Search

This paper aims to identify construction robotics' potential to reduce airborne virus transmission, review factors limiting the technology's adoption and highlight how similar barriers have been addressed in other industries. Construction robotics were identified and classified into 8 themes with 25 categories through a critical literature review. We undertook interviews with 4 construction contractors and conducted an online questionnaire with 32 experts from the UK (n=14) and China (n=18) who reviewed the robotic systems we identified and ranked the potential ability of each to reduce airborne virus transmission within the construction industry. The results of this study showed that construction robotics is not only beneficial to reduce airborne virus transmission, but may also help to reduce the spread of future contagious viruses. We found no significant difference (P>0.05) in practical usage and implementation barriers to construction robotics between the UK and China. Cost, training and limited awareness of robotic technologies were the main implementation barriers we identified in both countries. Both the UK and China may need to adopt strategies such as providing more financial support to small construction industries and skill training which are utilised successfully in other sectors to realise the potential of construction robotic technologies.

In the eastern edge of the Ordos Basin in China, coalbed methane geological resources are very abundant, and efficient extraction of coalbed methane has become an important demand for energy development strategies and coal safety production. Therefore, this article uses IoT detection technology to optimize the coal seam pressure fracturing fluid system in this area, in order to improve its efficiency and reliability. Through on-site experiments, the relationship between different concentrations of fracturing fluid systems and coal seam permeability was studied. Divide the architecture of the Internet of Things to achieve more efficient information transmission and application. Based on the actual situation of the coal industry, we have constructed a system architecture for the Internet of Things in coal mines. Based on in-depth research on the occurrence characteristics of coalbed methane in the eastern edge of the Ordos Basin and the characteristics of underground fracturing fluid technology in coal mines, we have obtained the viscosity, rheological properties, viscoelasticity of underground fracturing fluid in coal mines, as well as specific requirements for the action of coalbed methane. On this basis, an interaction model between coal seam fracturing proppant and coal reservoir was established, and its mechanical response process was analyzed using numerical simulation methods. Selecting the optimal fracturing fluid ratio can significantly improve the surface wettability and strength of coal samples, while reducing the content of clay minerals and increasing the porosity of coal samples.

Penile cancer is a rare malignancy with poor prognosis. Advanced penile cancer that invades the penile shaft and causes urinary retention could be rarely seen. We reported a 72-year-old male suffered from advanced penile cancer with penile self-amputation and acute urinary retention. We reckoned the self-amputation of penis as a new sign of advanced penile cancer.

Botrytis cinerea, the causative agent of gray mold disease (GMD), invades plants to obtain nutrients and disseminates through airborne conidia in nature. Bacillus amyloliquefaciens strain GD4a, a beneficial bacterium isolated from switchgrass, shows great potential in managing GMD in plants. However, the precise mechanism by which GD4a confers benefits to plants remains elusive. In this study, an A. thaliana-B. cinerea-B. amyloliquefaciens multiple-scale interaction model was used to explore how beneficial bacteria play essential roles in plant growth promotion, plant pathogen suppression, and plant immunity boosting. Arabidopsis Col-0 wild-type plants served as the testing ground to assess GD4a’s efficacy. Additionally, bacterial enzyme activity and targeted metabolite tests were conducted to validate GD4a’s potential for enhancing plant growth and suppressing plant pathogens and diseases. GD4a was subjected to co-incubation with various bacterial, fungal, and oomycete pathogens to evaluate its antagonistic effectiveness in vitro. In vivo pathogen inoculation assays were also carried out to investigate GD4a’s role in regulating host plant immunity. Bacterial extracellular exudate (BEE) was extracted, purified, and subjected to untargeted metabolomics analysis. Benzocaine (BEN) from the untargeted metabolomics analysis was selected for further study of its function and related mechanisms in enhancing plant immunity through plant mutant analysis and qRT-PCR analysis. Finally, a comprehensive model was formulated to summarize the potential benefits of applying GD4a in agricultural systems. Our study demonstrates the efficacy of GD4a, isolated from switchgrass, in enhancing plant growth, suppressing plant pathogens and diseases, and bolstering host plant immunity. Importantly, GD4a produces a functional bacterial extracellular exudate (BEE) that significantly disrupts the pathogenicity of B. cinerea by inhibiting fungal conidium germination and hypha formation. Additionally, our study identifies benzocaine (BEN) as a novel small molecule that triggers basal defense, ISR, and SAR responses in Arabidopsis plants. Bacillus amyloliquefaciens strain GD4a can effectively promote plant growth, suppress plant disease, and boost plant immunity through functional BEE production and diverse gene expression.

