Diagnostic accuracy of serological tests and kinetics of severe acute respiratory syndrome coronavirus 2 antibody: A systematic review and meta-analysis.

This study aimed to assess the diagnostic test accuracy (DTA) of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) serological test methods and the kinetics of antibody positivity. Systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We included articles evaluating the diagnostic accuracy of serological tests and the kinetics of antibody positivity. MEDLINE through PubMed, Scopus, medRxiv and bioRxiv were sources of articles. Methodological qualities of included articles were appraised using QUADAS-2 while Metandi performs bivariate meta-analysis of DTA using a generalized linear mixed-model approach. Stata 14 and Review Manager 5.3 were used for data analysis. The summary sensitivity/specificity of chemiluminescence immunoassay (CLIA), enzyme-linked immunosorbent assay (ELISA) and lateral flow immunoassay (LFIA) were 92% (95% CI: 86%-95%)/99% (CI: 97%-99%), 86% (CI: 82%-89%)/99% (CI: 98%-100%) and 78% (CI: 71%-83%)/98% (95% CI: 96%-99%), respectively. Moreover, CLIA-based assays produced nearly 100% sensitivity within 11-15 days post-symptom onset (DPSO). Based on antibody type, the sensitivity of ELISA-total antibody, CLIA-IgM/G and CLIA-IgG gauged at 94%, 92% and 92%, respectively. The sensitivity of CLIA-RBD assay reached 96%, while LFIA-S demonstrated the lowest sensitivity, 71% (95% CI: 58%-80%). CLIA assays targeting antibodies against RBD considered the best DTA. The antibody positivity rate increased corresponding with DPSO, but there was some decrement when moving from acute phase to convalescent phase of infection. As immunoglobulin isotope-related DTA was heterogeneous, our data have insufficient evidence to recommend CLIA/ELISA for clinical decision-making, but likely to have comparative advantage over RT-qPCR in certain circumstances and geographic regions.

Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling.

OBJECTIVE: Macrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined. DESIGN: We used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models. RESULTS: Anti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF. CONCLUSION: The therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

IL-6 Promotes T Cell Proliferation and Expansion under Inflammatory Conditions in Association with Low-Level RORγt Expression.

IL-6 is a critical driver of acute and chronic inflammation and has been reported to act as a T cell survival factor. The influence of IL-6 on T cell homeostasis is not well resolved. We demonstrate that IL-6 signaling drives T cell expansion under inflammatory conditions but not during normal homeostasis. During inflammation, IL-6Rα-deficient T cells are unable to effectively compete with wild type T cells. IL-6 promotes T cell proliferation, and this is associated with low-level expression of the RORγt transcription factor. T cells upregulate Rorc mRNA at levels substantially diminished from that seen in Th17 cells. Blockade of RORγt through genetic knockout or a small molecule inhibitor leads to T cell expansion defects comparable to those in IL-6Rα-deficient T cells. Our results indicate that IL-6 plays a key role in T cell expansion during inflammation and implicates a role for the transient induction of low-level RORγt.

Interleukin-10 Family Cytokines Immunobiology and Structure.

The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.

Differential T Cell Cytokine Receptivity and Not Signal Quality Distinguishes IL-6 and IL-10 Signaling during Th17 Differentiation.

How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.

The transcription factor PLZF directs the effector program of the NKT cell lineage.

The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naive phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4(+) thymocytes to acquire effector differentiation and migrate to nonlymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.

Evaluation of Empirical Tropospheric Models Using Satellite-Tracking Tropospheric Wet Delays with Water Vapor Radiometer at Tongji, China.

