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This article explores the onomastic necessity of renaming gender-derogatory toponyms in the South African landscape. It contends that there is a need to interrogate the reasons behind gender-derogatory names and how society relates to these names. Four theories: Critical Discourse Analysis (CDA), Critical Toponymic, Socio-onomastic and Feminism theories guided, shaped and informed the authors’ argument. Qualitative in nature, the article employed content analysis for data collection and analysis purposes. A database of over twenty-five (25) toponyms that are considered gender-derogatory was purposively collected and analysed. These toponyms were further grouped into different categories for easy presentation and analysis. It was found that there are gender-derogatory toponyms among South African geographical features, many of which were named using African languages. Furthermore, there is an existing intersectionality between gender-derogatory toponyms with toxic masculinity and feminism. For these reasons, the article postulated that there should be synergy, resonance and constructive alignment among toponyms, renaming, transformation agenda and identity construction. The article further recommends renaming gender-derogatory toponyms and raising awareness about the renaming process and its approach. It emphasises that renaming should be guided by semantics and linguistic ideology rather than race, language, or political power and its influence.

Background: MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play key roles in diabetic kidney disease (DKD). The miR-379 megacluster of miRNAs and its host transcript lnc-megacluster (lncMGC) are regulated by transforming growth factor-β (TGF-β), increased in the glomeruli of diabetic mice, and promote features of early DKD. However, biochemical functions of lncMGC are unknown. Here, we identified lncMGC-interacting proteins by in vitro-transcribed lncMGC RNA pull down followed by mass spectrometry. We also created lncMGC-knockout (KO) mice by CRISPR-Cas9 editing and used primary mouse mesangial cells (MMCs) from the KO mice to examine the effects of lncMGC on the gene expression related to DKD, changes in promoter histone modifications, and chromatin remodeling.Methods:In vitro-transcribed lncMGC RNA was mixed with lysates from HK2 cells (human kidney cell line). lncMGC-interacting proteins were identified by mass spectrometry. Candidate proteins were confirmed by RNA immunoprecipitation followed by qPCR. Cas9 and guide RNAs were injected into mouse eggs to create lncMGC-KO mice. Wild-type (WT) and lncMGC-KO MMCs were treated with TGF-β, and RNA expression (by RNA-seq and qPCR) and histone modifications (by chromatin immunoprecipitation) and chromatin remodeling/open chromatin (by Assay for Transposase-Accessible Chromatin using sequencing, ATAC-seq) were examined.Results: Several nucleosome remodeling factors including SMARCA5 and SMARCC2 were identified as lncMGC-interacting proteins by mass spectrometry, and confirmed by RNA immunoprecipitation–qPCR. MMCs from lncMGC-KO mice showed no basal or TGF-β-induced expression of lncMGC. Enrichment of histone H3K27 acetylation and SMARCA5 at the lncMGC promoter was increased in TGF-β-treated WT MMCs but significantly reduced in lncMGC-KO MMCs. ATAC peaks at the lncMGC promoter region and many other DKD-related loci including Col4a3 and Col4a4 were significantly lower in lncMGC-KO MMCs compared to WT MMCs in the TGF-β-treated condition. Zinc finger (ZF), ARID, and SMAD motifs were enriched in ATAC peaks. ZF and ARID sites were also found in the lncMGC gene.Conclusion: lncMGC RNA interacts with several nucleosome remodeling factors to promote chromatin relaxation and enhance the expression of lncMGC itself and other genes including pro-fibrotic genes. The lncMGC/nucleosome remodeler complex promotes site-specific chromatin accessibility to enhance DKD-related genes in target kidney cells.

Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response. LEENE expression was decreased in diabetic conditions in cultured endothelial cells (ECs), mouse hind limb muscles, and human arteries. Inhibition of LEENE in human microvascular ECs reduced their angiogenic capacity with a dysregulated angiogenic gene program. Diabetic mice deficient in Leene demonstrated impaired angiogenesis and perfusion following hind limb ischemia. Importantly, overexpression of human LEENE rescued the impaired ischemic response in Leene-knockout mice at tissue functional and single-cell transcriptomic levels. Mechanistically, LEENE RNA promoted transcription of proangiogenic genes in ECs, such as KDR (encoding VEGFR2) and NOS3 (encoding eNOS), potentially by interacting with LEO1, a key component of the RNA polymerase II–associated factor complex and MYC, a crucial transcription factor for angiogenesis. Taken together, our findings demonstrate an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis for tissue repair and regeneration may represent a potential strategy to tackle ischemic vascular diseases.