The isolation of B. proteolyticus OSUB18 from switchgrass unveiled its significant potential in both the enhancement of plant growth and the suppression of plant diseases in our previous study. The elucidation of the related mechanisms governing this intricate plant–microbe interaction involved the utilization of the model plant Arabidopsis thaliana. In our comprehensive study on Arabidopsis, OSUB18 treatment was found to significantly alter root architecture and enhance plant growth under various abiotic stresses. An RNA-seq analysis revealed that OSUB18 modified gene expression, notably upregulating the genes involved in glucosinolate biosynthesis and plant defense, while downregulating those related to flavonoid biosynthesis and wound response. Importantly, OSUB18 also induces systemic resistance in Arabidopsis against a spectrum of bacterial and fungal pathogens and exhibits antagonistic effects on phytopathogenic bacteria, fungi, and oomycetes, highlighting its potential as a beneficial agent in plant stress management and pathogen resistance. Overall, our findings substantiate that OSUB18 exerts a stimulatory influence on plant growth and health, potentially attributed to the remodeling of root architecture, defense signaling, and the comprehensive mitigation of various biotic and abiotic stresses.

To study the effect of cyclic impacts and confining pressure on the damage evolution of rock materials, numerical simulations of cyclic impact tests on rock materials under confining pressure were carried out by LS-DYNA using dynamic relaxation and full restart analysis. The static confining pressure was applied by dynamic relaxation, and cyclic impacts were realized by full restart analysis. As the crack generation and propagation result in the failure of elements in the finite element model, the damage variable defined by the crack density method was characterized by volume reduction. Numerical simulation indicates that both the confining pressure and amplitude of incident stress waves significantly affect the damage evolution of rock materials. High incident stress waves lead to severe damage, while large confining pressure results in minor damage. Under confining pressure, the damage to rock materials is alleviated due to the constraint effect on crack propagation. The number of cyclic impacts before macroscopic fracture increases as the confining pressure increases and decreases when the amplitude of the incident stress waves increases. The cumulative damage of rock materials under confining pressure progressively increases with the number of cyclic impacts, and the damage evolution exhibits three distinct stages: rapid rising, steady development, and sharp rising.

The influence of joint roughness and inclination on the dynamic mechanical properties of rocks is a prominent research area. In order to investigate the effects of joint roughness and inclination on the dynamic mechanical properties of jointed rocks, impact tests were conducted using a spilt Hopkinson pressure bar (SHPB) apparatus for prefabricated serrated joint cement mortar specimens with varying joint roughness and inclination. The failure mode, stress wave propagation characteristics, peak stress, and stress wave energy transfer law under impact load were analyzed. The results indicate that both joint inclinations and joint roughness coefficients (JRC) have a strong influence on the failure mode, peak stress, and stress wave energy transfer of jointed specimens. The jointed specimens exhibit three distinct failure modes under impact load, namely splitting tensile failure, shear slip failure, and compound failure of splitting tensile and shear. The peak stress initially decreases then increases with the increase in joint inclination angle, namely a V-shape variation, while it gradually increases with JRC increasing from 0 to 20. Jointed specimens exhibit the lowest peak stress at an inclination angle of 45° and JRC of 0. The variation of transmitted energy coefficient is similar to the peak stress, while the variation of reflected energy coefficient is opposite to the peak stress. At joint inclination angles of 0° or 90°, the reflected energy coefficient increases with the increase of JRC from 0 to 20, while the transmitted energy decreases. However, when the joint inclination angle is in the range of 30° to 60°, the reflected energy coefficient gradually decreases with JRC increasing, while the transmitted energy coefficient gradually increases.

