Publications by authors named "David Hall"

695 Publications

Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.

Aging Cell 2021 Nov 27:e13488. Epub 2021 Nov 27.

Nelson Biological Laboratories, Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.

Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.
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http://dx.doi.org/10.1111/acel.13488DOI Listing
November 2021

Identification of Components of the Aggregation Pheromone of the Guam Strain of Coconut Rhinoceros Beetle, Oryctes rhinoceros, and Determination of Stereochemistry.

J Chem Ecol 2021 Nov 11. Epub 2021 Nov 11.

New Britain Palm Oil Limited, Quadalcanal Plains, PO Box 2001, Honiara, Solomon Islands.

The coconut rhinoceros beetle, Oryctes rhinoceros (Linnaeus 1758) (Coleoptera: Scarabaeidae: Dynastinae) (CRB), is endemic to tropical Asia where it damages both coconut and oil palm. A new invasion by CRB occurred on Guam in 2007 and eradication attempts failed using commonly applied Oryctes rhinoceros nudivirus (OrNV) isolates. This and subsequent invasive outbreaks were found to have been caused by a previously unrecognized haplotype, CRB-G, which appeared to be tolerant to OrNV. The male-produced aggregation pheromone of the endemic, susceptible strain of O. rhinoceros (CRB-S) was previously identified as ethyl 4-methyloctanoate. Following reports from growers that commercial lures containing this compound were not attractive to CRB-G, the aim of this work was to identify the pheromone of CRB-G. Initial collections of volatiles from virgin male and female CRB-G adults from the Solomon Islands failed to show any male- or female-specific compounds as candidate pheromone components. Only after five months were significant quantities of ethyl 4-methyloctanoate and 4-methyloctanoic acid produced by males but not by females. No other male-specific compounds could be detected, in particular methyl 4-methyloctanoate, 4-methyl-1-octanol, or 4-methyl-1-octyl acetate, compounds identified in volatiles from some other species of Oryctes. Ethyl 4-methyloctanoate elicited a strong electroantennogram response from both male and female CRB-G, but these other compounds, including 4-methyloctanoic acid, did not. The enantiomers of ethyl 4-methyloctanoate and 4-methyloctanoic acid were conveniently prepared by enzymatic resolution of the commercially-available acid, and the enantiomers of the acid, but not the ester, could be separated by gas chromatography on an enantioselective cyclodextrin phase. Using this approach, both ethyl 4-methyloctanoate and 4-methyloctanoic acid produced by male CRB-G were shown to be exclusively the (R)-enantiomers whereas previous reports had suggested male O. rhinoceros produced the (S)-enantiomers. However, re-examination of the ester and acid produced by male CRB-S from Papua New Guinea showed that these were also the (R)-enantiomers. In field trapping experiments carried out in the Solomon Islands, both racemic and ethyl (R)-4-methyloctanoate were highly attractive to both male and female CRB-G beetles. The (S)-enantiomer and the corresponding acids were only weakly attractive. The addition of racemic 4-methyloctanoic acid to ethyl 4-methyloctanoate did significantly increase attractiveness, but the addition of (R)- or (S)-4-methyloctanoic acid to the corresponding ethyl esters did not. Possible reasons for the difference in assignment of configuration of the components of the CRB pheromone are discussed along with the practical implications of these results.
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http://dx.doi.org/10.1007/s10886-021-01329-zDOI Listing
November 2021

Announcement of WormAtlas partnership with the Journal of Nematology.

J Nematol 2021 3;53. Epub 2021 Nov 3.

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 14061.

A detailed understanding of nematode anatomy can be leveraged for the development of new parasitic nematode control strategies and for fundamental biological insights through nematode model organisms. The Center for Anatomy, with its websites WormAtlas and WormImage, is the central anatomical resource for researchers studying the model organism . Here, we announce our expansion of the WormAtlas and WormImage resources beyond to include additional nematode species. Towards this goal, we will partner with the Journal of Nematology to write and solicit anatomically focused review chapters for publication in the Journal and corresponding inclusion on the WormAtlas website.
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http://dx.doi.org/10.21307/jofnem-2021-090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571904PMC
November 2021

Successful Lung Transplantation for Severe Post COVID-19 Pulmonary Fibrosis.

Ann Thorac Surg 2021 Nov 5. Epub 2021 Nov 5.

