Large carnivores face serious threats and are experiencing massive declines in their populations and geographic ranges around the world. We highlight how these threats have affected the conservation ...status and ecological functioning of the 31 largest mammalian carnivores on Earth. Consistent with theory, empirical studies increasingly show that large carnivores have substantial effects on the structure and function of diverse ecosystems. Significant cascading trophic interactions, mediated by their prey or sympatric mesopredators, arise when some of these carnivores are extirpated from or repatriated to ecosystems. Unexpected effects of trophic cascades on various taxa and processes include changes to bird, mammal, invertebrate, and herpetofauna abundance or richness; subsidies to scavengers; altered disease dynamics; carbon sequestration; modified stream morphology; and crop damage. Promoting tolerance and coexistence with large carnivores is a crucial societal challenge that will ultimately determine the fate of Earth's largest carnivores and all that depends upon them, including humans.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit ...SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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•Adenovirus transduction of human ACE2 enables SARS-CoV-2 infection of BALB/c mice•High levels of viral RNA and infectious SARS-CoV-2 accumulate in lungs•Mice transduced with human ACE2 develop viral pneumonia after SARS-CoV-2 infection•Neutralizing mAbs protect from SARS-CoV-2-induced lung infection and inflammation
Laboratory mice transduced with adenoviruses encoding human ACE2 are permissive for SARS-CoV-2 and develop pneumonia. Passive transfer of a neutralizing monoclonal antibody reduces lung infection, inflammation, and disease.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine ...countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.
Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies
. Individuals who have recovered from COVID-19 have a substantially lower risk of ...reinfection with SARS-CoV-2
. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived
. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n = 77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.
SARS-CoV-2 mRNA-based vaccines are about 95% effective in preventing COVID-19
. The dynamics of antibody-secreting plasmablasts and germinal centre B cells induced by these vaccines in humans remain ...unclear. Here we examined antigen-specific B cell responses in peripheral blood (n = 41) and draining lymph nodes in 14 individuals who had received 2 doses of BNT162b2, an mRNA-based vaccine that encodes the full-length SARS-CoV-2 spike (S) gene
. Circulating IgG- and IgA-secreting plasmablasts that target the S protein peaked one week after the second immunization and then declined, becoming undetectable three weeks later. These plasmablast responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals who had previously been infected with SARS-CoV-2 (who produced the most robust serological responses). By examining fine needle aspirates of draining axillary lymph nodes, we identified germinal centre B cells that bound S protein in all participants who were sampled after primary immunization. High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks after the booster immunization. S-binding monoclonal antibodies derived from germinal centre B cells predominantly targeted the receptor-binding domain of the S protein, and fewer clones bound to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. These latter cross-reactive B cell clones had higher levels of somatic hypermutation as compared to those that recognized only the SARS-CoV-2 S protein, which suggests a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.
Non‐consumptive predator effects (NCEs) are now widely recognised for their capacity to shape ecosystem structure and function. Yet, forecasting the propagation of these predator‐induced trait ...changes through particular communities remains a challenge. Accordingly, focusing on plasticity in prey anti‐predator behaviours, we conceptualise the multi‐stage process by which predators trigger direct and indirect NCEs, review and distil potential drivers of contingencies into three key categories (properties of the prey, predator and setting), and then provide a general framework for predicting both the nature and strength of direct NCEs. Our review underscores the myriad factors that can generate NCE contingencies while guiding how research might better anticipate and account for them. Moreover, our synthesis highlights the value of mapping both habitat domains and prey‐specific patterns of evasion success (‘evasion landscapes’) as the basis for predicting how direct NCEs are likely to manifest in any particular community. Looking ahead, we highlight two key knowledge gaps that continue to impede a comprehensive understanding of non‐consumptive predator–prey interactions and their ecosystem consequences; namely, insufficient empirical exploration of (1) context‐dependent indirect NCEs and (2) the ways in which direct and indirect NCEs are shaped interactively by multiple drivers of context dependence.