A key element of successful psychotherapy for the treatment of psychosomatic disorders is that patients recognize and change the meaning of their experiences. Such changes are brought about by appropriate verbal referencing of symptoms currently experienced within a given narrative. The present theoretical paper argues that changes are not based on better, more adaptive narratives per se, but on the transition (or linkage) process itself that is experienced between different narratives. This view is theoretically justified in various ways: first, it is accounted for through contemporary spatiotemporal neuroscience, which aims to connect mental and structural aspects via a common dynamic property or, according to Northoff, the “common currency” of a brain’s orientation along its embeddedness in its contextual world, i.e., body and environment. Second, it is justified through the physics concept of “spontaneous symmetry breaking,” which is used analogously to “suffering from symptoms.” If the sufferer is willing to experience a process of “going back,” that is, moving away from the previous narrative (or aspect) by verbally relating to the felt aspects of the symptom in question (i.e., approaching its meaning), they are moving toward symmetry or an underlying dynamic alignment with their world context. Clinical predictions are derived from the theoretical arguments.

Kato, Abdollahi et al. identify a redox protein thioredoxin and mitochondrial fission-1 (FIS1) protein as miR-379 targets in mouse kidney. They find that miR-379 knockout mice are protected from diabetic kidney disease by enhancing mitophagy via FIS1, suggesting miR-379 as a potential therapeutic target for diabetic kidney disease.

Abstract Background Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive, translocation-associated soft-tissue sarcoma that primarily affects children, adolescents, and young adults, with a striking male predominance. It is characterized by t(11;22) generating a novel EWSR1-WT1 fusion gene. Secondary genomic alterations are rarely described. Methods Tumor tissue from 83 DSRCT patients was assayed by hybrid-capture based comprehensive genomic profiling, FoundationOne® Heme next generation sequencing analysis of 406 genes and RNA sequencing of 265 genes. Tumor mutation burden was calculated from a minimum of 1.4 Mb sequenced DNA. Microsatellite instability status was determined by a novel algorithm analyzing 114 specific loci. Results Comprehensive genomic profiling identified several genomically-defined DSRCT subgroups. Recurrent genomic alterations were most frequently detected in FGFR4, ARID1A, TP53, MSH3, and MLL3 genes. With the exception of FGFR4, where the genomic alterations predicted activation, most of the alterations in the remaining genes predicted gene inactivation. No DSRCT were TMB or MSI high. Conclusions In summary, recurrent secondary somatic alterations in FGFR4, ARID1A, TP53, MSH3, and MLL3 were detected in 82% of DSRCT, which is significantly greater than previously reported. These alterations may have both prognostic and therapeutic implications.

Background: Aganang Local Municipality (ALM) was disestablished, and its municipal area was amalgamated into Blouberg Local Municipality, Molemole Local Municipality and Polokwane Local Municipality on 03 August 2016. The municipality was disestablished with a view to optimise the financial viability of municipalities in the Capricorn District Municipality. This development brought about challenges in a variety of areas as the move meant merging of the disestablished municipality to the other three municipalities. Aim: This article explored the underlying human resources management problems that emanated from the disestablishment of ALM. The guiding question for this article was what are some of the salient human resource management challenges that emanated from ALM’s disestablishment? In addition, what lessons can be drawn for future municipal disestablishment exercises? Setting: The setting for this study was the Polokwane Municipality, South Africa. Methods: A qualitative approach, with interviews being the major data-collecting instrument, was applied. Results: A key finding of this study is that there is a general dissatisfaction among staff from Aganang Municipality who were moved to Polokwane Municipality (PM) because of disparities in remuneration between them and their counterparts working for PM. Conclusion: A major recommendation proffered in this article is that all human-resource-related issues need to be ironed out with staff members of the disestablished municipality before they are moved to other municipalities. This assists in minimising labour disputes in the merging process.

