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448 results on '"Ann Harris"'

1. Stellate cells are in utero markers of pancreatic disease in cystic fibrosis

Author

Shih-Hsing Leir, Svyatoslav Tkachenko, Alekh Paranjapye, Frederick Meckler, Arnaud J. Van Wettere, Jenny L. Kerschner, Elizabeth Kuznetsov, Makayla Schacht, Pulak Gillurkar, Misha Regouski, Iuri Viotti Perisse, Cheyenne M. Marriott, Ying Liu, Ian Bunderson, Kenneth L. White, Irina A. Polejaeva, and Ann Harris

Subjects
Pancreatic disease, Cystic fibrosis (CF), CFTR, In utero development, Stellate cells, Single-cell RNA-seq, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
Abstract

Abstract Background Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR −/− ) to examine the evolution of pancreatic disease through gestation. Methods Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. Results Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR −/− pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR −/− animals at 80- and 120-days gestation, as are stellate cells at term. Conclusion The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

Published
2024
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2. A systematic review on the role of mitochondrial dysfunction/disorders in neurodevelopmental disorders and psychiatric/behavioral disorders

Author

Daniela V. Pinto Payares, Logan Spooner, Jennifer Vosters, Samantha Dominguez, Lauren Patrick, Ann Harris, and Shibani Kanungo

Subjects
mitochondrial disorder, mitochondrial dysfunction, neurodevelopmental disorder, psychiatric disorder, ASD, ADHD, Psychiatry, RC435-571
Abstract

IntroductionMitochondrial diseases are known inborn errors affecting energy metabolism and are as common as chronic diseases such as diabetes, affecting approximately 1 in 5,000 people. The role of mitochondrial diseases/dysfunction has been highlighted in neurodevelopmental disorders like ASD, ADHD, intellectual disability, and speech delay, as well as various psychiatric conditions. Neurodevelopmental disorders are increasingly recognized as having behavioral and psychiatric symptoms. Our study aimed to investigate reports of mitochondrial disorders, noting neurodevelopmental disorders and psychiatric/behavioral conditions.MethodsThis was done through a systematic review of literature from PubMed/MEDLINE, Scopus, and Cochrane Library up to November 2022.ResultsWe found 277 publications, of which 139 met the inclusion criteria. We mostly found review articles with mention of mitochondrial dysfunction/disorder in relation to ASD with brief mentions of psychiatric/behavioral comorbidities.DiscussionThis suggests a need for broader research efforts beyond ASD to understand the relationship between mitochondrial disorder or dysfunction and various neurodevelopmental and psychiatric/behavioral comorbidities.

Published
2024
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3. Investigating adverse genomic and regulatory changes caused by replacement of the full-length CFTR cDNA using Cas9 and AAV

Author

Sriram Vaidyanathan, Jenny L. Kerschner, Alekh Paranjapye, Vrishti Sinha, Brian Lin, Tracy A. Bedrosian, Adrian J. Thrasher, Giandomenico Turchiano, Ann Harris, and Matthew H. Porteus

Subjects
MT: RNA/DNA Editing, cystic fibrosis, CFTR super-exon, CFTR gene regulation, airway basal cell differentiation, genetic rearrangements, Therapeutics. Pharmacology, RM1-950
Abstract

A “universal strategy” replacing the full-length CFTR cDNA may treat >99% of people with cystic fibrosis (pwCF), regardless of their specific mutations. Cas9-based gene editing was used to insert the CFTR cDNA and a truncated CD19 (tCD19) enrichment tag at the CFTR locus in airway basal stem cells. This strategy restores CFTR function to non-CF levels. Here, we investigate the safety of this approach by assessing genomic and regulatory changes after CFTR cDNA insertion. Safety was first assessed by quantifying genetic rearrangements using CAST-seq. After validating restored CFTR function in edited and enriched airway cells, the CFTR locus open chromatin profile was characterized using ATAC-seq. The regenerative potential and differential gene expression in edited cells was assessed using scRNA-seq. CAST-seq revealed a translocation in ∼0.01% of alleles primarily occurring at a nononcogenic off-target site and large indels in 1% of alleles. The open chromatin profile of differentiated airway epithelial cells showed no appreciable changes, except in the region corresponding to the CFTR cDNA and tCD19 cassette, indicating no detectable changes in gene regulation. Edited stem cells produced the same types of airway cells as controls with minimal alternations in gene expression. Overall, the universal strategy showed minor undesirable genomic changes.

Published
2024
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4. Early developmental phenotypes in the cystic fibrosis sheep model

Author

Arnaud J. Van Wettere, Shih‐Hsing Leir, Calvin U. Cotton, Misha Regouski, Iuri Viotti Perisse, Jenny L. Kerschner, Alekh Paranjapye, Zhiqiang Fan, Ying Liu, Makayla Schacht, Kenneth L. White, Irina A. Polejaeva, and Ann Harris

Subjects
CF development, CFTR, CF GI tract, CF liver, CF lung, CF pancreas, Biology (General), QH301-705.5
Abstract

Abstract Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investigate the in utero origins of CF disease since the sheep closely mirrors critical aspects of human development. Wildtype (WT) and CFTR ‐/‐ sheep tissues were collected at 50, 65, 80, 100, and 120 days of gestation and term (147 days) and used for histological, electrophysiological, and molecular analysis. Histological abnormalities are evident in CFTR‐/‐ ‐/‐ animals by 80 days of gestation, equivalent to 21 weeks in humans. Acinar and ductal dilation, mucus obstruction, and fibrosis are observed in the pancreas; biliary fibrosis, cholestasis, and gallbladder hypoplasia in the liver; and intestinal meconium obstruction, as seen at birth in all large animal models of CF. Concurrently, cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent short circuit current is present in WT tracheal epithelium by 80 days gestation and is absent from CFTR ‐/‐ tissues. Transcriptomic profiles of tracheal tissues confirm the early expression of CFTR and suggest that its loss does not globally impair tracheal differentiation.

Published
2023
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5. Cellular heterogeneity in the 16HBE14o− airway epithelial line impacts biological readouts

Author

Jenny L. Kerschner, Alekh Paranjapye, and Ann Harris

Subjects
16HBE14o− cell line, cellular heterogeneity, CFTR, transcriptome, Physiology, QP1-981
Abstract

Abstract The airway epithelial cell line, 16HBE14o−, is an important cell model for studying airway disease. 16HBE14o− cells were originally generated from primary human bronchial epithelial cells by SV40‐mediated immortalization, a process that is associated with genomic instability through long‐term culture. Here, we explore the heterogeneity of these cells, with respect to expression of the cystic fibrosis transmembrane conductance regulator (CFTR) transcript and protein. We isolate clones of 16HBE14o− with stably higher and lower levels of CFTR in comparison to bulk 16HBE14o−, designated CFTRhigh and CFTRlow. Detailed characterization of the CFTR locus in these clones by ATAC‐seq and 4C‐seq showed open chromatin profiles and higher order chromatin structure that correlate with CFTR expression levels. Transcriptomic profiling of CFTRhigh and CFTRlow cells showed that the CFTRhigh cells had an elevated inflammatory/innate immune response phenotype. These results encourage caution in interpreting functional data from clonal lines of 16HBE14o− cells, generated after genomic or other manipulations.

Published
2023
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6. Enhancement of airway epithelial cell differentiation by pulmonary endothelial cell co-culture

Author

Umida Burkhanova, Ann Harris, and Shih-Hsing Leir

Subjects
Air–liquid interface, Endothelial cells, Lung progenitor cells, Matrix proteins, Biology (General), QH301-705.5
Abstract

Cross-talk between lung epithelial cells and their microenvironment has an important physiological role in development. Using an in vitro model of differentiation of human induced pluripotent stem cells (iPSCs) to air–liquid interface (ALI)-cultured lung epithelial cells, we investigated the contribution of the microenvironment to maintenance of the lung progenitor cell state. Our protocol modeled in vivo cell-to-matrix and cell-to-cell interactions. These included growth of iPSCs on inserts coated with different basement membrane proteins (collagen I, IV, fibronectin, heparan sulfate or Matrigel plus collagen IV) and co-culture with human pulmonary microvascular endothelial cells (HPMECs). Marker gene expression was measured by RT-qPCR and protein expression and localization was confirmed by immunocytochemistry. The results showed that iPSCs grown on collagen IV had the highest success rate in terms of differentiation to robust ALI-cultured lung epithelial cells, followed by fibronectin, collagen I and heparan sulfate. Coating with Matrigel mixed with collagen IV further increased the success rate to > 97 %. Co-culture of iPSCs with HPMECs enhanced the expression of key airway lineage markers (NKX2.1, KRT5, TP63, MUC5AC, MUC16, FOXJ1, CFTR and SCGB1A1) during ALI culture. Cross-talk between iPSCs and their microenvironment during cell differentiation had a significant effect on lung epithelial cell differentiation in these 3D in vitro models. Both matrix proteins and endothelial cells play critical roles in the differentiation of lung progenitor cells.

Published
2022
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7. Sheep models of F508del and G542X cystic fibrosis mutations show cellular responses to human therapeutics

Author

Iuri Viotti Perisse, Zhiqiang Fan, Arnaud Van Wettere, Ying Liu, Shih‐Hsing Leir, Jacob Keim, Misha Regouski, Michael D. Wilson, Kelly M. Cholewa, Sara N. Mansbach, Thomas J. Kelley, Zhongde Wang, Ann Harris, Kenneth L. White, and Irina A. Polejaeva

Subjects
animal models, CFTR, cloning, CRISPR/Cas9, human drugs, Biology (General), QH301-705.5
Abstract

Abstract Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively. The F508del causes deletion of the phenylalanine residue at position 508 and is associated with impaired CFTR protein folding. The G542X is a nonsense mutation that introduces a stop codon into the mRNA, thus preventing normal CFTR protein synthesis. Here, we describe the generation of CFTRF508del/F508del and CFTRG542X/G542X lambs using CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). First, we introduced either F508del or G542X mutations into sheep fetal fibroblasts that were subsequently used as nuclear donors for SCNT. The newborn CF lambs develop pathology similar to CFTR−/− sheep and CF patients. Moreover, tracheal epithelial cells from the CFTRF508del/F508del lambs responded to a human CFTR (hCFTR) potentiator and correctors, and those from CFTRG542X/G542X lambs showed modest restoration of CFTR function following inhibition of nonsense‐mediated decay (NMD) and aminoglycoside antibiotic treatments. Thus, the phenotype and electrophysiology of these novel models represent an important advance for testing new CF therapeutics and gene therapy to improve the health of patients with this life‐limiting disorder.

Published
2021
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8. Cell function and identity revealed by comparative scRNA-seq analysis in human nasal, bronchial and epididymis epithelia

Author

Alekh Paranjapye, Shih-Hsing Leir, Felix Huang, Jenny L. Kerschner, and Ann Harris

Subjects
Single cell RNA-seq, Cell identity, Human epithelia, Nasal, Bronchial, Epididymis, Cytology, QH573-671
Abstract

The evolutionary relationship of cells within tissues having a similar function but located in different anatomical sites is of considerable biological interest. The development of single-cell RNA sequencing (scRNA-seq) protocols has greatly enhanced opportunities to address this topic. Here we focus on cells in the epithelium which lines two regions of the human respiratory tract and the male genital ducts to delineate the shared, differentiated functions of the different cell populations. Transcriptomic data were used to assess the gene expression profiles of human bronchial, nasal, and epididymal epithelium (HBE, HNE, and HEE). Bulk RNA-seq showed many shared genes expressed in cells from the nasal and bronchial epithelium and highlighted their divergence from the epididymal epithelium. ScRNA-seq in HBE and HNE cells demonstrated overlapping gene expression patterns within basal and secretory cell populations. Moreover, the distribution of cell types was altered in HNE cells derived from donors with cystic fibrosis (CF) when compared to cells from healthy donors. Next, the HBE and HNE datasets were merged and confirmed intersection of cell type gene expression profiles from the two sites. However, secretory and ciliated cells were the most abundant types in the HBE samples, while more basal cells were seen in the HNE populations. We then merged single-cell data from the epididymis to determine if overlapping functions of these cells corresponded to those in the airway. Of note, only the pulmonary ionocytes/epididymis clear cells showed a strongly conserved identity, which was confirmed by imputation in bulk RNA-seq datasets from the same cells.

Published
2022
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9. Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials

Author

Sara Jane Webb, Frederick Shic, Michael Murias, Catherine A. Sugar, Adam J. Naples, Erin Barney, Heather Borland, Gerhard Hellemann, Scott Johnson, Minah Kim, April R. Levin, Maura Sabatos-DeVito, Megha Santhosh, Damla Senturk, James Dziura, Raphael A. Bernier, Katarzyna Chawarska, Geraldine Dawson, Susan Faja, Shafali Jeste, James McPartland, the Autism Biomarkers Consortium for Clinical Trials, Adham Atyabi, Madeline Aubertine, Carter Carlos, Shou-An A Chang, Scott Compton, Kelsey Dommer, Alyssa Gateman, Simone Hasselmo, Bailey Heit, Toni Howell, Ann Harris, Kathryn Hutchins, Julie Holub, Beibin Li, Samantha Major, Samuel Marsan, Takumi McAllister, Andriana S. Méndez Leal, Lisa Nanamaker, Charles A. Nelson, Helen Seow, Dylan Stahl, and Andrew Yuan

Subjects
autism spectrum disorder, biomarkers, clinical trial methods, guidelines, EEG, eye tracking, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol.

Published
2020
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10. Region-specific microRNA signatures in the human epididymis

Author

James A Browne, Shih-Hsing Leir, Scott E Eggener, and Ann Harris

Subjects
caput, cauda, corpus, human epididymis, microRNA, Diseases of the genitourinary system. Urology, RC870-923
Abstract

The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.

Published
2018
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11. An optimized protocol for isolating primary epithelial cell chromatin for ChIP.

Author

James A Browne, Ann Harris, and Shih-Hsing Leir

Subjects
Medicine, Science
Abstract

A critical part of generating robust chromatin immunoprecipitation (ChIP) data is the optimization of chromatin purification and size selection. This is particularly important when ChIP is combined with next-generation sequencing (ChIP-seq) to identify targets of DNA-binding proteins, genome-wide. Current protocols refined by the ENCODE consortium generally use a two-step cell lysis procedure that is applicable to a wide variety of cell types. However, the isolation and size selection of chromatin from primary human epithelial cells may often be particularly challenging. These cells tend to form sheets of formaldehyde cross-linked material in which cells are resistant to membrane lysis, nuclei are not released and subsequent sonication produces extensive high molecular weight contamination. Here we describe an optimized protocol to prepare high quality ChIP-grade chromatin from primary human bronchial epithelial cells. The ENCODE protocol was used as a starting point to which we added the following key steps to separate the sheets of formaldehyde-fixed cells prior to lysis. (1) Incubation of the formaldehyde-fixed adherent cells in Trypsin-EDTA (0.25% room temperature) for no longer than 5 min. (2) Equilibration of the fixed cells in detergent-free lysis buffers prior to each lysis step. (3) The addition of 0.5% Triton X-100 to the complete cell membrane lysis buffer. (4) Passing the cell suspension (in complete cell membrane lysis buffer) through a 25-gauge needle followed by continuous agitation on ice for 35 min. Each step of the modified protocol was documented by light microscopy using the Methyl Green-Pyronin dual dye, which stains cytoplasm red (Pyronin) and the nuclei grey-blue (Methyl green). This modified method is reproducibly effective at producing high quality sheared chromatin for ChIP and is equally applicable to other epithelial cell types.

Published
2014
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12. Collagen XV inhibits epithelial to mesenchymal transition in pancreatic adenocarcinoma cells.

Author

Anthony G Clementz, Michael J Mutolo, Shih-Hsing Leir, Kirsten J Morris, Karolina Kucybala, Henry Harris, and Ann Harris

Subjects
Medicine, Science
Abstract

Collagen XV (COLXV) is a secreted non-fibrillar collagen found within basement membrane (BM) zones of the extracellular matrix (ECM). Its ability to alter cellular growth in vitro and to reduce tumor burden and increase survival in vivo support a role as a tumor suppressor. Loss of COLXV during the progression of several aggressive cancers precedes basement membrane invasion and metastasis. The resultant lack of COLXV subjacent to the basement membrane and subsequent loss of its interactions with other proteins in this zone may directly impact tumor progression. Here we show that COLXV significantly reduces invasion of pancreatic adenocarcinoma cells through a collagen I (COLI) matrix. Moreover, we demonstrate that epithelial to mesenchymal transition (EMT) in these cells, which is recapitulated in vitro by cell scattering on a COLI substrate, is inhibited by over-expression of COLXV. We identify critical collagen-binding surface receptors on the tumor cells, including the discoidin domain receptor 1 (DDR1) and E-Cadherin (E-Cad), which interact with COLXV and appear to mediate its function. In the presence of COLXV, the intracellular redistribution of E-Cad from the cell periphery, which is associated with COLI-activated EMT, is inhibited and concurrently, DDR1 signaling is suppressed. Furthermore, continuous exposure of the pancreatic adenocarcinoma cells to high levels of COLXV suppresses endogenous levels of N-Cadherin (N-Cad). These data reveal a novel mechanism whereby COLXV can function as a tumor suppressor in the basement membrane zone.

Published
2013
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13. The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.

Author

Nicolas Jonckheere, Nicolas Skrypek, Johann Merlin, Anne Frédérique Dessein, Patrick Dumont, Emmanuelle Leteurtre, Ann Harris, Jean-Luc Desseyn, Christiane Susini, Frédéric Frénois, and Isabelle Van Seuningen

Subjects
Medicine, Science
Abstract

The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells.

Published
2012
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14. Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: significant association with MUC5AC.

Author

Xueliang Guo, Rhonda G Pace, Jaclyn R Stonebraker, Clayton W Commander, Anthony T Dang, Mitchell L Drumm, Ann Harris, Fei Zou, Dallas M Swallow, Fred A Wright, Wanda K O'Neal, and Michael R Knowles

Subjects
Medicine, Science
Abstract

Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.

Published
2011
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16. Refinement of a Community Service Attitude Scale.

Author

Shiarella, Ann Harris, McCarthy, Anne M., and Tucker, Mary L.

Abstract

The multi-stage development of the Community Service Attitudes Scale (CSAS), an instrument for measuring college students' attitudes about community service, is reported. The CSAS was developed based on the helping behavior model of S. Schwartz (1977). The developed instrument was tested with two samples of 437 and 332 college students. The scales of the CSAS show strong reliability evidence (coefficient alphas ranging from 0.72 to 0.93). Principal components analysis results are consistent with the Schwartz model. In addition, construct validity evidence also supports the model. The CSAS scales are positively correlated with gender, college major, community service experience, and intentions to engage in community service. The CSAS will be useful to researchers for conducting further research on the effects of service-learning and community service experiences for students. (Contains 7 tables and 25 references.) (SLD)

Published
1999

17. Scale of Community Service Attitudes for College Students.

Author

Shiarella, Ann Harris

Abstract

This paper describes the development of a scale that measures college students' attitudes about community service, based on Schwartz' process model of altruistic helping behavior. The development of such a scale is seen as essential for research, evaluation of interventions, and the prediction of outcomes of community service participation. The model identifies eight sequential steps in four phases in a helping action: (1) activation steps (awareness of need, actions to relieve need, ability to provide help, sense of connectedness), which involve perceptions of a need to respond; (2) obligation step (empathy), or the moral obligation to respond; (3) defense steps (costs and benefits, seriousness of need and responsibility to respond), or reassessment of potential responses; and (4) response step (desire) for engagement in helping behavior. Scale development involved writing 85 survey questions; 74 on community service attitudes, six on demographics, and five on intention to engage in community service. Testing was conducted with 437 college students and was followed by reliability and validity analyses. The scale is continuing to be refined. Tables present results of the analyses done with the pilot test population. (Contains 16 references.) (DB)

Published
1998

18. Berwyn Heights

Author

Davidson, Ann Harris. and Davidson, Ann Harris.

