The SARS-CoV-2 Antibody and Drug Research Based on the Structure of the Spike Protein and the Mechanism of Cell Entry.

COVID-19 is a severe acute respiratory syndrome caused by a novel coronavirus, SARS-CoV- 2.COVID-19 is now a pandemic, and is not yet fully under control.As the surface spike protein (S) mediates the recognition between the virus and cell membrane and the process of cell entry, it plays an important role in the course of disease transmission.The study on the S protein not only elucidates the structure and function of virus-related proteins and explains their cellular entry mechanism, but also provides valuable information for the prevention, diagnosis and treatment of COVII)-19.Concentrated on the S protein of SARS-CoV-2, this review covers four aspects: (1 ) The structure of the S protein and its binding with angiotensin converting enzyme II (ACE2) , the specific receptor of SARS-CoV-2, is introduced in detail.Compared with SARS-CoV, the receptor binding domain (RBD) of the SARS-CoV- 2 S protein has a higher affinity with ACE2, while the affinity of the entire S protein is on the contrary.(2) Currently, the cell entry mechanism of SARS-CoV-2 meditated by the S protein is proposed to include endosomal and non-endosomal pathways.With the recognition and binding between the S protein and ACE2 or after cell entry, transmembrane protease serine 2(TMPRSS2) , lysosomal cathepsin or the furin enzyme can cleave S protein at S1/S2 cleavage site, facilitating the fusion between the virus and target membrane.(3) For the progress in SARS-CoV-2 S protein antibodies, a collection of significant antibodies are introduced and compared in the fields of the target, source and type.(4) Mechanisms of therapeutic treatments for SARS-CoV-2 varied.Though the antibody and medicine treatments related to the SARS-CoV-2 S protein are of high specificity and great efficacy, the mechanism, safety, applicability and stability of some agents are still unclear and need further assessment.Therefore, to curb the pandemic, researchers in all fields need more cooperation in the development of SARS-CoV-2 antibodies and medicines to face the great challenge.Copyright © Palaeogeography (Chinese Edition).All right reserved.

Surface enhanced Raman spectroscopy based analysis of SARS-CoV-2 spike protein binding to ACE2 receptor

The SARS-CoV-2 virus is still a challenge because of its diversity and mutations. The binding interactions of the angiotensin converting enzyme 2 (ACE2) receptor and the spike protein are relevant for the SARS-CoV-2 virus to enter the cell. Consequently, it is important and helpful to analyze binding activities and the changes in the structure of the ACE2 receptor and the spike protein. Surface enhanced Raman spectroscopy is able to analyze small concentrations of the proteins without contact, non-invasively and label-free. In this work, we present a SERS based approach in the visible wavelength range to analyze and study the binding interactions of the ACE2 receptor and the spike protein. SERS measurements of the ACE2 receptor, the spike protein and the ACE2-spike complex were performed. Additionally, an inhibitor was used to prevent the spike protein from binding to ACE2 and to compare the results. The analysis of the measured SERS spectra reveals structural differences and changes due to binding activities. Thus, we show that the performed SERS based approach can help for rapid and non-invasive analysis of binding interactions of the ACE2-spike complex and also of protein binding in general. © 2023 SPIE.

Findings from the ECHO Cohorts Regarding the Effects of the COVID-19 Pandemic

Background: Studies suggest perinatal infection with SARSCoV- 2 can induce adverse birth outcomes, but studies published to date have substantial limitations. Most have identified cases based upon their presentation for clinical care, and very few have examined pandemic-related stress which may also impact adverse birth outcomes. Objective(s): To evaluate the relationships between SARSCoV- 2 infection in pregnancy and pandemic-related stress with birth outcomes. Study Design: We conducted an observational study of 211 mother-newborn dyads in three urban cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program. Serology for SARS-CoV-2 was assessed in a convenience sample of prenatal maternal, cord serum or dried blood spots from births occurring between January 2020-September 2021. Specimens were assessed for IgG, IgM, and IgA antibodies to nucleocapsid, S1 spike, S2 spike, and receptor-binding domain. A Pandemic-related Traumatic Stress (PTS) scale was based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Acute Stress Disorder criteria. Result(s): 36% were positive for at least one antibody type, chiefly IgG. Self-report of infection was not significantly correlated with combined serology. There were no differences in gestational age (GA), birth weight, preterm birth (PTB), or low birth weight (LBW) among seropositive mothers. However, IgM seropositive mothers had children with lower BW (434g, 95% CI: 116- 752), BW Z score-for-GA (0.73 SD, 95% CI 0.10-1.36) and were more likely to deliver preterm (OR 8.75, 95% CI 1.22-62.4). Associations with LBW sustained in sensitivity analyses limited to pre-vaccine samples, and PTS symptoms were not associated with birth outcomes. The addition of PTS did not substantially change associations with BW, although associations with PTB attenuated to near-significance. Conclusion(s): We identified decreased birth weight and increased prematurity in mothers IgM seropositive to SARS-CoV-2, independent of PTS. Though there are limits to interpretation, the data support efforts to prevent SARS-CoV-2 infections in pregnancy.

