Targeting ARF4-mediated intracellular transport as broad-spectrum antivirals (preprint)

Host factors that regulate cellular vesicular trafficking also contribute to progeny virions’ destination, thus representing as potential antiviral drug targets. Here we demonstrate that genetic deletion of ARF4, a regulator in vesicle transport, repressed multiple pathogenic RNA viral infections including Zika virus (ZIKV), influenza A virus (IAV), SARS-CoV-2 and Vesicular Stomatitis virus (VSV). ARF4 activation was stimulated upon viral infection, and viral production was rescued when reconstituted with the activated ARF4, but not the inactivated mutants. Mechanically, ARF4 deletion obstructed viral normal translocation into Golgi complex, but led to mis-sorting for lysosomal degradation, consequently caused the blockage of final release. More importantly, ARF4 targeting peptides achieved significant therapeutic efficacy against ZIKV and IAV challenge in mice by blocking ARF4 activation. Hence, we clarify the critical role of ARF4 during viral infection, providing a broad-spectrum antiviral target and the basis for further pharmaceutical development.

Influential Risk Spreaders and Systemic Risk in Chinese Financial Networks (preprint)

A novel approach of gravity strength centrality (GSC) model is proposed to identify the influential risk spreaders in Chinese financial networks. We also measure the systemic risk contribution of financial institutions via ∆CoVaR and detect the relationship between the risk spreading ability and the systemic risk contribution of financial institutions. Our findings show that (i) the novel GSC model has the best performance on identifying influential risk spreaders, (ii) financial institutions with larger risk spreading ability contribute more to the systemic risk, (iii) the COVID-19 pandemic has significantly enhanced the contribution of influential risk spreaders to the systemic risk.

The number of similar epitopes determines the longevity of immunological memory (preprint)

The half-life of specific antibodies against various antigens varies tremendously from a few months to over 10,000 years. The reasons are largely unknown. Through epitope analysis of representative viruses, we found that the longevity of immunological memory may be correlated with the number of epitopes with similar sequences (EWSS) within each virus. Accordingly, a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with 4.5-times higher antibody titers and over 100 months of half-life was developed in a rabbit model. The decay pattern of antibodies against each epitope or the entire SARS-CoV-2 spike protein was roughly correlated with the number of EWSS in immunizationtreatments, –that is, for every additional EWSS, the half-life of the antibody would be doubled. After immunization, proportions of antigen-specific memory B cells (MBC) first increased and then decreased. In the descending phase, the antibody titers were positively correlated with the numbers of MBC. This study also discusses improvement measures for vaccines against other viruses.

Tourism Demand Prediction after COVID-19 with Deep Learning Hybrid CNN–LSTM—Case Study of Vietnam and Provinces

The tourism industry experienced a positive increase after COVID-19 and is the largest segment in the foreign exchange contribution in developing countries, especially in Vietnam, where China has begun reopening its borders and lifted the pandemic limitation on foreign travel. This research proposes a hybrid algorithm, combined convolution neural network (CNN) and long short-term memory (LSTM), to accurately predict the tourism demand in Vietnam and some provinces. The number of new COVID-19 cases worldwide and in Vietnam is considered a promising feature in predicting algorithms, which is novel in this research. The Pearson matrix, which evaluates the correlation between selected features and target variables, is computed to select the most appropriate input parameters. The architecture of the hybrid CNN–LSTM is optimized by utilizing hyperparameter fine-tuning, which improves the prediction accuracy and efficiency of the proposed algorithm. Moreover, the proposed CNN–LSTM outperformed other traditional approaches, including the backpropagation neural network (BPNN), CNN, recurrent neural network (RNN), gated recurrent unit (GRU), and LSTM algorithms, by deploying the K-fold cross-validation methodology. The developed algorithm could be utilized as the baseline strategy for resource planning, which could efficiently maximize and deeply utilize the available resource in Vietnam.

Dynamic lead–lag relationship between Chinese carbon emission trading and stock markets under exogenous shocks

Using the non-parametric thermal optimal path method, we investigate the dynamic lead–lag relationship between carbon emission trading and stock markets in China, and further consider the impact of different types of exogenous shocks on the lead–lag relationship. The empirical results show that the stock market leads the carbon market on most trading days, and the relationship reverses when the mean values of carbon market return are significantly smaller than zero. In addition, the lead–lag relationships when the carbon market leads the high energy-consuming stock market sectors are more obvious. We also find that there exist significant heterogeneous effects of different types of exogenous shocks on the lead–lag relationship between the two markets, including government policy, the Sino-US trade war and the Covid-19 outbreak. These findings have the potential to help regulators understand the interrelationship between components of the financial market, and be of great value for investors to optimize portfolio allocation by incorporating carbon assets into the portfolio.

