Digital Commons Network^™

Fdg-Pet/Mri For Nonoperative Management Of Rectal Cancer: A Prospective Pilot Study, Semra Ince, Malak Itani, Lauren E Henke, Radhika K Smith, Paul E Wise, Matthew G Mutch, Sean C Glasgow, Matthew L Silviera, Katrina S Pedersen, Steven R Hunt, Hyun Kim, Tyler J Fraum

2020-Current year OA Pubs

Nonoperative management (NOM) is increasingly utilized for rectal cancer patients with a clinical complete response (cCR) following total neoadjuvant therapy (TNT). The objective of this pilot study was to determine whether FDG-PET/MRI alters clinical response assessments among stage I-III rectal cancer patients undergoing TNT followed by NOM, relative to MRI alone. This prospective study included 14 subjects with new rectal cancer diagnoses. Imaging consisted of FDG-PET/MRI for initial staging, post-TNT restaging, and surveillance during NOM. Two independent readers assessed treatment response on MRI followed by FDG-PET/MRI. Inter-reader differences were resolved by consensus review. The reference standard for post-TNT restaging consisted …

An Allosteric Modulator Activates Bk Channels By Perturbing Coupling Between Ca2+ Binding And Pore Opening, Guohui Zhang, Xianjin Xu, Zhiguang Jia, Yanyan Geng, Hongwu Liang, Jingyi Shi, Martina Marras, Carlota Abella, Karl L Magleby, Jonathan R Silva, Jianhan Chen, Xiaoqin Zou, Jianmin Cui

2020-Current year OA Pubs

BK type Ca

Ornithine Decarboxylase Supports Ilc3 Responses In Infectious And Autoimmune Colitis Through Positive Regulation Of Il-22 Transcription, Vincent Peng, Siyan Cao, Tihana Trsan, Jennifer K Bando, Julian Avila-Pacheco, John L Cleveland, Clary Clish, Ramnik J Xavier, Marco Colonna

2020-Current year OA Pubs

Group 3 innate lymphoid cells (ILC3s) are RORγT

The Evolution, Current Indications And Outcomes Of Cementless Total Knee Arthroplasty, Maria T Schwabe, Charles P Hannon

2020-Current year OA Pubs

Total knee arthroplasty (TKA) has been performed by orthopedic surgeons for decades, but the cementless TKA has only recently gained much interest in the world of arthroplasty. Initially, early designs had multiple complications, particularly with aseptic loosening due to osteolysis and micromotion. However, modifications have shown good outcomes and excellent survivorship. Over the last several decades, changes in implant designs as well as implant materials/coatings have helped with bone in growth and stability. Furthermore, surgeons have been performing TKA in younger and more obese patients as these populations have been increasing. Good results from the cementless TKA compared to cemented …

A Human Stat3 Gain-Of-Function Variant Confers T Cell Dysregulation Without Predominant Treg Dysfunction In Mice, Erica G Schmitt, Kelsey A Toth, Samuel I Risma, Ana Kolicheski, Nermina Saucier, Rafael J. Feliciano Berríos, Zev J. Greenberg, Jennifer W. Leiding, Jack J. Bleesing, Akaluck Thatayatikom, Laura G. Schuettpelz, John R. Edwards, Tiphanie P. Vogel, Megan A Cooper

2020-Current year OA Pubs

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) …

Tuft-Cell-Intrinsic And -Extrinsic Mediators Of Norovirus Tropism Regulate Viral Immunity, Madison S Strine, Mia Madel Alfajaro, Vincent R Graziano, Jaewon Song, Leon L Hsieh, Ryan Hill, Jun Guo, Kelli L Vandussen, Robert C Orchard, Megan T Baldridge, Sanghyun Lee, Craig B Wilen

2020-Current year OA Pubs

Murine norovirus (MNoV) is a model for human norovirus and for interrogating mechanisms of viral tropism and persistence. We previously demonstrated that the persistent strain MNoV

