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Ting Chen,1,2,* Lei Zhang,3,* Wenhua Huang,3,* Huijun Zong,1,2 Qian Li,3 Yuling Zheng,3 Qingyu Lv,3 Decong Kong,3 Yuhao Ren,3 Yongqiang Jiang,3 Yan Li,1,2 Peng Liu3 1The PLA 307 Clinical College of Anhui Medical University, The Fifth Clinical Medical College of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Critical Care Medicine, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100071, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Li, The PLA 307 Clinical College of Anhui Medical University, The Fifth Clinical Medical College of Anhui Medical University, Hefei, 230032, People’s Republic of China, Email liyanmdhuxi@163.com Peng Liu, Beijing Institute of Microbiology and Epidemiology, Dongdajie Road 20, Beijing, 100071, People’s Republic of China, Tel +86-010-66948487, Email ammsliupeng@163.comBackground: The early identification of pathogens and their antibiotic resistance are essential for the management and treatment of patients affected by ventilator-associated pneumonia (VAP). However, microbiological culture may be time-consuming and has a limited culturability of many potential pathogens. In this study, we developed a rapid nanopore-based metagenomic next-generation sequencing (mNGS) diagnostic assay for detection of VAP pathogens and antimicrobial resistance genes (ARGs).Patients and Methods: Endotracheal aspirate (ETA) samples from 63 patients with suspected VAP were collected between November 2021 and July 2022. Receiver operating characteristic (ROC) curves were established to compare the pathogen identification performance of the target pathogen reads, reads percent of microbes (RPM) and relative abundance (RA). The evaluation of the accuracy of mNGS was performed comparing with the gold standard and the composite standard, respectively. Then, the ARGs were analyzed by mNGS.Results: ROC curves showed that RA has the highest diagnostic value and the corresponding threshold was 9.93%. The sensitivity and specificity of mNGS test were 91.3% and 78.3%, respectively, based on the gold standard, while the sensitivity and specificity of mNGS test were 97.4% and 100%, respectively, based on the composite standard. A total of 13 patients were virus-positive based on mNGS results, while the coinfection rate increased from 27% to 46% compared to the rate obtained based on clinical findings. The mNGS test also performed well at predicting antimicrobial resistance phenotypes. Patients with a late-onset VAP had a significantly greater proportion of ARGs in their respiratory microbiome compared to those with early-onset VAP (P = 0.041). Moreover, the median turnaround time of mNGS was 4.43 h, while routine culture was 72.00 h.Conclusion: In this study, we developed a workflow that can accurately detect VAP pathogens and enable prediction of antimicrobial resistance phenotypes within 5 h of sample receipt by mNGS.Keywords: mechanical ventilation, endotracheal aspirate, pathogen diagnosis, antibiotic resistance, NGS

The invention of axenic media for culturing Coxiella burnetii has greatly promoted studies on this fastidious bacterium. In this study, we report a methylcellulose-supplemented ACCM-2 medium that allows the enumeration of C. burnetii colonies after growing for up to 15 days. Colony forming units (CFUs) of C. burnetii from both axenic and cell cultures were measured in this methylcellulose medium at various time points (8, 12, and 15 days post-plating). Increasing CFU numbers were observed for both cultures at these time points. The ratios of genome equivalents to CFUs at 15 days post-plating and the ratios of CFUs at 15 days to 8 days post-plating were employed to evaluate the viability and vitality of C. burnetii, respectively. We discovered that C. burnetii from cell and axenic cultures exhibit similar viability (7.72 vs 7.11), but that cell culture-derived C. burnetii demonstrates greater vitality than axenic cultures (1.63 vs 5.2). This work sheds light on the normal viability but low vitality of ACCM-2-derived C. burnetii.

