
 Abstract
 
 Fusion of the viral and host cell membranes is a necessary first step for infection by enveloped viruses and is mediated by the envelope glycoprotein. The transmembrane subunits from the structurally defined “class I” glycoproteins adopt an α-helical “trimer-of-hairpins” conformation during the fusion pathway. Here, we present our studies on the envelope glycoprotein transmembrane subunit, GP2, of the CAS virus (CASV). CASV was recently identified from annulated tree boas (Corallus annulatus) with inclusion body disease and is implicated in the disease etiology. We have generated and characterized two protein constructs consisting of the predicted CASV GP2 core domain. The crystal structure of the CASV GP2 post-fusion conformation indicates a trimeric α-helical bundle that is highly similar to those of Ebola virus and Marburg virus GP2 despite CASV genome homology to arenaviruses. Denaturation studies demonstrate that the stability of CASV GP2 is pH dependent with higher stability at lower pH; we propose that this behavior is due to a network of interactions among acidic residues that would destabilize the α-helical bundle under conditions where the side chains are deprotonated. The pH-dependent stability of the post-fusion structure has been observed in Ebola virus and Marburg virus GP2, as well as other viruses that enter via the endosome. Infection experiments with CASV and the related Golden Gate virus support a mechanism of entry that requires endosomal acidification. Our results suggest that, despite being primarily arenavirus like, the transmembrane subunit of CASV is extremely similar to the filoviruses.
 


From a Novel

Background SARS-CoV-2 antigen rapid diagnostic tests (Ag-RDTs) are increasingly being integrated in testing strategies around the world. Studies of the Ag-RDTs have shown variable performance. In this systematic review and meta-analysis, we assessed the clinical accuracy (sensitivity and specificity) of commercially available Ag-RDTs. Methods and findings We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched multiple databases (PubMed, Web of Science Core Collection, medRvix, bioRvix, and FIND) for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 up until 30 April 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity in comparison to reverse transcription polymerase chain reaction (RT-PCR) testing. We assessed heterogeneity by subgroup analyses, and rated study quality and risk of bias using the QUADAS-2 assessment tool. From a total of 14,254 articles, we included 133 analytical and clinical studies resulting in 214 clinical accuracy datasets with 112,323 samples. Across all meta-analyzed samples, the pooled Ag-RDT sensitivity and specificity were 71.2% (95% CI 68.2% to 74.0%) and 98.9% (95% CI 98.6% to 99.1%), respectively. Sensitivity increased to 76.3% (95% CI 73.1% to 79.2%) if analysis was restricted to studies that followed the Ag-RDT manufacturers’ instructions. LumiraDx showed the highest sensitivity, with 88.2% (95% CI 59.0% to 97.5%). Of instrument-free Ag-RDTs, Standard Q nasal performed best, with 80.2% sensitivity (95% CI 70.3% to 87.4%). Across all Ag-RDTs, sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values, i.e., <20 (96.5%, 95% CI 92.6% to 98.4%) and <25 (95.8%, 95% CI 92.3% to 97.8%), in comparison to those with Ct ≥ 25 (50.7%, 95% CI 35.6% to 65.8%) and ≥30 (20.9%, 95% CI 12.5% to 32.8%). Testing in the first week from symptom onset resulted in substantially higher sensitivity (83.8%, 95% CI 76.3% to 89.2%) compared to testing after 1 week (61.5%, 95% CI 52.2% to 70.0%). The best Ag-RDT sensitivity was found with anterior nasal sampling (75.5%, 95% CI 70.4% to 79.9%), in comparison to other sample types (e.g., nasopharyngeal, 71.6%, 95% CI 68.1% to 74.9%), although CIs were overlapping. Concerns of bias were raised across all datasets, and financial support from the manufacturer was reported in 24.1% of datasets. Our analysis was limited by the included studies’ heterogeneity in design and reporting. Conclusions In this study we found that Ag-RDTs detect the vast majority of SARS-CoV-2-infected persons within the first week of symptom onset and those with high viral load. Thus, they can have high utility for diagnostic purposes in the early phase of disease, making them a valuable tool to fight the spread of SARS-CoV-2. Standardization in conduct and reporting of clinical accuracy studies would improve comparability and use of data.

/pdf/accuracy-of-novel-antigen-rapid-diagnostics-for-sars-cov-2-a-50f6t960i2.pdf

Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: A living systematic review and meta-analysis.

Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020.To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design.We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions.We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample.We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status.We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed.Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening. 

Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection

Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell-based therapies. However, the efficacy and underlying mechanisms of EV-based treatment in hepatic ischemia-reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC-EVs (huc-MSC-EVs) could protect against IRI-induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc-MSC-EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress-induced cell death in vitro. Interestingly, we found that the mitochondria-located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc-MSC-EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc-MSCs decreased the level of MnSOD in huc-MSC-EVs and attenuated the antiapoptotic and antioxidant capacities of huc-MSC-EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc-MSC-EVs on hepatic IRI and evaluate their preclinical application.-Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201800131RR

Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. In the quest to circumvent these challenges, several modification techniques have been applied to the naive MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.

