Post-translational modifications: Host defence mechanism, pathogenic weapon, and emerged target of anti-infective drugs

Post-translational modifications are changes introduced to proteins after their translation. They are the means to generate molecular diversity, expand protein function, control catalytic activity and trigger quick responses to a wide range of stimuli. Moreover, they regulate numerous biological processes, including pathogen invasion and host defence mechanisms. It is well established that bacteria and viruses utilize post-translational modifications on their own or their host's proteins to advance their pathogenicity. Doing so, they evade immune responses, target signaling pathways and manipulate host cytoskeleton to achieve survival, replication and propagation. Many bacterial species secrete virulence factors into the host and mediate hostpathogen interactions by inducing post-translational modifications that subvert fundamental cellular processes. Viral pathogens also utilize post translational modifications in order to overcome the host defence mechanisms and hijack its cellular machinery for their replication and propagation. For example, many coronavirus proteins are modified to achieve host invasion, evasion of immune responses and utilization of the host translational machinery. PTMs are also considered potential targets for the development of novel therapeutics from natural products with antibiotic properties, like lasso peptides and lantibiotics. The last decade, significant progress was made in understanding the mechanisms that govern PTMs and mediate regulation of protein structure and function. This urges the identification of relevant molecular targets, the design of specific drugs and the discovery of PTM-based medicine. Therefore, PTMs emerge as a highly promising field for the investigation and discovery of new therapeutics for many infectious diseases.Copyright © 2021 Bentham Science Publishers.

Nanomedicine and Drug Delivery Systems: Roles, Advantages and Disadvantages

Nanotechnology is a new and rapidly evolving subject in the pharmacological and therapeutic professions. Nanoparticles have many advantages as medication delivery systems, including increased efficacy and fewer adverse drug reactions. This study investigated the roles of nanomedicine and drug delivery systems in the pharmaceutical industry, as well as the advantages and disadvantages of nanotechnology. The study used a qualitative research technique, with online survey questionnaires sent to medical professionals and experts in the field of nanomedicine. These surveys comprised open-ended questions that enabled respondents to record their responses in whatever way they deemed fit. The ten respondents were from a variety of medical and health institutes, as well as medical consulting firms. In terms of results, the research established that nanomedicine had been used in medical care for therapy and diagnostic purposes. They are being explored in clinical trials for several reasons. Nanoparticles are used to treat renal disease, Tuberculosis, skin problems, Alzheimer's disease, and various types of cancer and to create COVID-19 vaccines. Further information about the study findings may be found in the results and discussion chapter.Copyright © 2022 Dr. Yashwant Research Labs Pvt. Ltd.. All rights reserved.

In Silico Identification of Potential Inhibitors of SARS-CoV-2 Papain-like Protease From Natural Sources: A Natural Weapon to Fight COVID-19

Background: The rapid spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) globally has created unprecedented health care and economic crisis. The ever-in-creasing death toll highlights an urgent need for the development of specific antiviral to combat Novel Coronavirus Disease 2019 (COVID-19). Objective(s): In the present study, we aimed to identify potential SARS-CoV-2 papain-like protease inhibitors from regularly used spices. Method(s): A structure-based virtual screening (VS) of our in-house databank of 1152 compounds was employed to identify small molecule inhibitors of SARS-CoV-2 papain-like protease (PLpro), which are important protease for virus replication. The databank was built of the compounds from ten spices and two medicinal plants. Result(s): The top three potential hits that resulted from VS were myricetin (1) available in Alium cepa and Mentha piperita;alpha-hydroxyhydrocaffeic acid (2) available in M. Piperita;and luteolin (3) available in M. Piperita, Curcuma longa, A. cepa, and Trigonella foenum-graecum, which showed fair binding affinity to PLpro of SARS-CoV-2 compared to known SARS-CoV PLpro in-hibitors. The predicted Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the selected hits showed that all are drug-like. The compounds bind to biologically critical regions of the target protein, indicating their potential to inhibit the functionality of this component. Conclusion(s): There are only a few reports available in the literature on the in-silico identification of PLpro inhibitors and most of them used homology modeling of protein. Here, we used the recently uploaded X-ray crystal structure of PLpro (PDB ID: 6WX4) with a well-defined active site. Our computational approach has resulted in the identification of effective inhibitors of SARS-CoV-2PL-pro. The reported edible spices may be useful against COVID-19 as a home remedy after an in--vitro study.Copyright © 2021 Bentham Science Publishers.

Development of the Discussions on Lethal Autonomous Weapon Systems under Conventionon Certain Conventional Weapons

Since 2013 a debate on lethal autonomous weapon systems has come to the forefront under the Convention on Certain Conventional Weapons (CCW). These weapon systems are still under development, and individual states and non-state actors have different views on their potential deployment in the future, which had a decisive impact on proceedings of the CCW meetings. The aim of the study was to identify the key positive and negative outcomes of individual meetings, issues, on which parties have not yet reached a consensus, and to analyse the development of the CCW membership base in terms of involvement of governmental and non-governmental subjects, as well as the impact of the COVID-19 pandemic on the meetings. The study was conducted using a synthesis of data regarding individual CCW meetings of high contracting parties and other entities, which were basis for the qualitative analysis and comparison method. In conclusion, the author described the creation of a platform of experts for lethal autonomous weapon systems, eleven guiding principles and four approaches to defining these weapon systems as the most significant benefits of the CCW debates. In terms of COVID-19 pandemic, the negative impact was identified for developing countries. Based on the findings in the study the author does not expect creation of an international legislative act banning lethal autonomous weapon systems in the short- or medium-term period

Evaluation of biological and chemical weapons in the scope of the pandemic process and the measures to be taken

Biological attack or bioterrorism is one of the sides to cause disease or death in all living things by using biological causative agents of disease due to reasons such as political, ideological and economic. There were many biological attacks from the primitive ages when poisoned arrows were used to the use of anthrax spores in 2001 against USA. Although chemical attacks are not as deep-rooted as biological attacks, they have been used for a long time, but the period when they came to the stage of history was the 19th century with the development of the modern chemical industry. Chemical attacks caused injuries, permanent damage and death to many people especially during the period of World wars. The pandemic that can be caused by natural epidemic diseases is the spread of a factor or disease in a very wide area. With the spread of disease;panic, unrest and chaos environment occurs in the spreading area. Coronavirus (Covid-19), which causes the current pandemic, is the most recent example. Coronavirus out broke in Wuhan, China, and started to spread in China first, and then Iran, and had an impact on Italy as well as European continent and around the world with the American continent. It infected millions of people, hundreds of thousands of people died, and caused environmental, social, psychological and economic problems on a global scale. Recently, different pandemic processes related to influenza have been experienced, but states have not been able to demonstrate an effective and efficient defense against the new type of coronavirus since the necessary preparations were not made despite the death of millions of people. Since biological attack and natural epidemics have the same effects and characteristics, it is not possible to predict how the states will respond in a possible biological attack. As in the current pandemic process, the possible consequences that will arise when caught unprepared are doubtful. In this study, it is evaluated how biological agents and natural epidemics are similar to each other and how to take measures against a possible attack or a new disaster. © 2022,Turk Hijyen ve Deneysel Biyoloji Dergisi.All Rights Reserved.

