Machine-Learning-Assisted Procoagulant Extracellular Vesicle Barcode Assay toward High-Performance Evaluation of Thrombosis-Induced Death Risk in Cancer Patients.

Venous thromboembolism (VTE) is the most fatal complication in cancer patients. Unfortunately, the frequent misdiagnosis of VTE owing to the lack of accurate and efficient evaluation approaches may cause belated medical intervention and even sudden death. Herein, we present a rapid, easily operable, highly specific, and highly sensitive procoagulant extracellular vesicle barcode (PEVB) assay composed of TiO2 nanoflower (TiNFs) for visually evaluating VTE risk in cancer patients. TiNFs demonstrate rapid label-free EV capture capability by the synergetic effect of TiO2-phospholipids molecular interactions and topological interactions between TiNFs and EVs. From ordinary plasma samples, the PEVB assay can evaluate potential VTE risk by integrating TiNFs-based EV capture and in situ EV procoagulant ability test with machine-learning-assisted clinical data analysis. We demonstrate the feasibility of this PEVB assay in VTE risk evaluation by screening 167 cancer patients, as well as the high specificity (97.1%) and high sensitivity (96.8%), fully exceeding the nonspecific and posterior traditional VTE test. Together, we proposed a TiNFs platform allowing for highly accurate and timely diagnosis of VTE in cancer patients.

Direct annulation between glycine derivatives and thiiranes through photoredox/iron cooperative catalysis.

A visible-light-induced aerobic oxidative [2+3] cycloaddition reaction between glycine derivatives and thiiranes has been disclosed, which provides an efficient and atom-economical strategy for the rapid synthesis of thiazolidine-2-carboxylic acid derivatives and the post-modification of glycine-derived dipeptides under mild conditions with good yield and high diastereoselectivities. A preliminary mechanistic study favors a pathway involving a cooperative photoredox catalysis and iron catalysis.

Heterostructure particles enable omnidispersible in water and oil towards organic dye recycle.

Dispersion of colloidal particles in water or oil is extensively desired for industrial and environmental applications. However, it often strongly depends on indispensable assistance of chemical surfactants or introduction of nanoprotrusions onto the particle surface. Here we demonstrate the omnidispersity of hydrophilic-hydrophobic heterostructure particles (HL-HBPs), synthesized by a surface heterogeneous nanostructuring strategy. Photo-induced force microscopy (PiFM) and adhesion force images both indicate the heterogeneous distribution of hydrophilic domains and hydrophobic domains on the particle surface. These alternating domains allow HL-HBPs to be dispersed in various solvents with different polarity and boiling point. The HL-HBPs can efficiently adsorb organic dyes from water and release them into organic solvents within several seconds. The surface heterogeneous nanostructuring strategy provides an unconventional approach to achieve omnidispersion of colloidal particles beyond surface modification, and the omnidispersible HL-HBPs demonstrate superior capability for dye recycle merely by solvent exchange. These omnidispersible HL-HBPs show great potentials in industrial process and environmental protection.

Interfacial Polymerization Produced Magnetic Particles with Nano-Filopodia for Highly Accurate Liquid Biopsy in the PSA Gray Zone.

Magnetic particles are leading separation materials for biological purification and detection. Existing magnetic particles, which almost rely on molecule-level interactions, however, often encounter bottlenecks in highly efficient cell-level separation due to the underestimate of surface structure effects. Here, immune cell-inspired magnetic particles with nano-filopodia (NFMPs) produced by interfacial polymerization for highly efficient capture of circulating tumor cells (CTCs) and further accurate clinical diagnosis of prostate cancer are reported . The unprecedented construction of nano-filopodia on polymer-based magnetic particles is achieved by introducing electrostatic interactions in emulsion interfacial polymerization. Due to the unique nano-filopodia, the NFMPs allow remarkably enhanced CTCs capture efficiency (86.5% ± 2.8%) compared with smooth magnetic particles (SMPs, 35.7% ± 5.7%). Under the assistance of machine learning by combining with prostate-specific antigen (PSA) and free to total PSA (F/T-PSA), the NFMPs strategy demonstrates high sensitivity (100%), high specificity (93.3%), and a high area under the curve (AUC) value (98.1%) for clinical diagnosis of prostate cancer in the PSA gray zone. The NFMPs are anticipated as an efficient platform for CTCs-based liquid biopsy toward early cancer diagnosis and prognosis evaluation.

