Polylevodopa nanoplatform for lateral flow immunochromatography assay of SARS-CoV-2 and influenza A virus.

At the end of 2019, an unprecedented outbreak of novel coronavirus pneumonia ravaged the global landscape, inflicting profound harm upon society. Following numerous cycles of transmission, we find ourselves in an epoch where the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coexists alongside influenza viruses (Flu A). Swift and accurate diagnosis of SARS-CoV-2 and Flu A is imperative to stem the spread of these maladies and administer appropriate treatment. Presently, colloidal gold-based lateral flow immunoassays (Au-LFIAs) constructed through electrostatic adsorption are beset by challenges such as diminished sensitivity and feeble binding stability. In this context, we propose the adoption of black polylevodopa nanoparticles (PLDA NPs) featuring abundant carboxyl groups as labeling nanomaterials in LFIA to bolster the stability and sensitivity of SARS-CoV-2 antigens and influenza A virus identifications. The engineered PLDA-LFIAs exhibit the capacity to detect SARS-CoV-2 and Flu A within 30 min, boasting a detection threshold of 5 pg/ml for the SARS-CoV-2 antigen and 0.1 ng/ml for the Flu A H1N1 antigen, thereby underscoring their heightened sensitivity relative to Au-LFIAs. These PLDA-LFIAs hold promise for the early detection of SARS-CoV-2 and Flu A, underscoring the potential of PLDA NPs as a discerning labeling probe to heighten the sensitivity of LFIA across diverse applications.

Ultrathin, Mechanically Durable, and Scalable Polymer-in-Salt Solid Electrolyte for High-Rate Lithium Metal Batteries.

Polymer-in-salt solid-state electrolytes (PIS SSEs) are emerging for high room-temperature ionic conductivity and facile handling, but suffer from poor mechanical durability and large thickness. Here, Al2O3-coated PE (PE/AO) separators are proposed as robust and large-scale substrates to trim the thickness of PIS SSEs without compromising mechanical durability. Various characterizations unravel that introducing Al2O3 coating on PE separators efficiently improves the wettability, thermal stability, and Li-dendrite resistance of PIS SSEs. The resulting PE/AO@PIS demonstrates ultra-small thickness (25 µm), exceptional mechanical durability (55.1 MPa), high decomposition temperature (330 °C), and favorable ionic conductivity (0.12 mS cm-1 at 25 °C). Consequently, the symmetrical Li cells remain stable at 0.1 mA cm-2 for 3000 h, without Li dendrite formation. Besides, the LiFePO4|Li full cells showcase excellent rate capability (131.0 mAh g-1 at 10C) and cyclability (93.6% capacity retention at 2C after 400 cycles), and high-mass-loading performance (7.5 mg cm-2). Moreover, the PE/AO@PIS can also pair with nickel-rich layered oxides (NCM811 and NCM9055), showing a remarkable specific capacity of 165.3 and 175.4 mAh g-1 at 0.2C after 100 cycles, respectively. This work presents an effective large-scale preparation approach for mechanically durable and ultrathin PIS SSEs, driving their practical applications for next-generation solid-state Li-metal batteries.

A Self-Powered Lactate Sensor Based on the Piezoelectric Effect for Assessing Tumor Development.

The build-up of lactate in solid tumors stands as a crucial and early occurrence in malignancy development, and the concentration of lactate in the tumor microenvironment may be a more sensitive indicator for analyzing primary tumors. In this study, we designed a self-powered lactate sensor for the rapid analysis of tumor samples, utilizing the coupling between the piezoelectric effect and enzymatic reaction. This lactate sensor is fabricated using a ZnO nanowire array modified with lactate oxidase (LOx). The sensing process does not require an external power source or batteries. The device can directly output electric signals containing lactate concentration information when subjected to external forces. The lactate concentration detection upper limit of the sensor is at least 27 mM, with a limit of detection (LOD) of approximately 1.3 mM and a response time of around 10 s. This study innovatively applied self-powered technology to the in situ detection of the tumor microenvironment and used the results to estimate the growth period of the primary tumor. The availability of this application has been confirmed through biological experiments. Furthermore, the sensor data generated by the device offer valuable insights for evaluating the likelihood of remote tumor metastasis. This study may expand the research scope of self-powered technology in the field of medical diagnosis and offer a novel perspective on cancer diagnosis.