Combination Of Common Mtdna Variants Results In Mitochondrial Dysfunction And A Connective Tissue Dysregulation, Patrick M Schaefer, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA)

Genetic Addiction Risk Severity Assessment Identifies Polymorphic Reward Genes As Antecedents To Reward Deficiency Syndrome (Rds) Hypodopaminergia's Effect On Addictive And Non-Addictive Behaviors In A Nuclear Family, Catherine A Dennen, Kenneth Blum, Abdalla Bowirrat, Panayotis K Thanos, Igor Elman, Mauro Ceccanti, Rajendra D Badgaiyan, Thomas Mclaughlin, Ashim Gupta, Anish Bajaj, David Baron, B William Downs, Debasis Bagchi, Mark S Gold

2020-Current year OA Pubs

This case series presents the novel genetic addiction risk score (GARS), which shows a high prevalence of polymorphic risk alleles of reward genes in a nuclear family with multiple reward deficiency syndrome (RDS) behavioral issues expressing a hypodopaminergic antecedent. The family consists of a mother, father, son, and daughter. The mother experienced issues with focus, memory, anger, and amotivational syndrome. The father experienced weight issues and depression. The son experienced heavy drinking, along with some drug abuse and anxiety. The daughter experienced depression, lethargy, brain fog, focus issues, and anxiety, among others. A major clinical outcome of the results presented …

High-Throughput Analysis Of Tissue Microarrays Using Automated Desorption Electrospray Ionization Mass Spectrometry, Nicolás M Morato, Hannah Marie Brown, Diogo Garcia, Erik H Middlebrooks, Mark Jentoft, Kaisorn Chaichana, Alfredo Quiñones-Hinojosa, R Graham Cooks

2020-Current year OA Pubs

Tissue microarrays (TMAs) are commonly used for the rapid analysis of large numbers of tissue samples, often in morphological assessments but increasingly in spectroscopic analysis, where specific molecular markers are targeted via immunostaining. Here we report the use of an automated high-throughput system based on desorption electrospray ionization (DESI) mass spectrometry (MS) for the rapid generation and online analysis of high-density (6144 samples/array) TMAs, at rates better than 1 sample/second. Direct open-air analysis of tissue samples (hundreds of nanograms) not subjected to prior preparation, plus the ability to provide molecular characterization by tandem mass spectrometry (MS/MS), make this experiment versatile …

Socioeconomic Status And Modification Of Atherosclerotic Cardiovascular Disease Risk Prediction: Epidemiological Analysis Using Data From The Atherosclerosis Risk In Communities Study, Kamal Henderson, Brystana Kaufman, Jason S. Rotter, Sally Stearns, Carla A A Sueta, Randi Foraker, P Michael Ho, Patricia P Chang

2020-Current year OA Pubs

OBJECTIVE: Examine whether the relationship between the pooled cohort equations (PCE) predicted 10-year risk for atherosclerotic cardiovascular disease (ASCVD) and absolute risk for ASCVD is modified by socioeconomic status (SES).

DESIGN: Population-based longitudinal cohort study-Atherosclerosis Risk in Communities (ARIC)-investigating the development of cardiovascular disease across demographic subgroups.

SETTING: Four communities in the USA-Forsyth County, North Carolina, Jackson, Mississippi, suburbs of Minneapolis, Minnesota and Washington County, Maryland.

PARTICIPANTS: We identified 9782 ARIC men and women aged 54-73 without ASCVD at study visit 4 (1996-1998).

