Non-Invasive Detection of Early-Stage Fatty Liver Disease via an On-Skin Impedance Sensor and Attention-Based Deep Learning.

Early-stage nonalcoholic fatty liver disease (NAFLD) is a silent condition, with most cases going undiagnosed, potentially progressing to liver cirrhosis and cancer. A non-invasive and cost-effective detection method for early-stage NAFLD detection is a public health priority but challenging. In this study, an adhesive, soft on-skin sensor with low electrode-skin contact impedance for early-stage NAFLD detection is fabricated. A method is developed to synthesize platinum nanoparticles and reduced graphene quantum dots onto the on-skin sensor to reduce electrode-skin contact impedance by increasing double-layer capacitance, thereby enhancing detection accuracy. Furthermore, an attention-based deep learning algorithm is introduced to differentiate impedance signals associated with early-stage NAFLD in high-fat-diet-fed low-density lipoprotein receptor knockout (Ldlr-/-) mice compared to healthy controls. The integration of an adhesive, soft on-skin sensor with low electrode-skin contact impedance and the attention-based deep learning algorithm significantly enhances the detection accuracy for early-stage NAFLD, achieving a rate above 97.5% with an area under the receiver operating characteristic curve (AUC) of 1.0. The findings present a non-invasive approach for early-stage NAFLD detection and display a strategy for improved early detection through on-skin electronics and deep learning.

Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method.

Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using 'off-the-shelf' products, such as allogeneic CAR natural killer T (AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced AlloCAR-NKT cells with high yield and purity. We generated AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of AlloCAR-NKT cells support their potential for clinical translation.

Kilohertz volumetric imaging of in-vivo dynamics using squeezed light field microscopy.

Volumetric functional imaging of transient cellular signaling and motion dynamics poses a significant challenge to current microscopy techniques, primarily due to limitations in hardware bandwidth and the restricted photon budget within short exposure times. In response to this challenge, we present squeezed light field microscopy (SLIM), a computational imaging method that enables rapid detection of high-resolution three-dimensional (3D) light signals using only a single, low-format camera sensor area. SLIM pushes the boundaries of 3D optical microscopy, achieving over one thousand volumes per second across a large field of view of 550 µm in diameter and 300 µm in depth. Using SLIM, we demonstrated blood cell velocimetry across the embryonic zebrafish brain and in a free-moving tail exhibiting high-frequency swinging motion. The millisecond temporal resolution also enables accurate voltage imaging of neural membrane potentials in the leech ganglion. These results collectively establish SLIM as a versatile and robust imaging tool for high-speed microscopy applications.

Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.

Machine learning-directed electrical impedance tomography to predict metabolically vulnerable plaques.

The characterization of atherosclerotic plaques to predict their vulnerability to rupture remains a diagnostic challenge. Despite existing imaging modalities, none have proven their abilities to identify metabolically active oxidized low-density lipoprotein (oxLDL), a marker of plaque vulnerability. To this end, we developed a machine learning-directed electrochemical impedance spectroscopy (EIS) platform to analyze oxLDL-rich plaques, with immunohistology serving as the ground truth. We fabricated the EIS sensor by affixing a six-point microelectrode configuration onto a silicone balloon catheter and electroplating the surface with platinum black (PtB) to improve the charge transfer efficiency at the electrochemical interface. To demonstrate clinical translation, we deployed the EIS sensor to the coronary arteries of an explanted human heart from a patient undergoing heart transplant and interrogated the atherosclerotic lesions to reconstruct the 3D EIS profiles of oxLDL-rich atherosclerotic plaques in both right coronary and left descending coronary arteries. To establish effective generalization of our methods, we repeated the reconstruction and training process on the common carotid arteries of an unembalmed human cadaver specimen. Our findings indicated that our DenseNet model achieves the most reliable predictions for metabolically vulnerable plaque, yielding an accuracy of 92.59% after 100 epochs of training.

Profiling ovarian cancer tumor and microenvironment during disease progression for cell-based immunotherapy design.