Division of Cardiothoracic Surgery, Department of Surgery; Department of Pathology and Laboratory Medicine. Electronic address:

Lung transplantation has been well described for COVID-19 patients in the acute setting, but less so for the resulting pulmonary sequelae. We share one of the first cases of lung transplantation for post COVID-19 pulmonary fibrosis. A 52-year-old female developed COVID-19 in July 2020 and mounted a partial recovery, but went on to have declining function over the ensuing three months and developed fibrocystic lung changes. She underwent bilateral lung transplantation and recovered rapidly, was discharged home POD 14, and has done well in follow-up. We demonstrate that lung transplantation is an acceptable therapy to treat post COVID-19 pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.athoracsur.2021.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570389PMC
November 2021

Host plant adaptation drives changes in Diaphorina citri proteome regulation, proteoform expression and transmission of Candidatus Liberibacter asiaticus, the citrus greening pathogen.

Phytopathology 2021 Nov 5. Epub 2021 Nov 5.

USDA Agricultural Research Service, 17123, Emerging Pests and Pathogens Research Unit, 538 Tower Road, Ithaca, New York, United States, 14853.

The Asian citrus psyllid (ACP, Diaphorina citri) is a pest of citrus and the primary insect vector of the bacterial pathogen, 'Candidatus Liberibacter asiaticus' (CLas), which is associated with citrus greening disease. The citrus relative Murraya paniculata (orange jasmine) is a host plant of D. citri, but is more resistant to CLas compared to all tested Citrus genotypes. The effect of host switching of D. citri between Citrus medica (citron) and M. paniculata plants on the acquisition and transmission of CLas was investigated. The psyllid CLas titer and the proportion of CLas-infected psyllids decreased in the generations following transfer from CLas-infected citron to healthy M. paniculata plants. Furthermore, after several generations of feeding on M. paniculata, pathogen acquisition (20-40% reduction) and transmission rates (15-20% reduction) in psyllids transferred to CLas-infected citron were reduced compared to psyllids continually maintained on infected citron. Top-down (Difference Gel Electrophoresis) and bottom-up (shotgun MS/MS) proteomics methods were used to identify changes in D. citri protein expression resulting from host plant switching between Citrus macrophylla and M. paniculata. Changes in expression of insect metabolism, immunity, and cytoskeleton proteins were associated with host plant switching. Both transient and sustained feeding on M. paniculata induced distinct patterns of protein expression in D. citri compared to psyllids reared on C. macrophylla. The results point to complex interactions that affect vector competence, and may lead to strategies to control the spread of citrus greening disease.
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http://dx.doi.org/10.1094/PHYTO-06-21-0275-RDOI Listing
November 2021

The Intricate Interactions between Maternal Smoking and Drinking During Pregnancy and Birthweight Z-Scores of Preterm Births.

J Women's Health Care Manag 2021 27;2(2). Epub 2021 Mar 27.

Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.

Background: The extent to which smoking and drinking in a local community is associated with nutrition and Z-scores of infants from spontaneous preterm deliveries, is uncertain.

Aim: To investigate associations of different levels of maternal smoking and drinking in spontaneous preterm birth with infant birthweight Z-scores.

Methods: Information, including gestational age (determined by earliest ultrasound), maternal arm circumference (measured at enrolment), smoking-drinking data (obtained up to 4 occasions), birthweight data (obtained from medical records) and birthweight Z-scores (calculated from INTERGROWTH- 21st study), collected over a period of nine years was used to compare 407 spontaneous preterm births with 3 493 spontaneous term births Analyses of variance, correlations and multiple regression were performed in STATISTICA.

Results: Women with spontaneous preterm birth, had significantly lower gravidity and smaller arm circumference when compared to women with spontaneous birth at term. Women with spontaneous preterm birth drank more and heavier during pregnancy, and more smoked. Gestational age at birth was significantly longer in heavy-smokers-heavy-drinkers compared to heavy-smokers-no-drinkers (7.1 days) and in no-smokers-heavy-drinkers when compared to no-smokers-no-drinkers (11.2 days). Birthweight was significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-no-drinkers (240g) and in heavy-smokers-low-drinkers when compared to no-smokers-low-drinkers (273g). Birthweight Z-scores were significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-low-drinkers and low-smokers-no-drinkers; and, also significantly lower in heavy-smokers-low-drinkers when compared to low-smokers-low-drinkers and no-smokers-low-drinkers.

