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Anandakrishnan, A.

Publications and source records attributed to Anandakrishnan, A..

2 recordsLinked to original sources

A parsimonious murburn model for microbial motility connects metabolic water ejection to observable mechanical outcomes

The classical model of bacterial flagellar motility posits a rotary engine driven by proton motive force (pmf), with torque generated by stator-rotor interactions and transmitted through a flexible hook to a helical filament. Despite decades of acceptance, this model faces fundamental challenges in thermodynamics, structural mechanics, evolutionary parsimony, and direct observational evidence. We develop and quantitatively test the murburn model, a new paradigm for bacterial motility in which water, produced as an inevitable byproduct of metabolic redox activity, is ejected via the basal secretory module and channelled along the spiral grooves of the flagellar filament. The ejected flow creates a local shear field that induces a transverse bending wave; the precession of this wave is observed as apparent rotation and generates thrust through anisotropic viscous drag, without any rotary motor, ion gradient, or axial rotation. The principal contribution of this work is a self-contained, first-principles treatment of this mechanism: for a unipolar flagellated cell we derive the governing low-Reynolds-number elastohydrodynamic relations from slender-body theory and show that physiologically realistic rates of metabolic water production reproduce the observed swimming speeds and apparent-rotation frequencies at a small fraction of the cellular energy budget, while direct jet propulsion is quantitatively excluded. Building on this derivation, we provide a force-balance comparison of the competing propulsion mechanisms, obtain a set of falsifiable predictions that distinguish the murburn model from the rotary motor, and report a structural analysis of cryo-EM flagellar-hook architectures that reveals solvent-accessible radial canals consistent with lateral water transport. The same single principle accounts for swimming, tumbling, gliding, spirochete undulation, and archaeal motility, without requiring rotating shafts, ion-gradient coupling, or complex switching mechanisms.

biophysics↗

Prostaglandin E2 Reverses Myofibroblast Differentiation in Eosinophilic Esophagitis

Background & AimsUnchecked inflammation in Eosinophilic esophagitis (EoE) leads to esophageal fibrosis and eventual stricture. Differentiated fibroblasts, termed myofibroblasts, are the main effector cells in fibrosis, responsible for secreting extracellular matrix proteins leading to tissue stiffness. Regulating myofibroblasts has not been explored as a therapeutic possibility in the fibrostenotic esophagus. Herein, we aim to investigate the efficacy of Prostaglandin E2 (PGE2) in dedifferentiation of the EoE myofibroblast. MethodsWe evaluated the efficacy and mechanism of myofibroblast dedifferentiation using fetal esophageal fibroblasts (FEF3), patient-derived fibroblasts, and a murine model of EoE. ResultsFibrosis markers (SMA, FN1, and COL1A1) and contractility of myofibroblasts were significantly decreased by PGE2 via the cAMP pathway. PGE2 treatment decreased nuclear accumulation of phospho-Smad2/3-YAP complex and induced phospho-YAP proteasomal degradation. Transcriptome analyses of FEF3 treated with TGF{beta} or PGE2 revealed that the Integrin1 pathway, and specifically thrombospondin 1 (THBS-1), was significantly upregulated by TGF{beta} and downregulated by PGE2, as supported by pseudo-bulk single-cell RNA-seq of EoE biopsies. THBS-1 was shown to be regulated by PGE2 via the cAMP/YAP pathway, and its knockdown induced myofibroblasts dedifferentiation. In a murine model of EoE, Butaprost, agonist of the E-prostanoid G protein-coupled receptor 2, treatment significantly reduced the expression of THBS-1, SMA, and FN1 along with a decrease in YAP nuclear translocation. Additionally, collagen fiber organization in the lamina propria was markedly reduced. ConclusionPGE2 promotes dedifferentiation of myofibroblasts in EoE via the cAMP/YAP/ THBS-1 pathway. Our data suggest that PGE2 is a promising treatment strategy for EoE with stenosis. What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSIn Eosinophilic esophagitis, unchecked inflammation and tissue stiffness drives fibroblast differentiation and fibrostenosis of the esophagus, yet targeting myofibroblasts as regulators of extracellular matrix deposition in fibrostenotic disease remains clinically unexplored. New FindingsProstaglandin E2 promotes dedifferentiation of myofibroblasts in eosinophilic esophagitis via the cAMP/YAP pathway, with Thrombospondin-1 identified as a critical YAP regulated target driving fibrostenosis. LimitationsThis study focused on fibroblast-specific mechanisms. The effects of PGE2 on esophageal epithelial differentiation, barrier function, and immune cell recruitment in EoE remain to be determined. Clinical Research RelevanceThis study demonstrates proof-of-concept that pharmacological reversal of established fibrosis is achievable in EoE. PGE2 and its EP2-selective agonists represent translatable therapeutic targets for fibrostenotic EoE--a patient population that remains treatment-refractory to current immunosuppressive approaches. Basic Research RelevanceThe cAMP/YAP/THBS-1 signaling in fibroblasts emerges as a critical therapeutic target for esophageal fibrosis. Importantly, this work demonstrates that terminally differentiated myofibroblasts retain remarkable plasticity and can dedifferentiate--challenging the paradigm that fibrosis is irreversible.

cell biology↗