G protein-coupled receptors (GPCRs) are crucial players in various physiological processes, making them attractive candidates for drug discovery. However, traditional approaches to GPCR ligand discovery are time-consuming and resource-intensive. The emergence of artificial intelligence (AI) methods has revolutionized the field of GPCR ligand discovery and has provided valuable tools for accelerating the identification and optimization of GPCR ligands. In this study, we provide guidelines for effectively utilizing AI methods for GPCR ligand discovery, including data collation and representation, model selection, and specific applications. First, the online resources that are instrumental in GPCR ligand discovery were summarized, including databases and repositories that contain valuable GPCR-related information and ligand data. Next, GPCR and ligand representation schemes that can convert data into computer-readable formats were introduced. Subsequently, the key applications of AI methods in the different stages of GPCR drug discovery were discussed, ranging from GPCR function prediction to ligand design and agonist identification. Furthermore, an AI-driven multi-omics integration strategy for GPCR ligand discovery that combines information from various omics disciplines was proposed. Finally, the challenges and future directions of the application of AI in GPCR research were deliberated. In conclusion, continued advancements in AI techniques coupled with interdisciplinary collaborations will offer great potential for improving the efficiency of GPCR ligand discovery.
Transplantation represents the most effective treatment for end-stage liver diseases but is limited by the shortage of healthy donor organs. Extended criteria donor (ECD) liver grafts are increasingly utilized in clinical practice to mitigate this challenge. However, impaired ischemic tolerance of these grafts jeopardizes organ viability during cold storage. Machine perfusion (MP) was designed to improve organ preservation and reduce posttransplant complications. Nevertheless, it is increasingly evident that MP alone may not preserve ECD grafts optimally. Increasing emphasis has thus been placed on modified MP strategies, including the use of different perfusates, modified perfusion modalities, and different therapeutic interventions. Here, we introduce a novel term, “MP Plus,” denoting these additional strategies that are designed to restore organ function and potentially enable regeneration of ECD grafts. In this review, we summarize the existing and potential modified MP strategies and discuss their advantages in reconditioning different ECD grafts in clinical settings.
A universal vaccine is in high demand to address the uncertainties of antigenic drift and the reduced effectiveness of current influenza vaccines. In this study, a strategy called computationally optimized broadly reactive antigen (COBRA) was used to generate a consensus sequence of the hemagglutinin globular head portion (HA1) of influenza virus samples collected from 1918 to 2021 to trace evolutionary changes and incorporate them into the designed constructs. Constructs carrying different HA1 regions were delivered into eukaryotic cells by Salmonella -mediated bactofection using a Semliki Forest virus RNA-dependent RNA polymerase (RdRp)-based eukaryotic expression system, pJHL204. Recombinant protein expression was confirmed by Western blot and immunofluorescence assays. Mice immunized with the designed constructs produced a humoral response, with a significant increase in immunoglobulin G (IgG) levels, and a cell-mediated immune response, including a 1.5-fold increase in CD4 + and CD8 + T cells. Specifically, constructs #1 and #5 increased the production of interferon-γ (IFN-γ) producing CD4 + and CD8+ T cells, skewing the response toward the T helper type 1 cell (Th1) pathway. Additionally, interleukin-4 (IL-4)-producing T cells were upregulated 4-fold. Protective efficacy was demonstrated, with up to 4-fold higher production of neutralizing antibodies and a hemagglutination inhibition titer > 40 against the selected viral strains. The designed constructs conferred a broadly protective immune response, resulting in a notable reduction in viral titer and minimal inflammation in the lungs of mice challenged with the influenza A/PR8/34, A/Brisbane/59/2007, A/California/07/2009, KBPV VR-92, and NCCP 43021 strains. This discovery revolutionizes influenza vaccine design and delivery; Salmonella-mediated COBRA-HA1 is a highly effective in vivo antigen presentation strategy. This approach can effectively combat seasonal H1N1 influenza strains and potential pandemic outbreaks.
