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Article: Differences in Alu vs L1-rich chromosome bands underpin architectural reorganization of the inactive-X chromosome and SAHFs.

Hall, Lisa L / Creamer, Kevin M / Byron, Meg / Lawrence, Jeanne B

bioRxiv : the preprint server for biology

2024

Abstract: The linear DNA sequence of mammalian chromosomes is organized in large blocks of DNA with similar sequence properties, producing a pattern of dark and light staining bands on mitotic chromosomes. Cytogenetic banding is essentially invariant between ... ...

Abstract	The linear DNA sequence of mammalian chromosomes is organized in large blocks of DNA with similar sequence properties, producing a pattern of dark and light staining bands on mitotic chromosomes. Cytogenetic banding is essentially invariant between people and cell-types and thus may be assumed unrelated to genome regulation. We investigate whether large blocks of Alu-rich R-bands and L1-rich G-bands provide a framework upon which functional genome architecture is built. We examine two models of large-scale chromatin condensation: X-chromosome inactivation and formation of senescence-associated heterochromatin foci (SAHFs). XIST RNA triggers gene silencing but also formation of the condensed Barr Body (BB), thought to reflect cumulative gene silencing. However, we find Alu-rich regions are depleted from the L1-rich BB, supporting it is a dense core but not the entire chromosome. Alu-rich bands are also gene-rich, affirming our earlier findings that genes localize at the outer periphery of the BB. SAHFs similarly form within each territory by coalescence of syntenic L1 regions depleted for highly Alu-rich DNA. Analysis of senescent cell Hi-C data also shows large contiguous blocks of G-band and R-band DNA remodel as a segmental unit. Entire dark-bands gain distal intrachromosomal interactions as L1-rich regions form the SAHF. Most striking is that sharp Alu peaks within R-bands resist these changes in condensation. We further show that Chr19, which is exceptionally Alu rich, fails to form a SAHF. Collective results show regulation of genome architecture corresponding to large blocks of DNA and demonstrate resistance of segments with high Alu to chromosome condensation.
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.09.574742
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Article ; Online: ZNF146/OZF and ZNF507 target LINE-1 sequences.

Creamer, Kevin M / Larsen, Eric C / Lawrence, Jeanne B

G3 (Bethesda, Md.)

2022 Volume 12, Issue 3

Abstract: Repetitive sequences including transposable elements and transposon-derived fragments account for nearly half of the human genome. While transposition-competent transposable elements must be repressed to maintain genomic stability, mutated and fragmented ...

Abstract	Repetitive sequences including transposable elements and transposon-derived fragments account for nearly half of the human genome. While transposition-competent transposable elements must be repressed to maintain genomic stability, mutated and fragmented transposable elements comprising the bulk of repetitive sequences can also contribute to regulation of host gene expression and broader genome organization. Here, we analyzed published ChIP-seq data sets to identify proteins broadly enriched on transposable elements in the human genome. We show 2 of the proteins identified, C2H2 zinc finger-containing proteins ZNF146 (also known as OZF) and ZNF507, are targeted to distinct sites within LINE-1 ORF2 at thousands of locations in the genome. ZNF146 binding sites are found at old and young LINE-1 elements. In contrast, ZNF507 preferentially binds at young LINE-1 sequences correlated to sequence changes in LINE-1 elements at ZNF507's binding site. To gain further insight into ZNF146 and ZNF507 function, we disrupt their expression in HEK293 cells using CRISPR/Cas9 and perform RNA sequencing, finding modest gene expression changes in cells where ZNF507 has been disrupted. We further identify a physical interaction between ZNF507 and PRMT5, suggesting ZNF507 may target arginine methylation activity to LINE-1 sequences.
MeSH term(s)	Binding Sites ; DNA Transposable Elements ; Genome, Human/genetics ; HEK293 Cells ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Long Interspersed Nucleotide Elements ; Protein-Arginine N-Methyltransferases/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	DNA Transposable Elements ; Kruppel-Like Transcription Factors ; RNA-Binding Proteins ; ZNF146 protein, human ; PRMT5 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319)
Language	English
Publishing date	2022-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkac002
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Article ; Online: Correcting motion induced fluorescence artifacts in two-channel neural imaging.

