Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into ß-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Distinct Depth-Discrete Profiles of Microbial Communities and Geochemical Insights in the Subsurface Critical Zone.

Microbial assembly and metabolic potential in the subsurface critical zone (SCZ) are substantially impacted by subsurface geochemistry and hydrogeology, selecting for microbes distinct from those in surficial soils. In this study, we integrated metagenomics and geochemistry to elucidate how microbial composition and metabolic potential are shaped and impacted by vertical variations in geochemistry and hydrogeology in terrestrial subsurface sediment. A sediment core from an uncontaminated, pristine well at Oak Ridge Field Research Center in Oak Ridge, Tennessee, including the shallow subsurface, vadose zone, capillary fringe, and saturated zone, was used in this study. Our results showed that subsurface microbes were highly localized and that communities were rarely interconnected. Microbial community composition as well as metabolic potential in carbon and nitrogen cycling varied even over short vertical distances. Further analyses indicated a strong depth-related covariation of community composition with a subset of 12 environmental variables. An analysis of dissolved organic carbon (DOC) quality via ultrahigh resolution mass spectrometry suggested that the SCZ was generally a low-carbon environment, with the relative portion of labile DOC decreasing and that of recalcitrant DOC increasing along the depth, selecting microbes from copiotrophs to oligotrophs and also impacting the microbial metabolic potential in the carbon cycle. Our study demonstrates that sediment geochemistry and hydrogeology are vital in the selection of distinct microbial populations and metabolism in the SCZ. IMPORTANCE In this study, we explored the links between geochemical parameters, microbial community structure and metabolic potential across the depth of sediment, including the shallow subsurface, vadose zone, capillary fringe, and saturated zone. Our results revealed that microbes in the terrestrial subsurface can be highly localized, with communities rarely being interconnected along the depth. Overall, our research demonstrates that sediment geochemistry and hydrogeology are vital in the selection of distinct microbial populations and metabolic potential in different depths of subsurface terrestrial sediment. Such studies correlating microbial community analyses and geochemistry analyses, including high resolution mass spectrometry analyses of natural organic carbon, will further the fundamental understanding of microbial ecology and biogeochemistry in subsurface terrestrial ecosystems and will benefit the future development of predictive models on nutrient turnover in these environments.

Unfractionated Heparin Protects Microcirculation in Endotoxemic Rats by Antagonizing Histones.

INTRODUCTION: Levels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats. METHODS: Twenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells. RESULTS: UFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro. CONCLUSIONS: UFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis.

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation.

Ferrous iron (Fe2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe0 nanoparticles (Fe0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe0 -siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2 ). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0 -siRNA NPs. In addition to initiating chemodynamic process, Fe2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Comparison of five single-file systems in the preparation of severely curved root canals: an ex vivo study.

BACKGROUND: The ex vivo study is to compare the root canal preparation outcomes achieved by five nickel-titanium single-file instrumentation systems (M3-L, Reciproc Blue, V-Taper 2H, WaveOne Gold, XP-endo Shaper) in severely curved molar root canals. METHODS: A total of 60 root canals were selected from extracted human molar teeth with curvatures ranging from 25° to 50° and divided into five groups based on the instrumentation system employed (n = 12). Before and after root canal preparation, a Micro-CT scan was taken, and pre- and post-operative data were analyzed to evaluate the following parameters: volume increment of root canals (VI), untouched root canal areas (UTA), and canal transportation (CT). Apically extruded debris (AD) was collected during preparation. After that, all samples were separated into two parts and examined respectively by scanning electron microscope (SEM) to assess cleaning ability. Data were statistically analyzed with ANOVA (UTA, AD, VI) or Kruskal-Wallis test (CT, SEM-score), the level of significance was set at α = 0.05. RESULTS: There were no significant differences between the five systems regarding the AD, VI, and UTA parameters (P > 0.05). In terms of CT, no significant difference was noted at the straight section of canal and apical levels, while XP-endo Shaper showed less canal transportation than M3-L at the level of curved vertex (P < 0.05), and the centering ability of V-Taper 2H was significantly better than WaveOne Gold at the initial point of bending (P < 0.05). Debris and smear layers were present on the canal walls of all specimens, the apical thirds of the canal presented higher SEM scores than the coronal thirds in all groups (P < 0.05). Reciproc Blue and XP-endo Shaper showed fewer smear scores than WaveOne Gold in the apical thirds (P < 0.01 and P < 0.05, respectively), and no statistical difference was found between other groups in the middle and coronal thirds. CONCLUSION: The five single-file systems evaluated performed equally in apically debris extrusion, dentin removal, and untouched root canal areas, while XP-endo Shaper and V-Taper 2H resulted in less canal transportation compared to M3-L and WaveOne Gold. Regarding cleaning ability, Reciproc Blue and XP-endo Shaper were associated with less smear layer than WaveOne Gold in the apical thirds.