Investigating the adverse outcome pathways (AOP) of neurotoxicity induced by DBDPE with a combination of in vitro and in silico approaches.

Current studies have shown an association between DBDPE and neurotoxicity. In this study, the adverse outcome pathway (AOP) and mechanistic analysis of DBDPE-induced neurotoxicity were explored by a combination of in vitro and in silico approaches in SK-N-SH cells. DBDPE-induced oxidative stress caused DNA strand breaks, resulting in the activation of poly (ADP-ribose) (PAR) polymerase-1 (PARP-1). Activation of PARP1 could cause toxic damage in various organ systems, especially in the nervous system. DBDPE-induced apoptosis via the caspase-dependent intrinsic mitochondrial pathway and the PARP1-dependent pathway. Activation of PARP1 by DBDPE was deemed the initiating event, thereby affecting the key downstream biochemical events (e.g., ROS production, DNA damage, membrane potential changes, and ATP reduction), which induced apoptosis. Furthermore, excessive activation of PARP1 was accompanied by the translocation of the apoptosis-inducing factor (AIF), which was associated with PARP1-dependent cell death. The inhibition of PARP1 by PJ34 reduced DBDPE-induced apoptosis and maintained cellular ATP levels. PJ34 also prevented the translocation of AIF from the mitochondria to the nucleus. These findings improve the understanding of the mechanism of DBDPE-induced neurotoxic effects and provide a theoretical basis for the ecological risk of DBDPE.

DBDPE and ZnO NPs synergistically induce neurotoxicity of SK-N-SH cells and activate mitochondrial apoptosis signaling pathway and Nrf2-mediated antioxidant pathway.

Decabromodiphenyl ethane (DBDPE), a new brominated flame retardant, could negatively affect neurobehavior and pose health risks to humans. Humans are also exposed to widely used nanomaterials. This study investigated the combined toxic effects and action types of DBDPE and Zinc oxide nanoparticles (ZnO NPs) on human neuroblastoma SK-N-SH cells and the toxicity mechanisms. DBDPE inhibited the viability of SK-N-SH cells by 21.87% at 25 mg/L. ZnO NPs synergistically exacerbated the toxic effects of DBDPE. DBDPE and ZnO NPs caused excessive ROS production and inhibition of antioxidant enzyme (SOD and GSH) activity in cells, thus causing oxidative cellular damage. Moreover, DBDPE and ZnO NPs caused apoptosis by disrupting mitochondrial kinetic homeostasis, reducing mitochondrial membrane potential (MMP), increasing cytochrome C release and regulating Bax/Bcl-2 and Caspase-3 mRNA and protein expression. DBDPE and ZnO NPs increased the mRNA expression of nuclear factor erythroid 2- related factor (Nrf2) and its downstream genes. The molecular mechanisms revealed that oxidative stress, apoptosis and mitochondrial dysfunction were the critical factors in combined cytotoxicity. The bioinformatics analysis further indicated that co-exposure affected Nrf2 activation, apoptotic factors expression and mitochondrial fusion. The findings enrich the risk perception of neurotoxicity caused by DBDPE and ZnO NPs.

Integration of transcriptomic and proteomic reveals the toxicological molecular mechanisms of decabromodiphenyl ethane (DBDPE) on Pleurotus ostreatus.

