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Cancer immunotherapies have created a new generation of therapeutics to employ the immune system to attack cancer cells. However, these therapies are typically based on biologics that are nonspecific and often exhibit poor tumor penetration and dose-limiting toxicities. Nanocarriers allow the opportunity to overcome these barriers as they have the capabilities to direct immunomodulating drugs to tumor sites via passive and active targeting, decreasing potential adverse effects from nonspecific targeting. In addition, nanocarriers can be multifunctionalized to deliver multiple cancer therapeutics in a single drug platform, offering synergistic potential from co-delivery approaches.This review focuses on the delivery of cancer therapeutics using emerging nanocarriers to achieve synergistic results via co-delivery of immune-modulating components (i.e. chemotherapeutics, monoclonal antibodies, and genes).Nanocarrier-mediated delivery of combinatorial immunotherapy creates the opportunity to fine-tune drug release while achieving superior tumor targeting and tumor cell death, compared to free drug counterparts. As these nanoplatforms are constantly improved upon, combinatorial immunotherapy will afford the greatest benefit to treat an array of tumor types while inhibiting cancer evasion pathways.

There is an urgent need for animal models of coronavirus disease 2019 to study immunopathogenesis and test therapeutic intervenes. In this study, we showed that NOD/SCID IL2rg

The study aimed to identify BMI-related lipids and to explore the role of lipids linking BMI and gestational diabetes mellitus (GDM).Plasma lipidome, height, and weight were measured in early pregnancy among 1008 women. Pearson correlation analyses and least absolute shrinkage and selection operator regression (LASSO) were performed to identify BMI-associated lipids. Based on these lipids, a lipid score was created using LASSO, and its association with GDM risk was evaluated by conditional logistic regression. The causal relationships between BMI and lipids were tested by Mendelian randomization analysis with genotyping data. Mediation analysis was conducted to evaluate the mediating effect of lipids on the association of BMI with GDM.Of 366 measured lipids, BMI was correlated with 28 lipids, which mainly belong to glycerophospholipids and glycerolipids. A total of 10 lipid species were associated with BMI, and a lipid score was established. A causal relationship between BMI and lysophosphatidylcholine 14:0 was observed. The lipid score was associated with a 1.69-fold increased risk of GDM per 1-point increment (95% CI: 1.33-2.15). Furthermore, BMI-associated lipids might explain 66.4% of the relationship between BMI and GDM.Higher BMI in early pregnancy was associated with altered lipid metabolism that may contribute to the increased risk of GDM.

To develop and validate a pretreatment magnetic resonance imaging (MRI)-based radiomic-clinical model to assess the treatment response of whole-brain radiotherapy (WBRT) by using SHapley Additive exPlanations (SHAP), which is derived from game theory, and can explain the output of different machine learning models.We retrospectively enrolled 228 patients with brain metastases from two medical centers (184 in the training cohort and 44 in the validation cohort). Treatment responses of patients were categorized as a non-responding group vs. a responding group according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For each tumor, 960 features were extracted from the MRI sequence. The least absolute shrinkage and selection operator (LASSO) was used for feature selection. A support vector machine (SVM) model incorporating clinical factors and radiomic features wase used to construct the radiomic-clinical model. SHAP method explained the SVM model by prioritizing the importance of features, in terms of assessment contribution.Three radiomic features and three clinical factors were identified to build the model. Radiomic-clinical model yielded AUCs of 0.928 (95%CI 0.901-0.949) and 0.851 (95%CI 0.816-0.886) for assessing the treatment response in the training cohort and validation cohort, respectively. SHAP summary plot illustrated the feature's value affected the feature's impact attributed to model, and SHAP force plot showed the integration of features' impact attributed to individual response.The radiomic-clinical model with the SHAP method can be useful for assessing the treatment response of WBRT and may assist clinicians in directing personalized WBRT strategies in an understandable manner.• Radiomic-clinical model can be useful for assessing the treatment response of WBRT. • SHAP could explain and visualize radiomic-clinical machine learning model in a clinician-friendly way.

Due to the global climate anomaly, ecological environment damage, human activities, and other reasons, flood disaster has become a major threat to mankind. The emergency rescue resources under different subject management and different emergencies have different characteristics, attributes, and management modes, which restrict the unified dispatching, overall management, and efficient utilization of the comprehensive rescue command platform. The frequent occurrence of natural disasters can not only easily affect the public security of society but also pose a great threat to the safety of Chinese people’s lives and property. As the first-line person in charge of China’s response to natural disasters, local governments cannot deal with natural disasters well. More than thousands of people die from natural disasters in China every year. The economic losses caused amounted to hundreds of billions. The occurrence of various floods and natural disasters not only affects the local economic and social development but also relates to the production and life of the local people, and the stability of the local society and national unity. How to effectively deal with flood disaster is also an important index system to test the execution and management ability of the Party and the government. Therefore, it is necessary to deeply study flood disaster from the theoretical height, hoping to provide reference theoretical support and practical guidance for local county-level government flood disaster emergency management. At the beginning of the urban flood disaster, how to choose an appropriate response plan and implement it in time is an important way to effectively reduce disaster losses. Starting with the basic concept of flood disaster, this study studies and discusses the related theories of flood disaster emergency management, introduces the general situation of flood disaster emergency management, and analyzes the application of scenario construction technology in emergency management.

Lupus nephritis (LN) is a severe renal disease caused by the massive deposition of the immune complexes (ICs) in renal tissue, acting as one of the significant organ manifestations of systemic lupus erythematosus (SLE) and a substantial cause of death in clinical patients. As mesangium is one of the primary sites for IC deposition, mesangial cells (MCs) constantly undergo severe damage, resulting in excessive proliferation and increased extracellular matrix (ECM) production. In addition to playing a role in organizational structure, MCs are closely related toin situimmunomodulation by phagocytosis, antigen-presenting function, and inflammatory effects, aberrantly participating in the tissue-resident immune responses and leading to immune-mediated renal lesions. Notably, such renal-resident immune responses drive a second wave of MC damage, accelerating the development of LN. This review summarized the damage mechanisms and thein situimmune regulation of MCs in LN, facilitating the current drug research for exploring clinical treatment strategies.

