Biology subjects

Cayton, J.

Publications and source records attributed to Cayton, J..

3 recordsLinked to original sources

bioRxiv2023

Combined Right Ventricular Preload and Afterload Challenge Induces Contractile Dysfunction and Ventricular Arrhythmia in an Age-dependent Manner in Isolated Hearts of Dystrophin-deficient Mice

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy due to mutations in the dystrophin gene. Diaphragmatic weakness in DMD causes restrictive lung disease and excessive afterload on the right ventricle (RV). Thus, RV dysfunction in DMD develops early in disease progression. Herein, we deliver a 30-minute sustained RV preload and afterload challenge to isolated hearts of wildtype (Wt) and dystrophic (mdx4CV) mice at both young (2-6 month) and middle-age (8-12 month). Young dystrophic hearts exhibited greater pressure development than wildtype under unloaded conditions but following RV preload/afterload challenge exhibited similar contractile function as wildtype. Following RV preload/afterload challenge, young dystrophic hearts had an increased incidence of ventricular arrhythmias compared to wildtype. Hearts of middle-aged wildtype and dystrophic mice had similar contractile function during unloaded conditions, yet, after RV preload/afterload challenge, hearts of middle-aged dystrophic mice had severe RV contractile dysfunction and ventricular arrhythmogenesis, including ventricular tachycardia. Following load challenge, young and middle-aged dystrophic hearts had greater damage, measured via tissue LDH release, than wildtype mice of similar age. Our data indicate complex age-dependent changes in RV function and arrhythmogenesis with load in dystrophin deficiency, highlighting the need to avoid sustained RV load to forestall RV dysfunction and arrhythmia.

physiology↗

bioRxiv2023

The genome and transcriptome of the snail Biomphalaria sudanica s.l.: Immune gene diversification and highly polymorphic genomic regions in an important African vector of Schistosoma mansoni

BackgroundControl and elimination of schistosomiasis is an arduous task, with current strategies proving inadequate to break transmission. Exploration of genetic approaches to interrupt Schistosoma mansoni transmission, the causative agent for human intestinal schistosomiasis in sub-Saharan Africa and South America, has led to genomic research of the snail vector hosts of the genus Biomphalaria. Few complete genomic resources exist, with African Biomphalaria species being particularly underrepresented despite this being where the majority of S. mansoni infections occur. Here we generate and annotate the first genome assembly of Biomphalaria sudanica sensu lato, a species responsible for S. mansoni transmission in lake and marsh habitats of the African Rift Valley. Supported by whole-genome diversity data among five inbred lines, we describe orthologs of immune-relevant gene regions in the South American vector B. glabrata and present a bioinformatic pipeline to identify candidate novel pathogen recognition receptors (PRRs). ResultsDe novo genome and transcriptome assembly of inbred B. sudanica originating from the shoreline of Lake Victoria (Kisumu, Kenya) resulted in a haploid genome size of [~]944.2 Mb (6732 fragments, N50=1.067 Mb), comprising 23,598 genes (BUSCO=93.6% complete). The B. sudanica genome contains orthologues to all described immune genes/regions tied to protection against S. mansoni in B. glabrata. The B. sudanica PTC2 candidate immune genomic region contained many PRR-like genes across a much wider genomic region than has been shown in B. glabrata, as well as a large inversion between species. High levels of intra-species nucleotide diversity were seen in PTC2, as well as in regions linked to PTC1 and RADres orthologues. Immune related and putative PRR gene families were significantly over-represented in the sub-set of B. sudanica genes determined as hyperdiverse, including high extracellular diversity in transmembrane genes, which could be under pathogen-mediated balancing selection. However, no overall expansion in immunity related genes were seen in African compared to South American lineages. ConclusionsThe B. sudanica genome and analyses presented here will facilitate future research in vector immune defense mechanisms against pathogens. This genomic/transcriptomic resource provides necessary data for the future development of molecular snail vector control/surveillance tools, facilitating schistosome transmission interruption mechanisms in Africa.

genomics↗

bioRxiv2023

Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

IntroductionAtrial Fibrillation (AF) and atrial flutter (AFL) are the two most common cardiac arrhythmias in the United States. While advanced age has been correlated to AF/AFL, the lack of an appropriate animal model has hindered progress on better understanding the pathophysiology of atrial arrhythmogenesis. Both hypokalemic conditions and hemodynamic stretch have been associated with atrial tachyarrhythmias in patient populations. The purpose of this study was to examine the incidence of atrial tachyarrhythmias in an ex vivo aging C57BL/6 mouse model following hypokalemia and stretch challenges. MethodsHearts were isolated with combined cannulation of the aorta and superior vena cava in a modified right-sided working heart perfusion technique. Isolated hearts of Aged (26-29 month) male (n=14) and female (n=14) mice were subjected to normokalemic and hypokalemic conditions {+/-} atrial preload elevation to 12 cmH20 to induce atrial stretch. Heart rate, right ventricular (RV) pressure development, and incidence of atrial tachyarrhythmias were monitored using a pressure catheter and intracardiac electrocardiogram. ResultsIn response to hypokalemia, there were no changes in mean heart rate, RV pressure development, or RV Rate-Pressure Product (Rate x RV peak pressure). Atrial tachyarrhythmias were not observed under baseline conditions, and only 1 of 8 hearts exhibited atrial tachycardia following the hypokalemia challenge. In response to atrial preload elevation, there was an increase in heart rate (P=0.0006 versus baseline) with no change in RV pressure development. RV Rate-Pressure Product was significantly elevated (P=0.013 versus baseline) with atrial preload due to the increase in heart rate. Atrial tachyarrhythmias were not observed under both baseline conditions and following atrial preload elevation. In response to the combined hypokalemia and preload challenges, there was an increase in heart rate (P=0.008 versus baseline) with no change in RV pressure development or RV Rate Pressure product. Atrial tachyarrhythmias were not observed under baseline conditions, yet after the combined challenges 50% of aged hearts exhibited atrial tachycardia or AF/AFL. During bouts of AF/AFL, the AF/AFL led to a variable ventricular response and concomitant contractile dysfunction in the form of variable RV pressure development. ConclusionEx vivo aged mouse hearts exhibit atrial tachyarrhythmias in response to combined hypokalemia and right atrial stretch conditions. The aged C57BL/6 mouse model is therefore useful for pre-clinical studies of atrial arrhythmogenesis.

biophysics↗