bluuebunny/crossref_metadata_2025 huggingface dataset:
Adsorbents Reduce Aflatoxin M1 Residue in Milk of Healthy Dairy Cow Exposed to Moderate Level Aflatoxin B1 in Diet and Its Exposure Risk for Humans
Authors: Cha Manqian , Wang Erdan , Hao Yangyi , Ji Shoukun , Huang Shuai , Zhao Lihong , Wang Wei , Shao Wei , Wang Yajing , Li Shengli
Published: September 2021

This study investigated the effect of moderate risk level (8 µg/kg) AFB1 in diet supplemented with or without adsorbents on lactation performance, serum parameters, milk AFM1 content of healthy lactating cows and the AFM1 residue exposure risk in different human age groups. Forty late healthy lactating Holstein cows (270 ± 22 d in milk; daily milk yield 21 ± 3.1 kg/d) were randomly assigned to four treatments: control diet without AFB1 and adsorbents (CON), CON with 8 μg/kg AFB1 (dry matter basis, AF), AF + 15 g/d adsorbent 1 (AD1), AF + 15 g/d adsorbent 2 (AD2). The experiment lasted for 19 days, including an AFB1-challenge phase (day 1 to 14) and an AFB1-withdraw phase (day 15 to 19). Results showed that both AFB1 and adsorbents treatments had no significant effects on the DMI, milk yield, 3.5% FCM yield, milk components and serum parameters. Compared with the AF, AD1 and AD2 had significantly lower milk AFM1 concentrations (93 ng/L vs. 46 ng/L vs. 51 ng/L) and transfer rates of dietary AFB1 into milk AFM1 (1.16% vs. 0.57% vs. 0.63%) (p < 0.05). Children aged 2–4 years old had the highest exposure risk to AFM1 in milk in AF, with an EDI of 1.02 ng/kg bw/day and a HI of 5.11 (HI > 1 indicates a potential risk for liver cancer). Both AD1 and AD2 had obviously reductions in EDI and HI for all population groups, whereas, the EDI (≥0.25 ng/kg bw/day) and HI (≥1.23) of children aged 2–11 years old were still higher than the suggested tolerable daily intake (TDI) of 0.20 ng/kg bw/day and 1.00 (HI). In conclusion, moderate risk level AFB1 in the diet of healthy lactating cows could cause a public health hazard and adding adsorbents in the dairy diet is an effective measure to remit AFM1 residue in milk and its exposure risk for humans.
Neutralizing Concentrations of Anti-Botulinum Toxin Antibodies Positively Correlate with Mouse Neutralization Assay Results in a Guinea Pig Model
Authors: Tomic Milan T. , Farr-Jones Shauna , Syar Emily S. , Niemuth Nancy , Kobs Dean , Hackett Michael J. , Espinoza Yero , Martinez Zacchary , Pham Khanh , Snow Doris M. , Marks James D. , Cobb Ronald R.
Published: September 2021

Botulinum neurotoxins (BoNT) are some of the most toxic proteins known and can induce respiratory failure requiring long-term intensive care. Treatment of botulism includes the administration of antitoxins. Monoclonal antibodies (mAbs) hold considerable promise as BoNT therapeutics and prophylactics, due to their potency and safety. A three-mAb combination has been developed that specifically neutralizes BoNT serotype A (BoNT/A), and a separate three mAb combination has been developed that specifically neutralizes BoNT serotype B (BoNT/B). A six mAb cocktail, designated G03-52-01, has been developed that combines the anti-BoNT/A and anti-BoNT/B mAbs. The pharmacokinetics and neutralizing antibody concentration (NAC) of G03-52-01 has been determined in guinea pigs, and these parameters were correlated with protection against an inhalation challenge of BoNT/A1 or BoNT/B1. Previously, it was shown that each antibody demonstrated a dose-dependent mAb serum concentration and reached maximum circulating concentrations within 48 h after intramuscular (IM) or intraperitoneal (IP) injection and that a single IM injection of G03-52-01 administered 48 h pre-exposure protected guinea pigs against an inhalation challenge of up to 93 LD50s of BoNT/A1 and 116 LD50s of BoNT/B1. The data presented here advance our understanding of the relationship of the neutralizing NAC to the measured circulating antibody concentration and provide additional support that a single IM or intravenous (IV) administration of G03-52-01 will provide pre-exposure prophylaxis against botulism from an aerosol exposure of BoNT/A and BoNT/B.
Impact of Phytochemicals on Viability and Cereulide Toxin Synthesis in Bacillus cereus Revealed by a Novel High-Throughput Method, Coupling an AlamarBlue-Based Assay with UPLC-MS/MS
Authors: Kranzler Markus , Frenzel Elrike , Walser Veronika , Hofmann Thomas F. , Stark Timo D. , Ehling-Schulz Monika
Published: September 2021

