Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

From the Bretton Woods system to the global non-system: The trials and tribulations of slow learning

In this paper we analyse why an understanding of the global ‘non-system', in which we now live, took so long to arrive after the Bretton Woods system collapsed in 1971. We first describe how knowledge of how an inflation-targeting regime would operate—what we call ‘Taylor-rule macroeconomics'—was only gradually created during the 1970s, 1980s, and 1990s. We then describe how, subsequent to this, an awareness emerged, also gradually, of how the international non-system might work, depending, as it does, on Taylor-rule macroeconomics being already in place. We then discuss the Great Moderation, making clear that a well-functioning global non-system would require not just inflation targeting and floating exchange rates in each country, but also adequate fiscal discipline, and a satisfactory form of financial regulation. We describe how a well-functioning version of this global non-system would actually fit together. We then discuss how this non-system has responded to two enormous challenges of the last 15 years, namely the Global Financial Crisis and the Covid pandemic. This discussion of what has happened in the recent past provides the background to a discussion, in the companion paper by Subacchi and Vines in this issue of the Oxford Review of Economic Policy, of the challenges that the global non-system will face in the future. © The Author(s) 2023. Published by Oxford University Press.

Drug discovery for coronavirus disease 2019 based on text mining and biomedical databases.

Objective Based on text mining technology and biomedical database, data mining and analysis of coronavirus disease 2019 (COVID-19) were carried out, and COVID-19 and its main symptoms related to fever, cough and respiratory disorders were explored. Methods The common targets of COVID-19 and its main symptoms cough, fever and respiratory disorder were obtained by GenCLiP 3 website, Gene ontology in metascape database (GO) and pathway enrichment analysis, then STRING database and Cytoscape software were used to construct the protein interaction network of common targets, the core genes were screened and obtained. DGIdb database and Symmap database were used to predict the therapeutic drugs of traditional Chinese and Western medicine for the core genes. Results A total of 28 gene targets of COVID-19 and its main symptoms were obtained, including 16 core genes such as IL2, IL1B and CCL2. Through the screening of DGIdb database, 28 chemicals interacting with 16 key targets were obtained, including thalidomide, leflunomide and cyclosporine et al. And 70 kinds of Chinese meteria medica including Polygonum cuspidatum, Astragalus membranaceus and aloe. Conclusion The pathological mechanism of COVID-19 and its main symptoms may be related to 28 common genes such as CD4, KNG1 and VEGFA, which may participate in the pathological process of COVID-19 by mediating TNF, IL-17 and other signal pathways. Potentially effective drugs may play a role in the treatment of COVID-19 through action related target pathway.Copyright © 2022 Tianjin Press of Chinese Herbal Medicines. All Rights Reserved.

Broad-Spectrum Antivirals Derived from Natural Products.

Scientific advances have led to the development and production of numerous vaccines and antiviral drugs, but viruses, including re-emerging and emerging viruses, such as SARS-CoV-2, remain a major threat to human health. Many antiviral agents are rarely used in clinical treatment, however, because of their inefficacy and resistance. The toxicity of natural products may be lower, and some natural products have multiple targets, which means less resistance. Therefore, natural products may be an effective means to solve virus infection in the future. New techniques and ideas are currently being developed for the design and screening of antiviral drugs thanks to recent revelations about virus replication mechanisms and the advancement of molecular docking technology. This review will summarize recently discovered antiviral drugs, mechanisms of action, and screening and design strategies for novel antiviral agents.

Discussion of "The Asymmetric Impact of COVID-19: A Novel Approach to Quantifying Financial Distress across Industries".

The COVID-19 pandemic crisis and the associated lockdown measures have exerted significantly adverse effects on corporate sectors globally. Archanskaia et al. (2023) provide a novel empirical strategy to timely assess corporate financial distress in the EU. The contribution is two-fold. First, this paper's notion of financial distress considers both the equity position and corporate indebtedness. Second, the methodology proposed in this paper allows the authors to estimate corporate financial distress in the EU at a highly granular level and link micro-level simulations to sectoral macroeconomic outcomes. The methodology employed by Archanskaia et al. (2023) consists of three steps. First, the authors apply a nowcasting model to acquire monthly industrial turnover data. Second, they feed the obtained monthly industrial turnover into a profit-generating process via an accounting identity to estimate monthly firm profits at the firm level. Third, the authors use the estimated firm profits with a snapshot of information on pre-existing liquid assets to deduce the firm-level liquidity needs and the depletion of equity through the focus period during COVID-19. These estimated results on firm equity position and indebtedness enable the authors to quantity corporate financial distress in the EU via various angles (e.g., country-level heterogeneity, industry heterogeneity, and the targeting of COVID support policies). The primary advantage of this approach is that it deals with large datasets at the granular level and produces firm-level results almost in real-time. Therefore, it can help policymaking track the effects of crises over time. However, one can quickly critique this three-step approach for its susceptibility to the usual Lucas critique. That said, since the objective here is to estimate firm-level financial distress, a large structural model being more or less aggregate in nature, though able to mitigate the Lucas critique concern, will encounter significant challenges in estimating firm-level results with the requisite level of granularity offered by the available data. Therefore, I broadly concur with the authors' position that 'the specific contribution of this paper consists in striking a better balance between the need to carry out a multi-country evaluation of the pandemic's effects on industrial activity in a strongly integrated region like the EU and the difficulty of capturing time, industry, and country variation in turnover with sufficient granularity.'