PRIMARY OUTCOME MEASURES: Risk ratio (RR) differences in 10-year incident hospitalisations or death for ASCVD by SES …

Oxidative Stress-Induced Cellular Senescence In Aging Retina And Age-Related Macular Degeneration, Ryo Terao, Tazbir Ahmed, Ayana Suzumura, Hiroko Terasaki

2020-Current year OA Pubs

Aging leads to a gradual decline of function in multiple organs. Cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) are age-related ocular diseases. Because their pathogenesis is unclear, it is challenging to combat age-related diseases. Cellular senescence is a cellular response characterized by cell cycle arrest. Cellular senescence is an important contributor to aging and age-related diseases through the alteration of cellular function and the secretion of senescence-associated secretory phenotypes. As a driver of stress-induced premature senescence, oxidative stress triggers cellular senescence and age-related diseases by inducing senescence markers via reactive oxygen species and mitochondrial dysfunction. In this review, …

Preventive Behaviors And Information Sources During Covid-19 Pandemic: A Cross-Sectional Study In Japan, Manae Uchibori, Cyrus Ghaznavi, Michio Murakami, Akifumi Eguchi, Hiroyuki Kunishima, Satoshi Kaneko, Keiko Maruyama-Sakurai, Hiroaki Miyata, Shuhei Nomura

2020-Current year OA Pubs

BACKGROUND: individual preventive behaviors are one of the key measures needed to prevent the spread of COVID-19. This study sought to identify the factors associated with the adoption of COVID-19 preventive measures, focusing specifically on information sources.

METHODS: we conducted a nationally representative cross-sectional survey of 30,053 Japanese adults in February 2021. The survey asked about socioeconomic, health-related, and psychological characteristics, attitudes toward immunization, and the use of information sources regarding COVID-19. We have constructed multivariable logistic regression to estimate the factors associated with the adoption of three preventive measures: 3Cs avoidance, hand hygiene and respiratory hygiene.

RESULTS: socioeconomic variables, …

Single-Cell Multiomics Identifies Clinically Relevant Mesenchymal Stem-Like Cells And Key Regulators For Mpnst Malignancy, Lai Man Natalie Wu, Joshua Rubin, Et Al.

2020-Current year OA Pubs

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin

Phenome-Wide Analysis Of Taiwan Biobank Reveals Novel Glycemia-Related Loci And Genetic Risks For Diabetes, Chia-Jung Lee, Ting-Huei Chen, Aylwin Ming Wee Lim, Chien-Ching Chang, Jia-Jyun Sie, Pei-Lung Chen, Su-Wei Chang, Shang-Jung Wu, Chia-Lin Hsu, Ai-Ru Hsieh, Wei-Shiung Yang, Cathy S J Fann

2020-Current year OA Pubs

To explore the complex genetic architecture of common diseases and traits, we conducted comprehensive PheWAS of ten diseases and 34 quantitative traits in the community-based Taiwan Biobank (TWB). We identified 995 significantly associated loci with 135 novel loci specific to Taiwanese population. Further analyses highlighted the genetic pleiotropy of loci related to complex disease and associated quantitative traits. Extensive analysis on glycaemic phenotypes (T2D, fasting glucose and HbA

Bi-Allelic Camsap1 Variants Cause A Clinically Recognizable Neuronal Migration Disorder, Reham Khalaf-Nazzal, Jennifer L Griffith, Joseph R Walsh, Amber Neilson, Evguenia Kouranova, Xiaoxia Cui, David T Curiel, Et Al.

2020-Current year OA Pubs

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and …

Proteogenomic Markers Of Chemotherapy Resistance And Response In Triple-Negative Breast Cancer, Meenakshi Anurag, Shunqiang Li, Ian S Hagemann, Jeremy Hoog, Foluso O Ademuyiwa, Et Al.

2020-Current year OA Pubs

UNLABELLED: Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2-M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low …

The 5-Hydroxymethylcytosine Landscape Of Prostate Cancer, Martin Sjöström, Nupam P Mahajan, Christopher A Maher, Et Al.

2020-Current year OA Pubs

UNLABELLED: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, …

Phase Iii Trial Of Chemoradiotherapy With Temozolomide Plus Nivolumab Or Placebo For Newly Diagnosed Glioblastoma With Methylated Mgmt Promoter, Michael Lim, George Ansstas, Et Al.

2020-Current year OA Pubs

BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).