Multifunctional Nanoassembly for MRI-Trackable Dendritic Cell Dependent and Independent Photoimmunotherapy.

Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells' inadequate antigenicity and the tumor microenvironment's low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn2+) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn2+ into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.

Highly Sensitive Imaging of Tumor Metastasis Based on the Targeting and Polarization of M2-like Macrophages.

Tumor-associated macrophages, especially M2-like macrophages, are extensively involved in tumor growth and metastasis, suppressing the innate immunity to help tumor cells escape and reshaping the microenvironment to help metastatic cells grow. However, in vivo, real-time visualized migration of M2-like macrophages has never been explored to monitor the tumor metastasis process. Herein, we prepared an M2-like macrophage-targeting nitric oxide (NO)-responsive nanoprobe (NRP@M-PHCQ) consisting of an amphiphilic block copolymer with mannose and hydroxychloroquine (HCQ) moieties (denoted as M-PHCQ) and a NO-responsive NIR-II probe (denoted as NRP). The mannose moieties provided M2-like macrophage-targeting capacity, and the HCQ moieties polarized M2-like macrophages to M1-like ones with enhanced NO secretion. Consequently, NRP@M-PHCQ was lit up by the secreted NO to visualize the migration and polarization of M2-like macrophages in real time. In vivo metastasis imaging with NRP@M-PHCQ successfully tracked early tumor metastasis in the lymph nodes and the lungs with high sensitivity, even superior to Luci-labeled bioluminescence imaging, suggesting the extensive distribution and critical role of M2-like macrophages in tumor metastasis. In general, this work provided a new strategy to sensitively image metastatic tumors by tracking the polarization of M2-like macrophages and visually disclosed the critical role of M2-like macrophages in early tumor metastasis.

Plasma soluble suppression of tumorigenicity 2 and depression after acute ischemic stroke.

BACKGROUND AND PURPOSE: Soluble suppression of tumorigenicity 2 (sST2) might be related to stroke and depression, but the association of sST2 with poststroke depression (PSD) is unclear. The study aimed to prospectively assess the association between plasma sST2 levels and PSD. METHODS: A total of 635 acute ischemic stroke patients with sST2 measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24-item Hamilton Rating Scale for Depression to assess depression at 3 months, and PSD was defined as a score of ≥8. Logistic regression analysis was performed to estimate the risk of PSD associated with sST2, and net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive value of sST2. RESULTS: Two hundred fifty (39.4%) patients developed depression at 3 months after ischemic stroke. Patients with PSD had higher sST2 levels than patients without PSD (172.7 vs. 153.8 pg/ml; p = 0.003). After adjustment for age, sex, education, National Institutes of Health Stroke Scale score, and other covariates, the odds ratio for the highest quartile of sST2 compared with the lowest quartile was 1.84 (95% confidence interval, 1.10-3.08) for PSD. Adding sST2 to a conventional model notably improved risk prediction for PSD (category-free NRI = 19.34%, 95% confidence interval = 4.39%-34.28%, p = 0.017; IDI = 1.20%, 95% confidence interval = 0.25%-2.15%, p = 0.014). CONCLUSIONS: Increased plasma sST2 levels in the acute phase of ischemic stroke were significantly associated with the increased risk of PSD, independently of conventional risk factors.

Serum tissue inhibitor of metalloproteinase-1 and risk of cognitive impairment after acute ischaemic stroke.

The expression of tissue inhibitor metalloproteinase-1 (TIMP-1) significantly increased after acute cerebral ischaemia and involved in neurodegeneration. The purpose was to prospectively investigate the relationship between serum TIMP-1 with post-stroke cognitive impairment. Our participants were from an ancillary study of China Antihypertensive Trial in Acute Ischemic Stroke. 598 ischaemic stroke patients from seven participating hospitals were included. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months. 316 (52.84%) or 384 (64.21%) participants had cognitive impairment according to MMSE or MoCA, respectively. Compared with the first quartile of TIMP-1, the multivariate-adjusted odds ratios (95% confidence intervals) for the highest quartile were 1.80 (1.09-2.97) for cognitive impairment defined by MMSE and 2.55 (1.49-4.35) by MoCA. Multiple-adjusted spline regression models showed linear associations between TIMP-1 concentrations and cognitive impairment (P value for linearity < 0.01). The addition of TIMP-1 to models including conventional factors improved reclassification for cognitive impairment, as shown by net reclassification index or integrated discrimination improvement (P < 0.05). Participants with both higher TIMP-1 and matrix metalloproteinase-9 levels simultaneously had highest risk of cognitive impairment. Higher serum TIMP-1 levels were associated with increased risk of cognitive impairment after acute ischaemic stroke, independently of established risk factors.

High Density Glycopolymers Functionalized Perylene Diimide Nanoparticles for Tumor-Targeted Photoacoustic Imaging and Enhanced Photothermal Therapy.

Near-infrared (NIR) absorbing nanoagents with functions of photoacoustic imaging (PAI) and photothermal therapy (PTT) have received great attention for cancer therapy. However, endowing them with multifunctions, especially targeting ability, for enhancing in vivo PAI/PTT generally suffers from the problems of synthetic complexity and low surface density of function groups. We herein report high density glycopolymers coated perylenediimide nanoparticles (PLAC-PDI NPs), self-assembled by poly(lactose)-modified perylenediimide (PLAC-PDI), as tumor-targeted PAI/PTT nanoagents. Atom transfer radical polymerization and click reaction were used in sequence to prepare PLAC-PDI, which can accurately control the content of poly(lactose) (PLAC) in PLAC-PDI and endow PLAC-PDI NPs with high density PLAC surface. The high density PLAC surface provided NPs with long-time colloidal stability, outstanding stability in serum and light, and specific targeting ability to cancer cells and tumors. Meanwhile, PLAC-PDI NPs also presented high photothermal conversion efficiency of 42% by virtue of strong π-π interactions among perylenediimide molecules. In living mice, PAI experiments revealed that PLAC-PDI NPs exhibited effective targeting ability and enhanced PTT efficacy to HepG2 tumor compared with control groups, lactose blocking, and ASGP-R negative tumor groups. Overall, our work provids new insights for designing glycopolymers-based therapeutic nanoagents for efficient tumor imaging and antitumor therapy.

Unveiling the link: Neonicotinoids and elevated cardiometabolic risks in Chinese rural residents-from a prospective cohort study combing mendelian randomization study.

PURPOSE: This study aimed to evaluate the relationships of separate and mixed exposure of neonicotinoids on cardiometabolic risk at baseline and follow-up and its change over 3 years, and further explore whether inflammatory markers levels and platelet traits (PLT) mediate these relationships. METHODS: In this prospective cohort study from the Henan Rural Cohort Study, 2315 participants were involved at baseline, and 1841 participants completed cardiometabolic risk predictors determinations during the 3-year follow-up. Each neonicotinoid pesticide was normalized to imidacloprid (IMIeq) using the relative potency factor approach. Quantile-based g-computation (Qgcomp) regression was used to evaluate the effect of the mixtures of neonicotinoids mediation analysis was employed to explore whether inflammatory markers levels and platelet traits mediated these relationships. A two-sample mendelian randomization (MR) study was further used to causal association. RESULTS: Qgcomp regression revealed a statistically positive relationship between neonicotinoids mixture exposure and cardiometabolic risk score at baseline and follow-up over 3 years. Both neutrophils/monocytes and PLT were mediators in the relationship between IMIeq and cardiometabolic risk score at baseline and follow-up over 3 years. The causal risk effect of pesticide exposure were 2.50 (0.05, 4.95) and 5.24 (1.28, 9.19) for cardiometabolic risk indicators including insulin resistance and triglyceride, respectively. Nevertheless, there was no correlation discovered between pesticide exposure and other markers of cardiometabolic risk. CONCLUSION: Neonicotinoid insecticides exposure was connected to an increased cardiometabolic risk, especially in individuals with T2DM. Furthermore, inflammatory markers and PLT seem to be two vital mediators of these associations. Additionally, genetic evidence on pesticide exposure and cardiometabolic risk still needs to be validated by multiregional and multiethnic GWAS studies.

