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Ferrocene-Functionalized Atomically Precise Metal Clusters Exhibit Synergistically Enhanced Performance for CO2 Electroreduction
No full textThe integration of organometallic compounds with metal nanoparticles can, in principle, generate hybrid nanocatalysts endowed with augmented functionality, presenting substantial promise for catalytic applications. Herein, we synthesize an atomically precise metal cluster (Ag9Cu6) catalyst integrated with alkynylferrocene molecules (Ag9Cu6-Fc). This hybrid catalyst design facilitates a continuous electron transfer channel via an ethynyl bridge and establishes a distinctive local chemical environment, resulting in remarkably enhanced catalytic activity in CO2 electroreduction. The Ag9Cu6-Fc catalyst achieves a record-high product selectivity of CO Faradaic efficiency of 100 % and an industrial-level CO partial current density of -680 mA/cm(2), surpassing the performance of the Ag9Cu6 cluster (62 % and -230 mA/cm(2), respectively) without ferrocene functionalization in a membrane electrode assembly cell. Operando experimental and computational findings offer valuable insights into the role of ferrocene functionalization in synergistically improving the catalytic performance of metal clusters, propelling the advancement of metallic-organometallic hybrid nanoparticles for energy conversion technologies.N
Time-resolved Brownian tomography of single nanocrystals in liquid during oxidative etching
No full textColloidal nanocrystals inherently undergo structural changes during chemical reactions. The robust structure-property relationships, originating from their nanoscale dimensions, underscore the significance of comprehending the dynamic structural behavior of nanocrystals in reactive chemical media. Moreover, the complexity and heterogeneity inherent in their atomic structures require tracking of structural transitions in individual nanocrystals at three-dimensional (3D) atomic resolution. In this study, we introduce the method of time-resolved Brownian tomography to investigate the temporal evolution of the 3D atomic structures of individual nanocrystals in solution. The methodology is applied to examine the atomic-level structural transformations of Pt nanocrystals during oxidative etching. The time-resolved 3D atomic maps reveal the structural evolution of dissolving Pt nanocrystals, transitioning from a crystalline to a disordered structure. Our study demonstrates the emergence of a phase at the nanometer length scale that has received less attention in bulk thermodynamics.N
Controlled Structural Activation of Iridium Single Atom Catalyst for High-Performance Proton Exchange Membrane Water Electrolysis
No full textIridium single atom catalysts are promising oxygen evolution reaction (OER) electrocatalysts for proton exchange membrane water electrolysis (PEMWE), as they can reduce the reliance on costly Ir in the OER catalysts. However, their practical application is hindered by their limited stability during PEMWE operation. Herein, we report on the activation of Ir-doped CoMn2O4 in acidic electrolyte that leads to enhanced activity and stability in acidic OER for long-term PEMWE operation. In-depth material characterization combined with electrochemical analysis and theoretical calculations reveal that activating Ir-doped CoMn2O4 induces controlled restructuring of Ir single atoms to IrO x nanoclusters, resulting in an optimized Ir configuration with outstanding mass activity of 3562 A gIr (-1) at 1.53 V (vs RHE) and enhanced OER stability. The PEMWE using activated Ir-doped CoMn2O4 exhibited a stable operation for >1000 h at 250 mA cm(-2) with a low degradation rate of 0.013 mV h(-1), demonstrating its practical applicability. Furthermore, it remained stable for more than 400 h at a high current density of 1000 mA cm(-2), demonstrating long-term durability under practical operation conditions.N
Population pharmacokinetics and exposure-response analysis of durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer
No full textPURPOSE: Durvalumab in combination with gemcitabine/cisplatin has shown a favorable benefit-risk profile in the TOPAZ-1 study for advanced biliary tract cancers (BTC). This analysis evaluated the population pharmacokinetics (PopPK) of durvalumab, and exposure-response for efficacy and safety (ERES) of TOPAZ-1. METHODS: The PopPK model for durvalumab was updated using data from 5 previously analysed studies and TOPAZ-1. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for exposure-response (ER) analysis related to efficacy and safety. RESULTS: Consistent with previous analyses, the durvalumab pharmacokinetics in BTC followed a 2-compartment model with time-dependent clearance. The final population parameters were: CL, 0.298 L/day; V1, 3.42 L; V2, 1.99 L; Q, 0.452 L/day; and the time dependent clearance suggests that the clearance could decrease up to 39% over the time course of treatment. There were 111 patients (3.53%) with treatment-emergent ADA positive in the pooled group of 6 studies, and the exposure was comparable for ADA positive and negative patients. Covariates had minimal clinical impact on PopPK parameters. No significant associations were found between exposure and overall survival (OS), progression-free survival (PFS), using Cox proportional analysis (CPH). Logistic regression analysis indicated no significant relationship between the exposure and relevant adverse events measures of Grade 3 and higher treatment-related AE, Grade 3 and higher treatment-related AESI (AEs of special interest), or AE leading to treatment discontinuation. CONCLUSIONS: No dose adjustment for durvalumab is needed based on PopPK and ERES analyses. The analysis supports the TOPAZ-1 regimen for patients with advanced BTC.Y
Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides
No full textAnimal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with comprehensively constructing and expressing highly complex venom and venom-like molecule libraries have precluded their therapeutic evaluation via high-throughput screening. Here, we developed an innovative computational approach design a highly diverse library of animal venoms and "metavenoms". We used programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz-type domain containing proteins that target the human itch receptor Mas-related G-protein coupled receptor member X4, which plays crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI), and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of Masrelated G-protein coupled receptor member X4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.Y
Authorized Narrative, Excluded Memory: UNESCO Memory of the World, Return to Maizuru Port
No full textLayerwise-priority-based gradient adjustment for few-shot learning
No full textTo resolve the problem that deep neural networks (DNN) require a large amount of data, few-shot learning has been studied in many ways. Model-Agnostic Meta-Learning (MAML), one of the successful methods in gradient- based meta-learning, consists of the inner loop adapting new tasks by learning task-specific knowledge and the outer loop finding meta-initialization primed for rapid learning. Recent work BOIL (Body Only update in Inner Loop) tried to control the inner loop by freezing the classifier (last layers) to achieve representation change while ANIL (Almost No Inner Loop) only updates the classifier for feature reuse. We bring our intuition about adapting to new tasks from previous works that the degree of weight change in different layers differs a lot. We define the priority as the degree of change in each layer and propose a novel priority-based adaptation to adapt to new tasks named Gradient Adjustment in Inner Loop (GAIL) by multiplying the per-layer priority to the corresponding layer's gradient vector. We figure out that adjusted gradients with GAIL in the inner loop for different tasks have similar directions and compared to the original gradient, the mean direction of the adjusted gradients for different tasks from GAIL is statistically better aligned with the direction of the global solution in multiple tasks with a convex quadratic loss function. Experimental results show that GAIL has a faster and better convergence behavior than previous inner loop variation methods. The code is provided in here https://drive.google.com/file/d/1zkn2M_VEXRzzdBediIrJz4PhXN8uYEJ1/view?usp=sharing.N
Monolithically stacked VIA-free liquid metal circuit for stretchable ele ctronics
No full textResearchers are eagerly developing stretchable conductors because they constitute basic building blocks for stretchable electronic devices in the fields of wearable electronics, soft robotics, and human- machine interfaces. Though various stretchable conductors with high stability are being devised, fabricating stretchable stacked circuits with them leads to new challenges. The most critical problem is evoked by vertical interconnection access (VIA) structures, which inevitably become stress- concentrated areas when stretched. Consequently, stretchable circuits become much more unstable when manufactured as stacked circuits than single-layered circuits. Here, we demonstrate a monolithically stacked VIA-free stretchable liquid metal circuit that is mechanically one-body- merged and electrically stacked-circuit-designed. The circuit has no vertical structures, which endows extreme electromechanical stability with various features. It is realized by unique combinations of liquid metal conductor and selective surface treatment. The stacked circuit can be elongated over 1,100 % strain, demonstrating negligible difference in stretchability compared to a single-layered circuit. The circuit also possesses various distinctive characteristics of security, choosability, and extendability. As proof, we demonstrate an encryption element, a choosable circuit, an extendable circuit, and other functional circuits. We expect the proposed stacked circuit to give directions to stretchable stacked electronics with various functionalities.N
Molecular determinants of response to neoadjuvant pembrolizumab plus chemotherapy in patients with high-risk, early-stage, triple-negative breast cancer: exploratory analysis of the open-label, multicohort phase 1b KEYNOTE-173 study
No full textBackgroundThe multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response.MethodsCell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures using RNA sequencing) and pathologic complete response (pCR).ResultsAt baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c+ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63-1.00), CD11c+/MHCII+/CD163-/CD68- cells (DC: 0.76; 95% CI, 0.53-0.99), CD11c+/MHCII-/CD163-/CD68- cells (nonactivated/immature DC: 0.80; 95% CI 0.54-1.00), and CD11c+/CD163+ cells (M2 macrophage: 0.77; 95% CI 0.55-0.99). Other associations with pCR included baseline CD11c+/MHCII-/CD163-/CD68- (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51-1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52-0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on TcellinfGEP was 0.55 (95% CI 0.25-0.85); when detrended by TcellinfGEP, AUROC varied for the non-TcellinfGEP signatures. TcellinfGEP expression trended higher in responders than in nonresponders when evaluating pCR.ConclusionsMyeloid cell populations within the tumor compartment at baseline and TcellinfGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy.Trial registrationClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.Y
Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer
No full textBackground Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression.Methods Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade.Results In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-beta, TNF-alpha, IL-1 beta) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B+ or IFN gamma+ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFN gamma+ CD8 T-cells.Conclusions The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.N