bluuebunny/crossref_metadata_2025 huggingface dataset:
Oscillation of Emden–Fowler-Type Differential Equations with Non-Canonical Operators and Mixed Neutral Terms
Authors: Marappan Sathish Kumar , Almutairi Alanoud , Iambor Loredana Florentina , Bazighifan Omar
Published: February 2023

The study of the symmetric properties of differential equations is essential for identifying effective methods for solving them. In this paper, we examine the oscillatory behavior of solutions of Emden–Fowler-type mixed non-linear neutral differential equations with both canonical and non-canonical operators. By utilizing integral conditions and the integral averaging method, we present new sufficient conditions to ensure that all solutions are oscillatory. Our results enhance and extend previous findings in the literature and are illustrated with suitable examples to demonstrate their effectiveness.
Kant’s Modal Asymmetry between Truth-Telling and Lying Revisited
Authors: Fontanari José F.
Published: February 2023

The modal asymmetry between truth-telling and lying refers to the impossibility of a world in which everyone lies, while on the contrary, a world in which everyone tells the truth is possible. This ethical issue is relevant to modern concerns about epistemic security, or the safety of knowledge. The breakdown of epistemic security leads to the erosion of trust and, hence, to an ‘impossible’ world since a willingness to believe in others is essential for the functioning of society. Here, we examine the threat of disinformation to epistemic security using an individual-based model in which individuals are both senders and receivers of signals and are characterized by their credulity and deceptiveness, which are targets of natural selection. The possible worlds are those favored by natural selection. Lies that significantly harm believers lead to the Kantian scenario: trust is completely eroded and the winners of the evolutionary race are incredulous. However, if the lies are not too harmful, our game evolutionary model predicts a world in which the individuals are both credulous and mildly untruthful. These two possible worlds are separated by a discontinuous phase transition in the limit of infinite population size.
Minimizing the Gutman Index among Unicyclic Graphs with Given Matching Number
Authors: Liu Weijun , Wang Jiaqiu
Published: February 2023

For a connected graph G with vertex set V, denote by d(v) the degree of vertex v and d(u, v) the distance between u and v. The value Gut(G)=∑{u,v}⊆Vd(u)d(v)d(u,v) is called the Gutman index of G. Recently, the graph minimizing the Gutman index among unicyclic graphs with pendent edges was characterized. Denoted by U(n,m) the set of unicyclic graphs on n vertices with matching number m. Motivated by that work, in this paper, we obtain a sharp lower bound for Gutman index of graphs in U(n,m), and the extremal graph attaining the bound is also obtained. It is worth noticing that all the extremal graphs are of high symmetry, that is, they have large automorphic groups.
Topological Indices, Graph Spectra, Entropies, Laplacians, and Matching Polynomials of n-Dimensional Hypercubes
Authors: Balasubramanian Krishnan
Published: February 2023

We obtain a large number of degree and distance-based topological indices, graph and Laplacian spectra and the corresponding polynomials, entropies and matching polynomials of n-dimensional hypercubes through the use of Hadamard symmetry and recursive dynamic computational techniques. Moreover, computations are used to provide independent numerical values for the topological indices of the 11- and 12-cubes. We invoke symmetry-based recursive Hadamard transforms to obtain the graph and Laplacian spectra of nD-hypercubes and the computed numerical results are constructed for up to 23-dimensional hypercubes. The symmetries of these hypercubes constitute the hyperoctahedral wreath product groups which also pave the way for the symmetry-based elegant computations. These results are used to independently validate the exact analytical expressions that we have obtained for the topological indices as well as graph, Laplacian spectra and their polynomials. We invoke a robust dynamic programming technique to handle the computationally intensive generation of matching polynomials of hypercubes and compute all matching polynomials up to the 6-cube. The distance degree sequence vectors have been obtained numerically for up to 108-dimensional cubes and their frequencies are found to be in binomial distributions akin to the spectra of n-cubes.
Numerical and Experimental Investigation on Bending Behavior for High-Performance Fiber Yarns Considering Probability Distribution of Fiber Strength
Authors: Wang Yu , Li Xuejiao , Xie Junbo , Wu Ning , Jiao Yanan , Wang Peng
Published: February 2023

