Heterogeneous Sensor-Carrier Microswarms for Collaborative Precise Drug Delivery toward Unknown Targets with Localized Acidosis.

Micro/nanorobots hold the potential to revolutionize biomedicine by executing diverse tasks in hard-to-reach biological environments. Nevertheless, achieving precise drug delivery to unknown disease sites using swarming micro/nanorobots remains a significant challenge. Here we develop a heterogeneous swarm comprising sensing microrobots (sensor-bots) and drug-carrying microrobots (carrier-bots) with collaborative tasking capabilities for precise drug delivery toward unknown sites. Leveraging robust interspecific hydrodynamic interactions, the sensor-bots and carrier-bots spontaneously synchronize and self-organize into stable heterogeneous microswarms. Given that the sensor-bots can create real-time pH maps employing pH-responsive structural-color changes and the doxorubicin-loaded carrier-bots exhibit selective adhesion to acidic targets via pH-responsive charge reversal, the sensor-carrier microswarm, when exploring unknown environments, can detect and localize uncharted acidic targets, guide itself to cover the area, and finally deploy therapeutic carrier-bots precisely there. This versatile platform holds promise for treating diseases with localized acidosis and inspires future theranostic microsystems with expandability, task flexibility, and high efficiency.

Explainable artificial intelligence model for mortality risk prediction in the intensive care unit: a derivation and validation study.

BACKGROUND: The lack of transparency is a prevalent issue among the current machine-learning (ML) algorithms utilized for predicting mortality risk. Herein, we aimed to improve transparency by utilizing the latest ML explicable technology, SHapley Additive exPlanation (SHAP), to develop a predictive model for critically ill patients. METHODS: We extracted data from the Medical Information Mart for Intensive Care IV database, encompassing all intensive care unit admissions. We employed nine different methods to develop the models. The most accurate model, with the highest area under the receiver operating characteristic curve, was selected as the optimal model. Additionally, we used SHAP to explain the workings of the ML model. RESULTS: The study included 21 395 critically ill patients, with a median age of 68 years (interquartile range, 56-79 years), and most patients were male (56.9%). The cohort was randomly split into a training set (N = 16 046) and a validation set (N = 5349). Among the nine models developed, the Random Forest model had the highest accuracy (87.62%) and the best area under the receiver operating characteristic curve value (0.89). The SHAP summary analysis showed that Glasgow Coma Scale, urine output, and blood urea nitrogen were the top three risk factors for outcome prediction. Furthermore, SHAP dependency analysis and SHAP force analysis were used to interpret the Random Forest model at the factor level and individual level, respectively. CONCLUSION: A transparent ML model for predicting outcomes in critically ill patients using SHAP methodology is feasible and effective. SHAP values significantly improve the explainability of ML models.

Folding and Unfolding of a Fully Synthetic Transmembrane Receptor for ON/OFF Signal Transduction.

Signal transduction processes in living organisms are mainly transmitted through conformational changes in transmembrane protein receptors. So far, the development of signal transduction models induced by artificial simulation of conformational changes remains limited. We herein report a new artificial receptor that achieves controllable "ON/OFF" signal transduction through conformational changes between the folding and unfolding of a transmembrane foldamer moiety. The receptor contains three functional modules: a lipid-anchored cholic acid headgroup, a foldamer transmembrane moiety, and a precatalyst tailgroup. After inserting in the lipid membrane, the addition of Zn2+ induces unfolding of the foldamer, which changes the molecular conformation and activates the tailgroup to enter the cavity to perform its catalytic task, resulting in signal transduction in an "ON" state. By further adding a competitive ligand to bind Zn2+, the transduction can be turned "OFF". External signals can be used to reversibly switch intravesicular catalysis on and off, which provides a new model for constructing artificial signal transduction systems.

Amoeba-Inspired Magnetic Venom Microrobots.

