Alveolar macrophage phagocytosis-evading inhaled microgels incorporating nintedanib-PLGA nanoparticles and pirfenidone-liposomes for improved treatment of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory and fibrotic response-driven lung disease that is difficult to cure because it manifests excessive profibrotic cytokines (e.g., TGF-ß), activated myofibroblasts, and accumulated extracellular matrix (ECM). In an attempt to develop an inhalation formulation with enhanced antifibrotic efficacy, we sought to fabricate unique aerosolizable inhaled microgels (µGel) that contain nintedanib-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs; n-PN) and pirfenidone-liposomes (p-LP). The aero-µGel was ∼12 µm, resisted phagocytosis by alveolar macrophages in vitro and in vivo, and protected inner-entrapped n-PN and p-LP. The n-PN/p-LP@aero-µGel caused enhanced/extended antifibrotic efficacy in a bleomycin-induced pulmonary fibrosis mouse presumably due to prolonged lung residence. Consequently, the results obtained by intratracheal aerosol insufflation of our n-PN/p-LP@aero-µGel twice a week were much better than those by as many as seven doses of single or mixed applications of n-PN or p-LP. The antifibrotic/pharmacokinetic results for the n-PN/p-LP@aero-µGel included reduced fibrosis progression, restored lung physiological functions, deactivated myofibroblasts, inhibited TGF-ß progression, and suppressed ECM component production (collagen I and α-SMA) along with prolonged lung retention time. We believe that our n-PN/p-LP@aero-µGel increased the local availability of both nintedanib and pirfenidone due to evasion of alveolar macrophage phagocytosis and prolonged lung retention with reduced systemic distribution. Through this approach, our inhalation formulation subsequently attenuated fibrosis progression and improved lung function. Importantly, these results hold profound implications in the therapeutic potential of our n-PN/p-LP@aero-µGel to serve as a clinically promising platform, providing significant advancements for improved treatment of many respiratory diseases including IFP.

EMPHASISCHECKER: A Tool for Guiding Chart and Caption Emphasis.

Recent work has shown that when both the chart and caption emphasize the same aspects of the data, readers tend to remember the doubly-emphasized features as takeaways; when there is a mismatch, readers rely on the chart to form takeaways and can miss information in the caption text. Through a survey of 280 chart-caption pairs in real-world sources (e.g., news media, poll reports, government reports, academic articles, and Tableau Public), we find that captions often do not emphasize the same information in practice, which could limit how effectively readers take away the authors' intended messages. Motivated by the survey findings, we present EMPHASISCHECKER, an interactive tool that highlights visually prominent chart features as well as the features emphasized by the caption text along with any mismatches in the emphasis. The tool implements a time-series prominent feature detector based on the Ramer-Douglas-Peucker algorithm and a text reference extractor that identifies time references and data descriptions in the caption and matches them with chart data. This information enables authors to compare features emphasized by these two modalities, quickly see mismatches, and make necessary revisions. A user study confirms that our tool is both useful and easy to use when authoring charts and captions.

Macrophage-reprogramming upconverting nanoparticles for enhanced TAM-mediated antitumor therapy of hypoxic breast cancer.

In an attempt to achieve antitumor effects by switching the phenotype of macrophages from the tumor-promoting M2 type to the tumor-suppressing M1 type, we fabricated mannose-decorated/macrophage membrane-coated, silica-layered NaErF4@NaLuF4 upconverting nanoparticles (UCNPs) co-doped with perfluorocarbon (PFC)/chlorin e6 (Ce6) and loaded with paclitaxel (PTX) (UCNP@mSiO2-PFC/Ce6@RAW-Man/PTX: ∼61 nm; -11.6 mV). These nanoparticles were designed to have two major functionalities, (i) efficient singlet oxygen generation aided by an oxygen supply and (ii) good targeting to tumor-associated macrophage (TAMs) (M2-type), to induce polarization to M1 type macrophages that release proinflammatory cytokines and suppress breast cancers. The primary UCNPs consisted of lanthanide elements (erbium and lutetium) in a core@shell structure, and they facilely emitted 660 nm light in response to a deep-penetrating 808 nm near-infrared laser. Moreover, the UCNPs@mSiO2-PFC/Ce6@RAW-Man/PTX were able to release O2 and generate 1O2 because of the co-doped PFC/Ce6 and upconversion. Our nanocarriers' excellent uptake to RAW 264.7 macrophage cells (M2 type) and efficient M1-type polarization activity were clearly demonstrated using qRT-PCR and immunofluorescence-based confocal laser scanning microscopy. Our nanocarriers displayed significant cytotoxicity to 4T1 cells in 2D culture and 3D co-culture systems of 4T1/RAW 264.7 cells. More importantly, UCNPs@mSiO2-PFC/Ce6@RAW-Man/PTX (+808 nm laser) noticeably suppressed tumor growth in 4T1-xenografted mice, compared with the other treatment groups (332.4 vs. 709.5-1185.5 mm3). We attribute this antitumor efficacy to the prominent M1-type macrophage polarization caused by our nanocarriers through efficient ROS/O2 generation and targeting of M2-type TAMs via mannose ligands on coated macrophage-membrane.

