Todd J.

Obesity is a major risk factor for atrial fibrillation (AF), the most common serious cardiac arrhythmia, but the molecular mechanisms underlying obesity-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation to investigate how obesity promotes AF. Surface electrocardiography revealed that obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, this combination facilitated delayed afterdepolarizations in atrial myocytes, implicating altered Ca2+ dynamics. Interestingly, obesity did not affect the expression of key atrial Ca2+-handling proteins, including the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a). However, obesity increases the proportion of inhibitory phospholamban (PLN) monomers and decreases PLN phosphorylation, suggesting reduced SERCA2a activity. Paradoxically, Ca2+ reuptake in atrial myocytes from obese mice was similar to that achieved by potent small-molecule SERCA2a activators. We found that adrenergic stimulation increased Ca2+ transient amplitude without altering Ca2+ reuptake in myocytes from obese mice. Transcriptomic analysis revealed that a high-fat diet upregulated neuronatin, a protein involved in obesity that enhances SERCA2-mediated Ca2+ reuptake in neurons. We propose that obesity enables SERCA2a activation independently of PLN regulation, while adrenergic stimulation triggers arrhythmogenic Ca2+-induced Ca2+ release, promoting AF. In conclusion, this study demonstrates that obesity causes a paradoxical dysregulation of SERCA2a in atrial myocytes, with increased activity despite higher levels of inhibitory PLN monomers and reduced PLN phosphorylation. These findings offer new insights into the cellular mechanisms of obesity-induced AF and suggest potential therapeutic targets.

Copper can be toxic to aquatic organisms at high concentrations and has been previously used successfully to control zebra mussels (Dreissena polymorpha). Because copper’s toxicity changes with water chemistry, using the same copper concentration in different waterbodies could yield different outcomes. We demonstrate how measuring water chemistry parameters and using the Biotic Ligand Model (BLM) and multiple linear regression (MLR) models can predict a suitable, site-specific copper concentration for management. We exposed zebra mussel adults and non-target organisms to varying concentrations of copper over 10 d in a mobile laboratory. We found that one non-target species, Daphnia magna, had a 50% chance of survival at 9.50 µg Cu/L (i.e., the 50% lethal concentration, LC50), within our BLM-predicted range of 3.38–16.95 µg Cu/L LC50 values. In the future, managers could make similar predictions and tailor their copper concentrations to their management goals. We also measured zebra mussel larvae mortality at copper concentrations ranging from 0 to 191 µg Cu/L. While those results were inconclusive, we present the results of this work as a foundation for future projects. Our study underscores the importance of developing site-specific copper concentration recommendations and demonstrates the potential utility of the BLM and MLR approaches for informing those recommendations.

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Biomedical research techniques that don’t involve the use of animals are gaining momentum, but those using innovative approaches still face resistance from some quarters.

Many regions of the world have seen an increase in highly destructive wildfires, driven by well-documented increases in burned area and growth of h...

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Background/Objectives: The emergence of SARS-CoV-2 variants and breakthrough infections underscores the need for next-generation vaccines capable of protecting from natural infection and/or preventing virus transmission. Intranasal vaccination offers a promising approach by eliciting local immune responses in the nasal mucosa, the primary site of infection and reservoir for transmissible virus. We evaluated two live-attenuated, respiratory syncytial virus-vectored vaccines in which the RSV F and G surface glycoproteins were replaced with a chimeric SARS-CoV-2 Spike protein from the ancestral USA/WA-1/2020 strain (MV-014-212) or the Delta variant (MV-014-212-delta). Methods: K18-hACE2 mice and LVG Syrian hamsters were vaccinated with a single intranasal dose of MV-014-212 or MV-014-212-delta. Systemic and mucosal immunity were assessed following vaccination, and protection was evaluated following Delta SARS-CoV-2 challenge. In vaccinated hamsters, morbidity, viral shedding, and lung inflammation and injury were also assessed following natural exposure to infected cagemates. Results: A single intranasal dose of either vaccine elicited systemic and mucosal immunity in K18-hACE2 mice, including serum neutralizing antibodies, Spike-specific memory B cells and plasmablasts, and Spike-specific CD8+ lung-resident memory T cells. Although MV-014-212-delta vaccination provided the best protection against the Delta variant virus challenge, both vaccines decreased viral loads in nasal discharge, lung, and brain, and reduced weight loss and mortality. In naturally acquired infection studies, vaccinated hamsters exposed to infected cagemates exhibited minimal weight loss, limited viral replication within the nasal mucosa, and attenuated lung pathology. Conclusions: Intranasal RSV-vectored vaccines can elicit broad protective respiratory immunity, suggesting that this platform could be leveraged for other respiratory pathogens.

The wildland-urban interface (WUI) is the area where houses and wildland vegetation meet or intermingle, and where wildfire problems are most prono...

Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the r...