An empirical tropospheric delay model, together with a mapping function, is commonly used to correct the tropospheric errors in global navigation satellite system (GNSS) processing. As is well-known, the accuracy of tropospheric delay models relies mainly on the correction efficiency for tropospheric wet delays. In this paper, we evaluate the accuracy of three tropospheric delay models, together with five mapping functions in wet delays calculation. The evaluations are conducted by comparing their slant wet delays with those measured by water vapor radiometer based on its satellite-tracking function (collected data with large liquid water path is removed). For all 15 combinations of three tropospheric models and five mapping functions, their accuracies as a function of elevation are statistically analyzed by using nine-day data in two scenarios, with and without meteorological data. The results show that (1) no matter with or without meteorological data, there is no practical difference between mapping functions, i.e., Chao, Ifadis, Vienna Mapping Function 1 (VMF1), Niell Mapping Function (NMF), and MTT Mapping Function (MTT); (2) without meteorological data, the UNB3 is much better than Saastamoinen and Hopfield models, while the Saastamoinen model performed slightly better than the Hopfield model; (3) with meteorological data, the accuracies of all three tropospheric delay models are improved to be comparable, especially for lower elevations. In addition, the kinematic precise point positioning where no parameter is set up for tropospheric delay modification is conducted to further evaluate the performance of tropospheric delay models in positioning accuracy. It is shown that the UNB3 model is best and can achieve about 10 cm accuracy for the N and E coordinate component while 20 cm accuracy for the U coordinate component no matter the meteorological data is available or not. This accuracy can be obtained by the Saastamoinen model only when meteorological data is available, and degraded to 46 cm for the U component if the meteorological data is not available.

Improved PPP Ambiguity Resolution Considering the Stochastic Characteristics of Atmospheric Corrections from Regional Networks.

With the increased availability of regional reference networks, Precise Point Positioning (PPP) can achieve fast ambiguity resolution (AR) and precise positioning by assimilating the satellite fractional cycle biases (FCBs) and atmospheric corrections derived from these networks. In such processing, the atmospheric corrections are usually treated as deterministic quantities. This is however unrealistic since the estimated atmospheric corrections obtained from the network data are random and furthermore the interpolated corrections diverge from the realistic corrections. This paper is dedicated to the stochastic modelling of atmospheric corrections and analyzing their effects on the PPP AR efficiency. The random errors of the interpolated corrections are processed as two components: one is from the random errors of estimated corrections at reference stations, while the other arises from the atmospheric delay discrepancies between reference stations and users. The interpolated atmospheric corrections are then applied by users as pseudo-observations with the estimated stochastic model. Two data sets are processed to assess the performance of interpolated corrections with the estimated stochastic models. The results show that when the stochastic characteristics of interpolated corrections are properly taken into account, the successful fix rate reaches 93.3% within 5 min for a medium inter-station distance network and 80.6% within 10 min for a long inter-station distance network.

Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis.

The fate of Foxp3(+) regulatory T (Treg) cells responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1(+) (where KLRG1 stands for killer cell lectin-like receptor G1) CNS-infiltrating Treg cells in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1(+) Treg cells showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1(-) cells. KLRG1(-) Treg cells converted into KLRG1(+) cells and this was increased in autoimmune inflammation. Conversion was unidirectional; KLRG1(+) Treg cells did not revert to a KLRG1(-) state. KLRG1(+) but notKLRG1(-) Treg cells survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was also upregulated on iTreg cells after transfer and EAE induction or on iTreg cells developing spontaneously during EAE. KLRG1(+) Treg cells produced more IL-10 and had altered effector cytokine production compared with their KLRG1(-) counterparts. Despite their differences, KLRG1(+) and KLRG1(-) Treg cells proved similarly potent in suppressing EAE. KLRG1(+) and KLRG1(-) populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg cells during EAE, and associate KLRG1 with altered Treg-cell function and senescence.

The new progress in cancer immunotherapy.