Host circular RNAs (circRNAs) play critical roles in the pathogenesis of viral infections. However, how viruses modulate the biogenesis of host proviral circRNAs to facilitate their replication remains unclear. We have recently shown that Middle East respiratory syndrome coronavirus (MERS-CoV) infection increases co-expression of circRNAs and their cognate messenger RNAs (mRNAs), possibly by hijacking specific host RNA binding proteins (RBPs). In this study, we systemically analysed the interactions between the representative circRNA–mRNA pairs upregulated upon MERS-CoV infection and host RBPs. Our analysis identified heterogeneous nuclear ribonucleoprotein C (hnRNP C) as a key host factor that governed the expression of numerous MERS-CoV-perturbed circRNAs, including hsa_circ_0002846, hsa_circ_0002061, and hsa_circ_0004445. RNA immunoprecipitation assay showed that hnRNP C could bind physically to these circRNAs. Specific knockdown of hnRNP C by small interfering RNA significantly (P

Introduction Early systemic and central nervous system viral replication and inflammation may impact brain integrity in people with HIV (PWH), leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART. Methods HIV-infected MSM and transgender women (average age: 27 and education: 13 years) enrolled within 100 days from estimated date of detectable infection [EDDI]. A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n=87) and cerebrospinal fluid (CSF; n=29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ. Results Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ=.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART. Conclusions Biomarkers of CNS inflammation, immune activation and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.

There are urgent needs for humanized mouse models of viral respiratory diseases to study immunopathogenesis and therapeutic interventions. Although human immune system (HIS) mice permit analysis in real time of human immune responses in vivo, evolutionary divergences preclude their usefulness for the respiratory viruses that do not infect mouse lungs. In this study, we sought to use HIS mice with human lung (HL) tissue xenografts (HISL mice) to address this issue. The grafted HL tissue maintained histologically normal structure, and populated with human tissue-resident immune cells, including CD11c+ dendritic cells and CD4+ and CD8+ tissue-resident memory T cells. HISL mice showed a marked expansion of tissue-resident memory T cells and generation of viral Ag-specific T cells in the HL xenografts, and production of antiviral IgM and IgG Abs upon immunization of the HL xenograft by H1N1 influenza viruses. RNA-seq analysis on H1N1-infected and control HL xenografts identified a total of 5089 differentially expressed genes with enrichments for genes involved in respiratory diseases, viral infections, and associated immune responses. Furthermore, prophylactic viral exposures resulted in protection against subsequent lethal challenge by intranasal viral inoculation. This study supports the usefulness of this preclinical model in exploring the immunopathology and therapies of respiratory viral diseases.

Surface contact with virus is ubiquitous in the transmission pathways of respiratory diseases such as Coronavirus Disease 2019 (COVID-19), by which contaminated surfaces are infectious fomites intensifying the transmission of the disease. To date, the influence of surface wettability on fomite formation remains elusive. Here, we report that superhydrophobicity prevents the attachment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on surfaces by repelling virus-laden droplets. Compared to bare surfaces, superhydrophobic (SHPB) surfaces exhibit a significant reduction in SARS-CoV-2 attachment of up to 99.99995%. We identify the vital importance of solid-liquid adhesion in dominating viral attachment, where the viral activity (N) is proportional to the cube of solid-liquid adhesion (A), N ∝ A3. Our results predict that a surface would be practically free of SARS-CoV-2 deposition when solid-liquid adhesion is ≤1 mN. Engineering surfaces with superhydrophobicity would open an avenue for developing a general approach to preventing fomite formation against the COVID-19 pandemic and future ones.

Cadmium (Cd) is a widespread heavy metal pollutant in the environment that damages human health. In this study, the bioaccessibility and bioavailability of Cd in different Cd-contaminated rice (low pollution level cadmium rice (Rice-L, 0.111 mg/kg), medium pollution level cadmium rice (Rice-M, 0.400 mg/kg), and high pollution level cadmium rice (Rice-H, 0.655 mg/kg)) were estimated and determined by an in vitro digestion model Rijksinstituut voor volksgezondheiden milieu (RIVM), Caco-2 cell model, and mouse model. The results indicated that Cd in the oral cavity (15.65-28.28%) displayed the lowest bioaccessibility comparing with small intestine (90.04-94.73%) and the stomach (99.30-100.70%) in vitro after cooking. In addition, the results showed that the bioaccessibility of Cd in CdCl2 , CdCl2 +normal rice (Rice-N), Rice-H, Rice-M, Rice-L group were 99.29%, 92.57%, 90.04%, 94.73%, and 91.11%, respectively; the in vitro bioavailability of Cd in CdCl2 , CdCl2 +Rice-N, Rice-H, Rice-M, and Rice-L group were 27.50%, 20.78%, 21.90%, 26.90%, 36.46%, respectively, we found that the group of CdCl2 is significantly higher than CdCl2 +Rice-N and Rice-H (p

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease. Methods In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home. RNA from the fingerstick blood was tested using DxTerity’s 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method. Results Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease. From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to patients with mild to moderate disease conditions. These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases. These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA). Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives). Conclusions Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity. These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits.

Zinc, which is the second most abundant trace element in the human central nervous system, is closely associated with Alzheimer's disease (AD). However, attempts to develop highly sensitive and selective sensing systems for Zn

Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Methyl mercaptan (MM) is a typical malodorous gas and low-concentration MM makes human uncomfortable. Adsorption is applied in industry to remove MM. However, adsorptive-site agglomeration results in that adsorbent is not fully utilized. In this work, pore size and unsaturated-site amount of Cu-based metal-organic frameworks (MOFs) were regulated by using different ligands to increase adsorptive-site accessibility for MM. As a result, when Cu

The stable supply of water resources is an important foundation for maintaining human production and life. With the development of economy and society, climate, socioeconomic and land factors directly or indirectly affect surface Water yield ecosystem services (WY). The driving factors of WY in the Yellow River Economic Belt (YREB) show the spatial spillover effect, which has been neglected in previous related studies. The results show that: (1) From 2000 to 2015, WY in YREB showed an obvious downward trend, with Henan and Shandong having the largest declines; (2) The decrease of WY is positively correlated with climate factors and negatively correlated with socioeconomic and land factors. (3) WY of YREB presents is characterized by obvious spatial heterogeneity characteristics of uneven distribution in the north and south, which is mainly due to the spatial spillover effect caused by climate and socioeconomic factors. Scientifically identifying the spatial heterogeneity of WY and the spatial spillover effect of the driving factors can help managers better understand the spatial driving mechanism of the driving factors on WY. This conclusion provides support for the ecological protection and high-quality development strategy of YREB.

