E-cardiac patch to sense and repair infarcted myocardium.

Conductive cardiac patches can rebuild the electroactive microenvironment for the infarcted myocardium but their repair effects benefit by carried seed cells or drugs. The key to success is the effective integration of electrical stimulation with the microenvironment created by conductive cardiac patches. Besides, due to the concerns in a high re-admission ratio of heart patients, a remote medicine device will underpin the successful repair. Herein, we report a miniature self-powered biomimetic trinity triboelectric nanogenerator with a unique double-spacer structure that unifies energy harvesting, therapeutics, and diagnosis in one cardiac patch. Trinity triboelectric nanogenerator conductive cardiac patches improve the electroactivity of the infarcted heart and can also wirelessly monitor electrocardiosignal to a mobile device for diagnosis. RNA sequencing analysis from rat hearts reveals that this trinity cardiac patches mainly regulates cardiac muscle contraction-, energy metabolism-, and vascular regulation-related mRNA expressions in vivo. The research is spawning a device that truly integrates an electrical stimulation of a functional heart patch and self-powered e-care remote diagnostic sensor.

China's "coal-to-gas" policy had large impact on PM1.0 distribution during 2016-2019.

Particulate matter with an aerodynamic diameter of less than 1 µm (PM1.0) can be extremely hazardous to human health, so it is imperative to accurately estimate the spatial and temporal distribution of PM1.0 and analyze the impact of related policies on it. In this study, a stacking generalization model was trained based on aerosol optical depth (AOD) data from satellite observations, combined with related data affecting aerosol concentration such as meteorological data and geographic data. Using this model, the PM1.0 concentration distribution in China during 2016-2019 was estimated, and verified by comparison with ground-based stations. The coefficient of determination (R2) of the model is 0.94, and the root-mean-square error (RMSE) is 8.49 µg/m3, mean absolute error (MAE) is 4.10 µg/m3, proving that the model has a very high performance. Based on the model, this study analyzed the PM1.0 concentration changes during the heating period (November and December) in the regions where the "coal-to-gas" policy was implemented in China, and found that the proposed "coal-to-gas" policy did reduce the PM1.0 concentration in the implemented regions. However, the lack of natural gas due to the unreasonable deployment of the policy in the early stage caused the increase of PM1.0 concentration. This study can provide a reference for the next step of urban air pollution policy development.

Green Space Morphology and School Myopia in China.

Importance: China has experienced both rapid urbanization and major increases in myopia prevalence. Previous studies suggest that green space exposure reduces the risk of myopia, but the association between myopia risk and specific geometry and distribution characteristics of green space has yet to be explored. These must be understood to craft effective interventions to reduce myopia. Objective: To evaluate the associations between myopia and specific green space morphology using novel quantitative data from high-resolution satellite imaging. Design, Setting, and Participants: This prospective cohort study included students grades 1 to 4 (aged 6 to 9 years) in Shenzhen, China. Baseline data were collected in 2016-2017, and students were followed up in 2018-2019. Data were analyzed from September 2020 to January 2022. Exposures: Eight landscape metrics were calculated using land cover data from high-resolution Gaofen-2 satellite images to measure area, aggregation, and shape of green space. Main Outcome and Measures: The 2-year cumulative change in myopia prevalence at each school and incidence of myopia at the student level after 2 years were calculated as main outcomes. The associations between landscape metrics and school myopia were assessed, controlling for geographical, demographic, and socioeconomic factors. Principal component analyses were performed to further assess the joint effect of landscape metrics at the school and individual level. Results: A total of 138 735 students were assessed at baseline. Higher proportion, aggregation, and better connectivity of green space were correlated with slower increases in myopia prevalence. In the principal component regression, a 1-unit increase in the myopia-related green space morphology index (the first principal component) was negatively associated with a 1.7% (95% CI, -2.7 to -0.6) decrease in myopia prevalence change at the school level (P = .002). At the individual level, a 1-unit increase in myopia-related green space morphology index was associated with a 9.8% (95% CI, 4.1 to 15.1) reduction in the risk of incident myopia (P < .001), and the association remained after further adjustment for outdoor time, screen time, reading time, and parental myopia (adjusted odds ratio, 0.88; 95% CI, 0.80 to 0.97; P = .009). Conclusions and Relevance: Structure of green space was associated with a decreased relative risk of myopia, which may provide guidance for construction and renovation of schools. Since risk estimates only indicate correlations rather than causation, further interventional studies are needed to assess the effect on school myopia of urban planning and environmental designs, especially size and aggregation metrics of green space, on school myopia.