Long-term passaging of pseudo-typed SARS-CoV-2 reveals the breadth of monoclonal and bispecific antibody cocktails.

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12 + 10D4 + 2G1 and 7B9-9D11 + 2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic.

The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.

The Sustainable Development and Strategic Approaches for Contemporary Higher Education

Due to the increasing appearance of global contagious diseases such as COVID-19, the goal of this research is to directly and explicitly advance the learning motivation, interests, and performance of online course participants into developing sustainable development and strategic approaches to discover the effective solution of the research question: how to provide the most effective online courses of sustainable development strategy for contemporary higher education in order to advance the student’s learning motivation, confidence, and desires? This is accomplished by integrating the three briefest analytical aspects of the Social Learning Theory, the main theoretical philosophies of Learning Community, and 10 core technological features to determine the most critical core determinants. Beyond the complex measured results, the most valuable conclusions were: (1) the highest Standardized Comparative Weight Scales (SCWS) was located in the Publicity Philosophy for contemporary online higher education sustainable development strategy, which meant the first hypothesis was accepted and the second and third hypotheses were denied. Hence, the Publicity Philosophy (PP) of the learning community directly and effectively advanced the contemporary online higher education sustainable development strategy for educational institutions as the best solution to the research question in order to achieve the main research objective. (2) Continuously, in detail, the PP of the learning community was directly and effectively enforced by the Professionalization Technology Feature of Course Function. This directly indicated that most online course participants focus on the professionalized technological features in the system operation, such as friendly operational platforms for easy uploads, convenient downloads of online course information, and real-time news during online courses at higher education institutions. Significantly, the aggregated technology in group discussions or teamwork assignments and the complete and fair evaluation of online course technological system can facilitate collaborative lesson preparation and lesson observation of the PP of the learning community in order to advance online course interests and learning performance to be the sustainable development strategic approach in contemporary higher education era.

Designing a Framework for Remote Cancer Care Through Community Co-design: Participatory Development Study.

BACKGROUND: Recent shifts to telemedicine and remote patient monitoring demonstrate the potential for new technology to transform health systems; yet, methods to design for inclusion and resilience are lacking. OBJECTIVE: The aim of this study is to design and implement a participatory framework to produce effective health care solutions through co-design with diverse stakeholders. METHODS: We developed a design framework to cocreate solutions to locally prioritized health and communication problems focused on cancer care. The framework is premised on the framing and discovery of problems through community engagement and lead-user innovation with the hypothesis that diversity and inclusion in the co-design process generate more innovative and resilient solutions. Discovery, design, and development were implemented through structured phases with design studios at various locations in urban and rural Kentucky, including Appalachia, each building from prior work. In the final design studio, working prototypes were developed and tested. Outputs were assessed using the System Usability Scale as well as semistructured user feedback. RESULTS: We co-designed, developed, and tested a mobile app (myPath) and service model for distress surveillance and cancer care coordination following the LAUNCH (Linking and Amplifying User-Centered Networks through Connected Health) framework. The problem of awareness, navigation, and communication through cancer care was selected by the community after framing areas for opportunity based on significant geographic disparities in cancer and health burden resource and broadband access. The codeveloped digital myPath app showed the highest perceived combined usability (mean 81.9, SD 15.2) compared with the current gold standard of distress management for patients with cancer, the paper-based National Comprehensive Cancer Network Distress Thermometer (mean 74.2, SD 15.8). Testing of the System Usability Scale subscales showed that the myPath app had significantly better usability than the paper Distress Thermometer (t63=2.611; P=.01), whereas learnability did not differ between the instruments (t63=-0.311; P=.76). Notable differences by patient and provider scoring and feedback were found. CONCLUSIONS: Participatory problem definition and community-based co-design, design-with methods, may produce more acceptable and effective solutions than traditional design-for approaches.

Testing an mHealth System for Individuals With Mild to Moderate Alcohol Use Disorders: Protocol for a Type 1 Hybrid Effectiveness-Implementation Trial.