The cross talk between immune and non-immune cells in the tumor microenvironment leads to immunosuppression, which promotes tumor growth and survival. Immunotherapy is an advanced treatment that boosts humoral and cellular immunity rather than using chemotherapy or radiation-based strategy associated with non-specific targets and toxic effects on normal cells. Immune checkpoint inhibitors and T cell-based immunotherapy have already exhibited significant effects against solid tumors and leukemia. Tumor cells that escape immune surveillance create a major obstacle to acquiring an effective immune response in cancer patients. Tremendous progress had been made in recent years on a wide range of innate and adaptive immune checkpoints which play a significant role to prevent tumorigenesis, and might therefore be potential targets to suppress tumor cells growth. This review aimed to summarize the underlying molecular mechanisms of existing immunotherapy approaches including T cell and NK-derived immune checkpoint therapy, as well as other intrinsic and phagocytosis checkpoints. Together, these insights will pave the way for new innate and adaptive immunomodulatory targets for the development of highly effective new therapy in the future.

ROR1/STAT3 positive feedback loop facilitates cartilage degeneration in Osteoarthritis through activation of NF-κB signaling pathway.

BACKGROUND: Osteoarthritis (OA) is a chronic joint disorder with a serious impact on society. The main pathological change in OA is articular cartilage degeneration, which is directly associated with imbalance of anabolic and catabolic activities in chondrocytes. OBJECTIVE: To evaluate the expression and biological effects of ROR1 in OA cartilage and determine whether knockdown of ROR1 attenuates cartilage degeneration. METHODS: ROR1 expression in OA clinical specimens was evaluated by western blotting and immunohistochemistry. The effects of ROR1 on anabolic and catabolic activities were evaluated in Wnt5a-treated human primary chondrocytes by western blotting, immunofluorescence, and luciferase assay. The effects of ROR1 knockdown on cartilage degeneration in a surgical OA mouse model were examined by X-ray imaging and Safranin O-Fast Green histological staining. RESULTS: ROR1 was considerably upregulated in cartilage tissues of OA patients. ROR1 knockdown alleviated the activation of the NF-κB signaling pathway and reversed the suppression of collagen II and aggrecan by Wnt5a, as well as upregulation of ADAMTS-5 and MMP-13 in chondrocytes. In addition, ROR1 knockdown significantly reduced Wnt5a-induced STAT3 nuclear translocation. STAT3 binding to the ROR1 promoter indicated a positive feedback loop between ROR1 and STAT3. ROR1 knockdown was confirmed to dramatically alleviate cartilage degradation in the DMM induced-OA mouse model. CONCLUSION: Increased expression of ROR1 in OA cartilage tissues leads to a positive feedback loop with STAT3, which activates the NF-κB signaling pathway, resulting in an imbalance between chondrocyte anabolism and catabolism. These results indicate a potential new therapeutic target for the treatment of OA.

Intense ocean freshening from melting glacier around the Antarctica during early twenty-first century.

With the accelerating mass loss of Antarctic ice sheets, the freshening of the Southern Ocean coastal oceans (SOc, seas around Antarctica) is gradually intensifying, which will reduce the formation of bottom water and weaken the meridional overturning circulation, thus having a significant negative impact on the ocean's role in regulating global climate. Due to the extreme environment of the Southern Ocean and the limitations of observational techniques, our understanding of the glacier-derived freshening of SOc is still vague. We developed a method that first provided us with an expansive understanding of glacier-derived freshening progress over the SOc. Applying this method to the observational data in the SOc from 1926 to 2016, revealed that the rate of glacier-derived freshwater input reached a maximum of 268 ± 134 Gt year-1 during the early twenty-first century. Our results indicate that during the same period, glacier melting accounted for 63%, 28%, and 92% of the total freshening occurred in the Atlantic, Indian, and Pacific sectors of the SOc, respectively. This suggests that the ice shelf basal melt in West Antarctica and the Antarctic Peninsula plays a dominant role in the freshening of the surrounding seas.

Hierarchically porous activated carbons prepared via a dissipative process: a high-capacity cathode for Li-ion capacitors.