Non‐consumptive predator effects are now widely recognised for their capacity to shape ecosystem structure and function, but forecasting their propagation through particular communities remains a challenge. Focusing on plasticity in prey anti‐predator behaviours, we conceptualise the multi‐stage process by which predators trigger direct and indirect NCEs, review potential drivers of contingencies into three key categories (properties of the prey, predator and setting), and provide a general framework for predicting both the nature and strength of direct NCEs. Looking ahead, we highlight two key knowledge gaps that continue to impede a comprehensive understanding of non‐consumptive predator–prey interactions and their ecosystem consequences; namely, insufficient empirical exploration of context‐dependent indirect NCEs and the ways in which direct and indirect NCEs are shaped interactively by multiple drivers of context dependence.
Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived ...bone marrow plasma cells
(BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans
. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.
Better vaccines against influenza virus are urgently needed to provide broader protection against diverse strains, subtypes, and types. Such efforts are assisted by the identification of novel ...broadly neutralizing epitopes targeted by protective antibodies. Influenza vaccine development has largely focused on the hemagglutinin, but the other major surface antigen, the neuraminidase, has reemerged as a potential target for universal vaccines. We describe three human monoclonal antibodies isolated from an H3N2-infected donor that bind with exceptional breadth to multiple different influenza A and B virus neuraminidases. These antibodies neutralize the virus, mediate effector functions, are broadly protective in vivo, and inhibit neuraminidase activity by directly binding to the active site. Structural and functional characterization of these antibodies will inform the development of neuraminidase-based universal vaccines against influenza virus.
•We functionally characterize the first OVATE-like transcription factor, OsOFP2, in rice.•A conserved putative NES motif is required for normal OsOFP2 localization.•OsOFP2 alters rice morphology and ...hormone, lignin, and vasculature gene expression.•OsOFP2 expression is vascular bundle-specific and influences vascular positioning.
OFP (Ovate Family Protein) is a transcription factor family found only in plants. In dicots, OFPs control fruit shape and secondary cell wall biosynthesis. OFPs are also thought to function through interactions with KNOX and BELL transcription factors. Here, we have functionally characterized OsOFP2, a member of the OFP subgroup associated with regulating fruit shape. OsOFP2 was found to localize to the nucleus and to the cytosol. A putative nuclear export signal was identified within the OVATE domain and was required for the localization of OsOFP2 to distinct cytosolic spots. Rice plants overexpressing OsOFP2 were reduced in height and exhibited altered leaf morphology, seed shape, and positioning of vascular bundles in stems. Transcriptome analysis indicated disruptions of genes associated with vasculature development, lignin biosynthesis, and hormone homeostasis. Reduced expression of the gibberellin biosynthesis gene GA 20-oxidase 7 coincided with lower gibberellin content in OsOFP2 overexpression lines. Also, we found that OsOFP2 was expressed in plant vasculature and determined that putative vascular development KNOX and BELL proteins interact with OsOFP2. KNOX and BELL genes are known to suppress gibberellin biosynthesis through GA20ox gene regulation and can restrict lignin biosynthesis. We propose that OsOFP2 could modulate KNOX-BELL function to control diverse aspects of development including vasculature development.
Influenza B virus (IBV) infections can cause severe disease in children and the elderly. Commonly used antivirals have lower clinical effectiveness against IBV compared to influenza A viruses (IAV). ...Neuraminidase (NA), the second major surface protein on the influenza virus, is emerging as a target of broadly protective antibodies that recognize the NA active site of IAVs. However, similarly broadly protective antibodies against IBV NA have not been identified. Here, we isolated and characterized human monoclonal antibodies (mAbs) that target IBV NA from an IBV-infected patient. Two mAbs displayed broad and potent capacity to inhibit IBV NA enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings. These mAbs inserted long CDR-H3 loops into the NA active site, engaging residues highly conserved among IBV NAs. These mAbs provide a blueprint for the development of improved vaccines and therapeutics against IBVs.
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•Generation of seven human monoclonal antibodies to influenza B virus neuraminidase•Two antibodies, 1G05 and 2E01, are broadly cross-reactive•1G05 and 2E01 are potently protective against lethal Influenza B infection in mice•1G05 and 2E01 bind conserved residues in the Influenza B neuraminidase active site
Influenza B virus (IBV) infections cause severe disease. Madsen et al. develop and characterize human monoclonal antibodies that possess broad and potent capacities to inhibit IBV neuraminidase enzymatic activity, neutralize the virus in vitro, and protect against lethal IBV infection in mice in prophylactic and therapeutic settings.
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