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Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multivalent forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors. This study reports the computational design of miniprotein binders of the pattern recognition receptor TLR3. When oligomerized, the miniprotein binders induce TLR3 signaling in cells, suggesting they may be useful components of vaccines or treatments for infectious disease or cancer.

A 3-year case study was undertaken of how North American farmers use yield monitors for on-farm trials in farm management decision making. Case study methods were used because relatively few farmers quantitatively analyze yield monitor data. At this early research stage, insufficient farm management information about the data was available to ask the right questions in a large-scale survey. In addition to the formal case study of farmers experienced at using yield monitors to collect on-farm trial data, the study evaluated the effect of yield monitor data quality on farm decisions. Two levels of yield data quality included standard output where the default settings of farm-level mapping software were accepted and where filtering of the data was undertaken. Results indicated that yield data quality affects farm management decisions. In addition, farmers receiving a spatial analysis of their on-farm trial data tended to use split-field designs instead of replicated split-planter designs. They were also more confident in their decisions than before participation in the spatial analysis project, and made decisions more quickly.

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery. Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.

This study examines the effects of the Section 1031 tax-deferred exchange provision on agricultural land values. The provision allows taxpayers to defer taxation for relinquished productive assets if a like-kind asset is acquired within the allotted time of 180 days. The analysis examines a set of 3,580 farm real estate transaction from 55 agricultural counties in Indiana over the period 2003–2006. Hedonic price analysis suggests that properties acquired under a like-kind exchange are associated with a 1.32% price premium.

This study examines the effects of the Section 1031 tax-deferred exchange provision on agricultural land values. The provision allows taxpayers to defer taxation for relinquished productive assets if a like-kind asset is acquired within the allotted time of 180 days. The analysis examines a set of 3,580 farm real estate transaction from 55 agricultural counties in Indiana over the period 2003-2006. Hedonic price analysis suggests that properties acquired under a like-kind exchange are associated with a 1.32% price premium.

Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multimeric forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and important for targeted delivery of biologics. We describe the design of octahedral non-porous nanoparticles with the three symmetry axes (four-fold, three-fold, and two-fold) occupied by three distinct protein homooligomers: a designed tetramer, an antibody of interest, and a designed trimer programmed to disassemble below a tunable pH transition point. The nanoparticles assemble cooperatively from independently purified components, and a cryo-EM density map reveals that the structure is very close to the computational design model. The designed nanoparticles can package a variety of molecular payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between to 5.9-6.7. To our knowledge, these are the first designed nanoparticles with more than two structural components and with finely tunable environmental sensitivity, and they provide new routes to antibody-directed targeted delivery.

Successful farm business managers must understand the determinants of profitability and have an overall long-term or strategic management focus. The objective of this research was to explore the use of an e-learning tool to help producers understand the impacts of different production, pricing, cost control, and investment decisions on their farm's financial performance. This objective was accomplished by developing and testing a computer-based training and application tool to facilitate determination of the financial health of farm businesses using the DuPont profitability analysis model. The results of the two experiments indicate that the computer software was effective for teaching techniques of profitability analysis contained within the DuPont model.