Due to its food-poisoning potential, Bacillus cereus has attracted the attention of the food industry. The cereulide-toxin-producing subgroup is of particular concern, as cereulide toxin is implicated in broadscale food-borne outbreaks and occasionally causes fatalities. The health risks associated with long-term cereulide exposure at low doses remain largely unexplored. Natural substances, such as plant-based secondary metabolites, are widely known for their effective antibacterial potential, which makes them promising as ingredients in food and also as a surrogate for antibiotics. In this work, we tested a range of structurally related phytochemicals, including benzene derivatives, monoterpenes, hydroxycinnamic acid derivatives and vitamins, for their inhibitory effects on the growth of B. cereus and the production of cereulide toxin. For this purpose, we developed a high-throughput, small-scale method which allowed us to analyze B. cereus survival and cereulide production simultaneously in one workflow by coupling an AlamarBlue-based viability assay with ultraperformance liquid chromatography–mass spectrometry (UPLC-MS/MS). This combinatory method allowed us to identify not only phytochemicals with high antibacterial potential, but also ones specifically eradicating cereulide biosynthesis already at very low concentrations, such as gingerol and curcumin.
Persufflation—Current State of Play
Authors: Buhagiar Aaron John , Freitas Leo , Scott William E.
Published: September 2021

With the ever-increasing disparity between the number of patients waiting for organ transplants and the number organs available, some patients are unable to receive life-saving transplantation in time. The present, widely-used form of preservation is proving to be incapable of maintaining organ quality during long periods of preservation and meeting the needs of an ever-changing legislative and transplantation landscape. This has led to the need for improved preservation techniques. One such technique that has been extensively researched is gaseous oxygen perfusion or Persufflation (PSF). This method discovered in the early 20th century has shown promise in providing both longer term preservation and organ reconditioning capabilities for multiple organs including the liver, kidneys, and pancreas. PSF utilises the organs own vascular network to provide oxygen to the organ tissue and maintain metabolism during preservation to avoid hypoxic damage. This review delves into the history of this technique, its multiple different approaches and uses, as well as in-depth discussion of work published in the past 15 years. Finally, we discuss exciting commercial developments which may help unlock the potential for this technique to be applied at scale.
Evolution of Public Health Prevention of Leptospirosis in a One Health Perspective: The Example of Mahasarakham Province (Thailand)
Authors: Viroj Jaruwan , Lajaunie Claire , Morand Serge
Published: September 2021

Leptospirosis is an endemic disease with moderate to high incidence in Mahasarakham province, Thailand. The present study was designed to assess the policy implementation mission regarding leptospirosis prevention and control from the national level to the local administrative levels, through a One Health perspective. A qualitative study was conducted, using documentation review, individual in-depth interviews with public health officers, local government officers, livestock officers who developed policy implementation tools or have responsibilities in leptospirosis prevention and control. The results show that Thailand has progressively developed a leptospirosis prevention and control policy framework at the national level, transferring the responsibility of its implementation to the local level. The province of Mahasarakham has decided to foster cooperation in leptospirosis prevention and control at the local level. However, there are insufficient linkages between provincial, district and sub-district departments to ensure comprehensive disease prevention activities at the local level concerning leptospirosis patients and the whole population.
Architecture of Hierarchical Stellar Systems and Their Formation
Authors: Tokovinin Andrei
Published: September 2021

Accumulation of new data on stellar hierarchical systems and the progress in numerical simulations of their formation open the door to genetic classification of these systems, where properties of a certain group (family) of objects are tentatively related to their formation mechanisms and early evolution. A short review of the structure and statistical trends of known stellar hierarchies is given. Like binaries, they can be formed by the disk and core fragmentation events happening sequentially or simultaneously and followed by the evolution of masses and orbits driven by continuing accretion of gas and dynamical interactions between stars. Several basic formation scenarios are proposed and associated qualitatively with the architecture of real systems, although quantitative predictions for these scenarios are still pending. The general trend of increasing orbit alignment with decreasing system size points to the critical role of the accretion-driven orbit migration, which also explains the typically comparable masses of stars belonging to the same system. The architecture of some hierarchies bears imprints of chaotic dynamical interactions. Characteristic features of each family are illustrated by several real systems.
Efficient Inhibition of HIV Using CRISPR/Cas13d Nuclease System
Authors: Nguyen Hoang , Wilson Hannah , Jayakumar Sahana , Kulkarni Viraj , Kulkarni Smita
Published: September 2021

Recently discovered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas13 proteins are programmable RNA-guided ribonucleases that target single-stranded RNA (ssRNA). CRISPR/Cas13-mediated RNA targeting has emerged as a powerful tool for detecting and eliminating RNA viruses. Here, we demonstrate the effectiveness of CRISPR/Cas13d to inhibit HIV-1 replication. We designed guide RNAs (gRNAs) targeting highly conserved regions of HIV-1. RfxCas13d (CasRx) in combination with HIV-specific gRNAs efficiently inhibited HIV-1 replication in cell line models. Furthermore, simultaneous targeting of four distinct, non-overlapping sites in the HIV-1 transcript resulted in robust inhibition of HIV-1 replication. We also show the effective HIV-1 inhibition in primary CD4+ T-cells and suppression of HIV-1 reactivated from latently infected cells using the CRISPR/Cas13d system. Our study demonstrates the utility of the CRISPR/Cas13d nuclease system to target acute and latent HIV infection and provides an alternative treatment modality against HIV.
The Pathobiology of H7N3 Low and High Pathogenicity Avian Influenza Viruses from the United States Outbreak in 2020 Differs between Turkeys and Chickens
Authors: Criado Miriã F. , Leyson Christina M. , Youk Sungsu , DeBlois Suzanne , Olivier Tim , Killian Mary Lea , Torchetti Mia L. , Parris Darren J. , Spackman Erica , Kapczynski Darrell R. , Suarez David L. , Swayne David E. , Pantin-Jackwood Mary J.
Published: September 2021