METHODS: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days …

Genome-Wide Meta-Analysis For Alzheimer's Disease Cerebrospinal Fluid Biomarkers, Iris E Jansen, Muhammad Ali, Yun Ju Sung, Carlos Cruchaga, Duber Gomez-Fonseca, Et Al.

2020-Current year OA Pubs

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for …

Risk-Adjusted Safety Analysis Of The Oral Jak2/Irak1 Inhibitor Pacritinib In Patients With Myelofibrosis, Naveen Pemmaraju, Claire Harrison, Vikas Gupta, Srdan Verstovsek, Bart Scott, Stephen T Oh, Francesca Palandri, Haifa Kathrin Al-Ali, Marta Sobas, Mary Frances Mcmullin, Ruben Mesa, Sarah Buckley, Karisse Roman-Torres, Alessandro Vannucchi, Abdulraheem Yacoub

2020-Current year OA Pubs

The safety profile of the novel oral JAK2/IRAK1 inhibitor pacritinib in patients with cytopenic myelofibrosis was described in the Phase 2 PAC203 and Phase 3 PERSIST-2 studies. To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk-adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia.

Dose-Dependent Seizure Control With Mek Inhibitor Therapy For Progressive Glioma In A Child With Neurofibromatosis Type 1, Evan Cantor, Ashley Meyer, Stephanie M Morris, Judith L Z Weisenberg, Nicole M Brossier

2020-Current year OA Pubs

BACKGROUND: Low-grade gliomas (LGGs) occurring in children can result in many different neurologic complications, including seizures. MEK inhibitors are increasingly being used to treat LGG, but their effect on associated neurologic symptoms has not been established.

RESULTS: Here, we report a patient with neurofibromatosis type 1 (NF1), medically refractory epilepsy (MRE), and an extensive optic pathway glioma (OPG) who developed dose-dependent seizure control while being treated with selumetinib. Seizure frequency rebounded after dose reduction for cardiac toxicity, then improved, and finally ceased after restarting full dosing, allowing confidence in the cause of improvement.

CONCLUSION: Selumetinib may have promise in epilepsy …

Inositol Phosphorylceramide Synthase Null Leishmania Are Viable And Virulent In Animal Infections Where Salvage Of Host Sphingomyelin Predominates, F Matthew Kuhlmann, Phillip N Key, Suzanne M Hickerson, John Turk, Fong-Fu Hsu, Stephen M Beverley

2020-Current year OA Pubs

Many pathogens synthesize inositol phosphorylceramide (IPC) as the major sphingolipid (SL), differing from the mammalian host where sphingomyelin (SM) or more complex SLs predominate. The divergence between IPC synthase and mammalian SL synthases has prompted interest as a potential drug target. However, in the trypanosomatid protozoan Leishmania, cultured insect stage promastigotes lack de novo SL synthesis (Δspt2

To Calibrate Or Not To Calibrate? A Methodological Dilemma In Experimental Pain Research, Waclaw M Adamczyk, Tibor M Szikszay, Hadas Nahman-Averbuch, Jacek Skalski, Jakub Nastaj, Philip Gouverneur, Kerstin Luedtke

2020-Current year OA Pubs

To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body …

Real-World Evidence Supporting Tandem Control-Iq Hybrid Closed-Loop Success In The Medicare And Medicaid Type 1 And Type 2 Diabetes Populations, Gregory P Forlenza, Anders L Carlson, Rodolfo J Galindo, Davida F Kruger, Carol J Levy, Janet B Mcgill, Guillermo Umpierrez, Grazia Aleppo

2020-Current year OA Pubs

No abstract provided.

