Digital Commons Network^™

Context-Dependent Contribution Of Peptidyl Arginine Deiminase 4 (Pad4) To Neutrophil Extracellular Trap Formation And Liver Injury In Acute And Chronic Hepatotoxicant Challenge, Gina E Capece, Amish K Patel, Daniel Hu, Tayana Roychowdhury, Bianca Hazel, Jessica Kothapalli, Noah A Mac, Frederik Denorme, Robert A Campbell, Lauren G Poole

2020-Current year OA Pubs

Neutrophils play a complex role in the pathogenesis of chronic liver disease and have been linked to both liver damage and injury resolution. Recent reports propose that neutrophils drive liver injury and fibrosis through the formation of neutrophil extracellular traps (NETs). This study tests the hypothesis that the enzyme peptidyl arginine deiminase-4 (PAD4) drives NET formation and liver fibrosis in experimental chronic liver injury. Wild-type (PAD4+/+) and PAD4-deficient (PAD4-/-) mice were chronically challenged twice weekly with carbon tetrachloride (CCl4, 1 ml/kg, i.p) or vehicle (corn oil) for 6 weeks, and samples were collected 24 h after the final challenge. In …

Comparison Of Rule- And Large Language Model-Based Phenotype Extraction From Clinical Notes For Neurofibromatosis Type 1, Levi Kaster, Ethan Hillis, Inez Y Oh, Elizabeth C Cordell, Randi E Foraker, Albert M Lai, Stephanie M Morris, David H Gutmann, Philip R O Payne, Aditi Gupta

2020-Current year OA Pubs

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a rare genetic disorder affecting multiple organ systems with significant clinical heterogeneity. Managing individuals with NF1 is challenging due to variability in disease progression and outcomes and limited early risk assessment tools.

OBJECTIVE: This study aims to develop an effective, generalizable, user-friendly clinical entity extraction pipeline for identifying NF1-related phenotypes from unstructured clinical notes to enhance research and risk-modeling efforts. We compare the benefits of rule-based natural language processing (NLP) vs large language models (LLMs) for this purpose.

MATERIALS AND METHODS: Four phenotype extraction pipelines (3 LLM-based vs 1 rule-based) were developed to automatically …

Importance Of Defining Anatomy: Uncovering An Unexpected Finding With Ct Coronary Angiography After Abnormal Spect Results, Anushree Puttur, Laith Alhuneafat, Omar Obeidat, Andreas Kyvernitakis, Ahmad Jabri, Abdallah Naser, Ahmad Al-Abdouh, Farhan Katchi

2020-Current year OA Pubs

Coronary CT angiography extends beyond detecting obstructive coronary artery disease by providing vital anatomical insights into extra-coronary pathologies, including acute aortic syndromes. This non-invasive modality enables early identification of life-threatening conditions and informs multidisciplinary management strategies, underscoring its critical role in comprehensive diagnostic evaluation and patient-centered care.

Comparing Effectiveness And Safety Of Left Atrial Appendage Closure Devices: A Network Meta-Analysis Of Randomized Controlled Trials, John W Davis, Steven L Mai, Wissam Harmouch, Jenna Reisler, Micaela Mackay, Elizabeth Davis, Pavel Osmancik, Michael W Rich

2020-Current year OA Pubs

INTRODUCTION: Atrial fibrillation-related stroke is a leading cause of morbidity and mortality. The comparative effectiveness and safety of left atrial appendage closure (LAAC) devices, compared with one another and with anticoagulation, is unclear.

METHODS: We conducted a systematic review and network meta-analysis (NMA) of all clinical trials comparing the Watchman and Amplatzer Amulet LAAC devices with each other or with warfarin or direct oral anticoagulants (DOACs). The primary comparison was between LAAC devices with secondary comparisons to anticoagulation. The primary effectiveness outcomes were any stroke and all-cause death. Safety outcomes included any thromboembolism, device embolization, and pericardial effusion.

