Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sub-lineages in the face of maturing antibody breadth at the population level.

BACKGROUND: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies. METHODS: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab. FINDINGS: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022. INTERPRETATION: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants. FUNDING: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M.

Soft Palate Modification Using a Collagen Crosslinking Reagent for Equine Dorsal Displacement of the Soft Palate and Other Upper Airway Breathing Disorders.

The mechanical properties of the soft palate can be associated with breathing abnormalities. Dorsal displacement of the soft palate (DDSP) is a naturally occurring equine soft palate disorder caused by displacement of the caudal edge of the soft palate. Snoring and a more serious, sometimes life-threatening, condition called obstructive sleep apnea (OSA) are forms of sleep-related breathing disorders in humans which may involve the soft palate. The goal of this study was to investigate the effect of injecting the protein crosslinker genipin into the soft palate to modify its mechanical properties for the treatment of equine DDSP with potential implications for the treatment of snoring and OSA in humans. Ex vivo experiments consisted of mechanical testing and a wind tunnel study to examine the effect of genipin on the mechanical properties, displacement, and vibration of equine soft palates. A pilot in vivo study was completed using DDSP and control horses to test the safety and effectiveness of injecting a genipin reagent into the soft palate. The wind tunnel testing demonstrated a greater than 50% decrease in transient deformation and a greater than 33% decrease in steady-state vibrations for all doses of genipin tested. Ultimate tensile stress, yield stress, and Young's modulus were higher in the genipin-treated distal soft palate specimens by 52%, 53%, and 63%, respectively. The pilot in vivo study showed a reduction of snoring loudness in all DDSP horses and elimination of DDSP in at least one of three horses. The difficulty of using a 1-meter-long endoscopic injection needle contributed to a consistent overinjection of the equine soft palates, causing excessive stretching (pillowing) and related degradation of the tissue. These ex vivo and in vivo results demonstrated reduced vibration amplitude and flaccidity and increased strength of genipin-treated soft palates, suggesting that genipin crosslinking could become an effective and safe treatment for soft palate related breathing abnormalities.

Soy-deficient diet induces renal lesions in juvenile rats.

Certified LabDiet® 5K96 Advanced Protocol™ Verified Casein Diet 10 IF (5K96) is a commercial diet low in soy isoflavones developed for use in developmental and reproductive toxicity (DART) studies, especially those designed to detect endocrine disruptors. The objective of this study was to determine the incidences and severities of 5K96-associated renal lesions in control F0 and F1 cohorts of rats fed the 5K96 diet. Kidneys from control animals of four DART studies involving Sprague-Dawley rats fed the 5K96 diet, were evaluated microscopically. Mineralization and basophilic tubules were present in high incidence/severity in males and females compared to historical controls fed conventional diets. F1 cohorts were affected to a far greater degree than F0 cohorts, and females were affected more than males. Consideration of target tissue and mode of action should be given before automatically incorporating the 5K96 diet into DART study designs, and caution should be exercised when identifying and interpreting renal toxicity in the F1 cohorts of such studies.

The foliar endophytic fungal community composition in Cirsium arvense is affected by mycorrhizal colonization and soil nutrient content.

Foliar fungal endophytes are ubiquitous, but understudied symbionts of most plant species; relatively little is known about the factors affecting their occurrence, diversity and abundance. We tested the effects of soil nutrient content and arbuscular mycorrhizal (AM) colonization on the occurrence of foliar endophytic fungi in Cirsium arvense in two field studies. In the first study, we assessed relationships between soil moisture, organic matter, carbon and nitrogen content and plant water, nitrogen and carbon content and AM colonization and the occurrence of foliar endophytic fungal species. In the second study, we manipulated soil nutrient content and AM colonization of potted seedlings and identified differences in endophytic fungal species composition of the leaves and stems. The results reveal that endophytes can occur either more or less frequently, depending on soil nutrient and plant water content and AM colonization. We propose that these patterns were the result of differences in fungal growth responses to nutrient availability in the leaves, which can be affected by resources obtained from the soil or symbiotic fungi in the roots.