Decabromodiphenyl ethane (DBDPE), as one of the most widely used new brominated flame retardants (NBFRs), can pose a potential threat to human health and the environment. An integrated transcriptome and proteome was performed for investigating the toxicological molecular mechanisms of Pleurotus ostreatus (P. ostreatus) during the biodegradation of DBDPE at the concentrations of 5 and 20 mg/L. A total of 1193/1018 and 92/126 differentially expressed genes/proteins (DEGs/DEPs) were found, respectively, with DBDPE exposure at 5 and 20 mg/L. These DEGs and DEPs were mainly involved in the cellular process as well as metabolic process. DEPs for oxidation-reduction process and hydrolase activity were up-regulated, and those for membrane, lipid metabolic process and transmembrane transport were down-regulated. The DEGs and DEPs related to some key enzymes were down-regulated, such as NADH dehydrogenase/oxidoreductase, succinate dehydrogenase, cytochrome C1 protein, cytochrome-c oxidase/reductase and ATP synthase, which indicated that DBDPE affected the oxidative phosphorylation as well as tricarboxylic acid (TCA) cycle. Cytochrome P450 enzymes (CYPs) might be involved in DBDPE degradation through hydroxylation and oxidation. Some stress proteins were induced to resist DBDPE toxicity, including major facilitator superfamily (MFS) transporter, superoxide dismutase (SOD), molecular chaperones, heat shock proteins (HSP20, HSP26, HSP42), 60S ribosomal protein and histone H4. The findings help revealing the toxicological molecular mechanisms of DBDPE on P. ostreatus, aiming to improve the removal of DBDPE.

Synergistically Promoting Bone Regeneration by Icariin-Incorporated Porous Microcarriers and Decellularized Extracellular Matrix Derived From Bone Marrow Mesenchymal Stem Cells.

Multifunctionality has becoming essential for bone tissue engineering materials, such as drug release. In this study, icariin (ICA)-incorporated poly(glycolide-co-caprolactone) (PGCL) porous microcarriers were fabricated and then coated with decellularized extracellular matrix (dECM) which was derived from bone marrow mesenchymal stem cells (BMSC). The porous structure was generated due to the soluble gelatin within the microcarriers. The initial released ICA in microcarriers regulated osteogenic ECM production by BMSCs during ECM formation. The dECM could further synergistically enhance the migration and osteogenic differentiation of BMSCs together with ICA as indicated by the transwell migration assay, ALP and ARS staining, as well as gene and protein expression. Furthermore, in vivo results also showed that dECM and ICA exhibited excellent synergistic effects in repairing rat calvarial defects. These findings suggest that the porous microcarriers loaded with ICA and dECM coatings have great potential in the field of bone tissue engineering.

Space-Confinment-Enhanced Fluorescence Detection of DNA on Hydrogel Particles Array.

Fluorescent biosensors have been widely applied in DNA detection because of their reliability and reproducibility. However, low kinetics in DNA hybridization often brings out long test terms, thus restricting their practical use. Here, we demonstrate unexpected fast DNA fluorescence detection on the confined surface of hydrogel particles. When the pore size and surface charge of hydrogel particles are tailored, DNA molecules can be confined in the outer water layer of hydrogel particles. We fabricated a fluorescence-on DNA sensor based on the hydrogel particle array by utilizing the fluorescence quenching property of graphene oxide and its different adsorption behaviors toward single-strand DNA or double-strand DNA. Benefiting from the confinement effect of hydrogel particle surface and the enrichment effect of water evaporation, the DNA-recognition time was descreased significantly from 3000 s to less than 10 s under the target concentration of 400 nM. Moreover, rapid detection can be achieved at concentrations between 50 and 400 nM. The study provides another insight to fabricate fast biosensors and shows great potential in DNA diagnostics, gene analysis, and liquid biopsy.

Toxicity evaluation of decabromodiphenyl ethane (DBDPE) to Pleurotus ostreatus: Oxidative stress, morphology and transcriptomics.

Decabromodiphenyl ethane (DBDPE), one widely used new brominated flame retardant, was of great concern due to its biotoxicity. The toxic evaluation of DBDPE (1-50 mg/L) to white-rot fungus (Pleurotus ostreatus), including oxidative stress, morphology and transcriptomics was conducted aiming at improving its biodegradation. Fungal growth and ATPase activity were obviously inhibited by DBDPE at ≥ 10 mg/L with the exposure from 48 h to 96 h. DBDPE could induce oxidative stress to P. ostreatus. The activity of SOD (superoxide dismutase), CAT (catalase) and GSH (glutathione) were all promoted by DBDPE at ≤ 5 mg/L and inhibited at > 5 mg/L with 96-h exposure. MDA (malondialdehyde) content rose obviously with DBDPE exposure (10-50 mg/L). The mycelium was wizened under 20 mg/L DBDPE exposure according to SEM observation. Transcriptomics analysis suggested that DBDPE could change many functional genes expression of P. ostreatus. GO analysis indicated DBDPE could affect biological process and cellular component by inhibiting electron transport, mitochondrial ATP synthesis, oxidoreductase activity as well as transporter activity. KEGG enrichment pathways analysis indicated DBDPE could inhibit oxidative phosphorylation, tricarboxylic acid (TCA) cycle and carbon metabolism by down-regulating the genes related to NADH reductase/dehydrogenase, succinate dehydrogenase, cytochrome-c reductase/oxidase, cytochrome C1 protein and ATP synthase.