"Pan-coronavirus" antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound's broad-spectrum antiviral activity and the lack of resistant mutants.

Background Among various cooking methods, steaming is favored by many because it can cause less damage to nutrient components in muscle, retain the inherent food flavor, and reduce the generation of harmful substances. Steaming conditions are closely related to fish flavor, fat and protein oxidation, and digestibility. Results The black carp steamed for 4 to 14 min was studied in this article based on sensory assessment, electronic tongue, free amino acids, adenosine triphosphate (ATP)-related compounds, total nitrogen and non-protein nitrogen to explore the effect of steaming time on the taste substances and protein degradation of pickled black carp. The experimental result showed that the meat steamed within 8 min tasted better, showing high tastiness. The sensory assessment score increased significantly to the maximum value of 82.33 at 6 min. The content of umami and sweet amino acids increased significantly to the maximum value of 1.6801 g kg-1 at 6 min. In the meantime, the IMP (inosine monophosphate) content was 1.9128 g kg-1 , with its taste activity value (TAV) reaching 7.65, which proved that IMP affected the taste most. Furthermore, the total nitrogen content was 30.77 g kg-1 , which meant protein degraded a great deal. Based on equivalent umami concentration (EUC) and its TAV, the meat tasted best at 6-8 min. The longer the steaming time, the faster the protein degradation and the more the flavor precursors. Conclusion The black carp pickled products (with a weight of 20 g, with the size of 3 cm × 3 cm × 2 cm) is suggested to be steamed for 6 to 8 min. This conclusion provides a theoretical basis for its better taste quality. © 2020 Society of Chemical Industry.

Next generation sequencing (NGS) assays with large targeted gene panels can comprehensively profile cancer somatic mutations in a tumor sample. Given the rapid adoption of such assays for circulating tumor DNA (ctDNA) analysis in clinical oncology, it is essential for the community to understand their analytical performance in liquid biopsy settings. Here, we directly compared five ctDNA NGS assays, most of which having a panel of 400 or more genes, with simulated samples harboring mutations relevant to solid tumors or myeloid malignancy. Our results indicate that the detection sensitivity and reproducibility of all five assays was 90% or higher when the mutations were at 0.5% or 1.0% allele frequency, and with optimal DNA input of 30 ng or 50 ng per vendor’s protocol. The performances decreased and varied dramatically, when mutations were at a 0.1% allele frequency and/or when a lower genomic input of 10 ng DNA was used. Interestingly, one of the assays repeatedly showed higher rate of false positivity than the others across two different sample sets. Multiple intrinsic technical factors pertaining to the NGS assays were further investigated. Notable differences among the assays were seen for depth of coverage and background noise, which profoundly impacted assay performance. The results derived from this study are highly informative and provide a framework to assess and select suitable assays for specific application in cancer monitoring and potential clinical use.

Extracting retinal vessels accurately is very important for diagnosing some diseases such as diabetes retinopathy, hypertension, and cardiovascular. Clinically, experienced ophthalmologists diagnose these diseases through segmenting retinal vessels manually and analysing its structural feature, such as tortuosity and diameter. However, manual segmentation of retinal vessels is a time-consuming and laborious task with strong subjectivity. The automatic segmentation technology of retinal vessels can not only reduce the burden of ophthalmologists but also effectively solve the problem that is a lack of experienced ophthalmologists in remote areas. Therefore, the automatic segmentation technology of retinal vessels is of great significance for clinical auxiliary diagnosis and treatment of ophthalmic diseases. A method using SegNet is proposed in this paper to improve the accuracy of the retinal vessel segmentation. The performance of the retinal vessel segmentation model with SegNet is evaluated on the three public datasets (DRIVE, STARE, and HRF) and achieved accuracy of 0.9518, 0.9683, and 0.9653, sensitivity of 0.7580, 0.7747, and 0.7070, specificity of 0.9804, 0.9910, and 0.9885, F 1 score of 0.7992, 0.8369, and 0.7918, MCC of 0.7749, 0.8227, and 0.7643, and AUC of 0.9750, 0.9893, and 0.9740, respectively. The experimental results showed that the method proposed in this research presented better results than many classical methods studied and may be expected to have clinical application prospects.

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population

Zika virus (ZIKV) is an emerging flavivirus that may be associated with congenital anomalies in infected fetuses and severe neurological and genital tract complications in infected adults. Currently, antiviral treatments to revert these ZIKV-induced complications are lacking. ZIKV infection has recently been suggested to upregulate the host unfolded protein response, which may contribute to the congenital neurological anomalies. As an extension from these findings, we thoroughly investigated the ZIKV-induced unfolded protein response using a combination of the neuronal cell line, induced pluripotent stem cell-derived human neuronal stem and progenitor cells, and an interferon receptor-deficient A129 mouse model. Our results revealed a critical contribution of the inositol-requiring enzyme-1 (IRE1) arm of the unfolded protein response to ZIKV-induced neurological and testicular complications. Importantly, the inhibition of the IRE1 signaling pathway activation with KIRA6 (kinase-inhibiting RNAse attenuator 6), a selective small molecule IRE1 inhibitor that promotes cell survival, potently reverted the ZIKV-induced perturbations of the key gene expressions associated with neurogenesis and spermatogenesis in vitro and in vivo, highlighting the potential of IRE1 inhibition as a novel host-targeting antiviral strategy in combating against ZIKV-induced neurological and testicular pathologies.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that has resulted in more than 2 000 000 laboratory-confirmed cases including over 145 000 deaths. Although SARS-CoV-2 and SARS-CoV share a number of common clinical manifestations, SARS-CoV-2 appears to be highly efficient in person-to-person transmission and frequently causes asymptomatic or presymptomatic infections. However, the underlying mechanisms that confer these viral characteristics of high transmissibility and asymptomatic infection remain incompletely understood.MethodsWe comprehensively investigated the replication, cell tropism, and immune activation profile of SARS-CoV-2 infection in human lung tissues with SARS-CoV included as a comparison.ResultsSARS-CoV-2 infected and replicated in human lung tissues more efficiently than SARS-CoV. Within the 48-hour interval, SARS-CoV-2 generated 3.20-fold more infectious virus particles than did SARS-CoV from the infected lung tissues (P < .024). SARS-CoV-2 and SARS-CoV were similar in cell tropism, with both targeting types I and II pneumocytes and alveolar macrophages. Importantly, despite the more efficient virus replication, SARS-CoV-2 did not significantly induce types I, II, or III interferons in the infected human lung tissues. In addition, while SARS-CoV infection upregulated the expression of 11 out of 13 (84.62%) representative proinflammatory cytokines/chemokines, SARS-CoV-2 infection only upregulated 5 of these 13 (38.46%) key inflammatory mediators despite replicating more efficiently.ConclusionsOur study provides the first quantitative data on the comparative replication capacity and immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Our results provide important insights into the pathogenesis, high transmissibility, and asymptomatic infection of SARS-CoV-2.

The purposes of this study were to evaluate the mental health among patients with diabetic retinopathy (DR) and to explore its’ influencing factors. A cross-sectional survey was conducted in Liaoning Province, China. A total of 200 patients volunteered to participate in the survey. Psycho-social variables included stress, self-efficacy, resilience, and social support. logistic regression analysis was used to explore the effect of psycho-social factors on depression and anxiety in DR patients. The prevalence of depression and anxiety was 25% and 13.5% among DR patients. Regression analysis showed that social support had a significant protective effect on depression (95%CI 0.931–0.997) and anxiety (95%CI 0.900–0.995). Stress had a significant acceleration of depression (95%CI 1.055–1.253) and anxiety (95%CI 1.120–1.457). Family history of diabetes (95%CI 1.856–18.057) and other chronic diseases (95%CI 1.485–12.508) were risk factors for anxiety. The high prevalence of depression (25.0%) and anxiety (13.5%) among DR patients should receive more attention in Chinese medical settings. Stress, social support, family history of diabetes and other chronic diseases seemed to be crucial in relation to depressive symptoms. Efficient interventions such as improving social support and decreasing stress with patients should be considered by health administrators aiming at alleviating depressive and anxiety among Chinese DR patients.

Background Wildtype mice are not susceptible to SARS-CoV-2 infection. Emerging SARS-CoV-2 variants, including B.1.1.7, B.1.351, P.1, and P.3, contain mutations in spike that has been suggested to associate with an increased recognition of mouse ACE2, raising the postulation that these SARS-CoV-2 variants may have evolved to expand species tropism to wildtype mouse and potentially other murines. Our study evaluated this possibility with substantial public health importance. Methods We investigated the capacity of wildtype (WT) SARS-CoV-2 and SARS-CoV-2 variants in infecting mice (Mus musculus) and rats (Rattus norvegicus) under in vitro and in vivo settings. Susceptibility to infection was evaluated with RT-qPCR, plaque assays, immunohistological stainings, and neutralization assays. Findings Our results reveal that B.1.1.7 and other N501Y-carrying variants but not WT SARS-CoV-2 can infect wildtype mice. High viral genome copies and high infectious virus particle titres are recovered from the nasal turbinate and lung of B.1.1.7-inocluated mice for 4-to-7 days post infection. In agreement with these observations, robust expression of viral nucleocapsid protein and histopathological changes are detected from the nasal turbinate and lung of B.1.1.7-inocluated mice but not that of the WT SARS-CoV-2-inoculated mice. Similarly, B.1.1.7 readily infects wildtype rats with production of infectious virus particles. Interpretation Our study provides direct evidence that the SARS-CoV-2 variant, B.1.1.7, as well as other N501Y-carrying variants including B.1.351 and P.3, has gained the capability to expand species tropism to murines and public health measures including stringent murine control should be implemented to facilitate the control of the ongoing pandemic. Funding A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Context Fetuin-A was reported to be associated with risk of type 2 diabetes, but its association with incident gestational diabetes mellitus (GDM) was less studied. Objective We aimed to examine the association between fetuin-A levels in early pregnancy and risk of incident GDM and to evaluate whether this association was causal. Methods A total of 332 pregnant women with GDM and 664 matched controls were included in this nested case-control study. Multivariable conditional logistic regression was applied to investigate the prospective association between serum fetuin-A in early pregnancy and subsequent risk of GDM. Two-sample Mendelian randomization (MR) analysis was used to examine the causal association, using summary statistics from the CHARGE Consortium and the FinnGen consortium. Results The mean age of the participants was 28.0 years, and the mean gestational age was 11.0 weeks (range 6-15) at enrollment. In the final model, the odds ratio (OR) for GDM comparing the extreme quartiles of fetuin-A levels was 1.78 (95% CI 1.06, 2.98; P for trend = 0.009), and the restricted cubic spline analysis indicated a linear association (P for nonlinearity = 0.83). This positive association was found in women with waist circumference Conclusions Serum fetuin-A levels in early pregnancy were positively associated with risk of GDM, particularly in those with normal waist circumference. However, we found no genetic evidence for a causal association.

