Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 ...(COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, ...the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.
Objectives and methodsWith 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and ...estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them.ResultsLower eBMD were observed in patients with PsA than in controls in both model0 (β-coefficient=−0.014, p=0.0006) and model1 (β-coefficient=−0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (β-coefficient=−0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture.ConclusionsThe effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.
Antibiotics and heavy metals have caused serious contamination of the environment and even resulted in public health concerns. It has therefore become even more urgent to adopt a sustainable approach ...to combating these polluted environments. In this paper, we investigated the microbial community of marine sediment samples after 255 days of enrichment culture under Cu (II) and lincomycin stress and ZC255 was the most resistant strain obtained. The 16S rRNA gene sequence confirmed that it belonged to the genus Rossellomorea. Strain ZC255 was resistant to 12 kinds of antibiotics, and had a superior tolerance to Cu (II), Pb (II), Ni (II), Zn (II), Cr (III), and Cd (II). Moreover, it exhibits strong bioremoval ability of Cu and lincomycin. The removal efficiency of Cu (II) and lincomycin can achieve 651 mg/g biomass and 32.5 mg/g biomass, respectively. Strain ZC255 was a promising isolate for pollution bioremediation applications.
Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide ...association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10−8) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10−26), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10−20 and P = 1.0 × 10−27, respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10−12) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10−11 and P = 6.2 × 10−13, respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.
Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown ...potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.
•Specification of melanophores and xanthophores but not of iridophores was suppressed by AgNPs in zebrafish embryos.•AgNPs suppressed melanogenesis and xanthogenesis by their releasing Ag+ ...mostly.•AgNPs might act up-stream of genes mitfa and pax7 to suppress specification of melanophore and xanthophore lineages.
Silver_nanoparticles (AgNPs) have been reported to inhibit specification of erythroid cells and to induce spinal cord deformities and cardiac arrhythmia in vertebrates, but have not been implicated in development of neural crest (NC) and pigment cells in an in vivo model yet. In current study, down-regulated expressions of NC genes pax7 and foxd3, melanophore genes mitfa and dct, and xanthophore gene gch2 in AgNPs-exposed embryos were revealed by microarray, qRT-PCR and whole-mount in situ hybridization (WISH). Then, the down-regulated expressions of melanophore genes mitfa and dct but not xanthophore gene gch2 in AgNPs-exposed embryos were found to be recovered by melanogenesis agonists palmitic acid and dibutyryl cyclic AMP (dbcAMP). Finally, Ag+ chelating and AgNPs coating compound l-cysteine was found to neutralize AgNPs-induced hypopigmentation in AgNPs-exposed embryos, and to recover the down-regulated expressions of both dct and gch2 to nearly normal level in embryos, suggesting that AgNPs-releasing Ag+ might mediate their biological effects on zebrafish pigmentation mostly. This study was firstly to unveil that AgNPs might specifically act up-stream of mitfa and pax7 genes to suppress specification and differentiation of melanophore and xanthophore lineages respectively by their releasing Ag+ during vertebrate embryogenesis.
To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended ...validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10(-8)) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10(-10)), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10(-9)) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10(-8)). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10(-8)) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10(-6)). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10(-10), P = 5.07 × 10(-3), P = 6.77 × 10(-3) and P = 4.49 × 10(-2) for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.
This paper introduces some latest developments regarding the X-ray imaging methodology and applications of the X-ray imaging and biomedical application beamline (BL13W1) at Shanghai Synchrotron ...Radiation Facility in the past 5 years. The photon energy range of the beamline is 8–72.5 keV. Several sets of X-ray imaging detectors with different pixel sizes (0.19–24 μm) are used to realize X-ray microcomputed tomography (X-ray micro-CT) and X-ray in-line phase-contrast imaging. To satisfy the requirements of user experiments, new X-ray imaging methods and image processing techniques are developed. In vivo dynamic micro-CT experiments with living insects are performed in 0.5 s (sampling rate of 2 Hz, 2 tomograms/s) with a monochromatic beam from a wiggler source and in 40 ms (sampling rate of 25 Hz, 25 tomograms/s) with a white beam from a bending magnet source. A new X-ray imaging method known as move contrast X-ray imaging is proposed, with which blood flow and moving tissues in raw images can be distinguished according to their moving frequencies in the time domain. Furthermore, X-ray speckle-tracking imaging with twice exposures to eliminate the edge enhancement effect is developed. A high-precision quantification method is realized to measure complex three-dimensional blood vessels obtained via X-ray micro-CT. X-ray imaging methods such as three-dimensional X-ray diffraction microscopy, small-angle X-ray scattering CT, and X-ray fluorescence CT are developed, in which the X-ray micro-CT imaging method is combined with other contrast mechanisms such as diffraction, scattering, and fluorescence contrasts respectively. Moreover, an X-ray nano-CT experiment is performed with a 100 nm spatial resolution. Typical user experimental results from the fields of material science, biomedicine, paleontology, physics, chemistry, and environmental science obtained on the beamline are provided.
Improved markers for predicting recurrence are needed to stratify patients with localised (stage I–III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel ...assay integrating three modalities—clinical, genomic, and histopathological—to improve the predictive accuracy for localised renal cell carcinoma recurrence.
In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI).
The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825–0·876 vs 0·608–0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio HR 4·57, 95% CI 2·49–8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19–6·59; p<0·0001).
Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy.
National Natural Science Foundation of China, and National Key Research and Development Program of China.
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