Differentiating Immune Checkpoint Inhibitor-Related Pneumonitis From COVID-19 Pneumonia Using a CT-based Radiomics Nomogram (preprint)

Objectives This study aimed to develop and validate a radiomics nomogram that effectively distinguishes between immune checkpoint inhibitor-related pneumonitis (CIP) and COVID-19 pneumonia using radiographic imaging features. Methods We included 97 patients in this study, identifying 269 pneumonia lesions—159 from COVID-19 and 110 from CIP. The dataset was randomly divided into a training set (70% of the data) and a validation set (30%). We extracted radiomics features from corticomedullary and nephrographic phase-contrast computed tomography (CT) images, constructed a radiomics signature, and calculated a radiomics score (Rad-score). Using these features, we built models with three classifiers and assessed demographics and CT findings to create a clinical factors model. We then constructed a radiomics nomogram that combines the Rad-score with independent clinical factors and evaluated its performance in terms of calibration, discrimination, and clinical usefulness. Results In constructing the radiomics signature, 33 features were critical for differentiating between CIP and COVID-19 pneumonia. The support vector machine classifier was the most accurate of the three classifiers used. The Rad-score, gender, lesion location, radiological features, and lesion borders were included in the nomogram. The nomogram demonstrated superior predictive performance, significantly outperforming the clinical factors model in the training set (AUC comparison, p = 0.02638). Calibration curves indicated good fit in both training and validation sets, and the nomogram displayed greater net benefit compared to the clinical model. Conclusion The radiomics nomogram emerges as a noninvasive, quantitative tool with significant potential to differentiate between CIP and COVID-19 pneumonia. It enhances diagnostic accuracy and supports radiologists, especially in overburdened medical systems, through the use of machine learning predictions.

Tracking the first SARS-CoV-2 Omicron BA.5.1.3 outbreak in China.

The SARS-CoV-2 is still undergoing rapid evolution, resulting in the emergence of several variants of concern, especially the Omicron variants (B.1.1.529), which are surging worldwide. In this study, we tracked Omicron subvariant BA.5.1.3 as the causative agent in the Hainan Province wave in China, which started on 1 August 2022. This was China's first case of Omicron subvariant BA.5.1.3 and led to an indefinite total lockdown in Hainan with more than 8,500 confirmed cases. We obtained 391 whole genomes from positive nasopharyngeal swab samples in the city of Sanya in Hainan Province, which was the center of this outbreak. More than half of the infected cases were female (58%, 227/391) with a median age of 37.0 years (IQR 23.0-53.0). Median Ct values were 24.9 (IQR 22.6-27.3) and 25.2 (IQR 22.9-27.6) for ORF1ab and N genes, respectively. The total single-nucleotide polymorphism (SNP) numbers of Omicron BA.5.1.3 sampled in Sanya (median 69.0, IQR = 69.0-70.0) compared to those worldwide (median 63.0, IQR = 61.0-64.0) showed a significant difference (p < 0.05). Unique core mutations, including three non-synonymous mutations in ORF1ab (Y1064N, S2844G, and R3574K) and one synonymous mutation in ORF3a (S74S), were found. Phylogenetic analysis showed that virus from Sanya formed an independent sub-clade within the BA.5.1.3 subvariant, and could be divided into 15 haplotypes based on the S gene. The most recent common ancestor for the virus from Sanya was estimated as appearing on 5 July 2022, with 95% HPD ranging from 15 May to 20 September 2022. Thanks to our results, we were also able to delineate the mutational profile of this outbreak and highlight the importance of global genomic surveillance and data sharing.

