Designer DNA NanoGripper (preprint)

DNA has shown great biocompatibility, programmable mechanical properties, and structural addressability at the nanometer scale, making it a versatile material for building high precision nanorobotics for biomedical applications. Herein, we present design principle, synthesis, and characterization of a DNA nanorobotic hand, called the "NanoGripper", that contains a palm and four bendable fingers as inspired by human hands, bird claws, and bacteriophages evolved in nature. Each NanoGripper finger has three phalanges connected by two flexible and rotatable joints that are bendable in response to binding to other entities. Functions of the NanoGripper have been enabled and driven by the interactions between moieties attached to the fingers and their binding partners. We showcase that the NanoGripper can be engineered to interact with and capture various objects with different dimensions, including gold nanoparticles, gold NanoUrchins, and SARS-CoV-2 virions. When carrying multiple DNA aptamer nanoswitches programmed to generate fluorescent signal enhanced on a photonic crystal platform, the NanoGripper functions as a sensitive viral biosensor that detects intact SARS-CoV-2 virions in human saliva with a limit of detection of ~ 100 copies/mL, providing RT-PCR equivalent sensitivity. Additionally, we use confocal microscopy to visualize how the NanoGripper-aptamer complex can effectively block viral entry into the host cells, indicating the viral inhibition. In summary, we report the design, synthesis, and characterization of a complex nanomachine that can be readily tailored for specific applications. The study highlights a path toward novel, feasible, and efficient solutions for the diagnosis and therapy of other diseases such as HIV and influenza.

Public Risk Perception Explains the Mitigation of COVID-19 (preprint)

Background Public awareness of self-protection (PASP) is of vital importance in predicting the spread of infectious diseases. It can change the way people travel and socialize, thereby curbing the spread of the infectious diseases and mitigating its impact. The objective of this study is to explore the impact of PASP on the transmission of COVID-19 and to predict its epidemic trend.Methods Based on large-scale Weibo and Twitter datasets, we analyzes the temporal patterns of PASP for COVID-19 and develop improved models integrating PASP to predict the spread of COVID-19 in both China and UK. Additionally, we implement the models to evaluate non-pharmaceutical intervention strategies such as travel restrictions.Results During the first two months of local outbreaks with mitigation actions, the rate of online users with PASP in China and UK increased by 53% and 26%, respectively. And the integrated models yield an improved\({R^2}\)of 96.57% and 95.12% for predicting outbreaks in China and UK.Conclusions This study presents a new attempt to quantify PASP and extend it to predict the epidemic trend with massive online social media data. And we demonstrate that measuring public response had instructional significance in epidemiological models and is important in infectious disease prevention and control.

Exploring the Dynamic Characteristics of Public Risk Perception and Emotional Expression during the COVID-19 Pandemic on Sina Weibo

(1) Background: Risk perception is a key factor in motivating people to comply with preventive behaviors during the COVID-19 pandemic. Appropriate risk perception is important to enhance beliefs and promote emergency management response to public health events. (2) Objective: This study developed a public risk perception measurement method for social media data to understand the dynamic characteristics of risk perception and emotional expression during public health emergencies. (3) Methods: Utilizing text-mining techniques and deep-learning algorithms, risk perception was calculated from two dimensions (dread and unknown) as well as the emotional expression characteristics of 185,025 posts from 10 January 2020 to 20 March 2020 on Sina Weibo. We also analyzed the characteristics of risk perception at different stages of the crisis life cycle. Furthermore, drawing on arousal theory, we constructed dynamic response relationships between emotion type (angry, fearful, sad, positive, and neutral) and risk perceptions by a vector autoregressive (VAR) model. (4) Results: The results revealed that the public expresses significantly more dread words than unknown words in shaping the risk perception process. As for the characteristics of evolution, public risk perception had been at a high level since the outbreak stage, and there was a sudden increase and a gradual decrease in the level of public risk perception. We also found that there is a significant response relationship between positive emotion, angry emotion, and risk perception. (5) Conclusion: This study provides a theoretical basis for more targeted epidemic crisis interventions. It points out the need for health communication strategy makers to consider the public's risk perception and emotional expression characteristics during public health emergencies.