Activated carbons with high specific surface area (SSA) and well-modulated pore structure are highly desirable for achieving high-performance capacitive energy storage. Herein, hierarchically porous activated carbons (PACs) are synthesized by a tableting-activation method. The quick release of high-pressure gaseous products from the inside of the tablets can be regarded as a dissipative process, which leads to the formation of well-ordered high density meso- or macropores in the resulting material. The porous structure of the PACs has been modulated by adjusting the dissipative process parameters, such as the tableting pressure and tablet thickness. As a result, the optimal PAC (PAC-10) possesses an ultrahigh SSA (up to 3211 m2 g-1) and a well-developed hierarchical porous structure, which leads to an excellent capacitive energy-storage performance both in an aqueous electrolyte supercapacitor system and a Li ion capacitor (LIC) system. In particular, as a cathode for LICs, PAC-10 exhibits an extremely high specific capacity of 251 mA h g-1 at 0.5 A g-1 and still retains 158 mA h g-1 at a high rate of 15 A g-1.

Evaluation and Comparison of Serological Methods for COVID-19 Diagnosis.

The worldwide pandemic of COVID-19 has become a global public health crisis. Various clinical diagnosis methods have been developed to distinguish COVID-19-infected patients from healthy people. The nucleic acid test is the golden standard for virus detection as it is suitable for early diagnosis. However, due to the low amount of viral nucleic acid in the respiratory tract, the sensitivity of nucleic acid detection is unsatisfactory. As a result, serological screening began to be widely used with the merits of simple procedures, lower cost, and shorter detection time. Serological tests currently include the enzyme-linked immunosorbent assay (ELISA), lateral flow immunoassay (LFIA), and chemiluminescence immunoassay (CLIA). This review describes various serological methods, discusses the performance and diagnostic effects of different methods, and points out the problems and the direction of optimization, to improve the efficiency of clinical diagnosis. These increasingly sophisticated and diverse serological diagnostic technologies will help human beings to control the spread of COVID-19.

Isolation and Detection of Murine iNKT Cells in Different Organs.

The invariant NKT (iNKT) cells are innate-like lymphocytes that share phenotypic and functional characteristics with NK cells and T cells, playing an important role in both human and mouse physiology and disease and bridging the gap between the innate and adaptive immune responses. The frequency and subtypes of iNKT cells in major immune organs are different, which also determines the regional immune characteristics of iNKT cells. Here, we report a protocol about the isolation of iNKT cells in the thymus, spleen, and liver of C57BL/6, CD1d-/-, and Jα18-/- mice.

Endometrial cavity fluid is associated with deleterious pregnancy outcomes in patients undergoing in vitro fertilization/intracytoplasmic sperm injection: a retrospective cohort study.

BACKGROUND: The effects of endometrial cavity fluid (ECF) on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancy outcomes following embryo transfer (ET) are still controversial. We conducted the present study to investigate whether the presence of ECF in infertile patients scheduled to undergo IVF or ICSI was associated with pregnancy outcomes. METHODS: A retrospective cohort study design was used. Among infertile patients undergoing IVF/ICSI, those with and without ECF were matched 1:1 using propensity score matching (PSM). After ensuring that the baseline levels of the two matched groups were consistent, the pregnancy and obstetrical outcomes of the two groups were compared. RESULTS: Patients with ECF had significantly lower clinical rates of pregnancy (1,061/1,862, 57% vs. 1,182/1,862, 63.5%; P<0.001), live birth (902/1,862, 48.4% vs. 1,033/1,862, 55.5%; P<0.001), biochemical pregnancy (1,182/1,862, 63.5% vs. 1,288/1,862, 69.2%; P<0.001), and embryo implantation (1,500/3,740, 40.1% vs. 1,661/3,740, 44.4%, P<0.001) than patients without ECF. Also, patients with ECF had a higher incidence of gestational diabetes (17/78, 22% vs. 8/94, 9%, P=0.014). However, there were no differences in gestational weeks at delivery or birth weight between the two groups. CONCLUSIONS: ECF was significantly associated with adverse pregnancy outcomes but showed no significant association with adverse obstetric outcomes (except for gestational diabetes).