/pdf/improved-therapeutics-of-modified-mesenchymal-stem-cells-an-2k7urbozfp.pdf

Improved therapeutics of modified mesenchymal stem cells: an update

Objective To study the effect of different doses of radiation on intestinal injury,with an attempt to find the optimal radiation dose for establishing intestinal injury models in NOD/SCID mice. Methods Forty healthy male SPF-grade NOD/SCID mice were divided randomly into four groups:blank control group and 4-,5-,6-Gy irradiatio groups,with 10 mice in each group. The irradiation rate was 1 Gy/min. The general conditions,body weight,intestinal bacterial translocation,and histopathologic changes were observed and compared. Results The survival rate was 60%,50%,and 30% in the 4-,5-,and 6-Gy groups 15 days after irradiation,and the intestinal bacterial translocation rate was 20%,50%,and 70%,respectively. The body weights in 5-Gy group (P=0.015) and 6-Gy group (P=0.011) were significantly higher than that in blank control group. The length of small intestinal villi decreased in the 4-Gy group. In the 5-Gy group,the structure of intestinal mucosa villi became wide,flat,and inverted,along with the shedding of epithelial cells,the atrophy of glands,and the damage of recess structures. In the 6-Gy group,the structure of intestinal mucosal villi was damaged,the villi were ruptured and smashed,and the recess structures were missing;meanwhile,there was a large amount of inflammatory cell infiltration between tissues,along with visible spotty bleeding and necrosis. The length of small intestine villi in the blank control group and 4-,5-,and 6-Gy groups were (361.77±22.77),(291.68±32.45),(248.03±51.09),and (195.90±26.39) μm,respectively. In particular,it was significantly shorter in 4-Gy group (P=0.005),5-Gy group (P<0.001),and 6-Gy (P<0.001) than in the blank control group,was significantly shorter in the 5-Gy group (P=0.041) and 6-Gy group (P=0.001) than in the 4-Gy group,and significantly shorter in 6-Gy group than in the 5-Gy group (P=0.020). Conclusion 5-Gy irradiation in mice models can decrease body weight,cause the damage of intestinal mucosa and the shedding of inflammatory cells,with stable survival rate and bacterial translocation rate.

Effect of Different Doses of Radiation on Intestinal Injury in NOD/SCID Mice.

The utility model discloses an auto blood reinfusion device, including vascular suction nozzle, pipeline, anticoagulant bag, the negative pressure pipe stores up blood ware and washing liquid bag, said negative pressure pipe one end with store up the blood ware and connect and communicate with each other, the other end is used for connecting installation vacuum device, it has the centrifugation cup through pipeline installation to store up the blood ware, be connected with the washing liquid bag for centrifugal glass and communicate with each other, the centrifugation cup is connected through pipeline and storage blood bag, pipeline installation has the filter between centrifugation cup and the storage blood bag, the centrifugation cup still is connected with the waste liquid bag. This auto blood reinfusion device, but install a filtering tumor cells's filter additional before ordinary auto blood reinfusion device's storage blood bag tumor cells can effectively be got rid of and to the unobvious influence of the collection of red blood cell to the filter. Tumor cells has effectively been solved and to the influence of the collection of red blood cell to be applicable to various blood transfusion patients.

Auto blood reinfusion device

Purpose To develop a rapid detection reagent for SARS-CoV-2 antigen for the auxiliary diagnosis of new coronary pneumonia (COVID-19), and perform the methodological evaluation and clinical evaluation of the reagent. Method SARS-CoV-2 N-protein test strip was created by combining fluorescent microsphere labeling technology and immunochromatographic technology, based on the principle of double antibody sandwich. Then we evaluated the analytical capability and clinical application of the strips. Result The limit of detection of the strips for recombinant N protein was 100 ng/ml and for activated SARS -CoV-2 virus was 1 × 103 TCID50/ml. The strips also have high analytical specificity and anti-interference capability. According to the predetermined cut-off value, the specificity of the test strip in healthy controls and patients with other respiratory disease was 100.00 and 97.29%, the sensitivity in COVID-19 cases at progress stage and cured stage was 67.15 and 7.02%. The positive percentage agreement and negative percentage agreement of antigen strip to RNA test were 83.16 and 94.45%. Conclusion SARS-CoV-2 fluorescence immunochromatographic test strip can achieve fast, sensitive and accurate detection, which can meet the clinical requirements for rapid detection of viruses on the spot.

/pdf/foundation-and-clinical-evaluation-of-a-new-method-for-ehkxzydt8c.pdf

Foundation and Clinical Evaluation of a New Method for Detecting SARS-CoV-2 Antigen by Fluorescent Microsphere Immunochromatography.

Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene–modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-β1, and the oxidative stress fa...

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.

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Effect of Different Doses of Radiation on Intestinal Injury in NOD/SCID Mice.

Auto blood reinfusion device

Foundation and Clinical Evaluation of a New Method for Detecting SARS-CoV-2 Antigen by Fluorescent Microsphere Immunochromatography.

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.