491 results on '"Edwards, RJ"'
Search Results
2. Comparative Effectiveness of Diversion of Cerebrospinal Fluid for Children With Severe Traumatic Brain Injury.
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Bell, MJ, Rosario, BL, Kochanek, PM, Adelson, PD, Morris, KP, Au, AK, Schober, M, Butt, W, Edwards, RJ, Zimmerman, J, Pineda, J, Le, TM, Dean, N, Whalen, MJ, Figaji, A, Luther, J, Beers, SR, Gupta, DK, Carpenter, J, Buttram, S, Wisniewski, SR, Approaches and Decisions for Acute Pediatric TBI (ADAPT) Investigators, Bell, MJ, Rosario, BL, Kochanek, PM, Adelson, PD, Morris, KP, Au, AK, Schober, M, Butt, W, Edwards, RJ, Zimmerman, J, Pineda, J, Le, TM, Dean, N, Whalen, MJ, Figaji, A, Luther, J, Beers, SR, Gupta, DK, Carpenter, J, Buttram, S, Wisniewski, SR, and Approaches and Decisions for Acute Pediatric TBI (ADAPT) Investigators
- Abstract
IMPORTANCE: Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies. OBJECTIVE: To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI. DESIGN, SETTING, AND PARTICIPANTS: This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022. EXPOSURES: Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group). MAIN OUTCOMES AND MEASURES: The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion. RESULTS: A total of 1000 children with TBI were enrolled, including 314 who received C
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- 2022
3. The Australian dingo is an early offshoot of modern breed dogs.
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Field, MA, Yadav, S, Dudchenko, O, Esvaran, M, Rosen, BD, Skvortsova, K, Edwards, RJ, Keilwagen, J, Cochran, BJ, Manandhar, B, Bustamante, S, Rasmussen, JA, Melvin, RG, Chernoff, B, Omer, A, Colaric, Z, Chan, EKF, Minoche, AE, Smith, TPL, Gilbert, MTP, Bogdanovic, O, Zammit, RA, Thomas, T, Aiden, EL, Ballard, JWO, Field, MA, Yadav, S, Dudchenko, O, Esvaran, M, Rosen, BD, Skvortsova, K, Edwards, RJ, Keilwagen, J, Cochran, BJ, Manandhar, B, Bustamante, S, Rasmussen, JA, Melvin, RG, Chernoff, B, Omer, A, Colaric, Z, Chan, EKF, Minoche, AE, Smith, TPL, Gilbert, MTP, Bogdanovic, O, Zammit, RA, Thomas, T, Aiden, EL, and Ballard, JWO
- Abstract
Dogs are uniquely associated with human dispersal and bring transformational insight into the domestication process. Dingoes represent an intriguing case within canine evolution being geographically isolated for thousands of years. Here, we present a high-quality de novo assembly of a pure dingo (CanFam_DDS). We identified large chromosomal differences relative to the current dog reference (CanFam3.1) and confirmed no expanded pancreatic amylase gene as found in breed dogs. Phylogenetic analyses using variant pairwise matrices show that the dingo is distinct from five breed dogs with 100% bootstrap support when using Greenland wolf as the outgroup. Functionally, we observe differences in methylation patterns between the dingo and German shepherd dog genomes and differences in serum biochemistry and microbiome makeup. Our results suggest that distinct demographic and environmental conditions have shaped the dingo genome. In contrast, artificial human selection has likely shaped the genomes of domestic breed dogs after divergence from the dingo.
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- 2022
4. Protective Transfer: Maternal passive immunization with a rotavirus-neutralizing dimeric IgA protects against rotavirus disease in suckling neonates
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Langel, SN, primary, Steppe, JT, additional, Chang, J, additional, Travieso, T, additional, Webster, H, additional, Otero, CE, additional, Williamson, LE, additional, Crowe, JE, additional, Greenberg, HB, additional, Wu, H, additional, Hornik, C, additional, Mansouri, K, additional, Edwards, RJ, additional, Stalls, V, additional, Acharya, P, additional, Blasi, M, additional, and Permar, SR, additional
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- 2021
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5. Intergenerational effects of manipulating DNA methylation in the early life of an iconic invader
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Sarma, RR, Crossland, MR, Eyck, Harrison, Devore, JL, Edwards, RJ, Cocomazzo, Michael, Zhou, J, Brown, GP, Shine, R, Rollins, Lee, Sarma, RR, Crossland, MR, Eyck, Harrison, Devore, JL, Edwards, RJ, Cocomazzo, Michael, Zhou, J, Brown, GP, Shine, R, and Rollins, Lee
- Abstract
In response to novel environments, invasive populations often evolve rapidly. Standing genetic variation is an important predictor of evolutionary response but epigenetic variation may also play a role. Here, we use an iconic invader, the cane toad (Rhinella marina), to investigate how manipulating epigenetic status affects phenotypic traits. We collected wild toads from across Australia, bred them, and experimentally manipulated DNA methylation of the subsequent two generations (G1, G2) through exposure to the DNA methylation inhibitor zebularine and/or conspecific tadpole alarm cues. Direct exposure to alarm cues (an indicator of predation risk) increased the potency of G2 tadpole chemical cues, but this was accompanied by reductions in survival. Exposure to alarm cues during G1 also increased the potency of G2 tadpole cues, indicating intergenerational plasticity in this inducible defence. In addition, the negative effects of alarm cues on tadpole viability (i.e. the costs of producing the inducible defence) were minimized in the second generation. Exposure to zebularine during G1 induced similar intergenerational effects, suggesting a role for alteration in DNA methylation. Accordingly, we identified intergenerational shifts in DNA methylation at some loci in response to alarm cue exposure. Substantial demethylation occurred within the sodium channel epithelial 1 subunit gamma gene (SCNN1G) in alarm cue exposed individuals and their offspring. This gene is a key to the regulation of sodium in epithelial cells and may help to maintain the protective epidermal barrier. These data suggest that early life experiences of tadpoles induce intergenerational effects through epigenetic mechanisms, which enhance larval fitness. This article is part of the theme issue 'How does epigenetics influence the course of evolution?'