Nature provides a successful evolutionary direction for single-celled organisms to solve complex problems and complete survival tasks - pseudopodium. Amoeba, a unicellular protozoan, can produce temporary pseudopods in any direction by controlling the directional flow of protoplasm to perform important life activities such as environmental sensing, motility, predation, and excretion. However, creating robotic systems with pseudopodia to emulate environmental adaptability and tasking capabilities of natural amoeba or amoeboid cells remains challenging. Here, this work presents a strategy that uses alternating magnetic fields to reconfigure magnetic droplet into Amoeba-like microrobot, and the mechanisms of pseudopodia generation and locomotion are analyzed. By simply adjusting the field direction, microrobots switch in monopodia, bipodia, and locomotion modes, performing all pseudopod operations such as active contraction, extension, bending, and amoeboid movement. The pseudopodia endow droplet robots with excellent maneuverability to adapt to environmental variations, including spanning 3D terrains and swimming in bulk liquids. Inspired by the "Venom," the phagocytosis and parasitic behaviors have also been investigated. Parasitic droplets inherit all the capabilities of amoeboid robot, expanding their applicable scenarios such as reagent analysis, microchemical reactions, calculi removal, and drug-mediated thrombolysis. This microrobot may provide fundamental understanding of single-celled livings, and potential applications in biotechnology and biomedicine.

TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury.

Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2flox/flox ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.

Alpha-ketoglutarate ameliorates induced premature ovarian insufficiency in rats by inhibiting apoptosis and upregulating glycolysis.

RESEARCH QUESTION: What are the effects of alpha-ketoglutarate (α-KG) treatment on the ovarian morphology and ovarian reserve function of rats with cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI)? DESIGN: Thirty female Sprague Dawley rats were randomly allocated to a control group (n = 10) and a POI group (n = 20). Cyclophosphamide was administered for 2 weeks to induce POI. The POI group was then divided into two groups: a CTX-POI group (n = 10), administered normal saline, and a CTX-POI + α-KG group (n = 10), administered α-KG 250 mg/kg per day for 21 days. Body mass and fertility was assessed at the end of the study. Serum samples were collected for hormone concentration measurement, and biochemical, histopathological, TUNEL, immunohistochemical and glycolytic pathway analyses were conducted for each group. RESULTS: The α-KG treatment increased body mass and ovarian index of rats, partially normalized their disrupted estrous cycles, prevented follicular loss, restored ovarian reserve, and increased pregnancy rate and litter sizes of rats with POI. It significantly reduced serum concentration of FSH (P < 0.001), increased that of oestradiol (P<0.001) and reduced apoptosis of granulosa cells (P = 0.0003). Moreover, α-KG increased concentrations of lactate (P = 0.015) and ATP (P = 0.025), reduced that of pyruvate (P<0.001) and increased expression of rate-limiting enzymes of glycolysis in the ovary. CONCLUSIONS: α-KG treatment ameliorates the deleterious effects of CTX on the fertility of female rats, possibly by reducing the apoptosis of ovarian granulosa cells and restoring glycolysis.

Tunable Rectification of Diffusion-Wave Fields by Spatiotemporal Metamaterials.

The diffusion process is the basis of many branches of science and engineering, and generally obeys reciprocity between two ports of a linear time-invariant medium. Recent research on classical wave dynamics has explored the spatiotemporal modulation to exhibit preferred directions in photons and plasmons. Here we report a distinct rectification effect on diffusion-wave fields by modulating the conductivity and observe nonreciprocal transport of charges. We experimentally create a spatiotemporal diffusion metamaterial, in which a mode transition to zero frequency is realized. A direct current component thereby emerges, showcasing a biased effect on the charge diffusion when the incident fundamental frequency is a multiple of the system modulation frequency. These results may find applications spanning a plethora of diffusive fields in general.

Highly Efficient Freestyle Magnetic Nanoswimmer.

The unique swimming strategies of natural microorganisms have inspired recent development of magnetic micro/nanorobots powered by artificial helical or flexible flagella. However, as artificial nanoswimmers with unique geometries are being developed, it is critical to explore new potential modes for kinetic optimization. For example, the freestyle stroke is the most efficient of the competitive swimming strokes for humans. Here we report a new type of magnetic nanorobot, a symmetric multilinked two-arm nanoswimmer, capable of efficient "freestyle" swimming at low Reynolds numbers. Excellent agreement between the experimental observations and theoretical predictions indicates that the powerful "freestyle" propulsion of the two-arm nanorobot is attributed to synchronized oscillatory deformations of the nanorobot under the combined action of magnetic field and viscous forces. It is demonstrated for the first time that the nonplanar propulsion gait due to the cooperative "freestyle" stroke of the two magnetic arms can be powered by a plane oscillatory magnetic field. These two-arm nanorobots are capable of a powerful propulsion up to 12 body lengths per second, along with on-demand speed regulation and remote navigation. Furthermore, the nonplanar propulsion gait powered by the consecutive swinging of the achiral magnetic arms is more efficient than that of common chiral nanohelical swimmers. This new swimming mechanism and its attractive performance opens new possibilities in designing remotely actuated nanorobots for biomedical operation at the nanoscale.