Intelligent Trust-based Artificial Intelligence for Identification of COVID-19

AI has the potential to be a highly effective weapon in combating the COVID-19 virus. Since the outbreak began, many individuals have expressed a desire to employ AI, and they want it done as soon as possible. This article provides an early, and inevitably biased, look at how artificial intelligence may aid in the battle against COVID-19, as well as the existing limitations. AI might be effective in the battle against COVID-19 in a variety of ways, including early warnings and alarms, monitoring and prediction, data dashboards, diagnosis and prognosis, medicines and cures, and social control. AI might also be utilized in the following six ways: COVID-19 has yet to be affected by AI. Its use is constrained by both a scarcity of data and an abundance of data. To overcome these constraints, it will be necessary to strike a balance between data privacy and public health, as well as engage in extensive human-AI interaction. These issues will not be resolved in time for the present pandemic to be alleviated. Meanwhile, a large amount of data regarding who is infectious will need to be collected in order to save lives, train AI, and protect companies from losing money. Copyright © 2022, Anka Publishers. All rights reserved.

Review: mRNA delivery systems in vaccinations and COVID-19

mRNA vaccines open promising avenues for overcoming a variety of diseases due to their high therapeutic utilities, rapid growth capacities, and safe administration potentials. With the emergence of COVID-19, the use of mRNA vaccines has become even more widespread and far-reaching. However, for mRNA to be delivered to target cells and tissues, several obstacles must be overcome. For instance, naked mRNAs get easily and hastily degraded by ribonucleases in tissues and the bloodstream, and since mRNAs are large and polyanionic molecules, they cannot passively diffuse across cell membranes. Even though mRNAs are internalized by APCs, they must be able to reach the cytoplasm and escape endo-lysosomal traffic. Therefore, distinctive transport systems for efficient encapsulation of mRNAs using nanocarrier systems are required to ensure their delivery to cells’ cytoplasm. At this point, non-viral gene delivery systems such as polymers and lipids come to the fore, in which they can overcome the biological barriers and provide efficient delivery of mRNAs. Recently, mRNA vaccines have been used as a powerful weapon against COVID-19 pandemic which has affected the whole world since December 2019. This was clear by the emergence of Pfizer-BioNTech and Moderna vaccines, which offered mRNA vaccines with auspicious treatment abilities. A variety of carrying candidates have been utilized in such vaccines as polymers, metal nanoparticles, as well as LNPs, which each comes with its cons and pros in delivering mRNA. All of these mentioned points will be clarified and discussed in detail in this review paper.

mRNA-Lipid Nanoparticle COVID-19 Vaccines: Structure and Stability

A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures (2). Understanding the root cause of the instability of these vaccines may help to rationally improve mRNALNP product stability and thereby ease the temperature conditions for storage. In this presentation we discuss proposed structures of mRNALNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Analysis of mRNA-LNP structures reveals that mRNA, the ionizable cationic lipid and water are present in the LNP core. The neutral helper lipids are mainly positioned in the outer, encapsulating, wall. mRNA hydrolysis is an important driver for mRNA-LNP instability. It is currently a matter of debate whether water in the LNP core can freely interact with the mRNA and to what extent the degradation prone sites of mRNA are protected through a coat of ionizable cationic lipids. To improve the stability of mRNALNP vaccines, optimization of the mRNA nucleotide composition should be prioritized. Secondly, a better understanding of the milieu the mRNA is exposed to in the core of LNPs may help to rationalize adjustments to the LNP structure to preserve mRNA integrity. Moreover, drying techniques, such as lyophilization, are promising options still to be explored. As vaccines turn out to be the major weapon against the COVID-19 viral attack, the urge to develop more stable formulations is still growing and alternative, not-mRNA based products, may come to the forefront in situations where the (ultra) cold chain cannot be guaranteed. (Table Presented).

