ; 1040-8711
ISSN (online)	1531-6963
ISSN	1040-8711
DOI	10.1097/BOR.0000000000000777
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Article: BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function.

Wright, Nathaniel E / Kennedy, Domenick E / Ai, Junting / Veselits, Margaret L / Attaway, Mary / Yoon, Young Me / Durkee, Madeleine S / Veselits, Jacob / Maienschein-Cline, Mark / Mandal, Malay / Clark, Marcus R

bioRxiv : the preprint server for biology

2024

Abstract: Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the ... ...

Abstract	Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation and
Language	English
Publishing date	2024-04-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.25.591154
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Article ; Online: Artificial Intelligence and Cellular Segmentation in Tissue Microscopy Images.

Durkee, Madeleine S / Abraham, Rebecca / Clark, Marcus R / Giger, Maryellen L

The American journal of pathology

2021 Volume 191, Issue 10, Page(s) 1693–1701

Abstract: With applications in object detection, image feature extraction, image classification, and image segmentation, artificial intelligence is facilitating high-throughput analysis of image data in a variety of biomedical imaging disciplines, ranging from ... ...

Abstract	With applications in object detection, image feature extraction, image classification, and image segmentation, artificial intelligence is facilitating high-throughput analysis of image data in a variety of biomedical imaging disciplines, ranging from radiology and pathology to cancer biology and immunology. Specifically, a growth in research on deep learning has led to the widespread application of computer-visualization techniques for analyzing and mining data from biomedical images. The availability of open-source software packages and the development of novel, trainable deep neural network architectures has led to increased accuracy in cell detection and segmentation algorithms. By automating cell segmentation, it is now possible to mine quantifiable cellular and spatio-cellular features from microscopy images, providing insight into the organization of cells in various pathologies. This mini-review provides an overview of the current state of the art in deep learning- and artificial intelligence-based methods of segmentation and data mining of cells in microscopy images of tissue.
MeSH term(s)	Animals ; Artificial Intelligence ; Cells/cytology ; Deep Learning ; Humans ; Image Processing, Computer-Assisted ; Microscopy ; Organ Specificity
Language	English
Publishing date	2021-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2021.05.022
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Article ; Online: Estimating the prevalence of discrepancies between study registrations and publications

Marcus R Munafò / Robert Thibault / Robbie Clark / Olmo van den Akker / Samuel Westwood / Jacqueline M Thompson

BMJ Open, Vol 13, Iss

a systematic review and meta-analyses

2023 Volume 10

Abstract: Objectives Prospectively registering study plans in a permanent time-stamped and publicly accessible document is becoming more common across disciplines and aims to reduce risk of bias and make risk of bias transparent. Selective reporting persists, ... ...

Abstract	Objectives Prospectively registering study plans in a permanent time-stamped and publicly accessible document is becoming more common across disciplines and aims to reduce risk of bias and make risk of bias transparent. Selective reporting persists, however, when researchers deviate from their registered plans without disclosure. This systematic review aimed to estimate the prevalence of undisclosed discrepancies between prospectively registered study plans and their associated publication. We further aimed to identify the research disciplines where these discrepancies have been observed, whether interventions to reduce discrepancies have been conducted, and gaps in the literature.Design Systematic review and meta-analyses.Data sources Scopus and Web of Knowledge, published up to 15 December 2019.Eligibility criteria Articles that included quantitative data about discrepancies between registrations or study protocols and their associated publications.Data extraction and synthesis Each included article was independently coded by two reviewers using a coding form designed for this review (osf.io/728ys). We used random-effects meta-analyses to synthesise the results.Results We reviewed k=89 articles, which included k=70 that reported on primary outcome discrepancies from n=6314 studies and, k=22 that reported on secondary outcome discrepancies from n=1436 studies. Meta-analyses indicated that between 29% and 37% (95% CI) of studies contained at least one primary outcome discrepancy and between 50% and 75% (95% CI) contained at least one secondary outcome discrepancy. Almost all articles assessed clinical literature, and there was considerable heterogeneity. We identified only one article that attempted to correct discrepancies.Conclusions Many articles did not include information on whether discrepancies were disclosed, which version of a registration they compared publications to and whether the registration was prospective. Thus, our estimates represent discrepancies broadly, rather than our target of undisclosed ...
Keywords	Medicine ; R
Subject code	001
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Pseudo-spectral angle mapping for automated pixel-level analysis of highly multiplexed tissue image data.

Durkee, Madeleine S / Ai, Junting / Casella, Gabriel / Cao, Thao / Chang, Anthony / Halper-Stromberg, Ariel / Jabri, Bana / Clark, Marcus R / Giger, Maryellen L

bioRxiv : the preprint server for biology

2024

Abstract: The rapid development of highly multiplexed microscopy systems has enabled the study of cells embedded within their native tissue, which is providing exciting insights into the spatial features of human disease [1]. However, computational methods for ... ...

Abstract	The rapid development of highly multiplexed microscopy systems has enabled the study of cells embedded within their native tissue, which is providing exciting insights into the spatial features of human disease [1]. However, computational methods for analyzing these high-content images are still emerging, and there is a need for more robust and generalizable tools for evaluating the cellular constituents and underlying stroma captured by high-plex imaging [2]. To address this need, we have adapted spectral angle mapping - an algorithm used widely in hyperspectral image analysis - to compress the channel dimension of high-plex immunofluorescence images. As many high-plex immunofluorescence imaging experiments probe unique sets of protein markers, existing cell and pixel classification models do not typically generalize well. Pseudospectral angle mapping (pSAM) uses reference pseudospectra - or pixel vectors - to assign each pixel in an image a similarity score to several cell class reference vectors, which are defined by each unique staining panel. Here, we demonstrate that the class maps provided by pSAM can directly provide insight into the prevalence of each class defined by reference pseudospectra. In a dataset of high-plex images of colon biopsies from patients with gut autoimmune conditions, sixteen pSAM class representation maps were combined with instance segmentation of cells to provide cell class predictions. Finally, pSAM detected a diverse set of structure and immune cells when applied to a novel dataset of kidney biopsies imaged with a 43-marker panel. In summary, pSAM provides a powerful and readily generalizable method for evaluating high-plex immunofluorescence image data.
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.09.574920
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Book ; Online ; Thesis: Adaptive Coarse Spaces for the Overlapping Schwarz Method and Multiscale Elliptic Problems

Knepper, Jascha [Verfasser] / Klawonn, Axel [Gutachter] / Sarkis, Marcus [Gutachter] / Dohrmann, Clark R. [Gutachter]

2022

Author's details	Jascha Knepper ; Gutachter: Axel Klawonn, Marcus Sarkis, Clark R. Dohrmann
Keywords	Naturwissenschaften ; Science
Subject code	sg500
Language	English
Publisher	Universitäts- und Stadtbibliothek Köln
Publishing place	Köln
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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