Homotypic CARD-CARD interaction is critical for the activation of NLRP1 inflammasome.

Cytosolic inflammasomes are supramolecular complexes that are formed in response to intracellular pathogens and danger signals. However, as to date, the detailed description of a homotypic caspase recruitment domain (CARD) interaction between NLRP1 and ASC has not been presented. We found the CARD-CARD interaction between purified NLRP1CARD and ASCCARD experimentally and the filamentous supramolecular complex formation in an in vitro proteins solution. Moreover, we determined a high-resolution crystal structure of the death domain fold of the human ASCCARD. Mutational and structural analysis revealed three conserved interfaces of the death domain superfamily (Type I, II, and III), which mediate the assembly of the NLRP1CARD/ASCCARD complex. In addition, we validated the role of the three major interfaces of CARDs in assembly and activation of NLRP1 inflammasome in vitro. Our findings suggest a Mosaic model of homotypic CARD interactions for the activation of NLRP1 inflammasome. The Mosaic model provides insights into the mechanisms of inflammasome assembly and signal transduction amplification.

Pulling-Force Spinning Top for Serum Separation Combined with Paper-Based Microfluidic Devices in COVID-19 ELISA Diagnosis.

The spread of Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), resulting in a global pandemic with around four million deaths. Although there are a variety of nucleic acid-based tests for detecting SARS-CoV-2, these methods have a relatively high cost and require expensive supporting equipment. To overcome these limitations and improve the efficiency of SARS-CoV-2 diagnosis, we developed a microfluidic platform that collected serum by a pulling-force spinning top and paper-based microfluidic enzyme-linked immunosorbent assay (ELISA) for quantitative IgA/IgM/IgG measurements in an instrument-free way. We further validated the paper-based microfluidic ELISA analysis of SARS-CoV-2 receptor-binding domain (RBD)-specific IgA/IgM/IgG antibodies from human blood samples as a good measurement with higher sensitivity compared with traditional IgM/IgG detection (99.7% vs 95.6%) for early illness onset patients. In conclusion, we provide an alternative solution for the diagnosis of SARS-CoV-2 in a portable manner by this smart integration of pulling-force spinning top and paper-based microfluidic immunoassay.

CD4+ CD25+ Foxp3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice.

Regulatory T cells (Tregs), which are characterized by expression of CD4, CD25, and Foxp3, play a crucial role in the control of immune responses to both self and non-self Ags. To date, there are only limited data on their role in physiological and pathological hepatic immune responses. In this study, we examined the role of hepatic Tregs in immune-mediated liver injury by using the murine Con A-induced hepatitis model. Con A treatment was associated with an increased number of Foxp3(+) Tregs in liver but not in spleen. Moreover, the expression levels of Foxp3, CTLA-4, glucocorticoid-induced TNF receptor, as well as the frequency of CD103 of Tregs were increased after Con A injection, being significantly higher in liver than in spleen. Depleting CD25(+) cells aggravated liver injury, whereas adoptively transferring CD25(+) cells or Tregs reduced liver injury in Con A-treated recipients. Con A treatment induced elevated serum levels and hepatic mononuclear mRNA expressions of TGF-beta, which were reduced by Tregs depletion. In addition, anti-TGF-beta mAbs blocked the suppressive function of Tregs from Con A-treated mice in vitro. Finally, TGF-beta receptor II dominant-negative mice, whose T cells express a dominant negative form of TGFbetaRII and therefore cannot respond to TGF-beta, had a higher mortality rate and severer liver injury than normal mice injected with the same dose of Con A. These results indicate that CD4(+)CD25(+) Tregs play an important role in limiting the liver injury in Con A-induced hepatitis via a TGF-beta-dependent mechanism.