Ovarian cancer (OC) is highly lethal due to late detection and frequent recurrence. Initial treatments, comprising surgery and chemotherapy, lead to disease remission but are invariably associated with subsequent relapse. The identification of novel therapies and an improved understanding of the molecular and cellular characteristics of OC are urgently needed. Here, we conducted a comprehensive analysis of primary tumor cells and their microenvironment from 16 chemonaive and 10 recurrent OC patient samples. Profiling OC tumor biomarkers allowed for the identification of potential molecular targets for developing immunotherapies, while profiling the microenvironment yielded insights into its cellular composition and property changes between chemonaive and recurrent samples. Notably, we identified CD1d as a biomarker of the OC microenvironment and demonstrated its targeting by invariant natural killer T (iNKT) cells. Overall, our study presents a comprehensive immuno-profiling of OC tumor and microenvironment during disease progression, guiding the development of immunotherapies for OC treatment, especially for recurrent disease.

A self-assembled implantable microtubular pacemaker for wireless cardiac electrotherapy.

The current cardiac pacemakers are battery dependent, and the pacing leads are prone to introduce valve damage and infection, plus a complete pacemaker retrieval is needed for battery replacement. Despite the reported wireless bioelectronics to pace the epicardium, open-chest surgery (thoracotomy) is required to implant the device, and the procedure is invasive, requiring prolonged wound healing and health care burden. We hereby demonstrate a fully biocompatible wireless microelectronics with a self-assembled design that can be rolled into a lightweight microtubular pacemaker for intravascular implantation and pacing. The radio frequency was used to transfer energy to the microtubular pacemaker for electrical stimulation. We show that this pacemaker provides effective pacing to restore cardiac contraction from a nonbeating heart and have the capacity to perform overdrive pacing to augment blood circulation in an anesthetized pig model. Thus, this microtubular pacemaker paves the way for the minimally invasive implantation of leadless and battery-free microelectronics.

Carotid-cavernous fistula following mechanical thrombectomy of the tortuous internal carotid artery: A case report.

BACKGROUND: A carotid-cavernous fistula (CCF) is an abnormal connection between the internal carotid artery (ICA) and the cavernous sinus. Although direct CCFs typically result from trauma or as an iatrogenic complication of neuroendovascular procedures, they can occur as surgery-related complications after mechanical thrombectomy (MT). With the widespread use of MT in patients with acute ischemic stroke complicated with large vessel occlusion, it is important to document CCF following MT and how to avoid them. In this study, we present a case of a patient who developed a CCF following MT and describe in detail the characteristics of ICA tortuosity in this case. CASE SUMMARY: A 60-year-old woman experienced weakness in the left upper and lower limbs as well as difficulty speaking for 4 h. The neurological examination revealed left central facial paralysis and left hemiplegia, with a National Institutes of Health Stroke Scale score of 9. Head magnetic resonance imaging revealed an acute cerebral infarction in the right basal ganglia and radial crown. Magnetic resonance angiography demonstrated an occlusion of the right ICA and middle cerebral artery. Digital subtraction angiography demonstrated distal occlusion of the cervical segment of the right ICA. We performed suction combined with stent thrombectomy. Then, postoperative angiography was performed, which showed a right CCF. One month later, CCF embolization was performed, and the patient's clinical symptoms have significantly improved 5 mo after the operation. CONCLUSION: Although a CCF is a rare complication after MT, it should be considered. Understanding the tortuosity of the internal carotid-cavernous sinus may help predict the complexity of MT and avoid this complication.

Integrating 4-D light-sheet fluorescence microscopy and genetic zebrafish system to investigate ambient pollutants-mediated toxicity.

Ambient air pollutants, including PM2.5 (aerodynamic diameter d ~2.5 µm), PM10 (d ~10 µm), and ultrafine particles (UFP: d < 0.1 µm) impart both short- and long-term toxicity to various organs, including cardiopulmonary, central nervous, and gastrointestinal systems. While rodents have been the principal animal model to elucidate air pollution-mediated organ dysfunction, zebrafish (Danio rerio) is genetically tractable for its short husbandry and life cycle to study ambient pollutants. Its electrocardiogram (ECG) resembles that of humans, and the fluorescent reporter-labeled tissues in the zebrafish system allow for screening a host of ambient pollutants that impair cardiovascular development, organ regeneration, and gut-vascular barriers. In parallel, the high spatiotemporal resolution of light-sheet fluorescence microscopy (LSFM) enables investigators to take advantage of the transparent zebrafish embryos and genetically labeled fluorescent reporters for imaging the dynamic cardiac structure and function at a single-cell resolution. In this context, our review highlights the integrated strengths of the genetic zebrafish system and LSFM for high-resolution and high-throughput investigation of ambient pollutants-mediated cardiac and intestinal toxicity.