Conclusion: Alcohol aggravates the detrimental effect of smoking on birthweight and birthweight Z-scores but seems to counteract the negative association of smoking with gestational age.
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http://dx.doi.org/10.47275/2692-0948-121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553154PMC
March 2021

One-Year Readmission Following Undifferentiated Acute Hypercapnic Respiratory Failure.

COPD 2021 Oct 18:1-10. Epub 2021 Oct 18.

Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.

Patients with acute hypercapnic respiratory failure (AHRF) often require hospitalization and respiratory support. Early identification of patients at risk of readmission would be helpful. We evaluated 1-y readmission and mortality rates of patients admitted for undifferentiated AHRF and identified the impact of initial severity on clinically important outcomes. We retrospectively analyzed patients who presented with AHRF to the emergency department of St Michael's Hospital in 2017. We collected data about patients' characteristics, hospital admission, readmission and mortality one year after the index admission. We analyzed predictors of readmission and mortality and conducted a survival analysis comparing patients who did and did not receive ventilatory support. A cohort of 212 patients with AHRF who survived their hospital admission were analyzed. At one year, 150 patients (70.8%) were readmitted and 19 (9%) had died. Main diagnoses included chronic obstructive pulmonary disease (60%), congestive heart failure (36%), asthma (22%) and obesity (19%), and these categories of patients had similar 1 y readmission rates. One third had more than one coexisting chronic illness. Although comorbidities were more frequent in readmitted patients, only a history of previous hospital admissions remained associated with 1 y readmission and mortality in multivariate analysis. Need for ventilatory support at admission was not associated with higher 1 y probability of readmission or death. Undifferentiated AHRF is the presentation of multiple chronic illnesses. Patients who survive one episode of AHRF and with previous history of admission have the highest risk of readmission and death regardless of whether they receive ventilatory support during index admission.
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http://dx.doi.org/10.1080/15412555.2021.1990240DOI Listing
October 2021

Estimating salivary carriage of severe acute respiratory syndrome coronavirus 2 in nonsymptomatic people and efficacy of mouthrinse in reducing viral load: A randomized controlled trial.

J Am Dent Assoc 2021 11 11;152(11):903-908. Epub 2021 Jun 11.

Background: Many people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) never develop substantial symptoms. With more than 34 million people in the United States already infected and highly transmissible variants rapidly emerging, it is highly probable that post- and presymptomatic people will form an important fraction of those seeking dental care. Salivary carriage rates in these populations are not known. Moreover, although preventing transmission is critical for controlling spread, the efficacy of mouthrinses in reducing oral viral load is poorly studied.

Methods: The authors recruited 201 asymptomatic, presymptomatic, postsymptomatic, and symptomatic people and measured copy numbers of SARS-CoV-2 in unstimulated saliva using real-time reverse transcriptase quantitative polymerase chain reaction. Subsequently, the authors inducted 41 symptomatic people into a randomized, triple-blinded study and instructed them to rinse with saline, 1% hydrogen peroxide, 0.12% chlorhexidine, or 0.5% povidone-iodine for 60 seconds. The authors measured viral load 15 and 45 minutes after rinsing.

Results: Salivary SARS-CoV-2 was detected in 23% of asymptomatic, 60% of postsymptomatic, and 28% of presymptomatic participants. Neither carriage rate nor viral load correlated with COVID-19 symptomatology, age, sex, or race or ethnicity. All 4 mouthrinses decreased viral load by 61% through 89% at 15 minutes and by 70% through 97% at 45 minutes. The extent of reduction correlated significantly with initial viral load.

Conclusions: Nonsymptomatic people can pose a risk of transmitting the virus, and mouthrinses are simple and efficacious means of reducing this risk, especially when the load is less than 10 copies per milliliter.

Practical Implications: At a time when resources are stretched, the findings of this study contribute to evidence-based selection of personal protection equipment and simple infection-control practices to reduce contagion at source. This clinical trial was registered at ClinicalTrials.gov. The registration number is NCT04603794.
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http://dx.doi.org/10.1016/j.adaj.2021.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193024PMC
November 2021

Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial.

BMJ 2021 09 22;374:n2103. Epub 2021 Sep 22.

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia.

Objective: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia.

Design: Randomised, double blind, placebo controlled trial.

Setting: Referral hospital in Cape Town, South Africa.

Participants: 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo.

Intervention: 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery.

Main Outcome Measure: The primary outcome was prolongation of gestation.