Unlocking CAR T cell potential: Inosine-induced stemness and enhanced potency.

Adenosine (Ado) drives immune suppression in the tumor microenvironment. In this issue of Cancer Cell, Klysz et al. investigate Ado-mediated immunosuppression. Overexpression of Ado deaminase (ADA-OE), metabolizing Ado to inosine (INO), induces stemness and improves CAR T cell functionality. Likewise, exposure to INO enhances CAR T cells' function and induces stemness features.

Robust algorithm for precise XCO2 retrieval using single observation of IPDA LIDAR.

CO2 column-weighted dry-air mixing ratio (XCO2) products with high precision and spatial resolution are essential for inverting CO2 fluxes and promoting our understanding of global climate change. Compared with passive remote sensing methods, IPDA LIDAR, as an active remote sensing technique, offers many advantages in measuring XCO2. However, a significant random error in IPDA LIDAR measurements causes XCO2 values calculated directly from LIDAR signals to be unqualified as the final XCO2 products. Hence, we propose an efficient particle filter-based inversion of CO2 for single observation (EPICSO) algorithm to precisely retrieve the XCO2 of every LIDAR observation while preserving the high spatial resolution of LIDAR measurements. The EPICSO algorithm adopts the sliding average results as the first estimate of the local XCO2; subsequently, it estimates the difference between two adjacent XCO2 points and calculates the posterior probability of XCO2 based on particle filter theory. To evaluate the performance of the EPICSO algorithm numerically, we perform an EPICSO to process pseudo-observation data. The simulation results show that the results retrieved by the EPICSO algorithm satisfy the required high precision and that the algorithm is robust to a significant amount of random errors. In addition, we utilize LIDAR observation data from actual experiments in Hebei, China, to validate the performance of the EPICSO algorithm. The results retrieved by the EPICSO algorithm are more consistent with the actual local XCO2 than those of the conventional method, indicating that the EPICSO algorithm is efficient and practical for retrieving XCO2 with high precision and spatial resolution.

Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models.

CD8+ exhausted T cells (Tex) are heterogeneous. PD-1 inhibitors reinvigorate progenitor Tex, which subsequently differentiate into irresponsive terminal Tex. The ability to maintain a capacity for durable proliferation of progenitor Tex is important, but the mechanism remains unclear. Here, we showed CD8+ progenitor Tex pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti-PD-1 treatment in vitro. Treatment with decitabine plus anti-PD-1 promoted the activation and expansion of tumor-infiltrated CD8+ progenitor Tex and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti-PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor Tex compared with anti-PD-1 monotherapy and restrained CD8+ T cell terminal differentiation. Strikingly, decitabine plus anti-PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8+ T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8+ progenitor Tex populations and improve responsiveness to anti-PD-1 therapy.

Origins of black carbon from anthropogenic emissions and open biomass burning transported to Xishuangbanna, Southwest China.

Black carbon (BC) has importance regarding aerosol composition, radiative balance, and human exposure. This study adopted a backward-trajectory approach to quantify the origins of BC from anthropogenic emissions (BCAn) and open biomass burning (BCBB) transported to Xishuangbanna in 2017. Haze months, between haze and clean months, and clean months in Xishuangbanna were defined according to daily PM2.5 concentrations of >75, 35-75, and <35 µg/m3, respectively. Results showed that the transport efficiency density (TED) of BC transported to Xishuangbanna was controlled by the prevailing winds in different seasons. The yearly contributions to the effective emission intensity of BCAn and BCBB transported to Xishuangbanna were 52% and 48%, respectively. However, when haze occurred in Xishuangbanna, the average BCAn and BCBB contributions were 23% and 77%, respectively. This suggests that open biomass burning (BB) becomes the dominant source in haze months. Myanmar, India, and Laos were the dominant source regions of BC transported to Xishuangbanna during haze months, accounting for 59%, 18%, and 13% of the total, respectively. Furthermore, India was identified as the most important source regions of BCAn transported to Xishuangbanna in haze months, accounting for 14%. The two countries making the greatest contributions to BCBB transported to Xishuangbanna were Myanmar and Laos in haze months, accounting for 55% and 13%, respectively. BC emissions from Xishuangbanna had minimal effects on the results of the present study. It is suggested that open BB in Myanmar and Laos, and anthropogenic emissions in India were responsible for poor air quality in Xishuangbanna.