Quantitative 4D imaging of biomechanical regulation of ventricular growth and maturation.

Abnormal cardiac development is intimately associated with congenital heart disease. During development, a sponge-like network of muscle fibers in the endocardium, known as trabeculation, becomes compacted. Biomechanical forces regulate myocardial differentiation and proliferation to form trabeculation, while the molecular mechanism is still enigmatic. Biomechanical forces, including intracardiac hemodynamic flow and myocardial contractile force, activate a host of molecular signaling pathways to mediate cardiac morphogenesis. While mechanotransduction pathways to initiate ventricular trabeculation is well studied, deciphering the relative importance of hemodynamic shear vs. mechanical contractile forces to modulate the transition from trabeculation to compaction requires advanced imaging tools and genetically tractable animal models. For these reasons, the advent of 4-D multi-scale light-sheet imaging and complementary multiplex live imaging via micro-CT in the beating zebrafish heart and live chick embryos respectively. Thus, this review highlights the complementary animal models and advanced imaging needed to elucidate the mechanotransduction underlying cardiac ventricular development.

Bubble-Mediated Large-Scale Hierarchical Assembly of Ultrathin Pt Nanowire Network Monolayer at Gas/Liquid Interfaces.

Extensive macroscale two-dimensional (2-D) platinum (Pt) nanowire network (NWN) sheets are created through a hierarchical self-assembly process with the aid of biomolecular ligands. The Pt NWN sheet is assembled from the attachment growth of 1.9 nm-sized 0-D nanocrystals into 1-D nanowires featuring a high density of grain boundaries, which then interconnect to form monolayer network structures extending into centimeter-scale size. Further investigation into the formation mechanism reveals that the initial emergence of NWN sheets occurs at the gas/liquid interfaces of the bubbles produced by sodium borohydride (NaBH4) during the synthesis process. Upon the rupture of these bubbles, an exocytosis-like process releases the Pt NWN sheets at the gas/liquid surface, which subsequently merge into a continuous monolayer Pt NWN sheet. The Pt NWN sheets exhibit outstanding oxygen reduction reaction (ORR) activities, with specific and mass activities 12.0 times and 21.2 times greater, respectively, than those of current state-of-the-art commercial Pt/C electrocatalysts.

Periodic Assembly of Diblock Pt-Au Heteronanowires for the Methanol Oxidation Reaction.

Periodic assembly of heterogeneous nanoparticles provides a strategy for integrating distinct nanocatalyst blocks where their synergic effects can be explored for diverse applications. To achieve the synergistic enhancement, an intimate clean interface is preferred which however is usually plagued by the bulky surfactant molecules used in the synthesis and assembly process. Herein, we showed the creation of one-dimensional Pt-Au nanowires (NWs) with periodic alternating Pt and Au nanoblocks, by assembling Pt-Au Janus nanoparticles with the assistance of peptide T7 (Ac-TLTTLTN-CONH2). It is demonstrated that the Pt-Au NWs showed much-improved performance in the methanol oxidation reaction (MOR), exhibiting 5.3 times higher specific activity and 2.5 times higher mass activity than the current state-of-the-art commercial Pt/C catalyst. In addition, the periodic heterostructure also improves the stability of Pt-Au NWs in the MOR, where the Pt-Au NWs retained 93.9% of their initial mass activity much higher than commercial Pt/C (30.6%).

Atomic Regulation of PGM Electrocatalysts for the Oxygen Reduction Reaction.