Results: Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm.

Conclusions: This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible.

Trial Registration: Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.
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http://dx.doi.org/10.1136/bmj.n2103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457042PMC
September 2021

Spiro-Based Thermally Activated Delayed Fluorescence Emitters with Reduced Nonradiative Decay for High-Quantum-Efficiency, Low-Roll-Off, Organic Light-Emitting Diodes.

ACS Appl Mater Interfaces 2021 Sep 13;13(37):44628-44640. Epub 2021 Sep 13.

Organic Semiconductor Centre, EaStCHEM School of Chemistry, University of St Andrews, Fife, St Andrews KY16 9ST, U.K.

Herein, we report the use of spiro-configured fluorene-xanthene scaffolds as a novel, promising, and effective strategy in thermally activated delayed fluorescence (TADF) emitter design to attain high photoluminescence quantum yields (Φ), short delayed luminescence lifetime, high external quantum efficiency (EQE), and minimum efficiency roll-off characteristics in organic light-emitting diodes (OLEDs). The optoelectronic and electroluminescence properties of (spiro-(fluorene-9,9'-xanthene))-based emitters (, , and ) were investigated both theoretically and experimentally. All three emitters exhibited sky blue to green emission enabled by a Herzberg-Teller mechanism in the excited state. They possess short excited-state delayed lifetimes (<10 μs), high photoluminescence quantum yields (Φ ∼ 70%), and small singlet-triplet splitting energies (Δ < 0.10 eV) in the doped films in an mCP host matrix. The OLEDs showed some of the highest EQEs using spiro-containing emitters where maximum external quantum efficiencies (EQE) of 11 and 16% were obtained for devices using and , respectively. Further, a record EQE of 23% for a spiro-based emitter coupled with a low efficiency roll-off (19% at 100 cd m) was attained with .
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http://dx.doi.org/10.1021/acsami.1c12234DOI Listing
September 2021

Prostaglandin E2 Signaling Mediates Oenocytoid Immune Cell Function and Lysis, Limiting Bacteria and Oocyst Survival in .

Front Immunol 2021 16;12:680020. Epub 2021 Aug 16.

Department of Entomology, Iowa State University, Ames, IA, United States.

Lipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet in arthropods of medical importance, studies have been limited. Here, we describe a prostaglandin E2 receptor (PGE2R) in the mosquito and demonstrate that its expression is most abundant in oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and silencing, we demonstrate that prostaglandin E2 signaling regulates a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs) that are strongly expressed in populations of oenocytoids. We demonstrate that PGE2 signaling the PGE2R significantly limits both bacterial replication and oocyst survival. Additional experiments establish that PGE2 treatment increases phenoloxidase (PO) activity through the increased expression of and , genes essential to anti- immune responses that promote oocyst killing. We also provide evidence that the mechanisms of PGE2 signaling are concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of lower concentrations of PGE2 on anti- immunity. Taken together, our results provide new insights into the role of PGE2 signaling on immune cell function and its contributions to mosquito innate immunity that promote pathogen killing.
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http://dx.doi.org/10.3389/fimmu.2021.680020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415482PMC
October 2021

Bumble bees show an induced preference for flowers when primed with caffeinated nectar and a target floral odor.

Curr Biol 2021 Sep 28;31(18):4127-4131.e4. Epub 2021 Jul 28.

Natural Resources Institute, University of Greenwich, Chatham Maritime, Kent ME4 4TB, UK; Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3DS, UK.

Caffeine is a widely occurring plant defense chemical that occurs in the nectar of some plants, e.g., Coffea or Citrus spp., where it may influence pollinator behavior to enhance pollination. Honey bees fed caffeine form longer lasting olfactory memory associations, which could give plants with caffeinated nectar an adaptive advantage by inducing more visits to flowers. Caffeinated free-flying bees show enhanced learning performance and are more likely to revisit a caffeinated target feeder or artificial flower, although it is not clear whether improved memory of the target cues or the perception of caffeine as a reward is the cause. Here, we show that inexperienced bumble bees (Bombus terrestris) locate new food sources emitting a learned floral odor more consistently if they have been fed caffeine. In laboratory arena tests, we fed bees a caffeinated food alongside a floral odor blend (priming) and then used robotic experimental flowers to disentangle the effects of caffeine improving memory for learned food-associated cues versus caffeine as a reward. Inexperienced bees primed with caffeine made more initial visits to target robotic flowers emitting the target odor compared to control bees or those primed with odor alone. Caffeine-primed bees tended to improve their floral handling time faster. Although the effects of caffeine were short lived, we show that food-locating behaviors in free-flying bumble bees can be enhanced by caffeine provided in the nest. Consequently, there is potential to redesign commercial colonies to enhance bees' forage focus or even bias bees to forage on a specific crop.
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http://dx.doi.org/10.1016/j.cub.2021.06.068DOI Listing
September 2021

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum.