Rapid degradation of chloroquine derivatives in a novel advanced reduction process: role of intramolecular hydrogen bond in the formation of excited triplet state compound

The role of triplet excited state compounds (TESC) in contaminants degradation by advanced reduction processes (ARPs) is rarely reported. In this study, Salicylic acid derivatives (SAD, e.g. Salicylic Acid (SA) and Sulfosalicylic acid (SSA)) were applied in ultraviolet activated sulfite process (UV/Sulfite) to generate TESC and enhance the decomposition of chloroquine derivatives (CQD, antiviral drugs being used for treating COVID-19 infection, e.g. chloroquine phosphate (CP)). The results indicated that the pseudo 1st order rate constant of CP (kobs-CP) increased by 2.76 and 6.26 fold, which increased from 9.10 × 10–4 s–1 in UV/Sulfite process to 2.51 × 10–3 s–1, 5.72 × 10–3 s–1 in UV/Sulfite/SA and UV/Sulfite/SSA process respectively. Similar phenomena were observed in other CQDs. Transient absorption spectra demonstrated that both triplet excited state SAD (3SAD*) and hydrated electron (eaq–) were the reactive intermediates in UV/Sulfite/SAD process, and contribute to the abatement of CP. The enhancement of SAD on contaminants degradation in UV/Sulfite/SAD process could attribute to the strong acceleration of eaq– toward the formation of 3SAD* in its photosensitive process, where SAD with intramoleuclar hydrogen bond would not undergo a directly photoionization process after absorbing a photon but undergo intersystem crossing to transform into 3SAD* which was then ionized to eaq– by biphotonic process, and constitute a hydrated electrons mediated photosensitization cycle with the supplement of eaq– from UV/Sulfite process. The higher CP degradation rate in UV/Sulfite/SSA process than that in UV/Sulfite/SA process was ascribed to a higher second order rate constant of 3SSA* toward CP and a higher yield of 3SSA*, which resulted from its higher intramolecular hydrogen bond energy enhancing photosensitization and photoionization.

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.

A novel bat coronavirus with a polybasic furin-like cleavage site.

The current pandemic of COVID-19 caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), threatens human health around the world. Of particular concern is that bats are recognized as one of the most potential natural hosts of SARS-CoV-2; however, coronavirus ecology in bats is still nascent. Here, we performed a degenerate primer screening and next-generation sequencing analysis of 112 bats, collected from Hainan Province, China. Three coronaviruses, namely bat betacoronavirus (Bat CoV) CD35, Bat CoV CD36 and bat alphacoronavirus CD30 were identified. Bat CoV CD35 genome had 99.5% identity with Bat CoV CD36, both sharing the highest nucleotide identity with Bat Hp-betacoronavirus Zhejiang2013 (71.4%), followed by SARS-CoV-2 (54.0%). Phylogenetic analysis indicated that Bat CoV CD35 formed a distinct clade, and together with Bat Hp-betacoronavirus Zhejiang2013, was basal to the lineage of SARS-CoV-1 and SARS-CoV-2. Notably, Bat CoV CD35 harbored a canonical furin-like S1/S2 cleavage site that resembles the corresponding sites of SARS-CoV-2. The furin cleavage sites between CD35 and CD36 are identical. In addition, the receptor-binding domain of Bat CoV CD35 showed a highly similar structure to that of SARS-CoV-1 and SARS-CoV-2, especially in one binding loop. In conclusion, this study deepens our understanding of the diversity of coronaviruses and provides clues about the natural origin of the furin cleavage site of SARS-CoV-2.

Monkeypox virus quadrivalent mRNA vaccine induces immune response and protects against vaccinia virus.

Monkeypox has been declared a public health emergency by the World Health Organization. There is an urgent need for efficient and safe vaccines against the monkeypox virus (MPXV) in response to the rapidly spreading monkeypox epidemic. In the age of COVID-19, mRNA vaccines have been highly successful and emerged as platforms enabling rapid development and large-scale preparation. Here, we develop two MPXV quadrivalent mRNA vaccines, named mRNA-A-LNP and mRNA-B-LNP, based on two intracellular mature virus specific proteins (A29L and M1R) and two extracellular enveloped virus specific proteins (A35R and B6R). By administering mRNA-A-LNP and mRNA-B-LNP intramuscularly twice, mice induce MPXV specific IgG antibodies and potent vaccinia virus (VACV) specific neutralizing antibodies. Further, it elicits efficient MPXV specific Th-1 biased cellular immunity, as well as durable effector memory T and germinal center B cell responses in mice. In addition, two doses of mRNA-A-LNP and mRNA-B-LNP are protective against the VACV challenge in mice. And, the passive transfer of sera from mRNA-A-LNP and mRNA-B-LNP-immunized mice protects nude mice against the VACV challenge. Overall, our results demonstrate that mRNA-A-LNP and mRNA-B-LNP appear to be safe and effective vaccine candidates against monkeypox epidemics, as well as against outbreaks caused by other orthopoxviruses, including the smallpox virus.