Robust self-cleaning membrane with superhydrophilicity and underwater superoleophobicity for oil-in-water separation.

The discharge of oily wastewater has increased dramatically and will bring serious environmental problems. In this work, a self-cleaning and anti-fouling g-C3N4/TiO2/PVDF composite membrane was fabricated via the layer-by-layer approach. The surface of as-prepared composite membrane displayed a superhydrophilic and underwater superoleophobic behavior under irradiation with visible light. Also, upon irradiation with visible light, the fabricated g-C3N4/TiO2/PVDF composite membrane displayed enhanced permeation flux and improved oil removal efficiency as a result of the generation of hydroxyl free radicals during the photocatalytic filtration process. Significantly, irradiation with visible light remarkably improved reusability of the composite membrane by initiating photocatalytic decomposition of deposited oil foulants, which enabled removal of over 99.75% of oils, thus reaching a nearly 100% flux recovery ratio. Furthermore, the g-C3N4/TiO2/PVDF composite membrane exhibited great anti-fouling behavior in photocatalysis-assisted filtration. The mechanistic study revealed that underwater superhydrophobicity and the generation of free hydroxyl radicals jointly contributed to membrane anti-fouling. The greatest advantages of this g-C3N4/TiO2/PVDF composite membrane are that not only does it degrades the oil pollutants, but it also makes the membrane less vulnerable to fouling.

Real-Time Objective Evaluation of the Ischemic Stroke through pH-Responsive Fluorescence Imaging.

A rapid and comprehensive assessment of ischemic stroke (IS) is critical for clinicians to take the most appropriate treatment. Currently, IS assessment is mainly carried out by computed tomography and magnetic resonance imaging in combination with observing the clinical symptoms and inquiring about contraindications. However, they cannot diagnose pathological conditions and judge the microenvironment in real-time. Near-infrared fluorescence imaging has advantages for IS imaging, such as high sensitivity, high spatiotemporal resolution, and straightforward real-time operation. Herein, a pH-responsive fluorescent liposomal probe (BOD@Lip) is prepared for in vivo real-time visualization of the degree of IS based on the different acid microenvironments in the progression of the disease. The fluorescence imaging with BOD@Lip shows the degree of IS, and the correlation between fluorescence signals and the neurological deficit scores is established for the first time. This work provides a new method to objectively evaluate the degree of IS through a visualized route and a new insight into the relationship between the acidic microenvironment and the progression of IS.

A ROS-responsive synergistic delivery system for combined immunotherapy and chemotherapy.

Immune checkpoint blockade (ICB) therapies that target programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway are currently used for the treatment of various cancer types. However, low response rates of ICB remain the major issue and limit their applications in clinic. Here, we developed a ROS-responsive synergistic delivery system (pep-PAPM@PTX) by integrating physically-encapsulated paclitaxel (PTX) and surface-modified anti-PD-L1 peptide (pep) for combined chemotherapy and ICB therapy. Pep-PAPM@PTX could bind the cell surface PD-L1 and drive its recycling to lysosomal degradation, thus reverting PTX-induced PD-L1 upregulation and downregulating PD-L1 expression. As a result, pep-PAPM@PTX significantly promoted T cell infiltration and increased tumor immunoactivating factors, synergizing PTX chemotherapy to achieve enhanced anticancer potency in a triple-negative breast cancer (TNBC) model.