Constraining China's land carbon sink from emerging satellite CO2 observations: Progress and challenges.

Land carbon sink is a vital component for the achievement of China's ambitious carbon neutrality goal, but its magnitude is poorly known. Atmospheric observations and inverse models are valuable tools to constrain the China's land carbon sink. Space-based CO2 measurements from satellites form an emerging data stream for application of such atmospheric inversions. Here, we reviewed the satellite missions that is dedicated to the monitoring of CO2 , and the recent progresses on the inversion of China's land carbon sink using satellite CO2 measurements. We summarized the limitations and challenges in current space platforms, retrieval algorithms, and the inverse modeling. It is shown that there are large uncertainties of contemporary satellite-based estimates of China's land carbon sink. We discussed future opportunities of continuous improvements in three aspects to better constrain China's land carbon sink with space-based CO2 measurements.

Bridging wounds: tissue adhesives' essential mechanisms, synthesis and characterization, bioinspired adhesives and future perspectives.

Bioadhesives act as a bridge in wound closure by forming an effective interface to protect against liquid and gas leakage and aid the stoppage of bleeding. To their credit, tissue adhesives have made an indelible impact on almost all wound-related surgeries. Their unique properties include minimal damage to tissues, low chance of infection, ease of use and short wound-closure time. In contrast, classic closures, like suturing and stapling, exhibit potential additional complications with long operation times and undesirable inflammatory responses. Although tremendous progress has been made in the development of tissue adhesives, they are not yet ideal. Therefore, highlighting and summarizing existing adhesive designs and synthesis, and comparing the different products will contribute to future development. This review first provides a summary of current commercial traditional tissue adhesives. Then, based on adhesion interaction mechanisms, the tissue adhesives are categorized into three main types: adhesive patches that bind molecularly with tissue, tissue-stitching adhesives based on pre-polymer or precursor solutions, and bioinspired or biomimetic tissue adhesives. Their specific adhesion mechanisms, properties and related applications are discussed. The adhesion mechanisms of commercial traditional adhesives as well as their limitations and shortcomings are also reviewed. Finally, we also discuss the future perspectives of tissue adhesives.

Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells.

Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors, and one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model and found that depletion of basic leucine zipper ATF-like transcription factor (BATF) improved the antitumor performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, loss of BATF endows T cells with improved resistance to exhaustion and superior tumor eradication efficacy. Mechanistically, we found that BATF binds to and up-regulates a subset of exhaustion-related genes in human CAR-T cells. BATF regulates the expression of genes involved in development of effector and memory T cells, and knocking out BATF shifts the population toward a more central memory subset. We demonstrate that BATF is a key factor limiting CAR-T cell function and that its depletion enhances the antitumor activity of CAR-T cells against solid tumors.

Pulsed low-dose rate radiotherapy has an improved therapeutic effect on abdominal and pelvic malignancies.

Until now, there has been a lack of standard and effective treatments for patients with recurrent malignant tumors or abdominal and pelvic malignancies with extensive invasion (Morris, 2000). Generally, these patients face problems such as inability to undergo surgery or chemotherapy resistance (Combs et al., 2016). Re-radiotherapy has achieved a prominent place in the treatment of patients who have received radiotherapy previously and developed in-field recurrences (Straube et al., 2018). However, re-radiotherapy is very complicated, requiring comprehensive consideration of appropriate radiation dose, interval from first radiotherapy, boundary of the radiotherapy target area, and damage to surrounding normal tissues (Straube et al., 2019). In other words, it is necessary to focus on the protection of surrounding normal tissues while maximizing the efficacy of re-radiotherapy in such patients.

Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors.

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7-14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

Clinical and laboratory characteristics of severe and non-severe patients with COVID-19: A retrospective cohort study in China.

BACKGROUND: Patients diagnosed with the novel coronavirus disease (COVID-19) who develop severe symptoms need to be determined in advance so that appropriate treatment strategies are in place. METHODS: To determine the clinic features of patients diagnosed definitely with COVID-19 and evaluate risk factors for severe outcome, the medical records of hospitalized patients were reviewed retrospectively by us and data were compiled. Laboratory data from 90 cases were analyzed, and COVID-19 patients were classified into two groups (severe and non-severe) based on the severity. RESULTS: Severe COVID-19 cases on admission had higher leukocyte and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), D-dimer, fibrinogen, C-reactive protein levels, and lower lymphocyte counts compared with those of non-severe cases (p < 0.05). The area under the curve (AUC) for leukocyte counts, neutrophil counts, and levels of C-reactive protein was 0.778, 0.831, and 0.800, respectively. The thresholds were 7.70 × 109 /L for leukocyte counts, 5.93 × 109/L for neutrophil counts, and 75.07 mg/L for C-reactive protein, respectively. Logistic regression analyses indicated that higher white blood cell (WBC) counts (OR, 1.34; 95% CI, 1.05-1.71), neutrophil counts (OR, 1.35; 95% CI, 1.06-1.73), and C-reactive protein levels (OR, 1.02; 95% CI, 1.0-1.04) were several predictive factors for severe outcome. Severe COVID-19 patients had a reduction in WBC counts, D-dimer, C-reactive protein, and fibrinogen upon discharge from hospital, while lymphocyte counts increased (p < 0.05). CONCLUSION: Counts of WBC, neutrophil, and lymphocyte, NLR, and levels of C-reactive protein, D-dimer, and fibrinogen are helpful for prediction of the deterioration trend in patients diagnosed with COVID-19.

In Situ Growth of Oriented Polyaniline Nanorod Arrays on the Graphite Flake for High-Performance Supercapacitors.

Polyaniline with oriented nanorod arrays could provide high surface area and relaxed nanostructure to optimize ion diffusion paths, thus enhancing the performance of the device. In this paper, we designed an all-solid symmetrical supercapacitor with good performance based on polyaniline nanorod arrays in situ-grown on a graphite flake free-standing substrate. The specific capacitance, cycle stability, and energy density of the prepared supercapacitor device were 135 F/g, 75.4% retention after 1500 cycles, and the energy density is 18.75 W h/kg at a power density of 500 W/kg. The good performance of the supercapacitor device was obviously related to the oriented nanorod arrays of polyaniline/graphite flakes. In order to find the application of the prepared supercapacitor device, the tandem device consisting of three single supercapacitor devices connected in series had been used to drive small electronic equipment. The red light-emitting diode and chronograph could be easily driven by the 3-series supercapacitor devices. These results indicated that the prepared supercapacitor device based on the polyaniline/graphite flake electrode had potential applications in energy storage devices.

Increased Expression of T-Box Transcription Factor Protein 21 (TBX21) in Skin Cutaneous Melanoma Predicts Better Prognosis: A Study Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) Databases.