The performance of fiber-reinforced composite materials is significantly influenced by the mechanical properties of the yarns. Predictive simulations of the mechanical response of yarns are, thus, necessary for fiber-reinforced composite materials. This paper developed a novel experiment equipment and approach to characterize the bending behavior of yarns, which was also analyzed by characterization parameters, bending load, bending stiffness, and realistic contact area. Inspired by the digital element approach, an improved modeling methodology with the probability distribution was employed to establish the geometry model of yarns and simulated bending behavior of yarns by defining the crimp strain of fibers in the yarn and the effective elastic modulus of yarns as random variables. The accuracy of the developed model was confirmed by the experimental approach. More bending behavior of yarns, including the twisted and plied yarns, was predicted by numerical simulation. Additionally, models revealed that twist level and number of plies affect yarn bending properties, which need to be adopted as sufficient conditions for the mechanical analysis of fiber-reinforced composite materials. This efficient experiment and modeling method is meaningful to be developed in further virtual weaving research.
Subchronic Low-Dose Methylmercury Exposure Accelerated Cerebral Telomere Shortening in Relevant with Declined Urinary aMT6s Level in Rats
Authors: Wu Xi , Li Ping , Tao Junyan , Chen Xiong , Zhang Aihua
Published: February 2023

Methylmercury (MeHg) is a global pollutant with established toxic effects on the central nervous system (CNS). However, early events and early-warning biomarkers of CNS damage following exposure to low-dose MeHg are still lacking. This study aimed to investigate whether subchronic low-dose MeHg exposure had adverse effects on the cerebral telomere length, as well as serum melatonin and its urinary metabolite 6-sulfatoxymelatonin (aMT6s) in rats. Sixteen male Sprague Dawley rats were divided into two groups. Group I was the control group. In group II, rats were exposed to MeHg by gavage at a dose of 0.1 mg/kg/day for 3 months. This study revealed that MeHg exposure resulted in impairment of learning and memory ability, a slightly reduced number of neurons and an irregular arrangement of neurons in the hippocampus. It also significantly accelerated telomere shortening in the cerebral cortex, hippocampus and hypothalamus. Moreover, MeHg exposure decreased the levels of melatonin in serum and aMT6s in urine, partly by suppressing the synthesis of 5-hydroxytryptamine (5-HT) in the brain but promoted the expression of melatonin-catalyzing AANAT and ASMT. Importantly, cerebral telomere length was positively correlated with MT and aMT6s after MeHg exposure. These results suggested that the shortened telomere length in the brain may be an early event in MeHg-induced CNS toxicity, and the level of aMT6s in urine may serve as an early-warning biomarker for MeHg-induced CNS damage.
Transcriptomic Analysis of Diethylstilbestrol in Daphnia Magna: Energy Metabolism and Growth Inhibition
Authors: Li Qi , Zhao Qian , Guo Jiahua , Li Xi , Song Jinxi
Published: February 2023