Swimming Microrobot Optical Nanoscopy.

Optical imaging plays a fundamental role in science and technology but is limited by the ability of lenses to resolve small features below the fundamental diffraction limit. A variety of nanophotonic devices, such as metamaterial superlenses and hyperlenses, as well as microsphere lenses, have been proposed recently for subdiffraction imaging. The implementation of these micro/nanostructured lenses as practical and efficient imaging approaches requires locomotive capabilities to probe specific sites and scan large areas. However, directed motion of nanoscale objects in liquids must overcome low Reynolds number viscous flow and Brownian fluctuations, which impede stable and controllable scanning. Here we introduce a new imaging method, named swimming microrobot optical nanoscopy, based on untethered chemically powered microrobots as autonomous probes for subdiffraction optical scanning and imaging. The microrobots are made of high-refractive-index microsphere lenses and powered by local catalytic reactions to swim and scan over the sample surface. Autonomous motion and magnetic guidance of microrobots enable large-area, parallel and nondestructive scanning with subdiffraction resolution, as illustrated using soft biological samples such as neuron axons, protein microtubulin, and DNA nanotubes. Incorporating such imaging capacities in emerging nanorobotics technology represents a major step toward ubiquitous nanoscopy and smart nanorobots for spectroscopy and imaging.

Magnetically Propelled Fish-Like Nanoswimmers.

The swimming locomotion of fish involves a complex interplay between a deformable body and induced flow in the surrounding fluid. While innovative robotic devices, inspired by physicomechanical designs evolved in fish, have been created for underwater propulsion of large swimmers, scaling such powerful locomotion into micro-/nanoscale propulsion remains challenging. Here, a magnetically propelled fish-like artificial nanoswimmer is demonstrated that emulates the body and caudal fin propulsion swimming mechanism displayed by fish. To mimic the deformable fish body for periodic shape changes, template-electrosynthesized multisegment nanowire swimmers are used to construct the artificial nanofishes (diameter 200 nm; length 4.8 µm). The resulting nanofish consists a gold segment as the head, two nickel segments as the body, and one gold segment as the caudal fin, with three flexible porous silver hinges linking each segment. Under an oscillating magnetic field, the propulsive nickel elements bend the body and caudal fin periodically to generate travelling-wave motions with speeds exceeding 30 µm s-1 . The propulsion dynamics is studied theoretically using the immersed boundary method. Such body-deformable nanofishes exhibit a high swimming efficiency and can serve as promising biomimetic nanorobotic devices for nanoscale biomedical applications.

One-Pot Synthesis of Fe3O4@PS@P(AEMH-FITC) Magnetic Fluorescent Nanocomposites for Bimodal Imaging.

Magnetic fluorescent nanocomposites have attracted much attention because of their merging magnetic and fluorescent properties for biomedical application. However, the procedure of synthesis of magnetic fluorescent nanocomposites is always complicated. In addition, the properties of fluorescent component could be easily influenced by magnetic component, retaining both of the magnetic and fluorescent properties into one single nanoparticle considered to be a significant challenge. Herein, we report one-pot method to synthesize multifunctional magnetic fluorescent Fe3O4@PS@P(AEMH-FITC) nanocomposites for bimodal imaging. The asprepared Fe3O4@PS@P(AEMH-FITC) nanocomposites with well-define spherical core/shell structure were stable properties. Moreover, the Fe3O4@PS@P(AEMH-FITC) nanocomposites displayed efficient fluorescent and magnetic properties, respectively. Meanwhile, the magnetic resonance imaging (MRI) and HePG2 cancer cell fluorescent images experiment results suggested that Fe3O4@PS@P(AEMH-FITC) nanocomposites could be used as MRI contrast agents and Fluorescence Imaging (FLI) agents for bioimaging application. Our investigation paves a facile avenue for synthesized magnetic fluorescent nanostructures with well biocompatibility for potential bioimaging application in MRI and FLI.