Urinary tract infection (UTI) is a common infectious disease. Urinary tract pathogenic Escherichia coli (UPEC) is the main cause of UTIs. At present, antibiotics are mainly used for the treatment of UTIs. However, with the increase of drug resistance, the course of the disease is prolonged. Therefore, identifying the receptors and signal pathways of host cells and tissues will further our understanding of the pathogenesis of UTIs and help in the development of new drug treatments. We used two public microarray datasets (GSE43790, GSE124917) in the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between UTI and normal cell samples. A functional analysis based on Gene Ontology (GO) data, a pathway enrichment analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) data and a protein-protein interaction analysis identified the main potential biomarkers and verified them in animal tissues. A total of 147 up-regulated genes and 40 down-regulated genes were identified. GO enrichment analysis showed that these functional changes relate to the terms response to lipopolysaccharide, regulation of cytokine production, and regulation of the inflammatory response. KEGG analysis indicated that urinary tract infections likely involve the TNF-αsignaling pathways. The 20 hub genes were selected from the protein-protein interaction network, and the highly significant hub genes were verified by animal experiments. Our findings provide potential targets for exploring new treatments for urinary tract infections. After a comprehensive analysis of the GEO database, these results may facilitate development of new diagnosis and treatment strategies for urinary tract infections.

Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.

Silicon (Si) is generally considered as a poor photon emitter, and various scenarios have been proposed to improve the photon emission efficiency of Si. Here, we report the observation of a burst of the hot electron luminescence from Si nanoparticles with diameters of 150-250 nm, which is triggered by the exponential increase of the carrier density at high temperatures. We show that the stable white light emission above the threshold can be realized by resonantly exciting either the mirror-image-induced magnetic dipole resonance of a Si nanoparticle placed on a thin silver film or the surface lattice resonance of a regular array of Si nanopillars with femtosecond laser pulses of only a few picojoules, where significant enhancements in two- and three-photon-induced absorption can be achieved. Our findings indicate the possibility of realizing all-Si-based nanolasers with manipulated emission wavelength, which can be easily incorporated into future integrated optical circuits.

Polymer passivation layers can improve the open-circuit voltage of perovskite solar cells when inserted at the perovskite-charge transport layer interfaces. Unfortunately, many such layers are poor conductors, leading to a trade-off between passivation quality (voltage) and series resistance (fill factor, FF). Here, we introduce a nanopatterned electron transport layer that overcomes this trade-off by modifying the spatial distribution of the passivation layer to form nanoscale localized charge transport pathways through an otherwise passivated interface, thereby providing both effective passivation and excellent charge extraction. By combining the nanopatterned electron transport layer with a dopant-free hole transport layer, we achieved a certified power conversion efficiency of 21.6% for a 1-square-centimeter cell with FF of 0.839, and demonstrate an encapsulated cell that retains ~91.7% of its initial efficiency after 1000 hours of damp heat exposure.

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso‑tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm

Cardiovascular diseases (CVDs) are the leading causes of premature death and disability in people around the world. Therefore, the prevention and treatment of CVDs has become an important subject. In this study, we verified the thrombolytic activities of a nattokinase‐like protease named NK‐01 in vivo. Label‐free liquid chromatography–tandem mass spectrometry (LC‐MS/MS) technique was used in our study. NK‐01 could inhibit the activity of coagulation factors though the up‐regulation of proteinase C inhibitors and protein S. NK‐01 also could inhibit the angiotensinogen conversion to AngII and promote the degradation of kininogen to reduce the blood pressure. In addition, NK‐01 could increase the content of paraoxonase 1, which could prevent atherosclerosis. In our study, we found that NK‐01 cloud effect some key proteins which participant in CVDs associated metabolic processes such as coagulation system, blood pressure, and atherosclerosis. Taken together, the underlying molecular mechanisms for the biological beneficial of NK‐01 were investigated. Our proteomic study will provide further theoretical basis for application of NK in prevention or adjuvant treatment in biomedicine areas.

