The small molecule Ebio3 inactivates the KCNQ2 channel without blocking the pore
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Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome
A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of “interactome mapping” and illustrate by example the multiple protein–protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.
Personalized bioceramic grafts for craniomaxillofacial bone regeneration
The reconstruction of craniomaxillofacial bone defects remains clinically challenging. To date, autogenous grafts are considered the gold standard but present critical drawbacks. These shortcomings have driven recent research on craniomaxillofacial bone reconstruction to focus on synthetic grafts with distinct materials and fabrication techniques. Among the various fabrication methods, additive manufacturing (AM) has shown significant clinical potential. AM technologies build three-dimensional (3D) objects with personalized geometry customizable from a computer-aided design. These layer-by-layer 3D biomaterial structures can support bone formation by guiding cell migration/proliferation, osteogenesis, and angiogenesis. Additionally, these structures can be engineered to degrade concomitantly with the new bone tissue formation, making them ideal as synthetic grafts. This review delves into the key advances of bioceramic grafts/scaffolds obtained by 3D printing for personalized craniomaxillofacial bone reconstruction. In this regard, clinically relevant topics such as ceramic-based biomaterials, graft/scaffold characteristics (macro/micro-features), material extrusion-based 3D printing, and the step-by-step workflow to engineer personalized bioceramic grafts are discussed. Importantly, in vitro models are highlighted in conjunction with a thorough examination of the signaling pathways reported when investigating these bioceramics and their effect on cellular response/behavior. Lastly, we summarize the clinical potential and translation opportunities of personalized bioceramics for craniomaxillofacial bone regeneration.
Vastly different energy landscapes of the membrane insertions of monomeric gasdermin D and A3
Gasdermin D and gasdermin A3 belong to the same family of pore-forming proteins and executors of pyroptosis, a form of programmed cell death. To unveil the process of their pore formation, we examine the energy landscapes upon insertion of the gasdermin D and A3 monomers into a lipid bilayer by extensive atomistic molecular dynamics simulations. We reveal a lower free energy barrier of membrane insertion for gasdermin D than for gasdermin A3 and a preference of gasdermin D for the membrane-inserted and of gasdermin A3 for the membrane-adsorbed state, suggesting that gasdermin D first inserts and then oligomerizes while gasdermin A3 oligomerizes and then inserts. Gasdermin D stabilizes itself in the membrane by forming more salt bridges and pulling phosphatidylethanolamine lipids and more water into the membrane. Gasdermin-lipid interactions support the pore formation. Our findings suggest that both the gasdermin species and the lipid composition modulate gasdermin pore formation.
Human-structure and human-structure-human interaction in electro-quasistatic regime
Augmented living equipped with electronic devices requires widespread connectivity and a low-loss communication medium for humans to interact with ambient technologies. However, traditional radiative radio frequency-based communications require wireless pairing to ensure specificity during information exchange, and with their broadcasting nature, these incur energy absorption from the surroundings. Recent advancements in electroquasistatic body-coupled communication have shown great promise by utilizing conductive objects like the human body as a communication medium. Here we propose a fundamental set of modalities of non-radiative interaction by guiding electroquasistatic signals through conductive structures between humans and surrounding electronic devices. Our approach offers pairing-free communication specificity and lower path loss during touch. Here, we propose two modalities: Human-Structure Interaction and Human-Structure Human Interaction with wearable devices. We validate our theoretical understanding with numerical electromagnetic simulations and experiments to show the feasibility of the proposed approach. A demonstration of the real-time transfer of an audio signal employing an human body communications-based Human-Structure Interaction link is presented to highlight the practical impact of this work. The proposed techniques can potentially influence Human-Machine Interaction research, including the development of assistive technology for augmented living and personalized healthcare.
TMEM41B is an endoplasmic reticulum Ca2+ release channel maintaining naive T cell quiescence and responsiveness
In mammalian cells, endoplasmic reticulum (ER) passively releases Ca2+ under steady state, but channels involved remain elusive. Here, we report that TMEM41B, an ER-resident membrane protein critical for autophagy, lipid metabolism, and viral infection, functions as an ER Ca2+ release channel. Biochemically, purified recombinant TMEM41B forms a concentration-dependent Ca2+ channel in single-channel electrophysiology assays. Cellularly, TMEM41B deficiency causes ER Ca2+ overload, while overexpression of TMEM41B depletes ER Ca2+. Immunologically, ER Ca2+ overload leads to upregulation of IL-2 and IL-7 receptors in naive T cells, which in turn increases basal signaling of JAK-STAT, AKT-mTOR, and MAPK pathways. This dysregulation drives TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca2+ overload also downregulates CD5, lowering the activation threshold of TMEM41B-deficient T cells and leading to heightened T cell responses during infections. In summary, we identify TMEM41B as a concentration-dependent ER Ca2+ release channel, revealing an unexpected role of ER Ca2+ in naive T cell quiescence and responsiveness.
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