Development of PCR diagnostic method for Trichomonas foetus infection based on 18S rRNA.

To establish a PCR detection method for Trichomonas foetus, the primers were designed and synthesized according to the 18S rRNA gene sequence of T. foetus published by GenBank. The positive recombinant plasmid pUCm-T-TF18S of T. foetus was used as the template, and the genomic DNA of Giardia felis, Coccidia +e-lis, feline parvovirus and cDNA of feline coronavirus were used as the control for PCR detection to analyze the specificity of this method. The positive T. foetus recombinant plasmid was serial to 8 different concentrations with a gap of 10 folds, and PCR was performed to analyze the sensitivity of this method. The pUCm-T-TF18S plasmids stored at -20 " for 3, 6, 9 and 12 months were detected by PCR to analyze the stability of the method. Twenty cat fecal samples were tested using this established PCR assay and compared with those of microscopic examination. The results showed that the recombinant plasmid pUCm-T- TF18S gave specific bands after PCR amplification. The sequencing results showed that the length of the product sequence was 1 264 bp, and the BLAST sequence comparison analysis showed 99.53% sequence identity, which is consistent with that of T. foetus from cats (GenBank registration number M81842.1). The PCR method for detection of T. foetus had no cross-reactivities with C. felis, G. felis, feline coronavirus and feline parvovirus;the minimum detectable template concentration is 4.52 X 105 copies/xl;The target band of T. foetus DNA can still be detected after being stored in the refrigerator at -20 " for 12 months. This method detected 16 positive samples of T. foetus nucleic acid from 20 cat fecal samples, which is more accurate and sensitive than the results from traditional microscopy (13 samples). It is suggested that the PCR method for the detection of T. foetus is highly specific, sensitive and stable, and can be used for clinical detection and epidemiological investigation of T. foetus.Copyright © 2022, National Institute of Parasitic Diseases. All rights reserved.

Shadow rates as a measure of the monetary policy stance: Some international evidence

This paper examines the usefulness of shadow rates to measure the monetary policy stance by comparing them to the official policy rates and those implied by three types of Taylor rules in both inflation-targeting countries (the UK, Canada, Australia and New Zealand) and others that have only targeted inflation at times (the United States, Japan, the Euro Area and Switzerland) over the period from the early 1990s to December 2021. Shadow rates estimated from a dynamic factor model are shown to suggest a much looser policy stance than either the official policy rates or those implied by the Taylor rules, and generally to provide a more accurate picture of the monetary policy stance during both ZLB and non-ZLB periods, since they reflect the full range of unconventional policy measures used by central banks. Furthermore, generalised impulse response analysis based on three alternative vector autoregression (VAR) models indicates that monetary shocks based on the shadow rates are more informative than those related to the official policy rates or to two- and three-factor shadow rates, especially during the Global Financial Crisis and the recent COVID-19 pandemic, when unconventional measures have been adopted. Finally, unconventional policy shocks seem to have less persistent effects on the economy in countries, which have adopted an inflation-targeting regime.

Identifying efficient policy mix under different targeting regimes: A tale of two crises

We examine the influence of demand shock, supply shock and the monetary policy shock on macroeconomic variables using the New Keynesian Dynamic Stochastic General Equilibrium framework. Our study tries to identify the efficient monetary policy mix as an antidote to the prevailing economic fragilities that originated due to the COVID-19 pandemic and geopolitical conflict in case of India and China. Under both simulated and Bayesian analysis, our findings revealed the inflationary effect of demand and supply shock with a target-oriented monetary policy under sticky prices as the efficient policy tool to counter these effects. The macroeconomic projections depicted the favourable influence of output due to active intervention of target-oriented monetary policy in both these economies.