Emission trading policy provides a new approach using economic incentives to control the environmental pollution efficiently. Legal polluters can trade emission permits with each other through a trusted trading system that lacks security and credibility due to its centralization nowadays. Permissioned blockchain utilize a decentralized way to store private data immutably, providing new approaches to solve those defects of the existing centralized systems. In this paper, we propose a Hyperledger-based Emission Trading System (HyperETS) on the permissioned blockchain. Using Hyperledger Fabric as the implementation platform, HyperETS integrates the fine-grained access control, distributed ledger, and consensus protocol, aiming to provide credible trading service for polluters. We achieve the business logic by designing the particular ledger structures and smart contract in blockchain. HyperETS stores all transactions immutably in a chain and makes it easy to share the data between organizations. Finally, several experiments are conducted to evaluate the performances of the proposed demonstration system.

Objective. To examine the gender, age, and region of residence in the anthropometric and nutritional profiles of children and adolescents aged 6–18 in Henan Province, China’s third most populous province. Design. This cross-sectional study of the China National Nutrition and Health survey (2010–2013) used a multistage cluster sampling technique. The sample included Chinese schoolchildren and adolescents aged 6 to 18 years (1,660 boys and 1,561 girls). Multiple logistic regression models were used to estimate the associations between sociodemographic correlates and overweight or obesity and stunting. Setting. Nine districts/counties in Henan Province. Participants. 3,221 subjects completed the questionnaire. Sociodemographic information was obtained. Body weight and height were measured. Results. There were statistically significant regional differences in average height and weight for boys in all age groups. Girls followed the same trends except for height when 15–18 years old. The urban-rural residence differences were found in relation to prevalence of stunting and weight status. Subjects in poor rural areas (15.43%) and ordinary rural areas (15.34%) had higher rates of stunting compared to their urban counterparts. Prevalence of overweight or obesity was highest in big city areas (15.71%) and lowest in ordinary rural areas (6.37%). Being a boy (OR = 1.69, 95% CI = 1.314–2.143), living in a big city (OR = 2.10, 95% CI = 1.431–3.073), or in a small-medium city (OR = 2.28, CI = 1.606–3.247), or being in a younger age group was associated with being overweight or obese. In addition, being a boy, living in a big city, or in a small-medium city, or being younger in age meant they were less likely to be stunted. Conclusions. A substantial dual burden of malnutrition among children and adolescents in Henan Province was revealed. The urban-rural differences in nutritional status were found. Stunting was more prevalent in rural areas than in urban. In contrast, while the rising problem of childhood and adolescent obesity still exists in the big city, we also found a great spike in obesity in small-medium cities. Evidence also indicated that boys were more likely to be overweight or obese. Our findings suggest that nutrition education, as well as environmental and policy interventions, is needed to target specific geographic regions.

The tensile failure of rocks is a common failure mode in rock engineering. Many studies have been conducted on the tensile strength and failure mode of rocks after high-temperature treatment under dynamic loading. However, research on the effects of high temperature on the dynamic splitting tensile characteristics of sandstone at actual high temperatures is lacking. To investigate the dynamic tensile characteristics of rocks at actual high temperatures, split Hopkinson pressure bar (SHPB) test apparatus and high-temperature environment box were used to perform dynamic splitting tensile tests under six striker velocities for sandstone specimens at 25°C–800°C. The dynamic splitting tensile strength, radial strain, average strain rate, and failure mode of sandstone under different test conditions were investigated. Test results revealed that the brittleness of sandstone specimens is enhanced at 200°C and 400°C, but slight ductility is observed at 600°C and 800°C. The strain rate effect of dynamic tensile strength is closely related to temperature. When the striker velocity exceeds 2.3 m/s, the dynamic radial strain first decreases and then increases with rising temperature. A quadratic polynomial relationship between the dynamic radial strain and temperature was observed. The temperature effect on the average strain rate is strong at low striker velocity and weak at high striker velocity. In the dynamic splitting tensile tests, high-temperature sandstone specimens are split into two semicylinders along the radial loading direction.

