Risk Factor Analysis and Genetic Parameter Estimation for Pre-Weaning Mortality Traits in Boer, Spanish, and Crossbred Goat Kids.

The objectives of this study were to evaluate fixed risk factors associated with PWM and to estimate genetic parameters for PWM. A total of 927 birth records from a mixed population of purebred and crossbred Boer and Spanish goats born between 2016 and 2023 at the International Goat Research Center (IGRC) were used for this study. Four binary traits were studied: D0-3 (death within 3 days after birth), D4-60 (death between 4 and 60 days), D61-90 (death between 61 and 90 days), and D0-90 (death within 90 days).

Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα.

Structure-Guided Chemical Optimization of Bicyclic Peptide () Inhibitors of Angiotensin-Converting Enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease that cleaves angiotensin II, a peptide substrate involved in the regulation of hypertension. Here, we identified a series of constrained bicyclic peptides, , inhibitors of human ACE2 by panning highly diverse bacteriophage display libraries. These were used to generate X-ray crystal structures which were used to inform the design of additional with increased affinity and inhibition of ACE2 enzymatic activity.

Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer.

Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a Nectin-4 targeting BTC currently under clinical evaluation. Nectin-4 is overexpressed in multiple tumor types and is a clinically validated target for selective delivery of cytotoxic payloads.

BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors.

Multiple tumor types overexpress Nectin-4 and the antibody-drug conjugate (ADC), enfortumab vedotin (EV) shows striking efficacy in clinical trials for metastatic urothelial cancer, which expresses high levels of Nectin-4, validating Nectin-4 as a clinical target for toxin delivery in this indication. Despite excellent data in urothelial cancer, little efficacy data are reported for EV in other Nectin-4 expressing tumors and EV therapy can produce significant toxicities in many patients, frequently leading to discontinuation of treatment. Thus, additional approaches to this target with the potential to extend utility and reduce toxicity are warranted.

Antibacterial effect of CuO/TiO photocatalytic composite on Pseudomonas marginalis pv. marginalis.

CuO/TiO visible-light photocatalytic composite was successfully synthesized by supercritical solvothermal route. CuO/TiO presented excellent bacterial inactivation activity for Pseudomonas marginalis pv. marginalis, which was related to the concentration of bacteria and the antibacterial time.

Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist.

Background: In contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides ().

Methods: Phage libraries displaying were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1.

An Assay for Periplasm Entry Advances the Development of Chimeric Peptide Antibiotics.

The treatment of infection by Gram-negative bacteria is increasingly challenging as resistance to existing antibiotics spreads. Constrained peptides, selected for high target specificity and affinity via library display technologies, are an emerging therapeutic modality in many disease areas and may be a fertile source of new antibiotics. Currently, the utility of constrained peptides and other large molecules as antibiotics is limited by the outer membrane (OM) barrier of Gram-negative bacteria.

MMAE Delivery Using the Toxin Conjugate BT5528.

The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, and nanoparticle-based approaches (1-3). However, until now only EphA2-targeting antibody-drug conjugates (ADC) have entered clinical development.

DirectMX - One-Step Reconstitution of Membrane Proteins From Crude Cell Membranes Into Salipro Nanoparticles.

Integral membrane proteins (IMPs) are central to many physiological processes and represent ∼60% of current drug targets. An intricate interplay with the lipid molecules in the cell membrane is known to influence the stability, structure and function of IMPs. Detergents are commonly used to solubilize and extract IMPs from cell membranes.

Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads.

Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker.

Genetic architecture of quantitative traits in beef cattle revealed by genome wide association studies of imputed whole genome sequence variants: I: feed efficiency and component traits.

Background: Genome wide association studies (GWAS) on residual feed intake (RFI) and its component traits including daily dry matter intake (DMI), average daily gain (ADG), and metabolic body weight (MWT) were conducted in a population of 7573 animals from multiple beef cattle breeds based on 7,853,211 imputed whole genome sequence variants. The GWAS results were used to elucidate genetic architectures of the feed efficiency related traits in beef cattle.

Results: The DNA variant allele substitution effects approximated a bell-shaped distribution for all the traits while the distribution of additive genetic variances explained by single DNA variants followed a scaled inverse chi-squared distribution to a greater extent.

Genetic architecture of quantitative traits in beef cattle revealed by genome wide association studies of imputed whole genome sequence variants: II: carcass merit traits.

Background: Genome wide association studies (GWAS) were conducted on 7,853,211 imputed whole genome sequence variants in a population of 3354 to 3984 animals from multiple beef cattle breeds for five carcass merit traits including hot carcass weight (HCW), average backfat thickness (AFAT), rib eye area (REA), lean meat yield (LMY) and carcass marbling score (CMAR). Based on the GWAS results, genetic architectures of the carcass merit traits in beef cattle were elucidated.

Results: The distributions of DNA variant allele substitution effects approximated a bell-shaped distribution for all the traits while the distribution of additive genetic variances explained by single DNA variants conformed to a scaled inverse chi-squared distribution to a greater extent.