Bharat Electronics Ltd marches forward

Some of the major orders executed during the year included Long Range Surface to Air Missile;Akash Weapon System;Fire Control System;Integrated Air Command & Control System;Advanced Composite Communication System;Integrated Electronic Warfare Suite and Coastal Surveillance System. Some of the new products/systems introduced during the year included Laser Fence System, IR Jammer for Active Tank Protection System, Gimbal for Tethered UAV, Drainage Intrusion Detection System, Solid State Power Controller Cards for Akash NG / QRSAM, S-Band 150W Power Amplifier, GNSS Receiver, Managed Ethernet Switch -12 Port, IP EPABX System, Navigation Complex System, C BAND GaN PA & C BAND GaAs MMICs and Oxygen Concentrator 5LPM & 10 LPM and Dialysis Machines. Signifi cant among these orders included avionics package for LCA, Advanced Electronic Warfare (EW) suite for fighter aircraft, Instrumented Electronic Warfare Range (IEWR), CDR TI cum Day Light Sights for T-90 Tanks, Electronic Voting Machine & VVPAT, RWR & MAWS for C-295 aircraft, Gun Electronic Upgrade, Electronic Warfare Systems for Ships, Weapon Locating Radar and Integrated Observation Equipment.

Synthetic antiviral peptides: a new way to develop targeted antiviral drugs

The global concern over emerging and re-emerging viral infections has spurred the search for novel antiviral agents. Peptides with antiviral activity stand out, by overcoming limitations of the current drugs utilized, due to their biocompatibility, specificity and effectiveness. Synthetic peptides have been shown to be viable alternatives to natural peptides due to several difficulties of using of the latter in clinical trials. Various platforms have been utilized by researchers to predict the most effective peptide sequences against HIV, influenza, dengue, MERS and SARS. Synthetic peptides are already employed in the treatment of HIV infection. The novelty of this study is to discuss, for the first time, the potential of synthetic peptides as antiviral molecules. We conclude that synthetic peptides can act as new weapons against viral threats to humans.

Antibody Cocktail in Moderate to Severe COVID-19 Infection: A Series of 10 Cases

In the wake of the Coronavirus Disease 2019 (COVID-19) pandemic, scientists all over the world are in a relentless search for a cure. None of the therapies advised till date have shown significant benefit in treating COVID-19 infection. An antibody cocktail consisting of a combination of casirivimab and imdevimab is the newest weapon in the armamentarium against the disease. Currently, it has shown great promise in treating mild non hospitalized cases. The authors present the results of a series of 10 cases aged 18-70 years that demonstrate the efficacy of this cocktail in treating moderate to severe cases as well. All the patients received Roche's Antibody cocktail

COVID-19 CONVICTIONS? LEARNING THE BOUNDARIES OF PSYCHIATRY THROUGH A CASE STUDY

Background: The aggressive spread of COVID-19 and its heavy societal impacts have culminated in alternative explanations around government guidelines such as vaccination programmes and quarantine facilities. Some of these theories, especially those with paranoid themes, may raise concern for psychotic illness. This confers a unique challenge to mental health (MH) clinicians when presented with these beliefs. Objectives: We discuss a case study of a patient admitted to a MH unit in Western Australia who presented with a well-systematised belief system of a conspiratorial nature related to COVID-19 that contributed to weapon collection and preparing for 'doomsday'. We look at this case in relation to current literature to establish the difference between overvalued ideas vs mental illness in the context of COVID-19. Methods: Using the keywords 'COVID' and a combination of MH keywords, we searched for relevant articles on PubMed to help identify learning points in assessments of patients with themes of uncommon ideas surrounding COVID-19. Findings: The main themes suggest that conspiracy theories are common among the general population and some aspects of the belief have overlap with persecutory delusions. Important points to distinguish include the plausibility of the belief, the tendency to find like-minded individuals and the ability to contain those thoughts during appropriate events. Conclusion: As clinicians we have a duty to reduce unnecessary detainment and stress for those who have alternative theories but are not mentally unwell. Clinicians should be equipped with the ability to distinguish between overvalued ideas and mental illness to establish valid diagnoses and management.

Integrating Deep Learning-Based IoT and Fog Computing with Software-Defined Networking for Detecting Weapons in Video Surveillance Systems.