RESULTS: There …

Adolescent Coronal Shear Fractures Of The Distal Humerus: Surgical Approach And Outcomes, David Wright, Zachary Meyer, Charles A Goldfarb, Lindley B Wall

2020-Current year OA Pubs

PURPOSE: Isolated coronal shear fractures of the distal humerus in adolescents are rare injuries with unique surgical challenges. Respect for the posterior blood supply, open physes, and need for direct visualization to achieve anatomic reduction are critical considerations in surgical fixation. This study presents a case series and a surgical approach used in treating these patients.

METHODS: A retrospective review of patients aged 10-19 presenting to a single quaternary-care academic center from 2016 to 2023 with isolated capitellar and trochlear shear fractures was performed. Demographic data, injury mechanism, fracture classification, and surgical approach were recorded. Outcomes included elbow range of …

A Glial Circadian Gene Expression Atlas Reveals Cell-Type And Disease-Specific Reprogramming In Response To Amyloid Pathology Or Aging, Patrick W. Sheehan, Stuart B Fass, Darshan Sapkota, Sylvia Kang, Henry C Hollis, Jennifer H Lawrence, Sohui Park, Ashish Sharma, Dorothy P Schafer, Ron C Anafi, Joseph D Dougherty, John D Fryer, Erik S Musiek

2020-Current year OA Pubs

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, …

Identifying Performance Differences Between Two Pulse Oximetry Systems In Simulated Critical Neonatal Conditions, Brian King, Jake Dove, Scott J Mcgonigle, Warwick A Ames, Zachary A Vesoulis

2020-Current year OA Pubs

OBJECTIVE: Pulse oximetry is used to guide critical clinical decisions in neonatology. We used a vital signs simulator to compare performance of two pulse oximetry systems in conditions not tested in standardized clinical verification studies.

STUDY DESIGN: We devised a set of simulated tissue translucency, perfusion, peripheral oxygen saturation (SpO

RESULTS: The mean SpO

CONCLUSION: Significant performance differences can be observed when comparing pulse oximeters at low translucency and perfusion conditions. Patient simulators cannot replace clinical testing but provide a safe and cost-effective method for additional performance profiling.

Management Of The Patent Ductus Arteriosus Among Infants Born At 23 To 32 Weeks' Gestation Between 2011 To 2022: A Report From In The Children's Hospitals Neonatal Consortium, Mark F Weems, Molly K Ball, Isabella Zaniletti, Sharifa Habib, Shannon Hamrick, Theresa R Grover, Sarah Keene, Karna Murthy, Michael Padula, Ranjit Philip, Rakesh Rao, Shawn Sen, Philip T Levy, Sharada H Gowda, Chnc Cardiac Focus Group

2020-Current year OA Pubs

OBJECTIVE: This study reports on patent ductus arteriosus (PDA) therapy trends across the Children's Hospital Neonatal Consortium.

STUDY DESIGN: We performed a 12-year (2011-2022) retrospective study of premature infants (<  33 weeks) with a PDA. We utilized descriptive statistics to compare demographic, inpatient, and discharge characteristics in 3-year epochs.

RESULT: From 54,813 infants, 19,843 (36%) had a diagnosis of PDA. Use of pharmacotherapy increased 44% (relative) over time, mostly with increased acetaminophen use. There was a 12.7-fold increase in exposure to multiple PDA medications over the study period. While the rate of definitive closure did not change, use of transcatheter PDA closure increased from 0 to 20.3% and surgical ligation decreased from 25.1% to 3.6%.

CONCLUSION: There has been …

Degenerating Intervertebral Discs In The Streptozotocin-High-Fat Diet Model Of Type 2 Diabetes Show Extensive Inflammation, Christian E Gonzalez, Rachana S Vaidya, Sade W Clayton, Simon Y Tang

2020-Current year OA Pubs

The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite confounding factors, such as obesity, studies show that, after adjusting for age, body mass index and genetics (e.g. twins), patients with T2D experience disproportionate severity of IVD degeneration and/or back pain than individuals without T2D. We hypothesized that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts homeostasis. To test this, we evaluated two common mouse models of T2D - leptin-receptor deficient (db/db) mice and mice with a chronic high-fat diet …

Six Drivers Of Aging Identified Among Genes Differentially Expressed With Age, Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller, Roberto Civitelli

