The Yield and Market Function Effects of the Reserve Bank of Australia's Bond Purchases*

We examine the effect on government bond yields of three policy measures by the Reserve Bank of Australia implemented following the onset of the COVID-19 pandemic. We also assess their impact on bond market functioning. The measures were purchases to support government bond market function over early 2020, the yield target on 3-year Australian government bonds, and the bond purchase programme to lower longer-term yields from late 2020 through early 2022. For purchases to support market function, we find that the announcement lowered short-dated Australian Government Securities (AGS) yields but did not lower longer-dated AGS yields. We also find that purchases led to lower yields as and when they were implemented and that they supported market function by lowering bid–offer spreads. For the yield target, we find a substantial announcement effect and moderate implementation effects on yields. Conversely, the yield target appears to have detrimentally affected some aspects of the bond market function. For the bond purchase programme, we find an announcement effect of approximately 30 basis points for longer-term AGS yields;however, any implementation effects were small and temporary. © 2023 Reserve Bank of Australia. Economic Record © 2023 Economic Society of Australia.

Vaccination with Span, an antigen guided by SARS-CoV-2 S protein evolution, protects against challenge with viral variants in mice

SARS-CoV-2 continues to accumulate mutations to evade immunity, leading to breakthrough infections after vaccination. How researchers can anticipate the evolutionary trajectory of the virus in advance in the design of next-generation vaccines requires investigation. Here, we performed a comprehensive study of 11,650,487 SARS-CoV-2 sequences, which revealed that the SARS-CoV-2 spike (S) protein evolved not randomly but into directional paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance. The viral infectivity and immune resistance of variants are generally incompatible, except for limited variants such as Beta and Kappa. The Omicron variant has the highest immune resistance but showed high infectivity in only one of the tested cell lines. To provide cross-clade immunity against variants that undergo diverse evolutionary pathways, we designed a new pan-vaccine antigen (Span). Span was designed by analyzing the homology of 2675 SARS-CoV-2 S protein sequences from the NCBI database before the Delta variant emerged. The refined Span protein harbors high-frequency residues at given positions that reflect cross-clade generality in sequence evolution. Compared with a prototype wild-type (Swt) vaccine, which, when administered to mice, induced serum with decreased neutralization activity against emerging variants, Span vaccination of mice elicited broad immunity to a wide range of variants, including those that emerged after our design. Moreover, vaccinating mice with a heterologous Span booster conferred complete protection against lethal infection with the Omicron variant. Our results highlight the importance and feasibility of a universal vaccine to fight against SARS-CoV-2 antigenic drift.

Neutrophil extracellular traps (NETs): The role of inflammation and coagulation in COVID-19

COVID-19 has swept quickly across the world with a worrisome death toll. SARS-CoV-2 infection induces cytokine storm, acute respiratory distress syndrome with progressive lung damage, multiple organ failure, and even death. In this review, we summarize the pathophysiologic mechanism of neutrophil extracellular traps (NETs) and hypoxia in three main phases, focused on lung inflammation and thrombosis. Furthermore, microparticle storm resulted from apoptotic blood cells are central contributors to the generation and propagation of thrombosis. We focus on microthrombi in the early stage and describe in detail combined antithrombotic with fibrinolytic therapies to suppress microthrombi evolving into clinical events of thrombosis. We further discuss pulmonary hypertension causing plasmin, fibrinogen and albumin, globulin extruding into alveolar lumens, which impedes gas exchange and induces severe hypoxia. Hypoxia in turn induces pulmonary hypertension, and amplifies ECs damage in this pathophysiologic process, which forms a positive feedback loop, aggravating disease progression. Understanding the mechanisms paves the way for current treatment of COVID-19 patients.

Polymer Composites Completely Derived from Waste: The Crystalline Structure and the Mechanical Enhancement Effect

During the recent COVID-19 pandemic, wearing face masks has become the simplest and most effective way to block the spread of the disease. However, after people wear masks, thousands of tons of medical waste caused by used disposable masks is being generated every day in the world, causing great pressure on the environment. Herein, polymer composites completely derived from waste are manufactured by simple melt blending of disposable mask fragments (mask polypropylene, short for mPP) and discarded loofah sponge (LS). LS was used as a reinforcing agent for the composites because of its unique micron channel structure. The crystalline structure and the mechanical enhancement effect of the composites were investigated. LS powders played a role in promoting the crystallization of mPP by expediting the crystalline nucleation, leading to an improvement in the amount of crystalline nuclei. After being incorporated within the mPP with high fluidity, the LS fiber changing from hollow to solid provides reinforcement for composite materials. With 12 wt % LS loading, the tensile strength of the composites was increased by 326%. The findings may open a way for high-value utilization of disposable masks. © 2021 American Chemical Society.

COVID-19 cases from the first local outbreak of SARS-CoV-2 B.1.1.7 variant in China presented more serious clinical features: a prospective, comparative cohort study (preprint)