Increases in expression of carbohydrate sulfotransferases CHST11 and CHST15 and decline in N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB) require phospho-p38-MAPK following exposure to SARS-CoV-2 spike protein receptor binding domain in human a

Objective: Immunohistochemistry of post-mortem lung tissue from Covid-19 patients with diffuse alveolar damage demonstrated marked increases in chondroitin sulfate and CHST15 and decline in N-acetylgalactosamine-4-sulfatase. Studies were undertaken to identify the mechanisms involved in these effects. Method(s): Human primary small airway epithelial cells (PCS 301-010;ATCC) were cultured and exposed to the SARSCoV- 2 spike protein receptor binding domain (SPRBD;AA: Lys310-Leu560;Amsbio). Expression of the spike protein receptor, angiotensin converting enzyme 2 (ACE2), was enhanced by treatment with Interferon-beta. Promoter activation, DNA-binding, RNA silencing, QPCR, Western blots, ELISAs, and specific enzyme inhibitors were used to elucidate the underlying molecular mechanisms. Result(s): Treatment of the cultured cells by the SPRBD led to increased CHST15 and CHST11 expression and decline in ARSB expression. Sulfotransferase activity, total chondroitin sulfate, and sulfated glycosaminoglycan (GAG) content were increased. Phospho-T180/T182-p38-MAPK and phospho- S423/S425-Smad3 were required for the activation of the CHST15 and CHST11 promoters. Inhibition by SB203580, a phospho-p38 MAPK inhibitor, and by SIS3, a Smad3 inhibitor, blocked the CHST15 and CHST11 promoter activation. SB203580 reversed the SPRBD-induced decline in ARSB expression, but SIS3 had no effect on ARSB expression or promoter activation. Phospho-p38 MAPK was shown to reduce retinoblastoma protein (RB) S807/S811 phosphorylation and increase RB S249/T252 phosphorylation. E2F-DNA binding declined following exposure to SPRBD, and SB203580 reversed this effect. This indicates a mechanism by which SPRBD, phospho-p38 MAPK, E2F, and RB can regulate ARSB expression and thereby impact on chondroitin 4-sulfate and dermatan sulfate and molecules that bind to these sulfated GAGs, including Interleukin-8, bone morphogenetic protein-4, galectin-3 and SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2). Conclusion(s): The enzyme ARSB is required for the degradation of chondroitin 4-sulfate and dermatan sulfate, and accumulation of these sulfated GAGs can contribute to lung pathophysiology, as evident in Covid-19. Some effects of the SPRBD may be attributable to unopposed Angiotensin II, when Ang1-7 counter effects are diminished due to binding of ACE2 with the SARS-CoV-2 spike protein and reduced production of Ang1-7. Aberrant cell signaling and activation of the phospho-p38 MAPK and Smad3 pathways increase CHST15 and CHST11 production, which can contribute to increased chondroitin sulfate in infected cells. Decline in ARSB may occur as a consequence of effects of phospho-p38 MAPK on RB phosphorylation and E2F1 availability. Decline in ARSB and the resulting impaired degradation of sulfated GAGs have profound consequences on cellular metabolic, signaling, and transcriptional events. Funding is VA Merit Award.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Antibody levels of COVID-19 vaccine: A comparison between healthy subjects and psychiatric patients on antidepressants