Hepatocyte nuclear factor 1 alpha (HNF1A), hepatocyte nuclear factor 4 alpha (HNF4A), and forkhead box protein A2 (FOXA2) are key transcription factors that regulate a complex gene network in the liver, creating a regulatory transcriptional loop. The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes. Our in silico analysis of HNF1A, HNF4A, and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrichment of these transcription factors specifically in the liver. Our previous studies identified HNF1A as a master regulator of fucosylation, glycan branching, and galactosylation of plasma glycoproteins. Here, we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype. We used the state-of-the-art clustered regularly interspaced short palindromic repeats/dead Cas9 (CRISPR/dCas9) molecular tool for the downregulation of the HNF1A, HNF4A, and FOXA2 genes in HepG2 cells—a human liver cancer cell line. The results show that the downregulation of all three genes individually and in pairs affects the transcriptional activity of many glyco-genes, although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures. The effect is better seen as an overall change in the total HepG2 N-glycome, primarily due to the extension of biantennary glycans. We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure. We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
Highway maintenance mileage reached 5.25 million kilometers in China by 2021. Ultra-thin overlay is one of the most commonly used maintenance technologies, which can significantly enhance the economic and environmental benefits of pavements. To promote the low-carbon development of ultra-thin overlays, this paper mainly studied the mechanism and influencing factors of several ultra-thin overlay functions. Firstly, the skid resistance, noise reduction, rutting resistance, and crack resistance of ultra-thin overlays were evaluated. The results indicated that the high-quality aggregates improved the skid and rutting resistance of ultra-thin overlay by 5%-20%. The optimized gradations and modified binders reduced noise of ultra-thin overlay by 0.4-6.0 dB. The high viscosity modified binders improved the rutting resistance of ultra-thin overlay by about 10%-130%. Basalt fiber improved the cracking resistance of ultra-thin overlay by more than 20%. Due to the thinner thickness and better road performance, the performance-based engineering cost of ultra-thin overlay was reduced by about 30%-40% compared with conventional overlays. Secondly, several environmentally friendly functions of ultra-thin overlay were investigated, including snow melting and deicing, exhaust gas purification and pavement cooling. The lower thickness of ultra-thin overlay was conducive to the diffusion of chloride-based materials to the pavement surface. Therefore, the snow melting effect of self-ice-melting was better. In addition, the ultra-thin overlay mixture containing photocatalytic materials could decompose 20%-50% of the exhaust gas. The colored ultra-thin overlay was able to reduce the temperature of the pavement by up to 8.1 °C. The temperature difference between the upper and lower surfaces of the ultra-thin overlay containing thermal resistance materials could reach up to 12.8 °C. In addition, numerous typical global engineering applications of functional ultra-thin overlay were summarized. This review can help better understand the functionality of ultra-thin overlays and promote the realization of future multi-functional and low-carbon road maintenance.
Over the past few decades, one of the most significant advances in dam construction has been the invention of the rock-filled concrete (RFC) dam, which is constructed by pouring high-performance self-compacting concrete (HSCC) to fill the voids in preplaced large rocks. The innovative use of large rocks in dam construction provides engineers with a material that requires less cement consumption and hydration heat while enhancing construction efficiency and environmental friendliness. However, two fundamental scientific issues related to RFC need to be addressed: namely, the pouring compactness and the effect of large rocks on the mechanical and physical properties of RFC. This article provides a timely review of fundamental research and innovations in the design, construction, and quality control of RFC dams. Prospects for next-generation concrete dams are discussed from the perspectives of environmental friendliness, intrinsic safety, and labor savings.
Understanding the vertical distribution of ozone is crucial when assessing both its horizontal and vertical transport, as well as when analyzing the physical and chemical properties of the atmosphere. One of the most effective ways to obtain high spatial resolution ozone profiles is through satellite observations. The Environmental Trace Gases Monitoring Instrument (EMI) deployed on the Gaofen-5 satellite is the first Chinese ultraviolet–visible hyperspectral spectrometer. However, retrieving ozone profiles using backscattered radiance values measured by the EMI is challenging due to unavailable measurement errors and a low signal-to-noise ratio. The algorithm developed for the Tropospheric Monitoring Instrument did not allow us to retrieve 87% of the EMI pixels. Therefore, we developed an algorithm specific to the characteristics of the EMI. The fitting residuals are smaller than 0.3% in most regions. The retrieved ozone profiles were in good agreement with ozonesonde data, with maximum mean biases of 20% at five latitude bands. By applying EMI averaging kernels to the ozonesonde profiles, the integrated stratospheric column ozone and tropospheric column ozone also showed excellent agreement with ozonesonde data. The lower layers (0–7.5 km) of the EMI ozone profiles reflected the seasonal variation in surface ozone derived from the China National Environmental Monitoring Center (CNEMC). However, the upper layers (9.7–16.7 km) of the ozone profiles show different trends, with the ozone peak occurring at an altitude of 9.7–16.7 km in March, 2019. A stratospheric intrusion event in central China from August 11 to 15, 2019, is captured using the EMI ozone profiles, potential vorticity data, and relative humidity data. The increase in the CNEMC ozone concentration showed that downward transport enhanced surface ozone pollution.