Published
2007

19. Early developmental phenotypes in the cystic fibrosis sheep model

Author

Arnaud J. Van Wettere, Shih‐Hsing Leir, Calvin U. Cotton, Misha Regouski, Iuri Viotti Perisse, Jenny L. Kerschner, Alekh Paranjapye, Zhiqiang Fan, Ying Liu, Makayla Schacht, Kenneth L. White, Irina A. Polejaeva, and Ann Harris

Subjects
Cancer Research, Physiology, Molecular Medicine, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Published
2022

20. Tracing sediment source within a glaciated landscape: new observations from detrital thermochronology and Raman spectroscopy in the Southern Alps of New Zealand

Author

Dru-Ann Harris, Karl Lang, Duna Roda Boluda, and Marcus Kurth

Abstract

The erosion of mountain landscapes is the greatest source of terrestrial sediment to global ocean basins and a critical part of the global carbon cycle regulating Earth’s climate over geologically relevant timescales. In particular, the expansion of mountain glaciers may accelerate bedrock erosion and rapidly increase the flux of terrestrial sediment from source areas. However, the mechanisms by which glaciation augments sediment flux are complex, and understanding them requires further research. Our research adopts a novel approach to determine the source of sediment in rivers exiting a glaciated landscape, combining detrital zircon fission-track “tracer” thermochronology and Raman spectroscopy of carbonaceous material (RSCM). Our research focuses on the Southern Alps of New Zealand as a model landscape with well-constrained lithology and a predictable exhumation gradient. In 5 west-draining transverse river catchments, we test the hypothesis that modern sediment is preferentially derived from glaciated, high-elevation areas of the catchment. Our 5 rivers span a range of glacial coverage, allowing us to further test the hypothesis that glacially-sourced sediment increases with the degree of glaciation in the catchment. Our preliminary results suggest that sediment is not exclusively derived from glaciated areas of the catchment, but may instead reflect additional deglaciated source areas affected by landsliding, possibly induced by seismicity along the Alpine Fault. Our research demonstrates a powerful and novel approach to tracing sediment sources within an individual catchment area and highlights complex interrelationships between mountain glaciation and changes in the magnitude and sources of sediment fluxes.

Published
2023

21. Partisans are more likely to entrench their beliefs in misinformation when political outgroup members fact-check claims

Author

Diego A. Reinero, Elizabeth Ann Harris, Steve Rathje, Annie Duke, and Jay Joseph Van Bavel

Abstract

The spread of misinformation has become a global issue with potentially dire consequences. There has been debate over whether misinformation corrections (or "fact-checks") sometimes "backfire," causing people to become more entrenched in misinformation. While recent studies suggest that an overall "backfire effect" is uncommon, we found that fact-checks were more likely to backfire when they came from a political outgroup member across three experiments (N = 1,217). We found that corrections reduced belief in misinformation; however, the effect of partisan congruence on belief was 5x more powerful than the effect of corrections. Moreover, corrections from political outgroup members were 52% more likely to backfire–leaving people with more entrenched beliefs in misinformation. In sum, corrections are effective on average, but have small effects compared to partisan identity congruence, and sometimes backfire--especially if they come from a political outgroup member. This suggests that partisan identity may drive irrational belief updating.

Published
2023

22. Transcriptomic analysis of lung development in wildtype and CFTR−/− sheep suggests an early inflammatory signature in the CF distal lung

Author

Jenny L. Kerschner, Alekh Paranjapye, Makayla Schacht, Frederick Meckler, Felix Huang, Gurkan Bebek, Arnaud J. Van Wettere, Misha Regouski, Iuri Viotti Perisse, Kenneth L. White, Irina A. Polejaeva, Shih-Hsing Leir, and Ann Harris

Subjects
Genetics, General Medicine
Abstract

The precise molecular events initiating human lung disease are often poorly characterized. Investigating prenatal events that may underlie lung disease in later life is challenging in man, but insights from the well-characterized sheep model of lung development are valuable. Here, we determine the transcriptomic signature of lung development in wild-type sheep (WT) and use a sheep model of cystic fibrosis (CF) to characterize disease associated changes in gene expression through the pseudoglandular, canalicular, saccular, and alveolar stages of lung growth and differentiation. Using gene ontology process enrichment analysis of differentially expressed genes at each developmental time point, we define changes in biological processes (BP) in proximal and distal lung from WT or CF animals. We also compare divergent BP in WT and CF animals at each time point. Next, we establish the developmental profile of key genes encoding components of ion transport and innate immunity that are pivotal in CF lung disease and validate transcriptomic data by RT-qPCR. Consistent with the known pro-inflammatory phenotype of the CF lung after birth, we observe upregulation of inflammatory response processes in the CF sheep distal lung during the saccular stage of prenatal development. These data suggest early commencement of therapeutic regimens may be beneficial.

Published
2023

24. An ectopic enhancer restores CFTR expression through de novo chromatin looping

Author

Jenny L. Kerschner, Alekh Paranjapye, Nirbhayaditya Vaghela, Michael D. Wilson, and Ann Harris

Subjects
Genetics, Molecular Medicine, Molecular Biology
Abstract

Transcription of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is regulated by both ubiquitous and cell-type selective cis-regulatory elements (CREs). These CREs include extragenic and intronic enhancers that bind lineage-specific transcription factors, and architectural protein-marked structural elements. Deletion of the airway-selective -35 kb enhancer in 16HBE14o

Published
2022

25. BACH1, the master regulator of oxidative stress, has a dual effect on CFTR expression

Author

Shiyi Yin, Alekh Paranjapye, Monali NandyMazumdar, Shih Hsing Leir, James A. Browne, and Ann Harris

Subjects
NF-E2-Related Factor 2, Bioinformatics, Glutamate-Cysteine Ligase, Respiratory System, Cystic Fibrosis Transmembrane Conductance Regulator, Locus (genetics), epithelial function, Biochemistry, Molecular Bases of Health & Disease, Cell Line, Tumor, transcription factors, Humans, oxidative stress, RNA, Small Interfering, Promoter Regions, Genetic, Enhancer, Molecular Biology, Transcription factor, Gene, Research Articles, Cell Proliferation, chromatin structure, Regulation of gene expression, Molecular Interactions, Gene Expression & Regulation, biology, Chemistry, Gene Expression Profiling, Epithelial Cells, Promoter, Hydrogen Peroxide, Cell Biology, Glutathione, Cystic fibrosis transmembrane conductance regulator, Chromatin, Cell biology, Oxygen, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, biology.protein, regulation of gene expression, Heme Oxygenase-1, Signal Transduction
Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a topologically associated domain (TAD) in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB domain and CNC homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here, we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (∼8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.

Published
2021

26. Keith Davidson: linguistics and English education

Author

John Hodgson and Ann Harris

Subjects
Linguistics and Language, Literature and Literary Theory, English education, Sociology, Language and Linguistics, Linguistics, Education
Abstract

A tribute to Keith Davidson, who died in April 2021. Keith combined a deep and passionate knowledge of linguistics with an equally deep and passionate understanding of the teaching and assessment of English. His insight and engagement with key issues of linguistics and English education is an invaluable legacy to students and teachers of language across the English-speaking world – and beyond.

Published
2021

27. The Iberian Hebrew Bible: Rabbinic Writings and Ornamental Carpet Pages

Author

Julie Ann Harris

Subjects
Visual Arts and Performing Arts, media_common.quotation_subject, Judaism, Middle Ages, Art, Classics, Hebrew Bible, media_common
Abstract

The Jewish Middle Ages have produced little in the way of writing on aesthetics, and what exists was largely generated by rabbis issuing opinions on legal matters concerning art objects. Wh...

Published
2021

28. Make grammar great again?

Author

John Hodgson and Ann Harris

Subjects
Linguistics and Language, Literature and Literary Theory, Higher education, Grammar, business.industry, Teaching method, media_common.quotation_subject, Perspective (graphical), Language and Linguistics, Linguistics, Education, Standard English, Evaluation methods, Rhetoric, Sociology, business, media_common
Abstract

The teaching of grammar has been strongly debated for decades, often with reference to an alleged decline in the 1960s. This article takes a historical perspective on grammar, or knowledge about language, within English Education. In the eighteenth century, Adam Smith’s Lectures in Rhetoric and Belles-lettres offered a discernibly modern combination of English language and literature. In the nineteenth century, however, university English courses were divided between belles-lettres and philology, while the conditions of elementary schooling favoured “factual” instruction in grammatical “correctness” based on an ideology rooted in the emergence of Standard English. In the twentieth century, the Newbolt Report and Blue Books questioned grammar teaching, but grammatical analysis remained part of public examinations until the 1960s. The last fifty years have seen major advances in linguistic education, but curriculum and assessment procedures continue to conceptualise grammar as the prescriptive teaching of “correct” forms of language.

Published
2021

29. OTX2 regulatesCFTRexpression during endoderm differentiation and occupies 3′cis‐regulatory elements

Author

Shih Hsing Leir, Monali NandyMazumdar, Alekh Paranjapye, Shiyi Yin, Jenny L. Kerschner, and Ann Harris

Subjects
0301 basic medicine, Induced Pluripotent Stem Cells, Cystic Fibrosis Transmembrane Conductance Regulator, Respiratory Mucosa, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Humans, Regulatory Elements, Transcriptional, Enhancer, Cells, Cultured, Regulation of gene expression, Otx Transcription Factors, biology, Endoderm, Cell Differentiation, respiratory system, Cystic fibrosis transmembrane conductance regulator, Cell biology, Chromatin, 030104 developmental biology, medicine.anatomical_structure, Histone, biology.protein, 030217 neurology & neurosurgery, Developmental Biology, Definitive endoderm
Abstract

Background Cell-specific and developmental mechanisms contribute to expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, however, its developmental regulation is poorly understood. Here we use human induced pluripotent stem cells (hiPSCs) differentiated into pseudostratified airway epithelial cells to study these mechanisms. Results Changes in gene expression and open chromatin profiles were investigated by RNA-seq and ATAC-seq, and revealed that alterations in CFTR expression are associated with differences in stage-specific open chromatin. Additionally, 2 novel open chromatin regions, at +19.6kb and +22.6kb 3' to the CFTR translational stop signal, were observed in definitive endoderm (DE) cells, prior to an increase in CFTR expression in anterior foregut endoderm (AFE) cells. Chromatin studies in DE and AFE cells revealed enrichment of active enhancer marks and occupancy of OTX2 at these sites in DE cells. Loss of OTX2 in DE cells alters histone modifications across the CFTR locus and results in a 2.5-fold to 5-fold increase in CFTR expression. However, deletion of the +22.6kb site alone does not affect CFTR expression in DE or AFE cells. Conclusions These results suggest that a network of interacting cis-regulatory elements recruit OTX2 to the locus to impact CFTR expression during early endoderm differentiation. This article is protected by copyright. All rights reserved.