This study compares the serological antibody level post-COVID-19 vaccine among healthy subjects and psychiatric patients on antidepressant therapy. It also examines the difference in antidepressants' side effects experienced by psychiatric patients following the completion of two vaccine doses. A comparative posttest quasi-experimental study was conducted among healthy subjects and psychiatric patients on antidepressant medication in a teaching hospital in Malaysia. Elecsys Anti-SARS-CoV-2 assay was used to detect the antibody titre between weeks 4 and 12 post vaccination. The antidepressant side-effect checklist (ASEC) was used to monitor the occurrence of antidepressant-related side effects pre-and post-vaccination. 24 psychiatric patients and 26 healthy subjects were included. There was no significant difference in the antibody level between the patients (median = 1509 u/ml) and the healthy subjects (median = 995 u/ml). There was no significant worsening in the antidepressant-related side effects. The antibody level post-COVID-19 vaccine did not differ significantly between patients on antidepressant therapy and healthy subjects. Additionally, there was no change in the antidepressant side effects experienced by the patients following the completion of the vaccine.Copyright © 2022, Research Trends (P) LTD.. All rights reserved.

SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse model

Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARSCoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1- induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer.

Bioactive compounds of Jingfang Granules against SARS-CoV-2 virus proteases 3CLpro and PLpro.

OBJECTIVE: Jingfang Granules have been recommended for the prevention and treatment of corona virus disease 2019 (COVID-19). Through chemical analysis and bioactivity evaluation, this study aims to elucidate the potential effective components of Jingfang Granules. METHOD(S): The inhibitory acti-vities of Jingfang Granules extract against 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro), spike protein receptor-binding domain (S-RBD) and human cyclooxygenase-2 (COX-2) were evaluated using enzyme assay. The antitussive effects were evaluated using the classical ammonia-induced cough model. The chemical constituents of Jingfang Granules were qualitatively and quantitatively analyzed by liquid chromatography-mass spectrometry (LC/MS). The 3CLpro and PLpro inhibitory activities of the major compounds were determined by enzyme assay, molecular docking, and site-directed mutagenesis. RESULT(S): Jingfang Granules exhibited 3CLpro and PLpro inhibitory activities, as well as COX-2 inhibitory and antitussive activities. By investigating the MS/MS behaviors of reference standards, a total of fifty-six compounds were characterized in Jingfang Granules. Sixteen of them were unambiguously identified by comparing with reference standards. The contents of the 16 major compounds were also determined, and their total contents were 2 498.8 mug/g. Naringin, nodakenin and neohesperidin were three dominating compounds in Jingfang Granules, and their contents were 688.8, 596.4 and 578.7 mug/g, respectively. In addition, neohesperidin and naringin exhibited PLpro inhibitory activities, and the inhibition rates at 8 mumol/L were 53.5% and 46.1%, respectively. Prim-O-glucosylcimifugin showed significant inhibitory activities against 3CLpro and PLpro, and the inhibitory rates at 8 mumol/L were 76.8% and 78.2%, respectively. Molecular docking indicated that hydrogen bonds could be formed between prim-O-glucosylcimifugin and amino acid residues H163, E166, Q192, T190 of 3CLpro (binding energy, -7.7 kcal/mol) and K157, D164, R166, E167, T301 of PLpro(-7.3 kcal/mol), respectively. Site-directed mutagenesis indicated amino acid residue K157 was a key active site for the interaction between prim-O-glucosylcimifugin and PLpro. CONCLUSION(S): Prim-O-glucosylcimifugin, neohesperidin, and naringin as the major compounds from Jingfang Granules could inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus proteases 3CLpro and PLpro. The results are valuable for rational clinical use of Jingfang Granules.

Angiotensin-converting enzyme 2 (ACE2) in COVID-19 and other diseases.

