In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not ...fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4
effector-GNLY (granulysin), CD8
effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to ...analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.
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•Quantitative lipidomic and metabolomic profiling of COVID-19 plasma•Plasma metabolite panel distinguished COVID-19 from healthy controls (AUC = 0.975)•Differential correlation analyses uncovered metabolic dysregulation in COVID-19•GM3-enriched exosomes are positively correlated with COVID-19 pathogenesis
Plasma metabolite panel effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma monosialodihexosyl gangliosides (GM3s) were negatively correlated with CD4+ T cell count in COVID-19 patients, and GM3-enriched exosomes were positively correlated with disease severity. These observations suggest that GM3-enriched exosomes may participate in pathological processes associated with COVID-19 progression.
•The cryogenic magnetocaloric effect in different magnetic systems is discussed.•The assembly strategies toward 3d-, 4f- and 3d–4f based molecular magnetic coolants are described.•The recent advance ...in cryogenic molecular magnetic coolants is summarized.•The different nature of 3d and 4f ions must be considered in the design of molecular magnetic coolants.
This review outlines recent advances in the design of 3d-, 4f-, and 3d–4f type magnetic molecules for use as excellent cryogenic magnetic coolants based on the magnetocaloric effect (MCE), and the structure-magnetocaloric correlations of reported molecular coolants. Further improvements in the MCE values of molecular magnetic materials are also proposed based on assembly strategies from molecular chemistry and crystal engineering.
Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to ...treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 10
cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.
Background
Mesenchymal stem cell (MSC) infusion was reported to improve liver function in patients with decompensated liver cirrhosis (DLC); however, whether the medication can improve outcome of ...these patients is poorly understood.
Methods
This prospective, open-labeled, randomized controlled study enrolled 219 patients with HBV-related DLC who were divided into control group (
n
= 111) and umbilical cord-derived MSC (UC-MSC)-treated group (
n
= 108), then all of them received a follow-up check from October 2010 to October 2017. The treated patients received three times of UC-MSC infusions at 4-week intervals plus conventional treatment that was only used for control group. The overall survival rate and HCC-free survival rate were calculated as primary endpoints and the liver function and adverse events associated with the medication were also evaluated.
Results
During the follow-up check period from 13 to 75th months, there was a significantly higher overall survival rate in the treated group than the control group, while the difference of the hepatocellular carcinoma event-free survival rate between the treated and control groups was not observed during the 75-month follow-up. UC-MSC treatment markedly improved liver function, as indicated by the levels of serum albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up. No significant side effects or treatment-related complications were observed in the UC-MSC group.
Conclusions
Therapy of UC-MSC is not only well tolerated, but also significantly improves long-term survival rate, as well as the liver function in patients with HBV-related DLC. UC-MSC medication, therefore, might present a novel therapeutic approach for the disease.
Graphic abstract
The field-induced blockage of magnetization behavior was first observed in an YbIII-based molecule with a trigonally distorted octahedral coordination environment. Ab initio calculations and ...micro-SQUID measurements were performed to demonstrate the exhibition of easy-plane anisotropy, suggesting the investigated complex is the first pure lanthanide field-induced single-ion magnet (field-induced SIM) of this type. Furthermore, we found the relaxation time obeys a power law instead of an exponential law, indicating that the relaxation process should be involved a direct process rather than an Orbach process.
Abstract
We propose a double-parameter regularization scheme for dealing with the backward diffusion process. Considering the smoothing effect of Yosida approximation for PDE, we propose to ...regularize this ill-posed problem by modifying original governed system in terms of a pseudoparabolic equation together with a quasi-boundary condition simultaneously, which consequently contains two regularizing parameters. Theoretically, we establish the optimal error estimates between the regularizing solution and the exact one in terms of suitable choice strategy for the regularizing parameters, under
a-priori
regularity assumptions on the exact solution. The
a-posteriori
choice strategy for the regularizing parameters based on the discrepancy principle is also studied. To weaken the heavy computational cost for solving the discrete nonsymmetric linear regularizing system by finite difference scheme, especially in higher spatial dimensional cases, the block divide-and-conquer method together with the properties of the Schur complement is applied to decompose the linear system into two half-size linear systems, one of which can be solved by the diagonalization technique, and consequently an efficient parallel-in-time algorithm originally developed for direct problem is applicable. Our proposed method is of much lower complexity than the standard solver for the corresponding linear system. Finally, some numerical examples are presented to verify the efficiency of our proposed method.
Interleukin‐17 (IL‐17)‐producing CD4+ T cells (Th17)‐mediated immune response has been demonstrated to play a critical role in inflammation‐associated disease; however, its role in chronic hepatitis ...B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV‐infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV‐associated acute‐on‐chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL‐17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and IL‐23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17‐associated cytokines was also increased in CHB and ACLF patients. Conclusion: Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection. (HEPATOLOGY 2009.)
Autophagy is an intracellular "self-eating" process that is closely related to inflammation and cellular immunity. New studies indicate that autophagy is also involved in tumor suppression. The ...anti-inflammatory cytokine interleukin-37 (IL-37) has been shown to have tumor-suppressive abilities in hepatocellular carcinoma (HCC). Notably, autophagy appears to play a dual role in the development of HCC and may be involved in both tumorigenesis and tumor suppression. However, the potential role of IL-37 in autophagy is currently unknown. In this study, we investigated the effect of IL-37 on autophagy in multiple HCC cell lines. In doing so, we found that IL-37 inhibits proliferation in HCC cells and also induces autophagy and apoptosis in the SMMC-7721 and Huh-7 cell lines. Further experiments revealed that IL-37 treatment reduced the levels of phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), phosphorylated p70 ribosomal protein s6 kinase (p-p70S6K) and phosphorylated 4E-binding protein 1 (4E-BP1). Moreover, treatment with an AKT agonist, insulin-like growth factor 1 (IGF-1), reversed these IL-37-mediated effects on autophagy, and treatment with an phosphoinositide-3-kinase (PI3K)/AKT inhibitor, LY294002, mimicked the effects of IL-37. Taken together, these results indicate that IL-37 regulates autophagy in SMMC-7721 and Huh-7 cells via inhibition of the PI3K/AKT/mTOR signaling pathway.
We consider a nonlinear inverse problem for identifying an unknown time-dependent potential coefficient in a linear pseudoparabolic equation from nonlocal inversion input, which is quite different ...from the cases of parabolic equation due to the appearance of the mixed derivatives of third order in the governed equation. Based on the established positive property of the solution to the direct problem, the uniqueness and the Lipschitz conditional stability of this inverse problem are addressed by the principle of contraction mappings for specially chosen weight function in the average observation input data. Then, in terms of the fixed point equation, an iterative algorithm is established to construct the approximate solution to this inverse problem with explicit error estimate, which also leads to the optimal error bounds for specified choice strategy of the iteration times. Some numerical results are presented to validate our proposed reconstruction scheme.
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