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Metastasis is the leading cause of cancer-related deaths; until now, the detection of tumor metastasis is mainly located at the period that secondary tumors have been formed, which usually results in poor prognosis. Thus, fast and precise positioning of organs, where tumor metastases are likely to occur at its earliest stages, is essential for improving patient outcomes. Here, we demonstrated a phosphorescence imaging method by organic nanoparticles to detect early tumor metastasis progress with microenvironmental changes, putting the detection period ahead to the formation of secondary tumors. In the orthotopic and simulated hematological tumor metastasis models, the microenvironmental changes could be recognized by phosphorescence imaging at day 3, after tumor implantation in liver or intravenous injection of cancer cells. It was far ahead those of other reported imaging methods with at least 7 days later, providing a sensitive and convenient method to monitor tumor metastases at the early stage.

Task scheduling is important in cloud manufacturing because of customers’ increasingly individualized demands. However, when various changes occur, a previous optimal schedule may become non-optimal or even infeasible owing to the uncertainty of the real manufacturing environment where dynamic task arrival over time is a vital source. In this paper, we propose a novel collaborative task scheduling (CTS) model dealing with new task arrival which considers multi-supply chain collaboration. We present an improved multi-population biogeography-based optimization (IMPBBO) algorithm that uses a matrix-based solution representation and integrates the multi-population strategy, local search for the best solution, and the collaboration mechanism, for determining the optimal schedule. A series of experiments are conducted for verifying the effectiveness of the IMPBBO algorithm for solving the CTS model by comparing it with five other algorithms. The experimental results concerning average best values obtained by the IMPBBO algorithm are better than that obtained by comparison algorithms for 41 out of 45 cases, showing its superior performance. Wilcoxon-test has been employed to strengthen the fact that IMPBBO algorithm performs better than five comparison algorithms.

Tumour metastasis is a main barrier in fully recovery of cancer, in most cases, metastasis has already occurred before the detection of cancer. Until now, the detection limit of tumour sizes is still ~1 mm in mouse models, thus, it is difficult to track tumour metastasis in the early stage by current imaging techniques and related others. Herein, we demonstrated a novel way to detect early tumour metastasis by utilizing background-negligible phosphorescence imaging at room-temperature, putting the detection limits ahead to the stage of tumour metastatic niches. Ultra-bright phosphorescence nanoparticles (NPs) with good biocompatibility and long lifetime (49 ms) were prepared by the simply enveloping process, which achieved high signal to background ratio (SBR) of 2278 ± 242 in subcutaneous imaging. This is the highest one among phosphorescent nanoparticles of organic molecules reported, partially assuring the detection of early metastases from orthotopic liver tumours to lungs with high sensitivity. Finally, the metastatic niches in lungs before the formation of secondary tumours, as confirmed by immunohistochemistry, which appeared after tumour implantation in liver for three days, can be detected by phosphorescent NPs with SBR of 62 ± 23, far ahead of other reported imaging methods under the same conditions, thus providing an efficient approach to early diagnosis of cancer.