Full-color micro-LED display with photo-patternable and highly ambient-stable perovskite quantum dot/siloxane composite as color conversion layers.

In this paper, we successfully fabricated color conversion layers (CCLs) for full-color-mico-LED display using a perovskite quantum dot (PQD)/siloxane composite by ligand exchanged PQD with silane composite followed by surface activation by an addition of halide-anion containing salt. Due to this surface activation, it was possible to construct the PQD surface with a silane ligand using a non-polar organic solvent that does not damage the PQD. As a result, the ligand-exchanged PQD with a silane compound exhibited high dispersibility in the siloxane matrix and excellent atmospheric stability due to sol-gel condensation. Based on highly ambient stable PQD/siloxane composite based CCLs, full-color micro-LED display has a 1 mm pixel pitch, about 25.4 pixels per inch (PPI) resolution was achieved. In addition, due to the thin thickness of the black matrix to prevent blue light interference, the possibility of a flexible display that can be operated without damage even with a bending radius of 5 mm was demonstrated.

WavelNet: A novel convolutional neural network architecture for arrhythmia classification from electrocardiograms.

BACKGROUND AND OBJECTIVE: Automated detection of arrhythmias from electrocardiograms (ECGs) can be of considerable assistance to medical professionals in providing efficient treatment for patients with cardiovascular diseases. In recent times, convolutional neural network (CNN)-based arrhythmia classification models have been introduced, but their decision-making processes remain unclear and their performances are not reproducible. This paper proposes an accurate, interpretable, and reproducible end-to-end arrhythmia classification model based on a novel CNN architecture named WavelNet, which is interpretable and optimal for dealing with ECGs. METHODS: Inspired by SincNet, which is capable of band-pass filtering-based spectral analysis, WavelNet was devised to achieve wavelet transform-based spectral analysis. WavelNet was trained using a subject-oriented five-class ECG arrhythmia dataset generated from the MIT-BIH Arrhythmia Database while following a benchmark scheme. By adopting various mother wavelets, multiple WavelNet-based arrhythmia classification models were implemented. To investigate whether our wavelet transform-based approach outperforms original end-to-end and band-pass filtering-based approaches, our proposed models were compared with vanilla CNN- and SincNet-based models. Model implementation and evaluation processes were repeated ten times in a Google Colab Pro+ environment. Furthermore, our most successful model was compared with state-of-the-art arrhythmia classification models for performance evaluation. RESULTS: The proposed WavelNet-based models showed excellent performance on classifying non-ectopic, supraventricular ectopic, and ventricular ectopic beats because of their ability to perform adaptive spectral analysis while preserving temporal ECG information compared with vanilla CNN- and SincNet-based models. In particular, a Symlet 4 wavelet-adopting WavelNet-based model achieved the best performance with nearly 90% overall accuracy as well as the highest levels of sensitivity in classifying each arrhythmia class: 91.4%, 49.3%, and 91.4% for non-ectopic, supraventricular ectopic, and ventricular ectopic beat classifications, respectively. These results were comparable to those of state-of-the-art models. In addition, the results are reproducible, which differentiates our study from previous studies. CONCLUSIONS: Our proposed WavelNet-based arrhythmia classification model achieved remarkable performance based on a reasonable decision-making process, in comparison with other models. As its noteworthy performance is clinically reasonable and reproducible, our proposed model can contribute toward implementing a real-world precision healthcare system for patients with cardiovascular diseases.

Amplified Fenton-Based Oxidative Stress Utilizing Ultraviolet Upconversion Luminescence-Fueled Nanoreactors for Apoptosis-Strengthened Ferroptosis Anticancer Therapy.