Persistently higher serum sCD40L levels are associated with outcome in septic patients.

BACKGROUND: Soluble CD40 ligand (sCD40L) exhibits proinflammatory and procoagulant effects. Recent data indicated that sCD40L plays a significant role in septic patients. The aim of the present study was to determine sCD40L changes in surgical patients without sepsis (SWS) and surgical sepsis patients (SS) during the first 3 days after intensive care unit (ICU) admission and to observe the association between sCD40L and mortality. METHODS: Time changes in sCD40L levels were assessed for 3 days after ICU admission in 49 patients with SS and compared with those in 19 SWS patients. Serum sCD40L concentration was detected by ELISA. Survival at 28 days served as the endpoint. RESULTS: SS had significantly higher sCD40L levels than SWS and control patients. We observed an association between sCD40L levels ≥1028.75 pg/mL at day 2 and 28-day mortality (odds ratio = 7.888; 95% confidence interval = 1.758 to 35.395; P = 0.007). We could not discover any significant differences in sex, presence of septic shock, site of infection, length of stay in the ICU, PaO2/FiO2 ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors. CONCLUSIONS: Septic patients show persistently higher circulating sCD40L levels in the first 3 days after ICU admission, and serum sCD40L levels are associated with the mortality of patients with sepsis. Thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.

LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma.

Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1ß, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1ß, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.

Unfractionated Heparin Alleviates Sepsis-Induced Acute Lung Injury by Protecting Tight Junctions.

BACKGROUND: Unfractionated heparin (UFH) has been shown to ameliorate lung edema and lung vascular leakage in lipopolysaccharide-induced lung injury. Impaired tight junction (TJ) function is a sign of sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which is closely related to the downregulated expression of TJ-specific proteins or the upregulated expression of inflammatory cytokines. Because UFH has been intensively studied in modulating inflammation, we hypothesize that UFH may play a positive role in treating sepsis-induced ARDS/ALI by protecting TJs. MATERIAL AND METHODS: Rat sepsis-induced lung injury was induced by cecal ligation and puncture and treated with UFH. Hematoxylin and eosin staining, lung wet/dry weight (W/D) ratio, and pulmonary microvascular leakage were evaluated to assess lung injury. Cytokines in bronchoalveolar lavage fluid were detected to determine lung inflammation. A transendothelial electrical resistance assay, a Transwell permeability assay, and transmission electron microscopy were used to study endothelial TJs in human lung microvascular endothelial cells. TJ protein expression was measured by western blotting or immunohistochemistry. RESULTS: UFH treatment alleviated lung injury in vivo by reducing IL-6 in bronchoalveolar lavage fluid and protecting TJs in LMVECs. UFH also protected TJs against lipopolysaccharide-stimulated damage and functioned upstream by inhibiting the ERK1/2 MAPK pathway to attenuate endothelial hyperpermeability and downregulating the expression of TJ proteins such as claudin-5, occludin, and ZO-1. CONCLUSIONS: These findings suggested that UFH has therapeutic potential for sepsis-induced ARDS or ALI through protecting TJs in LMVECs.