Cell 2021 08 17;184(16):4220-4236.e13. Epub 2021 Jun 17.

NIHR Oxford Biomedical Research Centre, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.
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http://dx.doi.org/10.1016/j.cell.2021.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218332PMC
August 2021

The initial expansion of the C. elegans syncytial germ line is coupled to incomplete primordial germ cell cytokinesis.

Development 2021 09 21;148(18). Epub 2021 Jul 21.

Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, C.P. 6128, Succ. Centre-ville, Montréal, QC H3C 3J7, Canada.

The C. elegans germline is organized as a syncytium in which each germ cell possesses an intercellular bridge that is maintained by a stable actomyosin ring and connected to a common pool of cytoplasm, termed the rachis. How germ cells undergo cytokinesis while maintaining this syncytial architecture is not completely understood. Here, we use live imaging to characterize primordial germ cell (PGC) division in C. elegans first-stage larvae. We show that each PGC possesses a stable intercellular bridge that connects it to a common pool of cytoplasm, which we term the proto-rachis. We further show that the first PGC cytokinesis is incomplete and that the stabilized cytokinetic ring progressively moves towards the proto-rachis and eventually integrates with it. Our results support a model in which the initial expansion of the C. elegans syncytial germline occurs by incomplete cytokinesis, where one daughter germ cell inherits the actomyosin ring that was newly formed by stabilization of the cytokinetic ring, while the other inherits the pre-existing stable actomyosin ring. We propose that such a mechanism of iterative cytokinesis incompletion underpins C. elegans germline expansion and maintenance.
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http://dx.doi.org/10.1242/dev.199633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327289PMC
September 2021

Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study.

Pulm Ther 2021 Dec 26;7(2):487-501. Epub 2021 Jun 26.

Department of Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.

Introduction: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions.

Methods: In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3-14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation.

Results: Seventeen adults aged 18-40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active.

Conclusions: A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.
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http://dx.doi.org/10.1007/s41030-021-00164-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241405PMC
December 2021

Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.

J Clin Oncol 2021 09 24;39(26):2859-2871. Epub 2021 Jun 24.

Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.

Purpose: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome.

Patients And Methods: Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed.

Results: DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. (15%), (15%), and (13%) mutations were found at a higher incidence than previously reported and mutations were associated with worse outcomes in both fusion-negative and fusion-positive cases. Interestingly, mutations in isoforms predominated in infants < 1 year (64% of cases). Mutation of was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data.

Conclusion: This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
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http://dx.doi.org/10.1200/JCO.20.03060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425837PMC
September 2021

The Prop1-like homeobox gene specifies the identity of synaptically connected neurons.

Elife 2021 06 24;10. Epub 2021 Jun 24.

Department of Biological Sciences, Columbia University, Howard Hughes Medical Institute, New York, United States.

Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby potentially leaving overarching themes in gene function undiscovered. We show here that the Prop1-like homeobox gene is expressed in 15 distinct sensory, inter- and motor neuron classes throughout the entire nervous system. Strikingly, all 15 neuron classes expressing are synaptically interconnected, prompting us to investigate whether controls the functional properties of this circuit and perhaps also the assembly of these neurons into functional circuitry. We found that defines the routes of communication between these interconnected neurons by controlling the expression of neurotransmitter pathway genes, neurotransmitter receptors, neuropeptides, and neuropeptide receptors. Anatomical analysis of mutant animals reveals defects in axon pathfinding and synaptic connectivity, paralleled by expression defects of molecules involved in axon pathfinding, cell-cell recognition, and synaptic connectivity. We conclude that establishes functional circuitry by acting as a terminal selector of functionally connected neuron types. We identify a number of additional transcription factors that are also expressed in synaptically connected neurons and propose that terminal selectors may also function as 'circuit organizer transcription factors' to control the assembly of functional circuitry throughout the nervous system. We hypothesize that such organizational properties of transcription factors may be reflective of not only ontogenetic, but perhaps also phylogenetic trajectories of neuronal circuit establishment.
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http://dx.doi.org/10.7554/eLife.64903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225392PMC
June 2021

Quantitative Chemical Proteomics Reveals Interspecies Variations on Binding Schemes of L-FABP with Perfluorooctanesulfonate.