Mitochondria-Targeting Polymer Micelle of Dichloroacetate Induced Pyroptosis to Enhance Osteosarcoma Immunotherapy.

Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.

Novel Cyclic Peptides from Lethal Amanita Mushrooms through a Genome-Guided Approach.

Most species in the genus Amanita are ectomycorrhizal fungi comprising both edible and poisonous mushrooms. Some species produce potent cyclic peptide toxins, such as α-amanitin, which places them among the deadliest organisms known to mankind. These toxins and related cyclic peptides are encoded by genes of the "MSDIN" family (named after the first five amino acid residues of the precursor peptides), and it is largely unknown to what extent these genes are expressed in the basidiocarps. In the present study, Amanita rimosa and Amanita exitialis were sequenced through the PacBio and Illumina techniques. Together with our two previously sequenced genomes, Amanita subjunquillea and Amanita pallidorosea, in total, 46 previously unknown MSDIN genes were discovered. The expression of over 80% of the MSDIN genes was demonstrated in A. subjunquillea. Through a combination of genomics and mass spectrometry, 12 MSDIN genes were shown to produce novel cyclic peptides. To further confirm the results, three of the cyclic peptides were chemically synthesized. The tandem mass spectrometry (MS/MS) spectra of the natural and the synthetic peptides shared a majority of the fragment ions, demonstrating an identical structure between each peptide pair. Collectively, the results suggested that the genome-guided approach is reliable for identifying novel cyclic peptides in Amanita species and that there is a large peptide reservoir in these mushrooms.

Learning From Large-Scale Noisy Web Data With Ubiquitous Reweighting for Image Classification.

Many important advances of deep learning techniques have originated from the efforts of addressing the image classification task on large-scale datasets. However, the construction of clean datasets is costly and time-consuming since the Internet is overwhelmed by noisy images with inadequate and inaccurate tags. In this paper, we propose a Ubiquitous Reweighting Network (URNet) that can learn an image classification model from noisy web data. By observing the web data, we find that there are five key challenges, i.e., imbalanced class sizes, high intra-classes diversity and inter-class similarity, imprecise instances, insufficient representative instances, and ambiguous class labels. With these challenges in mind, we assume every training instance has the potential to contribute positively by alleviating the data bias and noise via reweighting the influence of each instance according to different class sizes, large instance clusters, its confidence, small instance bags, and the labels. In this manner, the influence of bias and noise in the data can be gradually alleviated, leading to the steadily improving performance of URNet. Experimental results in the WebVision 2018 challenge with 16 million noisy training images from 5000 classes show that our approach outperforms state-of-the-art models and ranks first place in the image classification task.

Conjugated Polymer Brush Based on Poly(l-lysine) with Efficient Ovalbumin Delivery for Dendritic Cell Vaccine.

Dendritic cell (DC)-based vaccines consist of antigens and antigen-presenting cells, such as DCs, that can induce antitumor immune response and extend the lives of patients. In this research, a water-soluble conjugated polymer brush (WSCPB) made of poly(l-lysine) (PLL) and poly(p-phenyleneethynylene) (PPE) was applied to an antigen delivery system for the development of a DC vaccine. We synthesized the WSCPB with a lower proportion of the rigid PPE polymer backbone and a large amount of PLL side chains. The rigid backbone retained a stable optical performance within the experimental range, which enabled the visualization of the payload and cellular imaging as a reporter. Because of the unique brushlike structure, PPE-PLL exhibited not only excellent water solubility but also outstanding antigen-loading capacity. Ovalbumin (OVA), a model antigen in different research, could be adsorbed onto PPE-PLL and then taken up by DCs. Subsequently, DC maturation and cytokine release would be induced by the antigen. In vivo, strong immune responses were induced after the injection of antigen-pulsed DCs, and the level of cytokines in the serum was significantly increased. In addition, the study of the in vivo tumor-suppressor activity of these antigen-pulsed DCs revealed that the DC vaccine induced strong immune responses and thereby effectively inhibited tumor development.