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Claudins are one of the major components of tight junctions that play a key role in the formation and maintenance of the epithelial barrier function. Tight junction strands are dynamic and capable of adapting their structure in response to large-scale tissue rearrangement and cellular movement. Here, we present molecular dynamics simulations of claudin-15 strands of up to 225 nm in length in two parallel lipid membranes and characterize their mechanical properties. The persistence length of claudin-15 strands is comparable with those obtained from analyses of freeze-fracture electron microscopy. Our results indicate that lateral flexibility of claudin strands is due to an interplay of three sets of interfacial interaction networks between two antiparallel double rows of claudins in the membranes. In this model, claudins are assembled into interlocking tetrameric ion channels along the strand that slide with respect to each other as the strands curve over submicrometer-length scales. These results suggest a novel molecular mechanism underlying claudin-15 strand flexibility. It also sheds light on intermolecular interactions and their role in maintaining epithelial barrier function. 

Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels. 

Background:Postoperative delirium (POD) is a common and serious clinical condition that occurs after anesthesia/surgery. While its clinical impact is well recognized, the underlying electrophysiologic mechanisms remain largely unknown, posing challenges for effective treatment. This study aims to investigate hippocampal neural dynamics before and after anesthesia/surgery in aged mice, which have a tendency to develop POD. Methods:This study included adult and aged mice with a POD model. POD-like behavior was assessed in N = 10 mice at baseline (the day before surgery), as well as at 9 h and 24 h after anesthesia/surgery. A behavioral battery, including the open field test, Y maze, buried food test, and novel object recognition, was used for assessment.In vivochronic brain recordings were performed on awake, restrained mice using a high-density silicon probe during the same time intervals. To further investigate hippocampal neural dynamics,in vivotwo-photon calcium imaging was also conducted. Additionally, aged mice were pretreated with indole-3-propionic acid (IPA), and its effects on POD-like behavior and neural activity were evaluated using electrophysiology and calcium imaging. Results:The first observation was that aged mice exhibited significant POD-like behavior, as measured by Z scores, compared to adult mice after anesthesia/surgery. Analysis revealed significant age-related differences in hippocampal neuronal activities. At 9 h after surgery, aged mice exhibited a marked increase in pyramidal cell activity and a reduction in interneuron activity compared to adult mice. These changes in neuronal dynamics were associated with the onset of POD-like symptoms in aged mice. By 24 h after surgery, both pyramidal cell and interneuron activity in aged mice had returned to presurgery levels, which coincided with an improvement in POD-like behavior. Additionally, IPA pretreatment modulated neuronal activity in aged mice, attenuating pyramidal cell hyperactivity and partially ameliorating interneuron dysfunction, changes associated with mitigated POD-like behavior. Conclusions:Alterations in hippocampal neural activity may significantly contribute to brain dysfunction and POD-like behavior. IPA pretreatment may modulate neural circuit imbalances in aged mice, potentially mitigating POD incidence.