The present study examined the associations of polycyclic aromatic hydrocarbon (PAH) exposure with metabolic syndrome (MetS) and its components. Data were from 5181 US adults recruited in the National Health and Nutrition Examine Survey 2001-2012. Environmental PAH exposure was estimated as concentrations of urinary PAH metabolites. Weighted quantile sum (WQS) regression and modified Poisson regression were separately conducted to estimate the associations of mixed and single PAH metabolites with MetS and its components. WQS regression analyses showed that participants with higher mixed PAH exposure had increased prevalence of MetS (prevalence ratio, 1.12; 95 % confidence interval, 1.06, 1.19), elevated waist circumference (1.07; 1.02, 1.12), elevated fasting blood glucose (1.07; 1.00, 1.14), elevated triglycerides (1.19; 1.09, 1.30), and reduced high-density lipoprotein cholesterol (1.11; 1.03, 1.20). In the models for single PAH metabolites, higher levels of 1-hydroxynaphthalene (1.15; 1.00, 1.32), 2-hydroxynaphthalene (1.20; 1.05, 1.38), 1-hydroxyphenanthrene (1.18; 1.04, 1.34), 2-hydroxyphenanthrene (1.38; 1.22, 1.57), and 1-pyrene (1.19; 1.05, 1.34) were respectively associated with increased prevalence of MetS (highest tertile vs lowest tertile). In addition, linear trends were noted for the associations of these PAH metabolites with MetS (all P for linear association ≤0.047). Smokers, drinkers, and participants with poor diet quality showed stronger associations between certain PAH metabolite with MetS. The findings suggest that the prevalence of MetS and its components increases when PAH exposure is at a high level, and that lifestyle factors, such as cigarette smoking, alcohol consumption, and diet quality, could modify the positive associations of certain PAH exposure with MetS.

Background:Military personnel are widely exposed to risk factors for heat-related illnesses. Knowledge, attitudes, and practices (KAP) are three of the most important means by which to prevent such illnesses, but there has been a lack of investigations into and correlation analyses of KAP. This study aimed to explore the heat-related KAP of military personnel in China.Methods:We conducted a cross-sectional study (June 1-25, 2019). A total of 646 military personnel were recruited from two Chinese Navy troops in the tropical zone and one troop in the temperate zone. We collected data on demographic characteristics and KAP scores using questionnaires. Univariate analysis and Scheffe's method were used for data analyses.Results:The mean KAP scores were 10.37 (range = 3–13, standard deviation = 1.63) for knowledge (K-score), 7.76 (range = 0–16, SD = 2.65) for attitudes (A-score), and 3.80 (range = 1–6, SD = 1.12) for practices (P-score). There were noticeable differences in mean K-score according to age, military rank, and educational level (P< 0.05). Participants from the tropical zone had higher A-scores (P< 0.05) and higher P-scores (P< 0.001) than those from the temperate zone. Additionally, participants with relevant experience also had higher A-scores (P< 0.05) than those without such experience.Conclusions:Military personnel's awareness of preventive and first-aid measures against heat-related illnesses need to be strengthened. It will be very important to develop educational programmes and enrich systematic educational resources to raise this awareness.

Background Endometriosis is a chronic hormonal inflammatory disease characterized by the presence of endometrial tissue outside the uterus. Endometriosis often causes infertility, which brings physical and mental pain to patients and their families. Methods We examined the functions of heat shock factor 1 (HSF1) in endometriosis development through cell count assay, cell-scratch assay and clone formation experiments. We used quantitative real-time PCR (qRT-PCR) and Western blot (WB) to detect HSF1 expression. Glucose and lactate levels were determined using a glucose (GO) assay kit and a lactate assay kit. Furthermore, we used a HSF1 inhibitor-KRIBB11 to establish a mouse model of endometriosis. Results Our data demonstrated that HSF1 promoted endometriosis development. Interestingly, HSF1 enhanced glycolysis via up-regulating PFKFB3 expression in endometriosis cells, which was a key glycolysis enzyme. Consistently, the HSF1 inhibitor KRIBB11 could abrogate endometriosis progression in vivo and in vitro. Conclusions Findings indicate that HSF1 plays an important role in endometriosis development, which might become a new target for the treatment of endometriosis. Electronic supplementary material Supplementary data are available.

Background: The COVID-19 global pandemic has posed unprecedented challenges to health care systems all over the world. The speed of the viral spread results in a tsunami of patients, which begs for a reliable screening tool using readily available data to predict disease progression.Methods: Multicenter retrospective cohort study was performed to develop and validate a triage model. Patient demographic and non-laboratory clinical data were recorded. Using only the data from Zhongnan Hospital, step-wise multivariable logistic regression was performed, and a prognostic nomogram was constructed based on the independent variables identifies. The discrimination and calibration of the model were validated. External independent validation was performed to further address the utility of this model using data from Jinyintan Hospital.Results: A total of 716 confirmed COVID-19 cases from Zhongnan Hospital were included for model construction. Men, increased age, fever, hypertension, cardio-cerebrovascular disease, dyspnea, cough, and myalgia are independent risk factors for disease progression. External independent validation was carried out in a cohort with 201 cases from Jinyintan Hospital. The area under the curve (AUC) was 0.787 (95% confidence interval [CI]: 0.747–0.827) in the training group and 0.704 (95% CI: 0.632–0.777) in the validation group.Conclusions: We developed a novel triage model based on basic and clinical data. Our model could be used as a pragmatic screening aid to allow for cost efficient screening to be carried out such as over the phone, which may reduce disease propagation through limiting unnecessary contact. This may help allocation of limited medical resources.

School disciplinary practices affect student academic and life outcomes. Many schools have recently shifted towards the prevention of behavioral disorders rather than the punishment of such disorders, but disciplinary actions are still disproportionately meted out to Black students. We took advantage of a natural experiment in a large school district to investigate the costs and effects of a school-wide intervention based on the principles of restorative justice on suspensions, referrals, and three school climate constructs. The study involved 14 elementary and middle schools, each of which was already implementing Positive Behavioral Interventions and Supports (PBIS). Six of the schools integrated Restorative Practices into their PBIS framework during the first year of the study, whereas the other eight served as comparison schools and implemented the program the following year. We tested a difference-in-difference regression model for each of our five outcomes of interest after 1 year of implementation using Quasi-Poisson models for referrals and suspensions. We found no statistically significant effects on four of the outcomes, either for the overall sample or by racial subgroup. We found negative effects on student-reported personal safety. An additional analysis 1 year later showed that Black students in schools implementing Restorative Practices for 2 years experienced a greater reduction in suspensions than Black students in schools implementing the program for only 1 year. We used the ingredients method to estimate start-up costs and ongoing costs for the first full year of implementation. Our reference case analysis results using a societal perspective, national average prices, and a 3% discount rate were $57,450 per school and $139 per student for the first year of Restorative Practices implementation. These estimates included training costs from the prior year and were incremental to the costs of PBIS, which served as the business-as-usual condition. We compared these costs to those of a number of other behavioral interventions and concluded that Restorative Practices are relatively low cost but may need to be implemented for several years with greater fidelity in order to produce the desired improvements in behavior events and school climate.