Creamer, Matthew S / Chen, Kevin S / Leifer, Andrew M / Pillow, Jonathan W

PLoS computational biology

2022 Volume 18, Issue 9, Page(s) e1010421

Abstract: Imaging neural activity in a behaving animal presents unique challenges in part because motion from an animal's movement creates artifacts in fluorescence intensity time-series that are difficult to distinguish from neural signals of interest. One ... ...

Abstract	Imaging neural activity in a behaving animal presents unique challenges in part because motion from an animal's movement creates artifacts in fluorescence intensity time-series that are difficult to distinguish from neural signals of interest. One approach to mitigating these artifacts is to image two channels simultaneously: one that captures an activity-dependent fluorophore, such as GCaMP, and another that captures an activity-independent fluorophore such as RFP. Because the activity-independent channel contains the same motion artifacts as the activity-dependent channel, but no neural signals, the two together can be used to identify and remove the artifacts. However, existing approaches for this correction, such as taking the ratio of the two channels, do not account for channel-independent noise in the measured fluorescence. Here, we present Two-channel Motion Artifact Correction (TMAC), a method which seeks to remove artifacts by specifying a generative model of the two channel fluorescence that incorporates motion artifact, neural activity, and noise. We use Bayesian inference to infer latent neural activity under this model, thus reducing the motion artifact present in the measured fluorescence traces. We further present a novel method for evaluating ground-truth performance of motion correction algorithms by comparing the decodability of behavior from two types of neural recordings; a recording that had both an activity-dependent fluorophore and an activity-independent fluorophore (GCaMP and RFP) and a recording where both fluorophores were activity-independent (GFP and RFP). A successful motion correction method should decode behavior from the first type of recording, but not the second. We use this metric to systematically compare five models for removing motion artifacts from fluorescent time traces. We decode locomotion from a GCaMP expressing animal 20x more accurately on average than from control when using TMAC inferred activity and outperforms all other methods of motion correction tested, the best of which were ~8x more accurate than control.
MeSH term(s)	Algorithms ; Animals ; Artifacts ; Bayes Theorem ; Motion ; Movement
Language	English
Publishing date	2022-09-28
Publishing country	United States
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	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010421
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Article ; Online: Practice Makes Better: Making the Case for a Novel Hospitalist Resuscitation Curriculum.

Creamer, Kevin M / Ismail, Lana / Smith, Karen

Hospital pediatrics

2020 Volume 10, Issue 9, Page(s) 820–822

MeSH term(s)	Curriculum ; Hospitalists ; Humans ; Resuscitation
Language	English
Publishing date	2020-08-14
Publishing country	United States
Document type	Journal Article
ISSN	2154-1671
ISSN (online)	2154-1671
DOI	10.1542/hpeds.2020-0147
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Article: Pediatric Hospitalist Resuscitation Skills Refresher Training With Pauses for Deliberate Practice.

Ismail, Lana / Bhansali, Priti / Creamer, Kevin M

Cureus

2021 Volume 13, Issue 12, Page(s) e20538

Abstract: Introduction Pediatric hospitalists are expected to lead resuscitative efforts for cardiopulmonary arrests, but the infrequency of these events and pediatric advanced life support (PALS) re-certifications are insufficient to maintain skill proficiency.We ...

Abstract	Introduction Pediatric hospitalists are expected to lead resuscitative efforts for cardiopulmonary arrests, but the infrequency of these events and pediatric advanced life support (PALS) re-certifications are insufficient to maintain skill proficiency.We created a novel resuscitation refresher curriculum for pediatric hospitalists with strategic pauses during simulations for expert and peer coaching of procedural skills. Methods In a tertiary care academic pediatric hospital between September 2018 to June 2019, pediatric hospitalists and fellows voluntarily participated in a series of three quarterly two-hour training sessions taught by expert peer facilitators. Sessions focused on the thirty-second rapid cardiopulmonary assessment and each of the pediatric advanced life support (PALS) algorithms. Scenarios were strategically paused to practice critical hands-on skills. Cases centered on the themes of shock, respiratory, and cardiac emergencies and took place in a high-fidelity simulation lab requiring a technician and expert peer facilitator. Participants anonymously completed Likert scale-based evaluations after each session and again at the end of the year that focused on participants' own perceived change in their comfort levels in performing various resuscitation skills and in knowing basic resuscitation steps. As part of our institutional and personal assessment of the curriculum, an end-of-year survey additionally asked participants to reflect on the overall simulation curriculum and resultant changes in their clinical practice. Results Comfort in all skills practiced across the three sessions increased. The end-of-year survey showed a significant rise in comfort above baseline but some decrements when compared to that immediately post-training. Ninety-six percent of pediatric hospitalists rated the overall quality of the training "better" or "much better" than other resuscitation training (including PALS classes and traditional simulations with skills training after the scenario). The overall effect of the curriculum on perceived knowledge, skills, and confidence levels was significant (p <0.0001). Conclusion Serial resuscitation skills refreshers with expert peer coaching and strategic pauses for hands-on skills practice can result in significant improvements in perceived knowledge and comfort with skill performance as well as the leadership role among pediatric hospitalists.
Language	English
Publishing date	2021-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2747273-5
ISSN	2168-8184
ISSN	2168-8184
DOI	10.7759/cureus.20538
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Article: ERS International Congress 2023: highlights from the Thoracic Oncology Assembly.

