Umami taste perception and preferences of the domestic cat (Felis catus), an obligate carnivore.

The domestic cat (Felis catus) is an obligate carnivore, and as such has a meat-based diet. Several studies on the taste perception of cats have been reported, indicating that their sense of taste has evolved based on their carnivorous diet. Here, we propose that umami (mediated by Tas1r1-Tas1r3) is the main appetitive taste modality for the domestic cat by characterizing the umami taste of a range of nucleotides, amino acids, and their mixtures for cats obtained using complementary methods. We show for the first time that cats express Tas1r1 in taste papillae. The cat umami receptor responds to a range of nucleotides as agonists, with the purine nucleotides having the highest activity. Their umami receptor does not respond to any amino acids alone; however, 11 l-amino acids with a range of chemical characteristics act as enhancers in combination with a nucleotide. l-Glutamic acid and l-Aspartic acid are not active as either agonists or enhancers of the cat umami receptor due to changes in key binding residues at positions 170 and 302. Overall, cats have an appetitive behavioral response for nucleotides, l-amino acids, and their mixtures. We postulate that the renowned palatability of tuna for cats may be due, at least in part, to its specific combination of high levels of inosine monophosphate and free l-Histidine that produces a strong synergistic umami taste enhancement. These results demonstrate the critical role that the umami receptor plays in enabling cats to detect key taste compounds present in meat.

Psychosocial assessment of adolescents and young adults in paediatric hospital settings: patient and staff perspectives on implementation of the e-HEEADSSS.

BACKGROUND: The main causes of morbidity and mortality for adolescents and young adults are preventable and stem from psychosocial and behavioural concerns. Psychosocial assessments can help clinicians to identify and respond holistically to risks and strengths that may impact upon a young person's physical and mental health. Despite broad support at a policy level, the implementation of routine psychosocial screening for young people remains varied in Australian health settings. The current study focused on the pilot implementation of a digital patient-completed psychosocial assessment (the e-HEEADSSS) at the Sydney Children's Hospital Network. The aim of this research was to evaluate patient and staff barriers and facilitators to local implementation. METHODS: The research used a qualitative descriptive research design. Semi-structured interviews were conducted online with 8 young patients and 8 staff members who had completed or actioned an e-HEEADSSS assessment within the prior 5 weeks. Qualitative coding of interview transcripts was carried out in NVivo 12. The Consolidated Framework for Implementation Research guided the interview framework and qualitative analyses. RESULTS: Results demonstrated strong support for the e-HEEADSSS from patients and staff. Key reported facilitators included strong design and functionality, reduced time requirements, greater convenience, improved disclosure, adaptability across settings, greater perceived privacy, improved fidelity, and reduced stigma for young people. The key barriers were related to concerns over available resources, the sustainability and continuity of staff training, perceived availability of clinical pathways for follow-up and referrals, and risks related to off-site completions. Clinicians need to adequately explain the e-HEEADSSS assessment to patients, educate them about it, and make sure that they receive timely feedback on the results. Greater reassurance and education regarding the rigour of confidentiality and data handling procedures is required for patients and staff. CONCLUSIONS: Our findings indicate that continued work is required to support the integration and sustainability of digital psychosocial assessments for young people at the Sydney Children's Hospital Network. The e-HEEADSSS shows promise as an implementable intervention to achieve this goal. Further research is required to determine the scalability of this intervention across the broader health system.

Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase.

Novel analogues of C-2-substituted thienopyrimidine-based bisphosphonates (C2-ThP-BPs) are described that are potent inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class of compounds induce target-selective apoptosis of multiple myeloma (MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety that connects their (((2-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methylene)bisphosphonic acid core to various side chains. The structural diversity of this linker moiety, as well as the side chains attached to it, was investigated and found to significantly impact the toxicity of these compounds in MM cells. The most potent inhibitor identified was evaluated in mouse and rat for liver toxicity and systemic exposure, respectively, providing further optimism for the potential value of such compounds as human therapeutics.

Inhibition of farnesyl pyrophosphate (FPP) and/or geranylgeranyl pyrophosphate (GGPP) biosynthesis and its implication in the treatment of cancers.

Dysregulation of isoprenoid biosynthesis is implicated in numerous biochemical disorders that play a role in the onset and/or progression of age-related diseases, such as hypercholesterolemia, osteoporosis, various cancers, and neurodegeneration. The mevalonate metabolic pathway is responsible for the biosynthesis of the two key isoprenoid metabolites, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational prenylation of various proteins, including the small GTP-binding proteins (GTPases), with either FPP or GGPP is vital for proper localization and activation of these proteins. Prenylated GTPases play a critical role in cell signaling, proliferation, cellular plasticity, oncogenesis, and cancer metastasis. Pre-clinical and clinical studies strongly suggest that inhibition of protein prenylation can be an effective treatment for non-skeletal cancers. In this review, we summarize the most recent drug discovery efforts focusing on blocking protein farnesylation and/or geranylgeranylation and the biochemical and structural data available in guiding the current on-going studies in drug discovery. Furthermore, we provide a summary on the biochemical association between disruption of protein prenylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) signaling, and cancer.