With the increasing enthusiasm for the hydrogen economy and zero-emission fuel cell technologies, intensive efforts have been dedicated to the development of high-performance electrocatalytic materials for the cathodic oxygen reduction reaction (ORR). Some major fundamental breakthroughs have been made in the past few years. Therefore, reviewing the most recent development of platinum-group-metal (PGM) ORR electrocatalysts is of great significance to pushing it forward. It is known that the ORR on the fuel cell electrode is a heterogeneous reaction occurring at the solid/liquid interface, wherein the electron reduces the oxygen along with species in the electrolyte. Therefore, the ORR kinetic is in close correlation with the electronic density of states and wave function, which are dominated by the localized atomic structure including the atomic distance and coordination number (CN). In this review, the recent development in the regulation over the localized state on the catalyst surface is narrowed down to the following structural factors whereby the corresponding strategies include: the crystallographic facet engineering, phase engineering, strain engineering, and defect engineering. Although these strategies show distinctive features, they are not entirely independent, because they all correlate with the atomic local structure. This review will be mainly divided into four parts with critical analyses and comparisons of breakthroughs. Meanwhile, each part is described with some more specific techniques as a methodological guideline. It is hoped that the review will enhance an insightful understanding on PGM catalysts of ORR with a visionary outlook.

Direct correlation of oxygen adsorption on platinum-electrolyte interfaces with the activity in the oxygen reduction reaction.

The oxygen reduction reaction (ORR) on platinum catalysts is essential in fuel cells. Quantitative predictions of the relative ORR activity in experiments, in the range of 1 to 50 times, have remained challenging because of incomplete mechanistic understanding and lack of computational tools to account for the associated small differences in activation energies (<2.3 kilocalories per mole). Using highly accurate molecular dynamics (MD) simulation with the Interface force field (0.1 kilocalories per mole), we elucidated the mechanism of adsorption of molecular oxygen on regular and irregular platinum surfaces and nanostructures, followed by local density functional theory (DFT) calculations. The relative ORR activity is determined by oxygen access to platinum surfaces, which greatly depends on specific water adlayers, while electron transfer occurs at a similar slow rate. The MD methods facilitate quantitative predictions of relative ORR activities of any platinum nanostructures, are applicable to other catalysts, and enable effective MD/DFT approaches.

PLF-1 (Proliferin-1) Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia.

Background Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results Cathepsin K-mediated caspase-8 maturation is a key initial step for oxidative stress-induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth-stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF-1 (proliferin-1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3-kinase/protein kinase B/p38 mitogen-activated protein kinase)-dependent and -independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll-like receptor-2/caspase-8-mediated PLF-1 expression. Interestingly, PLF-1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild-type mice. Contrarily, administration of recombinant mouse PLF-1 accelerated injury-induced vascular actions. Conclusions This is the first study detailing PLF-1 as a communicator between apoptosis and proliferation during injury-related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis-driven expression of PLF-1 is thus a novel target for treatment of apoptosis-based hyperproliferative disorders.

Peptide-Assisted 2-D Assembly toward Free-Floating Ultrathin Platinum Nanoplates as Effective Electrocatalysts.

We demonstrate the 2-D anisotropic formation of ultrathin free-floating Pt nanoplates from the assembly of small nanocrystals using T7 peptide (Ac-TLTTLTN-CONH2). As-formed nanoplates are rich in grain boundaries that can promote their catalytic activities. Furthermore, we demonstrate that a minor number of Pd atoms can selectively deposit on and stabilize the grain boundaries, which leads to enhanced structure stability. The Pd-enhanced Pt polycrystal nanoplates show great oxygen reduction reaction activities with 15.5 times higher specific activity and 13.7 times higher mass activity than current state-of-the-art commercial Pt/C electrocatalysts as well as 2.5 times higher mass activity for hydrogen evolution reaction compared with Pt/C.

Maximizing the Current Output in Self-Aligned Graphene-InAs-Metal Vertical Transistors.