2020-Current year OA Pubs

Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most chronic diseases. However, these studies only identify associations without distinguishing drivers of aging from compensatory geroprotective responses or incidental downstream effects. Here, we introduce a workflow to characterize causal effects of differentially expressed genes on lifespan. First, we performed a meta-analysis of 25 gene expression datasets comprising samples of various tissues from healthy, untreated adult mammals (humans, dogs, and rodents) at two distinct ages. Genes were ranked by the number of datasets in which they exhibited consistent differential …

Maternal Separation Disrupts Noradrenergic Control Of Adult Coping Behaviors, Chayla R Vazquez, Léa J Becker, Chao-Cheng Kuo, Solana A Cariello, Ayah N Hamdan, Ream Al-Hasani, Susan E Maloney, Jordan G Mccall

2020-Current year OA Pubs

Early life stress (ELS) profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Using repeated maternal separation stress (MSS), we investigated the impact of ELS on the LC and stress-related behaviors in adulthood. We performed ex vivo cell-attached electrophysiology across the lifespan to reveal that MSS significantly increased LC firing during early development and adulthood but not in pre-adolescence and adolescence. We next examined potential changes in the expression of genes linked to LC …

Hospitalizations As An Outcome Measure In Courage-Als, Stacy A Rudnicki, Timothy M Miller, Et Al.

2020-Current year OA Pubs

No abstract provided.

Nirfasterff: An Accessible, Cross-Platform Python Package For Fast Photon Modeling, Jiaming Cao, Samuel Montero-Hernandez, Rickson C Mesquita, Adam T Eggebrecht, Hamid Dehghani

2020-Current year OA Pubs

SIGNIFICANCE: Accurate and efficient photon modeling plays an essential role in the rapidly developing field of diffuse optical imaging, whereby the use of model-based analysis and image reconstruction can provide both educational and research benefits.

AIM: NIRFASTerFF is a cross-platform (Linux, macOS, and Windows) Python package for finite element method (FEM)-based light propagation modeling, supporting continuous-wave, frequency-domain, and time-resolved data for both exogenous and endogenous optical imaging applications. It also enables modeling of the autocorrelation function (

APPROACH: NIRFASTerFF incorporates highly parallelized FEM solvers for efficient computation on both CPU and GPU, leveraging OpenMP and CUDA acceleration. To support image …

Arousal As A Universal Embedding For Spatiotemporal Brain Dynamics, Ryan V Raut, Zachary P Rosenthal, Xiaodan Wang, Hanyang Miao, Zhanqi Zhang, Jin-Moo Lee, Marcus E Raichle, Adam Q Bauer, Steven L Brunton, Bingni W Brunton, J Nathan Kutz

2020-Current year OA Pubs

Neural activity in awake organisms shows widespread, spatiotemporally diverse correlations with behavioural and physiological measurements

Upregulation Of Adenosine A2a Receptor In Astrocytes Is Sufficient To Trigger Hippocampal Multicellular Dysfunctions And Memory Deficits, Agathe Launay, Miranda E Orr, Et Al.

2020-Current year OA Pubs

Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A

Progresssive Maculopathy In A Child Resulting From Vitreopapillary Traction On A Congenitally Anomalous Nerve, Ross M. Kennamer-Chapman, Lee M. Jampol, Rithwick Rajagopal

2020-Current year OA Pubs

PURPOSE: To present a case of worsening maculopathy and vision loss because of vitreopapillary traction associated with an anomalous optic nerve head in a pediatric patient successfully managed with pars plana vitrectomy.

METHODS: Retrospective case report.

RESULTS: A 13-year-old boy presented with unilateral maculopathy that slowly progressed over a 4-year period. As his visual acuity declined, he became increasingly symptomatic. The macular pathology occurred in the setting of vitreopapillary traction overlying multiple congenital optic nerve abnormalities, including a myelinated nerve fiber layer and a Bergmeister papilla. After pars plana vitrectomy to alleviate the traction, the patient's macular appearance improved, and …

Atg-3 Limits Orsay Virus Infection In C. Elegans And Regulates Collagen Pathways, Gowri Kalugotla, Vivien Marmerstein, Lawrence A. Schriefer, Leran Wang, Stephanie A. Morrison, Luis Casorla Perez, Gary A. Silverman, Tim Schedl, Stephen C. Pak, Megan T. Baldridge