As an emerging anticancer strategy, ferroptosis has recently been developed in combination with current therapeutic modalities to overcome the existing limitations of conventional therapies. Herein, an ultraviolet (UV) upconversion luminescence-fueled nanoreactor is explored to combine ferroptosis and apoptosis through the UV-catalyzed Fenton reaction of an iron supplement (ferric ammonium citrate) loaded in a mesoporous silica layer in addition to the support of a chemotherapeutic agent (cisplatin) attached on the functionalized silica surface for the treatment of triple negative breast cancer (TNBC). The nanoplatform can circumvent the low penetration depth typical of UV light by upconverting near-infrared irradiation and emitting UV photons that convert Fe3+ to Fe2+ to boost the generation of hydroxyl radicals (·OH), causing devastating lipid peroxidation. Apart from DNA damage-induced apoptosis, cisplatin can also catalyze Fenton-based therapy by its abundant production of hydrogen peroxide (H2O2). As a bioinspired lipid membrane, the folate receptor-targeted liposome as the coating layer offers high biocompatibility and colloidal stability for the upconversion nanoparticles, in addition to prevention of the premature release of encapsulated hydrophilic compounds, before driving the nanoformulation to the target tumor site. As a result, superior antitumor efficacy has been observed in a 4T1 tumor-bearing mouse model with negligible side effects, suggesting that such a nanoformulation could play a pivotal role in effective apoptosis-strengthened ferroptosis TNBC therapy.

Stretchable Inorganic LED Displays with Double-Layer Modular Design for High Fill Factor.

The recent commercial success of flexible and foldable displays has resulted in growing interest in stretchable electronics which are considered to be the next generation of the optoelectronic technology. Stretchable display technologies are being intensively studied for versatile applications including wearable, attachable, and shape changeable electronics. In this paper, we present high fill factor, stretchable inorganic light-emitting diode (LED) displays fabricated by connecting mini-LEDs and stretchable interconnects in a double-layer modular design. The double-layer modular design enables an increased areal coverage of LEDs and stretchable interconnectors with both electrical and mechanical stability. The main features of the double-layer modular design, fabrication processes, and device characteristics for the high fill factor, stretchable inorganic LED display are discussed, with experimental and computational results. Demonstrations of a passive matrix LED display confirm the potential value of the multi-layer structured, stretchable electronics in a wide range of applications that need high fill factor with high stretchability.

The Tacotron-Based Signal Synthesis Method for Active Sonar.

The importance of active sonar is increasing due to the quieting of submarines and the increase in maritime traffic. However, the multipath propagation of sound waves and the low signal-to-noise ratio due to multiple clutter make it difficult to detect, track, and identify underwater targets using active sonar. To solve this problem, machine learning and deep learning techniques that have recently been in the spotlight are being applied, but these techniques require a large amount of data. In order to supplement insufficient active sonar data, methods based on mathematical modeling are primarily utilized. However, mathematical modeling-based methods have limitations in accurately simulating complicated underwater phenomena. Therefore, an artificial intelligence-based sonar signal synthesis technique is proposed in this paper. The proposed method modified the major modules of the Tacotron model, which is widely used in the field of speech synthesis, in order to apply the Tacotron model to the field of sonar signal synthesis. To prove the validity of the proposed method, spectrograms of synthesized sonar signals are analyzed and the mean opinion score was measured. Through the evaluation, we confirmed that the proposed method can synthesize active sonar data similar to the trained one.

An implantable optogenetic stimulator wirelessly powered by flexible photovoltaics with near-infrared (NIR) light.

Optogenetics is a cutting-edge tool in neuroscience that employs light-sensitive proteins and controlled illumination for neuromodulation. Its main advantage is the ability to demonstrate causal relationships by manipulating the activity of specific neuronal populations and observing behavioral phenotypes. However, the tethering system used to deliver light to optogenetic tools can constrain both natural animal behaviors and experimental design. Here, we present an optically powered and controlled wireless optogenetic system using near-infrared (NIR) light for high transmittance through live tissues. In vivo optogenetic stimulations using this system induced whisker movement in channelrhodopsin-expressing mice, confirming the photovoltaics-generated electrical power was sufficient, and the remote controlling system operated successfully. The proposed optogenetic system provides improved optogenetic applications in freely moving animals.

Sustainably Powered, Multifunctional Flexible Feedback Implant by the Bifacial Design and Si Photovoltaics.

Advanced design and integration of functioning devices with secured power is of interest for many applications that require complicated, sophisticated, or multifunctional processes in confined environments such as in human bodies. Here, strategies for design and realization are introduced for multifunctional feedback implants with the bifacial design and silicon (Si) photovoltaics in flexible forms. The approaches provide efficient design spaces for flexible Si photovoltaics facing up for sustainable powering and multiple electronic components for feedback functions facing down for sensing, processing, and stimulating in human bodies. The computational and experimental results including in vivo assessments ensure feasibility of the approaches by demonstrating feedback multifunctions, power-harvesting in milliwatts, and mechanical compatibility for operations in live tissues. This work should useful for wide range of applications that require sustainable power and advanced multifunctions.