Evaluation of a genomic-enhanced sorting system for feeder cattle1.

This study evaluated the use of molecular breeding values (MBVs) for carcass traits to sort steers into quality grid and lean meat yield (LMY) groups. A discovery set of 2,609 animals with genotypes and carcass phenotypes was used to predict MBVs for LMY and marbling score (MBS) for 299 Angus, 181 Charolais, and 638 Kinsella Composite steers using genomic best linear unbiased prediction. Steers were sorted in silico into four MBV groups namely Quality (with MBVs greater than the mean for LMY and MBS), Lean (with MBVs greater than the mean for LMY but less than or equal to the mean for MBS), Marbling (with MBVs greater than the mean for MBS but less than or equal to the mean for LMY), and Other (with MBVs lower than the mean for LMY and MBS).

Bicyclic Peptides as a New Modality for Imaging and Targeting of Proteins Overexpressed by Tumors.

Molecular imaging of cancers using probes specific for tumor-associated target proteins offers a powerful solution for providing information regarding selection of targeted therapy, patient stratification, and response to therapy. Here we demonstrate the power of bicyclic peptides as targeting probes, exemplified with the tumor-overexpressed matrix metalloproteinase MT1-MMP as a target. A bicyclic peptide with subnanomolar affinity towards MT1-MMP was identified, and its radioconjugate showed selective tumor uptake in an HT1080 xenograft mouse model.

Genome-wide association scan for heterotic quantitative trait loci in multi-breed and crossbred beef cattle.

Background: Heterosis has been suggested to be caused by dominance effects. We performed a joint genome-wide association analysis (GWAS) using data from multi-breed and crossbred beef cattle to identify single nucleotide polymorphisms (SNPs) with significant dominance effects associated with variation in growth and carcass traits and to understand the mode of action of these associations.

Methods: Illumina BovineSNP50 genotypes and phenotypes for 11 growth and carcass traits were available for 6796 multi-breed and crossbred beef cattle.

Modeling heterotic effects in beef cattle using genome-wide SNP-marker genotypes.

An objective of commercial beef cattle crossbreeding programs is to simultaneously optimize use of additive (breed differences) and non-additive (heterosis) effects. A total of 6,794 multibreed and crossbred beef cattle with phenotype and Illumina BovineSNP50 genotype data were used to predict genomic heterosis for growth and carcass traits by applying two methods assumed to be linearly proportional to heterosis. The methods were as follows: 1) retained heterozygosity predicted from genomic breed fractions (HET1) and 2) deviation of adjusted crossbred phenotype from midparent value (HET2).

Genome-wide association and genomic prediction of breeding values for fatty acid composition in subcutaneous adipose and longissimus lumborum muscle of beef cattle.

Background: Identification of genetic variants that are associated with fatty acid composition in beef will enhance our understanding of host genetic influence on the trait and also allow for more effective improvement of beef fatty acid profiles through genomic selection and marker-assisted diet management. In this study, 81 and 83 fatty acid traits were measured in subcutaneous adipose (SQ) and longissimus lumborum muscle (LL), respectively, from 1366 purebred and crossbred beef steers and heifers that were genotyped on the Illumina BovineSNP50 Beadchip. The objective was to conduct genome-wide association studies (GWAS) for the fatty acid traits and to evaluate the accuracy of genomic prediction for fatty acid composition using genomic best linear unbiased prediction (GBLUP) and Bayesian methods.

Design and structural analysis of aromatic inhibitors of type II dehydroquinase from Mycobacterium tuberculosis.

3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors.

Impact of genotype imputation on the performance of GBLUP and Bayesian methods for genomic prediction.

The aim of this study was to evaluate the impact of genotype imputation on the performance of the GBLUP and Bayesian methods for genomic prediction. A total of 10,309 Holstein bulls were genotyped on the BovineSNP50 BeadChip (50 k). Five low density single nucleotide polymorphism (SNP) panels, containing 6,177, 2,480, 1,536, 768 and 384 SNPs, were simulated from the 50 k panel.

Multi-population genomic prediction using a multi-task Bayesian learning model.

Background: Genomic prediction in multiple populations can be viewed as a multi-task learning problem where tasks are to derive prediction equations for each population and multi-task learning property can be improved by sharing information across populations. The goal of this study was to develop a multi-task Bayesian learning model for multi-population genomic prediction with a strategy to effectively share information across populations. Simulation studies and real data from Holstein and Ayrshire dairy breeds with phenotypes on five milk production traits were used to evaluate the proposed multi-task Bayesian learning model and compare with a single-task model and a simple data pooling method.

Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues.

The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, thiamine pyrophosphate (TPP or thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch-ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring.

Identification of novel ligands for thiamine pyrophosphate (TPP) riboswitches.

Riboswitches are regions of mRNA to which a metabolite binds in the absence of proteins, resoulting in alteration of transcription, translation or splicing. The most widespread forms of riboswitches are those responsive to TPP (thiamine pyrophosphate) the active form of vitamin B1, thiamine. TPP-riboswitches have been found in all bacterial genomes examined, and are the only ones found in eukaryotes.