An outbreak caused by H7N3 low pathogenicity avian influenza virus (LPAIV) occurred in commercial turkey farms in the states of North Carolina (NC) and South Carolina (SC), United States in March of 2020. Subsequently, H7N3 high pathogenicity avian influenza virus (HPAIV) was detected on a turkey farm in SC. The infectivity, transmissibility, and pathogenicity of the H7N3 HPAIV and two LPAIV isolates, including one with a deletion in the neuraminidase (NA) protein stalk, were studied in turkeys and chickens. High infectivity [<2 log10 50% bird infectious dose (BID50)] and transmission to birds exposed by direct contact were observed with the HPAIV in turkeys. In contrast, the HPAIV dose to infect chickens was higher than for turkeys (3.7 log10 BID50), and no transmission was observed. Similarly, higher infectivity (<2–2.5 log10 BID50) and transmissibility were observed with the H7N3 LPAIVs in turkeys compared to chickens, which required higher virus doses to become infected (5.4–5.7 log10 BID50). The LPAIV with the NA stalk deletion was more infectious in turkeys but did not have enhanced infectivity in chickens. These results show clear differences in the pathobiology of AIVs in turkeys and chickens and corroborate the high susceptibility of turkeys to both LPAIV and HPAIV infections.
Advancing Our Understanding of Corneal Herpes Simplex Virus-1 Immune Evasion Mechanisms and Future Therapeutics
Authors: Greenan Emily , Gallagher Sophie , Khalil Rana , Murphy Conor C. , Ní Gabhann-Dromgoole Joan
Published: September 2021

Herpes stromal keratitis (HSK) is a disease that commonly affects the cornea and external eye and is caused by Herpes Simplex Virus type 1 (HSV-1). This virus infects approximately 66% of people worldwide; however, only a small portion of these people will develop symptoms in their lifetime. There is no cure or vaccine available for HSV-1; however, there are treatments available that aim to control the inflammation caused by the virus and prevent its recurrence. While these treatments are beneficial to those suffering with HSK, there is a need for more effective treatments to minimise the need for topical steroids, which can have harmful effects, and to prevent bouts of disease reactivation, which can lead to progressive corneal scarring and visual impairment. This review details the current understanding of HSV-1 infection and discusses potential novel treatment options including microRNAs, TLRs, mAbs, and aptamers.
The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence
Authors: Yeh Yang-Hui Jimmy , Yang Kerui , Razmi Anya , Ho Ya-Chi
Published: September 2021

More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected cells. In individuals under long-term suppressive antiretroviral therapy (ART), HIV-1 integration sites are enriched in specific locations in certain cancer-related genes in the same orientation as the host transcription unit. Single-cell transcriptome analysis revealed that HIV-1 drives aberrant cancer-related gene expression through HIV-1-to-host RNA splicing. Furthermore, the HIV-1 promoter dominates over the host gene promoter and drives high levels of cancer-related gene expression. When HIV-1 integrates into cancer-related genes and causes gain of function of oncogenes or loss of function of tumor suppressor genes, HIV-1 insertional mutagenesis drives the proliferation of HIV-1-infected cells and may cause cancer in rare cases. HIV-1-driven aberrant cancer-related gene expression at the integration site can be suppressed by CRISPR-mediated inhibition of the HIV-1 promoter or by HIV-1 suppressing agents. Given that ART does not suppress HIV-1 promoter activity, therapeutic agents that suppress HIV-1 transcription and halt the clonal expansion of HIV-1-infected cells should be explored to block the clonal expansion of the HIV-1 latent reservoir.
Cytokine Response to SARS-CoV-2 Infection in Children
Authors: Curatola Antonietta , Chiaretti Antonio , Ferretti Serena , Bersani Giulia , Lucchetti Donatella , Capossela Lavinia , Sgambato Alessandro , Gatto Antonio
Published: September 2021

The causal connection between serum biomarkers and COVID-19 severity or pathogenicity in children is unclear. The aim of this study was to describe clinical and immunological features of children affected by COVID-19. The secondary aim was to evaluate whether these cytokines could predict severity of COVID-19. All children (aged 0−18) admitted to the Pediatric Emergency Department and tested with nasopharyngeal swab for SARS-CoV-2 were recruited and assigned to three groups: COVID-19, other infections, control group. Clinical and laboratory data of these patients, including circulating cytokine levels, were analyzed in three groups. Fever was the most frequent symptom in COVID-19 (67.3%). Neutropenia was found in the COVID-19 group (p < 0.05); no difference was observed for lymphocyte counts in the three groups. Higher levels of IL-6 and TNF-alpha were found in the COVID-19 group compared to other infections and control groups (p = 0.014 and p = 0.001, respectively). Whereas, in the COVID-19 group, no difference was observed as for the same cytokines among sub-groups of different disease severity (p = 0.7 and p = 0.8). Serum levels of IL-6 and TNF-alpha were higher in COVID-19 children than in children with other infectious diseases, but those levels did not correlate with disease severity. Clinical studies in a large pediatric population are necessary to better define the role of the immune-mediated response in SARS-CoV-2 infections in children.
Multiple Occurrences of a 168-Nucleotide Deletion in SARS-CoV-2 ORF8, Unnoticed by Standard Amplicon Sequencing and Variant Calling Pipelines
Authors: Brandt David , Simunovic Marina , Busche Tobias , Haak Markus , Belmann Peter , Jünemann Sebastian , Schulz Tizian , Klages Levin Joe , Vinke Svenja , Beckstette Michael , Pohl Ehmke , Scherer Christiane , Sczyrba Alexander , Kalinowski Jörn
Published: September 2021

Genomic surveillance of the SARS-CoV-2 pandemic is crucial and mainly achieved by amplicon sequencing protocols. Overlapping tiled-amplicons are generated to establish contiguous SARS-CoV-2 genome sequences, which enable the precise resolution of infection chains and outbreaks. We investigated a SARS-CoV-2 outbreak in a local hospital and used nanopore sequencing with a modified ARTIC protocol employing 1200 bp long amplicons. We detected a long deletion of 168 nucleotides in the ORF8 gene in 76 samples from the hospital outbreak. This deletion is difficult to identify with the classical amplicon sequencing procedures since it removes two amplicon primer-binding sites. We analyzed public SARS-CoV-2 sequences and sequencing read data from ENA and identified the same deletion in over 100 genomes belonging to different lineages of SARS-CoV-2, pointing to a mutation hotspot or to positive selection. In almost all cases, the deletion was not represented in the virus genome sequence after consensus building. Additionally, further database searches point to other deletions in the ORF8 coding region that have never been reported by the standard data analysis pipelines. These findings and the fact that ORF8 is especially prone to deletions, make a clear case for the urgent necessity of public availability of the raw data for this and other large deletions that might change the physiology of the virus towards endemism.
Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV
Authors: Shoukry Naglaa H.
Published: September 2021

Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied to understand correlates of protective immunity against hepatitis C virus (HCV) infection and to inform vaccine development. This review focuses on recent progress in understanding immunity to HCV using systems biology, specifically transcriptomic and epigenetic studies. It also examines proposed strategies moving forward towards an integrated systems immunology approach for predicting and evaluating the efficacy of the next generation of HCV vaccines.
Whole Genome Analysis of Human Rotaviruses Reveals Single Gene Reassortant Rotavirus Strains in Zambia
Authors: Maringa Wairimu M. , Simwaka Julia , Mwangi Peter N. , Mpabalwani Evans M. , Mwenda Jason M. , Mphahlele M. Jeffrey , Seheri Mapaseka L. , Nyaga Martin M.
Published: September 2021

Rotarix® vaccine was implemented nationwide in Zambia in 2013. In this study, four unusual strains collected in the post-vaccine period were subjected to whole genome sequencing and analysis. The four strains possessed atypical genotype constellations, with at least one reassortant genome segment within the constellation. One of the strains (UFS-NGS-MRC-DPRU4749) was genetically and phylogenetically distinct in the VP4 and VP1 gene segments. Pairwise analyses demonstrated several amino acid disparities in the VP4 antigenic sites of this strain compared to that of Rotarix®. Although the impact of these amino acid disparities remains to be determined, this study adds to our understanding of the whole genomes of reassortant strains circulating in Zambia following Rotarix® vaccine introduction.
West Nile Virus and Tick-Borne Encephalitis Virus Are Endemic in Equids in Eastern Austria
Authors: de Heus Phebe , Kolodziejek Jolanta , Hubálek Zdenĕk , Dimmel Katharina , Racher Victoria , Nowotny Norbert , Cavalleri Jessika-M. V.
Published: September 2021

The emergence of West Nile virus (WNV) and Usutu virus (USUV) in addition to the autochthonous tick-borne encephalitis virus (TBEV) in Europe causes rising concern for public and animal health. The first equine case of West Nile neuroinvasive disease in Austria was diagnosed in 2016. As a consequence, a cross-sectional seroprevalence study was conducted in 2017, including 348 equids from eastern Austria. Serum samples reactive by ELISA for either flavivirus immunoglobulin G or M were further analyzed with the plaque reduction neutralization test (PRNT-80) to identify the specific etiologic agent. Neutralizing antibody prevalences excluding vaccinated equids were found to be 5.3% for WNV, 15.5% for TBEV, 0% for USUV, and 1.2% for WNV from autochthonous origin. Additionally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect WNV nucleic acid in horse sera and was found to be negative in all cases. Risk factor analysis did not identify any factors significantly associated with seropositivity.
Lymphopenia Caused by Virus Infections and the Mechanisms Beyond
Authors: Guo Zijing , Zhang Zhidong , Prajapati Meera , Li Yanmin
Published: September 2021