Detecting evolutionary patterns of cancers using consensus trees.

MOTIVATION: While each cancer is the result of an isolated evolutionary process, there are repeated patterns in tumorigenesis defined by recurrent driver mutations and their temporal ordering. Such repeated evolutionary trajectories hold the potential to improve stratification of cancer patients into subtypes with distinct survival and therapy response profiles. However, current cancer phylogeny methods infer large solution spaces of plausible evolutionary histories from the same sequencing data, obfuscating repeated evolutionary patterns. RESULTS: To simultaneously resolve ambiguities in sequencing data and identify cancer subtypes, we propose to leverage common patterns of evolution found in patient cohorts. We first formulate the Multiple Choice Consensus Tree problem, which seeks to select a tumor tree for each patient and assign patients into clusters in such a way that maximizes consistency within each cluster of patient trees. We prove that this problem is NP-hard and develop a heuristic algorithm, Revealing Evolutionary Consensus Across Patients (RECAP), to solve this problem in practice. Finally, on simulated data, we show RECAP outperforms existing methods that do not account for patient subtypes. We then use RECAP to resolve ambiguities in patient trees and find repeated evolutionary trajectories in lung and breast cancer cohorts. AVAILABILITY AND IMPLEMENTATION: https://github.com/elkebir-group/RECAP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Active photonic wireless power transfer into live tissues.

Recent advances in soft materials and mechanics activate development of many new types of electrical medical implants. Electronic implants that provide exceptional functions, however, usually require more electrical power, resulting in shorter period of usages although many approaches have been suggested to harvest electrical power in human bodies by resolving the issues related to power density, biocompatibility, tissue damage, and others. Here, we report an active photonic power transfer approach at the level of a full system to secure sustainable electrical power in human bodies. The active photonic power transfer system consists of a pair of the skin-attachable photon source patch and the photovoltaic device array integrated in a flexible medical implant. The skin-attachable patch actively emits photons that can penetrate through live tissues to be captured by the photovoltaic devices in a medical implant. The wireless power transfer system is very simple, e.g., active power transfer in direct current (DC) to DC without extra circuits, and can be used for implantable medical electronics regardless of weather, covering by clothes, in indoor or outdoor at day and night. We demonstrate feasibility of the approach by presenting thermal and mechanical compatibility with soft live tissues while generating enough electrical power in live bodies through in vivo animal experiments. We expect that the results enable long-term use of currently available implants in addition to accelerating emerging types of electrical implants that require higher power to provide diverse convenient diagnostic and therapeutic functions in human bodies.

Atomically thin three-dimensional membranes of van der Waals semiconductors by wafer-scale growth.

We report wafer-scale growth of atomically thin, three-dimensional (3D) van der Waals (vdW) semiconductor membranes. By controlling the growth kinetics in the near-equilibrium limit during metal-organic chemical vapor depositions of MoS2 and WS2 monolayer (ML) crystals, we have achieved conformal ML coverage on diverse 3D texture substrates, such as periodic arrays of nanoscale needles and trenches on quartz and SiO2/Si substrates. The ML semiconductor properties, such as channel resistivity and photoluminescence, are verified to be seamlessly uniform over the 3D textures and are scalable to wafer scale. In addition, we demonstrated that these 3D films can be easily delaminated from the growth substrates to form suspended 3D semiconductor membranes. Our work suggests that vdW ML semiconductor films can be useful platforms for patchable membrane electronics with atomic precision, yet large areas, on arbitrary substrates.

Epitaxial van der Waals Contacts between Transition-Metal Dichalcogenide Monolayer Polymorphs.

We have achieved heteroepitaxial stacking of a van der Waals ( vdW) monolayer metal, 1T'-WTe2, and a semiconductor, 2H-WSe2, in which a distinctively low contact barrier was established across a clean epitaxial vdW gap. Our epitaxial 1T'-WTe2 films were identified as a semimetal by low temperature transport and showed the robust breakdown current density of 5.0 × 107 A/cm2. In comparison with a series of planar metal contacts, our epitaxial vdW contact was identified to possess intrinsic Schottky barrier heights below 100 meV for both electron and hole injections, contributing to superior ambipolar field-effect transistor (FET) characteristics, i.e., higher FET mobilities and higher on-off current ratios at smaller threshold gate voltages. We discuss our observations around the critical roles of the epitaxial vdW heterointerfaces, such as incommensurate stacking sequences and absence of extrinsic interfacial defects that are inaccessible by other contact methods.