BACKGROUND T-box transcription factor protein 21 (TBX21) is expressed in immune cells and some tumor cells. Defects in TBX21 gene can cause Th1/Th2 imbalance, which is closely related to tumorigenesis. The expression and clinical value of TBX21 in skin cutaneous melanoma (SKCM) are not clear. MATERIAL AND METHODS RNA-Seq expression and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Wilcoxon signed-rank test and logistic regression were used to explore the relationship between TBX21 expression and clinical parameters such as gender, stage, etc. The correlation between clinicopathological characteristics and overall survival of SKCM patients was estimated by Cox regression and the Kaplan-Meier method. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) were conducted to analyze the potential mechanism of TBX21 in the progression of SKCM. RESULTS Compared with normal samples, TBX21 was significantly upregulated in SKCM tissues. SKCM patients with lower TBX21 expression might have a worse prognosis than those with higher TBX21 expression according to Kaplan-Meier survival analysis. Cox analysis also reached the same conclusion: TBX21 was an independent prognostic indicator. GSEA showed that the highly expressed phenotypes in TBX21 were enriched to varying degrees with various signaling pathways. PPI network showed the top 10 proteins that were closely related to TBX21. CONCLUSIONS TBX21 expression was significantly correlated with the prognosis of SKCM patients and was found to be involved in a great many immunological pathways that affect the occurrence and development of tumors.

Engineering T Cells Using CRISPR/Cas9 for Cancer Therapy.

Recent advances in the development of gene editing technologies, especially the CRISPR/Cas 9 system, have substantially enhanced our ability to make precise and efficient changes in the genomes of various cells. In particular, the genetic engineering of T cells holds huge potential to improve the efficacy and safety of T cells-based cancer therapy. Due to its ease of use and high efficiency, CRISPR/Cas9 enables efficient gene knockout, site-specific knock-in, and genome-wide screen in T cells. Here we review the current progress of applying gene editing to T-cell therapy, focusing on the technical aspects of the CRISPR/Cas9 platform. We also discuss the challenges and future prospects.

TGF-ß inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors.

In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-ß receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-ß-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors.

Improving radio-chemotherapy efficacy of prostate cancer by co-deliverying docetaxel and dbait with biodegradable nanoparticles.

Combining DNA damage repair inhibitors and chemotherapeutic agents is an emerging strategy in cancer treatment. In this study, we engineered the polycation nanoparticle (NP), which co-encapsulated DNA damage repair inhibitor Dbait and chemotherapeutic drug Docetaxel (Dtxl), using H1 nanopolymer (folate--polyethylenimine600-cyclodextrin), and the size of H1/Dbait/Dtxl was about 117 nm. We demonstrated that H1/Dbait/Dtxl enhanced the efficiency of radio-chemotherapy in prostate cancer cells by CCK-8 assay and colony-forming assay. Importantly, the improvement of radio-chemotherapy of H1/Dbait/Dtxl in prostate cancer was also validated in vivo, and the NP did not have a high toxicity profile. The results of immunohistochemistry and western blot supported that the improved therapeutic efficacy was through inhibiting DNA damage repair signalling pathway. Our study supports further investigations using NP to co-deliver DNA damage repair inhibitors and chemotherapeutics to improve the therapeutic efficacy of cancer.

A facile method in removal of PVP ligands from silver nanowires for high performance and reusable SERS substrate.

Silver nanowires (i.e., AgNWs) can act as effective surface-enhanced Raman spectroscopy (i.e., SERS) substrates to detect small molecules. However, a lot of prepared AgNWs were often wrapped by polyvinylpyrrolidone (i.e., PVP) thin film to form an insulating layer to produce ill-defined AgNWs-PVP-AgNWs interface, limiting the plasmonic coupling among the stacked AgNWs. Herein, we reported a facile method in removal of PVP ligands from AgNWs for high performance and reusable SERS substrate. Sodium borohydride (NaBH4) was used to completely remove the PVP ligands from the surface of AgNWs and produce a clean AgNWs-AgNWs interface that effectively enhances the localized surface plasmon resonance (i.e., LSPR) was produced, greatly improving the SERS activity of the AgNWs thin film. The SERS detection of rhodamine 6G (i.e., R6G) used with PVP AgNWs and without PVP AgNWs is 1.0 × 10-9 and 1.0 × 10-15 M, and the average enhancement factor (EF) is about 0.86 × 104 and 9.35 × 104, respectively. Moreover, the recyclable behavior of the AgNWs with several analyte molecules is much more interesting than that of the PVP@AgNWs. The SERS detection of AgNWs for R6G, the 3-mercaptopropionic acid (i.e., 3-MPA) and melamine with good recyclability in nanomolar and millimolar concentration can be easily detected.