Viral infections can give rise to a systemic decrease in the total number of lymphocytes in the blood, referred to as lymphopenia. Lymphopenia may affect the host adaptive immune responses and impact the clinical course of acute viral infections. Detailed knowledge on how viruses induce lymphopenia would provide valuable information into the pathogenesis of viral infections and potential therapeutic targeting. In this review, the current progress of viruses-induced lymphopenia is summarized and the potential mechanisms and factors involved are discussed.
Neonatal Development in Prenatally Zika Virus-Exposed Infant Macaques with Dengue Immunity
Authors: Ausderau Karla , Kabakov Sabrina , Razo Elaina , Mitzey Ann M. , Bach Kathryn M. , Crooks Chelsea M. , Dulaney Natalie , Keding Logan , Salas-Quinchucua Cristhian , Medina-Magües Lex G. , Weiler Andrea M. , Bliss Mason , Eickhoff Jens , Simmons Heather A. , Mejia Andres , Antony Kathleen M. , Morgan Terry , Capuano Saverio , Schneider Mary L. , Aliota Matthew T. , Friedrich Thomas C. , O’Connor David H. , Golos Thaddeus G. , Mohr Emma L.
Published: September 2021

Infants exposed to Zika virus (ZIKV) prenatally may develop birth defects, developmental deficits, or remain asymptomatic. It is unclear why some infants are more affected than others, although enhancement of maternal ZIKV infection via immunity to an antigenically similar virus, dengue virus (DENV), may play a role. We hypothesized that DENV immunity may worsen prenatal ZIKV infection and developmental deficits in offspring. We utilized a translational macaque model to examine how maternal DENV immunity influences ZIKV-exposed infant macaque neurodevelopment in the first month of life. We inoculated eight macaques with prior DENV infection with ZIKV, five macaques with ZIKV, and four macaques with saline. DENV/ZIKV-exposed infants had significantly worse visual orientation skills than ZIKV-exposed infants whose mothers were DENV-naive, with no differences in motor, sensory or state control development. ZIKV infection characteristics and pregnancy outcomes did not individually differ between dams with and without DENV immunity, but when multiple factors were combined in a multivariate model, maternal DENV immunity combined with ZIKV infection characteristics and pregnancy parameters predicted select developmental outcomes. We demonstrate that maternal DENV immunity exacerbates visual orientation and tracking deficits in ZIKV-exposed infant macaques, suggesting that human studies should evaluate how maternal DENV immunity impacts long-term neurodevelopment.
The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients
Authors: Dęborska-Materkowska Dominika , Kamińska Dorota
Published: September 2021

Since its outbreak in December 2019, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to an enormous rise in scientific response with an excess of COVID-19-related studies on the pathogenesis and potential therapeutic approaches. Solid organ transplant (SOT) recipients are a heterogeneous population with long-lasting immunosuppression as a joining element. Immunocompromised patients are a vulnerable population with a high risk of severe infections and an increased infection-related mortality rate. It was postulated that the hyperinflammatory state due to cytokine release syndrome during severe COVID-19 could be alleviated by immunosuppressive therapy in SOT patients. On the other hand, it was previously established that T cell-mediated immunity, which is significantly weakened in SOT recipients, is the main component of antiviral immune responses. In this paper, we present the current state of science on COVID-19 immunology in relation to solid organ transplantation with prospective therapeutic and vaccination strategies in this population.
How Viruses Use the VCP/p97 ATPase Molecular Machine
Authors: Das Poulami , Dudley Jaquelin P.
Published: September 2021

Viruses are obligate intracellular parasites that are dependent on host factors for their replication. One such host protein, p97 or the valosin-containing protein (VCP), is a highly conserved AAA ATPase that facilitates replication of diverse RNA- and DNA-containing viruses. The wide range of cellular functions attributed to this ATPase is consistent with its participation in multiple steps of the virus life cycle from entry and uncoating to viral egress. Studies of VCP/p97 interactions with viruses will provide important information about host processes and cell biology, but also viral strategies that take advantage of these host functions. The critical role of p97 in viral replication might be exploited as a target for development of pan-antiviral drugs that exceed the capability of virus-specific vaccines or therapeutics.
Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics
Authors: Domingo Esteban , García-Crespo Carlos , Lobo-Vega Rebeca , Perales Celia
Published: September 2021

The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus–host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10−3 to 10−6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3′ to 5′ exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.
Molecular Basis of Antigenic Drift in Serotype O Foot-and-Mouth Disease Viruses (2013–2018) from Southeast Asia
Authors: Upadhyaya Sasmita , Mahapatra Mana , Mioulet Valerie , Parida Satya
Published: September 2021