Environ Sci Technol 2021 07 16;55(13):9012-9023. Epub 2021 Jun 16.

Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.

Evaluating interspecies toxicity variation is a long-standing challenge for chemical hazard assessment. This study developed a quantitative interspecies thermal shift assay (QITSA) for , quantitative, and modest-throughput investigation of chemical-protein interactions in cell and tissue samples across species. By using liver fatty acid binding protein (L-FABP) as a case study, the QITSA method was benchmarked with six per- and polyfluoroalkyl substances, and thermal shifts (Δ) were inversely related to their dissociation constants ( = 0.98). The QITSA can also distinguish binding modes of chemicals exemplified by palmitic acid. The QITSA was applied to determine the interactions between perfluorooctanesulfonate (PFOS) and L-FABP in liver cells or tissues from humans, mice, rats, and zebrafish. The largest thermal stability enhancement by PFOS was observed for human L-FABP followed by the mouse, rat, and zebrafish. While endogenous ligands were revealed to partially contribute to the large interspecies variation, recombinant proteins were employed to confirm the high binding affinity of PFOS to human L-FABP, compared to the rat and mouse. This study implemented an experimental strategy to characterize chemical-protein interactions across species, and future application of QITSA to other chemical contaminants is of great interest.
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http://dx.doi.org/10.1021/acs.est.1c00509DOI Listing
July 2021

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

JCO Precis Oncol 2021 11;5. Epub 2021 Jan 11.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts.

Materials And Methods: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort.

Results: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (, ) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with fusion-negative RMS patients versus the patients with fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (, , , mismatch repair genes), rarely (, , , ), or never () reported in RMS. Numerous genes (, , mismatch repair) were on the ACMG Secondary Findings 2.0 list.

Conclusion: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.
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http://dx.doi.org/10.1200/PO.20.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169077PMC
January 2021

Toxicity and pharmacokinetics of actinomycin-D and vincristine in children and adolescents: Children's Oncology Group Study ADVL06B1.

Cancer Chemother Pharmacol 2021 08 22;88(2):359-365. Epub 2021 May 22.

Mayo Clinic, Rochester, MN, USA.

Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.
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http://dx.doi.org/10.1007/s00280-021-04295-1DOI Listing
August 2021

The Impact of Experiences and Perceptions of Highly Pathogenic Avian Influenza (HPAI) on Water-Related Biosecurity Behaviour in Rural Vietnam.

Risk Anal 2021 May 16. Epub 2021 May 16.

Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: In Southeast Asia from 2004 to 2006, highly pathogenic avian influenza (HPAI) resulted in culling 45 million birds and jeopardizing sustainable agricultural production. HPAI is highly virulent; small-scale farms present a high-risk environment for disease transmission between animals and humans. We investigated how attitudes toward HPAI influence water-related biosecurity mitigation behaviors on small-scale farms in Vietnam using the conceptual framework Social Cognitive Theory.

Method: We analyzed a secondary cross-sectional data set from northern (Thai Binh) and southern (An Giang) provinces in Vietnam, describing a stratified randomized selection of 600 small-scale farmers who were interviewed using questionnaires and in-person interviews. Logistic regression analysis and odds ratios were used to examine relationships between factors influencing HPAI attitudes, social norms, perceived importance, and behaviors (α = 0.10) RESULTS: Concern about the severity of HPAI was significantly associated with increased perceived importance for all water management biosecurity methods (p < 0.01). Media and/or peer influence had negative effects on perceived importance to practice water-related biosecurity (p < 0.10). High importance of practice water-related biosecurity resulted in high uptake (p < 0.05). Past experiences with HPAI were significant in predicting perceived importance; none were significant in describing behavior uptake.

Discussion: Biosecurity guidelines may not be consistent with management styles of Vietnamese small-scale farms; perceived importance of a behavior may be an important mediating variable. Gaps exist in uptake of water management practices as biosecurity for HPAI, potentially negatively affected by peer and media influence. Our results should be of interest to public health and policy authorities addressing HPAI mitigation.
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http://dx.doi.org/10.1111/risa.13753DOI Listing
May 2021

PROVE-Pre-Eclampsia Obstetric Adverse Events: Establishment of a Biobank and Database for Pre-Eclampsia.