Highlights
• Capturing different trends of ozone between near-surface and tropopause in Beijing-Tianjin_Hebei region.
Mechanical pretreatment is an indispensable process in biological treatment plants that remove plastics and other impurities from household biogenic waste (HBW). However, the imperfect separation of plastics in these pretreatment methods has raised concerns that they pose a secondary formation risk for microplastics (MPs). To validate this presumption, herein, quantities and properties of plastic debris and MPs larger than 50 μm were examined in the full chain of three different pretreatment methods in six plants. These facilities received HBW with or without prior depackaging at the source. The key points in the secondary formation of MPs were identified. Moreover, flux estimates of MPs were released, and an analysis of MPs sources was provided to develop an overview of their fate in HBW pretreatment. Pretreated output can contain a maximum of (1673 ± 279) to (3198 ± 263) MP particles per kilogram of wet weight (particles·kg −1 ww) for those undepackaged at source, and secondary MPs formation is primarily attributed to biomass crushers, biohydrolysis reactors, and rough shredders. Comparatively, HBW depackaged at the source can greatly reduce MPs by 8%–72%, regardless of pretreatment processes. Before pretreatment, 4.6–205.6 million MP particles were present in 100 tonnes of HBW. MPs are produced at a rate of 741.11–33 124.22 billion MP particles annually in anaerobic digester feedstock (ADF). This study demonstrated that HBW pretreatment is a competitive source of MPs and emphasized the importance of implementing municipal solid waste segregation at the source. Furthermore, depackaging biogenic waste at the source is recommended to substantially alleviate the negative effect of pretreatment on MPs formation.
Achieving historically anticipated improvement in the performance of integrated circuits is challenging, due to the increasing cost and complexity of the required technologies with each new generation. To overcome this limitation, the exploration and development of novel interconnect materials and processes are highly desirable in the microelectronics field. Molybdenum (Mo) is attracting attention as an advanced interconnect material due to its small resistivity size effect and high cohesive energy; however, effective processing methods for such materials have not been widely investigated. Here, we investigate the electrochemical behavior of ions in the confined nanopores that affect the electrical properties and microstructures of nanoscale Mo and Mo–Co alloys prepared via template-assisted electrodeposition. Additives in an electrolyte allow the deposition of extremely pure metal materials, due to their interaction with metal ions and nanopores. In this study, boric acid and tetrabutylammonium bisulfate (TBA) were added to an acetate bath to inhibit the hydrogen evolution reaction. TBA accelerated the reduction of Mo at the surface by inducing surface conduction on the nanopores. Metallic Mo nanowires with a 130 nm diameter synthesized through high-aspect-ratio nanopore engineering exhibited a resistivity of (63.0 ± 17.9) μΩ·cm. We also evaluated the resistivities of Mo–Co alloy nanowires at various compositions toward replacing irreducible conventional barrier/liner layers. An intermetallic compound formed at a Mo composition of 28.6 at%, the resistivity of the Mo–Co nanowire was (58.0 ± 10.6) μΩ·cm, indicating its superior electrical and adhesive properties in comparison with those of conventional barriers such as TaN and TiN. Furthermore, density functional theory and non-equilibrium Green’s function calculations confirmed that the vertical resistance of the via structure constructed from Mo-based materials was 21% lower than that of a conventional Cu/Ta/TaN structure.
Fluid flow at nanoscale is closely related to many areas in nature and technology (e.g., unconventional hydrocarbon recovery, carbon dioxide geo-storage, underground hydrocarbon storage, fuel cells, ocean desalination, and biomedicine). At nanoscale, interfacial forces dominate over bulk forces, and nonlinear effects are important, which significantly deviate from conventional theory. During the past decades, a series of experiments, theories, and simulations have been performed to investigate fluid flow at nanoscale, which has advanced our fundamental knowledge of this topic. However, a critical review is still lacking, which has seriously limited the basic understanding of this area. Therefore herein, we systematically review experimental, theoretical, and simulation works on single- and multi-phases fluid flow at nanoscale. We also clearly point out the current research gaps and future outlook. These insights will promote the significant development of nonlinear flow physics at nanoscale and will provide crucial guidance on the relevant areas.