With finite density of states and electrostatically tunable work function, graphene can function as a tunable contact for a semiconductor channel to enable vertical field-effect transistors (VFETs). However, the overall performance, especially the output current density, is still limited by the low conductance of the vertical semiconductor channel, as well as large series resistance of the graphene electrode. To overcome these limitations, we construct a VFET by using single-crystal InAs film as the high-conductance vertical channel and self-aligned metal contact as the source-drain electrodes, resulting in a record high current density over 45 000 A/cm2 at a low bias voltage of 1 V. Furthermore, we construct a device-level VFET model using the resistor network method, and experimentally validate the impact of each geometry parameter on device performance. Importantly, we found the device performance is not only a function of the intrinsic channel material, but also greatly influenced by device geometries and footprint. Our study not only pushes the performance limit of graphene VFETs, but also sheds light on van der Waals integration between two-dimensional material and conventional bulk material for high-performance VFETs and circuits.

Long-Range Hierarchical Nanocrystal Assembly Driven by Molecular Structural Transformation.

The hierarchical control in biogenic minerals, from precise nanomorphology control to subsequent macroscopic assembly, remains a formidable challenge in artificial synthesis. Studies in biomineralization, however, are largely limited to atomic andmolecular scale crystallization, devoting little attention to biomolecular higher-order structures (HOSs) which critically impact long-range assembly of biominerals. Here we demonstrate a biomimetic route and quantitative simulations that explore peptide HOSs on guiding nanocrystal formation and anisotropic assembly into hierarchical structures. It is found that the Pt{100}-specific peptide T7 (Ac-TLTTLTN-CONH2) adopts ST-turn secondary structure, promoting cubic Pt nanocrystal formation at low concentration, and spontaneously transforms into a ß-sheet with increased concentration. The ß-sheet T7-Pt{100} specificity drives cubic Pt nanocrystals to self-assemble into large-area, long-range, [100] linear assemblies. This study provides a robust demonstration for bio/nonbiogenic material specificity, nanoscale synthesis, and long-range self-organization with biomolecular HOSs and opens vast opportunities for multiscale programmable structures.

Building two-dimensional materials one row at a time: Avoiding the nucleation barrier.

Assembly of two-dimensional (2D) molecular arrays on surfaces produces a wide range of architectural motifs exhibiting unique properties, but little attention has been given to the mechanism by which they nucleate. Using peptides selected for their binding affinity to molybdenum disulfide, we investigated nucleation of 2D arrays by molecularly resolved in situ atomic force microscopy and compared our results to molecular dynamics simulations. The arrays assembled one row at a time, and the nuclei were ordered from the earliest stages and formed without a free energy barrier or a critical size. The results verify long-standing but unproven predictions of classical nucleation theory in one dimension while revealing key interactions underlying 2D assembly.

Approaching the Schottky-Mott limit in van der Waals metal-semiconductor junctions.

The junctions formed at the contact between metallic electrodes and semiconductor materials are crucial components of electronic and optoelectronic devices 1 . Metal-semiconductor junctions are characterized by an energy barrier known as the Schottky barrier, whose height can, in the ideal case, be predicted by the Schottky-Mott rule2-4 on the basis of the relative alignment of energy levels. Such ideal physics has rarely been experimentally realized, however, because of the inevitable chemical disorder and Fermi-level pinning at typical metal-semiconductor interfaces2,5-12. Here we report the creation of van der Waals metal-semiconductor junctions in which atomically flat metal thin films are laminated onto two-dimensional semiconductors without direct chemical bonding, creating an interface that is essentially free from chemical disorder and Fermi-level pinning. The Schottky barrier height, which approaches the Schottky-Mott limit, is dictated by the work function of the metal and is thus highly tunable. By transferring metal films (silver or platinum) with a work function that matches the conduction band or valence band edges of molybdenum sulfide, we achieve transistors with a two-terminal electron mobility at room temperature of 260 centimetres squared per volt per second and a hole mobility of 175 centimetres squared per volt per second. Furthermore, by using asymmetric contact pairs with different work functions, we demonstrate a silver/molybdenum sulfide/platinum photodiode with an open-circuit voltage of 1.02 volts. Our study not only experimentally validates the fundamental limit of ideal metal-semiconductor junctions but also defines a highly efficient and damage-free strategy for metal integration that could be used in high-performance electronics and optoelectronics.