Catarata, Maria Joana / Creamer, Andrew W / Dias, Margarida / Toland, Sile / Chaabouni, Malek / Verbeke, Koen / Vieira Naia, Joana / Hassan, Maged / Naidu, Sindhu Bhaarrati / Lynch, Geraldine A / Blyth, Kevin G / Rahman, Najib M / Hardavella, Georgia

ERJ open research

2024 Volume 10, Issue 1

Abstract: Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients' quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational ...

Abstract	Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients' quality of life, and is thus a challenge for the daily practice in respiratory medicine. Advances in the genetic knowledge of thoracic tumours' mutational landscape, and the development of targeted therapies and immune checkpoint inhibitors, have led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the 2023 European Respiratory Society Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.
Language	English
Publishing date	2024-02-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2827830-6
ISSN	2312-0541
ISSN	2312-0541
DOI	10.1183/23120541.00860-2023
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Article ; Online: SAF-A mutants disrupt chromatin structure through dominant negative effects on RNAs associated with chromatin.

Kolpa, Heather J / Creamer, Kevin M / Hall, Lisa L / Lawrence, Jeanne B

Mammalian genome : official journal of the International Mammalian Genome Society

2021 Volume 33, Issue 2, Page(s) 366–381

Abstract: Here we provide a brief review of relevant background before presenting results of our investigation into the interplay between scaffold attachment factor A (SAF-A), chromatin-associated RNAs, and DNA condensation. SAF-A, also termed heterogenous nuclear ...

Abstract	Here we provide a brief review of relevant background before presenting results of our investigation into the interplay between scaffold attachment factor A (SAF-A), chromatin-associated RNAs, and DNA condensation. SAF-A, also termed heterogenous nuclear protein U (hnRNP U), is a ubiquitous nuclear scaffold protein that was implicated in XIST RNA localization to the inactive X-chromosome (Xi) but also reported to maintain open DNA packaging in euchromatin. Here we use several means to perturb SAF-A and examine potential impacts on the broad association of RNAs on euchromatin, and on chromatin compaction. SAF-A has an N-terminal DNA binding domain and C-terminal RNA binding domain, and a prominent model has been that the protein provides a single-molecule bridge between XIST RNA and chromatin. Here analysis of the impact of SAF-A on broad RNA-chromatin interactions indicate greater biological complexity. We focus on SAF-A's role with repeat-rich C
MeSH term(s)	Chromatin/genetics ; Euchromatin ; Nuclear Proteins/genetics ; RNA, Long Noncoding/genetics ; X Chromosome
Chemical Substances	Chromatin ; Euchromatin ; Nuclear Proteins ; RNA, Long Noncoding
Language	English
Publishing date	2021-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1058547-3
ISSN	1432-1777 ; 0938-8990
ISSN (online)	1432-1777
ISSN	0938-8990
DOI	10.1007/s00335-021-09935-8
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Book ; Online: Correcting motion induced fluorescence artifacts in two-channel neural imaging

Creamer, Matthew S. / Chen, Kevin S. / Leifer, Andrew M. / Pillow, Jonathan W.