Foot and mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals with serious economic consequences. FMD is endemic in Southeast Asia (SEA) and East Asia (EA) with the circulation of multiple serotypes, posing a threat to Australia and other FMD-free countries. Although vaccination is one of the most important control measures to prevent FMD outbreaks, the available vaccines may not be able to provide enough cross-protection against the FMD viruses (FMDVs) circulating in these countries due to the incursion of new lineages and sub-lineages as experienced in South Korea during 2010, a FMD-free country, when a new lineage of serotype O FMDV (Mya-98) spread to the country, resulting in devastating economic consequences. In this study, a total of 62 serotype O (2013–2018) viruses selected from SEA and EA countries were antigenically characterized by virus neutralization tests using three existing (O/HKN/6/83, O/IND/R2/75 and O/PanAsia-2) and one putative (O/MYA/2009) vaccine strains and full capsid sequencing. The Capsid sequence analysis revealed three topotypes, Cathay, SEA and Middle East-South Asia (ME-SA) of FMDVs circulating in the region. The vaccines used in this study showed a good match with the SEA and ME-SA viruses. However, none of the recently circulating Cathay topotype viruses were protected by any of the vaccine strains, including the existing Cathay topotype vaccine (O/HKN/6/83), indicating an antigenic drift and, also the urgency to monitor this topotype in the region and develop a new vaccine strain if necessary, although currently the presence of this topotype is mainly restricted to China, Hong Kong, Taiwan and Vietnam. Further, the capsid sequences of these viruses were analyzed that identified several capsid amino acid substitutions involving neutralizing antigenic sites 1, 2 and 5, which either individually or together could underpin the observed antigenic drift.
COVID-19: Mechanistic Model of the African Paradox Supports the Central Role of the NF-κB Pathway
Authors: Kircheis Ralf , Schuster Manfred , Planz Oliver
Published: September 2021

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has expanded into a global pandemic, with more than 220 million affected persons and almost 4.6 million deaths by 8 September 2021. In particular, Europe and the Americas have been heavily affected by high infection and death rates. In contrast, much lower infection rates and mortality have been reported generally in Africa, particularly in the sub-Saharan region (with the exception of the Southern Africa region). There are different hypotheses for this African paradox, including less testing, the young age of the population, genetic disposition, and behavioral and epidemiological factors. In the present review, we address different immunological factors and their correlation with genetic factors, pre-existing immune status, and differences in cytokine induction patterns. We also focus on epidemiological factors, such as specific medication coverage, helminth distribution, and malaria endemics in the sub-Saharan region. An analysis combining different factors is presented that highlights the central role of the NF-κB signaling pathway in the African paradox. Importantly, insights into the interplay of different factors with the underlying immune pathological mechanisms for COVID-19 can provide a better understanding of the disease and the development of new targets for more efficient treatment strategies.
Current Status of HIV-1 Vaccines
Authors: Hargrave Anna , Mustafa Abu Salim , Hanif Asma , Tunio Javed H. , Hanif Shumaila Nida M.
Published: September 2021

HIV-1 infection and its progression to AIDS remains a significant global health challenge, particularly for low-income countries. Developing a vaccine to prevent HIV-1 infections has proven to be immensely challenging with complex biological acquisition and infection, unforeseen clinical trial disappointments, and funding issues. This paper discusses important landmarks of progress in HIV-1 vaccine development, various vaccine strategies, and clinical trials.
A Review of Australian Tick Vaccine Research
Authors: Tabor Ala E.
Published: September 2021

Tick vaccine research in Australia has demonstrated leadership worldwide through the development of the first anti-tick vaccine in the 1990s. Australia’s Commonwealth Scientific and Industrial Research Organisation’s (CSIRO) research led to the development of vaccines and/or precursors of vaccines (such as crude extracts) for both the cattle tick and the paralysis tick. CSIRO commercialised the Bm86 vaccine in the early 1990s for Rhipicephalus australis; however, issues with dosing and lack of global conservation led to the market closure of Tick-GARD in Australia. New research programs arose both locally and globally. The Australian paralysis tick Ixodes holocyclus has perplexed research veterinarians since the 1920s; however, not until the 2000s did biotechnology exist to elucidate the neurotoxin—holocyclotoxin family of toxins leading to a proof of concept vaccine cocktail. This review revisits these discoveries and describes tributes to deceased tick vaccine protagonists in Australia, including Sir Clunies Ross, Dr Bernard Stone and Dr David Kemp.
Challenges of Storage and Stability of mRNA-Based COVID-19 Vaccines
Authors: Uddin Mohammad N. , Roni Monzurul A.
Published: September 2021

