Biology subjects

Swanson, B. J.

Publications and source records attributed to Swanson, B. J..

5 recordsLinked to original sources

bioRxiv2025

An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia

The browning and atrophy of white adipose tissue (WAT) are early events in cachexia, a lethal metabolic disorder affecting nearly half of cancer patients, including those with pancreatic ductal adenocarcinoma (PDA). Using patient-derived specimens and PDA mouse models, we identified perturbations in iron metabolism and proteinaceous methionine oxidation as key initiating events of adipose browning. In particular, the iron influxes that accompany WAT browning induce the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding motifs (E203-xx-H206) of two MSRA polypeptides serves to multimerize, stabilize, and enzymatically activate MSRA. This in turns facilitates adipose browning by maintaining the reduced state of two methionines near the ATP-binding site of Protein Kinase A (PKA). Remarkably, in mouse models of PDA, MsrA deletion impairs WAT browning, significantly mitigates cachexia, and improves the overall survival of tumor-bearing animals. By establishing the iron-MSRA-PKA axis as a key nexus of cancer-associated cachexia, our study offers new perspectives for the treatment of this condition.

cancer biology↗

bioRxiv2025

AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors

Pancreatic ductal adenocarcinoma (PDAC) evolves through non-invasive precursor lesions, yet its earliest molecular events remain unclear. We established the first spatially resolved proteomic atlas of these lesions using Deep Visual Proteomics (DVP). AI-driven computational pathology classified normal ducts, acinar-ductal metaplasia (ADM), and pancreatic intraepithelial neoplasia (PanIN) from cancer-free organ donors (incidental, "iPanINs") and PDAC patients (cancer-associated, "cPanINs"). Laser microdissection of 96 discrete regions containing as few as 100 phenotypically matched cells and ultrasensitive mass spectrometry quantified a total of 8,512 proteins from formalin-fixed tissues. Distinct molecular signatures stratifying cPanINs from iPanINs, and remarkably, many cancer-associated proteins already marked histologically normal epithelium. Four core programs - stress adaptation, immune engagement, metabolic reprogramming, mitochondrial dysfunction - emerged early and intensified during progression. By integrating DVP with AI-guided tissue annotation, we demonstrate that molecular reprogramming precedes histological transformation, creating opportunities for earlier detection and interception of a near-uniformly lethal cancer. SignificanceOur spatially-resolved proteomics atlas uncovers distinct molecular signatures in pancreatic cancer adjacent precursor lesions, clearly diverging from those in incidental, cancer-free pancreatic lesions. Our deep proteomics dataset offers a valuable resource for identifying novel biomarkers and therapeutic targets, informed by the earliest cancer-associated molecular events in archival pancreatic tissues.

cancer biology↗

bioRxiv2024

Complete mitochondrial genomes of Eastern Massasauga (Sistrurus catenatus) and North American Racer (Coluber constrictor)

We report the complete mitochondrial genomes of two snake species of conservation concern, Eastern Massasauga (Sistrurus catenatus) and North American Racer (Coluber constrictor). The mitogenome length is 17,245bp for S. catenatus and 17,142bp for C. constrictor. Both mitogenomes include 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and two control regions. Gene arrangements are similar between two species, except that tRNA-Pro is located between tRNA-Ile and Control Region 2 in S. catenatus, but between tRNA-Thr and Control Region 1 in C. constrictor. Such gene arrangements are typical of their respective families, Viperidae and Colubridae. A phylogenetic tree with 21 additional snake species using concatenated 12 protein-coding genes (without ND6) supported current taxonomy of two reported species. We also found that North American racers in Ohio, Michigan (USA) and Pelee Island (Canada) were more closely allied to Pennsylvania individuals from the Eastern United States.

genomics↗

bioRxiv2024

First endangered black-footed ferrets, Mustela nigripes, cloned for genetic rescue

An endangered black-footed ferret female that died in 1988 with no living descendants in the current population was successfully cloned from cryopreserved cells using cross-species somatic cell nuclear transfer, producing three healthy kits. Incorporating progeny from these clones would provide an 8th founder to the breeding program and increase genetic variation to the species limited gene-pool. This marks the first time a native U.S. endangered species has been cloned.

zoology↗

bioRxiv2020

Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-Derived NRXN1-Mutant Neurons

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation predisposing to schizophrenia. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

neuroscience↗