Cells 2021 04 20;10(4). Epub 2021 Apr 20.

Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, South Africa.

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery.
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http://dx.doi.org/10.3390/cells10040959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074755PMC
April 2021

Antibody evasion by the P.1 strain of SARS-CoV-2.

Cell 2021 05 30;184(11):2939-2954.e9. Epub 2021 Mar 30.

Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.
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http://dx.doi.org/10.1016/j.cell.2021.03.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008340PMC
May 2021

A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage.

Elife 2021 04 13;10. Epub 2021 Apr 13.

Calico Life Sciences LLC, South San Francisco, United States.

Somatic cells age and die, but the germ-cell lineage is immortal. In , germline immortality involves proteostasis renewal at the beginning of each new generation, when oocyte maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in endoplasmic reticulum activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. Many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and somatic longevity.
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http://dx.doi.org/10.7554/eLife.62653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043744PMC
April 2021

Hero Turned Villain: Identification of Components of the Sex Pheromone of the Tomato Bug, Nesidiocoris tenuis.

J Chem Ecol 2021 May 12;47(4-5):394-405. Epub 2021 Apr 12.

NIAB EMR, New Road, East Malling, Kent, UK.

Nesidiocoris tenuis (Reuter) (Heteroptera: Miridae) is a tropical mirid bug used as a biocontrol agent in protected crops, including tomatoes. Although N. tenuis predates important insect pests, especially whitefly, it also causes damage by feeding on tomato plants when prey populations decline, resulting in significant economic losses for growers. The pest is now established in some all-year-round tomato crops in Europe and control measures involve the application of pesticides which are incompatible with current IPM programs. As part of future IPM strategies, the pheromone of N. tenuis was investigated. Volatile collections were made from groups and individuals of mated and unmated, females and males. In analyses of these collections by gas chromatography coupled with electroantennographic (EAG) recording from antennae of male bugs, two EAG-active components were detected and identified as 1-octanol and octyl hexanoate. Unlike other mirids, both male and female N. tenuis produced the two compounds, before and after mating, and both sexes gave EAG responses to both compounds. Furthermore, only octyl hexanoate was detected in whole body solvent washes from both sexes. These compounds are not related to the derivatives of 3-hydroxybutyrate esters found as pheromone components in other members of the Bryocrinae sub-family, and the latter could not be detected in volatiles from N. tenuis and did not elicit EAG responses. Nevertheless, experiments carried out in commercial glasshouses showed that traps baited with a blend of the synthetic pheromone components caught essentially only male N. tenuis, and significantly more than traps baited with octyl hexanoate alone. The latter caught significantly more N. tenuis than unbaited traps which generally caught very few bugs. Traps at plant height caught more N. tenuis males than traps 1 m above or at the base of the plants. The trap catches provided an indication of population levels of N. tenuis and were greatly reduced following an application of insecticide.
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http://dx.doi.org/10.1007/s10886-021-01270-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116296PMC
May 2021

Hypoxia-inducible factor-1α-dependent induction of miR122 enhances hepatic ischemia tolerance.

J Clin Invest 2021 04;131(7)

Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA.

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
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http://dx.doi.org/10.1172/JCI140300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011886PMC
April 2021

The antigenic anatomy of SARS-CoV-2 receptor binding domain.

Cell 2021 04 18;184(8):2183-2200.e22. Epub 2021 Feb 18.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.
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http://dx.doi.org/10.1016/j.cell.2021.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891125PMC
April 2021

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.

Cell 2021 04 18;184(8):2201-2211.e7. Epub 2021 Feb 18.

NIHR Oxford Biomedical Research Centre, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.
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http://dx.doi.org/10.1016/j.cell.2021.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891044PMC
April 2021

Corrigendum: Effectiveness and Economic Viability of Johne's Disease (Paratuberculosis) Control Practices in Dairy Herds.

Front Vet Sci 2021 22;8:657453. Epub 2021 Feb 22.

Department of Ecosystem and Public Health, University of Calgary, Calgary, AB, Canada.

[This corrects the article DOI: 10.3389/fvets.2020.614727.].
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http://dx.doi.org/10.3389/fvets.2021.657453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938331PMC
February 2021
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