Given that many people suffer from extensive skin damage, wound repair has drawn tremendous attention in research. Among the various assistant dressing materials that promote healing, a porcine acellular dermal matrix (PADM), as a skin substitute, can efficiently accelerate healing by promoting cell migration and proliferation. However, a simple, low-cost preparation process remains a challenge facing PADM development, particularly because of the inferior elasticity. To overcome these drawbacks, a CaCl2-ethanol-H2O solution (ternary solution) combined with an additional enzyme treatment was used to obtain a transparent, porous, and elastic PADM that retained the major extracellular matrix composition of the dermis. Our results indicated that alterations in the fiber organization and secondary structural changes in the collagen occurred after treatment. Furthermore, the in vivo wound healing and histological analyses clearly revealed an extremely expedited wound repair process following the application of the biocompatible PADM. In conclusion, this study provides new insights into the development of a transparent PADM with a porous structure and good elasticity that can be used as a skin substitute to accelerate the wound healing process. Moreover, this effective technique could potentially be used to extrapolate other decellularized materials in the future.

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs.

Non-suicidal self-injury (NSSI) refers to any intentional, self-inflicted behavior that causes direct damage to body tissues (Kerr et al., 2010), and has emerged as a challenging public health issue worldwide, especially among adolescents. The most common presentations of NSSI include skin-cutting, severe scratching, and burning (Whitlock et al., 2006). In a community-based study conducted in England, 6% of 5506 adolescents reported self-harm in 2014, and 1320 adolescents (74% aged 15‒17 years) presented to hospitals due to non-fatal self-harm (Geulayov et al., 2018). In Australia, 8% of adolescents aged less than 20 years reported a history of self-harm (Hiscock et al., 2018). In addition, the prevalence of NSSI has significantly increased in recent years. It was reported by McManus et al. (2019) that the prevalence of self-reported lifetime NSSI increased from 2.4% in 2000 to 6.4% in 2014, with the largest increase in females aged 16–24 years (from 6.5% to 19.7%). Researchers have also proposed an "iceberg" model of self-harm, indicating that the phenomenon of NSSI is often concealed and that most individuals with NSSI do not seek help from others (McMahon et al., 2014; Geulayov et al., 2018).

Background Pigeon crop has the unique ability to produce a nutrient rich substance termed pigeon ‘milk’ (PM), which has functional resemblance with the mammalian milk. Previous researches have demonstrated that a large number of exosomes and exosomal miRNAs exist in mammalian milk, and many of them are associated with immunity, growth and development. However, to date, little is known about the exosomes and exosomal miRNAs in PM. Results In this study, we isolated the exosomes from PM and used small RNA sequencing to investigate the distribution and expression profiles of exosomal miRNAs. A total of 301 mature miRNAs including 248 conserved and 53 novel miRNAs were identified in five lactation stages i.e. 1d, 5d, 10d, 15d, and 20d. From these, four top 10 conserved miRNAs (cli-miR-21-5p, cli-miR-148a-3p, cli-miR-10a-5p and cli-miR-26a-5p) were co-expressed in all five stages. We speculate that these miRNAs may have important role in the biosynthesis and metabolism of PM. Moreover, similar to the mammalian milk, a significant proportion of immune and growth-related miRNAs were also present and enriched in PM exosomes. Furthermore, we also identified 41 orthologous miRNAs group (giving rise to 81 mature miRNA) commonly shared with PM, human, bovine and porcine breast milk. Additionally, functional enrichment analysis revealed the role of exosomal miRNAs in organ development and in growth-related pathways including the MAPK, Wnt and insulin pathways. Conclusions To sum-up, this comprehensive analysis will contribute to a better understanding of the underlying functions and regulatory mechanisms of PM in squabs. Electronic supplementary material The online version of this article (10.1186/s12864-018-5201-0) contains supplementary material, which is available to authorized users.

Semi-supervised learning has substantially advanced medical image segmentation since it alleviates the heavy burden of acquiring the costly expert-examined annotations. Especially, the consistency-based approaches have attracted more attention for their superior performance, wherein the real labels are only utilized to supervise their paired images via supervised loss while the unlabeled images are exploited by enforcing the perturbation-based \textit{"unsupervised"} consistency without explicit guidance from those real labels. However, intuitively, the expert-examined real labels contain more reliable supervision signals. Observing this, we ask an unexplored but interesting question: can we exploit the unlabeled data via explicit real label supervision for semi-supervised training? To this end, we discard the previous perturbation-based consistency but absorb the essence of non-parametric prototype learning. Based on the prototypical network, we then propose a novel cyclic prototype consistency learning (CPCL) framework, which is constructed by a labeled-to-unlabeled (L2U) prototypical forward process and an unlabeled-to-labeled (U2L) backward process. Such two processes synergistically enhance the segmentation network by encouraging more discriminative and compact features. In this way, our framework turns previous \textit{"unsupervised"} consistency into new \textit{"supervised"} consistency, obtaining the \textit{"all-around real label supervision"} property of our method. Extensive experiments on brain tumor segmentation from MRI and kidney segmentation from CT images show that our CPCL can effectively exploit the unlabeled data and outperform other state-of-the-art semi-supervised medical image segmentation methods., Comment: 11 pages