2022

Abstract	Imaging neural activity in a behaving animal presents unique challenges in part because motion from an animal's movement creates artifacts in fluorescence intensity time-series that are difficult to distinguish from neural signals of interest. One approach to mitigating these artifacts is to image two channels; one that captures an activity-dependent fluorophore, such as GCaMP, and another that captures an activity-independent fluorophore such as RFP. Because the activity-independent channel contains the same motion artifacts as the activity-dependent channel, but no neural signals, the two together can be used to remove the artifacts. Existing approaches for this correction, such as taking the ratio of the two channels, do not account for channel independent noise in the measured fluorescence. Moreover, no systematic comparison has been made of existing approaches that use two-channel signals. Here, we present Two-channel Motion Artifact Correction (TMAC), a method which seeks to remove artifacts by specifying a generative model of the fluorescence of the two channels as a function of motion artifact, neural activity, and noise. We further present a novel method for evaluating ground-truth performance of motion correction algorithms by comparing the decodability of behavior from two types of neural recordings; a recording that had both an activity-dependent fluorophore (GCaMP and RFP) and a recording where both fluorophores were activity-independent (GFP and RFP). A successful motion-correction method should decode behavior from the first type of recording, but not the second. We use this metric to systematically compare five methods for removing motion artifacts from fluorescent time traces. We decode locomotion from a GCaMP expressing animal 15x more accurately on average than from control when using TMAC inferred activity and outperform all other methods of motion correction tested. Comment: 11 pages, 3 figures
Keywords	Quantitative Biology - Neurons and Cognition
Subject code	290
Publishing date	2022-04-26
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pediatric Thoracic Trauma Mortality in Iraq and Afghanistan Compared to the United States National Trauma Data Bank.

Keneally, Ryan J / Meyers, Brittney A / Shields, Cynthia H / Ricca, Robert / Creamer, Kevin M

Military medicine

2021 Volume 187, Issue 3-4, Page(s) e338–e342

Abstract: Introduction: The authors compared pediatric thoracic patients in the Joint Theatre Trauma Registry (JTTR) to those in the National Trauma Data Bank (NTDB) to assess differences in patient mortality rates and mortality risk accounting for age, injury ... ...

Abstract	Introduction: The authors compared pediatric thoracic patients in the Joint Theatre Trauma Registry (JTTR) to those in the National Trauma Data Bank (NTDB) to assess differences in patient mortality rates and mortality risk accounting for age, injury patterns, and injury severity. Materials and methods: Patients less than 19 years of age with thoracic trauma were identified in both the JTTR and NTDB. Multiple logistic regression, χ2, Student's t-test, or Mann-Whitney U test were used as indicated to compare the two groups. Results: Pediatric thoracic trauma patients seen in Iraq and Afghanistan (n = 955) had a significantly higher mortality rate (15.1 vs. 6.0%, P <.01) than those in the NTDB (n = 9085). After controlling for covariates between the JTTR and the NTDB, there was no difference in mortality (odds ratio for mortality for U.S. patients was 0.74, 95% CI 0.52-1.06, P = .10). The patients seen in Iraq or Afghanistan were significantly younger (8 years old, interquartile ratio (IQR) 2-13 vs. 15, IQR 10-17, P <.01) had greater severity of injuries (injury severity score 17, IQR 12-26 vs. 12, IQR 8-22, P <.01), had significantly more head injuries (29 vs. 14%, P <.01), and over half were exposed to a blast. Discussion: Pediatric patients with thoracic trauma in Iraq and Afghanistan in the JTTR had similar mortality rates compared to the civilian population in the NTDB after accounting for confounding covariates. These findings indicate that deployed military medical professionals are providing comparable quality of care in extremely challenging circumstances. This information has important implications for military preparedness, medical training, and casualty care.
MeSH term(s)	Afghan Campaign 2001- ; Afghanistan/epidemiology ; Child ; Humans ; Iraq/epidemiology ; Iraq War, 2003-2011 ; Military Personnel ; Registries ; Retrospective Studies ; Thoracic Injuries/epidemiology ; United States/epidemiology
Language	English
Publishing date	2021-01-28
Publishing country	England
Document type	Journal Article
ZDB-ID	391061-1
ISSN	1930-613X ; 0026-4075
ISSN (online)	1930-613X
ISSN	0026-4075
DOI	10.1093/milmed/usab020
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Book: Pediatric surgery and medicine for hostile environments

Creamer, Kevin M / Fuenfer, Michael M

2016

Institution	Borden Institute (U.S.), United States. / Department of the Army
Author's details	senior medical and critical care editor, Kevin M. Creamer ; senior surgical editor, Michael M. Fuenfer
MeSH term(s)	Emergencies ; Wounds and Injuries/surgery ; Child ; Infant ; Military Medicine
Language	English
Size	p. ;, cm.
Edition	Second edition.
Document type	Book
Database	Catalogue of the US National Library of Medicine (NLM)

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