2020-Current year OA Pubs

Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay virus infection of Caenorhabditis elegans. Orsay virus infection does not modulate autophagic flux, and re-feeding after starvation limits Orsay virus infection and blocks autophagic flux, suggesting that the role of ATG-3 in Orsay virus susceptibility is independent of its role in maintaining autophagic flux. atg-3 mutants phenocopy rde-1 mutants, which have a defect in RNA interference (RNAi), in susceptibility to Orsay virus infection …

Episodic Memory Involves Transient And Sparse Connectivity Aligned To Both Internal And External Events, Adam J. O. Dede, Peter Brunner, Jarod L. Roland, Et Al.

2020-Current year OA Pubs

Episodic memory depends on the coordination of local processing, indexed by high-frequency broadband (HFB) activity, with global organization, indexed by theta oscillations. However, theta and HFB exhibit asynchronous timing, raising the question of how results of local processing are communicated. Using intracranial EEG in patients performing a recognition memory task, we examined this coordination across medial temporal (MTL) and prefrontal (PFC) regions. HFB peaks occurred earlier in the MTL than in the PFC. Contrasting analyses were anchored either to these internally driven HFB peaks or to the external event of stimulus presentation. We discovered three key results. First, the role …

Real-World Effectiveness And Safety Of Upadacitinib In Crohn's Disease: A Multicenter Study, Jalpa Devi, Katherine Huang, Fnu Jaiprada, Julia Huecker, Parakkal Deepak, Et Al.

2020-Current year OA Pubs

BACKGROUND & AIMS: We aimed to describe the real-world effectiveness and safety of upadacitinib (UPA), an oral Janus kinase 1 inhibitor, in patients with Crohn's disease (CD).

METHODS: A retrospective analysis was conducted across 9 centers in the United States, focusing on adults with CD treated with UPA, 45 mg, as induction therapy for active luminal disease. The coprimary end points were clinical remission at 12 weeks (Harvey Bradshaw Index ≤4 or absence of symptoms on physician's global assessment) and endoscopic remission at 6 months (Simplified Endoscopic Mucosal Assessment for Crohn's Disease score of 0-1 or absence of ulcers). Secondary …

The Ifit2-Ifit3 Antiviral Complex Targets Short 5' Untranslated Regions On Viral Mrnas For Translation Inhibition, Dustin R Glasner, James Brett Case, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Recognition of foreign RNA is critical for the innate immune response to viruses. Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFIT) 2 and 3 are highly upregulated following viral infection, but mechanistic insight into their antiviral role is lacking. Here we demonstrate that short 5' untranslated regions (UTRs), a characteristic of many viral mRNAs, can serve as a molecular pattern for innate immune recognition via IFIT2 and IFIT3. Structure determination of the IFIT2-IFIT3 complex at 3.2 Å using cryo-EM reveals a domain-swapped heterodimer that is required for recognition of the viral mRNA 5' end, translation inhibition and antiviral activity. Critically, viral …

Diagnostic Efficacy And Clinical Impact Of Image-Guided Core Needle Biopsy Of Suspected Adult Nonvertebral Osteomyelitis, Winston L Winkler, Ige A George, Sumanth Gandra, Jonathan C Baker, Anderanik Tomasian, Benjamin Northrup, Theodore L Vander Velde, Travis J Hillen, Chongliang Luo, Resten Imaoka, Gino M Dettorre, Jack W Jennings

2020-Current year OA Pubs

OBJECTIVES: The diagnostic yield and clinical impact of image-guided core needle biopsy (ICNB) of suspected nonvertebral osteomyelitis in adults is heterogenous in published studies because of small sample size, indicating the need for large cohort studies.