WET-Induced Layered Organohydrogel as Bioinspired "Sticky-Slippy Skin" for Robust Underwater Oil-Repellency.

Underwater superoleophobic surfaces featuring anti-oil-fouling properties are of great significance in widespread fields. However, their complicated engineering process and weak interfacial adhesion strength with underlying substrates severely hamper these ideal surfaces toward practical applications. Here, a moss-inspired sticky-slippy skin composed of layered organohydrogel is reported through a one-step wetting-enabled-transfer (WET) strategy, which unprecedentedly integrates robust inherent adhesion with durable anti-oil-fouling properties. The sticky organogel layer can be simply attached to various substrates, from metals and plastics to glass, independent of any surface pretreatment. The slippy hydrogel layer enables stable underwater superoleophobicity and ultralow oil adhesion for diverse kinds of oils. The sticky-slippy skin features outstanding comprehensive properties including easy-pasting, anti-swelling/anti-bending, compatibility with commercial adhesives, acid/alkali resistance, environmental friendliness, and substrate universality. The design strategy with integrated functions provides a clue to accelerate the development of bioinspired multifunctional interfacial materials toward real-world applications.

Reconstructable Uterus-Derived Materials for Uterus Recovery toward Efficient Live Births.

Uterine factor infertility is increasingly common in modern society and has severely affected human life and health. However, the existing biomaterial scaffold-mediated systems remain limited in efficient uterus recovery, leading to low pregnancy rate and live births. Here, reconstructable uterus-derived materials (RUMs) are demonstrated by combining uterus-derived extracellular matrix and seeded chorionic villi mesenchymal stem cells for uterus recovery, achieving highly efficient live births in rats with severe uterine injury. The RUMs can be designed into different states (such as, liquid RUMs and solid RUMs) and shapes (such as, cuboid, triangular-prism, and cube) in terms of requirements. The RUMs can effectively prevent intrauterine adhesion, and promote endometrial regeneration and muscle collagen reconstruction, as well as, accelerate wound healing by constructing a physical barrier and secreting cytokines, allowing efficient uterus recovery. The injured uterus nearly achieves complete recovery after treating with the RUMs and has normal pregnancies for supporting fetal development and live births, similar to the normal rats. The study provides a regenerative medicine therapeutics for uterine factor infertility.

A novel co-catalyzed system between persulfate and chlorite by sonolysis for removing triphenylmethane derivative.

Triphenylmethane (tpm) derivatives (e.g. tpmCV) have threatened the safety of the aquatic environment due to the potential toxicity and carcinogenicity. In this study, the novel ultrasonic/persulfate/chlorite (US/S2O82-/ClO2-) oxidation process was developed for the effective removal of tpmCV in wastewater. The apparent non-integer kinetics (n around 1.20) of tpmCV degradation under different factors (R2Adj > 0.990) were investigated, respectively. Inhibiting effects of anions were greater than those of cations (except Fe(II/III)). The adding of micromolecule organic acids could regulate degradation towards positive direction. The double response surface methodology (RSM) was designed to optimize tpmCV removal process, and the acoustic-piezoelectric interaction was simulated to determine the propagation process of acoustic wave in the reactor. The possible degradation pathway was explored to mainly include carbonylation, carboxylation, and demethylation. The estimated effective-mean temperature at the bubble-water interface was calculated from 721 to 566 K after introducing the ClO2-, however, the adsorption or partitioning capacity of tpmCV in the reactive zone was widened from 0.0218 to 0.0982. The proposed co-catalysis of US/S2O82-/ClO2- was based on the determined active species mainly including ClO2, SO4⋅-, and ⋅OH. Compared with other US-based processes, the operating cost (3.97 $/m3) of US/S2O82-/ClO2- with the EE/O value (16.8 kWh/m3) was relatively reduced.