The coronavirus SARS-CoV-2 was detected in isolates of pneumonia patients in January 2020. The virus cannot multiply extracellularly but requires access to the cells of a host organism. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, to which it docks with its spikes. ACE2 belongs to the renin angiotensin system (RAS), whose inhibitors have been used for years against high blood pressure. Renin is an endopeptidase that is predominantly formed in the juxtaglomerular apparatus of the kidney and cleaves the decapeptide angiotensin I (Ang I) from angiotensinogen. Through the angiotensin-converting enzyme (ACE), another 2 C-terminal amino acids are removed from Ang I, so that finally the active octapeptide angiotensin II (Ang II) is formed. The biological effect of Ang II via the angiotensin II receptor subtype 1 (AT1-R) consists of vasoconstriction, fibrosis, proliferation, inflammation, and thrombosis formation. ACE2 is a peptidase that is a homolog of ACE. ACE2 is predominantly expressed by pulmonary alveolar epithelial cells in humans and has been detected in arterial and venous endothelial cells. In contrast to the dicarboxy-peptidase ACE, ACE2 is a monocarboxypeptidase that cleaves only one amino acid from the C-terminal end of the peptides. ACE2 can hydrolyze the nonapeptide Ang-(1-9) from the decapeptide Ang I and the heptapeptide Ang-(1-7) from the octapeptide Ang II. Ang-(1-7) acts predominantly antagonistically (vasodilatory, anti-fibrotic, anti-proliferative, anti-inflammatory, anti-thrombogenetically) via the G protein-coupled Mas receptor to the AT1-R-mediated effects of Ang II. In the pathogenesis of COVID-19 infection, it is therefore assumed that there is an imbalance due to overstimulation of the AT1 receptor in conjunction with a weakening of the biological effects of the Mas receptor.Copyright © 2022 Dustri-Verlag Dr. K. Feistle.

Correlation between two methodologies for the measure- ment of antibodies against the spike protein of coronavi- rus of the Severe Acute Respiratory Syndrome 2

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has sev-eral structural proteins including the spike (S) protein, which is the main target of current vaccines. There are various methodologies for the mea-surement of antibodies against it that provide information about the im-mune response to vaccination. The objective of this study was to determine the correlation between chemiluminescence (CLIA) and enzyme-linked im-munoassay (ELISA) for the measurement of IgG anti-S protein (IgG anti-S) antibodies. Serological results were collected from 169 individuals and antibody levels were determined by both methodologies. Out of the total samples, 106 were positive by both methodologies and 15 were discordant (CLIA+, ELISA-), with a Kappa index of 0.80. The correlation between both methodologies was good. This study could contribute to the management and follow-up of the vaccinated population, in order to obtain a cut-off value to evaluate the appli-cation of an additional dose.

Inhibition of Spike Protein of SARS-CoV2 from (Merremia mammosa (Lour) Hall. F.) Bioactive Compounds: Molecular Docking and ADMET Study

Spike protein is a receptor protein that has e role in the entry step of SARS-CoV2. This protein will bind to the ACE2 receptor in the human body and activate TMPRSS2. Inhibition of this protein will prevent the binding of the virus to host cells to spread the infection. This study aims to identify the activity of bioactive compounds of Merremia mammosa (Lour) tuber obtained from LC-MS/MS QTOF analysis of a previous study against the Spike protein of SARS-CoV2 using molecular docking and ADMET analysis. Molecular docking was conducted using SARS-CoV2 spike protein (PDB id. 6M0J) using Maestro Schrodinger software. Results showed that from 206 compounds there are 8 compounds of Merremia mammosa (Lour) that have lower predictive binding energies than standard drugs arbidol, hydroxychloroquine, and chloroquine. Result(s): 206 compounds of Merremia mammosa (Lour) tuber were successfully docked, there were 8 compounds that have docking scores more negative than standard drugs. It indicates that 8 compounds are more active than the positive controls. ADMET study revealed all of those potential ligands had the possibility to be developed as drugs. Conclusion(s): Molecular docking simulations were successfully utilized to identify the potential compounds from Merremia mammosa (Lour) tuber with the activity as an inhibitor for spike protein of SARS-CoV2. Further in vitro assay and purification are needed for future research.Copyright © 2021 Muslim OT et al.

Transient Spike in Open Colon Resections During Covid-19 Pandemic

Introduction: Shortly after the onset of the COVID-19 pandemic, SARS-CoV-2 virus was discovered in non-respiratory bodily fluids. This raised the potential of aerosolizing virus with insufflation. The aim of this study was to compare trends in surgical approach and indication at the start of the pandemic. Method(s): A retrospective cohort study was performed using the National Surgical Quality Improvement (NSQIP) Participant Use File and Targeted Colectomy databases to identify patients undergoing colon resections in 2020. Cohorts were divided by quarter of operation (Q1-Q4). The minimally invasive cohort included all cases using an insufflation-based approach. Primary outcomes included planned open operation. Multivariate analysis was used to assess confounders and effect modification on open operation. Result(s): Univariate analysis found the percentage of open colonic resections was greater in Q2 of 2020 with a subsequent return to pre-pandemic levels (38% Q2 vs 32%, 34%, and 33% for Q1, Q3, Q4 respectively;p< 0.001). There was a concordant increase in emergent surgeries (20% in Q2 vs 15% Q1), but multivariate analysis revealed having operation in Q2 independently increased the odds of having open operation (OR 1.11, p=0.004). Serious complication rate was highest in Q2 (17% vs 14%, 16%, 16% for Q1, Q3, Q4;p <0.001). Conclusion(s): There was an increase in the percentage of open colon resections in Q2 of 2020. Multivariate analysis found having operation in Q2 independently increased the odds of an open operation. The increase in planned open operation was potentially related to concern for SARS-CoV-2 becoming aerosolized in minimally invasive cases.

COVID-19: AFTER TWO YEARS OF IATROGENIC AND BIOLOGIC IMMUNIZATION/ VACCINATION DO WE ACTUALLY NEED FURTHER BOOSTER IMMUNIZATION/ VACCINATION?

BackgroundThe Covid19 pandemic started in late 2019 and went through different phases by spreading from China around the whole globe. During the pandemic different mutation types got predominant from original Wuhan type through Alpha, Delta and Omicron variate BA 1/2 to BA 4/5 with different infectiousity and different potential to harm people´s health status. Immunization/ vaccination program started late 2020, first booster phase started midst of 2021, second booster phase in late 2021/ beginning of 2022 and Omicron specific booster phase midst of 2022.ObjectivesIs there a need of further iatrogenic (booster) immunization/ vaccination after 2 years of immunization/ vaccination program from efficacy driven analysis and safety issues standpoint?MethodsAnalysis of Covid-19 antibody development every three months since August 2021 with comparison of infection rates and assessment of safety parameters by assessing D-Dimers as potential endothelium damage marker in 725 patients (600 female, 125 male, age mean: 62,2 years) of a German rheumatological practice to improve the medical care.ResultsIn 99 % of the patients longstanding immune memory could be shown by analyzing the antibody curves in different exemplary shown biologic and iatrogenic immunization pathways after 2 years of immunization/ vaccination program and biologic immunization, mainly by Delta variate since late 2021 and Omicron variate since beginning of 2022. In 38.5 % of the patients the safety concerns of potential endothelium damage by analysing D-Dimers every 3 months showed a side effect potential of at least 8 months after every MRNA/ Vector immunization, but not after protein based vaccination and even not after infections in that amount.ConclusionOut of the obligation "nil nocere” no further iatrogenic Covid-19 immunization/ vaccination is of need in nearly all (99 %) already immunized people. At present only adult people with very low antibody levels (at least below 64 BAU/ml) (considering the infection or iatrogenic immunization/ vaccination status and time since last spike protein contact) and not yet immunized adult people should be forseen for iatrogenic immunization/ vaccination with protein based or attenuated viral vaccines or in rare cases one Omicron specific MRNA immunization drug. In that case D-Dimer controls for up to 8 months should be obligatory to detect endothelial damage side effect of MRNA (or Vector) technique. Intense cardiovascular monitoring (small vessels) of MRNA/ Vector immunized people in the next 10 – 20 years is necessary.Figure 1.References[1] Pohl C;SAFETY AND EFFICACY ASSESSMENT OF COVID-19 IMMUNIZATIONS/ VACCINATIONS IN PATIENTS OF A GERMAN GENERAL RHEUMATOLOGICAL PRACTICE;EULAR 2022 Poster POS1213;https://doi.org/10.1136/annrheumdis-2022-eular.1389[2] McConeghy KW et al. Effectiveness of a Second COVID-19 Vaccine Booster Dose Against Infection, Hospitalization, or Death Among Nursing Home Residents - 19 States, March 29-July 25, 2022. MMWR Morb Mortal Wkly Rep. 2022 Sep 30;71(39):1235-1238. doi: 10.15585/mmwr.mm7139a2. PMID: 36173757;PMCID: PMC9533729.[3] Bowe, B. Et al. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med 28, 2398–2405 (2022). https://doi.org/10.1038/s41591-022-02051-3[4] Hui-Lee Wong et al. Surveillance of COVID-19 vaccine safety among elderly persons aged 65 years and older, Vaccine, Volume 41, Issue 2, 2023, Pages 532-539, ISSN 0264-410X, https://doi.org/10.1016/j.vaccine.2022.11.069.[5] Maher AK et al. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19. Nat Commun. 2022 Dec 26;13(1):7947. doi: 10.1038/s41467-022-35638-y. PMID: 36572683;PMCID: PMC9791976.[6] Erich Freisleben;Sie wollten alles richtig machen – Dokumentation eines verschwiegenen Leidens – Bericht eines Hausarztes über die Nebenwirkungen der Corona Impfungen;Nov 11, 2022;Cajus Verlag[7] Positive Testrate Germany – https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Testzahl.htmlAcknowledgementsThanks to my fami y, all my patients and my collegues for supporting me in my research to improve my personal patient care.Disclosure of InterestsNone Declared.

