Designing Covalent Organic Framework-Based Light-Driven Microswimmers toward Therapeutic Applications.

While micromachines with tailored functionalities enable therapeutic applications in biological environments, their controlled motion and targeted drug delivery in biological media require sophisticated designs for practical applications. Covalent organic frameworks (COFs), a new generation of crystalline and nanoporous polymers, offer new perspectives for light-driven microswimmers in heterogeneous biological environments including intraocular fluids, thus setting the stage for biomedical applications such as retinal drug delivery. Two different types of COFs, uniformly spherical TABP-PDA-COF sub-micrometer particles and texturally nanoporous, micrometer-sized TpAzo-COF particles are described and compared as light-driven microrobots. They can be used as highly efficient visible-light-driven drug carriers in aqueous ionic and cellular media. Their absorption ranging down to red light enables phototaxis even in deeper and viscous biological media, while the organic nature of COFs ensures their biocompatibility. Their inherently porous structures with ≈2.6  and ≈3.4 nm pores, and large surface areas allow for targeted and efficient drug loading even for insoluble drugs, which can be released on demand. Additionally, indocyanine green (ICG) dye loading in the pores enables photoacoustic imaging, optical coherence tomography, and hyperthermia in operando conditions. This real-time visualization of the drug-loaded COF microswimmers enables unique insights into the action of photoactive porous drug carriers for therapeutic applications.

Light-driven carbon nitride microswimmers with propulsion in biological and ionic media and responsive on-demand drug delivery.

We propose two-dimensional poly(heptazine imide) (PHI) carbon nitride microparticles as light-driven microswimmers in various ionic and biological media. Their high-speed (15 to 23 micrometer per second; 9.5 ± 5.4 body lengths per second) swimming in multicomponent ionic solutions with concentrations up to 5 M and without dedicated fuels is demonstrated, overcoming one of the bottlenecks of previous light-driven microswimmers. Such high ion tolerance is attributed to a favorable interplay between the particle's textural and structural nanoporosity and optoionic properties, facilitating ionic interactions in solutions with high salinity. Biocompatibility of these microswimmers is validated by cell viability tests with three different cell lines and primary cells. The nanopores of the swimmers are loaded with a model cancer drug, doxorubicin (DOX), resulting in a high (185%) loading efficiency without passive release. Controlled drug release is reported under different pH conditions and can be triggered on-demand by illumination. Light-triggered, boosted release of DOX and its active degradation products are demonstrated under oxygen-poor conditions using the intrinsic, environmentally sensitive and light-induced charge storage properties of PHI, which could enable future theranostic applications in oxygen-deprived tumor regions. These organic PHI microswimmers simultaneously address the current light-driven microswimmer challenges of high ion tolerance, fuel-free high-speed propulsion in biological media, biocompatibility, and controlled on-demand cargo release toward their biomedical, environmental, and other potential applications.

3D Microprinting of Iron Platinum Nanoparticle-Based Magnetic Mobile Microrobots.

Wireless magnetic microrobots are envisioned to revolutionize minimally invasive medicine. While many promising medical magnetic microrobots are proposed, the ones using hard magnetic materials are not mostly biocompatible, and the ones using biocompatible soft magnetic nanoparticles are magnetically very weak and, therefore, difficult to actuate. Thus, biocompatible hard magnetic micro/nanomaterials are essential toward easy-to-actuate and clinically viable 3D medical microrobots. To fill such crucial gap, this study proposes ferromagnetic and biocompatible iron platinum (FePt) nanoparticle-based 3D microprinting of microrobots using the two-photon polymerization technique. A modified one-pot synthesis method is presented for producing FePt nanoparticles in large volumes and 3D printing of helical microswimmers made from biocompatible trimethy- lolpropane ethoxylate triacrylate (PETA) polymer with embedded FePt nanoparticles. The 30 µm long helical magnetic microswimmers are able to swim at speeds of over five body lengths per second at 200 Hz, making them the fastest helical swimmer in the tens of micrometer length scale at the corresponding low- magnitude actuation fields of 5-10 mT. It is also experimentally in vitro verified that the synthesized FePt nanoparticles are biocompatible. Thus, such 3D-printed microrobots are biocompatible and easy to actuate toward creating clinically viable future medical microrobots.

Falling off a limit cycle using phase-agnostic stimuli: Definitions and conceptual framework.

Nearly a half-century of biomedical research has revealed methods and mechanisms by which an oscillator with bistable limit cycle kinetics can be stopped using critical stimuli applied at a specific phase. Is it possible to construct a stimulus that stops oscillation regardless of the phase at which the stimulus is applied? Using a radial isochron clock model, we demonstrate the existence of such stimulus waveforms, which can take on highly complex shapes but with a surprisingly simple mechanism of rhythm suppression. The perturbation, initiated at any phase of the limit cycle, first corrals the oscillator to a narrow range of new phases, then drives the oscillator to its phase singularity. We further constructed a library of waveforms having different durations, each achieving phase-agnostic suppression of rhythm but with varying rates of phase corralling prior to amplitude suppression. The optimal stimulus energy to achieve phase-agnostic suppression of rhythm is dependent on the rate of phase corralling and the configuration of the phaseless set. We speculate that these results are generic and suggest the existence of stimulus waveforms that can stop the rhythm of more complex oscillators irrespective of the applied phase.

Carbon nitride-based light-driven microswimmers with intrinsic photocharging ability.

Controlling autonomous propulsion of microswimmers is essential for targeted drug delivery and applications of micro/nanomachines in environmental remediation and beyond. Herein, we report two-dimensional (2D) carbon nitride-based Janus particles as highly efficient, light-driven microswimmers in aqueous media. Due to the superior photocatalytic properties of poly(heptazine imide) (PHI), the microswimmers are activated by both visible and ultraviolet (UV) light in conjunction with different capping materials (Au, Pt, and SiO2) and fuels (H2O2 and alcohols). Assisted by photoelectrochemical analysis of the PHI surface photoreactions, we elucidate the dominantly diffusiophoretic propulsion mechanism and establish the oxygen reduction reaction (ORR) as the major surface reaction in ambient conditions on metal-capped PHI and even with TiO2-based systems, rather than the hydrogen evolution reaction (HER), which is generally invoked as the source of propulsion under ambient conditions with alcohols as fuels. Making use of the intrinsic solar energy storage ability of PHI, we establish the concept of photocapacitive Janus microswimmers that can be charged by solar energy, thus enabling persistent light-induced propulsion even in the absence of illumination-a process we call "solar battery swimming"-lasting half an hour and possibly beyond. We anticipate that this propulsion scheme significantly extends the capabilities in targeted cargo/drug delivery, environmental remediation, and other potential applications of micro/nanomachines, where the use of versatile earth-abundant materials is a key prerequisite.

Multiwavelength-Steerable Visible-Light-Driven Magnetic CoO-TiO2 Microswimmers.

While current light-driven microswimmers require high-intensity light, UV light, or toxic fuels to propel them, powering them with low-intensity UV-free visible light without fuels is essential to enable their potential high-impact applications. Therefore, in this study, a new material for light-driven microswimmers in the form of CoO is introduced. Janus CoO-TiO2 microswimmers powered with low-intensity, UV-free visible light inside water without using any toxic fuels like H2O2 is proposed. The microswimmers show propulsion under full spectrum of visible light with 17 times lower intensity than the mean solar intensity. They propel by breaking down water into oxygen and oxide radicals, which enables their potential applications for photocatalysis and drug delivery. The microswimmers are multiwavelength responsive, from the ultraviolet to the infrared region. The direction of swimming changes with the change in the illumination from the visible to UV light. In addition to being responsive, they are wavelength steerable and exhibit inherent magnetic properties enabling magnetic steering control of the CoO-TiO2 microswimmers. Thus, these microswimmers, which are propelled under low-intensity visible light, have direction-changing capability using light of different wavelengths, and have steering control capability by external magnetic fields, could be used in future potential applications, such as active and local cargo delivery, active photocatalysis, and hydrogen evolution.

Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors.

Human tumors exhibit plasticity and evolving capacity over time. It is difficult to study the mechanisms of how tumors change over time in human patients, in particular during the early stages when a few oncogenic cells are barely detectable. Here, we used a Drosophila tumor model caused by loss of scribble (scrib), a highly conserved apicobasal cell polarity gene, to investigate the spatial-temporal dynamics of early tumorigenesis events. The fly scrib mutant tumors have been successfully used to model many aspects of tumorigenesis processes. However, it is still unknown whether Drosophila scrib mutant tumors exhibit plasticity and evolvability along the temporal axis. We found that scrib mutant tumors displayed different growth rates and cell cycle profiles over time, indicative of a growth arrest-to-proliferation transition as the scrib mutant tumors progress. Longitudinal bulk and single-cell transcriptomic analysis of scrib mutant tumors revealed that the MAPK pathway, including JNK and ERK signaling activities, showed quantitative changes over time. We found that high JNK signaling activity caused G2/M cell cycle arrest in early scrib mutant tumors. In addition, JNK signaling activity displayed a radial polarity with the JNKhigh cells located at the periphery of scrib mutant tumors, providing an inherent mechanism that leads to an overall decrease in JNK signaling activity over time. We also found that ERK signaling activity, in contrast to JNK activity, increased over time and promoted growth in late-stage scrib mutant tumors. Furthermore, high JNK signaling activity repressed ERK signaling activity in early scrib mutant tumors. Together, these data demonstrate that dynamic MAPK signaling activity, fueled by intratumor heterogeneity derived from tissue topological differences, drives a growth arrest-to-proliferation transition in scrib mutant tumors.This article has an associated First Person interview with the joint first authors of the paper.

Acute community acquired Aspergillus pneumonia in a presumed immunocompetent host.

Infection from Aspergillus results in a wide range of diseases from simple Aspergillus pneumonia to fatal invasive Aspergillosis. Though the fungus is known to predominantly affect the immunocompromised host, it has also been known to cause acute pneumonia in immunocompetent hosts which is invariably fatal. It presents as an acute pneumonia with bilateral chest infiltrates on radiograph. Early clinical suspicion and microbiological identification by measures such as broncho alveolar lavage and initiation of therapy with voricanozole significantly increase the chances of survival. In this article the authors discuss a case of acute community acquired Aspergillus pneumonia in an immunocompetent host who survived due to early identification and prompt treatment with appropriate antifungal medication.

The effect of stoma size on weight loss after laparoscopic gastric bypass surgery: results of a blinded randomized controlled trial.

BACKGROUND: To determine the effect of different stoma sizes on the percent excess weight loss (%EWL) following laparoscopic Roux-en-Y gastric bypass surgery (LRYGBP). METHODS: Blinded randomized prospective controlled study in two American Society for Bariatric Surgeons-designated Centers of Excellence hospitals. Two hundred gastric bypass patients between January 2005 and September 2005 were prospectively randomized into two groups of 100 patients each in the operating room, after the induction of anesthesia. Patients underwent LRYGBP with different stapler sizes of 21 and 25 mm for gastrojejunal (GJ) anastomosis from January 2005 to September 2005. Postoperative %EWL following LRYGBP in both patient groups were calculated using a multivariable linear mixed-effects model with an unstructured covariance matrix and a logistic regression was used to measure clinical comorbidities. RESULTS: Applying multivariable mixed models and logistical regression, circular stapler size of 21 and 25 mm, which predicted the need for dilations (odds ratio = 0.489), did not predict weight loss. The only predictors of weight loss were male gender and higher initial weight (p < 0.001). Follow-up at 2 years in the 21- and 25-mm groups was 68% and 66%, respectively. Both groups had > 80% EWL at 2 years. CONCLUSION: The level of restriction or the presence of stenosis achieved by different circular stapler sizes does not have a significant causative role in weight loss.