Due to the widespread proliferation of multimedia traffic resulting from Internet of Things (IoT) applications and the increased use of remote multimedia-based applications, as a consequence of COVID-19, there is an urgent need to develop intelligent adaptive techniques that improve the Quality of Service (QoS) perceived by end-users. In this work, we investigate the integration of deep learning techniques with Software-Defined Network (SDN) architecture to support delay-sensitive applications in IoT environments. Weapon detection in real-time video surveillance applications is deployed as our case study upon which multiple deep learning-based models are trained and evaluated for detection using precision, recall, and mean absolute precision. The deep learning model with the highest performance is then deployed within a proposed artificial intelligence model at the edge to extract the first detected video frames containing weapons for quick transmission to authorities, thus helping in the early detection and prevention of different kinds of crimes, and at the same time decreasing the bandwidth requirements by offloading the communication network from massive traffic transmission. Performance improvement is achieved in terms of delay, throughput, and bandwidth requirements by dynamically programming the network to provide different QoS based on the type of offered traffic and current traffic load, and based on the destination of the traffic. Performance evaluation of the proposed model was carried out using the mininet emulator, which revealed improvement of up to 75.0% in terms of average throughput, up to 14.7% in terms of mean jitter, and up to 32.5% in terms of packet loss.

Severe Neutropenia after Sarilumab Administration in Two COVID-19 Patients: Case Reports and Literature Review

BACKGROUND: Two years have passed since the WHO declared a pandemic state for SARS-CoV2 infection. COVID-19 pathogenesis consists of a first viral phase responsible for early symptoms followed by an inflammatory phase, which is cytokine-mediated, responsible for late-onset signs up to acute respiratory distress syndrome. Considering that interleukin (IL)6 plays a key role in the development and maintenance of inflammation, drugs targeting both IL6 and IL6 receptors have been evaluated. CASE REPORTS: The present study reports the cases of two hospitalized patients with severe respiratory COVID-19 treated with a single dose of intravenous sarilumab, a monoclonal anti-IL6 antibody, along with standard of care medications and high-flow oxygen therapy. Although a few days following sarilumab administration, clinical and biochemical conditions started ameliorating, these patients developed severe and self-limiting neutropenia. CONCLUSION: Sarilumab may represent a promising weapon to treat the fearsome hyperinflammatory phase;however, more trials are needed to decide whether to use it in combination with other drugs or alone, and to better understand pharmacokinetics and side effects.

News from BEL

Some of the major orders acquired during the year were Avionics Pack for Light Combat Aircraft (LCA), Advanced Electronic Warfare Suite for Fighter Aircraft, Instrumented Electronic Warfare Range (IEWR), Electronic Voting Machine (EVM) and Voter Verifiable Paper Audit Trail (VVPAT), Cdr TIT90 Tank, COMINT System, Radar Warning Receiver (RWR) and Missile Approach Warning System (MAWS) for C-295 Programme, Electronic Gun, IoT Gateway, etc. Some of the flagship projects executed during FY 2021-22 were Missile Systems (Air Defence Weapon System and LRSAM), Command and Control Systems, Communication and Encryption products, various Sonars, Electro-optic Systems, Fire Control Systems, Gun Upgrades, various Radars, Electronic Warfare Systems, Coastal Surveillance System, Un-manned Systems, Home Land Security Systems, Smart City projects, K-FON, Medical Electronics, etc. Major products exported included Coastal Surveillance System, Trans-Receive (TR) Modules, EO-IR Payload System, Compact Multi-Purpose Advanced Stabilization System (EOS CoMPASS), Solar Hybrid Power Plant, Data Link, Electro-Mechanical parts, Low Band Receivers (LBREC), Medical Electronics, Spares for Radars, etc.

Pneumomediastinum in ARDS (acute respiratory distress syndrome) caused by COVID-19 (coronavirus disease 2019): is protective lung ventilation really a weapon to our advantage?