As an important neurotropic enterovirus, enterovirus 71 (EV71) is occasionally associated with severe neurological diseases and high mortality rates in infants and young children. Understanding the interaction between host factors and EV71 will play a vital role in developing antivirals and optimizing vaccines. Here, we performed a genome-wide CRISPR-Cas9 knockout screen and revealed that scavenger receptor class B member 2 (SCARB2), solute carrier family 35 member B2 (SLC35B2), and beta-1,3-glucuronyltransferase 3 (B3GAT3) are essential in facilitating EV71 replication. Subsequently, the exploration of molecular mechanisms suggested that the knockout of SLC35B2 or B3GAT3, not SCARB2, led to a remarkable decrease in the binding of EV71 to cells and internalization into cells. Furthermore, we found that the infection efficiency for EV71 was positively correlated with the level of host cell sulfation, not simply with the amount of heparan sulfate, suggesting that an unidentified sulfated protein(s) must contribute to EV71 infection. In support of this idea, we screened possible sulfated proteins among the proteinous receptors for EV71 and confirmed that SCARB2 could uniquely interact with both tyrosyl protein sulfotransferases in humans. We then performed mass spectrometric analysis of SCARB2, identifying five sites with tyrosine sulfation. The function verification test indicated that there were more than five tyrosine-sulfated sites on SCARB2. Finally, we constructed a model for EV71 entry in which both heparan sulfate and SCARB2 are regulated by SLC35B2 and act cooperatively to support viral binding, internalization, and uncoating. Taken together, this is the first time that we performed the pooled CRISPR-Cas9 genetic screening to investigate the interplay of host cells and EV71. Furthermore, we found that a novel host factor, SLC35B2, played a dual role in regulating the overall sulfation comprising heparan sulfate sulfation and protein tyrosine sulfation, which are critical for EV71 entry. IMPORTANCE As the most important nonpolio neurotropic enterovirus lacking specific treatments, EV71 can transmit to the central nervous system, leading to severe and fatal neurological complications in infants and young children. The identification of new factors that facilitate or inhibit EV71 replication is crucial to uncover the mechanisms of viral infection and pathogenesis. To date, only a few host factors involved in EV71 infection have been characterized. Herein, we conducted a genome-wide CRISPR-Cas9 functional knockout (GeCKO) screen for the first time to study EV71 in HeLa cells. The screening results are presented as a ranked list of candidates, including 518 hits in the positive selection that facilitate EV71 replication and 1,044 hits in the negative selection that may be essential for cell growth and survival or for suppressing EV71 infection. We subsequently concentrated on the top three hits in the positive selection: SCARB2, SLC35B2, and B3GAT3. The knockout of any of these three genes confers strong resistance against EV71 infection. We confirmed that EV71 infection is codependent on two receptors, heparan sulfate and SCARB2. We also identified a host entry factor, SLC35B2, indirectly facilitating EV71 infection through regulation of the host cell sulfation, and determined a novel posttranslational modification, protein tyrosine sulfation existing in SCARB2. This study revealed that EV71 infectivity exhibits a significant positive correlation with the level of cellular sulfation regulated by SLC35B2. Due to the sulfation pathway being required for many distinct viruses, including but not limited to EV71 and respiratory syncytial virus (RSV), which were tested in this study, SLC35B2 represents a target of broad-spectrum antiviral therapy.

Ebola virus (EBOV) is an enveloped negative-sense RNA virus and a member of the filovirus family. Nucleoprotein (NP) expression alone leads to the formation of inclusion bodies (IBs), which are critical for viral RNA synthesis. The matrix protein, VP40, not only plays a critical role in virus assembly/budding, but also can regulate transcription and replication of the viral genome. However, the molecular mechanism by which VP40 regulates viral RNA synthesis and virion assembly/budding is unknown. Here, we show that within IBs the N-terminus of NP recruits VP40 and is required for VLP-containing NP release. Furthermore, we find four point mutations (L692A, P697A, P698A and W699A) within the C-terminal hydrophobic core of NP result in a stronger VP40–NP interaction within IBs, sequestering VP40 within IBs, reducing VP40–VLP egress, abolishing the incorporation of NC-like structures into VP40–VLP, and inhibiting viral RNA synthesis, suggesting that the interaction of N-terminus of NP with VP40 induces a conformational change in the C-terminus of NP. Consequently, the C-terminal hydrophobic core of NP is exposed and binds VP40, thereby inhibiting RNA synthesis and initiating virion assembly/budding. Electronic supplementary material The online version of this article (10.1007/s13238-020-00764-0) contains supplementary material, which is available to authorized users.

RNA-remodeling proteins, including RNA helicases and chaperones, play vital roles in the remodeling of structured RNAs. During viral replication, viruses require RNA-remodeling proteins to facilitate proper folding and/or re-folding the viral RNA elements. Coxsackieviruses B3 (CVB3) and Coxsackieviruses B5 (CVB5), belonging to the genus Enterovirus in the family Picornaviridae, have been reported to cause various infectious diseases such as hand-foot-and-mouth disease, aseptic meningitis, and viral myocarditis. However, little is known about whether CVB3 and CVB5 encode any RNA remodeling proteins. In this study, we showed that 2C proteins of CVB3 and CVB5 contained the conserved SF3 helicase A, B, and C motifs, and functioned not only as RNA helicase that unwound RNA helix bidirectionally in an NTP-dependent manner, but also as RNA chaperone that remodeled structured RNAs and facilitated RNA strand annealing independently of NTP. In addition, we determined that the NTPase activity and RNA helicase activity of 2C proteins of CVB3 and CVB5 were dependent on the presence of divalent metallic ions. Our findings demonstrate that 2C proteins of CVBs possess RNA-remodeling activity and underline the functional importance of 2C protein in the life cycle of CVBs.