Dynamic impact tests were carried out by implying split-Hopkinson pressure bar (SHPB) apparatus under three-dimensional stress state to investigate the influences of weakly filled joint at seven kinds of angles on dynamic behavior and energy evolution characteristic of deep roadway sandstone (985 m below the surface). The results indicated that rebound strain phenomenon was obvious and the growth rate of stress was in two kinds of phased variations. Dynamic peak strain was inversely proportional to joint angle under three different strain rates. Dynamic compressive strength, elastic deformation modulus, and plastic deformation modulus were in similar variable tendencies with incremental joint angles, showing firstly decrease to minimum value at joint angle of 45° and then increase to maximum value at joint angle of 90°. Moreover, the sensitivity of plastic deformation modulus to joint angle was obviously inferior to that of elastic deformation modulus when joint angle increased from 0° to 45°. Furthermore, both elastic deformation modulus and plastic deformation modulus were independent of strain rate, which was contrary to dynamic compressive strength and dynamic peak strain. Additionally, absorption energy release rate was introduced and defined to describe energy release and conversion characteristics of joint specimens. The changed trend of energy reflection coefficient was completely opposite to that of energy transmission coefficient and absorbed energy release rate. Absorbed energy density was linearly decreased with incremental joint angle and was increased with the increase of strain rate.

Split-Hopkinson pressure bar (SHPB) tests were conducted for sandstone after recurrent heat-cool (H-C) cycles. Physical and mechanical properties, damage, and fracture characteristics of sandstone after the H-C cycle were explored. Additionally, the damage variable and release rate of damage strain were defined to describe the damage degree of the sandstone specimen after recurrent H-C cycles. Finally, the relationship between mass fractal dimension of fragmentation and cycling number was discussed. Results show that the P-wave velocity and density decrease with the increase of cycling number, while the porosity increases. It was found that the dynamic compressive strength and relative elastic modulus decrease with the increase of cycling number. 20 cycles is the critical point for the low temperature (L-T) group and moderate temperature (M-T) group, while it is 4 cycles for the high temperature (H-T) group. With the increase of cycling number, both the damage variable and release rate of damage strain of rock increase, while the destruction degree of sandstone becomes greater, and the corresponding fragments show more evenly.

Considering the periodical moisture variation in deep rock masses, cyclic wetting and drying under high geothermal condition is a vital issue for the safety and stability of deep rock engineering. To investigate the coupled effect of water temperature and cyclic wetting and drying on dynamic mechanical characteristics of sandstone, dynamic uniaxial compressive tests were carried out under the same loading condition for sandstone specimens subjected to cyclic wetting and drying treatment. When the temperature was 60°C in both wetting and drying processes, cyclic wetting and drying treatment presents a detrimental effect on the tested sandstone. Both physical and dynamic uniaxial compressive characteristics deteriorate in an exponential function with the increase of wetting and drying cycles. Based on SEM image analyses, the initiation and propagation of microcracks is mainly the result of cyclic loading and unloading of tensile stresses induced by water absorption and desorption of kaolinite within sandstone during cyclic wetting and drying treatment. After 15 cycles of wetting and drying, the deterioration of both physical and dynamic uniaxial compressive characteristics first increase then decrease with water temperature in wetting process elevating from 20°C to 98°C. SEM images indicate that more microcracks generate when water temperatures increase from 20°C to 60°C, while the micromorphology is changed and fewer microcracks display due to kaolinite mobilization when water temperature increases from 60°C to 98°C. The threshold value for the effect of water temperature on cyclic wetting and drying is found to be about 60°C for the tested sandstone.

To evaluate the effect of nonparallel end face of rocklike specimens in SHPB tests, the characteristics of energy dissipation are analyzed based on numerical simulations for end-face nonparallelism from 0% to 0.40% and Young’s modulus from 14 GPa to 42 GPa. With the increment of end-face nonparallelism, both energy consumption density and dissipated energy density show a slight increase trend, while releasable elastic strain energy density presents a slight decrease trend. Existence of elastic unloading in the damaged rocklike specimen leads to a reduction of energy consumption density and a constant dissipated energy density during total strain shrinkage. At peak dynamic stress, dissipated energy density presents a linear upward trend with the increment of end-face nonparallelism and Young’s modulus, while releasable elastic strain energy density shows an inverse trend. A binary linear regression equation is deduced to estimate the energy dissipation ratio. Mechanical damage evolution of the rocklike specimen is divided into two regions in line with the two regions in dynamic stress-strain curves, and the transition between the slow-growth region and rapid-growth region is shifted to the right with the increment of end-face nonparallelism. Due to the presence of nonparallel end face, fluctuation presents in energy density evolution and mechanical damage evolution. The fluctuation is enhanced with the increment of end-face nonparallelism and weakened with the increase of Young’s modulus. Based on energy density evolution and mechanical damage evolution analyses, the maximum end-face nonparallelism should be controlled within 0.20%, twice the value in ISRM suggested methods, which reduces the cost and time for processing rocklike specimens.