Published
2021

30. Du Bois and Hegelian Idealism

Author

Kimberly Ann Harris

Subjects
Philosophy, Idealism, Hegelianism, Theology
Abstract

In a crossed-out section in his Fisk University commencement address on Otto von Bismarck, W. E. B. Du Bois mentions that Hegel was one of the figures that influenced him early on in his intellectual development. I argue that although Du Bois uses Hegelian language and employs a Hegelian conception of history in his address “The Conservation of Races,” he abandons both in his essay “Sociology Hesitant.” He became critical of the teleological conception of history because it rests on determinism, which in his view denies the possibility for social change. With what I call his “mystical holism,” Du Bois is at odds with Hegel’s methodological holism, a distinguishing characteristic of absolute idealism. Du Bois’s dynamic idealism, which grows out of opposition to Hegelian idealism, leaves us with hope for a world without racism or at the very least in a better position to develop idealism as an anti-racist system of philosophical thought.

Published
2021

31. Dual SMAD inhibition enhances the longevity of human epididymis epithelial cells

Author

Giuliana C. Coatti, Alekh Paranjapye, and Ann Harris

Subjects
Histology, Cell Biology, Pathology and Forensic Medicine
Abstract

Primary human epididymis epithelial (HEE) cells are valuable reagents for functional studies on the human epididymis. We used them previously to determine the transcriptional networks that establish cell identity along the length of the epididymis from caput, corpus, and cauda. These studies on HEE cells and organoids derived from them revealed important cellular properties. However, similar to other primary cells, HEE cells undergo replicative senescence and de-differentiation in culture. A cocktail of small molecules was shown elsewhere to extend longevity of epithelial basal cells. The components included transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP) antagonists, WNT agonist, and Rho-associated and coiled-coil containing protein kinase (ROCK) inhibitor (ROCKi), which together prevented the senescence-related upregulation of TGF-β signaling pathway members. Here, we treat HEE cells with the same cocktail and observed enhanced replicative potential and prolonged expression of markers of HEE differentiation. This treatment expands the differentiated HEE cell population available from individual epididymis tissue samples that can be used for molecular, cellular, and functional studies.

Published
2022

32. 'I'm making a positive change in my life': A mixed method evaluation of a well-being tertiary education unit

Author

Ben Piggott, Paola Chivers, Caroline Bulsara, Jenny Conlon, Kaine Grigg, Sarah Ann Harris, Michelle Lambert, Lynne Millar, and Christina M. Pollard

Subjects
Community and Home Care, Public Health, Environmental and Occupational Health
Abstract

Mental health disorders (MHDs) are prevalent amongst university students with detrimental impacts on individual students, universities and the wider community. There is an urgent need for proactive and preventative strategies to address the mental health crisis in the university population. This study evaluated the efficacy of a 13-week unit developed to directly educate university students about ways to improve and maintain well-being.Fifty-eight university students from five disciplines participated in a 13-week elective undergraduate unit "Well-Being Fundamentals for Success" as part of their degree. The Act Belong Commit mental health promotion campaign framework formed the basis of teaching materials. Outcome well-being measures were self-assessed at weeks 1, 6 and 12 using four scales: (1) Warwick-Edinburgh Mental Well-being Scale (WEMWBS); (2) Perceived Stress Scale (PSS); (3) Brief Resilience Scale (BRS) and (4) Mindful Attention Awareness Scale (MAAS). Post-unit group interviews (n = 11) were analysed for key themes.Linear mixed models demonstrated a significant improvement in BRS over the semester; well-being (WEMBS) and mindful attention (MAAS) did increase but not significantly. There was a significant increase in stress (PSS) over the semester. Key themes that emerged from the group interviews were that (1) University life contributes to well-being; (2) University life contributes to stress; (3) The well-being unit helped students see and do things differently; (4) An overall endorsement of the unit.University students' resilience increased over the semester following participation in a curriculum focused on well-being which featured a combination of theoretical content and experiential workshops. So what? Incorporating mental well-being curriculum into tertiary education is proactive preventive health strategy which may assist with the increasing prevalence of MHD in Australia.

Published
2022

33. Crohn Disease Presenting as the Cutaneous Rash of Pyoderma Gangrenosum

Author

Megan Bryce Laneiwcz, Elizabeth M. Lehto, and Corrie Ann Harris

Subjects
medicine.medical_specialty, Adolescent, Exacerbation, Disease, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, 030225 pediatrics, medicine, Humans, Crohn disease, business.industry, Soft tissue, 030208 emergency & critical care medicine, General Medicine, Emergency department, medicine.disease, Dermatology, Rash, Pyoderma Gangrenosum, Underlying disease, Pediatrics, Perinatology and Child Health, Emergency Medicine, Female, medicine.symptom, business, Pyoderma gangrenosum
Abstract

Pyoderma gangrenosum (PG) is a rare pediatric diagnosis, occurring in 3 to 10 patients per million per year, and most commonly seen in individuals between ages 20 and 50 years. This severe ulcerating skin rash is typically associated with an underlying systemic inflammatory condition. The appearance of PG often coincides with exacerbation of the underlying disease. In the absence of systemic symptoms, misdiagnosis of PG can occur, resulting in delay of appropriate treatment. The disease's visual similarity to soft tissue infections, which have dramatically increased in recent years (Ann Emerg Med. 2008;51,3:291-98), makes isolated dermatologic presentations particularly problematic. We present a case of Crohn disease presenting as the inflammatory rash of PG in the absence of significant bowel symptoms. This case highlights the importance of keeping PG in the differential for inflammatory lesions presenting to the emergency department.

Published
2020

34. A functional genomics approach to investigate the differentiation of iPSCs into lung epithelium at air‐liquid interface

Author

Dannielle L. Skander, Ann Harris, Shiyi Yin, Gurkan Bebek, Shih Hsing Leir, Jenny L. Kerschner, and Alekh Paranjapye

Subjects
Hepatocyte Nuclear Factor 3-alpha, 0301 basic medicine, CCCTC-Binding Factor, Cystic Fibrosis, Induced Pluripotent Stem Cells, Respiratory Mucosa, Biology, GATA Transcription Factors, Epithelium, Cell Line, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Humans, RNA-Seq, Induced pluripotent stem cell, Lung, Cells, Cultured, Air liquid interface, Cell Differentiation, Epithelial Cells, Genomics, Original Articles, Cell Biology, respiratory system, Chromatin, respiratory tract diseases, Cell biology, open chromatin, 030104 developmental biology, iPSC to HBE‐ALI, CTCF, 030220 oncology & carcinogenesis, Lung epithelium, Molecular Medicine, Original Article, transcriptional network, functional genomics, transcriptome, Functional genomics, Functional divergence
Abstract

The availability of robust protocols to differentiate induced pluripotent stem cells (iPSCs) into many human cell lineages has transformed research into the origins of human disease. The efficacy of differentiating iPSCs into specific cellular models is influenced by many factors including both intrinsic and extrinsic features. Among the most challenging models is the generation of human bronchial epithelium at air‐liquid interface (HBE‐ALI), which is the gold standard for many studies of respiratory diseases including cystic fibrosis. Here, we perform open chromatin mapping by ATAC‐seq and transcriptomics by RNA‐seq in parallel, to define the functional genomics of key stages of the iPSC to HBE‐ALI differentiation. Within open chromatin peaks, the overrepresented motifs include the architectural protein CTCF at all stages, while motifs for the FOXA pioneer and GATA factor families are seen more often at early stages, and those regulating key airway epithelial functions, such as EHF, are limited to later stages. The RNA‐seq data illustrate dynamic pathways during the iPSC to HBE‐ALI differentiation, and also the marked functional divergence of different iPSC lines at the ALI stages of differentiation. Moreover, a comparison of iPSC‐derived and lung donor‐derived HBE‐ALI cultures reveals substantial differences between these models.

Published
2020

35. Highly Efficient Gene Editing of Cystic Fibrosis Patient-Derived Airway Basal Cells Results in Functional CFTR Correction

Author

Jenny L. Kerschner, Brian R. Davis, Lei Zhang, Shingo Suzuki, Nadine Matthias, Matthew C. Mendel, Shiyi Yin, Eric J. Sorscher, Ann Harris, Andras Rab, Ana M. Crane, Anthony Conway, Scott H. Randell, Varada Anirudhan, Cristina Barillà, and Kenneth Kim

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, DNA, Complementary, Cystic Fibrosis, Cell, Cystic Fibrosis Transmembrane Conductance Regulator, Bronchi, Biology, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Complementary DNA, Drug Discovery, Genetics, medicine, Humans, Promoter Regions, Genetic, ΔF508, Molecular Biology, Cells, Cultured, 030304 developmental biology, Gene Editing, Pharmacology, 0303 health sciences, Intron, Cell Differentiation, Epithelial Cells, Sequence Analysis, DNA, respiratory system, medicine.disease, digestive system diseases, respiratory tract diseases, Chromatin, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Molecular Medicine, Original Article, Stem cell
Abstract

There is a strong rationale to consider future cell therapeutic approaches for cystic fibrosis (CF) in which autologous proximal airway basal stem cells, corrected for CFTR mutations, are transplanted into the patient's lungs. We assessed the possibility of editing the CFTR locus in these cells using zinc-finger nucleases and have pursued two approaches. The first, mutation-specific correction, is a footprint-free method replacing the CFTR mutation with corrected sequences. We have applied this approach for correction of ΔF508, demonstrating restoration of mature CFTR protein and function in air-liquid interface cultures established from bulk edited basal cells. The second is targeting integration of a partial CFTR cDNA within an intron of the endogenous CFTR gene, providing correction for all CFTR mutations downstream of the integration and exploiting the native CFTR promoter and chromatin architecture for physiologically relevant expression. Without selection, we observed highly efficient, site-specific targeted integration in basal cells carrying various CFTR mutations and demonstrated restored CFTR function at therapeutically relevant levels. Significantly, Omni-ATAC-seq analysis revealed minimal impact on the positions of open chromatin within the native CFTR locus. These results demonstrate efficient functional correction of CFTR and provide a platform for further ex vivo and in vivo editing. © 2020 The American Society of Gene and Cell TherapySuzuki et al. report correction of the CFTR defect in cystic fibrosis airway basal stem cells. They utilized gene-editing strategies either specific for the ΔF508 CFTR mutation or applicable to most CFTR mutations. Both approaches yielded highly efficient correction without selection, restoring CFTR function to therapeutically relevant levels.

