bioRxiv Science⌕ Search

Biology subjects

McGonagle, E. R.

Publications and source records attributed to McGonagle, E. R..

2 recordsLinked to original sources

A standardized, surgically relevant map of organ-spesific branch emergence in the human vagus nerve

IntroductionVagus nerve stimulation modulates airway, cardiac, pulmonary, and gastrointestinal functions through respective organ-specific branches. Knowledge of where along the nerve vagal branches emerge may support alternative surgical placement of stimulation devices to activate targeted functions while avoiding off-target effects. However, no quantified map of the emergence of vagal branches and their relationship to surgically relevant anatomical landmarks exists in humans. MethodsFifty-eight vagus nerves (29 left, 29 right) from 29 embalmed donor bodies (15 females) were dissected from the jugular foramen through the thoracic cavity. Branches were traced to end organs and allocated to one of seven groups (sympathetic, muscular, vascular, cardiac, pulmonary, esophageal, or multiple targets) and several sub-groups. Distances between branch emergence and jugular foramen (JF) were normalized to three anatomical landmarks: carotid bifurcation, laryngeal prominence, and superior border of clavicle. ResultsEmergence of branches follows a proximal-to-distal order (median [IQR] distance from JF): sympathetic (3.9 cm [3.0-6.6]), muscular (6.2 [3.4-17.0]), vascular (9.6 [5.5-15.1]), cardiac (20.1 [16.9-22.5]), pulmonary (25.0 [22.8-27.6]), and esophageal (26.5 [24.3-29.1]). Branches emerge into two embryological domains separated at the clavicle: pharyngeal arch branches cluster proximally (7.3 cm [3.9-14.0]) and primitive mediastinum branches cluster distally (24.2 cm [20.9-27.1]), with sympathetic, muscular, and vascular sub-groups occupying distinct zones within the proximal domain. The longest branch-free intervals are all left-sided, occurring around the laryngeal prominence (3.0 cm [1.8-5.7]), the superior border of the clavicle (2.7 cm [1.3- 5.2]), and the carotid bifurcation (2.2 cm [0.9-5.7]). Several "target" branches are maximally separated from "off-target" branches at specific distances: sympathetic vs. cervical/ muscular/ vascular at 6/8 cm (L/R), cardiac vs. carotid sinus at 14/10 cm, and recurrent laryngeal vs. other muscular at 18/13 cm. Minimal differences are found between male and female donors. ConclusionThis study describes a quantified, landmark-registered map of cervical and thoracic vagal branch emergence and provides an anatomical reference that may help guide more selective device design and placement.

neuroscience↗

The 9p21.3 Coronary Artery Disease Risk Locus Modulates Vascular Cell-State Transitions via Enhancer-Driven Regulation of MTAP

The 9p21.3 locus is the strongest genetic association with coronary artery disease (CAD), yet its causal mechanisms remain unresolved. We map the regulatory architecture of 9p21.3 in disease-relevant vascular cells, identifying 12 enhancers within the CAD risk haplotype that respond dynamically to inflammatory and metabolic stress in fibroblasts and smooth muscle cells. These activated states are enriched for CAD heritability, implicating stress-responsive vascular wall cells in disease pathophysiology. Dense CRISPRi tiling integrated with fine-mapping and genomic constraint across >500,000 individuals nominates MTAP as the effector gene, with rs1537371 as a likely causal variant. Perturbation and multi-modal analyses show that MTAP loss induces pro-fibrotic and angiogenic programs and sensitizes vascular cells to TGF-{beta}-driven pathological transitions. Our findings reveal a vascular-specific enhancer network through which noncoding variation at 9p21.3 modulates CAD risk via MTAP--a previously unrecognized regulator of vascular remodeling located 269 kb from the risk haplotype. HighlightsO_LI9p21.3 CAD risk locus harbors 12 functional enhancers active in vascular wall cell types C_LIO_LICAD heritability is enriched in stressed vascular fibroblasts and smooth muscle cells C_LIO_LIHigh-resolution CRISPRi-MAC-seq maps 9p21.3 enhancer-gene and SNP-gene interactions C_LIO_LIMTAP identified as a causal effector gene regulated by 9p21.3 fine-mapped and constrained variants C_LIO_LIMTAP modulates TGF-{beta}-driven pathological vascular cell transitions C_LI

genomics↗