Purpose: Accurate segmentation of lung and infection in COVID-19 CT scans plays an important role in the quantitative management of patients. Most of the existing studies are based on large and private annotated datasets that are impractical to obtain from a single institution, especially when radiologists are busy fighting the coronavirus disease. Furthermore, it is hard to compare current COVID-19 CT segmentation methods as they are developed on different datasets, trained in different settings, and evaluated with different metrics. Methods: To promote the development of data-efficient deep learning methods, in this paper, we built three benchmarks for lung and infection segmentation based on 70 annotated COVID-19 cases, which contain current active research areas, e.g., few-shot learning, domain generalization, and knowledge transfer. For a fair comparison among different segmentation methods, we also provide standard training, validation and testing splits, evaluation metrics and, the corresponding code. Results: Based on the state-of-the-art network, we provide more than 40 pre-trained baseline models, which not only serve as out-of-the-box segmentation tools but also save computational time for researchers who are interested in COVID-19 lung and infection segmentation. We achieve average Dice Similarity Coefficient (DSC) scores of 97.3\%, 97.7\%, and 67.3\% and average Normalized Surface Dice (NSD) scores of 90.6\%, 91.4\%, and 70.0\% for left lung, right lung, and infection, respectively. Conclusions: To the best of our knowledge, this work presents the first data-efficient learning benchmark for medical image segmentation and the largest number of pre-trained models up to now. All these resources are publicly available, and our work lays the foundation for promoting the development of deep learning methods for efficient COVID-19 CT segmentation with limited data., accepted for publication in Medical Physics

Infection of highly pathogenic coronaviruses triggers apoptosis that can be targeted to reduce disease severity., Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R–like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2– and SARS-CoV–induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2–inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

Background and Objective Brain tumors are among the most deadly cancers worldwide. Due to the development of deep convolutional neural networks, many brain tumor segmentation methods help clinicians diagnose and operate. However, most of these methods insufficiently use multi-scale features, reducing their ability to extract brain tumors' features and details. To assist clinicians in the accurate automatic segmentation of brain tumors, we built a new deep learning network to make full use of multi-scale features for improving the performance of brain tumor segmentation. Methods We propose a novel cross-level connected U-shaped network (CLCU-Net) to connect different scales' features for fully utilizing multi-scale features. Besides, we propose a generic attention module (Segmented Attention Module, SAM) on the connections of different scale features for selectively aggregating features, which provides a more efficient connection of different scale features. Moreover, we employ deep supervision and spatial pyramid pooling (SSP) to improve the method's performance further. Results We evaluated our method on the BRATS 2018 dataset by five indexes and achieved excellent performance with a Dice Score of 88.5%, a Precision of 91.98%, a Recall of 85.62%, a Params of 36.34M and Inference Time of 8.89ms for the whole tumor, which outperformed six state-of-the-art methods. Moreover, the performed analysis of different attention modules' heatmaps proved that the attention module proposed in this study was more suitable for segmentation tasks than the other existing popular attention modules. Conclusion Both the qualitative and quantitative experimental results indicate that our cross-level connected U-shaped network with selective feature aggregation attention module can achieve accurate brain tumor segmentation and is considered quite instrumental in clinical practice implementation.

Aims Myosin phosphatase targeting protein 1 (MYPT1) was identified to function as a tumor suppressor in several kinds of cancers, but its role and the molecular mechanisms in non-small cell lung cancer (NSCLC) remain undiscovered. Herein, we aimed to reveal MYPT1 expression pattern and role in NSCLC, and investigate the underlying mechanisms. Main methods Sixty-eight paired NSCLC tissues and the adjacent normal tissues were included in this study. Western blotting and quantitative reverse transcription-polymerase chain (qPCR) technologies were applied for protein and RNA detection. CCK-8, colony formation, flow cytometry, wound healing, transwell chambers coated with Matrigel and in vivo experiments were applied to detect cell viability, colony formation, apoptosis, migration, invasiveness and tumorigenesis, respectively. Key findings MYPT1 expressed at a lower level in NSCLC tissues as compared with the adjacent normal tissues, which predicted advanced clinic process and poor prognosis. Overexpression of MYPT1 resulted in obvious inhibitions in cell viability, colony formation, migration, invasiveness and tumorigenesis, and induced cell apoptotic rates, as well as decreased the expression levels of β-catenin and TCF4. Besides, overexpression of β-catenin weakened the above roles of MYPT1. In addition, the luciferase gene reporter assay verified that MYPT1 was a target of miR-19b-3p. Further experiments showed that miR-19b-3p promoted cell viability, invasiveness and migration and repressed cell apoptosis by targeting MYPT1. Significance In conclusion, this study demonstrates that MYPT1, regulated by miR-19b-3p, inhibits the progression of NSCLC via inhibiting the activation of wnt/β-catenin signaling.

There is a large body of literature linking anatomic and geometric characteristics of kidney tumors to perioperative and oncologic outcomes. Semantic segmentation of these tumors and their host kidneys is a promising tool for quantitatively characterizing these lesions, but its adoption is limited due to the manual effort required to produce high-quality 3D segmentations of these structures. Recently, methods based on deep learning have shown excellent results in automatic 3D segmentation, but they require large datasets for training, and there remains little consensus on which methods perform best. The 2019 Kidney and Kidney Tumor Segmentation challenge (KiTS19) was a competition held in conjunction with the 2019 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) which sought to address these issues and stimulate progress on this automatic segmentation problem. A training set of 210 cross sectional CT images with kidney tumors was publicly released with corresponding semantic segmentation masks. 106 teams from five continents used this data to develop automated systems to predict the true segmentation masks on a test set of 90 CT images for which the corresponding ground truth segmentations were kept private. These predictions were scored and ranked according to their average So rensen-Dice coefficient between the kidney and tumor across all 90 cases. The winning team achieved a Dice of 0.974 for kidney and 0.851 for tumor, approaching the inter-annotator performance on kidney (0.983) but falling short on tumor (0.923). This challenge has now entered an "open leaderboard" phase where it serves as a challenging benchmark in 3D semantic segmentation., 24 pages, 11 figures