With the widespread use of diethylstilbestrol (DES), it has become a common contaminant in the aquatic environment. It is toxic to a wide range of aquatic organisms, disrupting the water flea growth and further interfering with several ecosystem services. Nevertheless, the molecular mechanism of DES in water fleas is still unexplicit. In this study, the 21-day chronic test showed that a negative effect of growth and reproduction can be observed with DES exposure. Subsequently applied transcriptomic analysis illustrated the molecular mechanism in mode freshwater invertebrate Daphnia magna (D. magna) exposed to 2, 200, and 1000 μg·L−1 of DES for 9 days. Meanwhile, exposure to DES at 200 and 1000 μg·L−1 significantly restrains the growth (body length) and reproduction (first spawning time) of D. magna. Identified differentially expressed genes (DEGs) are majorly enriched relative to energy metabolism, lipid metabolism, the digestive system, transport and catabolism pathways which were remarkably changed. These repressed and up-regulated pathways, in relation to energy synthesis and metabolism, may be the reasons for the reduced body length and delayed first spawning time. Taken together, this study revealed that DES is a threat to D. magna in the aquatic environment and clarifies the molecular mechanism of the toxicity.
Role of Urological Botulinum Toxin-A Injection for Overactive Bladder and Voiding Dysfunction in Patients with Parkinson’s Disease or Post-Stroke
Authors: Hu Ju-Chuan , Hsu Lin-Nei , Lee Wei-Chia , Chuang Yao-Chi , Wang Hung-Jen
Published: February 2023

Botulinum toxin A (BoNT-A) paralyzes muscle by blocking acetylcholine release at the synaptic junction. BoNT-A has shown its therapeutic effects in neurological disorders such as Parkinson’s disease (PD) and post-stroke spasticity. A high proportion of patients with PD and post-stroke develop neurogenic detrusor overactivity (nDO) and then develop urinary incontinence and overactive bladder (OAB) symptoms. This study aimed to disclose the safety and efficacy of BoNT-A injection in treating bladder and voiding dysfunction in PD and post-stroke patients by reviewing the current evidence. At present, intradetrusor injection of BoNT-A is a Food and Drug Administration (FDA)-approved third-line therapy for nDO and idiopathic OAB. Although intradetrusor injection of onaBoNT-A 200 U is already approved for nDO treatment, most researchers would like to manage PD and post-stroke patients by using onaBoNT-A 100 U intradetrusor injection to achieve long-term efficacy and reduce adverse effects. However, in contrast to its inclusion in the International Continence Society guidelines for PD treatment, the clinical use of BoNT-A for post-stroke patients is limited to experimental use due to the development of urinary retention in about one-fifth of patients. For treating urethral pseudodyssynergia, half of patients may respond to onaBoNT-A 100 U urethral injection. However, refinement is needed to reduce unwanted urinary incontinence.
Mutation of a Threonine Residue in αD-β4 Loop of Cyt2Aa2 Protein Influences Binding on Fluid Lipid Membranes
Authors: Tangsongcharoen Chontida , Toca-Herrera Jose L. , Promdonkoy Boonhiang , Tharad Sudarat
Published: February 2023

Cyt proteins are insecticidal proteins originally from Bacillus thuringiensis. The lipid binding of the Cyt2Aa2 protein depends on the phase of the lipid bilayer. In this work, the importance of the conserved T144 residue in the αD-β4 loop for lipid binding on fluid lipid membranes was investigated via atomic force microscopy (AFM). Lipid membrane fluidity could be monitored for the following lipid mixture systems: POPC/DPPC, POPC/SM, and DOPC/SM. AFM results revealed that the T144A mutant was unable to bind to pure POPC bilayers. Similar topography between the wildtype and T144A mutant was seen for the POPC/Chol system. Small aggregates of T144A mutant were observed in the POPC and DOPC domains of the lipid mixture systems. In addition, the T144A mutant had no cytotoxic effect against human colon cancer cells. These results suggest that alanine replacement into threonine 144 hinders the binding of Cyt2Aa2 on liquid lipid membranes. These observations provide a possibility to modify the Cyt2Aa2 protein to specific cells via lipid phase selection.
Comparison of Benefits and Risks Associated with Anti-T-Lymphocyte Globulin (ATLG) Serotherapy in Methotrexate (MTX)- versus Mycophenolate Mofetil (MMF)-Based Hematopoietic Stem Cell Transplantation
Authors: Nikoloudis Alexander , Strassl Irene , Binder Michaela , Stiefel Olga , Wipplinger Dagmar , Milanov Robert , Aichinger Christoph , Kaynak Emine , Machherndl-Spandl Sigrid , Buxhofer-Ausch Veronika , Böhm Alexandra , Petzer Andreas , Weltermann Ansgar , Wolf Dominik , Nachbaur David , Clausen Johannes
Published: February 2023