Self-Propelled Nanomotors Autonomously Seek and Repair Cracks.

Biological self-healing involves the autonomous localization of healing agents at the site of damage. Herein, we design and characterize a synthetic repair system where self-propelled nanomotors autonomously seek and localize at microscopic cracks and thus mimic salient features of biological wound healing. We demonstrate that these chemically powered catalytic nanomotors, composed of conductive Au/Pt spherical Janus particles, can autonomously detect and repair microscopic mechanical defects to restore the electrical conductivity of broken electronic pathways. This repair mechanism capitalizes on energetic wells and obstacles formed by surface cracks, which dramatically alter the nanomotor dynamics and trigger their localization at the defects. By developing models for self-propelled Janus nanomotors on a cracked surface, we simulate the systems' dynamics over a range of particle speeds and densities to verify the process by which the nanomotors autonomously localize and accumulate at the cracks. We take advantage of this localization to demonstrate that the nanomotors can form conductive "patches" to repair scratched electrodes and restore the conductive pathway. Such a nanomotor-based repair system represents an important step toward the realization of biomimetic nanosystems that can autonomously sense and respond to environmental changes, a development that potentially can be expanded to a wide range of applications, from self-healing electronics to targeted drug delivery.

Magneto-Acoustic Hybrid Nanomotor.

Efficient and controlled nanoscale propulsion in harsh environments requires careful design and manufacturing of nanomachines, which can harvest and translate the propelling forces with high spatial and time resolution. Here we report a new class of artificial nanomachine, named magneto-acoustic hybrid nanomotor, which displays efficient propulsion in the presence of either magnetic or acoustic fields without adding any chemical fuel. These fuel-free hybrid nanomotors, which comprise a magnetic helical structure and a concave nanorod end, are synthesized using a template-assisted electrochemical deposition process followed by segment-selective chemical etching. Dynamic switching of the propulsion mode with reversal of the movement direction and digital speed regulation are demonstrated on a single nanovehicle. These hybrid nanomotors exhibit a diverse biomimetic collective behavior, including stable aggregation, swarm motion, and swarm vortex, triggered in response to different field inputs. Such adaptive hybrid operation and controlled collective behavior hold considerable promise for designing smart nanovehicles that autonomously reconfigure their operation mode according to their mission or in response to changes in their surrounding environment or in their own performance, thus holding considerable promise for diverse practical biomedical applications of fuel-free nanomachines.

Hydrodynamics and propulsion mechanism of self-propelled catalytic micromotors: model and experiment.

The hydrodynamic behavior and propulsion mechanism of self-propelled micromotors are studied theoretically and experimentally. A hydrodynamic model to describe bubble growth and detachment is proposed to investigate the mechanism of a self-propelled conical tubular catalytic micromotor considering bubble geometric asymmetry and buoyancy force. The growth force caused by the growth of the bubble surface against the fluid is the driving force for micromotor motion. Also, the buoyancy force plays a primary role in bubble detachment. The effect of geometrical parameters on the micromotor velocity and drag force is presented. The bubble radius ratio is investigated for different micromotor radii to determine its hydrodynamic behavior during bubble ejection. The average micromotor velocity is found to be strongly dependent on the semi-cone angle, expelling frequency and bubble radius ratio. The semi-cone angle has a significant effect on the expelling frequency for conical tubular micromotors. The predicted results are compared to already existing experimental data for cylindrical micromotors (semi-cone angle δ = 0°) and conical micromotors. A good agreement is found between the theoretical calculation and experimental results. This model provides a profound explanation for the propulsion mechanism of a catalytic micromotor and can be used to optimize the micromotor design for its biomedical and environmental applications.

RNA modifications in pulmonary diseases.

Threatening public health, pulmonary disease (PD) encompasses diverse lung injuries like chronic obstructive PD, pulmonary fibrosis, asthma, pulmonary infections due to pathogen invasion, and fatal lung cancer. The crucial involvement of RNA epigenetic modifications in PD pathogenesis is underscored by robust evidence. These modifications not only shape cell fates but also finely modulate the expression of genes linked to disease progression, suggesting their utility as biomarkers and targets for therapeutic strategies. The critical RNA modifications implicated in PDs are summarized in this review, including N6-methylation of adenosine, N1-methylation of adenosine, 5-methylcytosine, pseudouridine (5-ribosyl uracil), 7-methylguanosine, and adenosine to inosine editing, along with relevant regulatory mechanisms. By shedding light on the pathology of PDs, these summaries could spur the identification of new biomarkers and therapeutic strategies, ultimately paving the way for early PD diagnosis and treatment innovation.

Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury.

Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.

Magnetic-acoustic actuated spinous microrobot for enhanced degradation of organic pollutants.

A growing interest in the development of efficient strategies for the removal of organic pollutants from polluted water is emerging. As such, artificial micro/nano machines performing excellent water purification tasks have recently attracted more research attention of scientists. Hereby a spinous Fe3O4@PPy microrobot is presented that towards an efficient organic pollutant removal by enhancing Fenton-like reaction. The microrobot is fabricated by wrapping polypyrrole (PPy) on a spiny magnetic template prepared from sunflowers pollen. Modulating the sound pressure and frequency of the ultrasonic field enables the Fe3O4@PPy microrobot to present multimode motion, such as violent eruption-like motion caused by local cavitation (ELM), march-like unific motion (MLM), and typhoon-like rotation toward the center gathered motion (TLM). This multimode motion achieves the sufficient locomotion of microrobots in three-dimensional space and effective contact with organic pollutants in polluted water. Furthermore, a 5.2-fold increase in the degradation rate of methylene blue has been realized using Fe3O4@PPy microrobots under low-concentration hydrogen peroxide conditions. Also, the magnetically controlled recovery of microrobots from water after the completion of the degradation task has been demonstrated. The magnetic-acoustic actuated spinous microrobot can be extrapolated to other catalytic microrobot, developing a new strategy for an easier implementation and recovery of microrobot in real applications of water purification.

Case Report: Can preoperative implantation of veno-arterial extracorporeal membrane oxygenation lead to embolic events in infective endocarditis?

Early-stage infective endocarditis (IE) can lead to severe complications, including infarctions and metastatic infections caused by inflammatory embolus shedding. Common embolism sites include the brain, spleen, kidneys, lungs, and intestines. Additionally, acute heart failure (AHF) can occur in up to 40% of cases, and its presence can impact the clinical outcomes of patients with IE. Cardiogenic shock (CGS) is often more likely to occur after AHF has taken place. If bacteria invade the blood, infectious shock can occur. Patients with IE can experience simple CGS, septic shock, or a combination of the two. Extracorporeal membrane oxygenation (ECMO) typically serves as a Bridge for Heart failure and Cardiogenic shock. Previous research indicates that there are limited reports of ECMO support for patients with IE after CGS has occurred. Because CGS may occur at any time during IE treatment, it is important to understand the timing of ECMO auxiliary support and how to carry out comprehensive treatment after support. Timely treatment can help to reduce or avoid the occurrence of serious complications and improve the prognosis of patients with IE. Our work combines a case study to review the ECMO support of IE patients after CGS through a literature review. Overall, we suggest that when patients with IE have large bacterial thrombosis and a greater risk of shedding, it is recommended to carefully evaluate the indications and contraindications for ECMO after discussion by a multidisciplinary team (MDT). Still, active surgical treatment at an early stage is recommended.

α-Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3-Mediated Pyroptosis of Granulosa Cells.

SCOPE: Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α-ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. METHODS AND RESULTS: POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate-limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase-1, Interleukin-18 (IL-18), and Interleukin-1 beta (IL-1ß). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect. CONCLUSION: AKG ameliorates CTX-induced POI by inhibiting NLRP3-mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients.

The impact of group ownership on memory.

The influence of the self on memory processes has been extensively investigated (the self-reference effect) both explicitly (trait-rating paradigm) and implicitly (ownership paradigm). The groups that are closely related to the self are an important part of self-concept, and group-reference facilitated recall to the same extent as self-referencing using trait-rating paradigm. The current research employed an ownership procedure to investigate the impact of group ownership on memory using the participants' family served as the reference group. In both experiments, participants were asked to sort items into baskets that belonged to their family or a fictitious family. A subsequent recognition test showed that there was a significant memory advantage for objects that owned by their family, and the ownership effect was found in remember, but not know, responses. This finding suggests that transient ingroup-ownership of items had a significant memory dominance effect, and the enhancing effect of ownership leads to recollective experience.