In December 2019, a new and highly pathogenic coronavirus emerged—coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), quickly spread throughout the world. In response to this global pandemic, a few vaccines were allowed for emergency use, beginning in November 2020, of which the mRNA-based vaccines by Moderna (Moderna, Cambridge, MA, USA) and BioNTech (BioTech, Mainz, Germany)/Pfizer (Pfizer, New York, NY, USA) have been identified as the most effective ones. The mRNA platform allowed rapid development of vaccines, but their global use is limited by ultracold storage requirements. Most resource-poor countries do not have cold chain storage to execute mass vaccination. Therefore, determining strategies to increase stability of mRNA-based vaccines in relatively higher temperatures can be a game changer to address the current global pandemic and upcoming new waves. In this review, we summarized the current research strategies to enhance stability of the RNA vaccine delivery system.
Development of a Conserved Chimeric Vaccine for Induction of Strong Immune Response against Staphylococcus aureus Using Immunoinformatics Approaches
Authors: Chatterjee Rahul , Sahoo Panchanan , Mahapatra Soumya Ranjan , Dey Jyotirmayee , Ghosh Mrinmoy , Kushwaha Gajraj Singh , Misra Namrata , Suar Mrutyunjay , Raina Vishakha , Son Young-Ok
Published: September 2021

Staphylococcus aureus is one of the most notorious Gram-positive bacteria with a very high mortality rate. The WHO has listed S. aureus as one of the ESKAPE pathogens requiring urgent research and development efforts to fight against it. Yet there is a major layback in the advancement of effective vaccines against this multidrug-resistant pathogen. SdrD and SdrE proteins are attractive immunogen candidates as they are conserved among all the strains and contribute specifically to bacterial adherence to the host cells. Furthermore, these proteins are predicted to be highly antigenic and essential for pathogen survival. Therefore, in this study, using the immunoinformatics approach, a novel vaccine candidate was constructed using highly immunogenic conserved T-cell and B-cell epitopes along with specific linkers, adjuvants, and consequently modeled for docking with human Toll-like receptor 2. Additionally, physicochemical properties, secondary structure, disulphide engineering, and population coverage analysis were also analyzed for the vaccine. The constructed vaccine showed good results of worldwide population coverage and a promising immune response. For evaluation of the stability of the vaccine-TLR-2 docked complex, a molecular dynamics simulation was performed. The constructed vaccine was subjected to in silico immune simulations by C-ImmSim and Immune simulation significantly provided high levels of immunoglobulins, T-helper cells, T-cytotoxic cells, and INF-γ. Lastly, upon cloning, the vaccine protein was reverse transcribed into a DNA sequence and cloned into a pET28a (+) vector to ensure translational potency and microbial expression. The overall results of the study showed that the designed novel chimeric vaccine can simultaneously elicit humoral and cell-mediated immune responses and is a reliable construct for subsequent in vivo and in vitro studies against the pathogen.
A Novel Approach against Salmonella: A Review of Polymeric Nanoparticle Vaccines for Broilers and Layers
Authors: Acevedo-Villanueva Keila Y. , Akerele Gabriel O. , Al Hakeem Walid Ghazi , Renu Sankar , Shanmugasundaram Revathi , Selvaraj Ramesh K.
Published: September 2021

This work discusses the present-day limitations of current commercial Salmonella vaccines for broilers and layers and explores a novel approach towards poultry vaccination using biodegradable nanoparticle vaccines against Salmonella. With the increasing global population and poultry production and consumption, Salmonella is a potential health risk for humans. The oral administration of killed or inactivated vaccines would provide a better alternative to the currently commercially available Salmonella vaccines for poultry. However, there are currently no commercial oral killed-vaccines against Salmonella for use in broilers or layers. There is a need for novel and effective interventions in the poultry industry. Polymeric nanoparticles could give way to an effective mass-administered mucosal vaccination method for Salmonella. The scope of this work is limited to polymeric nanoparticles against Salmonella for use in broilers and layers. This review is based on the information available at the time of the investigation.
Age and Smoking Predict Antibody Titres at 3 Months after the Second Dose of the BNT162b2 COVID-19 Vaccine
Authors: Nomura Yushi , Sawahata Michiru , Nakamura Yosikazu , Kurihara Momoko , Koike Ryousuke , Katsube Otohiro , Hagiwara Koichi , Niho Seiji , Masuda Norihiro , Tanaka Takaaki , Sugiyama Kumiya
Published: September 2021

Objective: We aimed to determine antibody (Ab) titres 3 months after the second dose of the BNT162b2 coronavirus disease-2019 (COVID-19) vaccine and to explore clinical variables predicting these titres in Japan. Methods: We enrolled 378 healthcare workers (255 women, 123 men) whose blood samples were collected 91 ± 15 days after the second of two inoculations of the BNT162b2 COVID-19 mRNA vaccine (Pfizer/BioNTech) given 3 weeks apart. Medical histories and demographic characteristics were recorded using a structured self-reported questionnaire. The relationships between Ab titres and these factors were analysed. Results: Median age (interquartile range (IQR)) of the participants was 44 (32–54) years. Median Ab titre (IQR) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen was 764 (423–1140) U/mL. Older participants had significantly lower Ab titres; median (IQR) Ab titres were 942 (675–1390) and 1095 (741–1613) U/mL in men and women in their 20s, respectively, but 490 (297–571) and 519 (285–761) U/mL in men and women in their 60–70s, respectively. In the age-adjusted analysis, the only risk factors for lower Ab titres were male sex and smoking. However, the sex difference may have arisen from the sex difference in smoking rate. Moreover, Ab titres were significantly lower in current smokers than in ex-smokers. Conclusions: The most important factors associated with low Ab titres were age and smoking habit. In particular, current smoking status caused lower Ab titres, and smoking cessation before vaccination may improve the individual efficacy of the BNT162b2 vaccine.
Selection of Filovirus Isolates for Vaccine Development Programs
Authors: Wolfe Daniel N. , Sabourin Carol L. , Merchlinsky Michael J. , Florence William C. , Wolfraim Larry A. , Taylor Kimberly L. , Ward Lucy A.
Published: September 2021

