Flow-Induced Shear Stress Primes NLRP3 Inflammasome Activation in Macrophages via Piezo1

The NLRP3 inflammasome is a crucial component of the innate immune system, playing a pivotal role in initiating and regulating the body’s inflammatory response to various pathogens and cellular damage. Environmental stimuli, such as temperature, pH level, and nutrient availability, can influence the behavior and functions of innate immune cells, including immune cell activity, proliferation, and cytokine production. However, there is limited understanding regarding how mechanical forces, like shear stress, govern the intrinsic inflammatory reaction, particularly the activation of the NLRP3 inflammasome, and how shear stress impacts NLRP3 inflammasome activation through its capacity to induce alterations in gene expression and cytokine secretion. Here, we investigated how shear stress can act as a priming signal in NLRP3 inflammasome activation by exposing immortalized bone marrow-derived macrophages (iBMDMs) to numerous physiologically relevant magnitudes of shear stress before chemically inducing inflammasome activation. We demonstrated that shear stress of large magnitudes was able to prime iBMDMs more effectively for inflammasome activation compared to lower shear stress magnitudes, as quantified by the percentage of cells where ASC-CFP specks formed and IL-1β secretion, the hallmarks of inflammasome activation. Testing this in NLRP3 and caspase-1 knockout iBMDMs showed that the NLRP3 inflammasome was primarily primed for activation due to shear stress exposure. Quantitative polymerase chain reaction (qPCR) and a small-molecule inhibitor study mechanistically determined that shear stress regulates the NLRP3 inflammasome by upregulating Piezo1, IKKβ, and NLRP3. These findings offer insights into the mechanistic relationship among physiological shear stresses, inflammasome activation, and their impact on the progression of inflammatory diseases and their interconnected pathogenesis

Effect of Electron Transporting Layer on Bismuth-Based Lead-Free Perovskite (CH₃NH₃)₃ Bi₂I₉ for Photovoltaic Applications

Methylammonium iodo bismuthate ((CH₃NH₃)₃Bi₂I₉) (MBI) perovskite is a promising alternative to rapidly progressing hybrid organic–inorganic lead perovskites because of its better stability and low toxicity compared to lead-based perovskites. Solution-processed perovskite fabricated by single-step spin-coating and subsequent heating produced polycrystalline films of hybrid perovskite (CH₃NH₃)₃Bi₂I₉), whose morphology was influenced drastically by the nature of substrates. The optical measurements showed a strong absorption band around 500 nm. The devices made on anatase TiO₂ mesoporous layer showed good performance with current density over 0.8 mA cm^–2 while the devices on brookite TiO₂ layer and planar (free of porous layer) was inefficient. However, all the MBI devices were stable to ambient conditions for more than 10 weeks

Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy

A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers <i>in vivo</i>, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer

Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy

A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers <i>in vivo</i>, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer

Vapor Annealing Controlled Crystal Growth and Photovoltaic Performance of Bismuth Triiodide Embedded in Mesostructured Configurations

Low stability of organic–inorganic lead halide perovskite and toxicity of lead (Pb) still remain a concern. Therefore, there is a constant quest for alternative nontoxic and stable light-absorbing materials with promising optoelectronic properties. Herein, we report about nontoxic bismuth triiodide (BiI₃) photovoltaic device prepared using TiO₂ mesoporous film and spiro-OMeTAD as electron- and hole-transporting materials, respectively. Effect of annealing methods (e.g., thermal annealing (TA), solvent vapor annealing (SVA), and Petri dish covered recycled vapor annealing (PR-VA)) and different annealing temperatures (90, 120, 150, and 180 °C for PR-VA) on BiI₃ film morphology have been investigated. As found in the study, grain size increased and film uniformity improved as temperature was raised from 90 to 150 °C. The photovoltaic devices based on BiI₃ films processed at 150 °C with PR-VA treatment showed power conversion efficiency (PCE) of 0.5% with high reproducibility, which is, so far, the best PCE reported for BiI₃ photovoltaic device employing organic hole-transporting material (HTM), owing to the increase in grain size and uniform morphology of BiI₃ film. These devices showed stable performance even after 30 days of exposure to 50% relative humidity, and after 100 °C heat stress and 20 min light soaking test. More importantly, the study reveals many challenges and room (discussed in the details) for further development of the BiI₃ photovoltaic devices

Carbohydrate-Based Label-Free Detection of <i>Escherichia coli</i> ORN 178 Using Electrochemical Impedance Spectroscopy