Published
2020

36. Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells

Author

Shiyi Yin, Ann Harris, Jenny L. Kerschner, Hannah Swahn, Monali NandyMazumdar, Shih Hsing Leir, Alex Ge, and Alekh Paranjapye

Subjects
AcademicSubjects/SCI00010, Cystic Fibrosis Transmembrane Conductance Regulator, Respiratory Mucosa, Biology, Cell Line, 03 medical and health sciences, Transcription (biology), Genetics, Humans, Promoter Regions, Genetic, Enhancer, Gene, Sequence Deletion, 030304 developmental biology, 0303 health sciences, Activator (genetics), CCAAT-Enhancer-Binding Protein-beta, Gene regulation, Chromatin and Epigenetics, 030302 biochemistry & molecular biology, High-Throughput Nucleotide Sequencing, Epithelial Cells, Promoter, Chromatin, Cell biology, Enhancer Elements, Genetic, CTCF, Trans-Activators, Respiratory epithelium, RNA Polymerase II, CRISPR-Cas Systems, Caco-2 Cells
Abstract

The CFTR gene lies within an invariant topologically associated domain (TAD) demarcated by CTCF and cohesin, but shows cell-type specific control mechanisms utilizing different cis-regulatory elements (CRE) within the TAD. Within the respiratory epithelium, more than one cell type expresses CFTR and the molecular mechanisms controlling its transcription are likely divergent between them. Here, we determine how two extragenic CREs that are prominent in epithelial cells in the lung, regulate expression of the gene. We showed earlier that these CREs, located at −44 and −35 kb upstream of the promoter, have strong cell-type-selective enhancer function. They are also responsive to inflammatory mediators and to oxidative stress, consistent with a key role in CF lung disease. Here, we use CRISPR/Cas9 technology to remove these CREs from the endogenous locus in human bronchial epithelial cells. Loss of either site extinguished CFTR expression and abolished long-range interactions between these sites and the gene promoter, suggesting non-redundant enhancers. The deletions also greatly reduced promoter interactions with the 5′ TAD boundary. We show substantial recruitment of RNAPII to the −35 kb element and identify CEBPβ as a key activator of airway expression of CFTR, likely through occupancy at this CRE and the gene promoter.

Published
2020

37. The impulse wheel as hydropower converter for irrigation systems

Author

Gerald Müller, Hannah Williams, Kieran Atkinson, Rory Fleminger, Alexander Goodwin, and Natasha Ann Harris

Subjects
Fluid Flow and Transfer Processes, Environmental Engineering, Water Science and Technology, Civil and Structural Engineering
Abstract

There is a significant hydropower potential in irrigation canals worldwide. Much of this potential exists as energy dissipating ramp-type fall structures. Hydropower could be employed to pump water for water saving irrigation, or to generate electricity. This hydropower is unused, since there are no cost-effective hydropower converters for the specific conditions in irrigation canals, i.e. head differences from 0.3 to 5 m and flow volumes ranging from 0.1 to 15 m3/s. At Southampton University, a simple undershot impulse-type waterwheel with 180° jet deflection was developed specifically for this application. Large scale tests, with a scaling ratio of 1:2.4, showed efficiencies of 53%, confirming predictions from theory. The model employed a novel roller-type power take-off which eliminates the requirement for a cost-intensive gearbox. The impulse wheel has considerable development potential, and could be a cost-effective solution for small hydropower sites at ramp structures.

Published
2022

38. How social identity shapes conspiratorial belief

Author

Claire Robertson, Clara Pretus, Steve Rathje, Elizabeth Ann Harris, and Jay Joseph Van Bavel

Subjects
Social Identification, Surveys and Questionnaires, Conspiracy theories, Misinformation, Humans, Social identity, Public Health, General Psychology
Abstract

While conspiracy theories may offer benefits to those who believe in them, they can also foster intergroup conflict, threaten democracy, and undercut public health. We argue that the motivations behind conspiracy theory belief are often related to social identity. Conspiracy theories are well-positioned to fulfill social identity needs such as belongingness goals, the need to think highly of one’s in-group, and the need to feel secure in one’s group status. Understanding the social motives that attract people to conspiracy theories should be a focus of future research and may be key to creating more successful interventions to reduce socially harmful conspiracy theories.

Published
2022

39. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Author

Harry D Wilson, Elaine O'Toole, Andrew Bassett, Moritz U. G. Kraemer, Beth Blane, Scott Goodwin, Giri Shankar, Joseph Hughes, Lucy R. Frost, Alicia Thornton, Scott Elliott, Tammy V Merrill, Sheila Waugh, Alexander Adams, Peter Muir, Graciela Sluga, Rebecca Williams, Hannah Dent, Christophe Fraser, Shavanthi Rajatileka, John C. Hartley, Luke B Snell, Benjamin J Cogger, Lance Turtle, Alex Makunin, John A. Todd, Victoria Wright, Daniela De Angelis, James McKenna, Dinesh Aggarwal, Jonathan K. Ball, Jillian Durham, Garren Scott, Thushan I de Silva, Veena Raviprakash, Hannah M Pymont, Jason Coombes, Anita Lucaci, Luke R. Green, Leigh M Jackson, Hermione J. Webster, Louis du Plessis, David A. Jackson, Minal Patel, Áine O'Toole, Ravi Gupta, Marc Niebel, Garry Scarlett, Rajiv Shah, Guy Mollett, Kathy Li, Rory Gunson, Matthew Bashton, Carl Jones, Sara Kumziene-Summerhayes, Zoltan Molnar, Siona Silveira, Malte L Pinckert, Catherine Ludden, Angeliki Karamani, Leanne Kane, Brendan A I Payne, Alan McNally, Clare M. McCann, Holli Carden, Mohammad Raza, Alison E. Mather, Kate B. Cook, Amy Gaskin, David J. Williams, Shaun R. Seaman, Christopher I. Jones, Gilberto Betancor, Matthew T. G. Holden, Jennifier Liddle, Meera Unnikrishnan, Angie Green, Ben Taylor, Kelly Bicknell, Alexander J. Trotter, Emma Meader, Leanne M Kermack, Nathaniel Storey, Michelle Cronin, Sally Forrest, Sarah Jeremiah, Asad Zaidi, M Morgan, Alasdair MacLean, Thomas R. Connor, Johnathan M Evans, Rachael Stanley, Ryan P George, Nadine Holmes, Richard H. Myers, Christine Sambles, Bernardo Gutierrez, Jeffrey K. J. Cheng, Tim Wyatt, Natasha Jesudason, Lindsay Coupland, Monika Pusok, Manon Ragonnet-Cronin, Jenifer Mason, Joshua Maksimovic, Russell Hope, Alison Holmes, David Simpson, Radoslaw Poplawski, Amelia Joseph, Erwan Acheson, James Bonfield, Mara K. N. Lawniczak, Sascha Ott, Lesley-Anne Williams, Jessica Lynch, Graham P. Taylor, Anita Kenyon, Elizabeth Wastenge, Megan Mayhew, Adhyana I K Mahanama, Stavroula F Louka, Chloe Bishop, Esther Robinson, Darren Smith, Anne M. Presanis, Matthew Carlile, Thomas D Stanton, Dennis Wang, Katerina Galai, Adam P Westhorpe, Flavia Flaviani, Michelle Wantoch, Max Whiteley, Yann Bourgeois, Matthew Gemmell, Mary Ramsay, A Lloyd, Simon Thelwall, Hannah C. Howson-Wells, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Robert Impey, Siddharth Mookerjee, Steven Platt, Emma Swindells, Laura Letchford, Alex Alderton, Lee Graham, Safiah Afifi, David C. Lee, Cassie Breen, Melisa Louise Fenton, Benita Percival, Adrian W Signell, Tanya Golubchik, Ian B Vipond, Eleri Wilson-Davies, Angie Lackenby, Laura Atkinson, Sarojini Pandey, Nazreen F. Hadjirin, Michael A Chapman, Huw Gulliver, Joana Dias, Grant Hall, Antony D Hale, Hassan Hartman, Alp Aydin, Louise Smith, Ashok Dadrah, Johnny Debebe, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Bridget Knight, Hannah E Bridgewater, Nadua Bayzid, Gemma L. Kay, Richard Gregory, Sally Kay, Ellena Brooks, Andre Charlett, Georgina M McManus, Riaz Jannoo, Victoria Blakey, Carol Scott, Rachel Nelson, Liz Ratcliffe, Gerry Tonkin-Hill, Verity Hill, Joanne D. Stockton, Danielle Leek, Steven Leonard, Stephanie Hutchings, Jonathan D. Moore, Kathryn Ann Harris, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Tanzina Haque, Katherine L. Bellis, Khalil Abudahab, Dianne Irish-Tavares, Gaia Nebbia, Kathryn A Jackson, Stephen W Attwood, Daniel Mair, Sreenu Vattipally, Susanne Stonehouse, Ian Merrick, Lucille Rainbow, Mathew A. Beale, Angela Helen Beckett, Ember Hilvers, Thomas Helmer, Jenna Nichols, Giselda Bucca, Salman Goudarzi, Christopher Ruis, Surendra Parmar, Angela Cowell, Alberto C Cerda, Divya K. Shah, Judith Heaney, E. Thomson, Kyriaki Nomikou, Nicole Pacchiarini, Katherine L Harper, Fatima Downing, M. Estée Török, Michelle L Michelsen, Aaron R. Jeffries, Jennifer Collins, Christopher Williams, Katie F. Loveson, Steven Rudder, Theocharis Tsoleridis, Robert Davies, David Robertson, Katherine Smollett, Kathryn McCluggage, Liam Crawford, Inigo Martincorena, Charlotte Beaver, Oliver Megram, Karla Spellman, Sam Haldenby, Emma Betteridge, William D. Fuller, Will P. M. Rowe, Cherian Koshy, Tim E. A. Peto, Alison Cox, Natasha Johnson, Tanya Curran, Sharif Shaaban, Tamyo Mbisa, Cordelia Langford, Eric Witele, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Paul W Bird, Louise Aigrain, Ronan Lyons, Amy Trebes, Sally Corden, Steven Rushton, Jack Cd Lee, Jane Greenaway, Hibo Asad, Amanda Bradley, Mohammed O Hassan-Ibrahim, Shane McCarthy, Fei Sang, Matthew Loose, Hannah Jones, Keith D. James, Chloe L Fisher, Chrystala Constantinidou, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Anna Price, Amy Ash, Michaela John, Alex Zarebski, Fenella D. Halstead, John Danesh, Christine Kitchen, Aminu S Jahun, Mark Whitehead, Julianne R Brown, Catherine Bresner, Marius Cotic, Stefanie V Lensing, Nick Levene, Louissa R Macfarlane-Smith, Wendy Hogsden, Cressida Auckland, Eleanor Drury, Richard Eccles, Jennifer Hart, Seema Nickbakhsh, Alisha Davies, David M. Aanensen, Shirelle Burton-Fanning, Ben Farr, Buddhini Samaraweera, Sarah Wyllie, Hannah Lowe, Richard J. Orton, Martin D. Curran, Carol Churcher, Karen Oliver, Elihu Aranday-Cortes, Wen Yew, Thanh Le-Viet, Matthew Parker, Katherine A Twohig, Shahjahan Miah, Samuel M. Nicholls, G MacIntyre-Cockett, Tranprit Saluja, Charlotte Nelson, Vicki Chalker, Roberto Amato, Ellen Higginson, Timothy M. Freeman, Christopher W Holmes, Yasmin Chaudhry, Elias Allara, Alec Birchley, Iraad Bronner, Emma Moles-Garcia, Angus I. Best, Anna L. Casey, Audrey Farbos, Nicholas W Machin, David W Eyre, Tim Boswell, Charlotte A Williams, Elen De Lacy, Matthew J. Bull, Matilde Mori, Carmen F. Manso, Peijun Zhang, Sahar Eldirdiri, Dimitris Grammatopoulos, Corin Yeats, Claudia Wierzbicki, David G Partridge, Kordo Saeed, Nichola Duckworth, David J. Studholme, Harmeet K Gill, Juan Ledesma, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Husam Osman, Julian A. Hiscox, Helen Adams, Christopher Fearn, Fabrícia F. Nascimento, Ulf Schaefer, James W. Harrison, Andrew J. Nelson, Joshua Quick, Mohammad Tauqeer Alam, Liam Prestwood, Nikos Manesis, Julian Tang, Justin O'Grady, Sophia T Girgis, Louise Berry, Gemma Clark, Marina Escalera Zamudio, Karlie Fallon, Tim J Sloan, Joanne Watkins, Clare Pearson, Andrew D Beggs, Rachel Williams, Luke Bedford, Trevor Robinson, Nicholas M Redshaw, Richard Hopes, Mirko Menegazzo, Katherine Twohig, Gabrielle Vernet, Steven Liggett, Mariateresa de Cesare, Derrick W. Crook, Dominic P. Kwiatkowski, Mark Kristiansen, Miren Iturriza-Gomara, Christopher I. Moore, Claire Cormie, Olivia Boyd, Nikki Smith, Noel Craine, Kathleen A. Williamson, John Boyes, Sian Ellard, Cristina V. Ariani, Wendy Chatterton, David Bonsall, Kevin Lewis, David Jorgensen, Ian Harrison, Christopher Jackson, Martin P McHugh, Danni Weldon, Michael A. Quail, Amita Patel, Lily Geidelberg, Myra Hosmillo, Judith Breuer, Cariad Evans, Edward Barton, Trudy Workman, Derek Fairley, Vineet Patel, Daniel Bradshaw, Robin Manley, Scott Aj Thurston, John Sillitoe, Monique Andersson, Sharon J. Peacock, Jamie Lopez-Bernal, Thomas Thompson, Nabil-Fareed Alikhan, Ben Temperton, Paul Baker, Robin J Moll, Laura Gifford, Nicholas J. Loman, Jayna Raghwani, Jacqui Prieto, Andrew Hesketh, Oliver G. Pybus, Adela Alcolea-Medina, David Buck, Gregory R Young, Alistair C. Darby, Sónia Gonçalves, Aileen G. Rowan, Tabitha Mahungu, Nicholas Ellaby, Jon-Paul Keatley, Lily Tong, Robert Beer, Martyn Guest, Lisa J Levett, Ali R Awan, Iliana Georgana, Paul E Brown, Li Xu-McCrae, Stephen P. Kidd, Sara Rey, Shazaad Ahmad, Danielle C. Groves, Tetyana I. Vasylyeva, David F. Bibby, Nathan Moore, Fiona Ashcroft, Igor Starinskij, Hannah Paul, Claire McMurray, Michael Spencer Chapman, Carlos Balcazar, Joanna Warwick-Dugdale, Pinglawathee Madona, Edith Vamos, Lesley Shirley, Kate Templeton, Luke Foulser, Igor Siveroni, Ewan M. Harrison, Sian Morgan, Diana Rajan, S Taylor, Laia Fina, Naomi Park, Sarah J. O'Brien, Alessandro M Carabelli, Angela Marchbank, Sunando Roy, Leonardo de Oliveira Martins, Steve Palmer, Jonathan Hubb, Alexander J Keeley, Francesc Coll, Malorie Perry, Paul J. Parsons, Anthony Underwood, Patawee Asamaphan, William L Hamilton, Tommy Nyberg, Sophie Palmer, Amanda Symmonds, Anoop Chauhan, Robert Johnson, Christopher J. R. Illingworth, James Shepherd, Wendy Smith, Rich Livett, Rachel Blacow, Margaret Hughes, Jeremy Mirza, Joanne Watts, Jonathan D. Edgeworth, Sarah François, Sue Edwards, Adrienn Angyal, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Paul Randell, Kate Johnson, Eileen Gallagher, Nick Cortes, Yusri Taha, Leah Ensell, Emanuela Pelosi, Stefan Rooke, Michelle Lister, Ana da Silva Filipe, Cassandra S Malone, Themoula Charalampous, Benjamin B Lindsey, Natalie Groves, Colin Smith, Ross J Harris, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Nicola Sheriff, Helen L Lowe, Rachel Jones, Ben Warne, Rose K Davidson, Declan Bradley, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Shirin Aliabadi, Andrew Whitwham, Patrick McClure, Samuel Robson, Sharon Glaysher, Robert J. Munn, Emma L. Wise, Laura Baxter, Kim S Smith, Catherine Moore, Bree Gatica-Wilcox, Alice Broos, Sarah Essex, David Baker, Manjinder Khakh, Dorota Jamrozy, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Robin Howe, Meera Chand, James I. Price, Marina Gourtovaia, Debra Padgett, Jaime Tovar-Corona, Stephen L. Michell, Matthew J. Dorman, Lizzie Meadows, David Heyburn, Iona Willingham, Rocio Martinez Nunez, Grace Taylor-Joyce, Claire M Bewshea, Anita Justice, Simon Cottrell, Rebecca C H Brown, Jamie Young, Gavin Dabrera, Matthew Wyles, Stephen Carmichael, Lisa Berry, Frances Bolt, Andrew Rambaut, Samir Dervisevic, Erik M. Volz, Rahul Batra, Caoimhe McKerr, Samantha McGuigan, Katie Jones, Mailis Maes, Rebecca Dewar, Mary Sinnathamby, Joel Southgate, and Lynn Monaghan

Subjects
medicine.medical_specialty, business.industry, Proportional hazards model, Public health, Hazard ratio, Attendance, C500, Vaccination, Infectious Diseases, Relative risk, Internal medicine, Cohort, medicine, business, Cohort study
Abstract

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Published
2022

41. Development and Construct Validity of Scores on the Community Service Attitudes Scale.

Author

Shiarella, Ann Harris, McCarthy, Anne M., and Tucker, Mary L.

Abstract

Reports the multistage development of the Community Service Attitudes Scale, an instrument for measuring college students' attitudes toward community service. Analysis of scores for samples of 437 and 332 students yields strong reliability evidence, and principal components analysis supports the helping behavior model of S. Schwartz. (SLD)