In recent years, a great deal of attention has been focused on the environmental impact of plastics, including the carbon emissions related to plastics, which has promoted the application of biodegradable plastics. Countries worldwide have shown high interest in replacing traditional plastics with biodegradable plastics. However, no systematic comparison has been conducted on the carbon emissions of biodegradable versus traditional plastic products. This study evaluates the carbon emissions of traditional and biodegradable plastic products (BPPs) over four stages and briefly discusses environmental and economic perspectives. Four scenarios—namely, the traditional method, chemical recycling, industrial composting, and anaerobic digestion—are considered for the disposal of waste BPPs (WBPPs). The analysis takes China as a case study. The results show that the carbon emissions of 1000 traditional plastic products (plastic bags, lunch boxes, cups, etc.) were 52.09–150.36 carbon emissions equivalent of per kilogram (kg CO 2eq), with the stage of plastic production contributing 50.71%–50.77%. In comparison, 1000 similar BPPs topped out at 21.06–56.86 kg CO2 eq, approximately 13.53%–62.19% lower than traditional plastic products. The difference was mainly at the stages of plastic production and waste disposal, and the BPPs showed significant carbon reduction potential at the raw material acquisition stage. Waste disposal plays an important role in environmental impact, and composting and anaerobic digestion are considered to be preferable disposal methods for WBPPs. However, the high cost of biodegradable plastics is a challenge for their widespread use. This study has important reference significance for the sustainable development of the biodegradable plastics industry.
The emergence and spread of the mobile colistin-resistance gene, mcr-1, and its variants pose a challenge to the use of colistin, a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant (XDR) Gram-negative pathogens. Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens; however, few studies have considered the effects of adjuvants on limiting resistance-gene transmission. We found that chelerythrine (4 mg∙L −1) derived from Macleaya cordata extract, which is used as an animal feed additive, reduced the minimal inhibitory concentration (MIC) of colistin against an mcr-1 positive Escherichia coli (E. coli) strain by 16-fold (from 2.000 to 0.125 mg∙L−1), eliminated approximately 104 colony-forming units (CFUs) of an mcr-1 -carrying strain in a murine intestinal infection model, and inhibited the conjugation of an mcr-1-bearing plasmid in vitro (by > 100-fold) and in a mouse model (by up to 5-fold). A detailed analysis revealed that chelerythrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity, thereby impairing respiration, disrupting proton motive force (PMF), generating reactive oxygen species (ROS), and decreasing intracellular adenosine triphosphate (ATP) levels, which subsequently downregulates mcr-1 and conjugation-associated genes. These dual effects of chelerythrine can expand the use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance.
Chronic hepatitis B virus (HBV) infection, which threatens global public health, is a major contributor to liver-related morbidity and mortality. Examinations for liver diseases related to chronic HBV infection—including laboratory tests, ultrasounds, computed tomography (CT), and liver biopsies—may take up medical resources, particularly since they overlap in most instances. Thus, there is an urgent need to establish an economical and effective diagnosis method in order to streamline the medical process for HBV-related diseases. Using complex network models constructed based on clinical blood tests, we provide such a method by defining the novel measure of functional resilience to assess patients’ liver conditions. By combining network models and dynamics, we discovered the pivotal items and their corresponding thresholds, which can guide further research on preventing disease deterioration in critical states of these diseases. The macro-averaged precision of our method, functional resilience, is 84.74%, whereas the macro-averaged precision of physicians’ experience without assistance from imaging or biopsy is 55.63%. From an economic perspective, our approach could save the equivalent of at least 30 USD per visit for most Chinese patients and at least 400 USD per visit for most US patients, compared with general diagnostic methods. Globally, this will add to savings of at least 10.5 billion USD annually. Our method can comprehensively evaluate the condition of patients’ livers and help avert the waste of medical resources during the diagnosis of liver disease by reducing excessive imaging exams.