A label-free biosensor for <i>Escherichia coli</i> (<i>E. coli</i>) ORN 178 based on faradaic electrochemical impedance spectroscopy (EIS) was developed. α-Mannoside or β-galactoside was immobilized on a gold disk electrode using a self-assembled monolayer (SAM) via a spacer terminated in a thiol functionality. Impedance measurements (Nyquist plot) showed shifts due to the binding of <i>E. coli</i> ORN 178, which is specific for α-mannoside. No significant change in impedance was observed for <i>E. coli</i> ORN 208, which does not bind to α-mannoside. With increasing concentrations of <i>E. coli</i> ORN 178, electron-transfer resistance (<i>R</i>_et) increases before the sensor is saturated. After the Nyquist plot of <i>E. coli</i>/mixed SAM/gold electrode was modeled, a linear relationship between normalized <i>R</i>_et and the logarithmic value of <i>E. coli</i> concentrations was found in a range of bacterial concentration from 10² to 10³ CFU/mL. The combination of robust carbohydrate ligands with EIS provides a label-free, sensitive, specific, user-friendly, robust, and portable biosensing system that could potentially be used in a point-of-care or continuous environmental monitoring setting

Rationally Designed 2‑in‑1 Nanoparticles Can Overcome Adaptive Resistance in Cancer

The development of resistance is the major cause of mortality in cancer. Combination chemotherapy is used clinically to reduce the probability of evolution of resistance. A similar trend toward the use of combinations of drugs is also emerging in the application of cancer nanomedicine. However, should a combination of two drugs be delivered from a single nanoparticle or should they be delivered in two different nanoparticles for maximal efficacy? We explored these questions in the context of adaptive resistance, which emerges as a phenotypic response of cancer cells to chemotherapy. We studied the phenotypic dynamics of breast cancer cells under cytotoxic chemotherapeutic stress and analyzed the data using a phenomenological mathematical model. We demonstrate that cancer cells can develop adaptive resistance by entering into a predetermined transitional trajectory that leads to phenocopies of inherently chemoresistant cancer cells. Disrupting this deterministic program requires a unique combination of inhibitors and cytotoxic agents. Using two such combinations, we demonstrate that a 2-in-1 nanomedicine can induce greater antitumor efficacy by ensuring that the origins of adaptive resistance are terminated by deterministic spatially constrained delivery of both drugs to the target cells. In contrast, a combination of free-form drugs or two nanoparticles, each carrying a single payload, is less effective, arising from a stochastic distribution to cells. These findings suggest that 2-in-1 nanomedicines could emerge as an important strategy for targeting adaptive resistance, resulting in increased antitumor efficacy

Algorithm for Designing Nanoscale Supramolecular Therapeutics with Increased Anticancer Efficacy

In the chemical world, evolution is mirrored in the origin of nanoscale supramolecular structures from molecular subunits. The complexity of function acquired in a supramolecular system over a molecular subunit can be harnessed in the treatment of cancer. However, the design of supramolecular nanostructures is hindered by a limited atomistic level understanding of interactions between building blocks. Here, we report the development of a computational algorithm, which we term Volvox after the first multicellular organism, that sequentially integrates quantum mechanical energy-state- and force-field-based models with large-scale all-atomistic explicit water molecular dynamics simulations to design stable nanoscale lipidic supramolecular structures. In one example, we demonstrate that Volvox enables the design of a nanoscale taxane supramolecular therapeutic. In another example, we demonstrate that Volvox can be extended to optimizing the ratio of excipients to form a stable nanoscale supramolecular therapeutic. The nanoscale taxane supramolecular therapeutic exerts greater antitumor efficacy than a clinically used taxane <i>in vivo</i>. Volvox can emerge as a powerful tool in the design of nanoscale supramolecular therapeutics for effective treatment of cancer

Algorithm for Designing Nanoscale Supramolecular Therapeutics with Increased Anticancer Efficacy

In the chemical world, evolution is mirrored in the origin of nanoscale supramolecular structures from molecular subunits. The complexity of function acquired in a supramolecular system over a molecular subunit can be harnessed in the treatment of cancer. However, the design of supramolecular nanostructures is hindered by a limited atomistic level understanding of interactions between building blocks. Here, we report the development of a computational algorithm, which we term Volvox after the first multicellular organism, that sequentially integrates quantum mechanical energy-state- and force-field-based models with large-scale all-atomistic explicit water molecular dynamics simulations to design stable nanoscale lipidic supramolecular structures. In one example, we demonstrate that Volvox enables the design of a nanoscale taxane supramolecular therapeutic. In another example, we demonstrate that Volvox can be extended to optimizing the ratio of excipients to form a stable nanoscale supramolecular therapeutic. The nanoscale taxane supramolecular therapeutic exerts greater antitumor efficacy than a clinically used taxane <i>in vivo</i>. Volvox can emerge as a powerful tool in the design of nanoscale supramolecular therapeutics for effective treatment of cancer