A Bioinspired Adhesive-Integrated-Agent Strategy for Constructing Robust Gas-Sensing Arrays.

Gas sensors based on organic molecules are attractive for their tailored molecular structures and controllable functions, but weak interfacial adhesion between sensing materials and supporting substrates has severely hampered their practical applications, particularly in harsh environments. Here, inspired by the combined anchoring-recognizing feature of natural olfactory systems, an adhesive-integrated-agent strategy to integrate the adhesive unit (poly(dimethylsiloxane)) with the sensing unit (organoplatinum(II)) into one chemistry entity, creating robust and sensitive nanobelt array gas sensors is demonstrated. Systematic theoretical and experimental studies reveal that incorporating adhesive units significantly enhances the interfacial adhesion of the array sensors and gas-bridged super-exchange electronic couplings of sensing units ensure their efficient gas-sensing performance. The high shear strength of ≈7.05 × 106 N m-2 allows these arrays to resist aggressive ultrasonication, tape peeling, or repeated bending without compromising their sensing performance. This molecular engineering strategy opens a new guideline to develop robust gas sensors.

Ultrasonic role to activate persulfate/chlorite with foamed zero-valent-iron: Sonochemical applications and induced mechanisms.

The novel system, consisting of composite oxidants (persulfate/chlorite, S2O82-/ClO2-) and stationary phase activator (zero-valent-iron foam, Fe0f) driven by ultrasonic (US) field, was applied to treat the triphenylmethane derivative effectively even at low temperature (≈ 289 K). By comparisons of sub-systems, the US roles to S2O82-, ClO2-, and Fe0f were seriatim analyzed. US made the reaction order of multi-component system tend to within 1 (leading to de-order reaction), and widened pH activating range of the Fe0f by sonicate-polishing during the process of ClO2- co-activating S2O82-. US and Fe0f were affected by fluid eddy on activating S2O82-/ClO2-. The Fe0f had slight effect on the temperature of US bubble-water interface but the addition of ClO2- lowered it. The partitioning capacity of the above US reactive zone increased during the reaction. US and ClO2- could enrich the kinds of degradation intermediates. The contributions of free radicals (ClOx-based radicals, sulfate radicals (SO4-), and hydroxyl radicals (OH)) and non-free radicals (ClO2, and O = FeIV/V from ionic Fe under "-O-O-" of S2O82- and cyclic adjustment reaction of ClO2-) processes by sonochemical induction were equally important by corresponding detection means. Especially, real-time and online high-resolution mass spectrum by self-developing further confirmed the chain transfers of different free radicals due to US role. The findings expanded the application of sono-persulfate-based systems and improved understanding on activation mechanism.

Evaporation-Induced rGO Coatings for Highly Sensitive and Non-Invasive Diagnosis of Prostate Cancer in the PSA Gray Zone.

The prostate-specific antigen (PSA) has been widely used for the early diagnosis of prostate cancer during routine check-ups. However, the low sensitivity of regular PSA tests in the PSA gray zone often means that patients are required to undergo further invasive needle biopsy for the diagnosis of prostate cancer, which may lead to potential overdiagnosis and overtreatment. In this study, a circulating tumor cell (CTC)-chip based on an evaporation-induced reduced graphene oxide (rGO) coating is presented, which enables a highly specific and non-invasive diagnosis of prostate cancer in the PSA gray zone. During the evaporation process of the rGO dispersion, the Marangoni effect induces the self-assembly of a hierarchical micro/nanowrinkled rGO coating, which can capture CTCs after subsequent surface modification of capture agents. Compared to the low diagnostic sensitivity (58.3%) of regular PSA tests, a combination of CTC detection and PSA-based hematological tests via machine-learning analysis can greatly upgrade the diagnostic sensitivity of this disease to 91.7% in clinical trial. Therefore, this study provides a non-invasive alternative with high sensitivity for the diagnosis of prostate cancer in the PSA gray zone.

Advanced Nanotechnologies for Extracellular Vesicle-Based Liquid Biopsy.

