Coffee is an important crop globally. Improving coffee quality is a primary breeding target that would benefit from understanding of trait inheritance and ancestral genetic information. However, comparatively little information exists on the genetics of quality and the relationships between wild and cultivated coffee genotypes, especially arabica coffee (Coffea arabica L.) which accounts for almost 60% of coffee production globally. The complex polyploidy genome and limited genomic information for C. arabica have impeded the progress of genetic studies. Arabica coffee is among the major organisms that do not have a reference genome. This project aimed to develop and utilise genomic resources in genetic studies of arabica coffee quality. The relationship between coffee species and the position of arabica within the Coffeeae tribe were investigated using complete chloroplast genome sequences to determine the value of these genetic resources in breeding. A draft genome sequence of arabica coffee was developed. Marker-trait associations were studied for caffeine and trigonelline, the two principal compounds known to be related to coffee quality, paving the way for developing new improved varieties with preferred levels of these compounds in the coffee beans.Chloroplast genomes of 16 coffee species were sequenced and their phylogeny constructed. Results support distinct Psilanthus and Coffea clades. It is likely that C. canephora is a hybrid that has a Psilanthus maternal genome but received much of its nuclear genome from Coffea. The maternal genomes of C. arabica and C. canephora are divergent. This result is in agreement with the fact that the chloroplast genome of arabica should be that of the maternal parent i.e. C. eugenioides. There were two species (C. humblotiana and C. tetragona) close to C. arabica and one species (P. ebracteolatus) close to C. canephora containing almost no caffeine. They could serve as important materials in arabica quality breeding and research.For the association study, 232 diverse arabica coffee accessions originating from 27 countries were harvested from the germplasm collection at CATIE (Tropical Agricultural Research and Higher Education Centre), Costa Rica. Substantial variation between genotypes was observed for bean morphology attributes. Non-volatiles including caffeine and trigonelline showed larger variation in range than was previously reported. Results of targeted analysis of 18 volatiles from 35 accessions also showed significant variation. No strong correlation was found between bean morphology and the levels of non-volatile or volatile compounds, implying that it is difficult to select for low or high non-volatile and volatile compounds based on bean physical characteristics. However, it also indicates that breeding for desirable combinations of traits (i.e. large bean size, low caffeine, high trigonelline, and favourable volatiles) is possible.ii The genome of the most popular arabica variety (K7) in Australia was sequenced. Genome assembly was performed using b...

The blood–brain barrier (BBB) is a major obstacle to the development of effective therapeutics for central nervous system (CNS) disorders, including Alzheimer’s disease (AD). This has been particularly true in the case of monoclonal antibody (mAbs) therapeutic candidates, due to their large size. To tackle this issue, we developed new nanoformulations, comprising bio-based Triozan polymers along with kinin B1 and B2 receptor (B1R and B2R) peptide agonist analogues, as potent BBB-permeabilizers to enhance brain delivery of a new anti-C1q mAb for AD (ANX005). The prepared B1R/B2R-TRIOZAN™ nanoparticles (NPs) displayed aqueous solubility, B1R/B2R binding capacity and uniform sizes (~130–165 nm). The relative biodistribution profiles of the mAb loaded into these NPs versus the naked mAb were assessed in vivo through two routes of administrations (intravenous (IV), intranasal (IN)) in the Tg-SwDI mouse model of AD. At 24 h post-administration, brain levels of the encapsulated mAb were significantly increased (up to 12-fold (IV) and 5-fold (IN), respectively) compared with free mAb in AD brain affected regions, entorhinal cortex and hippocampus of aged mice. Liver uptakes remained relatively low with similar values for the nanoformulations and free mAb. Our findings demonstrate the potential of B1R/B2R-TRIOZAN™ NPs for the targeted delivery of new CNS drugs, which could maximize their therapeutic effectiveness.

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Prostate cancer (PCa) is a complex disease progressing from in situ to invasive or metastatic tumors while also being capable of modulating its androgen dependence. Understanding how novel therapies are working across the different stages of the disease is critical for their proper positioning in the spectrum of PCa treatments. The targeting of proprotein convertase PACE4 (Paired basic Amino Acid-Cleaving Enzyme 4) has been proposed as a novel approach to treat PCa. Animal studies performed on LNCaP xenografts, an androgen-dependent model, already yielded positive results. In this study, we tested PACE4 inhibition on JHU-LNCaP-SM, a newly described androgen-independent model, in cell-based and xenograft assays. Like LNCaP, JHU-LNCaP-SM cells express PACE4 and its oncogenic isoform PACE4-altCT. Using isoform-specific siRNAs, downregulation of PACE4-altCT resulted in JHU-LNCaP-SM growth inhibition. Furthermore, JHU-LNCaP-SM responded to the PACE4 pharmacological inhibitor known as C23 in cell-based assays as well as in athymic nude mice xenografts. These data support the efficacy of PACE4 inhibitors against androgen independent PCa thereby demonstrating that PACE4 is a key target in PCa. The JHU-LNCaP-SM cell line represents a model featuring important aspects of androgen-independent PCa, but it also represents a very convenient model as opposed to LNCaP cells for in vivo studies, as it allows rapid screening due to its high implantation rate and growth characteristics as xenografts.