The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.
The Adoption of Electric Vehicles in Qatar Can Contribute to Net Carbon Emission Reduction but Requires Strong Government Incentives
Authors: Al-Buenain Ahmad , Al-Muhannadi Saeed , Falamarzi Mohammad , Kutty Adeeb A. , Kucukvar Murat , Onat Nuri C.
Published: September 2021

Electric mobility is at the forefront of innovation. Cutting down greenhouse gases when low-carbon electricity sources are maintained has answered the concerns of skeptics when switching to electric mobility. This paper presents a life-cycle-based comparative study between the electric and conventional gasoline vehicles with respect to their environmental performance, taking the case of Qatar. A well-to-wheel life cycle assessment is used to understand the carbon footprint associated with the use of alternative mobility when powered by non-renewable energy sources such as natural gas for electricity production. A survey was also conducted to evaluate the economic and practical feasibility of the use of electric vehicles in Qatar. The analysis showed that electric vehicles (EVs) have passed conventional gasoline vehicles with a minimum difference between them of 12,000 gCO2eq/100 km traveled. This difference can roughly accommodate two additional subcompact electric vehicles on the roads of Qatar. Even though Qatar is producing all of its electricity from natural gas, EVs are still producing much less carbon footprint into the atmosphere with the results showing that almost identical alternatives produce triple the amount of GHG emissions. The results of the survey showed that, despite promising results shown in switching to carbon-neutral mobility solutions, a lack of willingness prevails within the State of Qatar to incline towards electric mobility among users. This implies that Qatar has to spend a lot of time and resources to achieve its ambitious goal to decarbonize mobility on roads with 10% electric vehicles by 2030. This research highlights the need for more practical incentives and generous subsidies by the government of Qatar on e-mobility solutions to switch the transportation system into an eco-friendly one.
Mice Treated Subcutaneously with Mouse LPS-Converted PrPres or LPS Alone Showed Brain Gene Expression Profiles Characteristic of Prion Disease
Authors: Hailemariam Dagnachew , Goldansaz Seyed Ali , Daude Nathalie , Wishart David S. , Ametaj Burim N.
Published: September 2021

Previously, we showed that bacterial lipopolysaccharide (LPS) converts mouse PrPC protein to a beta-rich isoform (moPrPres) resistant to proteinase K. In this study, we aimed to test if the LPS-converted PrPres is infectious and alters the expression of genes related to prion pathology in brains of terminally sick mice. Ninety female FVB/N mice at 5 weeks of age were randomly assigned to 6 groups treated subcutaneously (sc) for 6 weeks either with: (1) Saline (CTR); (2) LPS from Escherichia coli 0111:B4 (LPS), (3) one-time sc administration of de novo generated mouse recombinant prion protein (moPrP; 29-232) rich in beta-sheet by incubation with LPS (moPrPres), (4) LPS plus one-time sc injection of moPrPres, (5) one-time sc injection of brain homogenate from Rocky Mountain Lab (RLM) scrapie strain, and (6) LPS plus one-time sc injection of RML. Results showed that all treatments altered the expression of various genes related to prion disease and neuroinflammation starting at 11 weeks post-infection and more profoundly at the terminal stage. In conclusion, sc administration of de novo generated moPrPres, LPS, and a combination of moPrPres with LPS were able to alter the expression of multiple genes typical of prion pathology and inflammation.
Visual Search Asymmetry Due to the Relative Magnitude Represented by Number Symbols
Authors: Motz Benjamin A. , Goldstone Robert L. , Busey Thomas A. , Prather Richard W.
Published: September 2021

In visual search tasks, physically large target stimuli are more easily identified among small distractors than are small targets among large distractors. The present study extends this finding by presenting preliminary evidence of a new search asymmetry: stimuli that symbolically represent larger magnitude are identified more easily among featurally equivalent distractors that represent smaller magnitude. Participants performed a visual search task using line-segment digits representing the numbers 2 and 5, and the numbers 6 and 9, as well as comparable non-numeric control stimuli. In three experiments, we found that search times are faster when the target is a digit that represents a larger magnitude than the distractor, although this pattern was not evident in one additional experiment. The results provide suggestive evidence that the magnitude of a number symbol can affect perceptual comparisons between number symbols, and that the semantic meaning of a target stimulus can systematically affect visual search.