Herbal medicines in the treatment of coronavirus disease 2019 (Covid-19)

Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus, started in livestock within the markets of Wuhan, China and was consequently spread around the world. The virus has been rapidly spread worldwide due to the outbreak. COVID-19 is the third serious coronavirus outbreak in less than 20 years after Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012. The novel virus has a nucleotide identity closer to that of the SARS coronavirus than that of the MERS coronavirus. Since there is still no vaccine, the main ways to improve personal immunity against this disease are prophylactic care and self-resistance including an increased personal hygiene, a healthy lifestyle, an adequate nutritional intake, a sufficient rest, and wearing medical masks and increasing time spent in well ventilated areas. There is a need for novel antivirals that are highly efficient and economical for the management and control of viral infections when vaccines and standard therapies are absent. Herbal medicines and purified natural products have the potential to offer some measure of resistance as the development of novel antiviral drugs continues. In this review, we evaluated 41 articles related to herbal products which seemed to be effective in the prevention or treatment of COVID-19.Copyright © 2021 The Author(s).

SARS-CoV-2: Immunity, Challenges with Current Vaccines, and a Novel Perspective on Mucosal Vaccines.

The global rollout of COVID-19 vaccines has played a critical role in reducing pandemic spread, disease severity, hospitalizations, and deaths. However, the first-generation vaccines failed to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and transmission, partially due to the limited induction of mucosal immunity, leading to the continuous emergence of variants of concern (VOC) and breakthrough infections. To meet the challenges from VOC, limited durability, and lack of mucosal immune response of first-generation vaccines, novel approaches are being investigated. Herein, we have discussed the current knowledge pertaining to natural and vaccine-induced immunity, and the role of the mucosal immune response in controlling SARS-CoV2 infection. We have also presented the current status of the novel approaches aimed at eliciting both mucosal and systemic immunity. Finally, we have presented a novel adjuvant-free approach to elicit effective mucosal immunity against SARS-CoV-2, which lacks the safety concerns associated with live-attenuated vaccine platforms.

Pathological angiogenesis: mechanisms and therapeutic strategies.

In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

Chemistry towards Biology-Instruct: Snapshot.

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.

The distributive politics of social assistance targeting: Evidence from COVID-19 relief in Colombia

How do governments target social assistance? This article proposes a new typology of targeting that goes beyond the dominant focus on top-down technical solutions to highlight the important role of informal practices and non-state actors. Using evidence about the ways local governments in Colombia delivered relief during COVID-19, the typology identifies and illustrates four ideal types of targeting processes resulting from the intersection between programmatic (or not) eligibility criteria and the role of non-state actors. The article thus expands the politics of social policy research agenda to the question of targeting, a crucial aspect of policy implementation, in dialogue with scholarship on distributive politics. © 2023 John Wiley & Sons Ltd.

Phytomedicines for Covid-19: Opportunities and Obstacles

COVID-19 is a disease caused by SARS-CoV-2 that can trigger respiratory tract infection. Due to its tendency to affect the upper respiratory tract (sinuses, nose and throat) or lower respiratory tract (windpipe and lungs), this disease is life-threatening and affects a large number of populations. This virus's unique and complex nature enhances the scope to look into the direction of herbal plants and their constituents for its prevention and treatment. The herbal remedies can have preventive as well as therapeutic actions. This review focuses on various aspects of using herbal medicines for COVID-19, as herbal constituents may also have adverse effects. Various studies revealed that some medicinal plants show life-threatening adverse effects, so selecting plants, and their related studies should be appropriate and strategic. This article includes various factors that should be considered before herbal drug use in COVID-19 patients. These are clinical trials, safety, molecular mechanism, and self-medication, which have been elaborated. This article also discusses the targets of covid-19 and different coronavirus strains. As before, treatment diagnosis of the disease is very important. Various patents have been filed and granted for its proper diagnosis so that its treatment can be easy.Copyright © 2022 Society of Pharmaceutical Sciences and Research. All rights reserved.

Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: Molecular evidence and mechanisms

Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021

Progress on development of vaccines against 2019-nCoV.