Flexible-Device Injector with a Microflap Array for Subcutaneously Implanting Flexible Medical Electronics.

Implantable electronics in soft and flexible forms can reduce undesired outcomes such as irritations and chronic damages to surrounding biological tissues due to the improved mechanical compatibility with soft tissues. However, the same mechanical flexibility also makes it difficult to insert such implants through the skin because of reduced stiffness. In this paper, a flexible-device injector that enables the subcutaneous implantation of flexible medical electronics is reported. The injector consists of a customized blade at the tip and a microflap array which holds the flexible implant while the injector penetrates through soft tissues. The microflap array eliminates the need of additional materials such as adhesives that require an extended period to release a flexible medical electronic implant from an injector inside the skin. The mechanical properties of the injection system during the insertion process are experimentally characterized, and the injection of a flexible optical pulse sensor and electrocardiogram sensor is successfully demonstrated in vivo in live pig animal models to establish the practical feasibility of the concept.

Coplanar semiconductor-metal circuitry defined on few-layer MoTe2 via polymorphic heteroepitaxy.

Crystal polymorphism selectively stabilizes the electronic phase of atomically thin transition-metal dichalcogenides (TMDCs) as metallic or semiconducting, suggesting the potential to integrate these polymorphs as circuit components in two-dimensional electronic circuitry. Developing a selective and sequential growth strategy for such two-dimensional polymorphs in the vapour phase is a critical step in this endeavour. Here, we report on the polymorphic integration of distinct metallic (1T') and semiconducting (2H) MoTe2 crystals within the same atomic planes by heteroepitaxy. The realized polymorphic coplanar contact is atomically coherent, and its barrier potential is spatially tight-confined over a length of only a few nanometres, with a lowest contact barrier height of ∼25 meV. We also demonstrate the generality of our synthetic integration approach for other TMDC polymorph films with large areas.

Attachable Pulse Sensors Integrated with Inorganic Optoelectronic Devices for Monitoring Heart Rates at Various Body Locations.

Monitoring cardiovascular signals such as heart rate and blood flow provides critically important healthcare information about patients under medical care. However, when the sensors are worn for extended times, the sensors sometimes require higher mechanical compatibility with soft deformable tissues. In this paper, we report an attachable and flexible pulse sensor (bending radius: 2.4 mm), integrated with micro-inorganic photodetectors (thickness: 4.1 µm, photocurrent: 8.99 µA under 1.5 mW/cm2) and a red light emitting diode (620 nm), to monitor vital signals for extended times. Operating in a reflection mode, it can be attached and measure heart pulse waveforms from various locations on the human body including the finger, fingertip, nail, and forearm. The small form factor also enables integration on a finger ring. Electrical and mechanical performance assessments demonstrated the practical feasibility of the concept.

Mobility of Amphidinium carterae Hulburt measured by high-frequency ultrasound.

The over-growth of phytoplankton causes harmful algal blooms (HABs) in marine ecological environments. Mobility measurement is important in understanding the action of HABs. In this study, the mobility of Amphidinium carterae Hulburt (A. carterae) was investigated using high-frequency ultrasound in the laboratory. Mobility in response to light was illustrated with M-mode images reconstructed from echoed signals. This study suggests that mobility of the swimming speed of A. carterae in response to light can be measured and calculated with M-mode images through high-frequency ultrasound. This finding may be helpful in understanding the fundamental behavior of HABs.

SCALABLE VISUALIZATION FOR HIGH-DIMENSIONAL SINGLE-CELL DATA.

Single-cell analysis can uncover the mysteries in the state of individual cells and enable us to construct new models about the analysis of heterogeneous tissues. State-of-the-art technologies for single-cell analysis have been developed to measure the properties of single-cells and detect hidden information. They are able to provide the measurements of dozens of features simultaneously in each cell. However, due to the high-dimensionality, heterogeneous complexity and sheer enormity of single-cell data, its interpretation is challenging. Thus, new methods to overcome high-dimensionality are necessary. Here, we present a computational tool that allows efficient visualization of high-dimensional single-cell data onto a low-dimensional (2D or 3D) space while preserving the similarity structure between single-cells. We first construct a network that can represent the similarity structure between the high-dimensional representations of single-cells, and then, embed this network into a low-dimensional space through an efficient online optimization method based on the idea of negative sampling. Using this approach, we can preserve the high-dimensional structure of single-cell data in an embedded low-dimensional space that facilitates visual analyses of the data.