Aiming at training the feed-forward threshold neural network consisting of nondifferentiable activation functions, the approach of noise injection forms a stochastic resonance based threshold network that can be optimized by various gradient-based optimizers. The introduction of injected noise extends the noise level into the parameter space of the designed threshold network, but leads to a highly non-convex optimization landscape of the loss function. Thus, the hyperparameter on-line learning procedure with respective to network weights and noise levels becomes of challenge. It is shown that the Adam optimizer, as an adaptive variant of stochastic gradient descent, manifests its superior learning ability in training the stochastic resonance based threshold network effectively. Experimental results demonstrate the significant improvement of performance of the designed threshold network trained by the Adam optimizer for function approximation and image classification.

A rarely reported clinical specimen of Aspergillus spinulosporus was isolated from an immunocompetent 22-month-old boy who was suffering from central nervous system aspergillosis and meningitis. The patient had no comorbidity, organ transplantation, or other surgical operations that lead to invasive aspergillosis. A. spinulosporus is mostly a soil borne strain, and only three invasive aspergillosis cases involving this strain have been reported. We isolated this strain from cerebrospinal fluid, cultured it successfully on PDA medium, and named it BJCH M5. We performed a complete genomic and phenotypic analysis, evolutionary relationship, secondary metabolites analysis, identification of virulence factor, and pairwise synteny analysis. We sequenced the complete 31.6 MB genome of A. spinulosporus, including the eight chromosomes and mitochondria. 11,356 protein-coding genes were predicted. BJCHM 5 has a high sequence identity with ten virulent factors of Aspergillus fumigatus. It also encodes two unique BGCs (Biosynthetic gene clusters) which are involved in human infection. Pairwise synteny analysis demonstrated that this strain has chromosome arrangement differences from A. nidulans. In conclusion, we isolated a specimen of the rarely reported pathogen A. spinulosporus and performed a complete genome assembly and functional characteristic analysis.

Many sensors exhibit nonlinear characteristics [1]–[5] and are deployed in noisy environments [1]–[7]. In terms of device design and forming standards, this is a challenging area. However, it also presents opportunities for non-conventional signal processing methods based on stochastic resonance that have been shown to be of benefit for individual nonlinear sensors [1]–[7], sensor arrays [3]–[10], sensor networks [3], [8], [11], and even portable devices for people with reduced sensory capacity [12]–[14]. The most fascinating property of stochastic resonance is that nonlinear sensors connected in parallel or in a network yield improved performance over that achieved by using individual sensors [1]–[10]. Studies in stochastic resonance have led to evidence of noise-enhanced signal transmission and processing in nonlinear sensors, and noise can be exploited in the design of engineered devices [2]–[7], [10] and biological systems [1], [11]–[13]. This paper studies noise-enhanced signal transmission and processing in nonlinear sensors and also exploits the positive role of noise in the design of engineered devices that enhance the sensitivity of hand movements.

Random lasing (RL) from self-constructed localized cavities based on micropits scatters in a single GaN microwire (MW) was investigated. The spectra and spatial resolution of RL exhibits that the lasing modes originated from different regions in the MW. Temperature-dependent lasing measurement of GaN RL shows an excellent characteristic temperature of about 52 K. In addition, the dependence of spatial localized cavities’ dimension on the pumping intensity profile and temperature was studied by fast Fourier transform spectroscopy. For GaN RL, the optical feedback was supported by localized paths through the scattering effect of micropits in the MW. The scattering feedback mechanism for RL can avoid the enormous difficulty in fabricating artificial cavity structures for GaN. Hence, the results in this paper represent a low-cost technique to realize GaN-based ultraviolet laser diodes without the fabrication difficulty of cavity facets.

In this paper, the generalized energy (GE) detector is investigated for detecting weak random signals via vibrational resonance (VR). By artificially injecting the high-frequency sinusoidal interferences into an array of GE statistics formed for the detector, we show that the normalized asymptotic efficacy can be maximized when the interference intensity takes an appropriate non-zero value. It is demonstrated that the normalized asymptotic efficacy of the dead-zone-limiter detector, aided by the VR mechanism, outperforms that of the GE detector without the help of high-frequency interferences. Moreover, the maximum normalized asymptotic efficacy of dead-zone-limiter detectors can approach a quarter of the second-order Fisher information for a wide range of non-Gaussian noise types.