Since the outbreak of COVID-19 caused by the 2019-nCoV (SARS-CoV-2), with its high pathogenicity and contagiousness, it has posed a serious threat to global public health security. Up to now, the pathogenesis of 2019-nCoV is unclear, and there is no effective treatment. Vaccine as one of the most effective strategies to prevent virus infection has become a hot area. Based on the current understanding of 2019-nCoV, the development of 2019-nCoV vaccines covers all types: inactivated virus vaccine, recombinant protein vaccine, viral vector-based vaccine, mRNA vaccine, and DNA vaccine, etc. In this review, we focus on the candidate targets of the novel coronavirus, and the types, development status and progress of 2019-nCoV vaccines in order to provide information for further research and prevention.Copyright © 2021 Chinese Medical Association

Pyrrole-Imidazole Polyamides - A Frontrunner in Nucleic Acid-Based Small Molecule Drugs

The remarkable success of messenger RNA vaccines against the ongoing coronavirus-2019 (COVID-19) pandemic renews attention toward nucleic acid therapeutics. While nucleic acid therapy using unmodified DNA or RNA is the primary focus in disease treatment, there is growing need to develop nucleic acid-based small molecules owing to their potential clinical benefits as drugs in terms of cost and scalability. While small molecules targeting protein-protein interactions are known to alter the transcriptional status of a cell, they can result in a transient effect and variation of bio-efficacy among patients. Small molecules targeting DNA and/or RNA are in demand in the precision medicine approach as they have consistent bioactivity among patients. This review details the progress of sequence-specific DNA-binding pyrrole-imidazole polyamides (PIPs) in modulating the transcriptional status of target gene(s) without altering the underlying DNA sequence. Here, the different versions of PIPs are listed, and also, how conjugating them with DNA alkylating agents, epigenetic modulators, and other drugs can improve their clinical utility as targeted transcription therapeutics. Owing to their specificity, functional diversity, and limited toxicity, PIP technology holds enormous promise as frontrunner in small-molecule-based nucleic acid drugs to precisely regulate therapeutically important genes on demand and treat intractable diseases.Copyright © 2023 Wiley-VCH GmbH.

Molecular Docking Strategy for Multi-Target Inhibitor Discovery of Selected Plant Constituents in Bauhinia Acuminata

Objective: Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. This study aims to perform a molecular docking analysis of the thirteen plant components in Bauhinia acuminata against the target proteins in lung cancer (PDB IDs: 2ITY), breast cancer (1A52), diabetes (3L4U), obesity (IT02), inflammation (5COX) and corona viral infections (6VYO). Material(s) and Method(s): All the plant components used for the present study were retrieved from the plant Bauhinia acuminata and were evaluated for their biological activity results using molinspiration. Further in-silico docking analysis was performed using AutoDock Vina software and the binding interactions were visualized using Discovery studio program. Result and Discussion: The docking scores and analysis of the interactions of the plant components with targets suggest that all the selected plant components showed excellent binding to the chosen targets when compared to that of the standard drugs. As a result of the docking process on 6 different targets, the selected plant components like Quercetin, Beta-sitosterol, and Rheagenine were observed to show good binding energy values against all the 5 targets except 6VYO as shown in (Table 9). These results can further pave the way for getting better insights in identifying and designing potential lead candidates.Copyright © 2022 University of Ankara. All rights reserved.

Therapeutic mechanisms and impact of traditional Chinese medicine on COVID-19 and other influenza diseases

Coronavirus disease 2019 (COVID-19), first reported in Wuhan, China, has rapidly spread worldwide. Traditional Chinese medicine (TCM) has been used to prevent and treat viral epidemics and plagues for over 2,500 years. In the guidelines on fighting against COVID-19, the National Health Commission of the People's Republic of China has recommended certain TCM formulas, namely Jinhua Qinggan granule (JHQGG), Lianhua Qingwen granule (LHQWG), Qingfei Paidu decoction (QFPDD), Xuanfei Baidu granule (XFBD), Xuebijing injection (XBJ), and Huashi Baidu granule (HSBD) for treating COVID-19 infected individuals. Among these six TCM formulas, JHQGG and LHQWG effectively treated mild/moderate and severe COVID-19 infections. XFBD therapy is recommended for mild COVID-19 infections, while XBJ and HSBD effectively treat severe COVID-19 infections. The internationalization of TCM faces many challenges due to the absence of a clinical efficacy evaluation system, insufficient research evidence, and a lack of customer trust across the globe. Therefore, evidence-based research is crucial in battling this infectious disease. This review summarizes SARS-CoV-2 pathogenesis and the history of TCM used to treat various viral epidemics, with a focus on six TCM formulas. Based on the evidence, we also discuss the composition of various TCM formulas, their underlying therapeutic mechanisms, and their role in curing COVID-19 infections. In addition, we evaluated the roles of six TCM formulas in the treatment and prevention of other influenza diseases, such as influenza A (H1N1), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Furthermore, we highlighted the efficacy and side effects of single prescriptions used in TCM formulas.Copyright © 2021