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Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Interest in sustainable learning has been growing over the past 20 years but it has never been determined whether students--whose learning we are trying to sustain--can perceive either the sustainability of their learning or any of the features of this construct. A four-item survey was developed based on a published definition of "sustainable learning", and was sent to the 12 graduate students who have completed a new seminar in ethical reasoning. A thematic analysis of the narrative responses was submitted to a degrees-of-freedom analysis to determine the level and type of evidence for student perception of sustainability. Respondents (n = 9) endorsed each of the four dimensions of sustainable learning--and each gave examples for each dimension outside of, and after the end of, the course. One respondent endorsed all dimensions of sustainable learning, but was uncertain whether the course itself led to one particular sustainability dimension. While these results must be considered preliminary because our sample is small and the survey is the first of its kind, they suggest that graduate students can and do perceive each of the four features of sustainability. The survey needs refinement for future/wider use; but this four-dimensional definition could be useful to develop and promote (and assess) sustainable learning in higher education.

Spawning Pacific salmon (Oncorhynchus spp.) provide marine‐derived resources (MDR) to freshwater food webs in the form of eggs, flesh and maggots that consume salmon carcasses, all of which positively impact stream‐dwelling fish growth. Pink salmon (O. gorbuscha) are widely distributed throughout coastal catchments along the North Pacific Ocean and display increased spawning abundances in odd years, owing to a fixed 2‐year life history. While many studies have found that foraging and growth of stream‐dwelling salmonids are improved by increased adult salmon spawning abundance, few studies have investigated the importance of alternating pink salmon spawning abundance between years.Here, we examined how patterns of pink salmon spawning abundance impact the foraging and growth of juvenile coho salmon (O. kisutch). First, we used bioenergetic simulations to generate a hypothesis that coho salmon growth would increase during odd relative to even years. We then collected empirical juvenile coho salmon diet and growth data from a Southeast Alaska catchment in 2021 (pink salmon spawning) and 2022 (no pink salmon spawning). Field data were compared against simulation predictions to understand impacts of biennial pink salmon spawning patterns on juvenile coho salmon growth.Empirical growth data revealed similar patterns to bioenergetic simulations. Age‐1 coho salmon grew 16.6 mm longer and 5.5 g heavier on average in 2021 compared to 2022. Age‐0 coho salmon displayed minor growth differences between years.These results support bioenergetic model predictions and suggest that patterns of pink salmon spawning abundance can impart interannual growth disparities to juvenile coho salmon. Moreover, we show that distinct spawning characteristics of Pacific salmon species are important when understanding patterns of MDR transfer and growth responses in stream fishes. [ABSTRACT FROM AUTHOR]

We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer's disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n = 28) and a matched set of cognitively normal subjects (n = 73), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0-1.0, and 0.981-1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD.

Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA-GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA-GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA-GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.