Industrial robots are becoming increasingly vulnerable to cyber incidents and attacks, particularly with the dawn of the Industrial Internet-of-Things (IIoT). To gain a comprehensive understanding of these cyber risks, vulnerabilities of industrial robots were analyzed empirically, using more than three million communication packets collected with testbeds of two ABB IRB120 robots and five other robots from various original equipment manufacturers (OEMs). This analysis, guided by the confidentiality–integrity–availability (CIA) triad, uncovers robot vulnerabilities in three dimensions: confidentiality, integrity, and availability. These vulnerabilities were used to design Covering Robot Manipulation via Data Deception (CORMAND2), an automated cyber–physical attack against industrial robots. CORMAND2 manipulates robot operation while deceiving the Supervisory Control and Data Acquisition (SCADA) system that the robot is operating normally by modifying the robot's movement data and data deception. CORMAND2 and its capability of degrading the manufacturing was validated experimentally using the aforementioned seven robots from six different OEMs. CORMAND2 unveils the limitations of existing anomaly detection systems, more specifically the assumption of the authenticity of SCADA-received movement data, to which we propose mitigations for.
In this work, we present a reconfigurable data glove design to capture different modes of human hand-object interactions, which are critical in training embodied artificial intelligence (AI) agents for fine manipulation tasks. To achieve various downstream tasks with distinct features, our reconfigurable data glove operates in three modes sharing a unified backbone design that reconstructs hand gestures in real time. In the tactile-sensing mode, the glove system aggregates manipulation force via customized force sensors made from a soft and thin piezoresistive material; this design minimizes interference during complex hand movements. The virtual reality (VR) mode enables real-time interaction in a physically plausible fashion: A caging-based approach is devised to determine stable grasps by detecting collision events. Leveraging a state-of-the-art finite element method, the simulation mode collects data on fine-grained four-dimensional manipulation events comprising hand and object motions in three-dimensional space and how the object’s physical properties (e.g., stress and energy) change in accordance with manipulation over time. Notably, the glove system presented here is the first to use high-fidelity simulation to investigate the unobservable physical and causal factors behind manipulation actions. In a series of experiments, we characterize our data glove in terms of individual sensors and the overall system. More specifically, we evaluate the system’s three modes by ① recording hand gestures and associated forces, ② improving manipulation fluency in VR, and ③ producing realistic simulation effects of various tool uses, respectively. Based on these three modes, our reconfigurable data glove collects and reconstructs fine-grained human grasp data in both physical and virtual environments, thereby opening up new avenues for the learning of manipulation skills for embodied AI agents.
Chemical resistant textiles are vital for safeguarding humans against chemical hazards in various settings, such as industrial production, chemical accidents, laboratory activities, and road transportation. However, the ideal integration of chemical resistance, thermal and moisture management, and wearer condition monitoring in conventional chemically protective textiles remains challenging. Herein, the design, manufacturing, and use of stretchable hierarchical core–shell yarns (HCSYs) for integrated chemical resistance, moisture regulation, and smart sensing textiles are demonstrated. These yarns contain helically elastic spandex, wrapped silver-plated nylon, and surface-structured polytetrafluoroethylene (PTFE) yarns and are designed and manufactured based on a scalable fabrication process. In addition to their ideal chemical resistance performance, HCSYs can function as multifunctional stretchable electronics for real-time human motion monitoring and as the basic element of intelligent textiles. Furthermore, a desirable dynamic thermoregulation function is achieved by exploiting the fabric structure with stretching modulation. Our HCSYs may provide prospective opportunities for the future development of smart protective textiles with high durability, flexibility, and scalability.
Vitamin B1 is widely applied in the healthcare and food industry as an antineuritic and antioxidant to maintain the normal functioning of nerve conduction, the heart, and the gastrointestinal tract. This study reports on an integrated eight-step continuous-flow synthesis of vitamin B 1 from commercially available 2-cyanoacetamide. The proposed continuous-flow process is based on advances in chemistry, engineering, and equipment design, and affords improved performance and safety compared with batch-mode manufacturing. Several challenges were precisely investigated and controlled, including mixing, unexpected clogging, solvent switches, an exothermic reaction, and the prevention of side reactions, using various micro-channel flow reactors, mixers, separators, and continuous filters. Vitamin B 1 was produced with a separated yield of 47.7% and high purity, with a total residence time of about 3.5 h. This eight-step continuous-flow protocol enables technology involving up to six of the key principles of green chemistry. Hence, the application of flow technology is of paramount importance for improving security, reducing waste, and, in particular, improving the efficiency of batch operations that require several days for manufacturing.