Published
2000

43. Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

Author

Mohammad Raza, Alison E. Mather, Gilberto Betancor, Ian Merrick, Ben Taylor, Mathew A. Beale, Helen Ward, Samir Dervisevic, Michelle Cronin, Aaron R. Jeffries, Louise Smith, Steven Rudder, Mara K. N. Lawniczak, Sascha Ott, Ashok Dadrah, Luke Bedford, Gabrielle Vernet, Erik M. Volz, Rahul Batra, Johnny Debebe, Caoimhe McKerr, Samantha McGuigan, Oliver Megram, Katie Jones, Mailis Maes, Rebecca Dewar, Emma Swindells, Robert E. Johnson, Myra Hosmillo, Wen C Yew, Vineet Patel, Scott Aj Thurston, Matthew Bashton, Luke B Snell, Lynn Monaghan, David Buck, Gregory R Young, Garren Scott, Louis du Plessis, Sara Kumziene-Summerhayes, David M. Aanensen, Carl Jones, Nadine Holmes, Bernardo Gutierrez, Elizabeth Wastenge, Stavroula F Louka, Dennis Wang, Richard I. Gregory, M. Estée Török, Alistair C. Darby, Ulf Schaefer, Marc Niebel, David Robertson, E. Thomson, Carol Churcher, Patrick C McClure, Scott Elliott, Sarah Jeremiah, Katerina Galai, Matthew W. Loose, Megan Mayhew, Adhyana I K Mahanama, Angeliki Karamani, Naomi R Park, David J. Williams, Lance Turtle, Lucy R. Frost, Alicia Thornton, Jennifier Liddle, M Morgan, Tim Wyatt, Paul W Bird, Chloe Bishop, Esther Robinson, Alasdair MacLean, Inigo Martincorena, Bridget A. Knight, Emma Meader, Thomas R. Connor, Hermione J. Webster, Peter Muir, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Hannah E Bridgewater, David Simpson, Radoslaw Poplawski, Angus I. Best, David Baker, Laura Letchford, Cassie Breen, Yann Bourgeois, Matthew Gemmell, Nikki Smith, Alison Holmes, Iliana Georgana, Christophe Fraser, Natasha Jesudason, Johnathan M Evans, Rachael Stanley, Lesley-Anne Williams, Jessica Lynch, Hannah Lowe, Eleri Wilson-Davies, Paul A. Baker, Alex Makunin, James Bonfield, Helen Adams, Christopher Fearn, Peter J. Diggle, Harry D Wilson, Carmen F. Manso, Nichola Duckworth, D Haw, Anna L. Casey, Audrey Farbos, Sam Haldenby, Vicki Chalker, Roberto Amato, Elen De Lacy, Ben Farr, Eric Witele, Buddhini Samaraweera, G MacIntyre-Cockett, Husam Osman, Jane Greenaway, Justin O'Grady, Sally Forrest, Andrew Nelson, Monika Pusok, A Lloyd, Edward Barton, James W. Harrison, Sophie Palmer, Amanda Symmonds, James Shepherd, Nazreen F. Hadjirin, Stephen L. Michell, Mohammed O Hassan-Ibrahim, Fiona Ashcroft, Daniel Mair, Richard H. Myers, Dianne Irish-Tavares, Hannah C. Howson-Wells, Jacqui Prieto, Christine Sambles, Andrew Hesketh, Alp Aydin, Sónia Gonçalves, Tabitha Mahungu, Tanzina Haque, Nicholas Ellaby, Karen Oliver, Hannah Paul, Joanne Watts, Claire McMurray, Lisa J Levett, Darren Smith, Simon Cottrell, Joanna Warwick-Dugdale, Pinglawathee Madona, Matthew J. Dorman, Lizzie Meadows, Ali R Awan, Leanne M Kermack, Jennifer Hart, Angie Lackenby, Carol Scott, Michael Spencer Chapman, Lucille Rainbow, Kyriaki Nomikou, Julianne R Brown, Juan Ledesma, Adam P Westhorpe, Giri Shankar, Karlie Fallon, Tim J Sloan, Joanne Watkins, Robert Impey, Sue Edwards, Rebecca C H Brown, Robin J Moll, Karla Spellman, Laura Gifford, Jamie Young, Adrienn Angyal, Graham Phillip Taylor, Robin Manley, Gavin Dabrera, Michelle Wantoch, Rachel Williams, David Heyburn, Mirko Menegazzo, Derrick W. Crook, Gaia Nebbia, Rachel Nelson, Elaine O'Toole, Luke Foulser, Katherine L Harper, Fatima Downing, Hassan Hartman, Nathan Moore, Gemma L. Kay, Matthew Wyles, Thanh Le-Viet, Edith Vamos, John Sillitoe, Lesley Shirley, Nicholas J. Loman, Iona Willingham, Elihu Aranday-Cortes, Ian B Vipond, Jeremy Mirza, Alberto C Cerda, Michelle L Michelsen, Steven Riley, Alison Cox, Igor Siveroni, Nadua Bayzid, Shavanthi Rajatileka, Giselda Bucca, Benjamin J Cogger, Tim Boswell, Matthew J. Bull, Stephen Carmichael, Lisa Berry, Frances Bolt, Kylie E. C. Ainslie, Martyn Guest, Sarojini Pandey, Katherine L. Bellis, Shane A. McCarthy, Christopher Ruis, Fei Sang, David Bonsall, Danni Weldon, Alex Alderton, Lee Graham, Amy Trebes, Sally Corden, Adrian W Signell, Tanya Golubchik, Huw Gulliver, Rocio Martinez Nunez, Dinesh Aggarwal, Tanya Curran, Jonathan K. Ball, Sharif Shaaban, Paul Randell, Jillian Durham, Alec Birchley, Matilde Mori, Joana Dias, Katherine A Twohig, Grant Hall, Antony D Hale, Alan McNally, Jonathan D. Edgeworth, Safiah Afifi, Andrew Rambaut, Katherine Smollett, David N. Lee, Tamyo Mbisa, Shahjahan Miah, Steven Rushton, Grace Taylor-Joyce, Hannah M Pymont, Chloe L Fisher, Cordelia Langford, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Kathleen A. Williamson, Anna Price, Holli Carden, Khalil Abudahab, Joanne D. Stockton, Meera Unnikrishnan, Jennifer Collins, Emma Moles-Garcia, Michaela John, Christine Kitchen, Tranprit Saluja, Ian Harrison, Lily Tong, Thomas G. Thompson, Thomas Helmer, Amita Patel, Siona Silveira, Deborah Ashby, Claire M Bewshea, Anita Justice, Brendan A I Payne, Alexander J. Trotter, Nikos Manesis, Katie F. Loveson, Cristina V. Ariani, Wendy Chatterton, Robert J. Munn, Julian A. Hiscox, Robert Beer, Judith Breuer, Caroline E. Walters, Liam Crawford, Ara Darzi, Will P. M. Rowe, Cariad Evans, Matthew Parker, Tammy V Merrill, Louise Aigrain, Joshua Quick, Leigh M Jackson, Samuel M. Nicholls, Jonathan W. Moore, John A Hartley, Graham P. Taylor, Cherian Koshy, Shirelle Burton-Fanning, Sheila Waugh, Catherine Moore, Danielle C. Groves, Peijun Zhang, Sahar Eldirdiri, Derek Fairley, Tim E. A. Peto, Jack Cd Lee, Sharon Glaysher, Liam Prestwood, Hannah Dent, Anita Kenyon, Stephen P. Kidd, Nick Levene, Igor Starinskij, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Laia Fina, Angela Marchbank, Daniel Bradshaw, Marina Escalera Zamudio, Scott Goodwin, Andrew D Beggs, Seema Nickbakhsh, Trevor Robinson, Christina Atchison, David K. Jackson, Kathy Li, Rory Gunson, Sunando Roy, Graham S Cooke, Steven Liggett, Yasmin Chaudhry, Anoop Chauhan, Ben Temperton, Mariateresa de Cesare, Paul E Brown, Li Xu-McCrae, Martin P McHugh, Catherine Ludden, Wendy Smith, Danielle Leek, Divya K. Shah, Judith Heaney, Dominic P. Kwiatkowski, Kate M. Johnson, Robin Howe, Malorie Perry, Tetyana I. Vasylyeva, David F. Bibby, Haowei Wang, Steve Palmer, Nicholas W Machin, Charlotte A Williams, Bree Gatica-Wilcox, Angie Green, John A. Todd, Paul Elliott, Noel Craine, Jeffrey K. J. Cheng, Kate Templeton, Jonathan Hubb, Joshua Maksimovic, Christl A. Donnelly, Monique Andersson, Christopher Holmes, Dimitris Grammatopoulos, Christopher B. Williams, David G Partridge, Aminu S Jahun, Alexander Adams, Marius Cotic, Sarah Essex, Christopher J. Moore, Trudy Workman, Nicola Sheriff, Helen L Lowe, Ewan M. Harrison, Dorota Jamrozy, Rachel Jones, Ellen Higginson, Erwan Acheson, Christopher R. Jones, Oliver G. Pybus, Francesc Coll, Sian Morgan, Paul J. Parsons, Patawee Asamaphan, Veena Raviprakash, Andrew R. Bassett, Declan Bradley, Laura Atkinson, Anthony Underwood, Graciela Sluga, Sally Kay, Ellena Brooks, Oliver Eales, Andrew Whitwham, Surendra Parmar, Angela Cowell, Nicole Pacchiarini, Theocharis Tsoleridis, Jason Coombes, Robert Davies, Flavia Flaviani, Benita Percival, Jenna Nichols, Natasha M. Johnson, Salman Goudarzi, Hibo Asad, Amanda Bradley, Hannah Jones, Chrystala Constantinidou, Georgina M McManus, Minal Patel, Steven Leonard, Rebecca Williams Bmbs, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Amy Ash, John Danesh, Corin Yeats, Claudia Wierzbicki, Kordo Saeed, John Boyes, Michael A. Quail, Sharon J. Peacock, Nabil-Fareed Alikhan, Jon-Paul Keatley, Claudio Fronterre, Garry Scarlett, James McKenna, Thushan I de Silva, Malte L Pinckert, Kate B. Cook, Amy Gaskin, Rajiv Shah, Matthew T. G. Holden, Sophie J Prosolek, Nathaniel Storey, Ryan P George, Lindsay Coupland, Jenifer Mason, Matthew Carlile, Thomas D Stanton, Guy Mollett, Siddharth Mookerjee, Mary Ramsay, Steven Platt, Stephen W Attwood, Susanne Stonehouse, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Mark Whitehead, Catherine Bresner, Stefanie V Lensing, Louissa R Macfarlane-Smith, Colin P. Smith, Wendy Hogsden, Charlotte Nelson, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Samuel Robson, Zoltán Molnár, Emma L. Wise, Sian Ellard, Kim S Smith, Alice Broos, Manjinder Khakh, Kathryn A Jackson, Claire Cormie, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Meera Chand, Debra Padgett, Cassandra S Malone, James V. Price, Themoula Charalampous, Ronan A Lyons, Natalie Groves, Stefan Rooke, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Michelle Lister, Carlos Balcazar, Ana da Silva Filipe, Ben Warne, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Rose K Davidson, Angela Helen Beckett, Ember Hilvers, Kathryn McCluggage, Eileen Gallagher, Charlotte Beaver, Nick Cortes, Alisha Davies, Yusri Taha, Leah Ensell, Emanuela Pelosi, Elias Allara, Cressida Auckland, Eleanor Drury, Richard Eccles, Adela Alcolea-Medina, William L Hamilton, Rich Livett, Rachel Blacow, Margaret Hughes, Sarah François, Melisa Louise Fenton, Liz Ratcliffe, Verity Hill, Stephanie Hutchings, Kathryn Ann Harris, Emma Betteridge, William D. Fuller, Sophia T Girgis, Louise Berry, Gemma Clark, Nicholas M Redshaw, Richard Hopes, Leonardo de Oliveira Martins, Alexander J Keeley, Beth Blane, Wendy S. Barclay, Victoria Wright, Anita Lucaci, Luke R. Green, Fenella D. Halstead, Sarah Wyllie, Iraad F. Bronner, Áine O'Toole, Ravi Gupta, Leanne Kane, Clare M. McCann, Michael R Chapman, David W Eyre, Kelly Bicknell, Aileen G. Rowan, Sara Rey, Shazaad Ahmad, Diana Rajan, S Taylor, Sarah J. O'Brien, Alessandro M Carabelli, Amelia Joseph, Max Whiteley, Riaz Jannoo, Victoria Blakey, Martin D. Curran, David J. Studholme, Harmeet K Gill, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Julian Tang, Clare Pearson, Mark Kristiansen, Miren Iturriza-Gomara, National Institute for Health Research, and UK Research and Innovation