Transgenic Force Sensors And Software To Measure Force Transmission Across The Mammalian Nuclear Envelope In Vivo, Kelli D Fenelon, Evan Thomas, Mohammad Samani, Min Zhu, Hirotaka Tao, Yu Sun, Helen Mcneill, Sevan Hopyan

2020-Current year OA Pubs

Nuclear mechanotransduction is a growing field with exciting implications for the regulation of gene expression and cellular function. Mechanical signals may be transduced to the nuclear interior biochemically or physically through connections between the cell surface and chromatin. To define mechanical stresses upon the nucleus in physiological settings, we generated transgenic mouse strains that harbour FRET-based tension sensors or control constructs in the outer and inner aspects of the nuclear envelope. We knocked-in a published esprin-2G sensor to measure tensions across the LINC complex and generated a new sensor that links the inner nuclear membrane to chromatin. To mitigate challenges …

A New Mouse Model Of Charcot-Marie-Tooth 2j Neuropathy Replicates Human Axonopathy And Suggest Alteration In Axo-Glia Communication, Ghjuvan'ghjacumu Shackleford, Yo Sasaki, Et Al.

2020-Current year OA Pubs

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 …

Ascertainment Of Vaccination Status By Self-Report Versus Source Documentation: Impact On Measuring Covid-19 Vaccine Effectiveness, Meagan Stephenson, Jennie H Kwon, Et Al

2020-Current year OA Pubs

BACKGROUND: During the COVID-19 pandemic, self-reported COVID-19 vaccination might facilitate rapid evaluations of vaccine effectiveness (VE) when source documentation (e.g., immunization information systems [IIS]) is not readily available. We evaluated the concordance of COVID-19 vaccination status ascertained by self-report versus source documentation and its impact on VE estimates.

METHODS: Hospitalized adults (≥18 years) admitted to 18 U.S. medical centers March-June 2021 were enrolled, including COVID-19 cases and SARS-CoV-2 negative controls. Patients were interviewed about COVID-19 vaccination. Abstractors simultaneously searched IIS, medical records, and other sources for vaccination information. To compare vaccination status by self-report and documentation, we estimated percent agreement …

Comparison Of Indirect Fungal Diagnostic Tests In Patients With Proven Histoplasmosis, Gayathri Krishnan, Margaret Power, J Ryan Bariola, Ryan Dare

2020-Current year OA Pubs

BACKGROUND: Histoplasmosis is a common cause of invasive fungal infection in endemic regions and accurate diagnosis is difficult without direct tissue culture or pathology. Indirect fungal antigen testing for various fungal pathogens are typically performed to assist with diagnostic workup, though cross-reaction can lead to difficulty in interpreting results. We aimed to compare indirect fungal diagnostic tests and evaluate prevalence of positive antigen testing for non-

METHODS: We performed a single-center retrospective review of adult patients with proven histoplasmosis diagnosed by fungal culture and/or cytology from January 2010 to March 2018. Patient demographics, clinical characteristics, and results of fungal antigen …

Assessment Of Infectious Diseases Risks From Dental Aerosols In Real-World Settings, Shruti Choudhary, Tracey Bach, Meghan A Wallace, Daniel C Stoeckel, Martin H Thornhill, Peter B Lockhart, Jennie H Kwon, Stephen Y Liang, Carey-Ann D Burnham, Pratim Biswas, Heidi M Steinkamp, Michael J Durkin

2020-Current year OA Pubs

BACKGROUND: Infectious diseases physicians are leaders in assessing the health risks in a variety of community settings. An understudied area with substantial controversy is the safety of dental aerosols. Previous studies have used in vitro experimental designs and/or indirect measures to evaluate bacteria and viruses from dental surfaces. However, these findings may overestimate the occupational risks of dental aerosols. The purpose of this study was to directly measure dental aerosol composition to assess the health risks for dental healthcare personnel and patients.

METHODS: We used a variety of aerosol instruments to capture and measure the bacterial, viral, and inorganic composition …

Profilin-1 Regulates Dna Replication Forks In A Context-Dependent Fashion By Interacting With Snf2h And Bod1l, Cuige Zhu, Mari Iwase, Ziqian Li, Faliang Wang, Annabel Quinet, Alessandro Vindigni, Jieya Shao

2020-Current year OA Pubs

DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected …