Publications by authors named "A M Millington Ward"

2,642 Publications

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The endocannabinoid system and retinoic acid signaling combine to influence bone growth.

Mol Cell Endocrinol 2021 Apr 8:111267. Epub 2021 Apr 8.

Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, Deakin University School of Medicine, Geelong VIC 3216, Australia; University of Mississippi Medical Center, Dept of Cell and Molecular Biology, 2500 North State Street, Jackson, MS 39216, USA. Electronic address:

Osteoporosis is an increasing burden on public health as the world-wide population ages and effective therapeutics are severely needed. Two pathways with high potential for osteoporosis treatment are the retinoic acid (RA) and endocannabinoid system (ECS) signaling pathways. We sought to elucidate the roles that these pathways play in bone development and maturation. Here, we use chemical treatments to modulate the RA and ECS pathways at distinct early, intermediate, and late times bone development in zebrafish. We further assessed osteoclast activity later in zebrafish and medaka. Finally, by combining sub-optimal doses of AR and ECS modulators, we show that enhancing RA signaling or reducing the ECS promote bone formation and decrease osteoclast abundance and activity. These data demonstrate that RA signaling and the ECS can be combined as sub-optimal doses to influence bone growth and may be key targets for potential therapeutics.
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http://dx.doi.org/10.1016/j.mce.2021.111267DOI Listing
April 2021

The Index of Attitudes toward Homosexuals: Factor Analysis in a National Sample of Oncology Clinicians.

J Homosex 2021 Apr 9:1-14. Epub 2021 Apr 9.

Epidemiology, Milken Institute School of Public Health, the George Washington University, Washington, DC, USA.

The Index of Attitudes toward Homosexuals (IAH) was published by Hudson and Ricketts in 1980 as a unidimensional index to measure affective responses to homosexuals. Siebert et al. identified two factors in a sample of predominantly female social science students: Cognitive/Social Distance (α = .91) and Affective/Attraction-Advances (α = .79). The present study sought to conduct a factor analysis to confirm the factor structure of the IAH in a national sample of oncology clinicians (n = 406). Exploratory factor analysis conducted on a random subset of 40% of survey respondents (n = 163) indicated three factors, termed: Avoidance (α = .92), Approach (α = .75) and Acceptance (α = .80). Confirmatory factor analysis conducted on the remaining 60% of respondents (n = 243) confirmed the three-factor structure (final Chi-square/DF = 1.988, RMSEA = 0.064, Bentler CFI = 0.949). Given the diversity, size, and strength of the sampling frame, future research using the IAH in clinical settings can obtain more precise findings by analyzing data according to these three factors.
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http://dx.doi.org/10.1080/00918369.2021.1909394DOI Listing
April 2021

Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting.

Front Immunol 2021 22;12:648216. Epub 2021 Mar 22.

Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ. We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, = 36), (iii) individuals with HIV infection (HIV, = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) () were analyzed using flow cytometry. MAIT cells were defined as CD3 CD161 Vα7.2 T cells. Circulating MAIT cell frequencies were depleted in individuals with HIV infection ( = 0.009). MAIT cells showed reduced CD107a expression in aTB ( = 0.006), and reduced IFNγ expression in aTB ( < 0.001) and in HIV-TB ( < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV ( < 0.001), aTB ( = 0.019), and HIV-TB ( = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB ( = 0.009) and HIV-TB ( = 0.002) after stimulation with BCG-GFP and HK-. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a ( = 0.020) and IFNγ ( = 0.010) expression. Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.
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http://dx.doi.org/10.3389/fimmu.2021.648216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019701PMC
March 2021

Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike.

Cell Rep 2021 Apr;35(1):108933

Department of Medical Microbiology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA. Electronic address:

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.
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http://dx.doi.org/10.1016/j.celrep.2021.108933DOI Listing
April 2021

Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer.

PLoS Pathog 2021 Apr 7;17(4):e1008977. Epub 2021 Apr 7.

Translational Health Science & Technology Institute, NCR Biotech Science Cluster, Faridabad, India.

Evaluating the structure-function relationship of viral envelope (Env) evolution and the development of broadly cross-neutralizing antibodies (bnAbs) in natural infection can inform rational immunogen design. In the present study, we examined the magnitude and specificity of autologous neutralizing antibodies induced in rabbits by a novel HIV-1 clade C Env protein (1PGE-THIVC) vis-à-vis those developed in an elite neutralizer from whom the env sequence was obtained that was used to prepare the soluble Env protein. The novel 1PGE-THIVC Env trimer displayed a native like pre-fusion closed conformation in solution as determined by small angle X-ray scattering (SAXS) and negative stain electron microscopy (EM). This closed spike conformation of 1PGE-THIVC Env trimers was correlated with weak or undetectable binding of non-neutralizing monoclonal antibodies (mAbs) compared to neutralizing mAbs. Furthermore, 1PGE-THIVC SOSIP induced potent neutralizing antibodies in rabbits to autologous virus variants. The autologous neutralizing antibody specificity induced in rabbits by 1PGE-THIVC was mapped to the C3/V4 region (T362/P401) of viral Env. This observation agreed with electron microscopy polyclonal epitope mapping (EMPEM) of the Env trimer complexed with IgG Fab prepared from the immunized rabbit sera. Our study demonstrated neutralization of sequence matched and unmatched autologous viruses by serum antibodies induced in rabbits by 1PGE-THIVC and also highlighted a comparable specificity for the 1PGE-THIVC SOSIP trimer with that seen with polyclonal antibodies elicited in the elite neutralizer by negative-stain electron microscopy polyclonal epitope (ns-EMPEM) mapping.
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http://dx.doi.org/10.1371/journal.ppat.1008977DOI Listing
April 2021

Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants.

bioRxiv 2021 Apr 1. Epub 2021 Apr 1.

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
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http://dx.doi.org/10.1101/2021.04.01.437942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020967PMC
April 2021

The Role of the Metzincin Superfamily in Prostate Cancer Progression: A Systematic-Like Review.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

School of Medicine, Deakin University, Geelong, VIC 3216, Australia.

Prostate cancer remains a leading cause of cancer-related morbidity in men. Potentially important regulators of prostate cancer progression are members of the metzincin superfamily of proteases, principally through their regulation of the extracellular matrix. It is therefore timely to review the role of the metzincin superfamily in prostate cancer and its progression to better understand their involvement in this disease. A systematic-like search strategy was conducted. Articles that investigated the roles of members of the metzincin superfamily and their key regulators in prostate cancer were included. The extracted articles were synthesized and data presented in tabular and narrative forms. Two hundred and five studies met the inclusion criteria. Of these, 138 investigated the role of the Matrix Metalloproteinase (MMP) subgroup, 34 the Membrane-Tethered Matrix Metalloproteinase (MT-MMP) subgroup, 22 the A Disintegrin and Metalloproteinase (ADAM) subgroup, 8 the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) subgroup and 53 the Tissue Inhibitor of Metalloproteinases (TIMP) family of regulators, noting that several studies investigated multiple family members. There was clear evidence that specific members of the metzincin superfamily are involved in prostate cancer progression, which can be either in a positive or negative manner. However, further understanding of their mechanisms of action and how they may be used as prognostic indicators or molecular targets is required.
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http://dx.doi.org/10.3390/ijms22073608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036576PMC
March 2021

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals.

Pharmaceutics 2021 Mar 20;13(3). Epub 2021 Mar 20.

Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, UK.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.
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http://dx.doi.org/10.3390/pharmaceutics13030419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004052PMC
March 2021

Maternal Vitamin and Mineral Supplementation and Rate of Maternal Weight Gain Affects Placental Expression of Energy Metabolism and Transport-Related Genes.

Genes (Basel) 2021 Mar 9;12(3). Epub 2021 Mar 9.

Center for Nutrition and Pregnancy, Department of Animal Sciences, North Dakota State University, Fargo, ND 58102, USA.

Maternal nutrients are essential for proper fetal and placental development and function. However, the effects of vitamin and mineral supplementation under two rates of maternal weight gain on placental genome-wide gene expression have not been investigated so far. Furthermore, biological processes and pathways in the placenta that act in response to early maternal nutrition are yet to be elucidated. Herein, we examined the impact of maternal vitamin and mineral supplementation (from pre-breeding to day 83 post-breeding) and two rates of gain during the first 83 days of pregnancy on the gene expression of placental caruncles (CAR; maternal placenta) and cotyledons (COT; fetal placenta) of crossbred Angus beef heifers. We identified 267 unique differentially expressed genes (DEG). Among the DEGs from CAR, we identified , and that underlie the cholesterol biosynthesis pathway. Furthermore, the transcription factors and were over-represented in biological processes related to kidney organogenesis. The DEGs from COT included , , , and Our over-representation analysis retrieved biological processes related to nutrient transport and ion homeostasis, whereas the pathways included insulin secretion, PPAR signaling, and biosynthesis of amino acids. Vitamin and mineral supplementation and rate of gain were associated with changes in gene expression, biological processes, and KEGG pathways in beef cattle placental tissues.
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http://dx.doi.org/10.3390/genes12030385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001966PMC
March 2021

Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects.

bioRxiv 2021 Mar 24. Epub 2021 Mar 24.

SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterized 198 antibodies isolated from four COVID19+ subjects and identified 14 SARS-CoV-2 neutralizing antibodies. One targeted the NTD, one recognized an epitope in S2 and twelve bound the RBD. Three anti-RBD neutralizing antibodies cross-neutralized SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs to the ACE2 receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency rather than the antibody epitope specificity regulates the protective potential of anti-SARS-CoV-2 antibodies. The anti-S2 antibody also neutralized SARS-CoV-1 and all four cross-neutralizing antibodies neutralized the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.
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http://dx.doi.org/10.1101/2021.03.23.436684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010719PMC
March 2021

A statistical method for identifying different rules of interaction between individuals in moving animal groups.

J R Soc Interface 2021 Mar 31;18(176):20200925. Epub 2021 Mar 31.

Animal Behaviour Lab, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.

The emergent patterns of collective motion are thought to arise from application of individual-level rules that govern how individuals adjust their velocity as a function of the relative position and behaviours of their neighbours. Empirical studies have sought to determine such rules of interaction applied by 'average' individuals by aggregating data from multiple individuals across multiple trajectory sets. In reality, some individuals within a group may interact differently from others, and such individual differences can have an effect on overall group movement. However, comparisons of rules of interaction used by individuals in different contexts have been largely qualitative. Here we introduce a set of randomization methods designed to determine statistical differences in the rules of interaction between individuals. We apply these methods to a case study of leaders and followers in pairs of freely exploring eastern mosquitofish (). We find that each of the randomization methods is reliable in terms of: repeatability of -values, consistency in identification of significant differences and similarity between distributions of randomization-based test statistics. We observe convergence of the distributions of randomization-based test statistics across repeat calculations, and resolution of any ambiguities regarding significant differences as the number of randomization iterations increases.
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http://dx.doi.org/10.1098/rsif.2020.0925DOI Listing
March 2021

Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults.

N Engl J Med 2021 03;384(12):1089-1100

From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (G.E.G., Z.M., N. Grunenberg, Y.H., D.G., B.P., J.J.K., J.H., C.B., S.R., S.T., M.J., M. Sikhosana, M. Andrasik, J.G.K., M.J.M., P.B.G., H.J., L.C.), Seattle; the Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand (G.E.G., F.L., E.L., B.M., T.P., S.T.), the National Institute for Communicable Diseases, National Health Laboratory Service (A.P.), and Aurum Institute (C.I., M. Sebe, W.B., P.S., T.A., G. Kobane), Johannesburg, Desmond Tutu HIV Centre (L.-G.B., S.K., C.N.N., M. Atujuna), the Department of Medicine, Wellcome Centre for Infectious Diseases Research in Africa, and Institute of Infectious Disease and Molecular Medicine (G.M., A.M.W.), and the Division of Clinical Pharmacology, Department of Medicine (L.W.), University of Cape Town, Cape Town, Setshaba Research Centre, Soshanguve (M.M., K.S.M.), Mecru Clinical Research Unit, Sefako Mkgatho Health Sciences University, Ga-Rankuwa (M.N., M.P.M.), Nelson Mandela Academic Clinical Research Unit and Department of Internal Medicine and Pharmacology, Walter Sisulu University, Mthatha (T.D., P.M.), the School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), the South African Medical Research Council (G.E.G., D.K., N.S., V.N., G. Kistnasami, Z.G.) and the Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal (N.N., N. Garrett), Durban, and Qhakaza Mbokodo Research Clinic, Ladysmith (P.K., P.B.M.) - all in South Africa; the Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (M. Allen), and GlaxoSmithKline Vaccines, Rockville (N.K.-T.) - both in Maryland; the Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta (D.B.); GSK Vaccines, Cambridge, MA (S.W.B.); Sanofi Pasteur, Swiftwater, PA (S.P., C.D.G.); GlaxoSmithKline, Siena, Italy (S.P.); GlaxoSmithKline, Wavre (M.K.), and GlaxoSmithKline, Rixensart (O.V.D.M.) - both in Belgium; and the Graduate Group in Biostatistics and the Center for Computational Biology, University of California, Berkeley (N.S.H.).

Background: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa.

Methods: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months.

Results: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84).

Conclusions: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).
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http://dx.doi.org/10.1056/NEJMoa2031499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888373PMC
March 2021

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.

bioRxiv 2021 Mar 10. Epub 2021 Mar 10.

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
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http://dx.doi.org/10.1101/2021.03.09.434529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987018PMC
March 2021

A cross-neutralizing antibody between HIV-1 and influenza virus.

PLoS Pathog 2021 Mar 22;17(3):e1009407. Epub 2021 Mar 22.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.

Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.
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http://dx.doi.org/10.1371/journal.ppat.1009407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016226PMC
March 2021

An electrochemical SARS-CoV-2 biosensor inspired by glucose test strip manufacturing processes.

Chem Commun (Camb) 2021 Apr 17;57(30):3704-3707. Epub 2021 Mar 17.

Biomedical Engineering, University of Strathclyde, Glasgow, G1 1XP, UK.

Accurate and rapid diagnostic tests are critical to reducing the impact of SARS-CoV-2. This study presents early, but promising measurements of SARS-CoV-2 using the ACE2 enzyme as the recognition element to achieve clinically relevant detection. The test provides a scalable route to sensitive, specific, rapid and low cost mass testing.
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http://dx.doi.org/10.1039/d1cc00936bDOI Listing
April 2021

Delayed miscarriage inside an infected decidual cast: a rare complication of the Depo medroxyprogesterone acetate injection.

BMJ Case Rep 2021 Mar 15;14(3). Epub 2021 Mar 15.

Obstetrics and Gynaecology, East Sussex Healthcare NHS Trust, Saint Leonards-on-Sea, UK.

Decidualisation of the endometrium is a progesterone-mediated reaction that naturally occurs during a woman's menstrual cycle. The hyperproliferated tissue is then usually dissolved and passed in a menstrual period. Occasionally, the natural dissolution does not happen, and the tissue maintains the shape of the endometrium, forming a decidual cast. These casts are known to be formed secondary to the use and/or cessation of various contraceptive methods. Here, we report a case of a patient presenting with passage of a decidual cast secondary to cessation of the Depo medroxyprogesterone acetate injection. This is the first reported case of the cast becoming infected, and also the first case of a decidual cast containing old products of conception.
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http://dx.doi.org/10.1136/bcr-2020-238583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959223PMC
March 2021

The Florida Pancreas Collaborative Next-Generation Biobank: Infrastructure to Reduce Disparities and Improve Survival for a Diverse Cohort of Patients with Pancreatic Cancer.

Cancers (Basel) 2021 Feb 15;13(4). Epub 2021 Feb 15.

College of Medicine, University of Florida, Gainesville, FL 32610, USA.

: Well-annotated, high-quality biorepositories provide a valuable platform to support translational research. However, most biorepositories have poor representation of minority groups, limiting the ability to address health disparities. : We describe the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective cohort study and biorepository designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L). We provide an overview of stakeholders; study eligibility and design; recruitment strategies; standard operating procedures to collect, process, store, and transfer biospecimens, medical images, and data; our cloud-based data management platform; and progress regarding recruitment and biobanking. : The FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and questionnaires (62%). : This biorepository addresses a critical gap in PaCa research and has potential to advance translational studies intended to minimize disparities and reduce PaCa-related morbidity and mortality.
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http://dx.doi.org/10.3390/cancers13040809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919015PMC
February 2021

Synergistic Killing and Re-Sensitization of to Antibiotics by Phage-Antibiotic Combination Treatment.

Pharmaceuticals (Basel) 2021 Feb 25;14(3). Epub 2021 Feb 25.

Wound Infections Department, Bacterial Diseases Branch, Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

Multidrug-resistant (MDR) infections pose a serious health threat. Bacteriophage-antibiotic combination therapy is a promising candidate for combating these infections. A 5-phage cocktail, PAM2H, was tested in combination with antibiotics (ceftazidime, ciprofloxacin, gentamicin, meropenem) to determine if PAM2H enhances antibiotic activity. Combination treatment in vitro resulted in a significant increase in susceptibility of MDR strains to antibiotics. Treatment with ceftazidime (CAZ), meropenem, gentamicin, or ciprofloxacin in the presence of the phage increased the number of strains susceptible to these antibiotics by 63%, 56%, 31%, and 81%, respectively. Additionally, in a mouse dorsal wound model, seven of eight mice treated with a combination of CAZ and PAM2H for three days had no detectable bacteria remaining in their wounds on day 4, while all mice treated with CAZ or PAM2H alone had ~10 colony forming units (CFU) remaining in their wounds. recovered from mouse wounds post-treatment showed decreased virulence in a wax worm model, and DNA sequencing indicated that the combination treatment prevented mutations in genes encoding known phage receptors. Treatment with PAM2H in combination with antibiotics resulted in the re-sensitization of to antibiotics and a synergistic reduction in bacterial burden .
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http://dx.doi.org/10.3390/ph14030184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996583PMC
February 2021

Endoscopic cyclophotocoagulation and Kahook Dual Blade trabeculotomy in combination with phacoemulsification.

Can J Ophthalmol 2021 Mar 3. Epub 2021 Mar 3.

Naval Hospital, Bremerton, Wash; Naval Medical Center, San Diego, Calif.

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http://dx.doi.org/10.1016/j.jcjo.2021.01.019DOI Listing
March 2021

Extremely potent human monoclonal antibodies from COVID-19 convalescent patients.

Cell 2021 04 23;184(7):1821-1835.e16. Epub 2021 Feb 23.

Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy; Faculty of Medicine, Imperial College, London, UK. Electronic address:

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions.
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http://dx.doi.org/10.1016/j.cell.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901298PMC
April 2021

Zebrafish Bacterial Infection Assay to Study Host-Pathogen Interactions.

Bio Protoc 2020 Mar 5;10(5):e3536. Epub 2020 Mar 5.

School of Medicine, Deakin University, Geelong, Victoria, Australia.

The study of host-pathogen interactions has improved our understanding of both pathogenesis and the response of the host to infection, including both innate and adaptive responses. Neutrophils and macrophages represent the first line of innate host defense against any infection. The zebrafish is an ideal model to study the response of these cells to a variety of pathogens. Zebrafish possess both neutrophils and macrophages exhibiting similar defense mechanisms to their human counterparts. The transparency of zebrafish embryos greatly facilitates tracking of infection dynamics in a non-invasive manner at high-resolution using labelled pathogens, while immune cells can also be labelled transgenically to enable even more in-depth analysis. Here we describe a procedure for performing a bacterial infection assay in zebrafish embryos using fluorescently-labelled bacteria and demonstrate the monitoring and quantification of the infection kinetics. Of note, this procedure helps in understanding the functional role of genes that are important in driving the innate immune response.
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http://dx.doi.org/10.21769/BioProtoc.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842644PMC
March 2020

A multiobserver study investigating the effectiveness of prostatic multiparametric magnetic resonance imaging to dose escalate corresponding histologic lesions using high-dose-rate brachytherapy.

Brachytherapy 2021 Feb 26. Epub 2021 Feb 26.

Baines Imaging Research Laboratory, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Medical Biophysics, Western University, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada. Electronic address:

Purpose: Using multiparametric MRI data and the pathologic data from radical prostatectomy specimens, we simulated the treatment planning of dose-escalated high-dose-rate brachytherapy (HDR-BT) to the Multiparametric MRI dominant intraprostatic lesion (mpMRI-DIL) to compare the dose potentially delivered to the pathologically confirmed locations of the high-grade component of the cancer.

Methods And Materials: Pathologist-annotated prostatectomy midgland histology sections from 12 patients were registered to preprostatectomy mpMRI scans that were interpreted by four radiologists. To simulate realistic HDR-BT, we registered each observer's mpMRI-DILs and corresponding histology to two transrectal ultrasound images of other HDR-BT patients with a 15-Gy whole-gland prescription. We used clinical inverse planning to escalate the mpMRI-DILs to 20.25 Gy. We compared the dose that the histopathology would have received if treated with standard treatment plans to the dose mpMRI-targeting would have achieved. The histopathology was grouped as high-grade cancer (any Gleason Grade 4 or 5) and low-grade cancer (only Gleason Grade 3).

Results: 212 mpMRI-targeted HDR-BT plans were analyzed. For high-grade histology, the mpMRI-targeted plans achieved significantly higher median [IQR] D98 and D90 values of 18.2 [16.7-19.5] Gy and 19.4 [17.8-20.9] Gy, respectively, in comparison with the standard plans (p = 0.01 and p = 0.003). For low-grade histology, the targeted treatment plans would have resulted in a significantly higher median D90 of 17.0 [16.1-18.4] Gy in comparison with standard plans (p = 0.015); the median D98 was not significantly higher (p = 0.2).

Conclusions: In this retrospective pilot study of 12 patients, mpMRI-based dose escalation led to increased dose to high-grade, but not low-grade, cancer. In our data set, different observers and mpMRI sequences had no substantial effect on dose to histologic cancer.
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http://dx.doi.org/10.1016/j.brachy.2021.01.005DOI Listing
February 2021

More Specialties, Less Problems: Using collaborative competency between Infectious Disease, Podiatry, and Pathology to improve the care of patients with diabetic foot osteomyelitis.

J Am Podiatr Med Assoc 2021 Feb 24. Epub 2021 Feb 24.

Background: Diabetic Foot Osteomyelitis (DFO) is a common infection where treatment involves multiple services including Infectious Disease (ID), Podiatry, and Pathology. Despite its ubiquity in the hospital, consensus on much of its management is lacking.

Methods: Representatives from ID, Podiatry, and Pathology interested in quality improvement (QI) developed multidisciplinary institutional recommendations culminating in an educational intervention describing optimal diagnostic and therapeutic approaches to DFO. Knowledge acquisition was assessed by pre- and post-intervention surveys. Inpatients with forefoot DFO were retrospectively reviewed pre- and post- intervention to assess frequency of recommended diagnostic and therapeutic maneuvers, including appropriate definition of surgical bone margins, definitive histopathology reports, and unnecessary intravenous antibiotics or prolonged antibiotic courses.

Results: A post-intervention survey revealed significant improvements in knowledge of antibiotic treatment duration and the role of oral antibiotics in managing DFO. There were 104 consecutive patients in the pre-intervention cohort (4/1/2018-4/1/2019) and 32 patients in the post-intervention cohort (11/5/2019-03/01/2020), the latter truncated by changes in hospital practice during the COVID-19 pandemic. Non-categorizable or equivocal pathology reports decreased from pre-intervention to post-intervention (27.0% vs 3.3%, respectively, P=0.006). We observed non-significant improvement in correct bone margin definition (74.0% vs 87.5%, p=0.11), unnecessary PICC line placement (18.3% vs 9.4%, p=0.23), and unnecessary prolonged antibiotics (21.9% vs 5.0%, p=0.10). Additionally, by working as an interdisciplinary group, many solvable misunderstandings were identified, and processes were adjusted to improve the quality of care provided to these patients.

Conclusions: This QI initiative regarding management of DFO led to improved provider knowledge and collaborative competency between these three departments, improvements in definitive pathology reports, and non-significant improvement in several other clinical endpoints. Creating collaborative competency may be an effective local strategy to improve knowledge of diabetic foot infection and may generalize to other common multidisciplinary conditions.
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http://dx.doi.org/10.7547/20-178DOI Listing
February 2021

Image-Guided Core Needle Biopsy of Adipocytic Tumors: Diagnostic Accuracy and Concordance With Final Surgical Pathology.

AJR Am J Roentgenol 2021 04 24;216(4):997-1002. Epub 2021 Feb 24.

Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215.

Diagnostic accuracy of core needle biopsy (CNB) for adipocytic tumors can be low because of sampling error from these often large, heterogeneous lesions. The purpose of this study was to evaluate the diagnostic accuracy of image-guided CNB for various adipocytic tumors in comparison with excisional pathology. Adipocytic tumors ( = 77) of all adult patients undergoing image-guided CNB and subsequent surgical excision of an adipocytic tumor at a tertiary referral center between 2005 and 2019 were studied. To determine concordance, we compared pathologic diagnoses based on CNB to the reference standard of pathologic diagnoses after surgical excision. Tumors were divided into three categories (benign lipomatous tumors [lipoma, lipoma variants, hibernomas], atypical lipomatous tumors [ALTs] or well-differentiated liposarcomas [WDLs], and higher grade liposarcomas [myxoid, dedifferentiated, pleomorphic]), and diagnostic accuracy was calculated for each category. In 73 of 77 adipocytic tumors (95%), diagnosis at CNB and diagnosis after excision were concordant. Accuracy of diagnosis was poorer for ALTs and WDLs than for the other two categories, and the difference was statistically significant ( < .002). For the 29 benign lipomatous tumors and the 27 higher-grade liposarcomas, diagnoses at CNB and after excision were concordant in all cases (100%). Seventeen of the 21 tumors (81%) diagnosed as ALTs or WDLs at CNB had a concordant diagnosis after excision; four of the 21 were upgraded (dedifferentiated liposarcoma, = 3; myxoid liposarcoma, = 1). CNB provides high diagnostic accuracy for adipocytic tumors, particularly for benign lipomatous tumors and higher grade liposarcomas. However, though still high at 81%, diagnostic accuracy of CNB is not as high for tumors diagnosed as ALTs or WDLs. Awareness of this limitation is important when determining management, particularly of cases of ALT or WDL for which surgery is not planned.
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http://dx.doi.org/10.2214/AJR.20.23080DOI Listing
April 2021

Disassembly of HIV envelope glycoprotein trimer immunogens is driven by antibodies elicited via immunization.

bioRxiv 2021 Feb 17. Epub 2021 Feb 17.

Rationally designed protein subunit vaccines are being developed for a variety of viruses including influenza, RSV, SARS-CoV-2 and HIV. These vaccines are based on stabilized versions of the primary targets of neutralizing antibodies on the viral surface, namely viral fusion glycoproteins. While these immunogens display the epitopes of potent neutralizing antibodies, they also present epitopes recognized by non or weakly neutralizing ("off-target") antibodies. Using our recently developed electron microscopy epitope mapping approach, we have uncovered a phenomenon wherein off-target antibodies elicited by HIV trimer subunit vaccines cause the otherwise highly stabilized trimeric proteins to degrade into cognate protomers. Further, we show that these protomers expose an expanded suite of off-target epitopes, normally occluded inside the prefusion conformation of trimer, that subsequently elicit further off-target antibody responses. Our study provides critical insights for further improvement of HIV subunit trimer vaccines for future rounds of the iterative vaccine design process.
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http://dx.doi.org/10.1101/2021.02.16.431310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899455PMC
February 2021

Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants.

bioRxiv 2021 Feb 17. Epub 2021 Feb 17.

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.
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http://dx.doi.org/10.1101/2021.02.16.430500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899451PMC
February 2021

Fate of moderate aortic regurgitation after cardiac surgery.

J Thorac Cardiovasc Surg 2021 Jan 21. Epub 2021 Jan 21.

Division of Cardiac Surgery, Department of Surgery, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine and Northwestern Medicine, Chicago, Ill.

Objective: To determine the prevalence of concomitant aortic regurgitation (AR) in cardiac surgery and the outcomes of treatment options.

Methods: Between April 2004 and June 2018, 3289 patients underwent coronary artery bypass, mitral valve, or aortic aneurysm surgery without aortic stenosis. AR was graded none/trivial (score = 0), mild (score = 1+), or moderate (score = 2+). Patients with untreated 2+ AR were compared with those with 0 or 1+ AR, and to those with 2+ AR who had aortic valve surgery. Thirty-day and late survival, echocardiography, and clinical outcomes were compared using propensity score matching.

Results: One hundred thirty-eight patients (4.2%) had 2+ AR; and 45 (33%) received aortic valve repair (n = 9) or replacement (n = 36) in the treated group and were compared with 2765 untreated patients with 0 AR and 386 patients with 1+ AR. Valve surgery was more common with anatomic leaflet abnormalities: bicuspid aortic valve (9% vs 0%; P < .01), rheumatic valve disease (16% vs 3%; P < .01), and calcification (47% vs 27%; P = .021). In unadjusted analysis, lower preoperative AR grade was associated with increased 10-year survival (P < .001). At year 10, progression to more-than-moderate AR among moderate AR patients was 2.6% and late intervention rate was 3.1%. In the untreated 2+ AR group, on last follow-up echocardiogram, 58% had improvement in AR, 41% remained 2+, and only 1% progressed to severe AR.

Conclusions: Aortic valve surgery in select patients with concomitant moderate AR can be added with minimal added risk, but untreated AR does not influence long-term survival after cardiac surgery and rarely required late intervention.
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http://dx.doi.org/10.1016/j.jtcvs.2020.12.114DOI Listing
January 2021

Eating up cognitive resources: Does attentional consumption lead to food consumption?

Appetite 2021 Feb 17;162:105165. Epub 2021 Feb 17.

Department of Psychology, University of Minnesota, 75 East River Parkway, Minneapolis, MN, 55455, USA. Electronic address:

What is the role played by attentional load in eating? Does attending to an unrelated task generally lead to overeating, perhaps by preventing individuals from focusing on a goal to limit consumption? Or does such attentional diversion typically lead to reductions in eating, perhaps by preventing people from noticing tempting features of relevant food cues? Past research has supported each of these two propositions, but comparisons between existing studies have been hampered to the extent that various experimental manipulations differ in the degree to which they occupy attention, as well as differing in the particular type of attentional resources they exploit. To resolve existing discrepancies in the literature, in a series of studies, we made use of a working memory manipulation, the n-back task (Kirchner, 1958), that can be systematically modified to induce varying levels of cognitive load, allowing for rigorous comparisons of the effects of different levels of attentional load on eating. These studies revealed a complex pattern of results. Analysis of findings from three studies employing within-subjects designs documented a linear relationship, in that participants consumed less food when completing a higher cognitive-load task than when completing a lower cognitive-load task. Three studies employing between-subjects designs highlighted a less consistent pattern of results, but when combined in a mini-meta-analysis, suggested the opposite linear relationship, with participants assigned to higher cognitive-load conditions generally consuming more food than participants assigned to lower cognitive-load conditions. We conducted two additional studies to reconcile these conflicting patterns of data. Neither finding received unequivocal support, although both studies found that participants ate less when engaged in higher cognitive-load tasks than lower cognitive-load tasks. The precise nature of the relationship between attentional load and eating remains elusive.
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http://dx.doi.org/10.1016/j.appet.2021.105165DOI Listing
February 2021

A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection.

bioRxiv 2021 Feb 12. Epub 2021 Feb 12.

Coronaviruses have caused several epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Some prophylactic vaccines and therapeutic antibodies have already showed striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody CV38-142 in complex with the receptor binding domains from SARS-CoV-2 and SARS-CoV. Our structural findings provide mechanistic insights into how this antibody can accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, in particular COVA1-16, to enhance neutralization of SARS-CoV-2 and SARS-CoV. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic coronaviruses.
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http://dx.doi.org/10.1101/2021.02.11.430866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885913PMC
February 2021

Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
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http://dx.doi.org/10.1073/pnas.2018102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923359PMC
February 2021