The division of neural progenitors is closely regulated but how is unclear. Here, the authors show that mitotic kinesin KIF20A/MKLP2 interacts with a regulator of G protein signaling RGS3 in neural progenitor cells, dislodging it from the intercellular bridge of dividing cortical cells.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-01691-4

Human CEACAM1 is a cell-cell adhesion molecule with multiple functions including insulin clearance in the liver, vasculogenesis in endothelial cells, lumen formation in the mammary gland, and binding of certain human pathogens.Three genomic BAC clones containing the human CEACAM1 gene were microinjected into pronuclei of fertilized FVB mouse oocytes. The embryos were implanted in the oviducts of pseudopregnant females and allowed to develop to term. DNA from newborn mice was evaluated by PCR for the presence of the human CEACAM1 gene. Feces of the PCR positive offspring screened for expression of human CEACAM1. Using this assay, one out of five PCR positive lines was positive for human CEACAM1 expression and showed stable transmission to the F1 generation with the expected transmission frequency (0.5) for heterozygotes. Liver, lung, intestine, kidney, mammary gland, and prostate were strongly positive for the dual expression of both murine and human CEACAM1 and mimic that seen in human tissue. Peripheral blood and bone marrow granulocytes stained strongly for human CEACAM1 and bound Neisseria Opa proteins similar to that in human neutrophils.These transgenic animals may serve as a model for the binding of human pathogens to human CEACAM1.

Ant communities in longleaf pine habitats are poorly known and hence the naturally occurring ant assemblages of a large portion of southeastern North America are not well understood. This study examined the diverse ant community found in the longleaf pine flatwoods of north Florida and tested how ant diversity changes along a herbaceous ground cover gradient. Restoring the ground cover to its original floral composition is an important focus of longleaf pine conservation and hence it is important to understand how native faunal communities vary with ground cover variation. Using 4 sampling methods, we characterized the ant community and analyzed its within-habitat variation among 12 study sites. We found the highest plot species richness (55 species) and within-habitat species richness (72 species) ever recorded for North American ants. The ants formed three distinct communities. The low-diversity arboreal and subterranean assemblages varied little across forest stands while the diversity of the species-rich ground foraging ant community was negatively correlated with percent herbaceous cover. The imported fire ant, Solenopsis invicta (monogyne form), was unexpectedly found to be abundant in high herbaceous cover sites. Floral restoration of the pine flatwoods, which is increasing the proportion of herbaceous cover, is likely to cause an increase in the abundance of the imported fire ant.

Objectives: Black patients have the highest overall incidence rate of early onset colorectal cancer, with many of these patients presenting with more aggressive disease at diagnosis, ultimately leading to decreased overall survival. We aimed to (1) evaluate how race and age affected overall survival in colorectal cancer patients, and (2) determine the different demographic and clinical covariables that may influence survival in younger individuals. Methods: The 2017 National Cancer Database (NCDB) was used to identify all patients that had colorectal cancer between 2004-2017. These patients were then divided into groups according to age (<45 and ≥45 years old) and race (white and black). Overall survival (OS) between white and black groups according to age was compared. Initial testing of survivor functions between groups revealed violations of the proportional hazards assumption. Accordingly, we used parametric maximum likelihood analyses fitting the survivor functions to Weibull distributions. Logistic regression analysis was used to determine univariate and multivariate relationships between the covariates and race for younger subjects. Propensity score matching analysis was also used to control for differences in the demographic or clinical variables between the young black versus white subgroups. Results: Out of 1.4 million potential cases initially identified, 207,823 unique cases were deemed eligible for evaluation based on study criteria. Black patients in the study population were more likely to be female, have medical comorbidities, and come from areas with lower average income and baseline education. OS was lower in older patients of both race categories when compared to the younger cohorts. Among patients older than 45 years, there were no significant differences in proportional hazard of death between black and white patients. However, among those younger than 45 years, younger black patients had significantly increased hazard of death. Regarding disease burden at diagnosis, pathologic characteristics and overall risk of death, there were no significant differences between black and white patients. Conclusions: Overall survival in young black patients with colorectal cancer is significantly reduced when compared to young white patients, even when controlling for demographic and pathologic factors. This suggests that the outcome disparities between black and white patients are complex, and the underlying factors are not well understood., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information.

Viruses are very attractive biomaterials owing to their capability as nanocarriers of genetic material. Efforts have been made to functionalize self-assembling viral protein capsids on their exterior or interior to selectively take up different payloads. PRD1 is a double-stranded DNA bacteriophage comprising an icosahedral protein outer capsid and an inner lipidic vesicle. Here, we report the three-dimensional structure of PRD1 in complex with the antipsychotic drug chlorpromazine (CPZ) by cryo-electron microscopy. We show that the jellyrolls of the viral major capsid protein P3, protruding outwards from the capsid shell, serve as scaffolds for loading heterocyclic CPZ molecules. Additional X-ray studies and molecular dynamics simulations show the binding modes and organization of CPZ molecules when complexed with P3 only and onto the virion surface. Collectively, we provide a proof of concept for the possible use of the lattice-like organisation and the quasi-symmetric morphology of virus capsomers for loading heterocyclic drugs with defined properties.

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., Competing Interests: Declaration of interests G.R.S. is on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is Chair of UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID19 committee and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is chair of the UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the World Health Organization’s (WHO’s) SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development.The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is Chair of UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in the JCVI COVID-19 committee, and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 50  < 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., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. G.R.S. sits on the GSK Vaccines Scientific Advisory Board. A.J.P. is Chair of UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not chair or participate in the JCVI COVID19 committee, and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. All other authors declare no competing financial interests. The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is Chair of UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID19 committee and is a member of the WHO’s SAGE. S.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine. T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and consultant to Vaccitech. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Enteroviruses cause a range of human and animal diseases, some life-threatening, but there remain no licenced anti-enterovirus drugs. However, a benzene-sulfonamide derivative and related compounds have been shown recently to block infection of a range of enteroviruses by binding the capsid at a positively-charged surface depression conserved across many enteroviruses. It has also been established that glutathione is essential for the assembly of many enteroviruses, interacting with the capsid proteins to facilitate the formation of the pentameric assembly intermediate, although the mechanism is unknown. Here we show, by high resolution structure analyses of enterovirus F3, that reduced glutathione binds to the same interprotomer pocket as the benzene-sulfonamide derivative. Bound glutathione makes strong interactions with adjacent protomers, thereby explaining the underlying biological role of this druggable binding pocket and delineating the pharmacophore for potential antivirals., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes frequent outbreaks of severe neurologic and respiratory disease in humans with high case fatality rates. The 2 glycoproteins displayed on the surface of the virus, NiV-G and NiV-F, mediate host-cell attachment and membrane fusion, respectively, and are targets of the host antibody response. Here, we provide a molecular basis for neutralization of NiV through antibody-mediated targeting of NiV-F. Structural characterization of a neutralizing antibody (nAb) in complex with trimeric prefusion NiV-F reveals an epitope at the membrane-distal domain III (DIII) of the molecule, a region that undergoes substantial refolding during host-cell entry. The epitope of this monoclonal antibody (mAb66) is primarily protein-specific and we observe that glycosylation at the periphery of the interface likely does not inhibit mAb66 binding to NiV-F. Further characterization reveals that a Hendra virus-F-specific nAb (mAb36) and many antibodies in an antihenipavirus-F polyclonal antibody mixture (pAb835) also target this region of the molecule. Integrated with previously reported paramyxovirus F-nAb structures, these data support a model whereby the membrane-distal region of the F protein is targeted by the antibody-mediated immune response across henipaviruses. Notably, our domain-specific sequence analysis reveals no evidence of selective pressure at this region of the molecule, suggestive that functional constraints prevent immune-driven sequence variation. Combined, our data reveal the membrane-distal region of NiV-F as a site of vulnerability on the NiV surface., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)