Nonlinear multiphoton absorption technology is crucial for developing novel optoelectronic devices and nanophotonics. The large enhancement of two-photon absorption (TPA) photoresponse by a high Q-factor whispering gallery mode (WGM) resonance based on a single-microwire (MW) self-formed hexagonal cavity was investigated comprehensively in this paper. The typical quadratic relationship of photocurrent as a function of incident power indicated that excited carriers resulted from a third-order nonlinear mechanism. Moreover, the photocurrent response had a dramatic dependence on the spatial location of the focus spot of the incident photons. It was demonstrated that the TPA photocurrent response in the resonant WGM mode was one-order of magnitude larger than the response in the Fabry-Perot mode. Furthermore, the photoresponse characteristics of TPA detection exhibited sensitive dependence on the incident laser polarization direction.

Semiconductor micro/nanowire is an attractive candidate for light-emitting devices (LED), especially laser diodes, due to its ideal geometric shape, excellent optical performance, and electrical transport properties. However, the realization of single micro/nanostructure semiconductor LED or lasers is still a challenge topic. In this Letter, we demonstrated a feasible route to fabricate electrically injection single microwire (MW) light-emitting devices. First, the excellent optical properties of single MW were investigated comprehensively, especially for the self-formed high-Q whisper gallery mode lasing. By properly engineering the band alignment of n-ZnO MW/p-GaN heterojunction using a dielectric MgO interlayer, the effective carrier injection and excitonic-type recombination electroluminescence was realized in the single MW active media. Our results present a significant step toward future fabrication of single micro/nanowire LED and laser diode.

Etoposide is one of the most used first-line chemotherapeutic drugs. However, its application is still limited by its side effects. Herein, we designed a novel H2O2 sensitive prodrug 6YT for selectively releasing the anti-cancer drug etoposide in cancer cells. In this paper, etoposide and a hydrogen peroxide (H2O2) sensitive aryl borate ester group were linked by a fluorescent coumarin and finally the prodrug 6YT was generated. The fluorescence of coumarin was quenched before the connected aryl borate ester group was cleaved by H2O2. However, in the high level H2O2 environment of the tumor, the fluorescence could be activated simultaneously with the release of etoposide, and the drug release state of the prodrug was monitored real-time. With the support of 6YT, we obtained direct and visual evidence of etoposide release in a high H2O2 environment both in cells and zebrafish. The prodrug 6YT was also verified with comparable activity and improved safety with etoposide both in cells and in a mouse model. As a safe and effective prodrug, 6YT is expected to be one of the promising candidates in chemotherapy against cancer.

Rock-ice avalanches pose serious risks to humans and infrastructures due to their extremely large volumes and high mobility in glacierized mountain regions. The mobility of rock-ice avalanches is supposed to be influenced by water, while the solid-liquid interactions induced by minor wetting remain an open issue. A series of flume tests was performed to investigate the influence of a small amount of water (no more than 4% of the gravel weight) on the behavior and mobility of gravel-ice mixtures. The test results show that intergranular refreezing bonds were created with a preliminary addition of water. The breakup of some weak refreezing bonds during particle rearrangement likely dissipated some kinetic energy, and thus, the mixture mobility was reduced. As the water content increased, the thermal conductivity could likely not remain efficient enough to refreeze all the trapped water and thus allowed unfrozen water to lubricate particle corners, which enhanced mixture mobility. With a further increase in the water content, suction-induced cohesion cemented particles as clusters and reduced mixture mobility. However, a high ice content resulted in mobility enhancement with increasing water content because more gravel was refrozen into the ice matrix, and thus, the basal friction was lowered by the occupation of ice cubes at the bottom. The redistribution pattern of trapped water during mass propagation changed at a characteristic water content. When the water content was lower than the characteristic content, superficially cohered water detached from the surface asperity of one particle and transferred to another during particle rearrangement, i.e., local redistribution of trapped water. When the water content was higher than the characteristic content, the downward transfer of a considerable amount of trapped water was triggered by particle rearrangement under the influence of gravity, i.e., bulk redistribution of trapped water. The water experiencing bulk redistribution influenced the mixture mobility by exerting intergranular drag force via the build-up and break-up of liquid bridges, while locally redistributed water influenced mixture mobility by altering the surface properties of particles. This study is expected to be helpful in better understanding the propagation mechanisms of water-poor rock-ice avalanches and in improving relevant hazard assessments.