Atmo-ecometabolomics: a novel atmospheric particle chemical characterization methodology for ecological research.

Aerosol particles play important roles in processes controlling the composition of the atmosphere and function of ecosystems. A better understanding of the composition of aerosol particles is beginning to be recognized as critical for ecological research to further comprehend the link between aerosols and ecosystems. While chemical characterization of aerosols has been practiced in the atmospheric science community, detailed methodology tailored to the needs of ecological research does not exist yet. In this study, we describe an efficient methodology (atmo-ecometabolomics), in step-by-step details, from the sampling to the data analyses, to characterize the chemical composition of aerosol particles, namely atmo-metabolome. This method employs mass spectrometry platforms such as liquid and gas chromatography mass spectrometries (MS) and Fourier transform ion cyclotron resonance MS (FT-ICR-MS). For methodology evaluation, we analyzed aerosol particles collected during two different seasons (spring and summer) in a low-biological-activity ecosystem. Additionally, to further validate our methodology, we analyzed aerosol particles collected in a more biologically active ecosystem during the pollination peaks of three different representative tree species. Our statistical results showed that our sampling and extraction methods are suitable for characterizing the atmo-ecometabolomes in these two distinct ecosystems with any of the analytical platforms. Datasets obtained from each mass spectrometry instrument showed overall significant differences of the atmo-ecometabolomes between spring and summer as well as between the three pollination peak periods. Furthermore, we have identified several metabolites that can be attributed to pollen and other plant-related aerosol particles. We additionally provide a basic guide of the potential use ecometabolomic techniques on different mass spectrometry platforms to accurately analyze the atmo-ecometabolomes for ecological studies. Our method represents an advanced novel approach for future studies in the impact of aerosol particle chemical compositions on ecosystem structure and function and biogeochemistry.

Tumour YAP1 and PTEN expression correlates with tumour-associated myeloid suppressor cell expansion and reduced survival in colorectal cancer.

The expansion of myeloid-derived suppressor cells (MDSCs) correlates with tumorigenesis in colorectal cancer (CRC). Here, we found a significant association between CD33+ MDSC number and Yes-associated protein 1 (YAP1) and phosphatase and tensin homologue (PTEN) levels in CRC patients (P < 0·05). Moreover, the CD33+ MDSCs, YAP1 and PTEN were identified as predictors for the prognosis of CRC patients (P < 0·05). Notably, CD33+ MDSCs were an independent survival predictor for CRC patients through a Cox model analysis. In vitro data determined that the expression levels of YAP1 and PTEN in CRC-derived cell lines were associated with CRC-derived MDSC induction, and the blockade of YAP1 and PTEN decreased CRC-derived MDSC induction. A mechanistic analysis revealed that YAP1 promoted CRC-derived MDSC induction by suppressing PTEN expression to up-regulate COX-2, P-AKT and P-p65 in CRC-derived cells, leading to secretion of the cytokine granulocyte-macrophage colony-stimulating factor. Our findings establish a novel mechanism of pro-tumorigenic MDSC induction mediated by ectopic YAP1 and PTEN expression in CRC.

Moving beyond the van Krevelen Diagram: A New Stoichiometric Approach for Compound Classification in Organisms.