Funding: Engineering and Physical Sciences Research Council. Grant Number: EP/L015331/1 European Research Council. Grant Number: ERC-2016-AdG-742222 Leverhulme Trust. Grant Number: 11715R. Raman spectroscopy is a powerful technique that enables fingerprinting of materials, molecules, and chemical environments by probing vibrational resonances. In many applications, the desired Raman signals are masked by fluorescence, either from the molecular system being studied, or from adjacent metallic nanostructures. Here, it is shown that wavelength-modulated Raman spectroscopy provides a powerful way to significantly reduce the strength of the fluorescence background, thereby allowing the desired Raman signals to be clearly recorded. This approach is made use of to explore Raman scattering in the context of vibrational strong coupling, an area that has thus far been problematic to visualise. Specifically, strong coupling between the vibrational modes in a polymer and two types of confined light field, the fundamental mode of a metal-clad microcavity, and the surface-plasmon modes of an adjacent thin metal film are looked at. While clear advantages in using the wavelength-modulated Raman approach are found, these results on strong coupling are inconclusive, and highlight the need for more work in this exciting topic area. Publisher PDF

Optical trapping describes the interaction between light and matter to manipulate micro-objects through momentum transfer. In the case of 3D trapping with a single beam, this is termed optical tweezers. Optical tweezers are a powerful and noninvasive tool for manipulating small objects, and have become indispensable in many fields, including physics, biology, soft condensed matter, among others. In the early days, optical trapping was typically accomplished with a single Gaussian beam. In recent years, we have witnessed rapid progress in the use of structured light beams with customized phase, amplitude, and polarization in optical trapping. Unusual beam properties, such as phase singularities on-axis and propagation invariant nature, have opened up novel capabilities to the study of micromanipulation in liquid, air, and vacuum. We summarize the recent advances in the field of optical trapping using structured light beams.

Fiber-shaped supercapacitors (FSCs) are promising power sources for wearable electronic devices due to their small size, excellent flexibility and deformability. The performance of FSCs has been severely affected by the framework of the fibrous electrodes and the interface between the electrode materials and current collector. Herein, we propose an ingenious strategy that combines anodizing etching and CVD methods to transform the less-active titanium wires into unique hierarchical carbon/TiO

Because of good thermal, electrical, and mechanical properties, low-temperature cofired ceramic (LTCC) has shown great potential in microelectronic applications. One of the most promising directions of LTCC technology development are integrating and packing sensors. In this article, a wireless passive capacitive pressure sensor operating in the MHz range based on cofiring of heterogeneous materials with LTCC technology is proposed, and the design, simulation, and fabrication of the sensor are demonstrated and discussed. It consists of a circular spiral inductor and a capacitor of two electrodes separated by a glass medium. Furthermore, a unique process of cofiring of heterogeneous materials was introduced to avoid deformation of the capacitive embedded cavity during lamination or sintering. The results show that the inductance of the inductor and the capacitance of the capacitor embedded in the sensor are .28 μH and 16.80 pF, respectively. The novel sensor has a sensitivity of approximately 847 Hz/MPa within the pressure range from atmospheric pressure to 100 MPa.

Glucosamine (GlcN), a dietary supplement widely utilized to promote joint health and effective in the treatment of osteoarthritis, is an effective macroautophagy/autophagy activator in vitro and in vivo. Previous studies have shown that autophagy is required for hepatitis B virus (HBV) replication and envelopment. The objective of this study was to determine whether and how GlcN affects HBV replication, using in vitro and in vivo experiments. Our data demonstrated that HBsAg production and HBV replication were significantly increased by GlcN treatment. Confocal microscopy and western blot analysis showed that the amount of autophagosomes and the levels of autophagic markers MAP1LC3/LC3-II and SQSTM1 were clearly elevated by GlcN treatment. GlcN strongly blocked autophagic degradation of HBV virions and proteins by inhibiting lysosomal acidification through its amino group. Moreover, GlcN further promoted HBV replication by inducing autophagosome formation via feedback inhibition of mechanistic target of rapamycin kinase complex 1 (MTORC1) signaling in an RRAGA (Ras related GTP binding A) GTPase-dependent manner. In vivo, GlcN application promoted HBV replication and blocked autophagic degradation in an HBV hydrodynamic injection mouse model. In addition, GlcN promoted influenza A virus, enterovirus 71, and vesicular stomatitis virus replication in vitro. In conclusion, GlcN efficiently promotes virus replication by inducing autophagic stress through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Thus, there is a potential risk of enhanced viral replication by oral GlcN intake in chronically virally infected patients. ACTB: actin beta; ATG: autophagy-related; CMIA: chemiluminescence immunoassay; ConA: concanavalin A; CQ: chloroquine; CTSD: cathepsin D; DAPI: 4ʹ,6-diamidino-2-phenylindole; EV71: enterovirus 71; GalN: galactosamine; GFP: green fluorescence protein; GlcN: glucosamine; GNPNAT1: glucosamine-phosphate N-acetyltransferase 1; HBP: hexosamine biosynthesis pathway; HBV: hepatitis B virus; HBcAg: hepatitis B core antigen; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis B e antigen; HBV RI: hepatitis B replicative intermediate; IAV: influenza A virus; LAMP1: lysosomal associated membrane protein 1; LAMTOR: late endosomal/lysosomal adaptor, MAPK and MTOR activator; ManN: mannosamine; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PHH: primary human hepatocyte; RAB7: RAB7A, member RAS oncogene family; RPS6KB1: ribosomal protein S6 kinase B1; RRAGA: Ras related GTP binding A; RT-PCR: reverse transcriptase polymerase chain reaction; SEM: standard error of the mean; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; UAP1: UDP-N-acetylglucosamine pyrophosphorylase 1; VSV: vesicular stomatitis virus.

With the development of the electric vehicle (EV) technology, the electric vehicle routing problems (EVRPs) have become a current focus for research. Although customer demands in the logistics service industry are often uncertain during the route planning stage, these demands have seldom been discussed in the existing literature on the EVRPs. This study presents an electric vehicle battery swap station (BSS) location-routing problem with stochastic demands, with the aim to determine a minimum cost scheme including the optimal number and location of BSSs with an optimal route plan based on stochastic customer demands. Furthermore, the classical recourse policy and preventive restocking policy are extended by considering the influences of both battery and vehicle capacity simultaneously. Subsequently, the concept of Pareto optimality is applied to the EVRP to expedite the selection of BSS sequences. To solve such a hybrid problem, a hybrid variable neighborhood search (HVNS) algorithm is proposed, which integrates the binary particle swarm optimization and variable neighborhood search to solve the location and routing problems interactively. In experimental studies, the HVNS is compared to five heuristic algorithms to verify its performance.

Manufacturing service supply chain (MSSC) optimization has been intensively studied to find an optimal service composition solution with the best quality of service (QoS) value. However, traditional MSSC optimization methods usually assume that candidate services are independent of one another. Therefore, potentially better MSSC solutions may have been neglected by not considering the positive influence of correlations between services on the QoS value. This study proposes a novel networked correlation-aware manufacturing service composition (NCMSC) mathematical model to characterize the influence of vertical and horizontal correlations between services on the QoS value of MSSC solution. To solve the NCMSC model, an extended artificial bee colony (ABC) algorithm is proposed to find a near-optimal solution with the best QoS value. The specific improvements to the original ABC algorithm include the following: (1) a new matrix-based encoding scheme is proposed to describe the MSSC solution in which each column contains a vertical composite structure and collaborative services for each subtask; (2) the migration operator of a biogeography-based optimization algorithm is combined with the original ABC algorithm to address the discrete MSSC optimization problem and improve the performance of the original ABC algorithm. The results of the experiments illustrate the importance of networked correlations between services, better practicality, effectiveness, and efficiency of the extended ABC algorithm in solving the optimization problem of MSSC.