Introduction: In mechanically ventilated patients suffering from ARDS as a consequence of COVID-19 interstitial pneumonia, we have often noted pneumomediastinum development despite the use of protective mechanical ventilation [1]. The purpose of this study is to determine whether the incidence of pneumomediastinum in patients with COVID-19 ARDS was higher than in ARDS patients without COVID-19 and whether this difference could be attributed to barotrauma or pulmonary fragility. Methods: We divided the patients into two groups: Group A (patients with ARDS from COVID-19), Group B (patients with ARDS from other causes). All patients were admitted to ICU (intensive care unit) and treated with protective mechanical ventilation-tidal volume 4-6 ml/ kg of IBW (ideal body weight), plateau pressure ≤ 28 cmH2O, driving pressure ≤ 12-14 cmH2O. Results: In group A, pneumomediastinum occurred in 8 of 59 patients(13.5%) while in group B in 1 of 59 (1.6%) (p < 0.001). Mortality was 58% in group A patients while 48% in group B patients (p = 0.32). In group A the mean of tidal volume used was 5.6 ± 0.7 ml/kg of IBW, the mean of plateau pressure 22 ± 5 cmH2O and driving pressure 11 ± 4 cmH2O. In group B the mean of tidal volume used was 5.9 ± 0.5 ml/kg of IBW, the mean of plateau pressure 23 ± 4 cmH2O and driving pressure 10 ± 3 cmH2O. Conclusions: The incidence of pneumomediastinum was approximately 8 times higher in the group of patients with COVID-19 ARDS despite the use of protective ventilation. This complication could be the consequence of greater lung fragility in patients with COVID-19 ARDS rather than in barotrauma which refers to elevated transpulmonary pressure.

Lessons learned from 2001-2021 - from the bioterrorism to the pandemic era.

INTRODUCTION AND OBJECTIVE: The aim of the study was to analyze available literature on the development of biological warfare and combating the SARS CoV-2 pandemic. Against the background of contemporary threats from biological factors, the strengths and weaknesses of response in the event of a bioterrorist attack during the ongoing COVID-19 pandemic have been identified. The scope and importance of international cooperation in the fight against the pandemic is assessed. REVIEW METHODS: The more important literature on bioterrorism, biological weapons and the COVID-19 pandemic, both from earlier work and recent publications, was analyzed, emphasizing new threats and adequate defence against them. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: The bio-warfare threat and the current COVID 19 pandemic that has hit mankind on a global scale has clearly shown how dangerous biological agents are and what effects they can cause, negatively affecting every sphere of human activity with catastrophic consequences. Data on examples of bioterrorist attacks carried out and research on the development of biological weapons and methods of combating pandemic COVID-19, were reviewed. New threats related to technological development,including those resulting from genetic manipulation, biosynthesis, and modern means of delivery, are pointed out. Attention has been paid to the implications of controlling the proliferation of biological weapons and the issues of international cooperation in the fight against bioterrorism and the COVD-19 pandemic. SUMMARY: The lesson learned clearly demonstrates the weakness of states in responding to such threats. The risks of uncontrolled scientific advances are still underestimated. Appropriate international control measures must be taken urgently to prepare for new pandemics, bioterrorist attacks, and the possibility of using modern biological weapons.

China's Strategic Objectives in a Post COVID-19 World

On 1 October 2019, the People's Republic of China (PRC) celebrated its 70th birthday, thus marking another important landmark of modern China under the leadership of the Chinese Communist Party (CCP). In commemorating the event, the Chinese government held a grand military parade with some 15,000 troops, more than 160 aircraft, and 580 active weapon systems during the event, including the latest generation nuclear missile systems such as the Dongfeng-41 mobile intercontinental ballistic missile. As the South China Morning Post reported, citing one insider, "the parade, which aims to showcase President Xi's achievement in military modernization and reforms in both hardware and software will carry a lot of political meaning." Given ongoing social protests in Hong Kong and problems in western societies at that time (such as Brexit talks in the UK and political opposition to President Trump in the United States) the contrast could not have been more stark: A powerful and prosperous China celebrates its international success while many western societies fail and flounder amidst their own domestic problems.