Teaching Performance of Chemistry Teachers in Chinese Mainland during the COVID-19 Pandemic: A Content Analysis Study.

Chemistry education has been affected in various aspects, especially teaching models, teaching technology, curriculum design, and teaching assessment, in Chinese Mainland since COVID-19 struck. To explore the change in teaching performance and differences in those teaching performances between middle school teachers and university teachers, this study analyzes 46 chemical education journal articles in three academic levels, including Junior High School (JHS), Senior High School (SHS), and university through content analysis method. The result shows that all levels of chemistry teachers (CTs) prefer to adopt two teaching models (live teaching or a combination of live and recorded teaching) and use Tencent Meeting as a teaching platform, but, university chemistry professors can integrate some software (MOOC and WeiXin as well as QQ) into their class to improve the effectiveness of teaching. As for curriculum design and teaching assessment, university teachers can employ the news in the context of the COVID-19 pandemic to carry out teaching more deeply than middle school teachers because university students learn more professional chemistry knowledge, but, all of them tend to evaluate students promptly (like oral assessment) through classroom interaction. Thus, it suggests the government and the school develop educational applications/software and teaching resources and a diverse curriculum to enhance online teaching work both domestically and foreign. And, it is also suggested that teachers should actively participate in the training of educational technology and strengthen cooperation with teachers in other disciplines to build interdisciplinary classrooms.

Seed amplification assay of nasal swab extracts for accurate and non-invasive molecular diagnosis of neurodegenerative diseases.

Nasal swabs are non-invasive testing methods for detecting diseases by collecting samples from the nasal cavity or nasopharynx. Dysosmia is regarded as an early sign of coronavirus disease 2019 (COVID-19), and nasal swabs are the gold standard for the detection. By nasal swabs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids can be cyclically amplified and detected using real-time reverse transcriptase-polymerase chain reaction after sampling. Similarly, olfactory dysfunction precedes the onset of typical clinical manifestations by several years in prion diseases and other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In neurodegenerative diseases, nasal swab tests are currently being explored using seed amplification assay (SAA) of pathogenic misfolded proteins, such as prion, α-synuclein, and tau. These misfolded proteins can serve as templates for the conformational change of other copies from the native form into the same misfolded form in a prion-like manner. SAA for misfolded prion-like proteins from nasal swab extracts has been developed, conceptually analogous to PCR, showing high sensitivity and specificity for molecular diagnosis of degenerative diseases even in the prodromal stage. Cyclic amplification assay of nasal swab extracts is an attractive and feasible method for accurate and non-invasive detection of trace amount of pathogenic substances for screening and diagnosis of neurodegenerative disease.

Gilteritinib: Repurposing of AXL-targeting kinase inhibitors against COVID-19.

The coronavirus disease-19 (COVID-19) is an ongoing infection outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel positive single-stranded, enveloped RNA virus belonging to the genus Betacoronavirus. During the pandemic, the SARS-CoV-2 subvariants evolved rapidly with enhanced transmissibility, and became a global public health threat as its alarmingly rising rate of infection led to excessive mortality. According to the WHO data, COVID-19 caused more than 6 million deaths and affected 215 countries. Although vaccines are beneficial for preventing hospitalization, reducing severe illness and deaths from COVID-19, the constantly mutated Spike protein under high selection pressure leading to off-target or immune evasion which warrants additional therapeutic strategies. Therefore, it is important to identify and test potential therapeutic targets against proteins that are highly conserved among multiple coronaviruses for clinical drug development to combat SARS-COV-2. While research for new therapies continues, the cost-effective and rapid repurposing of existing therapeutics may provide a viable treatment alternative for COVID-19.

More efforts are needed for background surveys of zoonotic coronaviruses in animals.

Recently, a novel dog-origin coronavirus has been found in humans. The low similarity between the receptor-binding domain from this novel virus and other human-infecting coronaviruses in genus Alphacoronavirus suggests it might use a novel receptor or mechanism to enter human cells and also might trigger a novel immune response.

Magneto-Nanomechanical Array Biosensor for Ultrasensitive Detection of Oncogenic Exosomes for Early Diagnosis of Cancers.

Exosomes are a class of nanoscale vesicles secreted by cells, which contain abundant information closely related to parental cells. The ultrasensitive detection of cancer-derived exosomes is highly significant for early non-invasive diagnosis of cancer. Here, an ultrasensitive nanomechanical sensor is reported, which uses a magnetic-driven microcantilever array to selectively detect oncogenic exosomes. A magnetic force, which can produce a far greater deflection of microcantilever than that produced by the intermolecular interaction force even with very low concentrations of target substances, is introduced. This method reduced the detection limit to less than 10 exosomes mL-1 . Direct detection of exosomes in the serum of patients with breast cancer and in healthy people showed a significant difference. This work improved the sensitivity by five orders of magnitude as compared to that of traditional nanomechanical sensing based on surface stress mode. This method can be applied parallelly for highly sensitive detection of other microorganisms (such as bacteria and viruses) by using different probe molecules, which can provide a supersensitive detection approach for cancer diagnosis, food safety, and SARS-CoV-2 infection.

Genomic Perspectives on the Emerging SARS-CoV-2 Omicron Variant.

A new variant of concern for SARS-CoV-2, Omicron (B.1.1.529), was designated by the World Health Organization on November 26, 2021. This study analyzed the viral genome sequencing data of 108 samples collected from patients infected with Omicron. First, we found that the enrichment efficiency of viral nucleic acids was reduced due to mutations in the region where the primers anneal to. Second, the Omicron variant possesses an excessive number of mutations compared to other variants circulating at the same time (median: 62 vs. 45), especially in the Spike gene. Mutations in the Spike gene confer alterations in 32 amino acid residues, more than those observed in other SARS-CoV-2 variants. Moreover, a large number of nonsynonymous mutations occur in the codons for the amino acid residues located on the surface of the Spike protein, which could potentially affect the replication, infectivity, and antigenicity of SARS-CoV-2. Third, there are 53 mutations between the Omicron variant and its closest sequences available in public databases. Many of these mutations were rarely observed in public databases and had a low mutation rate. In addition, the linkage disequilibrium between these mutations was low, with a limited number of mutations concurrently observed in the same genome, suggesting that the Omicron variant would be in a different evolutionary branch from the currently prevalent variants. To improve our ability to detect and track the source of new variants rapidly, it is imperative to further strengthen genomic surveillance and data sharing globally in a timely manner.

Ubiquitination of SARS-CoV-2 ORF7a Prevents Cell Death Induced by Recruiting BclXL To Activate ER Stress.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has emerged in the last 2 years. The accessory protein ORF7a has been proposed as an immunomodulating factor that can cause dramatic inflammatory responses, but it is unknown how ORF7a interacts with host cells. We show that ORF7a induces cell apoptosis by recruiting the prosurvival factor BclXL to the endoplasmic reticulum (ER) via the exposed C-terminal residues Lys117 and Lys119. Simultaneously, ORF7a activates ER stress via the PERK-elF2α-CHOP pathway and inhibits the expression of endogenous BclXL, resulting in enhanced cell apoptosis. Ubiquitination of ORF7a interrupts the interaction with BclXL in the ER and weakens the activation of ER stress, which to some extent rescues the cells. Our work demonstrates that SARS-CoV-2 ORF7a hires antiapoptosis protein and aggregates on the ER, resulting in ER stress and apoptosis initiation. On the other hand, ORF7a utilizes the ubiquitin system to impede and escape host elimination, providing a promising potential target for developing strategies for minimizing the COVID-19 pandemic. IMPORTANCE Viruses struggle to reproduce after infecting cells, and the host eliminates infected cells through apoptosis to prevent virus spread. Cells adopt a special ubiquitination code to protect against viral infection, while ORF7a manipulates and exploits the ubiquitin system to eliminate host cells' effect on apoptosis and redirect cellular pathways in favor of virus survival. Our results revealed that SARS-CoV-2-encoded accessory protein ORF7a recruits prosurvival factor BclXL to the ER and activates the cellular ER stress response resulting in the initiation of programmed death to remove virus-infected cells. Ubiquitination of ORF7a blocked the recruitment of BclXL and suppressed the ER stress response, which helps to counteract cell apoptosis and rescue cell fate. These findings help us understand the mechanism of SARS-CoV-2 invasion and contribute to a theoretical foundation for the clinical prevention of COVID-19.

"Authentic Warmth in These Uncertain Times”: The Impact of Authenticity in COVID-19 Advertising on Brand Warmth and Consumer Responses

This study investigated the impact of the perceived authenticity of brands' COVID-19 advertisements on consumers' perception of brand warmth and the subsequent responses on brand attitude and engagement intention. An online survey was used to acquire consumers' evaluations of COVID-19 video ads published between March and August in 2020. Results showed that the message authenticity significantly increased consumers' perception of brand warmth, brand attitude, and engagement intention. Furthermore, the serial mediation results revealed the underlying mechanism that authentic ads evoked positively valenced emotional responses, which increased perceived brand warmth and further resulted in positive brand attitudes and engagement intentions. Practical implications and theoretical advancement are also discussed.

High-Rise Residential Outdoor Space Value System: A Case Study of Yangtze River Delta Area.

The outbreak of COVID-19 has drawn wider attention from residents with growing demand for outdoor space in residential areas because of restrictions on residents' mobility, especially in China. However, the high-rise residential complex in China is featured with a high population density along with less outdoor space per household. This means that the current status of outdoor space in residential areas is far from satisfying residents' growing needs. This is consistent with our preliminary survey that highlights general low satisfaction of residents with outdoor space. According to the hierarchical theory of needs, a literature review, and a questionnaire survey, a framework is proposed in this study to examine the universal value system of high-rise residential outdoor space using the Yangtze River Delta Area as a case study. This framework consists of six dimensions, i.e., space physical comfort (physical environment and space size), space function (functional complexity and scale, age-range, and time-range), space safety (daily, social, and hygiene safety), space diversity (spatial layerings, forms, and scales diversity), accessibility (spatial attraction and concentration and path clarity) and sustainability (cultural, social, ecological, and financial sustainability). Consequently, a questionnaire was designed according to the framework and 251 valid questionnaires were received. Then, structural equation modeling (SEM) was undertaken to examine the impact of each dimension on the value of outdoor space and the framework was optimized into four dimensions, i.e., space physical comfort, space function, space safety, and DAT (space diversity, accessibility, and sustainability). Finally, the mechanism of how outdoor space quality influences the high-rise residential complex is analyzed. These findings provide useful input for the future planning and design of high-rise residential areas.

The Threat of Potentially Pathogenic Bacteria in the Feces of Bats.

Bats have attracted global attention because of their zoonotic association with severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Previous and ongoing studies have predominantly focused on bat-borne viruses; however, the prevalence or abundance of bat-borne pathogenic bacteria and their potential public health significance have largely been neglected. For the first time, this study used both metataxonomics (16S rRNA marker gene sequencing) and culturomics (traditional culture methods) to systematically evaluate the potential public health significance of bat fecal pathogenic bacteria. To this end, fecal samples were obtained from five bat species across different locations in China, and their microbiota composition was analyzed. The results revealed that the bat microbiome was most commonly dominated by Proteobacteria, while the strictly anaerobic phylum Bacteroidetes occupied 35.3% of the relative abundance in Rousettus spp. and 36.3% in Hipposideros spp., but less than 2.7% in the other three bat species (Taphozous spp., Rhinolophus spp., and Myotis spp.). We detected 480 species-level phylotypes (SLPs) with PacBio sequencing, including 89 known species, 330 potentially new species, and 61 potentially higher taxa. In addition, a total of 325 species were identified by culturomics, and these were classified into 242 named species and 83 potentially novel species. Of note, 32 of the 89 (36.0%) known species revealed by PacBio sequencing were found to be pathogenic bacteria, and 69 of the 242 (28.5%) known species isolated by culturomics were harmful to people, animals, or plants. Additionally, nearly 40 potential novel species which may be potential bacterial pathogens were identified. IMPORTANCE Bats are one of the most diverse and widely distributed groups of mammals living in close proximity to humans. In recent years, bat-borne viruses and the viral zoonotic diseases associated with bats have been studied in great detail. However, the prevalence and abundance of pathogenic bacteria in bats have been largely ignored. This study used high-throughput sequencing techniques (metataxonomics) in combination with traditional culture methods (culturomics) to analyze the bacterial flora in bat feces from different species of bats in China, revealing that bats are natural hosts of pathogenic bacteria and carry many unknown bacteria. The results of this study can be used as guidance for future investigations of bacterial pathogens in bats.

The network pharmacology of the mechanism of the drug pair on the treatment of new Coronavirus pneumonia offending lung health syndrome

Objective: To explore the main pathways and possible mechanisms of Lonicera japonica-forsythia in the treatment of COVID-19 using network pharmacology.

Monoclonal antibodies constructed from COVID-19 convalescent memory B cells exhibit potent binding activity to MERS-CoV spike S2 subunit and other human coronaviruses.

Introduction: The Middle East respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly contagious coronaviruses causing MERS and COVID-19, respectively, without an effective antiviral drug and a long-lasting vaccine. Approaches for diagnosis, therapeutics, prevention, etc., particularly for SARS-CoV-2 that is continually spreading and evolving, are urgently needed. Our previous study discovered that >60% of sera from convalescent COVID-19 individuals, but <8% from general population, showed binding activity against the MERS-CoV spike protein, indicating that SARS-CoV-2 infection boosted antibodies cross-reactive with MERS-CoV. Methods: To generate antibodies specific to both SARS-CoV-2 and MERS-CoV, here we screened 60 COVID-19 convalescent sera against MERS-CoV spike extracellular domain and S1 and S2 subunits. We constructed and characterized monoclonal antibodies (mAbs) from COVID-19 convalescent memory B cells and examined their binding and neutralizing activities against human coronaviruses. Results and Discussion: Of 60 convalescent serum samples, 34 showed binding activity against MERS-CoV S2, with endpoint titers positively correlated with the titers to SARS-CoV-2 S2. By sorting single memory B cells from COVID-19 convalescents, we constructed 38 mAbs and found that 11 mAbs showed binding activity with MERS-CoV S2, of which 9 mAbs showed potent cross-reactivity with all or a proportion of spike proteins of alphacoronaviruses (229E and NL63) and betacoronaviruses (SARS-CoV-1, SARS-CoV-2, OC43, and HKU1). Moreover, 5 mAbs also showed weak neutralization efficiency against MERS-CoV spike pseudovirus. Epitope analysis revealed that 3 and 8 mAbs bound to linear and conformational epitopes in MERS-CoV S2, respectively. In summary, we have constructed a panel of antibodies with broad-spectrum reactivity against all seven human coronaviruses, thus facilitating the development of diagnosis methods and vaccine design for multiple coronaviruses.