The dynamic stress-strain relationship of artificial frozen silty clay under one-dimensional coupled static and dynamic loads is obtained using modified split Hopkinson pressure bar (SHPB) equipment. The variation in dynamic compressive strength, dynamic deformation modulus, energy dissipation, and failure mode of artificial frozen silty clay with axial precompressive stress ratio are studied in this research. Experimental results indicate that the dynamic stress-strain curves under uniaxial state and one-dimensional coupled static and dynamic loads can be divided into four stages, i.e., compaction stage, elastic stage, plastic stage, and failure stage. The dynamic compressive strength, first-stage deformation modulus, second-stage deformation modulus, and absorbed energy density of artificial frozen silty clay present a trend of first increase and then decrease with the increase of axial compressive stress ratio, and the axial compressive stress ratio corresponding to the peak value is 0.7 in this test. In addition, there is a very similar effect of axial precompressive stress ratio on dynamic compressive strength and second-stage deformation modulus of artificial frozen silty clay. At 0.4 axial compressive stress ratio, spall phenomenon appears at circumferential direction and center position of the frozen soil specimen has no obvious failure. Shear failure appears at 0.7 to 0.9 axial compressive stress ratio, and the larger the axial compressive stress ratio applies, the more obvious the shearing surface appears; moreover, comminution failure mode appears at 1.0 axial compressive stress ratio.

Zonal disintegration phenomenon with alternative distribution of fracture zones and nonfracture zones is a characteristic failure in deep rock masses, especially for deep tunnel excavated by drill and blast method. To investigate the mechanism of zonal disintegration under coupled high axial geostress and blasting load, elastic stress field distribution for a circular tunnel in deep isotropic rock masses is obtained. Furthermore, Hoek-Brown criterion is amended by considering blast-induced damage effect. Both radial blasting load and blast-induced damage effect are assumed to decay in a negative exponential function. Taking the deep tunnel of Dingji coal mine in China as engineering background, the number and width of fracture zones are determined by deduced elastic stress field and modified Hoek-Brown criterion. Then numerical computation is conducted. Numerical computation results indicate that both the number and width of fracture zones mainly depend on high axial geostress and mechanical parameters of deep rock masses, and peak radial blasting load plays an important role in determining the width of fracture zone near the excavation.

To investigate the influence of nonparallel end-surface on stress uniformity during loading process in rock SHPB test, SHPB numerical simulations have been carried out by LS-DYNA when end-face nonparallelism is within 0.40% and Young’s modulus ranges from 14 GPa to 42 GPa. Isotropic linear elastic model is applied for elastic steel pressure bar, and HJC constitutive model is chosen for rock specimen. Numerical simulation results indicate that fluctuation effect exists in both reflected stress waves and transmitted stress waves, and it is enhanced with the increase of end-surface nonparallelism. The stress nonuniformity coefficient attenuates in a serrated fluctuation. With the increase of end-surface nonparallelism, the amplitude of transmitted stress wave gradually reduces, while stress nonuniformity coefficient increases. Stress equilibrium time first decreases slightly then increases in a step type. Therefore, nonparallel end-surface leads to two reverse results for stress uniformity during SHPB loading process, extending stress equilibrium time and shortening stress equilibrium time. And the influence on shortening stress equilibrium time is weak, while the influence on extending stress equilibrium time is great. When end-surface nonparallelism is 0.10%, stress equilibrium time achieves its lowest value whatever Young’s modulus is. Hence, end-surface nonparallelism of the rock specimen is suggested to be controlled within 0.10% when conducting SHPB tests.