Extracellular vesicles (EVs) are emerging as a new source of biomarkers in liquid biopsy because of their wide presence in most body fluids and their ability to load cargoes from disease-related cells. Owing to the crucial role of EVs in disease diagnosis and treatment, significant efforts have been made to isolate, detect, and analyze EVs with high efficiency. A recent overview of advanced EV detection nanotechnologies is discussed here. First, several key challenges in EV-based liquid biopsies are introduced. Then, the related pivotal advances in nanotechnologies for EV isolation based on physical features, chemical affinity, and the combination of nanostructures and chemical affinity are summarized. Next, a summary of high-sensitivity sensors for EV detection and advanced approaches for single EV detection are provided. Later, EV analysis is introduced in practical clinical scenarios, and the application of machine learning in this field is highlighted. Finally, future opportunities for the development of next-generation nanotechnologies for EV detection are presented.

Excitation emission matrix fluorescence spectroscopy and parallel factor framework-clustering analysis for oil pollutants identification.

Serious ecological damage can be caused due to increased oil pollution. Identifying the source of oil can inform effective mitigation strategies and policies. A novel method for oil pollutants identification has been presented based on excitation emission matrix (EEM) fluorescence spectroscopy and parallel factor framework-clustering analysis (PFFCA). First, the EEM spectroscopy of the oil samples was measured by a FS920 steady-state fluorescence spectrometer. Second, EEM was analyzed and characterized by PFFCA. A total 90 EEM were decomposed into six components using excitation wavelengths from 260 to 400 nm and emission wavelengths from 280 to 450 nm. Finally, oil samples were classified and matched by using concentration vectors. The results were compared with those obtained by using linear discriminant analysis (LDA) employing parallel factor analysis (PARAFAC) scores, and partial least squares discriminant analysis (PLS-DA). The best classification result was obtained by using LDA employing concentration vectors with 96.7% accuracy. The results indicate that PFFCA-LDA offers a robust approach for the oil samples, which is of great significance in discrimination of oil pollutants.

Bioinspired Superwettable Microspine Chips with Directional Droplet Transportation for Biosensing.

Directional droplet transportation without extra energy input remains a challenge in microfluidic biochips for clinical detections. Herein, inspired by the water-collecting behaviors on the cactus spine, we fabricate nanomaterial-based superwettable microspine (SMS) chips. The bioinspired SMS chips are capable of spontaneous and directional droplet transportation by synergistically combining geometric asymmetry and surface superhydrophilicity. Based on theoretical models, the gradient of the Laplace pressure arising from the geometric asymmetry of the SMS chip can dominate the directional transportation of the droplet, and the superhydrophilicity of the nanomaterial-based microspine can also contribute to the droplet self-transportation. The multimicrochannel SMS chips provide a simple and energy efficient technology to realize accurate detection of serum prostate-specific antigen (PSA) from prostate cancer patients, showing great potential as a biosensing platform for clinical applications. We believe that our bioinspired superwettable two-dimensional conical surface will offer effective means for the design of smart microfluidic devices and have great potential applications in multicomponent biosensing and clinical detection.

Focused ultrasound induced-blood-brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy.

OBJECTIVE: Investigate the temporal effects of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening in post-radiotherapy mouse brains. METHODS AND MATERIALS: C57B6 mice without tumors were used to simulate the scenario after gross total resection (GTR) of brain tumor. Radiation dose of 6 Gy x 5 was delivered to one-hemisphere of the mouse brain. FUS-induced BBB-opening was delivered to the irradiated and non-irradiated brain and was confirmed with MRI. Dynamic MRI was performed to evaluate blood vessel permeability. Two time points were selected: acute (2 days after radiation) and chronic (31 days after radiation). RESULTS: BBB opening was achieved after FUS in the irradiated field as compared to the contralateral non-irradiated brain without any decrease in permeability. In the acute group, a trend for higher gadolinium concentration was observed in radiated field. CONCLUSION: Localized BBB-opening can be successfully achieved without loss of efficacy by FUS as early as 2 days after radiotherapy. ADVANCES IN KNOWLEDGE: Adjuvant radiation after GTR is commonly used for brain tumors. Focused ultrasound facilitated BBB-opening can be achieved without loss of efficacy in the post-irradiated brain as early as 2 days after radiation therapy. This allows for further studies on early application of FUS-mediated BBB-opening.