We report that the output signal-to-noise ratio (SNR) of a parallel array of hard limiters can be maximized at an optimal high-frequency vibration amplitude, i.e. the vibrational resonance (VR) effect. As the external noise shape parameter varies, the bifurcation mode of maximal SNR gain is found, and the upper limit of SNR gain is discussed. We theoretically demonstrate a tractable realization of an infinite array approached by a finite array of two hard limiters, and design an electronic circuit experiment to verify the feasibility of this effective method. These results indicate the potential applications of vibrational devices to array signal processing.

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (KD) value of 3.8 μM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents.

Compared with conventional lasers, the random laser is realized through strong multiple scatterings in disordered gain system. In this paper, random lasing (RL) in one-dimensional metal surface plasmon (SP) waveguide with gold-plated self-formed silicon pyramids was investigated comprehensively. Consequently, the emission intensity of RL was enhanced dramatically and the RL threshold was reduced significantly through Au-coated Si spiky tips. Meanwhile, one-dimensional metal SP channel waveguides confined the emitting light in a certain direction with a small divergence angle. Using FDTD simulations, it was found that the enhancement effect for RL is likely attributed to the localized surface plasmon (LSP) field. In addition, the LSP field nearby the spiky tips can enhance field-molecule interaction, which was benefit for lasing in small scale. The results in this letter supplied a feasible method to realize the application of RL in subwavelength optical elements.

This paper investigates noise benefits to the statistics with sign function in robust estimation problems. Sign function, as the score function of a robust M-estimator in location estimation, composes a median estimator. We show that, the mean-square error (MSE) of this statistic can be effectively decreased both under the background of the symmetric and asymmetric contamination noise by adding additive noise. Furthermore, the noise-enhanced effect observed in the linear regression estimation demonstrates that the conclusions in the location parameter estimation can be extended to multidimensional parameter estimation tasks.

The realization of one-dimension random laser by using artificially fabricated scatterers in our experiment represents a novelty method towards the development of manipulated-RL, which will highlight the application of disordered system on optoelectronic devices.

Identifying strong third-order nonlinearities and low nonlinear optical losses, including photonic crystals and plasmonic structure1–4, are crucial for developing optoelectronic devices and nanophotonics technologies. We presented large enhancement of degenerate two-photon absorption through hexagonal cavity resonance in single-crystalline ZnO microwire involved Fabry-Perot (FP) cavity and whispering gallery mode (WGM) cavity. We reported it is feasible to fabricate degenerate two-photon absorption single microwire photodetector. The device photocurrent performed a typical parabola curve with the increasing of incident irradiance due to third-order nonlinearity. We experimentally demonstrated two-photon absorption enhancement resonated in WGM cavity is more excellent than that in FP cavity for the highly confined optical fields ability at room temperature.

Single microbelt (MB] photodetectors with metal-semiconductor-metal (MSM] structure have been demonstrated and characterized comprehensively. For single-photon absorption, the maximum responsivity of ZnO-MB photodetector can reach as high as 1.4×105 A/W at 20 V bias. The results about photoresponse of MB-detector reveals that two relaxation mechanisms contribute to the carrier decay time. Moreover, the two-photon absorption upconversion photoresponsivity in the single-MB detector has also been realized, which is first report about the two-photon absorption detector to the best of our knowledge. The excellent two-photon absorption photoresponsivity characteristic of MB device can be available not only for detector but also for solar cell and biomedical imaging. Above results present a significant step towards future fabrication of single micro/nano-structure based multiphoton excitation optoelectronic device.