Expansive soil is a source of risk to the foundations or subgrade engineering. Stabilization of expansive soil is imperative for practical engineering. A series of laboratory experiments were performed to analyze the physical-mechanical properties and microstructures of stabilized soil. Three stabilizers used in this study are fly ash, sand, and basalt fiber. Different percentages of fly ash (0, 5, 10, 15, and 20%), sand (0, 8, 16, and 24%), and basalt fiber (0 and 0.4%) were added by weight into natural soil. Experimental results indicate that the optimum moisture content of stabilized soil increases with the increase of fly ash content for a given sand content, whereas the maximum dry density shows a decreasing trend. The variation trend of optimum moisture content and maximum dry density turns reverse with the increase of sand content for a given fly ash content. Plasticity index is decreased by both increasing fly ash content and sand content. It is found that the maximum unconfined compressive strength and optimum growth rate of strength are obtained by selected mixtures of 10% fly ash, 8% sand, and 0.4% basalt fiber contents. As the analysis of complementary effect suggests, most of the mixt treatments applied in this study have produced good results associated with the strength enhancement of expansive soil. In line with the results of SEM tests, the connection among clay particles has been enhanced through the generation of hydration products (C-S-H and AFt) of fly ash. The filling effect of sand has increased the integrality and compactness of stabilized soil. Moreover, the gripping effect between fibers and soil particles notably improves the strength of stabilized soil. The effect of sand on reinforced soil with 0.4% basalt fiber increases the interfacial force between fibers and soil particles.

Dynamic compressive tests are performed in three frozen soil types under different stress states at freezing temperatures of −5°C and −15°C with impact loading pressures from 0.3 MPa to 0.6 MPa. The effects of frozen soil type, freezing temperature, impact loading pressures, and stress states on incident energy and energy absorption characteristics, such as absorbed energy and energy absorbency rate, are investigated. The experimental results show that most of the incident energy is reflected back to the incident bar, and incident energy linearly increases with the increase of impact loading pressures. Both absorbed energy and energy absorbency rate are found to be negatively correlated with freezing temperature, and there values under confining pressure state are larger than that under uniaxial condition. The effects of confining pressure on absorbed energy are quite different at different freezing temperatures. In addition, frozen soil type also affects absorbed energy and energy absorbency rate. Meanwhile, impact loading pressure shows an increased effect on the absorbed energy, but it has little effect on energy absorbency rate in the research.

Ebola virus (EBOV) can lead to severe hemorrhagic fever with a high risk of death in humans and other primates. To guide treatment and prevent spread of the viral infection, a rapid and sensitive detection method is required for clinical samples. Here, we described and evaluated a reverse transcription loop-mediated isothermal amplification (RT-LAMP) method to detect Zaire ebolavirus using the nucleoprotein gene (NP) as a target sequence. Two different techniques were used, a calcein/Mn2+ complex chromogenic method and real-time turbidity monitoring. The RT-LAMP assay detected the NP target sequence with a limit of 4.56 copies/μL within 45 min under 61°C, a similar even or increase in sensitivity than that of real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, all pseudoviral particles or non- Zaire EBOV genomes were negative for LAMP detection, indicating that the assay was highly specific for EBOV. To appraise the availability of the RT-LAMP method for use in clinical diagnosis of EBOV, of 417 blood or swab samples collected from patients with clinically suspected infections in Sierra Leone, 307 were identified for RT-LAMP-based surveillance of EBOV. Therefore, the highly specific and sensitive RT-LAMP method allows the rapid detection of EBOV, and is a suitable tool for clinical screening, diagnosis, and primary quarantine purposes.

To investigate the blast-induced damage effect on surrounding rock in vertical shaft excavation, 4 kinds of millisecond blasting model tests with three-circle blastholes were designed and carried out with excavation blasting in vertical shaft as the background. The longitudinal wave velocity on the side of concrete model was also measured before and after blasting. Then blast damage factor was then calculated by measuring longitudinal wave velocity before and after blasting. The test results show that the blast-induced damage factor attenuated gradually with the centre of three-circle blastholes as centre. With the threshold value of 0.19 for blast-induced damage factor, blast-induced damage zones for 4 kinds of model tests are described and there is an inverted cone blast-induced damage zone in concrete model. And analyses of cutting effect and blast-induced damage zone indicate that in order to minimize the blast-induced damage effect and ensure the cutting effect the reasonable blasting scheme for three-circle blastholes is the inner two-circle blastholes initiated simultaneously and the outer third circle blastholes initiated in a 25 ms delay.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.

A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2-4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.