The impact of deprivation on Respiratory Support Unit outcomes in COVID-19 patients, and highlights from wave 2 data in Portsmouth

Background: The second wave of the COVID-19 pandemic caused significant demand for beds capable of delivering enhanced respiratory support. NHS England recommended the use of CPAP for patients with COVID-19 respiratory failure, a treatment which can be offered outside of a critical care facility, and on a Respiratory High Care/ Support Unit (RSU). The enhancement of Portsmouth's RSU provided CPAP and NIV for patients with COVID-19 respiratory failure. With our intensive care facilities at 300% their normal capacity, this greatly alleviated bed pressures on critical care. Varied levels of deprivation exist in Portsmouth's dense population. Deprivation has an impact on overall health, however the effect of postcode on outcomes for people going onto support for COVID-19 respiratory failure, is unknown. Method(s): Retrospective cohort analysis of consecutive patients admitted to Respiratory Support Unit during the second wave of the COVID-19 pandemic, from 02/11/2020 to 31/01/2021. 227 patients were included in the study with 8 removed due to incomplete data, all of the patients received respiratory support in the form of CPAP or NIV. We collected multivariate data including biochemical markers, demographics, oxygenation status, co-morbidities and outcomes. Outcomes measured were: 1) Death in RSU, 2) Discharge from RSU or 3) Intubation and Ventilation. To measure deprivation, we linked a persons postcode to an area called an LSOA (Lower-layer Super Output Area). These are small areas of similar population size, each of which has a deprivation score (ie. top 10%, to the lowest 10% areas of deprivation in the UK). This is measured using an 'index of multiple deprivation'. An individual's outcome from the RSU was then analysed in relation to the deprivation score allocated to their postcode. Result(s): We observed a significant number of patients discharged from RSU, without needing invasive mechanical ventilation. 80/219 were discharged directly. 45/219 died in RSU, and 94 were eventually admitted to ITU. The average stay on CPAP or NIV before needing admission to ITU was 3 days. Some biochemical markers which stood out in relation to the outcomes described were as follows: average LDH, D-dimer and Troponin levels were higher in those who were admitted to intensive care. In patients who died, the PCT was significantly higher on average when compared to the other two groups. In the group who were discharged, mean lymphocyte count was >1, in the other two groups this was <1. From our observations in Portsmouth, there is a negative correlation between deprivation and lower aged individuals admitted for COVID-19 related respiratory support. Overall, we also saw disproportionate representation of those from the most deprived 50% of the UK in our respiratory support unit. Conclusion(s): CPAP and NIV can effectively be used in an RSU during a spike of COVID-19, to safely minimise demand on critical care services. Deprivation may have an impact on outcomes in patients needing respiratory support related to COVID-19. Deprivation levels may help predict risk of needing enhanced respiratory support in certain age groups. Multiple biochemical markers may be of prognostic value in COVID-19.

ACCELERATED WANING OF HUMORAL IMMUNE RESPONSE TO A THIRD COVID-19 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASES

BackgroundA 3rd COVID-19 vaccination is currently recommended for patients under immunosuppression. However, a fast decline of antibodies against the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein has been observed.ObjectivesIt remains unclear whether immunosuppressive therapy affects kinetics of humoral and cellular immune responses.Methods50 patients under immunosuppression and 42 healthy controls (HCs) received a 3rd dose of an mRNA-based vaccine and were monitored over a 12-weeks period. Humoral immune response was assessed 4 and 12 weeks after 3rd dose. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 Spike immunoassay against the receptor-binding domain (RBD) of the spike protein. SARS-CoV-2-specific T cell responses were quantified by IFN-γ ELISpot assays. Adverse events, including SARS-CoV-2 infections, were monitored over a 12-week period.ResultsAt week 12, reduced anti-RBD antibody levels were observed in IMID patients as compared to HCs (median antibody level 5345 BAU/ml [1781 – 10208] versus 9650 BAU/ml [6633 - 16050], p < 0.001). Reduction in relative antibody levels was significantly higher in IMID patients as compared to HCs at week 12 (p < 0.001). Lowest anti-RBD antibody levels were detected in IMID patients who received biological diseases modifying anti-rheumatic drugs (DMARDs) or a combination therapy with conventional synthetic and biological DMARDs. Number of SARS-CoV-2-specific T cells against wildtype and Omicron variants remained stable over 12 weeks in IMID patients. No serious adverse events were reported.ConclusionDue to a fast decline in anti-RBD antibodies in IMID patients an early 4th vaccination should be considered in this vulnerable group of patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsDaniel Mrak Consultant of: AstraZeneca, Felix Kartnig: None declared, Daniela Sieghart: None declared, Elisabeth Simader Speakers bureau: Lilly, Helga Radner Speakers bureau: Gilead, Merck Sharp and Pfizer, Peter Mandl: None declared, Lisa Göschl: None declared, Philipp Hofer: None declared, Thomas Deimel: None declared, Irina Gessl: None declared, Renate Kain Speakers bureau: Otsuka, Consultant of: AstraZeneca, Takeda Pharma, MEDahead and Janssen Cilag, Stefan Winkler: None declared, Josef S. Smolen Consultant of: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celltrion, Gilead-Galapagos, Janssen, Lilly, Pfizer, R-Pharma, Samsung, Sanofi, Chugai, Merck Sharp & Dohme, Novartis-Sandoz Roche, Samsung and UCB, Grant/research support from: Abbvie, AstraZeneca, Lilly, Novartis, and Roche, Thomas Perkmann: None declared, Helmuth Haslacher Grant/research support from: Glock Health, BlueSky Immunotherapies and Neutrolis, Daniel Aletaha Speakers bureau: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Consultant of: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Grant/research support from: Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Leonhard Heinz: None declared, Michael Bonelli Consultant of: EliLilly.

SARS-CoV-2 Variants Impact on Key Signaling Pathways Metamorphoses into Severity

The Severe Acute Respiratory Syndrome Coronavirus-2 causes a dreadful Coronavirus Disease namely COVID-19. Respiratory system is the primary target of the virus. It also impairs other major organs such as kidney, heart, liver, brain etc. Multiple novel variants of SARS-CoV-2 have appeared since the SARS-CoV-2 pandemic occurred which are linked to increased virulence, disease transmission and severity. The virus attacks the host signalling pathways to maintain a favourable environment for its spread. The present study focuses on the comprehensive analysis of major signaling pathways affected due to several variants of SARS-CoV-2 leading to abnormalities in cell growth and differentiation. The information was curated from the weblinks of several platforms like WHO, CDC, PANGO, Nextstrain clade and GISAID clade. The data on signaling pathways and comorbidities was generated by screening of different research and review articles. SARS-CoV-2 consolidates the cytoskeleton of the host for effective cell invasion and modulates the transcription processes to enable the translation of viral protein(s). These events lead to significant increase and prolonged hyper inflammation. Further, a decreased interferon (IFN) response along with increased interleukin production leading to cytokine storm is observed. Deregulation of interleukin pathways, TNF-alpha signalling through JAK/STAT-3 signalling, MAPK1, mTOR, PI3K are few other signalling pathways that are affected on SARS-CoV-2 infection. This review represents a comprehensive analysis of the vigorous life cycle of SARS CoV-2, its different variants affecting host signalling pathways which eventually cause dysfunctioning of several organs and development of comorbidities.

SARS-CoV-2 Vaccine Against Virus: Mission Accomplished!?

Since the beginning of the COVID-19 pandemic in late 2019, SARS-CoV-2 has started to optimize itself. After crossing the species barrier between bats and humans, it has developed mutations in the viral spike protein, in particular at positions 69/70, 452, 501, 614, and 681, that enhance binding to the ACE-2 receptor and entry into host cells, thereby promoting viral transmissibility and pathogenesis. Mutations at positions 417 and 484 have begun to undermine the effectiveness of convalescent plasma, monoclonal antibodies, and currently available vaccines. The targeted and convergent evolution of SARS-CoV-2, which occurred despite the proofreading activity of the exonuclease, has resulted so far in five variants of concern, which have replaced previous strains. This calls for a worldwide surveillance of viral evolution including animal transmission and the development of vaccines responding to escape variants and inducing mucosal immunity. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

