Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases.

The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

SARS-CoV-2 evolution has increased resistance to monoclonal antibodies and first-generation COVID-19 vaccines: Is there a future therapeutic role for soluble ACE2 receptors for COVID-19?

COVID-19 has caused calamitous health, economic and societal consequences. Although several COVID-19 vaccines have received full authorization for use, global deployment has faced political, financial and logistical challenges. The efficacy of first-generation COVID-19 vaccines is waning and breakthrough infections are allowing ongoing transmission and evolution of SARS-CoV-2. Furthermore, COVID-19 vaccine efficacy relies on a functional immune system. Despite receiving three primary doses and three or more heterologous boosters, some immunocompromised patients may not be adequately protected by COVID-19 vaccines and remain vulnerable to severe disease. The evolution of new SARS-CoV-2 variants has also resulted in the rapid obsolescence of monoclonal antibodies. Convalescent plasma from COVID-19 survivors has produced inconsistent results. New drugs such as Paxlovid (nirmatrelvir/ritonavir) are beyond the reach of low- and middle-income countries. With widespread use of Paxlovid, it is likely nirmatrelvir-resistant clades of SARS-CoV-2 will emerge in the future. There is thus an urgent need for new effective anti-SARS-CoV-2 treatments. The in vitro efficacy of soluble ACE2 against multiple SARS-CoV-2 variants including omicron (B.1.1.529), was recently described using a competitive ELISA assay as a surrogate marker for virus neutralization. This indicates soluble wild-type ACE2 receptors are likely to be resistant to viral evolution. Nasal and inhaled treatment with soluble ACE2 receptors has abrogated severe disease in animal models of COVID-19. There is an urgent need for clinical trials of this new class of antiviral therapeutics, which could complement vaccines and Paxlovid.

A Multi-Omic Huntington's Disease Transgenic Sheep-Model Database for Investigating Disease Pathogenesis.

BACKGROUND: The pathological mechanism of cellular dysfunction and death in Huntington's disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control 'omic' profiles and reported in literature. OBJECTIVE: Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. METHODS: To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort of 5-year-old OVT73 (n = 6) and control (n = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. RESULTS: We present the 'multi-omic' HD sheep database as a queryable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. CONCLUSION: We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort.

Extensive intraspecies cryptic variation in an ancient embryonic gene regulatory network.

Innovations in metazoan development arise from evolutionary modification of gene regulatory networks (GRNs). We report widespread cryptic variation in the requirement for two key regulatory inputs, SKN-1/Nrf2 and MOM-2/Wnt, into the C. elegans endoderm GRN. While some natural isolates show a nearly absolute requirement for these two regulators, in others, most embryos differentiate endoderm in their absence. GWAS and analysis of recombinant inbred lines reveal multiple genetic regions underlying this broad phenotypic variation. We observe a reciprocal trend, in which genomic variants, or knockdown of endoderm regulatory genes, that result in a high SKN-1 requirement often show low MOM-2/Wnt requirement and vice-versa, suggesting that cryptic variation in the endoderm GRN may be tuned by opposing requirements for these two key regulatory inputs. These findings reveal that while the downstream components in the endoderm GRN are common across metazoan phylogeny, initiating regulatory inputs are remarkably plastic even within a single species.