METHODS: A retrospective analysis of ICNBs was performed from 2010 to 2021 for patients with suspected nonvertebral osteomyelitis. For each biopsy, a series of factors were analyzed, as well as if histopathology was diagnostic of osteomyelitis and if microbiological cultures were positive. Additionally, it was recorded in what way biopsy influenced clinical management regarding antimicrobial treatment. Multivariate statistical analysis was performed to evaluate the …

Sarm1 Inhibition Maintains Axonal Integrity After Rat Sciatic Nerve Transection And Repair, Ryan Sachar, Tony Y Lee, Aaron Diantonio, Christopher J Dy, Jason Wever, Jeff Milbrandt, David M Brogan

2020-Current year OA Pubs

PURPOSE: Sterile alpha and TlR motif containing-1 (SARM1) protein has been demonstrated to play a critical role in the initiation of Wallerian degeneration after nerve injury. The goal of this study was to assess whether blockade of SARM1 activity inhibits Wallerian degeneration following nerve transection, potentially promoting more rapid recovery of axonal function.

METHODS: An adeno-associated virus plasmid encoded with a dominant-negative SARM1 protein fused with green fluorescent protein to impair SARM1 function, was injected into 24 juvenile rats to create a SARM1 dominant-negative (SARM1-DN) phenotype. Twenty-four control rats were injected with a control plasmid expressing only green fluorescent protein. …

Moderators Of Antidepressant Augmentation Versus Switch In The Optimum Randomised Controlled Trial, Helena K Kim, Jordan F Karp, Helen Lavretsky, Daniel M Blumberger, Patrick J Brown, Alastair J Flint, Emily Lenard, J Philip Miller, Charles F Reynolds, Steven P Roose, Eric J Lenze, Benoit H Mulsant

2020-Current year OA Pubs

BACKGROUND: Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.

AIMS: Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.

METHOD: We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (

RESULTS: Of …

The Multilevel Limb-Loss And Preservation Rehabilitation Continuum Model (Mlprc): An Evidence-Based Implementation Model Integrating Multiple Perspectives To Improve Outcomes For People Facing Limb Loss, Prateek Grover, Elvin Geng, Rachel G Tabak

2020-Current year OA Pubs

BACKGROUND: The patient journey from threatened to actual limb loss, subsequent rehabilitation, and limb preservation through the health system is complicated and prone to delays, attrition, and inequities. A shared multi(socioecological)-level conceptualization of this journey among the multiple stakeholders is the first step for systematically improving limb care through identification of bottlenecks and gaps, contributory factors, and responsive interventions and implementation strategies.

OBJECTIVE: To meet this knowledge gap by presenting a novel implementation model, the Multilevel Limb-loss and Preservation Rehabilitation Continuum (MLPRC), that can be used to develop multilevel applications.

METHODS: MLPRC was developed in three overlapping steps: (1) design …

Basal Cell Of Origin Resolves Neuroendocrine-Tuft Lineage Plasticity In Cancer, Abbie S Ireland, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes

Women With Persistent Atrial Fibrillation Need More Than Pulmonary Vein Isolation: Personalised Extra-Pulmonary Vein Ablation Strategy Vs. Pulmonary Vein Isolation Alone In The Tailored-Af Trial, Isabel Deisenhofer, Daniel H Cooper, Et Al.

2020-Current year OA Pubs

AIMS: There is still conflicting evidence if women with persistent atrial fibrillation (AF) profit from a pulmonary vein isolation (PVI) plus strategy. We evaluated the efficacy of a spatio-temporal dispersion-targeted ablation strategy in women from the TAILORED-AF trial.

METHODS AND RESULTS: In TAILORED-AF, 370 patients were randomised to either a personalised, artificial intelligence (AI)-guided tailored ablation or to PVI-only. AF substrate mapping data and 12-month ablation outcomes were compared between women and men. Overall, 21% patients were female (70.4 ± 6.9 vs. 64.5 ± 8.5 years for men, P < 0.001). While spatio-temporal dispersion extent was similar between groups, left atrial low-voltage surface area (< 0.2 mV) was significantly larger in women (P < 0.01). In women, the single-procedure freedom from AF (76% vs. 50%, log-rank P < 0.001) and any atrial arrhythmia (56% vs. 38%, log-rank P < 0.05) were significantly superior to PVI alone with a tailored procedure. In the PVI-only group, the single-procedure freedom from AF (50% vs. 70%, log-rank P < 0.001) and any atrial arrhythmia (38% vs. 61%, log-rank P < 0.001) were significantly lower in women. After a tailored ablation, no significant differences were observed between women and men regarding freedom from AF (76% vs. 91%, log-rank P = 0.07) or any atrial arrhythmia (56% vs. 62%, log-rank P = 0.69) free survival.

CONCLUSION: Compared to men, PVI-only in women with persistent AF leads …

How Augmin Establishes The Angle Of The Microtubule Branch Site, Sophie M Travis, Jodi Kraus, Collin T Mcmanus, Kiana Golden, Rui Zhang, Sabine Petry

2020-Current year OA Pubs

How microtubules (MTs) are generated in the proper orientation is essential to understanding how the cytoskeleton organizes a cell and MT-dependent events such as cell division. In the spindle, most MTs are generated through the branching MT nucleation pathway. In this pathway, new MTs are nucleated from the side of existing MTs and oriented at a shallow angle by the branching factor augmin, ensuring that both MTs have the same polarity. Yet, how augmin binds MTs and sets the branch angle has remained unclear. Here, we report the cryo-electron microscopy structure of an augmin subcomplex on the MT. This structure …

Complement Activation In Secondary Thrombotic Microangiopathies, Johann Morelle, Fernando Caravaca-Fontan, Fadi Fakhouri, Eleni Frangou, Annette Bruchfeld, Jürgen Floege, Safak Mirioglu, Sarah M Moran, Stefanie Steiger, Kate I Stevens, Onno Y K Teng, Selda Aydin, Anuja Java, Sjoerd A M E G Timmermans, Andreas Kronbichler

2020-Current year OA Pubs

Secondary thrombotic microangiopathies (TMAs) represent a heterogeneous group of diseases associated with a high risk of kidney failure and death despite available therapeutic strategies. Strong evidence implicates complement activation in the pathogenesis of secondary TMA, and emerging data increasingly suggest that pharmacological blockade of the complement improves the outcomes in patients with secondary TMA. Certain forms of secondary TMA, including postpartum TMA, TMA with coexisting hypertensive emergency and de novo TMA after kidney transplantation exhibit a high prevalence of pathogenic variants in complement genes, similar to those observed in primary atypical haemolytic uraemic syndrome. These conditions should be considered as …

Chromatin Profiling Identifies Putative Dual Roles For H3k27me3 In Regulating Cell Type-Specific Genes And Transposable Elements In Choanoflagellates, James M Gahan, Lily W Helfrich, Laura A Wetzel, Natarajan V Bhanu, Zuo-Fei Yuan, Benjamin A Garcia, Robert J Klose, Alex De Mendoza, David S Booth

2020-Current year OA Pubs

Chromatin-based mechanisms contribute to the exquisite regulation of gene expression during animal development. But how those mechanisms evolved remains elusive. Here we investigate chromatin regulatory features in the closest relatives of animals, choanoflagellates. In a model choanoflagellate Salpingoeca rosetta, we compare chromatin accessibility and histone modifications to gene expression. Accessible genomic regions in S. rosetta primarily correspond to gene promoters, and we find no evidence of distal gene regulatory elements that resemble enhancers deployed to regulate developmental genes in animals. Remarkably, the histone modification H3K27me3 decorates genes with cell type-specific expression, revealing a functional similarity in S. rosetta and animals. …

Brca2 Deficiency And Replication Stress Drive Apobec3-Mediated Genomic Instability, Kathy Situ, Abby M Green, Et Al.

2020-Current year OA Pubs

BRCA2 plays a critical role in stabilizing stalled replication forks, yet critical gaps remain in understanding how BRCA2 deficiency triggers fork collapse and drives genomic instability. Here, we identify cytidine deaminase APOBEC3B as a key driver of this process. Using a unique uracil-in-DNA probe, we show that BRCA2 loss promotes APOBEC3B-mediated uracil accumulation in single-stranded DNA (U-ssDNA) at stalled forks. These lesions when processed by UNG2 and APE1, trigger fork collapse and release ssDNA fragments into the cytoplasm, activating NF-κB signaling. This in turn upregulates APOBEC3B expression, establishing a self-reinforcing loop that amplifies cytidine deamination at stalled forks and exacerbates …