Subjects
Delta, Adult, Male, 2019-20 coronavirus outbreak, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Vaccine Efficacy, Biology, Young Adult, Exponential growth, Ethnicity, Prevalence, Humans, Child, Aged, Family Characteristics, Multidisciplinary, High prevalence, COVID-19 Genomics UK (COG-UK) Consortium11‡, SARS-CoV-2, Age Factors, COVID-19, Middle Aged, Virology, Hospitalization, England, Socioeconomic Factors, COVID-19 Nucleic Acid Testing, Child, Preschool, Female, Self Report
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Published
2021

44. Primum mobile

Author

John Hodgson and Ann Harris

Published
2021

45. The role of political devotion in sharing partisan misinformation and resistance to fact-checking

Author

Clara Pretus, Camila Servin, Elizabeth Ann Harris, William J. Brady, Oscar Vilarroya, and Jay Joseph Van Bavel

Abstract

Online misinformation poses a significant threat to global challenges such as pandemics and climate change. To understand what drives individuals to share misinformation, we conducted two pre-registered experiments with conservatives and far-right supporters in the US and Spain (N = 1,609) and a neuroimaging study with far-right supporters in Spain (N = 36). Individuals who felt their personal identity was fused with their political group were more likely to share misinformation, especially around sacred moral issues (e.g., immigration and nationalism). Far-right supporters showed increased activity in brain regions associated with theory of mind in response to posts with sacred values, highlighting the social nature of misinformation sharing. Analytical thinking was unrelated to misinformation sharing around sacred values (vs. non-sacred values) and fact-checks had little or no effect, especially among hyper-partisans. We provide evidence that political devotion plays a key role in misinformation sharing and discuss practical implications of our findings.

Published
2021

47. Do Sideline Tests of Vestibular and Oculomotor Function Accurately Diagnose Sports-Related Concussion in Adults? A Systematic Review and Meta-analysis

Author

Katherine E Mackie, Doug King, Myles C. Murphy, Mark Hecimovich, Sarah Ann Harris, and Alasdair R. Dempsey

Subjects
Vestibular system, medicine.medical_specialty, business.industry, Physical Therapy, Sports Therapy and Rehabilitation, Cognition, medicine.disease, Oculomotor function, Sports Medicine, Sensitivity and Specificity, Sport related concussion, Physical medicine and rehabilitation, Meta-analysis, Concussion, Athletic Injuries, Medicine, Humans, Orthopedics and Sports Medicine, business, Psychosocial, Brain Concussion, Sports
Abstract

Background: Sports-related concussion (SRC) assessment tools are primarily based on subjective assessments of somatic, cognitive, and psychosocial/emotional symptoms. SRC symptoms remain underreported, and objective measures of SRC impairments would be valuable to assist diagnosis. Measurable impairments to vestibular and oculomotor processing have been shown to occur after SRC and may provide valid objective assessments. Purpose: Determine the diagnostic accuracy of sideline tests of vestibular and oculomotor dysfunction to identify SRC in adults. Study Design: Systematic review; Level of evidence, 4. Methods: Electronic databases and gray literature were searched from inception until February 12, 2020. Physically active individuals (>16 years of age) who participated in sports were included. The reference standard for SRC was a combination of clinical signs and symptoms (eg, the Sport Concussion Assessment Tool [SCAT]), and index tests included any oculomotor assessment tool. The QUADAS tool was used to assess risk of bias, with the credibility of the evidence being rated according to GRADE. Results: A total of 8 studies were included in this review. All included studies used the King-Devick test, with no other measures being identified. Meta-analysis was performed on 4 studies with a summary sensitivity and specificity of 0.77 and 0.82, respectively. The overall credibility of the evidence was rated as very low. Conclusion: Caution must be taken when interpreting these results given the very low credibility of the evidence, and the true summary sensitivity and specificity may substantially differ from the values calculated within this systematic review. Therefore, we recommend that clinicians using the King-Devick test to diagnose SRC in adults do so in conjunction with other tools such as the SCAT. PROSPERO Registration: CRD42018106632.

Published
2021

48. Human Molecular Genetics and the long road to treating cystic fibrosis

Author

Ann Harris

Subjects
medicine.medical_specialty, Invited Review Article, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Computational biology, Biology, Cystic fibrosis, Molecular genetics, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Genetic Association Studies, Gene Editing, Causative gene, Disease Management, General Medicine, Genetic Therapy, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Gene Expression Regulation, Molecular Diagnostic Techniques, Mutation, biology.protein, CRISPR-Cas Systems, Single-Cell Analysis
Abstract

The causative gene in cystic fibrosis (CF) was identified in 1989, 3 years before the publication of the first issue of Human Molecular Genetics. The cystic fibrosis transmembrane conductance regulator (CFTR) gene was among the first underlying a common inherited disorder to be cloned, and hence, its subsequent utilization toward a cure for CF provides a roadmap for other monogenic diseases. Over the past 30 years, the advances that built upon knowledge of the gene and the CFTR protein to develop effective therapeutics have been remarkable, and yet, the setbacks have also been challenging. Technological progress in other fields has often circumvented the barriers. This review focuses on key aspects of CF diagnostics and current approaches to develop new therapies for all CFTR mutations. It also highlights the major research advances that underpinned progress toward treatments and considers the remaining obstacles.

Published
2021

49. Krüppel-like factor 5 regulates wound repair and the innate immune response in human airway epithelial cells

Author

Alekh Paranjapye, Shih Hsing Leir, James A. Browne, Monali NandyMazumdar, and Ann Harris

Subjects
0301 basic medicine, Chemokine, TF, transcription factor, RSAT, Regulatory Sequence Analysis Tools, ChIP-seq, chromatin immunoprecipitation followed by deep sequencing, HBE, human bronchial epithelial, Kruppel-Like Transcription Factors, Krüppel-like factor (KLF), AP-1, activator protein 1, Biochemistry, Proinflammatory cytokine, KLF, Krüppel-like factor, Cell Line, 03 medical and health sciences, wound repair, Humans, CFTR, cystic fibrosis transmembrane conductance regulator, Epithelial–mesenchymal transition, Cell adhesion, C/EBPβ, CCAAT/enhancer binding protein beta, Molecular Biology, Transcription factor, cellular immune response, GO, gene ontology, CINP, cyclin-dependent kinase 2 interacting protein, Innate immune system, 030102 biochemistry & molecular biology, biology, epigenetics, EHF, ETS homologous factor, airway epithelium, Epithelial Cells, Cell Biology, ELISA, enzyme-linked immunosorbent assay, SPDEF, SAM-pointed domain ETS factor, Immunity, Innate, Cell biology, HDAC1, histone deacetylase 1, 030104 developmental biology, Cistrome, biology.protein, Respiratory epithelium, LPS, lipopolysaccharide, EMT, epithelial-to-mesenchymal transition, Research Article
Abstract

A complex network of transcription factors regulates genes involved in establishing and maintaining key biological properties of the human airway epithelium. However, detailed knowledge of the contributing factors is incomplete. Here we characterize the role of Kruppel-like factor 5 (KLF5), in controlling essential pathways of epithelial cell identity and function in the human lung. RNA-seq following siRNA-mediated depletion of KLF5 in the Calu-3 lung epithelial cell line identified significant enrichment of genes encoding chemokines and cytokines involved in the proinflammatory response and also components of the junctional complexes mediating cell adhesion. To determine direct gene targets of KLF5, we defined the cistrome of KLF5 using ChIP-seq in both Calu-3 and 16HBE14o− lung epithelial cell lines. Occupancy site concordance analysis revealed that KLF5 colocalized with the active histone modification H3K27ac and also with binding sites for the transcription factor CCAAT enhancer-binding protein beta (C/EBPβ). Depletion of KLF5 increased both the expression and secretion of cytokines including IL-1β, a response that was enhanced following exposure to Pseudomonas aeruginosa lipopolysaccharide. Calu-3 cells exhibited faster rates of repair after KLF5 depletion compared with negative controls in wound scratch assays. Similarly, CRISPR-mediated KLF5-null 16HBE14o− cells also showed enhanced wound closure. These data reveal a pivotal role for KLF5 in coordinating epithelial functions relevant to human lung disease.

Published
2021

50. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian Saliba, Katja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta, Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O’Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Áine O’Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Grammatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. 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Subjects
0301 basic medicine, Resistance, MC UU 1201412, Plasma protein binding, Antibodies, Viral, medicine.disease_cause, MR/R024758/1, 0302 clinical medicine, Recurrence, Chlorocebus aethiops, deletion, Biology (General), Receptor, Phylogeny, Infectivity, Mutation, biology, infectivity, MC_UU_12014/12, C500, C700, UKRI, MRC, Antibody Escape, Spike Glycoprotein, Coronavirus, antibody escape, Antibody, Protein Binding, QH301-705.5, Sars-cov-2, Alpha (ethology), Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, resistance, Deletion, 03 medical and health sciences, spike mutation, medicine, Alpha Variant, Animals, Humans, neutralizing antibodies, B.1.1.7, Vero Cells, Pandemics, Immune Evasion, SARS-CoV-2, Biochemistry, Genetics and Molecular Biology(all), COVID-19, MR/P008801/1, Antibodies, Neutralizing, Virology, body regions, HEK293 Cells, 030104 developmental biology, Alpha variant, Spike Mutation, biology.protein, Vero cell, Neutralizing Antibodies, 030217 neurology & neurosurgery
Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Graphical abstract, Meng et al. report that the SARS-CoV-2 spike ΔH69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires ΔH69/V70 for efficient cell entry and cell-cell fusion activity.

Published
2021

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