Robust humoral and cellular immune responses in long-term convalescent COVID-19 individuals following one-dose SARS-CoV-2 inactivated vaccination

COVID-19, caused by SARS-CoV-2, has resulted in hundreds of millions of infections and millions of deaths worldwide. Preliminary results exhibited excellent efficacy of SARS-CoV-2 vaccine in preventing hospitalization and severe disease. However, data on inactivated vaccine-induced immune responses of naturally infected patients are limited. Here, we characterized SARS-CoV-2 RBD-specific IgG (anti-S-RBD IgG) and neutralizing antibodies (NAbs) against SARS-CoV-2 wild type and variants of concerns (VOCs), as well as RBD-specific IgG-secreting B cells and antigen-specific T cells respectively in 51 SARS-CoV-2 recovered subjects and 63 healthy individuals. In SARS-CoV-2 recovered patients, a single dose vaccine is sufficient to reactivate robust anti-S-RBD IgG and NAbs. The neutralizing capacity against VOCs increased significantly post-vaccination no matter healthy individuals or SARS-CoV-2 recovered patients. In addition, RBD-specific IgG-secreting B cells in SARS-CoV-2 recovered patients were significantly higher than that in healthy vaccine recipients. After the vaccine booster, the frequencies of specific IFN-γ+ CD4+ T cell, IL-2+ CD4+ T cell, and TNF-α+ CD4+ T cell responses were significantly increased in SARS-CoV-2 recovered patients. Our data highlighted the safety and utility of SARS-CoV-2 inactivated vaccine and demonstrated that robust humoral and cellular immune response can be reactivated by one-dose inactivated vaccine in SARS-CoV-2 recovered patients.

Opsonizing antibodies mediated SARS-CoV-2 entry into monocytes leads to inflammation

Opsonizing antibodies and CD16 permit the entry of severe acute respiratory syndrome coronavirus 2 into monocytes/macrophages, which further activate NLRP3 inflammasomes, leading to pyroptosis and the release of inflammatory cytokines.

Lymphocyte-C-reactive protein ratio can differentiate disease severity of COVID-19 patients and serve as an assistant screening tool for hospital and ICU admission (preprint)

In this study, we aimed to explore whether Lymphocyte-C-reactive protein ratio (LCR) can differentiate disease severity of Coronavirus disease 2019 (COVID-19) patients and its value as an assistant screening tool for admission to the hospital and the intensive care unit (ICU). A total of 184 adult COVID-19 patients from the COVID-19 Treatment Center in Heilongjiang Province at the First Affiliated Hospital of Harbin Medical University between January 2020 and March 2021 were included in this study. Patients were divided into asymptomatic infection group, mild group, moderate group, severe group, and critical group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (9th edition). Demographic and clinical data including gender, age, comorbidities, severity of COVID-19, white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), red blood cell distribution width (RDW), platelet (PLT), C-reaction protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), albumin (ALB), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL), and D-Dimer were obtained and collated from medical records at admission, from which sequential organ failure assessment (SOFA) score and LCR were calculated, and all above indicators were compared among groups. Multiple clinical parameters, including LYMPH, CRP and LCR, showed significant differences among groups. The related factors to classify COVID-19 patients into moderate, severe and critical groups included age, number of comorbidities, WBC, LCR, and AST. Among these factors, number of comorbidities showed the greatest effect, and only WBC and LCR were protective factors. The area under the receiver operating characteristic (ROC) curve of LCR to classify COVID-19 patients into moderate, severe and critical groups was 0.176. The cut-off value of LCR, and the sensitivity and specificity of ROC curve were 1780.7050, 84.6% and 66.2%, respectively. The related factors to classify COVID-19 patients into severe and critical groups included number of comorbidities, PLT, LCR, and SOFA score. Among these factors, SOFA score showed the greatest effect, and LCR was the only protective factor. The area under ROC curve of LCR to classify COVID-19 patients into severe and critical groups was 0.106. The cut-off value of LCR and the sensitivity and specificity of ROC curve were 571.2200, 81.3% and 90.0%, respectively. In summary, LCR can differentiate disease severity of COVID-19 patients and serve as a simple and objective assistant screening tool for hospital and ICU admission.

Backward Trajectory and Multifractal Analysis of Air Pollution in Zhengzhou Region of China

With the continuous promotion of industrialization and urbanization, China's environmental pollution is becoming increasingly serious, which has caused considerable damage to the natural balance. Air pollution seriously harms people's physical and mental health, the ecological environment, and the social sustainable development of society. In this study, the backward trajectory model and multifractal methods were adopted to analyze air pollution in Zhengzhou. The backward trajectory analysis showed that most clusters of air pollution were from southern Hebei, eastern Shandong, and mid-western Henan, which were then transported to Zhengzhou. For the PSCF and CWT analyses, we selected four representative cities to explore how close the air pollution of Zhengzhou is to other areas on the basis of air polluted concentration. The results of several multifractal methods indicated that multifractality existed in the AQI time series of Zhengzhou and cross-correlations between Zhengzhou and each of the four cities. The widths of multifractal spectra showed that the air pollution in Zhengzhou was closest to that in Jinan, followed by Shijiazhuang, Zibo, and Luoyang. The CDFA analysis showed that carbon monoxide (CO), nitrogen dioxide (NO2), and inhalable particulate matter (PM10) had important influences on air pollution in Zhengzhou. These findings offer a useful reference for air pollution sources and their potential contributions in Zhengzhou, which can support policy makers in environmental governance and in achieving sustainable urban development.

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Background: Acute lung injury (ALI) is characterized by dysfunction of the alveolar epithelial membrane caused by acute inflammation and tissue injury. Qingwenzhike (QWZK) prescription has been demonstrated to be effective against respiratory viral infections in clinical practices, including coronavirus disease 2019 (COVID-19) infection. So far, the chemical compositions, protective effects on ALI, and possible anti-inflammatory mechanisms remain unknown. Methods: In this study, the compositions of QWZK were determined via the linear ion trap/electrostatic field orbital trap tandem high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap MS). To test the protective effects of QWZK on ALI, an ALI model induced by lipopolysaccharide (LPS) in rats was used. The effects of QWZK on the LPS-induced ALI were evaluated by pathological changes and the number and classification of white blood cell (WBC) in bronchoalveolar lavage fluid (BALF). To investigate the possible underlying mechanisms, the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), interleukin-1β (IL-1β), interleukin-18 (IL-18), and immunoregulatory-related factors interferon-γ (IFN-γ) were detected by ELISA. Furthermore, the expression of Toll-like receptor 4 (TLR4), p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-NF-κB, nuclear factor-κB (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, pro-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), and β-actin were tested by Western blot. Results: A total of 99 compounds were identified in QWZK, including 33 flavonoids, 23 phenolic acids, 3 alkaloids, 3 coumarins, 20 triterpenoids, 5 anthraquinones, and 12 others. ALI rats induced by LPS exhibited significant increase in neutrophile, significant decrease in lymphocyte, and evidently thicker alveolar wall than control animals. QWZK reversed the changes in WBC count and alveolar wall to normal level on the model of ALI induced by LPS. ELISA results revealed that QWZK significantly reduced the overexpression of proinflammatory factors IL-6, TNF-α, MCP-1, IL-1β, IL-18, and IFN-γ induced by LPS. Western blot results demonstrated that QWZK significantly downregulated the overexpression of TLR4, p-IKKα/β, p-IκBα, p-NF-κB, NLRP3, cleaved caspase-1, and ASC induced by LPS, which suggested that QWZK inhibited TLR4/NF-κB signaling pathway and NLRP3 inflammasomes. Conclusions: The chemical compositions of QWZK were first identified. It was demonstrated that QWZK showed protective effects on ALI induced by LPS. The possible underlying mechanisms of QWZK on ALI induced by LPS was via inhibiting TLR4/NF-kB signaling pathway and NLRP3 inflammasome activation. This work suggested that QWZK is a potential therapeutic candidate for the treatments of ALI and pulmonary inflammation.

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction (preprint)

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 Å. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction (preprint)

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 angstrom. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

Impact of non-pharmacological interventions on COVID-19 boosting vaccine prioritization and vaccine-induced herd immunity: a population-stratified modelling study (preprint)

Background While the COVID-19 pandemic seemed far from the end, the booster vaccine project was proposed to further reduce the transmission risk and infections. However, handful studies have focused on questions that with limited vaccine capacity ether boosting high-risk workers first or prioritizing susceptible normal individuals is optimal, and vaccinating how many people can lead us to the goal of herd immunity. In this study we aimed to explore the conclusions of such two problems with consideration of non-pharmacological interventions including mandatory quarantine for international entrants, keeping social distance and wearing masks. Methods By implementing the corresponding proportion of individuals who remain infectious after four lengths of quarantine strategies to the novel population-stratified model, we quantified the impact of such measures on optimizing vaccine prioritization between high-risk workers and normal populations. Furthermore, by setting the hypothetical COVID-19 transmission severity (reproduction number, R0) to the level of the most contagious COVID-19 variant (B.1.617.2, delta variant, R0 = 5.0), we separately estimated the threshold vaccine coverage of five countries (China, United States, India, South Africa and Brazil) to reach herd immunity, with and without the consideration of interventions including wearings masks and keeping social distance. At last, the sensitive analysis of essential parameter settings was performed to examine the robustness of conclusions. Results For Chinese scenarios considered with moderate hypothetical transmission rate (R0 = 1.15-1.8), prioritizing high-risk workers the booster dose reached lower cumulative infections and deaths if at least 7-days of quarantine for international travelers is maintained, and the required screening time to remain such vaccinating strategy as optimal increased from 7-days to 21-days with the transmission severity. Although simply maintaining at least 7-days quarantine can lead to over 69.12% reduction in total infections, the improvement of longer quarantine strategies was becoming minimum and the least one was 2.28% between the 21 and the 28-days of quarantine. Besides, without the vaccination program, the impact of such measures on transmission control dropped significantly when R0 exceeded 1.5 and reached its minimal level when R0 equal to 2.5. On the other hand, when we combat the delta variant, the threshold vaccine coverage of total population to reach herd immunity lay within 74%-89% (corresponding to the vaccine efficiency from 70% to 50%), and such range decreased to 71%-84% if interventions including wearing mask and keeping social distance were implemented. Furthermore, Results of other countries with 85% vaccine efficiency were estimated at 79%, 91%, 94% and 96% for South Africa, Brazil, India and United States respectively. Conclusions Non-pharmacological interventions can substantially affect booster vaccination prioritization and the threshold condition to reach herd immunity. To combat the delta variant, restrictions need to be integrated with mass vaccination so that can reduce the transmission to the minimum level, and the 21-days might be the suggested maximum quarantine duration according to the cost-effectiveness. Besides, by implementing interventions, the requirement to reach herd immunity can be lower in all countries. Lastly, the following surveillance after vaccination can help ensure the real-time proportion of vaccinated individuals with sufficient protection.

Mitigation of SARS-CoV-2 Transmission at a Large Public University (preprint)

In the Fall of 2020, many universities saw extensive transmission of SARS-CoV-2 among their populations, threatening the health of students, faculty and staff, the viability of in-person instruction, and the health of surrounding communities.1, 2 Here we report that a multimodal "SHIELD: Target, Test, and Tell" program mitigated the spread of SARS-CoV-2 at a large public university, prevented community transmission, and allowed continuation of in-person classes amidst the pandemic. The program combines epidemiological modelling and surveillance (Target); fast and frequent testing using a novel and FDA Emergency Use Authorized low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD (Test); and digital tools that communicate test results, notify of potential exposures, and promote compliance with public health mandates (Tell). These elements were combined with masks, social distancing, and robust education efforts. In Fall 2020, we performed more than 1,000,000 covidSHIELD tests while keeping classrooms, laboratories, and many other university activities open. Generally, our case positivity rates remained less than 0.5%, we prevented transmission from our students to our faculty and staff, and data indicate that we had no spread in our classrooms or research laboratories. During this fall semester, we had zero COVID-19-related hospitalizations or deaths amongst our university community. We also prevented transmission from our university community to the surrounding Champaign County community. Our experience demonstrates that multimodal transmission mitigation programs can enable university communities to achieve such outcomes until widespread vaccination against COVID-19 is achieved, and provides a roadmap for how future pandemics can be addressed.

Multifaceted Optimization of MSC-Based Formulation upon Sodium Iodoacetate-Induced Osteoarthritis Models by Combining Advantageous HA/PG Hydrogel and Fluorescent Tracer

Owing to the boundedness of conventional remedies upon articular cartilage for self-rehabilitation and the incrementally senior citizens, the incidence of osteoarthritis (OA) is increasing worldwide. Empirical studies have revealed the advantageous and promising potentials of mesenchymal stem/stromal cells (MSCs) on the refractory OA, whereas the deficiency of systematic and detailed exploration of MSC-based therapy largely hampers the large-scale applications in regenerative medicine. Herein, we initially utilized the monosodium iodoacetate- (MIA-) induced OA rabbit models and investigated the therapeutic effect of human umbilical cord-derived UC-MSCs at serial dose gradients with the splendid hyaluronic acid and/or propylene glycol hydrogels (HA, HA/PG), respectively. Afterwards, we turned to a dual-luciferase reporter tracing system and evaluated the spatiotemporal distribution and metabolokinetics of bifluorescence expressing UC-MSCs (BF-MSCs) in OA rats. Of the aforementioned trials, we verified that the combination of HA/PG and middle-dose MSCs (0.5×107 cells/ml) eventually manifested the optimal efficacy on OA rabbits. Furthermore, with the aid of the bioluminescence imaging (BLI) technology for dynamic in vitro and in vivo tracking, we intuitively delineated the spatiotemporal distribution and therapeutic process of BF-MSCs in OA rats, which substantially confirmed the reinforcement of HA/PG on BF-MSCs for OA treatment. Collectively, our data conformably demonstrated that the middle dose of UC-MSCs combined with HA/PG hydrogel was sufficient for optimal MSC-based formulation for blocking OA progression and promoting cartilage repair, which supplied overwhelming new references and enlightened MSC-based therapeutic strategies for cartilage defects.

Stochastic social behavior coupled to COVID-19 dynamics leads to waves, plateaus and an endemic state (preprint)

It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic, in broad agreement with empirical data. Our Stochastic Social Activity model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of a long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to an endemic state.

Stochastic social behavior coupled to COVID-19 dynamics leads to waves, plateaus and an endemic state (preprint)

It is well recognized that population heterogeneity plays an important role in the spread of epidemics. While individual variations in social activity are often assumed to be persistent, i.e. constant in time, here we discuss the consequences of dynamic heterogeneity. By integrating the stochastic dynamics of social activity into traditional epidemiological models we demonstrate the emergence of a new long timescale governing the epidemic in broad agreement with empirical data. Our model captures multiple features of real-life epidemics such as COVID-19, including prolonged plateaus and multiple waves, which are transiently suppressed due to the dynamic nature of social activity. The existence of the long timescale due to the interplay between epidemic and social dynamics provides a unifying picture of how a fast-paced epidemic typically will transition to the endemic state.

Exploring the Regulatory Function of the N-terminal Domain of SARS-CoV-2 Spike Protein Through Molecular Dynamics Simulation (preprint)

SARS-CoV-2 is what has caused the COVID-19 pandemic. Early viral infection is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein with its receptor binding domains (RBDs) in the receptor-accessible state. We performed molecular dynamics simulation on the S protein with a focus on the function of its N-terminal domains (NTDs). Our study reveals that the NTD acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein. The complete RBD structural transition is allowed only when the neighboring NTD that typically prohibits the RBD's movements as a wedge detaches and swings away. Based on this NTD "wedge" model, we propose that the NTD-RBD interface should be a potential drug target.