BACKGROUND: The extent of human interaction needed to achieve effective and cost-effective use of mobile health (mHealth) apps for individuals with mild to moderate alcohol use disorder (AUD) remains largely unexamined. This study seeks to understand how varying levels of human interaction affect the ways in which an mHealth intervention for the prevention and treatment of AUDs works or does not work, for whom, and under what circumstances. OBJECTIVE: The primary aim is to detect the effectiveness of an mHealth intervention by assessing differences in self-reported risky drinking patterns and quality of life between participants in three study groups (self-monitored, peer-supported, and clinically integrated). The cost-effectiveness of each approach will also be assessed. METHODS: This hybrid type 1 study is an unblinded patient-level randomized clinical trial testing the effects of using an evidence-based mHealth system on participants' drinking patterns and quality of life. There are two groups of participants for this study: individuals receiving the intervention and health care professionals practicing in the broader health care environment. The intervention is a smartphone app that encourages users to reduce their alcohol consumption within the context of integrative medicine using techniques to build healthy habits. The primary outcomes for quantitative analysis will be participant data on their risky drinking days and quality of life as well as app use from weekly and quarterly surveys. Cost measures include intervention and implementation costs. The cost per participant will be determined for each study arm, with intervention and implementation costs separated within each group. There will also be a qualitative assessment of health care professionals' engagement with the app as well as their thoughts on participant experience with the app. RESULTS: This protocol was approved by the Health Sciences Minimal Risk Institutional Review Board on November 18, 2019, with subsequent annual reviews. Recruitment began on March 6, 2020, but was suspended on March 13, 2020, due to the COVID-19 pandemic restrictions. Limited recruitment resumed on July 6, 2020. Trial status as of November 17, 2021, is as follows: 357 participants were enrolled in the study for a planned enrollment of 546 participants. CONCLUSIONS: The new knowledge gained from this study could have wide and lasting benefits related to the integration of mHealth systems for individuals with mild to moderate AUDs. The results of this study will guide policy makers and providers toward cost-effective ways to incorporate technology in health care and community settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04011644; https://clinicaltrials.gov/ct2/show/NCT04011644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31109.

Poly-l-Lysine-Modified Graphene Field-Effect Transistor Biosensors for Ultrasensitive Breast Cancer miRNAs and SARS-CoV-2 RNA Detection.

(Mi)RNAs are important biomarkers for cancers diagnosis and pandemic diseases, which require fast, ultrasensitive, and economical detection strategies to quantitatively detect exact (mi)RNAs expression levels. The novel coronavirus disease (SARS-CoV-2) has been breaking out globally, and RNA detection is the most effective way to identify the SARS-CoV-2 virus. Here, we developed an ultrasensitive poly-l-lysine (PLL)-functionalized graphene field-effect transistor (PGFET) biosensor for breast cancer miRNAs and viral RNA detection. PLL is functionalized on the channel surface of GFET to immobilize DNA probes by the electrostatic force. The results show that PGFET biosensors can achieve a (mi)RNA detection range of five orders with a detection limit of 1 fM and an entire detection time within 20 min using 2 µL of human serum and throat swab samples, which exhibits more than 113% enhancement in terms of sensitivity compared to that of GFET biosensors. The performance enhancement mechanisms of PGFET biosensors were comprehensively studied based on an electrical biosensor theoretical model and experimental results. In addition, the PGFET biosensor was applied for the breast cancer miRNA detection in actual serum samples and SARS-CoV-2 RNA detection in throat swab samples, providing a promising approach for rapid cancer diagnosis and virus screening.

Imaging features of COVID-19: What we can learn from SARS and MERS (Review)

Coronavirus disease 2019 (COVID-19) is a highly infectious type of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has rapidly become a global pandemic. COVID-19, SARS and Middle East respiratory syndrome (MERS) are all caused by members of the Coronaviridae family. As expected, emerging genetic and clinical evidence from patients with COVID-19 has indicated that the pathway of infection is similar to that of SARS and MERS. Additionally, much like SARS and MERS, chest imaging serves an important role in the diagnosis, management and follow-up of patients with COVID-19. Although these related viruses present a similar pneumonic pathogenesis, the imaging results have distinguishable features. The current review evaluated the imaging results of patients with SARS and MERS and explored the potential similarities and differences among patients with COVID-19, SARS and MERS at early, progressive, severe and recovery stages, with the aim of improving our understanding of SARS-CoV-2 infections by comparing the features of COVID-19 images with those of SARS and MERS. The current review assessed whether imaging results had implications for the administration of corticosteroids as treatment for COVID-19. Whether corticosteroids can inhibit inflammatory cytokine storms and reduce the mortality of patients with viral pneumonia remains controversial. However, his review may help radiologists and clinicians to identify viral pneumonia and guide appropriate COVID-19 treatment. [ABSTRACT FROM AUTHOR] Copyright of Experimental & Therapeutic Medicine is the property of Spandidos Publications UK Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A SARS-CoV-2 neutralizing antibody with exceptional spike binding coverage and optimized therapeutic potentials (preprint)

The Coronavirus Disease of 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health and economy. Therapeutic options such as monoclonal antibodies (mAbs) against SARS-CoV-2 are in urgent need. We have identified potent monoclonal antibodies binding to SARS-CoV-2 Spike protein from COVID-19 convalescent patients and one of these antibodies, P4A1, interacts directly and covers the majority of the Receptor Binding Motif (RBM) of Spike receptor-binding domain (RBD), shown by high-resolution complex structure analysis. We further demonstrated P4A1 binding and neutralizing activities against wild type and mutant spike proteins. P4A1 was subsequently engineered to reduce the potential risk for antibody-dependent enhancement (ADE) of infection and to extend its half-life. The engineered mAb exhibits optimized pharmacokinetic and safety profile, and results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection.

Retrospective analysis on Mass Drug Administration of Deng's Herbal Tea Granula preventing from Novel Coronavirus Pneumonia (COVID-19) (preprint)

As the kinetics of novel coronavirus pneumonia (COVID-19) outbreak still going all over the world and we can't predict when it'll make that turnaround and start coming down, seeking ways to prevent and control this disease is particularly important. Here we describe the role of traditional Chinese medicine in preventing COVID-19. In this clinical observation study, we selected 65 people who came back from Hubei province as subjects and launched a mass drug administration with them. We collected the data of the days from Hubei, non-symptoms rate, temperature before and after administration of these people. We treated them by isolating for 14 days and taking Deng's Herbal Tea Granula once a day for seven days. Then we assessed the possible efficacy of Deng's Herbal Tea Granula on COVID-19. Enrolled people had an average age of 27 years old (3–66 years old), among which 34 (53.97%) were females, with a median temperature of 36.4℃ (36.1–36.8℃). The median of the days from Hubei was 16 days (10–27 days). None of them presents any abnormal clinical manifestation. Isolation is the most effective way to defend and control COVID-19, but accompanied by the treatment of Deng's Herbal Tea Granula may increase the power of prevention. Not only this plant solid beverage which made of Chinese medicine can keep the temperature of all the suspected people at a healthy and stable level, but also is suitable for a large group of ages.

TMPRSS2 Protease Inhibitors May Prolong But Heparins Accelerate SARS-CoV-2 Clearance (preprint)

The 2019 novel SARS-like coronavirus (SARS-CoV-2) entry depends on the host membrane serine protease TMPRSS2, which can be blocked by some clinically-proven drugs. Here we analyzed spatial relevance between glycosylation sequons and antibody epitopes and found that, different from SARS-CoV S, most high-surface-accessible epitopes of SARS-CoV-2 S are blocked by the glycosylation, and the optimal epitope with the highest surface accessibility is covered by the S1 cap. TMPRSS2 inhibitor treatments may prevent unmasking of this epitope and therefore prolong virus clearance and may induce antibody-dependent enhancement. Interestingly, a heparin-binding sequence immediately upstream of the S1/S2 cleavage site has been found in SARS-CoV-2 S but not in SARS-CoV S. Binding of SARS-CoV-2 with heparins may lead to exposure of S686, which then facilitates the S1/S2 cleavage, induces exposure of the optimal epitope, and therefore increases the antibody titres. A combination of heparin and vaccine (or convalescent serum) treatments thus is recommended.

[Biological Product Development Strategies for Prevention and Treatment of Coronavirus Disease 2019].

Coronavirus disease 2019 (COVID-19) caused by the novel coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), has become a Public Health Emergency of International Concern. Due to the large infection population, broad transmissibility and high mortality, it is urgent to find out the efficient and specific methods to prevent and treat COVID-19. As biological products have broadly applied in the prevention and treatment of severe epidemic diseases, they are promising in blocking novel coronavirus infection. According to the research advances of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), we reviewed the potential application of biological products such as interferon, convalescent plasma, intestinal micro-ecological regulators, vaccines and therapeutic antibodies, etc. , on prevention and treatment of COVID-19. May this review be helpful for conquering COVID-19 in the near future.

Management strategies of neonatal jaundice during the coronavirus disease 2019 outbreak.

The outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV) has become a most challenging health emergency. Owing to rigorous quarantine and control measures taken in China, routine neonatal health surveillance and follow-up have become challenging. Without follow-up surveillance, some rapid and progressive newborn diseases, such as bilirubin encephalopathy, may be ignored. The characteristics of onset age of kernicterus suggest that monitoring of bilirubin level at home provides a useful way to alert hospital visits and to prevent the development of extremely hyperbilirubinemia. Therefore, we developed an online follow-up program for convenient monitoring of bilirubin level of newborns that is based on our practical experiences. The aim is to make our management strategies of neonatal jaundice tailored to the infection prevention and control during the COVID-19 epidemic.