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- 2021
6. Chromosome-length genome assembly and structural variations of the primal Basenji dog (Canis lupus familiaris) genome
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Edwards, RJ, Field, M, Ferguson, J, Dudchenko, O, Keilwagen, J, Rosen, B, Johnston, G, Rice, E, Hillier, L, Hammond, J, Towarnicki, S, Omer, A, Skvortsova, K, Bogdanovic, O, Zammit, R, Aiden, E, Warren, W, Ballard, B, Edwards, RJ, Field, M, Ferguson, J, Dudchenko, O, Keilwagen, J, Rosen, B, Johnston, G, Rice, E, Hillier, L, Hammond, J, Towarnicki, S, Omer, A, Skvortsova, K, Bogdanovic, O, Zammit, R, Aiden, E, Warren, W, and Ballard, B
- Abstract
Background: Basenjis are considered an ancient dog breed of central African origins that still live and hunt with tribesmen in the African Congo. Nicknamed the barkless dog, Basenjis possess unique phylogeny, geographical origins and traits make understanding their genome structure relative to more modern dog breeds of great interest. Here, we report the de novo assemblies of two Basenji: a female, China, and a male, Wags. We conduct pairwise comparisons and report structural variations between assembled genomes of three dog breeds: Basenji (CanFam_Bas), Boxer (CanFam3.1) and German Shepherd Dog (GSD) (CanFam_GSD). We then align representative whole genome sequences from 58 dog breeds and show the importance of genome reference when assessing variation among dog breeds. Results: Here we present two high quality Basenji genome assemblies, CanFam_Bas (China) and Wags. CanFam_Bas is superior to CanFam v3,1 is terms of genome contiguity and comparable overall to the high quality CanFam_GSD assembly. The increasing number of available canid reference genomes allows us to examine the impact the choice of reference genome makes with regard to reference genome quality and breed relatedness. By aligning short read data from 58 representative dog breeds to three reference genomes, we demonstrate how the choice of reference genome significantly impacts both read mapping and variant detection. Further, we generate a conservative list of structural variant calls using a consensus of both Pacific Bioscience and Oxford Nanopore long reads to identify large structural breed differences. Collectively this work highlights the importance the choice of reference genome makes in canid variation studies. Conclusions: The growing number of high-quality canid reference genomes means the choice of reference genome is an increasingly critical decision in subsequent canid variant analyses. The basal position of the Basenji makes it suitable for variant analysis for targeted applications of sp
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- 2020
7. Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques
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Williams, Wilton B., primary, Meyerhoff, R. Ryan, additional, Edwards, RJ, additional, Li, Hui, additional, Nicely, Nathan I., additional, Henderson, Rory, additional, Zhou, Ye, additional, Janowska, Katarzyna, additional, Mansouri, Katayoun, additional, Manne, Kartik, additional, Stalls, Victoria, additional, Hsu, Allen L., additional, Borgnia, Mario J., additional, Stewart-Jones, Guillaume, additional, Lee, Matthew S., additional, Bronkema, Naomi, additional, Perfect, John, additional, Moody, M. Anthony, additional, Wiehe, Kevin, additional, Bradley, Todd, additional, Kepler, Thomas B., additional, Alam, S. Munir, additional, Parks, Robert J., additional, Foulger, Andrew, additional, Bonsignori, Mattia, additional, LaBranche, Celia C., additional, Montefiori, David C., additional, Seaman, Michael, additional, Santra, Sampa, additional, Francica, Joseph R., additional, Lynn, Geoffrey M., additional, Aussedat, Baptiste, additional, Walkowicz, William E., additional, Laga, Richard, additional, Kelsoe, Garnett, additional, Saunders, Kevin O., additional, Fera, Daniela, additional, Kwong, Peter D., additional, Seder, Robert A., additional, Bartesaghi, Alberto, additional, Shaw, George M., additional, Acharya, Priyamvada, additional, and Haynes, Barton F., additional
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- 2020
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8. Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements
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Henderson, Rory, primary, Lu, Maolin, additional, Zhou, Ye, additional, Mu, Zekun, additional, Parks, Robert, additional, Han, Qifeng, additional, Hsu, Allen L., additional, Carter, Elizabeth, additional, Blanchard, Scott C., additional, Edwards, RJ, additional, Wiehe, Kevin, additional, Saunders, Kevin O., additional, Borgnia, Mario J., additional, Bartesaghi, Alberto, additional, Mothes, Walther, additional, Haynes, Barton F., additional, Acharya, Priyamvada, additional, and Alam, S. Munir, additional
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- 2019
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9. Whole genome sequencing of a novel, dichloromethane-fermenting Peptococcaceae from an enrichment culture
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Holland, SI, Edwards, RJ, Ertan, H, Wong, YK, Russell, TL, Deshpande, NP, Manefield, MJ, Lee, M, Holland, SI, Edwards, RJ, Ertan, H, Wong, YK, Russell, TL, Deshpande, NP, Manefield, MJ, and Lee, M
- Abstract
Bacteria capable of dechlorinating the toxic environmental contaminant dichloromethane (DCM, CH2Cl2) are of great interest for potential bioremediation applications. A novel, strictly anaerobic, DCM-fermenting bacterium, ‘‘DCMF’’, was enriched from organochlorine-contaminated groundwater near Botany Bay, Australia. The enrichment culture was maintained in minimal, mineral salt medium amended with dichloromethane as the sole energy source. PacBio whole genome SMRTTM sequencing of DCMF allowed de novo, gap-free assembly despite the presence of cohabiting organisms in the culture. Illumina sequencing reads were utilised to correct minor indels. The single, circularised 6.44 Mb chromosome was annotated with the IMG pipeline and contains 5,773 predicted protein-coding genes. Based on 16S rRNA gene and predicted proteome phylogeny, the organism appears to be a novel member of the Peptococcaceae family. The DCMF genome is large in comparison to known DCM-fermenting bacteria. It includes an abundance of methyltransferases, which may provide clues to the basis of its DCM metabolism, as well as potential to metabolise additional methylated substrates such as quaternary amines. Full annotation has been provided in a custom genome browser and search tool, in addition to multiple sequence alignments and phylogenetic trees for every predicted protein, http://www.slimsuite.unsw.edu.au/research/dcmf/.
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- 2019
10. Establishing a distributed national research infrastructure providing bioinformatics support to life science researchers in Australia
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Schneider, MV, Griffin, PC, Tyagi, S, Flannery, M, Dayalan, S, Gladman, S, Watson-Haigh, N, Bayer, PE, Charleston, M, Cooke, I, Cook, R, Edwards, RJ, Edwards, D, Gorse, D, McConville, M, Powell, D, Wilkins, MR, Lonie, A, Schneider, MV, Griffin, PC, Tyagi, S, Flannery, M, Dayalan, S, Gladman, S, Watson-Haigh, N, Bayer, PE, Charleston, M, Cooke, I, Cook, R, Edwards, RJ, Edwards, D, Gorse, D, McConville, M, Powell, D, Wilkins, MR, and Lonie, A
- Abstract
EMBL Australia Bioinformatics Resource (EMBL-ABR) is a developing national research infrastructure, providing bioinformatics resources and support to life science and biomedical researchers in Australia. EMBL-ABR comprises 10 geographically distributed national nodes with one coordinating hub, with current funding provided through Bioplatforms Australia and the University of Melbourne for its initial 2-year development phase. The EMBL-ABR mission is to: (1) increase Australia's capacity in bioinformatics and data sciences; (2) contribute to the development of training in bioinformatics skills; (3) showcase Australian data sets at an international level and (4) enable engagement in international programs. The activities of EMBL-ABR are focussed in six key areas, aligning with comparable international initiatives such as ELIXIR, CyVerse and NIH Commons. These key areas-Tools, Data, Standards, Platforms, Compute and Training-are described in this article.
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- 2019
11. Abstracts from Hydrocephalus 2016
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Adam, A, Robison, J, Lu, J, Jose, R, Badran, N, Vivas-Buitrago, T, Rigamonti, D, Sattar, A, Omoush, O, Hammad, M, Dawood, M, Maghaslah, M, Belcher, T, Carson, K, Hoffberger, J, Jusué Torres, I, Foley, S, Yasar, S, Thai, QA, Wemmer, J, Klinge, P, Al-Mutawa, L, Al-Ghamdi, H, Carson, KA, Asgari, M, de Zélicourt, D, Kurtcuoglu, V, Garnotel, S, Salmon, S, Balédent, O, Lokossou, A, Page, G, Balardy, L, Czosnyka, Z, Payoux, P, Schmidt, EA, Zitoun, M, Sevestre, MA, Alperin, N, Baudracco, I, Craven, C, Matloob, S, Thompson, S, Haylock Vize, P, Thorne, L, Watkins, LD, Toma, AK, Bechter, K, Pong, AC, Jugé, L, Bilston, LE, Cheng, S, Bradley, W, Hakim, F, Ramón, JF, Cárdenas, MF, Davidson, JS, García, C, González, D, Bermudez, S, Useche, N, Mejía, JA, Mayorga, P, Cruz, F, Martinez, C, Matiz, MC, Vallejo, M, Ghotme, K, Soto, HA, Riveros, D, Buitrago, A, Mora, M, Murcia, L, Cohen, D, Dasgupta, D, Curtis, C, Domínguez, L, Remolina, AJ, Grijalba, MA, Whitehouse, KJ, Edwards, RJ, Eleftheriou, A, Lundin, F, Fountas, KN, Kapsalaki, EZ, Smisson, HF, Robinson, JS, Fritsch, MJ, Arouk, W, Garzon, M, Kang, M, Sandhu, K, Baghawatti, D, Aquilina, K, James, G, Thompson, D, Gehlen, M, Schmid Daners, M, Eklund, A, Adam, A, Robison, J, Lu, J, Jose, R, Badran, N, Vivas-Buitrago, T, Rigamonti, D, Sattar, A, Omoush, O, Hammad, M, Dawood, M, Maghaslah, M, Belcher, T, Carson, K, Hoffberger, J, Jusué Torres, I, Foley, S, Yasar, S, Thai, QA, Wemmer, J, Klinge, P, Al-Mutawa, L, Al-Ghamdi, H, Carson, KA, Asgari, M, de Zélicourt, D, Kurtcuoglu, V, Garnotel, S, Salmon, S, Balédent, O, Lokossou, A, Page, G, Balardy, L, Czosnyka, Z, Payoux, P, Schmidt, EA, Zitoun, M, Sevestre, MA, Alperin, N, Baudracco, I, Craven, C, Matloob, S, Thompson, S, Haylock Vize, P, Thorne, L, Watkins, LD, Toma, AK, Bechter, K, Pong, AC, Jugé, L, Bilston, LE, Cheng, S, Bradley, W, Hakim, F, Ramón, JF, Cárdenas, MF, Davidson, JS, García, C, González, D, Bermudez, S, Useche, N, Mejía, JA, Mayorga, P, Cruz, F, Martinez, C, Matiz, MC, Vallejo, M, Ghotme, K, Soto, HA, Riveros, D, Buitrago, A, Mora, M, Murcia, L, Cohen, D, Dasgupta, D, Curtis, C, Domínguez, L, Remolina, AJ, Grijalba, MA, Whitehouse, KJ, Edwards, RJ, Eleftheriou, A, Lundin, F, Fountas, KN, Kapsalaki, EZ, Smisson, HF, Robinson, JS, Fritsch, MJ, Arouk, W, Garzon, M, Kang, M, Sandhu, K, Baghawatti, D, Aquilina, K, James, G, Thompson, D, Gehlen, M, Schmid Daners, M, and Eklund, A
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- 2017
12. High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer.
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Glenn, WK, Ngan, CC, Amos, TG, Edwards, RJ, Swift, J, Lutze-Mann, L, Shang, F, Whitaker, NJ, Lawson, JS, Glenn, WK, Ngan, CC, Amos, TG, Edwards, RJ, Swift, J, Lutze-Mann, L, Shang, F, Whitaker, NJ, and Lawson, JS
- Abstract
BACKGROUND: Although high risk HPVs are associated with an increased risk of prostate cancer it is not known if they have a causal role. The purpose of this study is to investigate the potential role of human papilloma viruses (HPVs) in prostate cancer. The aims are (i) to investigate the presence and confirm the identity of high risk HPVs in benign prostate tissues prior to the development of HPV positive prostate cancer in the same patients, and (ii) to determine if HPVs are biologically active. METHODS: We used polymerase chain reaction (PCR) to identify HPVs in specimens from 52 Australian men with benign prostate biopsies who 1 to 10 years later developed prostate cancer. Immunohistochemistry (IHC) was used to assess the expression of HPV E7 oncoproteins, cytokeratin and prostate specific antigen (PSA). We used RNASeq data from The Cancer Genome Atlas (TCGA) to identify possible HPV RNA sequences in prostate cancer. RESULTS: HPV screening using standard PCR was conducted on 28 of the 52 sets of benign and later prostate cancers. HPV L1 genes were identified in 13 (46%) benign and 8 (29%) of 28 later prostate cancers in the same patients. HPV E7 genes were identified in 23 (82%) benign and 19 (68%) of 28 subsequent prostate cancers in the same patients. The same HPV types were present in both the benign and subsequent prostate cancers in 9 sets of specimens. HPV type 16 was identified in 15% of benign and 3% of prostate cancers. HPV type 18 was identified in 26% of benign and 16% of prostate cancers. Small numbers of HPV types 45, 47, 76 and 115 were also identified. High confidence RNA-Seq evidence for high risk HPV types 16 and 18 was identified in 12 (2%) of the 502 TCGA prostate cancer transcriptomes. High risk HPV E7 oncoprotein was positively expressed in 23 (82%) of 28 benign prostate specimens but only in 8 (29%) of 28 of the later prostate cancer specimens. This difference is statistically significant (p = 0.001). Prostate specific antigen (PSA) was mor
- Published
- 2017
13. Chemokine-cleaving Streptococcus pyogenes protease SpyCEP is necessary and sufficient for bacterial dissemination within soft tissues and the respiratory tract
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Kurupati, P, Turner, CE, Tziona, I, Lawrenson, RA, Alam, FM, Nohadani, M, Stamp, GW, Zinkernagel, AS, Nizet, V, Edwards, RJ, Sriskandan, S, University of Zurich, and Sriskandan, S
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Streptococcus pyogenes ,Virulence Factors ,Molecular Sequence Data ,Colony Count, Microbial ,610 Medicine & health ,10234 Clinic for Infectious Diseases ,Mice ,Streptococcal Infections ,1312 Molecular Biology ,Animals ,Humans ,Amino Acid Sequence ,Fasciitis, Necrotizing ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Lung ,Respiratory Tract Infections ,Research Articles ,Conserved Sequence ,Microscopy ,Histocytochemistry ,Muscles ,2404 Microbiology ,Lactococcus lactis ,Liver ,Female ,Chemokines ,Sequence Alignment ,Spleen ,Peptide Hydrolases - Abstract
SpyCEP is a Streptococcus pyogenes protease that cleaves CXCL8/IL-8 and its activity is associated with human invasive disease severity. We investigated the role of SpyCEP in S. pyogenes necrotizing fasciitis and respiratory tract infection in mice using isogenic strains differing only in SpyCEP expression. SpyCEP cleaved human CXCL1, 2, 6 and 8 plus murine CXCL1 and 2 at a structurally conserved site. Mice were infected in thigh muscle with a strain of S. pyogenes that expresses a high level of SpyCEP, or with an isogenic non-SpyCEP expressing strain. SpyCEP expression by S. pyogenes hindered bacterial clearance from muscle, and enhanced bacterial spread, associated with cleavage of murine chemoattractant CXCL1. Mice were then infected with Lactococcus lactis strains that differed only in SpyCEP expression. In contrast to the parent L. lactis strain (lacks SpyCEP), which was avirulent when administered intramuscularly, infection with a strain that expressed SpyCEP heterologously led to dramatic systemic illness within 24 h, failure to clear bacteria from muscle and marked dissemination to other organs. In the upper airways, SpyCEP expression was required for survival of L. lactis but not S. pyogenes. However, dissemination of S. pyogenes to the lung was SpyCEP-dependent and was associated with evidence of chemokine cleavage. Taken together, the studies provide clear evidence that SpyCEP is necessary and sufficient for systemic bacterial dissemination from a soft tissue focus in this model and also underlies dissemination in the respiratory tract.
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- 2010
14. SAFETY AND UTILITY OF BRAINSTEM BIOPSY AND RESECTION
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Porretta, E, primary, Jeffery, SM, additional, Jordan, SL, additional, Male, J, additional, Edwards, RJ, additional, Love, S, additional, Scolding, NJ, additional, and Rice, CM, additional
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- 2016
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15. Ocean-climate variability and sea level in the North Atlantic region since AD 0
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Plassche O van de, Edwards RJ, Wright AJ, Weber SL, Schrier G van der, Drijfhout SS, Gehrels WR, and NOP
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ad 0 ,geschiedenis ,analysis ,analyse ,klimaatverandering ,seas ,zeeen ,climatic changes ,water levels ,waterstand ,long term ,history ,lange termijn - Abstract
niet beschikbaar
- Published
- 2012
16. RocA Truncation Underpins Hyper-Encapsulation, Carriage Longevity and Transmissibility of Serotype M18 Group A Streptococci
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DeLeo, FR, Lynskey, NN, Goulding, D, Gierula, M, Turner, CE, Dougan, G, Edwards, RJ, Sriskandan, S, DeLeo, FR, Lynskey, NN, Goulding, D, Gierula, M, Turner, CE, Dougan, G, Edwards, RJ, and Sriskandan, S
- Abstract
Group A streptococcal isolates of serotype M18 are historically associated with epidemic waves of pharyngitis and the non-suppurative immune sequela rheumatic fever. The serotype is defined by a unique, highly encapsulated phenotype, yet the molecular basis for this unusual colony morphology is unknown. Here we identify a truncation in the regulatory protein RocA, unique to and conserved within our serotype M18 GAS collection, and demonstrate that it underlies the characteristic M18 capsule phenotype. Reciprocal allelic exchange mutagenesis of rocA between M18 GAS and M89 GAS demonstrated that truncation of RocA was both necessary and sufficient for hyper-encapsulation via up-regulation of both precursors required for hyaluronic acid synthesis. Although RocA was shown to positively enhance covR transcription, quantitative proteomics revealed RocA to be a metabolic regulator with activity beyond the CovR/S regulon. M18 GAS demonstrated a uniquely protuberant chain formation following culture on agar that was dependent on excess capsule and the RocA mutation. Correction of the M18 rocA mutation reduced GAS survival in human blood, and in vivo naso-pharyngeal carriage longevity in a murine model, with an associated drop in bacterial airborne transmission during infection. In summary, a naturally occurring truncation in a regulator explains the encapsulation phenotype, carriage longevity and transmissibility of M18 GAS, highlighting the close interrelation of metabolism, capsule and virulence.
- Published
- 2013
17. Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites
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Ghassabian, S, Rawling, T, Zhou, F, Doddareddy, MR, Tattam, BN, Hibbs, DE, Edwards, RJ, Cui, PH, Murray, M, Ghassabian, S, Rawling, T, Zhou, F, Doddareddy, MR, Tattam, BN, Hibbs, DE, Edwards, RJ, Cui, PH, and Murray, M
- Abstract
The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants of efficacy and toxicity the roles of these enzymes in the formation of multiple sorafenib metabolites are unclear. In the present study CYP-mediated pathways of sorafenib oxidation in human liver were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only ∼5% of the activity of CYP3A4 and eleven other CYPs and three flavin-containing monooxygenases were inactive. In human hepatic microsomes metabolite formation was correlated with CYP3A4-mediated midazolam 1′-hydroxylation, but not with other CYP-specific substrate oxidations. In accord with these findings the CYP3A4 inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation pathways. From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within ∼5.4 of the CYP3A4 heme. Important hydrogen bonding interactions between sorafenib and amino acids Ser-119 and Glu-374 in the active center of CYP3A4 were identified. These findings indicate that sorafenib is oxidized selectively by human CYP3A4. This information could be adapted in individualized approaches to optimize sorafenib safety and efficacy in cancer patients. © 2012 Elsevier Inc.
- Published
- 2012
18. Ocean-climate variability and sea level in the North Atlantic region since AD 0
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NOP, Plassche O van de, Edwards RJ, Wright AJ, Weber SL, Schrier G van der, Drijfhout SS, Gehrels WR, NOP, Plassche O van de, Edwards RJ, Wright AJ, Weber SL, Schrier G van der, Drijfhout SS, and Gehrels WR
- Abstract
RIVM rapport:Abstract niet beschikbaar, We used reconstructed and model-simulated sea-level variations during the past 1000-3000 years to investigate their cause(s) and assess their suitability as proxy for ocean-related climate variations in the North Atlantic region. We studied salt-marsh deposits in North Carolina, Connecticut, Newfoundland, and Wales (UK). Sea-level reconstructions obtained so far (for Connecticut) show that mean high water varied on centennial and sub-centennial timescales on the order of cms-dms during the past 3000 years. The mean high water fluctuations correlate more or less positively with proxy records of temperature change, but this broad correlation does not hold for the entire record. The most significant correlation found is a consistent phase shift of ca. 125 years between changes in solar activity (as expressed in variations in residual delta 14C) and sea level, suggesting a linkage by one or more mechanisms with a corresponding response time. The fact that sea level continued to fluctuate during periods of low solar variability indicates, however, that other factors are also involved.Sea-level change due to changes in the thermohaline structure of the North Atlantic ocean has been calculated using a coupled ocean-atmosphere model of intermediate complexity (ECBilt). Two 1000-yr simulations are made, one using a constant solar forcing and one using an estimate of historic solar activity. In the solar forced simulation, sea-level variations are a proxy for climate variations. Anomalies in sea-surface temperature (SST) of the northern North Atlantic are generated by the solar radiation changes. These SST anomalies modulate the ocean thermohaline circulation, affecting surface salinities in the northern North Atlantic which are subsequently advected to the deep ocean. The associated deep ocean geopotential thickness anomalies dominate sea level in the northern North Atlantic. Comparison of the simulated steric sea-level variations in the Gulf Stream area for the past 1000 yr
- Published
- 2002
19. Tyrosine phosphorylation of myosin heavy chain during skeletal muscle differentiation: an integrated bioinformatics approach
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Harney, DF, primary, Butler, RK, additional, and Edwards, RJ, additional
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- 2005
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20. The Anti-Arrhythmic and Anti-Ischaemic Effects of Angina in Patients with and without Collaterals
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Edwards, RJ, primary, Redwood, S, additional, Lambiase, P, additional, and Marber, MS, additional
- Published
- 2001
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21. External hydrocephalus and subdural bleeding in infancy associated with transplacental anti-Ro antibodies.
- Author
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Edwards RJ, Allport TD, Stoodley NG, O'Callaghan F, Lock RJ, Carter MR, and Ramanan AV
- Abstract
BACKGROUND: The isolated finding of an unexplained chronic subdural haematoma in an infant may suggest non-accidental head injury (NAHI). The authors report a previously undescribed cause of multifocal chronic subdural haematoma in infancy which could result in a misdiagnosis of previous NAHI. METHODS: Two infants, aged 3 and 4 months of age, presented with progressively increasing head circumference measurements from birth. There was no history of encephalopathy. Retinal haemorrhages were not present. CT and MRI demonstrated bilateral subdural fluid collections over the frontal regions that were consistent with either chronic subdural haematomas or haemorrhagic subdural effusions. In view of the possibility of NAHI, child protection investigations were initiated. FINDINGS: In neither case did the child protection investigations raise concerns. Comprehensive investigations for known haematological and metabolic disorders associated with subdural haematomas or effusions in infants were all normal. In both cases the infant's mother had a history of Sjögren's syndrome and both infants had positive anti-Ro antibody at presentation. CONCLUSIONS: Transplacental acquisition of anti-Ro antibodies has been associated with external hydrocephalus. External hydrocephalus has been recognised as a predisposing factor for subdural haemorrhage. These are the first reported cases linking the presence of anti-Ro antibodies and external hydrocephalus with subdural fluid collections in infancy. [ABSTRACT FROM AUTHOR]
- Published
- 2012
22. Visitation guidelines promote safe, satisfying environments.
- Author
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White SK and Edwards RJ
- Abstract
Encourage patient and staff satisfaction by implementing family centered care with a flexible structure and effective security. [ABSTRACT FROM AUTHOR]
- Published
- 2006
23. Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support.
- Author
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Lambiase PD, Edwards RJ, Anthopoulos P, Rahman S, Meng YG, Bucknall CA, Redwood SR, Pearson JD, Marber MS, Lambiase, Pier D, Edwards, Richard J, Anthopoulos, Prodromos, Rahman, Salman, Meng, Y Gloria, Bucknall, Clifford A, Redwood, Simon R, Pearson, Jeremy D, and Marber, Michael S
- Published
- 2004
24. The mutagenicity of benzo[α]pyrene in mouse small intestine.
- Author
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Brooks, RA, Gooderham, NJ, Edwards, RJ, Boobis, AR, and Winton, DJ
- Abstract
We have investigated the mutagenicity of benzo[α]pyrene (B[α]P) in small intestine using the Dlb-1 locus assay in the mouse. Administration of B[α]P by the oral and i.p. routes had markedly different effects on the number of Dlb-1 mutations and the pattern of induction of cytochrome P-4501A1 (CYP1A1). In Ahr-responsive animals i.p. injection resulted in marked induction in crypt cells along the length of the small intestine, with some induction in the villus cells. In contrast, after oral administration, CYP1A1 induction was evident only in the villus cells, and this declined distally. The intensity and speed of induction in Ahr-responsive animals was such that the genotoxic effect of a single injection of B[α]P could not be augmented by prior treatment with non-genotoxic inducers such as β-napthoflavone and TCDD. Oral B[α]P treatment resulted in a decrease in the number of mutations when compared with the i.p. route. Studies in congenic Ahr-non-responsive versus Ahr-responsive mice indicated that induction of CYP1A1 was associated with increased number of Dlb-1 mutations. Mutation induction in Ahr-non-responsive mice in the absence of detectable CYP1A1 in either liver or small intestine indicates that an appreciable portion of B[α]P activation to a genotoxin must be by other than a CYP1A1 mediated route. These data show that B[α]P is a potent small intestinal mutagen at the Dlb-1 locus. [ABSTRACT FROM PUBLISHER]
- Published
- 1999
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25. A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking.
- Author
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Sesardic, D, Boobis, AR, Edwards, RJ, and Davies, DS
- Abstract
1. In previous studies (Boobis et al., 1985b) it was shown that a monoclonal antibody (MAb 3/4/2), raised against rat cytochrome P450 form c, reacts with an isoenzyme(s) of cytochrome P450 in human liver. It was predicted that the epitope with which this antibody reacts should be present on both isoenzymes of the P450IA gene sub-family (the orthologues of forms c and d) in man (Edwards et al., 1987). 2. This antibody was used to probe 45 different samples of human liver, by the technique of Western blotting. With one exception, all of the samples contained immunoreactive protein, a single band at Mr 54,000 (orthologous to rat form d), which ranged in content from less than 0.5 to 33.5 pmol mg-1 microsomal protein. The content of the human orthologue of form c was below 0.5 pmol mg-1, the limit of detection of the assay. 3. Thirteen of the samples were from patients of known smoking status. Immunoreactive P450 content was 3.5-fold higher, and phenacetin O-deethylase activity was four-fold higher, in the smokers than in the non-smokers. 4. There was a highly significant correlation between the amount of immunoreactive cytochrome P450 and the high affinity component of phenacetin O-deethylase activity in both smokers and non-smokers. 5. It is concluded that the high affinity component of phenacetin O-deethylase activity in man is catalysed by the orthologue of rat cytochrome P450d, and that this isoenzyme is inducible by cigarette smoking. 6. In a number of previous publications it has been suggested that there is an association between the poor metaboliser (PM) phenotype for debrisoquine and impaired phenacetin O-deethylation. In the present study it was shown that not all subjects PM for debrisoquine are poor metabolisers of phenacetin. [ABSTRACT FROM AUTHOR]
- Published
- 1988
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26. Immunosuppression by immunoglobulin deaggregation is not effective in reducing the anti-xenogeneic immunoglobulin response: experimental and clinical studies.
- Author
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Sivolapenko, GB, Kanariou, M, Edwards, RJ, Epenetos, AA, and Ritter, MA
- Published
- 1989
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27. Australasian Southern Ocean frontal stucture during summer 1976-77
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Edwards, RJ and Emery, WJ
- Abstract
Fourteen north-south expendable bathythermograph temperature sections are used to define the positions of the Subtropical Convergence, the Subantarctic Front and the Polar Front in the Australasian sector of the Southern Ocean. The data were collected by supply vessels sailing to the Antarctic mainland during the austral summer of 1976-77. Frontal features are identified on the basis of both temperature structure and observations of surface salinity. The Polar Front is found to be more convoluted than the other fronts, leading to wide and narrow sections of the Antarctic Polar Frontal Zone between it and the Subantarctic Front. South-west of Australia the Subantarctic Front shifts north along with the Subtropical Convergence, and the Antarctic Polar Frontal Zone is at its widest. East of a southward shift of all three fronts, south of eastern Australia, they separate to give almost equal separations of about 700 km between fronts south-east of New Zealand. The homogeneous Subantarctic Mode Water between the Subantarctic Front and the Subtropical Convergence is found to be progressively warmer towards the west. Though the data is not truly synoptic, being spread over 3½ months, it does reflect the frontal structure during the period of observation.
- Published
- 1982
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28. MYOCARDIAL PRECONDITIONING: MECHANISMS AND MAN
- Author
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Edwards, RJ and Marber
- Abstract
SUMMARYMyocardial preconditioning describes the profound myocardial protection that follows a short episode of sublethal ischaemia. Adenosine is produced in ischaemic myocardium and is thought to be an important trigger of the protective mechanism. The exact pathway awaits full elucidation but activation of G proteins and subsequently protein kinase C appear to be important signals. End effectors responsible for delaying cell death include opening of K+ATPion channels and the transcription of a family of cytoprotective proteins. Absolute proof that preconditioning occurs in man is still awaited, although cross clamping of the aorta during cardiac surgery, balloon inflation during coronary angioplasty, warm‐up angina and preinfarction angina are surrogate models supporting its existence. A clearer understanding of the protective mechanisms involved could lead to the development of novel therapeutic agents that could save the infarcting myocardium.
- Published
- 1998
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29. Observations of a new Baroclinic current along the western continental slope of Bass Strait
- Author
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Baines, PG, primary, Edwards, RJ, additional, and Fandry, CB, additional
- Published
- 1983
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30. Macquarie Harbour, Tasmania-seasonal oceanographic surveys in 1985
- Author
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Cresswell, GR, primary, Edwards, RJ, additional, and Barker, BA, additional
- Published
- 1989
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31. Intravascular volume and protein responses to running exercise
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Edwards Rj and Harrison Mh
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Skin temperature ,Physical Therapy, Sports Therapy and Rehabilitation ,Blood volume ,Hematocrit ,Hemoconcentration ,Sitting ,Internal medicine ,Cardiology ,medicine ,Intravascular volume status ,Orthopedics and Sports Medicine ,business - Abstract
The roles of posture and mean skin temperature (Tsk) in determining intravascular volume and protein responses to running exercise were examined in 12 male subjects. Moving from a sitting to a standing position before exercise was always accompanied by a decrease in blood volume (BV), as indicated by increases in the hematocrit and hemoglobin concentration. Although neither the onset of running nor alterations in Tsk during running caused any further consistent change in BV, there was an acceleration of the rate at which protein entered the intravascular space. At the end of exercise and in recovery this led to an augmentation of intravascular protein. It is concluded that intravascular volume responses to running exercise are determined by the accompanying postural hemoconcentration, and that running per se and any imposed thermal stress have minimal effects on BV thereafter. A hypothesis is presented which accounts for the reportedly diverse effects of different forms of exercise on BV in terms of the posture-dependent BV being obtained immediately before exercise begins.
- Published
- 1984
32. Task saturation in orthopaedic nursing: recognising the dangers and formulating solutions (concurrent)
- Author
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Edwards RJ
- Published
- 2009
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33. Clinical picture: a syndrome lost in specialisation.
- Author
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Edwards RJ, Moss T, and Sandeman DR
- Published
- 2003
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34. Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells
- Author
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Alison, MR, Golding, M, Sarraf, CE, Edwards, RJ, and Lalani, EN
- Published
- 1996
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35. Long-Term Follow-Up of Persons Living with Perinatally Acquired HIV Infection at a Large HIV Treatment Clinic in Trinidad.
- Author
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Edwards J, Boyce G, Lyons N, Todd S, Samaroo Francis W, Raeburn E, and Edwards RJ
- Abstract
Data on persons with perinatally acquired HIV infection in the Caribbean are limited; thus, a chart review was conducted among these clients at an adult HIV treatment clinic in Trinidad over the period January 01, 2011-June 30, 2023. Sociodemographic, clinical, and laboratory data were extracted and analyzed using RStudio version 2021.09.0. Fifty-four study participants were followed up, age range 18-29 years, and there were 27 (50%) males. Eighteen participants (33.3%) were institutionalized until the age of 18 years, while 36 (66.7%) lived with caregivers/relatives and attended outpatient pediatric clinic. The transition from the sheltered environment of pediatric care to the adult HIV clinic was turbulent for some participants as they experienced HIV-related stigma, which may result in poor HIV outcomes. At the initial clinic visit, 28 (51.9%) study participants were virally suppressed (HIV viral load <1,000 copies/mL), which included 12 (66.7%) of 18 who were institutionalized as compared to 16 (44.4%) of 38 who lived with caregivers/relatives ( p = 0.387). Data from their last clinic visit showed 31 (57.4%) participants were virally suppressed; 13 (24.1%) were lost to follow-up from care, and there were 6 (11.1%) deaths; 29 (53.7%) were on antiretroviral therapy single-tablet regimens (STRs) and 25 (46.3%) on complex multiple-tablet regimens (MTRs). Institutionalized clients and those on STRs were more likely to be virally suppressed than those living with relatives ( p = 0.043) and those on MTR ( p < 0.001), respectively. Reported deaths were higher among clients who lived with caregivers/relatives and those on MTR. Participants of younger age were less likely to achieve viral suppression ( p = 0.02). Comprehensive programs that include STRs, the engagement of caregivers/relatives and health workers, life skills, and enhanced psychosocial interventions for youths living with perinatally acquired HIV are important to support the transition to adult care and reduce the complex challenges of living with a stigmatizing disease.
- Published
- 2024
- Full Text
- View/download PDF
36. Parental assigned chromosomes for cultivated cacao provides insights into genetic architecture underlying resistance to vascular streak dieback.
- Author
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Tobias PA, Downs J, Epaina P, Singh G, Park RF, Edwards RJ, Brugman E, Zulkifli A, Muhammad J, Purwantara A, and Guest DI
- Abstract
Diseases of Theobroma cacao L. (Malvaceae) disrupt cocoa bean supply and economically impact growers. Vascular streak dieback (VSD), caused by Ceratobasidium theobromae, is a new encounter disease of cacao currently contained to southeast Asia and Melanesia. Resistance to VSD has been tested with large progeny trials in Sulawesi, Indonesia, and in Papua New Guinea with the identification of informative quantitative trait loci (QTLs). Using a VSD susceptible progeny tree (clone 26), derived from a resistant and susceptible parental cross, we assembled the genome to chromosome-level and discriminated alleles inherited from either resistant or susceptible parents. The parentally phased genomes were annotated for all predicted genes and then specifically for resistance genes of the nucleotide-binding site leucine-rich repeat class (NLR). On investigation, we determined the presence of NLR clusters and other potential disease response gene candidates in proximity to informative QTLs. We identified structural variants within NLRs inherited from parentals. We present the first diploid, fully scaffolded, and parentally phased genome resource for T. cacao L. and provide insights into the genetics underlying resistance and susceptibility to VSD., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)
- Published
- 2024
- Full Text
- View/download PDF
37. Isolation and characterization of IgG3 glycan-targeting antibodies with exceptional cross-reactivity for diverse viral families.
- Author
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Vukovich MJ, Shiakolas AR, Lindenberger J, Richardson RA, Bass LE, Barr M, Liu Y, Go EP, Park CS, May AJ, Sammour S, Kambarami C, Huang X, Janowska K, Edwards RJ, Mansouri K, Spence TN, Abu-Shmais AA, Manamela NP, Richardson SI, Leonard SEW, Gripenstraw KR, Setliff I, Saunders KO, Bonami RH, Ross TM, Desaire H, Moore PL, Parks R, Haynes BF, Sheward DJ, Acharya P, Sautto GA, and Georgiev IS
- Subjects
- Humans, SARS-CoV-2 immunology, HIV-1 immunology, Hemagglutinin Glycoproteins, Influenza Virus immunology, Spike Glycoprotein, Coronavirus immunology, COVID-19 immunology, COVID-19 virology, Antibodies, Monoclonal immunology, HIV Infections immunology, HIV Infections virology, Cross Reactions, Polysaccharides immunology, Immunoglobulin G immunology, Antibodies, Viral immunology
- Abstract
Broadly reactive antibodies that target sequence-diverse antigens are of interest for vaccine design and monoclonal antibody therapeutic development because they can protect against multiple strains of a virus and provide a barrier to evolution of escape mutants. Using LIBRA-seq (linking B cell receptor to antigen specificity through sequencing) data for the B cell repertoire of an individual chronically infected with human immunodeficiency virus type 1 (HIV-1), we identified a lineage of IgG3 antibodies predicted to bind to HIV-1 Envelope (Env) and influenza A Hemagglutinin (HA). Two lineage members, antibodies 2526 and 546, were confirmed to bind to a large panel of diverse antigens, including several strains of HIV-1 Env, influenza HA, coronavirus (CoV) spike, hepatitis C virus (HCV) E protein, Nipah virus (NiV) F protein, and Langya virus (LayV) F protein. We found that both antibodies bind to complex glycans on the antigenic surfaces. Antibody 2526 targets the stem region of influenza HA and the N-terminal domain (NTD) region of SARS-CoV-2 spike. A crystal structure of 2526 Fab bound to mannose revealed the presence of a glycan-binding pocket on the light chain. Antibody 2526 cross-reacted with antigens from multiple pathogens and displayed no signs of autoreactivity. These features distinguish antibody 2526 from previously described glycan-reactive antibodies. Further study of this antibody class may aid in the selection and engineering of broadly reactive antibody therapeutics and can inform the development of effective vaccines with exceptional breadth of pathogen coverage., Competing Interests: M.J.V., A.R.S., and I.S.G. are listed as inventors on patents filed describing the antibodies discovered here. I.S.G. is listed as an inventor on the patent applications for the LIBRA-seq technology. I.S.G. is a co-founder of AbSeek Bio. I.S.G. has served as a consultant for Sanofi. The Georgiev laboratory at VUMC has received unrelated funding from Merck and Takeda Pharmaceuticals. D.J.S has served as a consultant for AstraZeneca AB., (Copyright: © 2024 Vukovich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
- Full Text
- View/download PDF
38. Comparison of the immunogenicity of mRNA-encoded and protein HIV-1 Env-ferritin nanoparticle designs.
- Author
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Mu Z, Whitley J, Martik D, Sutherland L, Newman A, Barr M, Parks R, Wiehe K, Cain DW, Hodges KZ, Venkatayogi S, Lee EM, Smith L, Mansouri K, Edwards RJ, Wang Y, Rountree W, Alameh M-G, Tam Y, Barbosa C, Tomai M, Lewis MG, Santrai S, Maughan M, Tian M, Alt FW, Weissman D, Saunders KO, and Haynes BF
- Subjects
- Animals, Mice, Humans, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus genetics, RNA, Messenger immunology, RNA, Messenger genetics, HIV Antibodies immunology, Female, Antibodies, Neutralizing immunology, AIDS Vaccines immunology, AIDS Vaccines administration & dosage, AIDS Vaccines genetics, Mice, Inbred BALB C, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, SARS-CoV-2 immunology, SARS-CoV-2 genetics, Immunogenicity, Vaccine, HIV Infections immunology, HIV Infections prevention & control, HIV Infections virology, Nanoparticles, HIV-1 immunology, HIV-1 genetics, Ferritins immunology, Ferritins genetics
- Abstract
Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials., Competing Interests: D.W., K.O.S., and B.F.H. are inventors on U.S. patent number 11,318,197 and U.S. application numbers 17/703,332 and 16/977,408 (Stabilization of Human Immunodeficiency Virus [HIV] Envelopes). B.F.H. and K.O.S. are inventors on international patent application number PCT/US2019/020436 (Compositions and Methods for Inducing HIV-1 Antibodies). M.T. is a contract employee for 3M Healthcare. All other authors declare no conflicts of interest.
- Published
- 2024
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- View/download PDF
39. Origin and maintenance of large ribosomal RNA gene repeat size in mammals.
- Author
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Macdonald E, Whibley A, Waters PD, Patel H, Edwards RJ, and Ganley ARD
- Subjects
- Animals, DNA, Ribosomal Spacer genetics, Humans, DNA, Ribosomal genetics, Genes, rRNA, Phylogeny, Mammals genetics, Evolution, Molecular
- Abstract
The genes encoding ribosomal RNA are highly conserved across life and in almost all eukaryotes are present in large tandem repeat arrays called the rDNA. rDNA repeat unit size is conserved across most eukaryotes but has expanded dramatically in mammals, principally through the expansion of the intergenic spacer region that separates adjacent rRNA coding regions. Here, we used long-read sequence data from representatives of the major amniote lineages to determine where in amniote evolution rDNA unit size increased. We find that amniote rDNA unit sizes fall into two narrow size classes: "normal" (∼11-20 kb) in all amniotes except monotreme, marsupial, and eutherian mammals, which have "large" (∼35-45 kb) sizes. We confirm that increases in intergenic spacer length explain much of this mammalian size increase. However, in stark contrast to the uniformity of mammalian rDNA unit size, mammalian intergenic spacers differ greatly in sequence. These results suggest a large increase in intergenic spacer size occurred in a mammalian ancestor and has been maintained despite substantial sequence changes over the course of mammalian evolution. This points to a previously unrecognized constraint on the length of the intergenic spacer, a region that was thought to be largely neutral. We finish by speculating on possible causes of this constraint., Competing Interests: Conflicts of interest: The author(s) declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)
- Published
- 2024
- Full Text
- View/download PDF
40. Author Correction: Extant and extinct bilby genomes combined with Indigenous knowledge improve conservation of a unique Australian marsupial.
- Author
-
Hogg CJ, Edwards RJ, Farquharson KA, Silver LW, Brandies P, Peel E, Escalona M, Jaya FR, Thavornkanlapachai R, Batley K, Bradford TM, Chang JK, Chen Z, Deshpande N, Dziminski M, Ewart KM, Griffith OW, Marin Gual L, Moon KL, Travouillon KJ, Waters P, Whittington CM, Wilkins MR, Helgen KM, Lo N, Ho SYW, Ruiz Herrera A, Paltridge R, Marshall Graves JA, Renfree M, Shapiro B, Ottewell K, and Belov K
- Published
- 2024
- Full Text
- View/download PDF
41. SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.
- Author
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Zhang QE, Lindenberger J, Parsons RJ, Thakur B, Parks R, Park CS, Huang X, Sammour S, Janowska K, Spence TN, Edwards RJ, Martin M, Williams WB, Gobeil S, Montefiori DC, Korber B, Saunders KO, Haynes BF, Henderson R, and Acharya P
- Subjects
- Humans, Protein Binding, Immune Evasion, Models, Molecular, Protein Domains, Binding Sites, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus metabolism, SARS-CoV-2 genetics, SARS-CoV-2 immunology, SARS-CoV-2 metabolism, SARS-CoV-2 chemistry, Cryoelectron Microscopy, COVID-19 virology, COVID-19 immunology, Mutation, Protein Conformation
- Abstract
A recombinant lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryoelectron microscopy (cryo-EM) structures of XBB.1.5, XBB.1.16, EG.5, and EG.5.1 spike (S) ectodomains to reveal reinforced 3-receptor binding domain (RBD)-down receptor-inaccessible closed states mediated by interprotomer RBD interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters, including stability, receptor binding, and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape., Competing Interests: Declaration of interests B.F.H., K.O.S., R.J.E., S.G., and P.A. are named in patents submitted on the SARS-CoV-2 monoclonal antibodies studied in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
42. Prevalence of HTLV-1 and Hepatitis B Surface Antigen (HBsAg) Positivity among MSM Attending a Large HIV Treatment Centre in Trinidad.
- Author
-
Edwards RJ, Todd S, Edwards J, Jack N, and Boyce G
- Subjects
- Humans, Male, Adult, Middle Aged, Trinidad and Tobago epidemiology, Aged, Young Adult, Prevalence, Aged, 80 and over, Coinfection epidemiology, Coinfection virology, Human T-lymphotropic virus 1 immunology, Adolescent, HIV-1, Risk Factors, HIV Infections epidemiology, HIV Infections virology, Hepatitis B Surface Antigens blood, Homosexuality, Male statistics & numerical data, Hepatitis B epidemiology, HTLV-I Infections epidemiology
- Abstract
HIV-1, Hepatitis B and HTLV-1 have similar risk factors and shared routes of transmission and MSM are disproportionately affected by HIV. The aim of the study was to determine the prevalence of HTLV-1 and HBsAg positivity at initial enrolment among MSM attending a large HIV Clinic in Trinidad. Chart reviews were conducted between 2 and 15 January 2024, among self-identified MSM and a comparative group of randomly selected self-identified heterosexual males where sociodemographic, clinical and laboratory data were collected and analysed using SPSS Version 25. During the period April 2002-31 October 2023, in total there were 10,424 patients registered at the clinic, of whom 1255 (12.0%) were self-identified MSM, with an age range of 19-85 years and a median age of 40 years. There were 1822 randomly selected heterosexual males, with an age range of 18-94 years old and a median age of 52 years. Among the MSM, there were 21 (1.67%) patients who were HIV-1/HTLV-1-coinfected, 64 (5.10%) who were HIV-1/HBsAg-coinfected and two (0.16%) who were coinfected with all three viruses (HIV-1/HTLV-1/HBsAg) as compared to 47 ((2.58%) HIV-1/HTLV-1-coinfected ( p = 0.12), 69 (3.79%) HIV-1/HBsAg-coinfected ( p = 0.10) and three (0.16%) patients coinfected with all three viruses among the heterosexual males. There were no patients with HTLV-1-related diseases among the HIV-1/HTLV-1-coinfected patients and there were no deaths from chronic liver disease in patients coinfected with HIV-1/HBsAg. Despite the availability of an efficacious vaccine, there is a prevalence of hepatitis B of 5.1% among MSM attending the HIV Clinic in Trinidad; therefore, programmes to increase health literacy, screening and immunization are urgently needed.
- Published
- 2024
- Full Text
- View/download PDF
43. The Evolution of Ultraconserved Elements in Vertebrates.
- Author
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Cummins M, Watson C, Edwards RJ, and Mattick JS
- Subjects
- Animals, Humans, Genome, Phylogeny, Evolution, Molecular, Conserved Sequence, Vertebrates genetics
- Abstract
Ultraconserved elements were discovered two decades ago, arbitrarily defined as sequences that are identical over a length ≥ 200 bp in the human, mouse, and rat genomes. The definition was subsequently extended to sequences ≥ 100 bp identical in at least three of five mammalian genomes (including dog and cow), and shown to have undergone rapid expansion from ancestors in fish and strong negative selection in birds and mammals. Since then, many more genomes have become available, allowing better definition and more thorough examination of ultraconserved element distribution and evolutionary history. We developed a fast and flexible analytical pipeline for identifying ultraconserved elements in multiple genomes, dedUCE, which allows manipulation of minimum length, sequence identity, and number of species with a detectable ultraconserved element according to specified parameters. We suggest an updated definition of ultraconserved elements as sequences ≥ 100 bp and ≥97% sequence identity in ≥50% of placental mammal orders (12,813 ultraconserved elements). By mapping ultraconserved elements to ∼200 species, we find that placental ultraconserved elements appeared early in vertebrate evolution, well before land colonization, suggesting that the evolutionary pressures driving ultraconserved element selection were present in aquatic environments in the Cambrian-Devonian periods. Most (>90%) ultraconserved elements likely appeared after the divergence of gnathostomes from jawless predecessors, were largely established in sequence identity by early Sarcopterygii evolution-before the divergence of lobe-finned fishes from tetrapods-and became near fixed in the amniotes. Ultraconserved elements are mainly located in the introns of protein-coding and noncoding genes involved in neurological and skeletomuscular development, enriched in regulatory elements, and dynamically expressed throughout embryonic development., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)
- Published
- 2024
- Full Text
- View/download PDF
44. Extant and extinct bilby genomes combined with Indigenous knowledge improve conservation of a unique Australian marsupial.
- Author
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Hogg CJ, Edwards RJ, Farquharson KA, Silver LW, Brandies P, Peel E, Escalona M, Jaya FR, Thavornkanlapachai R, Batley K, Bradford TM, Chang JK, Chen Z, Deshpande N, Dziminski M, Ewart KM, Griffith OW, Marin Gual L, Moon KL, Travouillon KJ, Waters P, Whittington CM, Wilkins MR, Helgen KM, Lo N, Ho SYW, Ruiz Herrera A, Paltridge R, Marshall Graves JA, Renfree M, Shapiro B, Ottewell K, and Belov K
- Subjects
- Animals, Australia, Polymorphism, Single Nucleotide, Extinction, Biological, Conservation of Natural Resources, Marsupialia genetics, Genome
- Abstract
Ninu (greater bilby, Macrotis lagotis) are desert-dwelling, culturally and ecologically important marsupials. In collaboration with Indigenous rangers and conservation managers, we generated the Ninu chromosome-level genome assembly (3.66 Gbp) and genome sequences for the extinct Yallara (lesser bilby, Macrotis leucura). We developed and tested a scat single-nucleotide polymorphism panel to inform current and future conservation actions, undertake ecological assessments and improve our understanding of Ninu genetic diversity in managed and wild populations. We also assessed the beneficial impact of translocations in the metapopulation (N = 363 Ninu). Resequenced genomes (temperate Ninu, 6; semi-arid Ninu, 6; and Yallara, 4) revealed two major population crashes during global cooling events for both species and differences in Ninu genes involved in anatomical and metabolic pathways. Despite their 45-year captive history, Ninu have fewer long runs of homozygosity than other larger mammals, which may be attributable to their boom-bust life history. Here we investigated the unique Ninu biology using 12 tissue transcriptomes revealing expression of all 115 conserved eutherian chorioallantoic placentation genes in the uterus, an XY
1 Y2 sex chromosome system and olfactory receptor gene expansions. Together, we demonstrate the holistic value of genomics in improving key conservation actions, understanding unique biological traits and developing tools for Indigenous rangers to monitor remote wild populations., (© 2024. The Author(s).)- Published
- 2024
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45. Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions.
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Pierre CN, Adams LE, Higgins JS, Anasti K, Goodman D, Mielke D, Stanfield-Oakley S, Powers JM, Li D, Rountree W, Wang Y, Edwards RJ, Alam SM, Ferrari G, Tomaras GD, Haynes BF, Baric RS, and Saunders KO
- Subjects
- Animals, Mice, Humans, Female, Protein Domains immunology, Viral Load, Lung virology, Lung immunology, Lung pathology, SARS-CoV-2 immunology, COVID-19 immunology, COVID-19 prevention & control, COVID-19 virology, Antibodies, Viral immunology, Antibodies, Neutralizing immunology, Immunoglobulin Fc Fragments immunology, Spike Glycoprotein, Coronavirus immunology
- Abstract
Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice and cynomolgus macaques from severe disease. The mechanisms of NTD non-neutralizing antibody-mediated protection are unknown. Here we show that Fc effector functions mediate NTD non-neutralizing antibody (non-nAb) protection against SARS-CoV-2 MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious viral titers in the lung as potently as neutralizing antibody (nAb) infusion, disease markers including gross lung discoloration were similar in nAb and non-nAb groups. Fc functional knockout substitutions abolished non-nAb protection and increased viral titers in the nAb group. Fc enhancement increased non-nAb protection relative to WT, supporting a positive association between Fc functionality and degree of protection from SARS-CoV-2 infection. For therapeutic administration of antibodies, non-nAb effector functions contributed to virus suppression and lessening of lung discoloration, but the presence of neutralization was required for optimal protection from disease. This study demonstrates that non-nAbs can utilize Fc-mediated mechanisms to lower viral load and prevent lung damage due to coronavirus infection., Competing Interests: KOS, DL, and BFH have patents related to the antibodies described in this manuscript., (Copyright: © 2024 Pierre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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46. Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.
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Williams WB, Alam SM, Ofek G, Erdmann N, Montefiori DC, Seaman MS, Wagh K, Korber B, Edwards RJ, Mansouri K, Eaton A, Cain DW, Martin M, Hwang J, Arus-Altuz A, Lu X, Cai F, Jamieson N, Parks R, Barr M, Foulger A, Anasti K, Patel P, Sammour S, Parsons RJ, Huang X, Lindenberger J, Fetics S, Janowska K, Niyongabo A, Janus BM, Astavans A, Fox CB, Mohanty I, Evangelous T, Chen Y, Berry M, Kirshner H, Van Itallie E, Saunders KO, Wiehe K, Cohen KW, McElrath MJ, Corey L, Acharya P, Walsh SR, Baden LR, and Haynes BF
- Subjects
- Humans, HIV Infections immunology, HIV Infections virology, Cell Lineage, Liposomes, env Gene Products, Human Immunodeficiency Virus immunology, Mutation, HIV Envelope Protein gp41 immunology, AIDS Vaccines immunology, HIV-1 immunology, Antibodies, Neutralizing immunology, B-Lymphocytes immunology, HIV Antibodies immunology
- Abstract
A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development., Competing Interests: Declaration of interests B.F.H. and S.M.A. have US patents 9402917, 9402893, 9717789, and 10588960 and US patent application 63/540482. B.F.H., S.M.A., and B.K. have US patent 10076567. B.F.H. and K.O.S. have patent applications PCT/US2023/077677 and PCT/US2023/077686. C.B.F. has patents on PEGylated liposomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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47. Comparison of Two Different Alfaxalone Concentrations Combined with Midazolam to Anesthetize Cynomolgus Macaques ( Macaca fascicularis ) for Plethysmography.
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Edwards RJ, Ghering JM, Frick OM, Pasloske KS, Santos KH, Astleford SM, White CE, and Marion BM
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- Animals, Female, Male, Injections, Intramuscular, Anesthetics administration & dosage, Anesthetics pharmacology, Anesthesia veterinary, Anesthetics, Combined administration & dosage, Anesthetics, Combined pharmacology, Pregnanediones administration & dosage, Pregnanediones pharmacology, Macaca fascicularis, Midazolam administration & dosage, Midazolam pharmacology, Plethysmography
- Abstract
Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.
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- 2024
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48. The Burden of Pretreatment HIV Drug Resistance in Trinidad and Tobago.
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Gbadamosi SO, Boyce G, Trepka MJ, and Edwards RJ
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- Humans, Reverse Transcriptase Inhibitors therapeutic use, Trinidad and Tobago epidemiology, Retrospective Studies, Mutation, Drug Resistance, Viral genetics, Viral Load, Anti-HIV Agents pharmacology, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Infections epidemiology
- Abstract
Strategies to improve the scale-up of antiretroviral therapy (ART) for patients with HIV in Trinidad and Tobago, including the adoption of the "Test and Treat All" policy, have accompanied an increase in the number of patients with pretreatment HIV drug resistance (PDR) in the country. However, the scale of this public health problem is not well established. The objective of this study was to estimate the prevalence of PDR and evaluate its impact on viral suppression among patients with HIV receiving care at a large HIV treatment center in Trinidad and Tobago. We retrospectively analyzed data from the Medical Research Foundation of Trinidad and Tobago of patients newly diagnosed with HIV who had HIV genotyping performed. PDR was defined as having at least one drug-resistant mutation. We assessed the impact of PDR on achieving viral suppression within 12 months of ART initiation, using a Cox extended model. Among 99 patients, 31.3% had PDR to any drug, 29.3% to a non-nucleoside reverse transcriptase inhibitor (NNRTI), 3.0% to a nucleoside reverse transcriptase inhibitor, and 3.0% to a protease inhibitor. Overall, 67.1% of the patients who initiated ART ( n = 82) and 66.7% (16/24) of patients with PDR achieved viral suppression within 12 months. We found no significant association between PDR status and achieving viral suppression within 12 months [adjusted hazard ratio: 1.08 (95% confidence interval: 0.57-2.04)]. There is a high prevalence of PDR in Trinidad and Tobago, specifically driven by NNRTI resistance. Although we found no difference in virologic suppression by PDR status, there is an urgent need for an effective HIV response to address the many drivers of virologic failure. Accelerating access to affordable, quality-assured generic dolutegravir and adopting it as the preferred first-line ART therapy are critical.
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- 2024
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49. A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.
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Erdmann NB, Williams WB, Walsh SR, Grunenberg N, Edlefsen PT, Goepfert PA, Cain DW, Cohen KW, Maenza J, Mayer KH, Tieu HV, Sobieszczyk ME, Swann E, Lu H, De Rosa SC, Sagawa Z, Moody MA, Fox CB, Ferrari G, Edwards RJ, Acharya P, Alam SM, Parks R, Barr M, Tomaras GD, Montefiori DC, Gilbert PB, McElrath MJ, Corey L, Haynes BF, and Baden LR
- Abstract
Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys., Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12., Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations., Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine., Competing Interests: SRW has received institutional funding from the National Institute of Allergy and Infectious Diseases/National Institutes of Health; and institutional grants or contracts from Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson and BioNTech; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. BFH, CBF and SMA have patents on the MPER peptide liposome.
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- 2024
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50. Is developmental plasticity triggered by DNA methylation changes in the invasive cane toad ( Rhinella marina )?
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Yagound B, Sarma RR, Edwards RJ, Richardson MF, Rodriguez Lopez CM, Crossland MR, Brown GP, DeVore JL, Shine R, and Rollins LA
- Abstract
Many organisms can adjust their development according to environmental conditions, including the presence of conspecifics. Although this developmental plasticity is common in amphibians, its underlying molecular mechanisms remain largely unknown. Exposure during development to either 'cannibal cues' from older conspecifics, or 'alarm cues' from injured conspecifics, causes reduced growth and survival in cane toad ( Rhinella marina ) tadpoles. Epigenetic modifications, such as changes in DNA methylation patterns, are a plausible mechanism underlying these developmental plastic responses. Here we tested this hypothesis, and asked whether cannibal cues and alarm cues trigger the same DNA methylation changes in developing cane toads. We found that exposure to both cannibal cues and alarm cues was associated with local changes in DNA methylation patterns. These DNA methylation changes affected genes putatively involved in developmental processes, but in different genomic regions for different conspecific-derived cues. Genetic background explains most of the epigenetic variation among individuals. Overall, the molecular mechanisms triggered by exposure to cannibal cues seem to differ from those triggered by alarm cues. Studies linking epigenetic modifications to transcriptional activity are needed to clarify the proximate mechanisms that regulate developmental plasticity in cane toads., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)
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- 2024
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