Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

Evidence of spatial competition, over resource scarcity, as a primary driver of conflicts between small-scale and industrial fishers

Accounts of fishing conflicts have been rising globally, particularly between small-scale and industrial vessels. These conflicts involve verbal or physical altercations, and may include destruction of boats, assault, kidnapping, and murder. Current scholarship around industrial/small-scale fishing conflicts theorizes them as a form of resource conflict, where fish scarcity is the dominant contributor to conflict and competition. Alternatively, conflicts may be driven by spatial competition, concentrating where there are increased encounters, unrelated to resource status. Current policies to address these conflicts focus on enforcing the separation of small-scale and industrial vessels; however, this broad spatial separation has yet to be evaluated for deterring conflicts. Here we employ a novel spatial analysis to estimate the locations of industrial/small-scale conflicts at sea in Ghana, West Africa. Using data from narrative reports over the period of 1985 to 2014, we combine qualitative information on depth and shoreline indicators to analyze conflict locations. We find virtually all expected conflict locations (98%) occurred within the zone meant to exclude industrial vessels, and conflicts concentrated primarily around major ports. Our results suggest conflicts are likely more related to spatial patterns of vessel presence than patterns of resource use. These findings suggest a critical need for evidence-based and contextual information on the drivers of fisheries conflicts, rather than continued reliance on assumptions of resource scarcity. They also suggest that nuanced policies that reduce vessel encounter and clarify exclusive spatial rights may be more important in responding to these conflicts than approaches designed to broadly separate fleets or increase fish stocks

GATA3 mutations found in breast cancers may be associated with aberrant nuclear localization, reduced transactivation and cell invasiveness

Somatic and germline mutations in the dual zinc-finger transcription factor GATA3 are associated with breast cancers expressing the estrogen receptor (ER) and the autosomal dominant hypoparathyroidism–deafness–renal dysplasia syndrome, respectively. To elucidate the role of GATA3 in breast tumorigenesis, we investigated 40 breast cancers that expressed ER, for GATA3 mutations. Six different heterozygous GATA3 somatic mutations were identified in eight tumors, and these consisted of: a frameshifting deletion/insertion (944_945delGGinsAGC), an in-frame deletion of a key arginine residue (991_993delAGG), a seven-nucleotide frameshifting insertion (991_992insTGGAGGA), a frameshifting deletion (1196_1197delGA), and two frameshifting single nucleotide insertions (1224_1225insG found in three tumors and 1224_1225insA). Five of the eight mutations occurred in tumors that retained GATA3 immunostaining, indicating that absence of GATA3 immunostaining is an unreliable predictor of the presence of GATA3 mutations. Luciferase reporter assays, electrophoretic mobility shift assays, immunofluorescence, invasion and proliferation assays demonstrated that the GATA3 mutations resulted in loss (or reduction) of DNA binding, decrease in transactivational activity, and alterations in invasiveness but not proliferation. The 991_992insTGGAGGA (Arg330 frameshift) mutation led to a loss of nuclear localization, yet the 991_993delAGG (Arg330deletion) retained nuclear localization. Investigation of the putative nuclear localization signal (NLS) sites showed that the NLS of GATA3 does not conform to either a classical mono- or bi-partite signal, but contains multiple cooperative NLS elements residing around the N-terminal zinc-finger which comprises residues 264–288. Thus, approximately 20 % ER-positive breast cancers have somatic GATA3 mutations that lead to a loss of GATA3 transactivation activity and altered cell invasiveness

Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2

Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/– mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/– mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/– mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/– embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3–/– embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function

Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.

Acknowledgements: This work was supported by the MRC (UK; U105181010), a Wellcome Trust Investigator Award (223054/Z/21/Z), a Wellcome Trust Collaborator Award (214344/A/18/Z) and Innovate-UK (UKRI Ideas to Address COVID-19 – Innovate UK Article 25 funding strand). AO and JPS acknowledge funding from EPSRC, Unitaid, Wellcome Trust and MRC for funding which supported development of preclinical models for SARS-CoV-2 infection. We would like to thank Viroclinics Xplore for in vivo studies, Evotec for contract research services, Rachel Dods and Gustavo Arruda Bezerra for structural analysis, Radu Aricescu for design of lentiviral S protein expression systems, Andrew Carter for cloning of S-pseudotyped vectors, Dean Clift for Incucyte analysis, Tyler Rhinesmith and Jakub Laptuk for cell culture and assay support and the Bicycle team and James lab for general scientific support.COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses

Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses