Cryptococcus neoformans, a global threat to human health.

BACKGROUND: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections. METHODS: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs. RESULTS: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden. CONCLUSION: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

Quality of online video resources concerning patient education for neck pain: A YouTube-based quality-control study.

Background: More than 70 percent of the world's population is tortured with neck pain more than once in their vast life, of which 50-85% recur within 1-5 years of the initial episode. With medical resources affected by the epidemic, more and more people seek health-related knowledge via YouTube. This article aims to assess the quality and reliability of the medical information shared on YouTube regarding neck pain. Methods: We searched on YouTube using the keyword "neck pain" to include the top 50 videos by relevance, then divided them into five and seven categories based on their content and source. Each video was quantitatively assessed using the Journal of American Medical Association (JAMA), DISCERN, Global Quality Score (GQS), Neck Pain-Specific Score (NPSS), and video power index (VPI). Spearman correlation analysis was used to evaluate the correlation between JAMA, GQS, DISCERN, NPSS and VPI. A multiple linear regression analysis was applied to identify video features affecting JAMA, GQS, DISCERN, and NPSS. Results: The videos had a mean JAMA score of 2.56 (SD = 0.43), DISCERN of 2.55 (SD = 0.44), GQS of 2.86 (SD = 0.72), and NPSS of 2.90 (SD = 2.23). Classification by video upload source, non-physician videos had the greatest share at 38%, and sorted by video content, exercise training comprised 40% of the videos. Significant differences between the uploading sources were observed for VPI (P = 0.012), JAMA (P < 0.001), DISCERN (P < 0.001), GQS (P = 0.001), and NPSS (P = 0.007). Spearman correlation analysis showed that JAMA, DISCERN, GQS, and NPSS significantly correlated with each other (JAMA vs. DISCERN, p < 0.001, JAMA vs. GQS, p < 0.001, JAMA vs. NPSS, p < 0.001, DISCERN vs. GQS, p < 0.001, DISCERN vs. NPSS, p < 0.001, GQS vs. NPSS, p < 0.001). Multiple linear regression analysis suggested that a higher JAMA score, DISCERN, or GQS score were closely related to a higher probability of an academic, physician, non-physician or medical upload source (P < 0.005), and a higher NPSS score was associated with a higher probability of an academic source (P = 0.001) than of an individual upload source. Conclusions: YouTube videos pertaining to neck pain contain low quality, low reliability, and incomplete information. Patients may be put at risk for health complications due to inaccurate, and incomplete information, particularly during the COVID-19 crisis. Academic groups should be committed to high-quality video production and promotion to YouTube users.

Green Innovation, Corporate Environmental Ethics, and Competitive Advantages of Chinese Automobile Industry During COVID-19: Corporate Environmental Management as Moderator

Objective The main purpose of this study is to investigate the impact of green product and process innovation on the competitive advantages of the Chinese automobile industry during coronavirus disease 2019 (COVID-19). This study also examined the mediating role of corporate environmental ethics (CEE) and the moderating role of corporate environmental management in the relationship between the green product and process innovation on the competitive advantages of the Chinese automobile industry during COVID-19. Methods This study used a quantitative approach of research with the cross-sectional method for the collection of data. This study also used purposive sampling for the collection of data from the production managers of the automobile industry of China. The structural equation modeling-partial least squares (SEM-PLS) is used to analyze the data. Results The results of direct effects indicated that green product innovation has a significant and positive effect on the corporate advantages (β = 0.294, t = 2.868) and green process innovation also has a significant and positive effect on the corporate advantages (β = 0.350, t = 3.276). Moreover, green product innovation has also a significant effect on corporate advantages (β = 0.334, t = 4.258) and green product innovation has also a significant effect on corporate advantages (β = 0.269, t = 3.202). Significance The research in this domain about the antecedents of green innovation is still minimal in the previous literature. One of the antecedents of the green innovation, corporate environmental ethics is discussed in this study;thus, it provides the understanding of green innovation as the mediator which would mediate the relationship between corporate environmental ethics and competitive advantage in the auto manufacturing industry of China. Novelty This study is among very few to examine the relationship between green innovation, corporate environmental ethics, corporate environmental management, and competitive advantages of the Chinese automobile industry during COVID-19.

Flexible Wearable Pressure Sensor Based on Collagen Fiber Material.

Flexible wearable pressure sensors play a pivotal role in healthcare monitoring, disease prevention, and humanmachine interactions. However, their narrow sensing ranges, low detection sensitivities, slow responses, and complex preparation processes restrict their application in smart wearable devices. Herein, a capacitive pressure sensor with high sensitivity and flexibility that uses an ionic collagen fiber material as the dielectric layer is proposed. The sensor exhibits a high sensitivity (5.24 kPa-1), fast response time (40 ms), long-term stability, and excellent repeatability over 3000 cycles. Because the sensor is resizable, flexible, and has a simple preparation process, it can be flexibly attached to clothes and the human body for wearable monitoring. Furthermore, the practicality of the sensor is proven by attaching it to different measurement positions on the human body to monitor the activity signal.

Comparative miRNA transcriptomics of macaques and mice reveals MYOC is an inhibitor for Cryptococcus neoformans invasion into the brain.

Cryptococcal meningoencephalitis (CM) is emerging as an infection in HIV/AIDS patients shifted from primarily ART-naive to ART-experienced individuals, as well as patients with COVID-19 and immunocompetent hosts. This fungal infection is mainly caused by the opportunistic human pathogen Cryptococcus neoformans. Brain or central nervous system (CNS) dissemination is the deadliest process for this disease; however, mechanisms underlying this process have yet to be elucidated. Moreover, illustrations of clinically relevant responses in cryptococcosis are currently limited due to the low availability of clinical samples. In this study, to explore the clinically relevant responses during C. neoformans infection, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feature of HIV/AIDS patients, was a centric pathway regulated in both infection models. Notably, assays of clinical immune cells confirmed an enhanced macrophage "Trojan Horse" in patients with HIV/AIDS, which could be shut down by cytoskeleton inhibitors. Furthermore, myocilin, encoded by MYOC, was found to be a novel enhancer for the macrophage "Trojan Horse," and an enhanced fungal burden was achieved in the brains of MYOC-transgenic mice. Taken together, the findings from this study reveal fundamental roles of the cytoskeleton and MYOC in fungal CNS dissemination, which not only helps to understand the high prevalence of CM in HIV/AIDS but also facilitates the development of novel therapeutics for meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.

Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients.

BACKGROUND: COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology. METHODS: To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients. RESULTS: Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans, Bacteroides nordii, Bifidobacterium longum, and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum) were detectable in blood samples from patients. CONCLUSIONS: Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis.

Pathogen-Host Interaction Repertoire at Proteome and Posttranslational Modification Levels During Fungal Infections.

Prevalence of fungal diseases has increased globally in recent years, which often associated with increased immunocompromised patients, aging populations, and the novel Coronavirus pandemic. Furthermore, due to the limitation of available antifungal agents mortality and morbidity rates of invasion fungal disease remain stubbornly high, and the emergence of multidrug-resistant fungi exacerbates the problem. Fungal pathogenicity and interactions between fungi and host have been the focus of many studies, as a result, lots of pathogenic mechanisms and fungal virulence factors have been identified. Mass spectrometry (MS)-based proteomics is a novel approach to better understand fungal pathogenicities and host-pathogen interactions at protein and protein posttranslational modification (PTM) levels. The approach has successfully elucidated interactions between pathogens and hosts by examining, for example, samples of fungal cells under different conditions, body fluids from infected patients, and exosomes. Many studies conclude that protein and PTM levels in both pathogens and hosts play important roles in progression of fungal diseases. This review summarizes mass spectrometry studies of protein and PTM levels from perspectives of both pathogens and hosts and provides an integrative conceptual outlook on fungal pathogenesis, antifungal agents development, and host-pathogen interactions.

Integrated bioinformatics analysis reveals dynamic candidate genes and signaling pathways involved in the progression and prognosis of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy with varied outcomes. However, the fundamental mechanisms remain to be fully defined. AIM: We aimed to identify core differentially co-expressed hub genes and perturbed pathways relevant to the pathogenesis and prognosis of DLBCL. METHODS: We retrieved the raw gene expression profile and clinical information of GSE12453 from the Gene Expression Omnibus (GEO) database. We used integrated bioinformatics analysis to identify differentially co-expressed genes. The CIBERSORT analysis was also applied to predict tumor-infiltrating immune cells (TIICs) in the GSE12453 dataset. We performed survival and ssGSEA (single-sample Gene Set Enrichment Analysis) (for TIICs) analyses and validated the hub genes using GEPIA2 and an independent GSE31312 dataset. RESULTS: We identified 46 differentially co-expressed hub genes in the GSE12453 dataset. Gene expression levels and survival analysis found 15 differentially co-expressed core hub genes. The core genes prognostic values and expression levels were further validated in the GEPIA2 database and GSE31312 dataset to be reliable (p < 0.01). The core genes' main KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichments were Ribosome and Coronavirus disease-COVID-19. High expressions of the 15 core hub genes had prognostic value in DLBCL. The core genes showed significant predictive accuracy in distinguishing DLBCL cases from non-tumor controls, with the area under the curve (AUC) ranging from 0.992 to 1.00. Finally, CIBERSORT analysis on GSE12453 revealed immune cells, including activated memory CD4+ T cells and M0, M1, and M2-macrophages as the infiltrates in the DLBCL microenvironment. CONCLUSION: Our study found differentially co-expressed core hub genes and relevant pathways involved in ribosome and COVID-19 disease that may be potential targets for prognosis and novel therapeutic intervention in DLBCL.

Ad5-spike COVID-19 vaccine does not aggravate heart damage after ischemic injury (preprint)

Hopes for a COVID-19 vaccine are now a reality. The spike protein of SARS-CoV-2, which majorly binds to the host receptor ACE2 for cell entry, is used by most of the COVID-19 vaccine candidates as a choice of antigen. ACE2 is highly expressed in the heart and is known to be protective in multiple organs. Interaction of spike with ACE2 has been reported to reduce ACE2 expression and affect ACE2-mediated signal transduction in the heart. However, whether a spike-encoding vaccine will aggravate myocardial damage after a heart attack via affecting ACE2 remains unclear. Therefore, for patients with or at risk of heart diseases, questions arise around the safety of the spike-based vaccines. Here, we demonstrate that ACE2 is up-regulated and protective in the injured mouse heart after myocardial ischemia/reperfusion (I/R). Infecting human cardiomyocyte, smooth muscle cells, endothelial cells, and cardiac fibroblasts with a recombinant adenovirus type-5 vectored COVID-19 vaccine expressing the spike protein (AdSpike) does not affect cell survival and cardiomyocyte function, whether the cells are subjected to hypoxia-reoxygenation injury or not. This observation is further confirmed in human engineered heart tissues. Furthermore, AdSpike vaccination does not aggravate heart damage in wild-type or humanized ACE2 mice after I/R injury, even at a dose that is ten-fold higher as used in human. This study represents the first systematic evaluation of the safety of a leading COVID-19 vaccine under a disease context and may provide important information to ensure maximal protection from COVID-19 in patients with or at risk of heart diseases.

A novel DNA and protein combination COVID-19 vaccine formulation provides full protection against SARS-CoV-2 in rhesus macaques.

The current study aims to develop a safe and highly immunogenic COVID-19 vaccine. The novel combination of a DNA vaccine encoding the full-length Spike (S) protein of SARS-CoV-2 and a recombinant S1 protein vaccine induced high level neutralizing antibody and T cell immune responses in both small and large animal models. More significantly, the co-delivery of DNA and protein components at the same time elicited full protection against intratracheal challenge of SARS-CoV-2 viruses in immunized rhesus macaques. As both DNA and protein vaccines have been proven safe in previous human studies, and DNA vaccines are capable of eliciting germinal center B cell development, which is critical for high-affinity memory B cell responses, the DNA and protein co-delivery vaccine approach has great potential to serve as a safe and effective approach to develop COVID-19 vaccines that provide long-term protection.

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

Evaluate severe acute respiratory syndrome coronavirus 2 infectivity by pseudoviral particles.

Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans in late 2019, it has rapidly spread worldwide. To identify the biological characteristics of SARS-CoV-2 in a normal laboratory environment (biosafety level 2 [BSL-2]), a lentiviral-based nucleocapsid was used to carry the spike protein of SARS-CoV-2 onto the surface of pseudoviral particles as a surrogate model to evaluate the infective characterization of SARS-CoV-2. This study indicated that SARS-CoV-2 has extensive tissue tropism for humans and may infect monkeys and tree shrews but not rodents. More importantly, the use of pseudoviral particles in this study allows rapid assessment of neutralizing antibodies in serum in a BSL-2 laboratory. This study will provide a quick and easy tool for evaluating neutralizing antibodies in the serum of recovering patients and assessing the potency of candidate vaccines.