Background: The SARS-CoV-2 B.1.1.7 variant which was first identified in the United Kingdom (U.K.) has increased sharply in numbers worldwide and was reported to be more contagious. On January 17, 2021, a COVID-19 clustered outbreak caused by B.1.1.7 variant occurred in a community in Daxing District, Beijing, China. Three weeks prior, another non-variant (lineage B.1.470) COVID-19 outbreak occurred in Shunyi District, Beijing. This study aimed to investigate the clinical features of B.1.1.7 variant infection. Methods: A prospective cohort study was conducted on COVID-19 cases admitted to Ditan hospital since January 2020. Data of 74 COVID-19 cases from two independent COVID-19 outbreaks in Beijing were extracted as study subjects from a Cloud Database established in Ditan hospital, which included 41 Shunyi cases (Shunyi B.1.470 group) and 33 Daxing cases (Daxing B.1.1.7 group) that have been hospitalized since December 25, 2020 and January 17, 2021, respectively. We conducted a comparison of the clinical characteristics, RT-qPCR results and genomic features between the two groups. Findings: Cases from Daxing B.1.1.7 group (15 [45.5%] male; median age, 39 years [range, 30.5, 62.5]) and cases from Shunyi B.1.470 group (25 [61.0%] male; median age, 31 years [range, 27.5, 41.0]) had a statistically significant difference in median age (P =0.014). Seven clinical indicators of Daxing B.1.1.7 group were significantly higher than Shunyi B.1.470 group including patients having fever over 38 (14/33 [46.43%] in Daxing B.1.1.7 group vs. 9/41 (21.95%) in Shunyi B.1.470 group [P = 0 .015]), C-reactive protein ([CRP, mg/L], 4.30 [2.45, 12.1] vs. 1.80, [0.85, 4.95], [P = 0.005]), Serum amyloid A ([SAA, mg/L], 21.50 [12.50, 50.70] vs. 12.00 [5.20, 26.95], [P = 0.003]), Creatine Kinase ([CK, U/L]), 110.50 [53.15,152.40] vs. 70.40 [54.35,103.05], [P = 0.040]), D-dimer ([DD, mg/L], 0.31 [0.20, 0.48] vs. 0.24 [0.17,0.31], [P = 0.038]), CD4+ T lymphocyte ([CD4+ T, mg/L], [P = 0.003]) , and Ground-glass opacity (GGO) in lung (15/33 [45.45%] vs. 5/41 [12.20%], [P =0.001]). After adjusting for the age factor, B.1.1.7 variant infection was the risk factor for CRP (P = 0.045, Odds ratio [OR] 2.791, CI [1.025, 0.8610]), SAA (0.011, 5.031, [1.459, 17.354]), CK (0.034, 4.34, [0.05, 0.91]), CD4+ T ( 0.029, 3.31, [1.13, 9.71]), and GGO (0.005, 5.418, [1.656, 17.729]) of patients. The median Ct value of RT-qPCR tests of the N-gene target in the Daxing B.1.1.7 group was significantly lower than the Shunyi B.1.470 group (P=0.036). The phylogenetic analysis showed that only 2 amino acid mutations in spike protein were detected in B.1.470 strains while B.1.1.7 strains had 3 deletions and 7 mutations. Interpretation: Clinical features including a more serious inflammatory response, pneumonia and a possible higher viral load were detected in the cases infected with B.1.1.7 SARS-CoV-2 variant. It could therefore be inferred that the B.1.1.7 variant may have increased pathogenicity.

Novel approaches for producing purified active recombinant human proteases, and the inability of dipeptidyl peptidase-4 to bind SARS-CoV-2 spike protein

Background and Aim: Proteases catalyze irreversible post-translational modifications that often alter biological function of the substrate. The protease dipeptidyl peptidase-4 (DPP-4) is a pharmacological target in type 2 diabetes and is abundant in liver. DPP-4 and its sister protease, fibroblast activation protein (FAP), are potential pharmacological targets in steatosis, insulin resistance, cancers, and inflammatory and fibrotic diseases. Recently, DPP-4 has been identified as a potential binding target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein.1,2 A detailed understanding of protein structure, function, and molecular interactions requires a reliable protocol for the large-scale production of highly stable and pure protein. We aimed to optimize production and purification strategies for soluble recombinant human DPP-4 and FAP from Spodoptera frugiperda 9 (Sf9) insect cells. Methods: The Bac-to-Bac Baculovirus Expression System (ThermoFisher) was used. Soluble DPP-4 (residues 29-766) was purified by a four-step procedure: differential ammonium sulfate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in tandem with immobilized metal affinity chromatography, and ion exchange chromatography. Soluble FAP (residues 27-760) was expressed similarly, except for adding a gp67 secretion signal, and then purified similarly. The binding affinities of DPP-4 to the SARS-CoV-2 full-length spike protein and its receptor binding domain were measured using surface plasmon resonance. Results: This optimized DPP-4 purification procedure yielded, on average, 1.36 mg of pure fully active soluble DPP-4 protein per liter of suspension insect cell culture with specific activity 36.4 U/mg. DPP-4 activity greater than 20 U/mg indicates that the enzyme is completely pure. No specific binding between DPP-4 and CoV-2 protein was detected. For FAP, a novel baculovirus expression construct was designed and used to generate abundant active soluble recombinant human FAP expression in Sf9 insect cells for protein purification. Unexpectedly, FAP and DPP-4 behaved differently in hydrophobic interaction chromatography. Nevertheless, soluble FAP was partially purified using a similar purification protocol to DPP-4. Compared with our previous work,3 the DPP-4 now has greater yield and purity, and the FAP has greater yield. Conclusion: A procedure for high-yield DPP-4 that is purified to homogeneity was achieved and used to show that, unlike in Middle East respiratory syndrome (MERS), SARS-CoV-2 does not bind DPP-4. A better understanding of FAP behavior in liquid chromatography was obtained and will be useful for developing an optimized purification strategy.

Advances in immunotherapy for COVID-19

COVID-19 caused by 2019-nCoV has posed a great threat to global public health. The immune system is essential for 2019-nCoV control and clearance, but excessive immune responses could result in inflammatory lung injury and other organ damages. Moreover, therapies against the abnormal immune responses to COVID-19 are controversial and of concern. This review summarized and analyzed the abnormal immune responses to 2019-nCoV infection and the potential immunotherapy, aiming to better understand the role of immunoregulation in COVID-19 and provide ideas for future research on COVID-19 immunotherapy.