ECONOMICS OF ALTERNATIVE STOCKING DENSITIES FOR DIRECT-SEEDED CENTRAL MICHIGAN ALFALFA PASTURES

A framework which permits estimation of economically optimal stocking rates for alternative economic parameters and alfalfa forage availability was developed and applied to a controlled grazing experiment conducted with Holstein steers (243 kg) placed on direct seeded alfalfa pastures in Central Michigan. Responses of ADG to alternative levels of forage availability per standard livestock unit (FA) were summarized by a quadratic function and the associated gains/ha were calculated. The ADG decreased as standard stocking rate (SSR; SLU/ha) increased except for the combination of the lowest observed SSR and highest FA, where ADG was curvilinear as SSR increased. The trend for gain/ha was curvilinear for all FA. The SSR which maximized gain/ha increased with FA and was greater than that which maximized ADG. Net returns to fixed resources(NRFR)/ha ($/ha)were calculated for alternative SSR and the economically optimal SSR were identified under various levels of herbage mass (kg/d). The SSR's which maximized NRFR were between the SSR's which maximized ADG and gain/ha. The magnitude of the sale price discount for heavier weight calves (slide) influenced the economically optimal SSR and the sensitivity of net return to SSR. The economically optimal SSR increased as slide increased because animals stocked under higher SSR weighed less off pasture and therefore received less price discount.Crop Production/Industries,

PRICING AND USE OF DROUGHT-STRESSED AND IMMATURE CORN AS SILAGE FOR BEEF CATTLE

Demand and Price Analysis,

Economically Optimal Distiller Grain Inclusion in Beef Feedlot Rations: Recognition of Omitted Factors

With the rapid expansion of the ethanol industry, the feeding landscape familiar to the feedlot industry is changing. While concerns regarding rising corn prices persist, many within the industry are looking at distiller’s grains, a by-product of ethanol production, to serve as a feed substitute. The question remains as to what extent these two feed sources are substitutable. The purpose of this study is to identify the economically optimal inclusion rate of distiller’s grains in beef feedlot rations, considering an array of often omitted factors. Most currently prevailing recommendation rates are strictly biologically based and frequently reference only one feeding trial. Unique economic factors considered in this research include the impact of by-product inclusion rates on animal performance (utilizing recently conducted meta-analysis from 17 relevant feeding trials), enhanced likelihood of death loss from heightened sulfur content, and manure disposal costs. Results indicate that excluding these factors can significantly impact optimal inclusion levels and that reliance on a single or few feeding trials may greatly bias results.distiller’s grains, livestock rations, manure disposal cost,

Economically Optimal Distiller Grain Inclusion in Beef Feedlot Rations: Recognition of Omitted Factors

With the rapid expansion of the ethanol industry, the feeding landscape familiar to the feedlot industry is changing. While concerns regarding rising corn prices persist, many within the industry are looking at distillers grains, a by-product of ethanol production, to serve as a feed substitute. The question remains as to what extent these two feed sources are substitutable. The purpose of this study is to identify the economically optimal inclusion rate of distillers grains in beef feedlot rations, considering an array of often omitted factors. Most currently prevailing recommendation rates are strictly biologically based and frequently reference only one feeding trial. Unique economic factors considered in this research include the impact of by-product inclusion rates on animal performance (utilizing recently conducted meta-analysis from 17 relevant feeding trials), enhanced likelihood of death loss from heightened sulfur content, and manure disposal costs. Results indicate that excluding these factors can significantly impact optimal inclusion levels and that reliance on a single or few feeding trials may greatly bias results.Livestock Production/Industries,

Report from the “What is Open?” Workgroup

The scholarly community’s current definition of “open” captures only some of the attributes of openness that exist across different publishing models and content types. Open is not an end in itself, but a means for achieving the most effective dissemination of scholarship and research. We suggest that the different attributes of open exist along a broad spectrum and propose an alternative way of describing and evaluating openness based on four attributes: discoverable, accessible, reusable, and transparent. These four attributes of openness, taken together, form the draft “DART Framework for Open Access.” This framework can be applied to both research artifacts as well as research processes. We welcome input from the broader scholarly community about this framework

Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion.

To maintain prolonged infection of mammals, African trypanosomes have evolved remarkable surface coats and a system of antigenic variation1. Within these coats are receptors for macromolecular nutrients such as transferrin2,3. These must be accessible to their ligands but must not confer susceptibility to immunoglobulin-mediated attack. Trypanosomes have a wide host range and their receptors must also bind ligands from diverse species. To understand how these requirements are achieved, in the context of transferrin uptake, we determined the structure of a Trypanosoma brucei transferrin receptor in complex with human transferrin, showing how this heterodimeric receptor presents a large asymmetric ligand-binding platform. The trypanosome genome contains a family of around 14 transferrin receptors4, which has been proposed to allow binding to transferrin from different mammalian hosts5,6. However, we find that a single receptor can bind transferrin from a broad range of mammals, indicating that receptor variation is unlikely to be necessary for promiscuity of host infection. In contrast, polymorphic sites and N-linked glycans are preferentially found in exposed positions on the receptor surface, not contacting transferrin, suggesting that transferrin receptor diversification is driven by a need for antigenic variation in the receptor to prolong survival in a host

Quantification of DNA-associated proteins inside eukaryotic cells using single-molecule localization microscopy

Development of single-molecule localization microscopy techniques has allowed nanometre scale localization accuracy inside cells, permitting the resolution of ultra-fine cell structure and the elucidation of crucial molecular mechanisms. Application of these methodologies to understanding processes underlying DNA replication and repair has been limited to defined in vitro biochemical analysis and prokaryotic cells. In order to expand these techniques to eukaryotic systems, we have further developed a photo-activated localization microscopy-based method to directly visualize DNA-associated proteins in unfixed eukaryotic cells. We demonstrate that motion blurring of fluorescence due to protein diffusivity can be used to selectively image the DNA-bound population of proteins. We designed and tested a simple methodology and show that it can be used to detect changes in DNA binding of a replicative helicase subunit, Mcm4, and the replication sliding clamp, PCNA, between different stages of the cell cycle and between distinct genetic backgrounds

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis.

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers

Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%). Compared to several other cancer types, including lung, and colorectal cancers, TILs from about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (>5%, reaching 30–50% of T cells in some patients). These DP T cells have an effector memory phenotype and express CD38, 4-1BB, and HLA-DR, suggesting antigen-driven expansion. In fact, TCR sequencing analysis revealed a high degree of clonality in DP T cells. Additionally, there were high levels of PD-1 and TIM-3 expression on DP T cells, which correlated with higher expression of PD-1 and TIM-3 in conventional single positive CD8 T cells from the same patients. These results suggest that DP T cells could be dysfunctional tumor-specific T cells with the potential to be reactivated by checkpoint inhibitors