van Krevelen diagrams (O/C vs H/C ratios of elemental formulas) have been widely used in studies to obtain an estimation of the main compound categories present in environmental samples. However, the limits defining a specific compound category based solely on O/C and H/C ratios of elemental formulas have never been accurately listed or proposed to classify metabolites in biological samples. Furthermore, while O/C vs H/C ratios of elemental formulas can provide an overview of the compound categories, such classification is inefficient because of the large overlap among different compound categories along both axes. We propose a more accurate compound classification for biological samples analyzed by high-resolution mass spectrometry based on an assessment of the C/H/O/N/P stoichiometric ratios of over 130 000 elemental formulas of compounds classified in 6 main categories: lipids, peptides, amino sugars, carbohydrates, nucleotides, and phytochemical compounds (oxy-aromatic compounds). Our multidimensional stoichiometric compound classification (MSCC) constraints showed a highly accurate categorization of elemental formulas to the main compound categories in biological samples with over 98% of accuracy representing a substantial improvement over any classification based on the classic van Krevelen diagram. This method represents a signficant step forward in environmental research, especially ecological stoichiometry and eco-metabolomics studies, by providing a novel and robust tool to improve our understanding of the ecosystem structure and function through the chemical characterization of biological samples.

Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury.

BACKGROUND: Endothelial barrier dysfunction is central to the pathogenesis of sepsis-associated acute lung injury (ALI). Microtubule (MT) dynamics in vascular endothelium are crucial for the regulation of endothelial barrier function. Unfractionated heparin (UFH) possesses various biological activities, such as anti-inflammatory activity and endothelial barrier protection during sepsis. METHODS: Here, we investigated the effects and underlying mechanisms of UFH on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. C57BL/6 J mice were randomized into vehicle, UFH, LPS and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received intravenous UFH 0.5 h prior to LPS injection. Human pulmonary microvascular endothelial cells (HPMECs) were cultured for analyzing the effects of UFH on LPS-induced and nocodazole-induced hyperpermeability, F-actin remodeling, and LPS-induced p38 MAPK activation. RESULTS: UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes, and increased the lung W/D ratio and Evans blue accumulation in vivo. Both in vivo and in vitro studies showed that UFH pretreatment blocked the LPS-induced increase in guanine nucleotide exchange factor (GEF-H1) expression and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, and microtubule (MT) disassembly in LPS-induced ALI mouse model and human pulmonary microvascular endothelial cells (HPMECs). These results suggested that UFH ameliorated LPS-induced endothelial barrier dysfunction by inhibiting MT disassembly and GEF-H1 expression. In addition, UFH attenuated LPS-induced hyperpermeability of HPMECs and F-actin remodeling. In vitro, UFH pretreatment inhibited LPS-induced increase in monomeric tubulin expression and decrease in tubulin polymerization and acetylation. Meanwhile, UFH ameliorates nocodazole-induced MTs disassembly and endothelial barrier dysfunction.Additionally, UFH decreased p38 phosphorylation and activation, which was similar to the effect of the p38 MAPK inhibitor, SB203580. CONCLUSIONS: UFH exert its protective effects on pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization and is associated with the p38 MAPK pathway.

Formularity: Software for Automated Formula Assignment of Natural and Other Organic Matter from Ultrahigh-Resolution Mass Spectra.

Ultrahigh resolution mass spectrometry, such as Fourier transform ion cyclotron resonance mass spectrometry (FT ICR MS), can resolve thousands of molecular ions in complex organic matrices. A Compound Identification Algorithm (CIA) was previously developed for automated elemental formula assignment for natural organic matter (NOM). In this work, we describe software Formularity with a user-friendly interface for CIA function and newly developed search function Isotopic Pattern Algorithm (IPA). While CIA assigns elemental formulas for compounds containing C, H, O, N, S, and P, IPA is capable of assigning formulas for compounds containing other elements. We used halogenated organic compounds (HOC), a chemical class that is ubiquitous in nature as well as anthropogenic systems, as an example to demonstrate the capability of Formularity with IPA. A HOC standard mix was used to evaluate the identification confidence of IPA. Tap water and HOC spike in Suwannee River NOM were used to assess HOC identification in complex environmental samples. Strategies for reconciliation of CIA and IPA assignments were discussed. Software and sample databases with documentation are freely available.

Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma.

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4+ and CD8+ T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dissolved organic matter composition drives the marine production of brominated very short-lived substances.

Brominated very short-lived substances (BrVSLS), such as bromoform, are important trace gases for stratospheric ozone chemistry. These naturally derived trace gases are formed via bromoperoxidase-mediated halogenation of dissolved organic matter (DOM) in seawater. Information on DOM type in relation to the observed BrVSLS concentrations in seawater, however, is scarce. We examined the sensitivity of BrVSLS production in relation to the presence of specific DOM moieties. A total of 28 model DOM compounds in artificial seawater were treated with vanadium bromoperoxidase (V-BrPO). Our results show a clear dependence of BrVSLS production on DOM type. In general, molecules that comprise a large fraction of the bulk DOM pool did not noticeably affect BrVSLS production. Only specific cell metabolites and humic acid appeared to significantly enhance BrVSLS production. Amino acids and lignin phenols suppressed enzyme-mediated BrVSLS production and may instead have formed halogenated nonvolatile molecules. Dibromomethane production was not observed in any experiments, suggesting it is not produced by the same pathway as the other BrVSLS. Our results suggest that regional differences in DOM composition may explain the observed BrVSLS concentration variability in the global ocean. Ultimately, BrVSLS production and concentrations are likely affected by DOM composition, reactivity, and cycling in the ocean.

Current progress in the regulation of endogenous molecules for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is a potential cancer treatment strategy, which relies on Fenton chemistry to transform hydrogen peroxide (H2O2) into highly cytotoxic reactive oxygen species (ROS) for tumor growth suppression. Although overproduced H2O2 in cancerous tissues makes CDT a feasible and specific tumor therapeutic modality, the treatment outcomes of traditional chemodynamic agents still fall short of expectations. Reprogramming cellular metabolism is one of the hallmarks of tumors, which not only supports unrestricted proliferative demands in cancer cells, but also mediates the resistance of tumor cells against many antitumor modalities. Recent discoveries have revealed that various cellular metabolites including H2O2, iron, lactate, glutathione, and lipids have distinct effects on CDT efficiency. In this perspective, we intend to provide a comprehensive summary of how different endogenous molecules impact Fenton chemistry for a deep understanding of mechanisms underlying endogenous regulation-enhanced CDT. Moreover, we point out the current challenges and offer our outlook on the future research directions in this field. We anticipate that exploring CDT through manipulating metabolism will yield significant advancements in tumor treatment.

Neuromorphic Computing-Assisted Triboelectric Capacitive-Coupled Tactile Sensor Array for Wireless Mixed Reality Interaction.

Flexible tactile sensors show promise for artificial intelligence applications due to their biological adaptability and rapid signal perception. Triboelectric sensors enable active dynamic tactile sensing, while integrating static pressure sensing and real-time multichannel signal transmission is key for further development. Here, we propose an integrated structure combining a capacitive sensor for static spatiotemporal mapping and a triboelectric sensor for dynamic tactile recognition. A liquid metal-based flexible dual-mode triboelectric-capacitive-coupled tactile sensor (TCTS) array of 4 × 4 pixels achieves a spatial resolution of 7 mm, exhibiting a pressure detection limit of 0.8 Pa and a fast response of 6 ms. Furthermore, neuromorphic computing using the MXene-based synaptic transistor achieves 100% recognition accuracy of handwritten numbers/letters within 90 epochs based on dynamic triboelectric signals collected by the TCTS array, and cross-spatial information communication from the perceived multichannel tactile data is realized in the mixed reality space. The results illuminate considerable application possibilities of dual-mode tactile sensing technology in human-machine interfaces and advanced robotics.

Ultrasensitive Wearable Pressure Sensors with Stress-Concentrated Tip-Array Design for Long-Term Bimodal Identification.

The great challenges for existing wearable pressure sensors are the degradation of sensing performance and weak interfacial adhesion owing to the low mechanical transfer efficiency and interfacial differences at the skin-sensor interface. Here, an ultrasensitive wearable pressure sensor is reported by introducing a stress-concentrated tip-array design and self-adhesive interface for improving the detection limit. A bipyramidal microstructure with various Young's moduli is designed to improve mechanical transfer efficiency from 72.6% to 98.4%. By increasing the difference in modulus, it also mechanically amplifies the sensitivity to 8.5 V kPa-1 with a detection limit of 0.14 Pa. The self-adhesive hydrogel is developed to strengthen the sensor-skin interface, which allows stable signals for long-term and real-time monitoring. It enables generating high signal-to-noise ratios and multifeatures when wirelessly monitoring weak pulse signals and eye muscle movements. Finally, combined with a deep learning bimodal fused network, the accuracy of fatigued driving identification is significantly increased to 95.6%.

Phenotypic and comparative transcriptomics analysis of RDS1 overexpression reveal tolerance of Saccharomyces cerevisiae to furfural.

The yeast Saccharomyces cerevisiae able to tolerate lignocellulose-derived inhibitors like furfural. Yeast strain performance tolerance has been measured by the length of the lag phase for cell growth in response to the furfural inhibitor challenge. The aims of this work were to obtain RDS1 yeast tolerant strain against furfural through overexpression using a method of in vivo homologous recombination. Here, we report that the overexpressing RDS1 recovered more rapidly and displayed a lag phase at about 12 h than its parental strain. Overexpressing RDS1 strain encodes a novel aldehyde reductase with catalytic function for reduction of furfural with NAD(P)H as the co-factor. It displayed the highest specific activity (24.8 U/mg) for furfural reduction using NADH as a cofactor. Fluorescence microscopy revealed improved accumulation of reactive oxygen species resistance to the damaging effects of inhibitor in contrast to the parental. Comparative transcriptomics revealed key genes potentially associated with stress responses to the furfural inhibitor, including specific and multiple functions involving defensive reduction-oxidation reaction process and cell wall response. A significant change in expression level of log2 (fold change >1) was displayed for RDS1 gene in the recombinant strain, which demonstrated that the introduction of RDS1 overexpression promoted the expression level. Such signature expressions differentiated tolerance phenotypes of RDS1 from the innate stress response of its parental strain. Overexpression of the RDS1 gene involving diversified functional categories is accountable for stress tolerance in yeast S. cerevisiae to survive and adapt the furfural during the lag phase.

Contribution of YPRO15C Overexpression to the Resistance of Saccharomyces cerevisiae BY4742 Strain to Furfural Inhibitor.

Lignocellulosic biomass is still considered a feasible source of bioethanol production. Saccharomyces cerevisiae can adapt to detoxify lignocellulose-derived inhibitors, including furfural. Tolerance of strain performance has been measured by the extent of the lag phase for cell proliferation following the furfural inhibitor challenge. The purpose of this work was to obtain a tolerant yeast strain against furfural through overexpression of YPR015C using the in vivo homologous recombination method. The physiological observation of the overexpressing yeast strain showed that it was more resistant to furfural than its parental strain. Fluorescence microscopy revealed improved enzyme reductase activity and accumulation of oxygen reactive species due to the harmful effects of furfural inhibitor in contrast to its parental strain. Comparative transcriptomic analysis revealed 79 genes potentially involved in amino acid biosynthesis, oxidative stress, cell wall response, heat shock protein, and mitochondrial-associated protein for the YPR015C overexpressing strain associated with stress responses to furfural at the late stage of lag phase growth. Both up- and down-regulated genes involved in diversified functional categories were accountable for tolerance in yeast to survive and adapt to the furfural stress in a time course study during the lag phase growth. This study enlarges our perceptions comprehensively about the physiological and molecular mechanisms implicated in the YPR015C overexpressing strain's tolerance under furfural stress. Construction illustration of the recombinant plasmid. a) pUG6-TEF1p-YPR015C, b) integration diagram of the recombinant plasmid pUG6-TEF1p-YPR into the chromosomal DNA of Saccharomyces cerevisiae.