Background And Aims Besides prominent respiratory involvement, gastrointestinal manifestations are commonly reported in Coronavirus Disease 2019 (COVID-19) patients. We compared infection of ex vivo human intestinal tissues by SARS-CoV-2 and SARS-CoV with respect to their replication kinetics and immune activation profile. Methods Human intestinal tissues were obtained from patients while undergoing surgical operations at the Queen Mary Hospital, Hong Kong. Upon surgical removal, the tissues were immediately processed and infected with SARS-CoV-2 or SARS-CoV. Replication kinetics were determined with immunohistochemistry, qRT-PCR, and plaque assays. Immune activation in the infected intestinal tissues was assessed by detecting the gene expression of interferons and representative pro-inflammatory cytokines and chemokines. Results SARS-CoV-2 could infect and productively replicate in the ex vivo human intestinal tissues with the release of infectious virus particles, but not in ex vivo human liver and kidney tissues. Importantly, SARS-CoV-2 replicated less efficiently than SARS-CoV, induced less cytopathology in the human intestinal epithelium, and induced a more robust innate immune response including the activation of both type I and type III interferons, than SARS-CoV in human intestinal tissues. Conclusion Using the ex vivo human intestinal tissues as a physiologically relevant model, our data indicated that SARS-CoV-2 could productively replicate in the human guts, suggesting the gastrointestinal tract might serve as an alternative route of virus dissemination. SARS-CoV-2 replicated less efficiently and induced less cytopathology than SARS-CoV in keeping with the clinical observations reported for SARS-2003 and COVID-19, which might be a result of the more robust immune activation by SARS-CoV-2 than SARS-CoV in the human intestine., SARS-CoV-2 induces a higher innate immune response while replicates less efficiently and induces less cytopathology than SARS-CoV in the human intestinal tissues. These findings potentially explained the differential gastrointestinal manifestations observed in COVID-19 and SARS-2003.

Coronavirus disease 2019 (COVID-19) is a highly contagious virus spreading all around the world. Deep learning has been adopted as an effective technique to aid COVID-19 detection and segmentation from computed tomography (CT) images. The major challenge lies in the inadequate public COVID-19 datasets. Recently, transfer learning has become a widely used technique that leverages the knowledge gained while solving one problem and applying it to a different but related problem. However, it remains unclear whether various non-COVID19 lung lesions could contribute to segmenting COVID-19 infection areas and how to better conduct this transfer procedure. This paper provides a way to understand the transferability of non-COVID19 lung lesions. Based on a publicly available COVID-19 CT dataset and three public non-COVID19 datasets, we evaluate four transfer learning methods using 3D U-Net as a standard encoder-decoder method. The results reveal the benefits of transferring knowledge from non-COVID19 lung lesions, and learning from multiple lung lesion datasets can extract more general features, leading to accurate and robust pre-trained models. We further show the capability of the encoder to learn feature representations of lung lesions, which improves segmentation accuracy and facilitates training convergence. In addition, our proposed Hybrid-encoder learning method incorporates transferred lung lesion features from non-COVID19 datasets effectively and achieves significant improvement. These findings promote new insights into transfer learning for COVID-19 CT image segmentation, which can also be further generalized to other medical tasks., Comment: 11 pages

To design and develop artificial intelligence (AI) hydrocephalus (HYC) imaging diagnostic model using a transfer learning algorithm and evaluate its application in the diagnosis of HYC by non-contrast material-enhanced head computed tomographic (CT) images. A training and validation dataset of non-contrast material-enhanced head CT examinations that comprised of 1000 patients with HYC and 1000 normal people with no HYC accumulating to 28,500 images. Images were pre-processed, and the feature variables were labeled. The feature variables were extracted by the neural network for transfer learning. AI algorithm performance was tested on a separate dataset containing 250 examinations of HYC and 250 of normal. Resident, attending and consultant in the department of radiology were also tested with the test sets, their results were compared with the AI model. Final model performance for HYC showed 93.6% sensitivity (95% confidence interval: 77%, 97%) and 94.4% specificity (95% confidence interval: 79%, 98%), with area under the characteristic curve of 0.93. Accuracy rate of model, resident, attending, and consultant were 94.0%, 93.4%, 95.6%, and 97.0%. AI can effectively identify the characteristics of HYC from CT images of the brain and automatically analyze the images. In the future, AI can provide auxiliary diagnosis of image results and reduce the burden on junior doctors.

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs., Here, using lung epithelial cells and ex vivo tissue explants, the authors show that, in addition to ACE2, host heparan sulfate is directly involved in SARS-CoV-2 attachment and entry and provide data suggesting that host sialic acids may act as viral restriction factor in lung tissues.

Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.

Highlights • SARS-CoV-2 infection was more robust than SARS-CoV in Calu3. In contrast, SARS-CoV infected intestinal epithelial cells more efficiently. • SARS-CoV-2 infection launched an attenuated interferon and pro-inflammatory cytokines/chemokines response in both Calu3 and Caco2 cells, despite robust virus infection and propagation. • SARS-CoV-2 was more sensitive to IFNβ and poly(I:C) pretreatment than that of SARS-CoV., Objectives Respiratory and intestinal tract were two primary target organs of SARS-CoV-2 infection. However, detailed characterization of the host-virus interplay in infected human lung and intestinal epithelial cells is lacking. Methods We utilized immunofluorescence assays, flow cytometry, and RT-qPCR to delineate the virological features and the innate immune response of the host cells against SARS-CoV-2 infection in two prototype human cell lines representing the human pulmonary (Calu3) and intestinal (Caco2) epithelium when compared with SARS-CoV. Results Lung epithelial cells were significantly more susceptible to SARS-CoV-2 compared to SARS-CoV. However, SARS-CoV-2 infection induced an attenuated pro-inflammatory cytokines/chemokines induction and type I and type II IFN responses. A single dose of 10 U/mL IFN-β (IFNβ) pretreatment potently protected both Calu3 and Caco2 against SARS-CoV-2 infection. Interestingly, SARS-CoV-2 was more sensitive to the pretreatment with IFNβ and IFN inducer than SARS-CoV in Calu3. Conclusions Despite robust infection efficiency in both the human lung and intestinal epithelial cells, SARS-CoV-2 could attenuate the virus-induced pro-inflammatory response and IFN response. Pre-activation of the type I IFN signaling pathway primed a highly efficient antiviral response in the host against SARS-CoV-2 infection, which could serve as a potential therapeutic and prophylactic maneuver to COVID-19 patients.

Summary: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus–host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown. Methods: We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA. Findings: SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004). Interpretation: As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV. Funding: May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.