MXene‐Based Aptameric Fluorosensor for Sensitive and Rapid Detection of COVID‐19

MXene‐Based Aptameric FluorosensorsThe aptamer‐functionalized MXene nanosheet acts as an effective bionanosensor for fluorescence‐enhanced detection of COVID‐19 with high sensitivity and specificity. This fluosensor is capable of detecting SARS‐CoV‐2 spike protein (limit of detection: 38.9 fg mL−1) and SARS‐CoV‐2 pseudovirus (limit of detection: 7.2 copies) within 30 min, and can also detect clinical samples. More details can be found in article number 2301146 by Binwu Ying and co‐workers.

Research on the 6XS6 of the SARS-CoV-2 Spike Protein

The 6XS6 is the structure of the SARS-CoV-2 spike protein. The physiological role of the spike protein is relative to the respiratory syndrome coronavirus and has a stronger infect on the human body than the ancestor virus. The purification of the 6XS6 is in the homo sapiens cell by the affinity chromatography, PBS supplemented and Size Exclusion chromatography. At last, using the Cryo-Electron Microscopy to see the structure. This paper is using the D614G mutation to illustrate the structure of the 6XS6. The N-terminal domain and C-terminal domain of the 6XS6 protein are ALA27 and VAL1137. Furthermore, the mutation doesn't have the hydrogen bond because the Asp614 is substituted by the Gly614, and the molecule that interacts with the Ala 647 may occur. While the 6XS6 structure has lots of non-covalent and disulfide bonds. Comparing the structure of the 6XS6 and 6VXX, both are glycoproteins, have three monomers, have two subunits, and have the same category of expression and classification. The different conformations of the two structures can affect the binding ability with the ACE2. This paper can help the researchers to further understand the structure and function of the 6XS6 which can be used in future experiments. © 2023 SPIE.

A phenoxy-bridged trinuclear Ni(ii) complex: synthesis, structural elucidation and molecular docking with viral proteins

A novel phenoxy-bridged trinuclear nickel(ii) complex [Ni3(mu-L)2(bipy)3](1) (where H3L= (E)-2-hydroxy-N-(2-hydroxy-3,5-diiodophenyl)-3,5-diiodobenzohydrazonic acid, bipy = 2,2'-bipyridyl) has been designed and synthesized as a potential antivirus drug candidate. The trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) was fully characterized via single crystal X-ray crystallography. The unique structure of the trinuclear nickel(ii) complex crystallized in a trigonal crystal system with P3221 space group and revealed distorted octahedral coordination geometry around each Ni(ii) ion. The X-ray diffraction analysis established the existence of a new kind of trinuclear metal system containing nickel(ii)-nickel(ii) interactions with an overall octahedral-like geometry about the nickel(ii) atoms. The non-bonded Ni-Ni distance seems to be 3.067 and 4.455 A from the nearest nickel atoms. The detailed structural analysis and non-covalent supramolecular interactions are also investigated by single crystal structure analysis and computational approaches. Hirshfeld surfaces (HSs) and 2D fingerprint plots (FPs) have been explored in the crystal structure to investigate the intermolecular interactions. The preliminary analysis of redox and magnetic characterization was conducted using cyclic voltammetry measurements and a vibrating sample magnetometer (VSM), respectively. This unique structure shows good inhibition performance for SARS-CoV-2, Omicron and HIV viruses. For insight into the potential application of the Ni(ii) coordination complex as an effective antivirus drug, we have examined the molecular docking of the trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) with the receptor binding domain (RBD) from SARS-CoV-2 (PDB ID: 7MZF), Omicron BA.3 variant spike (PDB ID: 7XIZ), and HIV protease (PDB ID: 7WCQ) viruses. This structure shows good inhibition performance for SARS-CoV-2, Omicron S protein and HIV protease viruses;the binding energies (DELTAG) and the respective Ki/Kd (inhibition/dissociation constants) correlation values are -8.9 (2.373 muM or 2373 nM), -8.1 (1.218 muM or 1218 nM) and -7.9 (0.874 muM or 874 nM), respectively. The results could be used for rational drug design against SARS-CoV-2 Omicron variant and HIV protease viruses.Copyright © 2023 The Royal Society of Chemistry.