Background: Serotherapy with anti-T lymphocyte globulin (ATLG, Grafalon, formerly ATG-Fresenius) is established for the prevention of severe graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). The evidence from prospective studies is predominantly derived from a setting where methotrexate (MTX) and a calcineurin inhibitor (CNI) are used as the backbone of GVHD prophylaxis. The efficacy of ATLG in combination with CNI and mycophenolate mofetil (MMF) has not been investigated as much, particularly in terms of a direct comparison with its effects when combined with CNI/MTX. A total of 401 HSCTs from two Austrian transplant centers were retrospectively evaluated. We included peripheral blood transplants from early- or intermediate-stage (excluding advanced/refractory) hematological diseases from matched siblings or 10/10 or 9/10 matched unrelated donors with CNI/MTX or CNI/MMF prophylaxis, either without (n = 219) or with ATLG (n = 182). Overall, ATLG significantly reduced the risk for all-cause mortality by multivariate Cox analysis (HR 0.53; p = 0.002). Stratification by postgrafting prophylaxis type revealed a significant survival advantage for ATLG in the CNI/MMF cohort (HR 0.49; p = 0.001; n = 193), while its effect on survival in the CNI/MTX cohort was not significant (HR 0.87; p = 0.56; n = 208). In unrelated HSCT with CNI/MMF prophylaxis, ATLG exhibited its greatest survival benefit (HR 0.34; p = 0.001; n = 104). In the context of CNI/MMF, ATLG may provide even greater benefits than in the setting of CNI/MTX for post-grafting immunosuppression. Future prospective studies on ATLG should therefore focus on CNI/MMF-based transplants, which are widely performed in elderly or comorbid patients not expected to tolerate a standard course of MTX.
Liver Injury in Favipiravir-Treated COVID-19 Patients: Retrospective Single-Center Cohort Study
Authors: Almutairi Amal Oweid , El-Readi Mahmoud Zaki , Althubiti Mohammad , Alhindi Yosra Zakariyya , Ayoub Nahla , Alzahrani Abdullah R. , Al-Ghamdi Saeed S. , Eid Safaa Yehia
Published: February 2023

(1) Background: Favipiravir (FVP) is a new antiviral drug used to treat COVID-19. It has been authorized to be used in the kingdom of Saudi Arabia in the treatment of COVID-19. The mechanism of action of FVP is working as a specific inhibitor for the RNA-dependent RNA polymerase of the RNA chain virus. FVP has the potential to be hepatotoxic because of the structure similarity with pyrazinamide. This retrospective study aimed to determine the prevalence of liver injury in FVP-treated COVID-19 patients in General East Jeddah Hospital, Saudi Arabia, during the COVID-19 pandemic. (2) Methods: A total of 6000 patients infected with COVID-19 and treated at the East Jeddah Hospital were included, with a sample size of 362 patients. The participants ranged from 18 to 70 years of age, both males and females, with normal hepatic and renal function and had a confirmed diagnosis of COVID-19 infection. Patients who had gouty arthritis, hepatic and renal dysfunction, dead patients, pregnant women, and breastfeeding mothers were all excluded from this study. A retrospective cohort study compared two groups of patients treated with and without FVP and who followed the Saudi Ministry of Health protocol to manage COVID-19 infection. (3) Results: An adverse effect of FVP on the liver was found that ranged from mild to severe. Stopping treatment with FVP was associated with an observed important increase in the levels of liver enzymes AST (p < 0.001), ALT (p < 0.001), alkaline phosphatase (p < 0.03), total bilirubin (p < 0.001), and direct bilirubin (p < 0.001) in the treated compared with the untreated group. (4) Conclusion: This study showed a significant difference between the treated and the untreated groups with FVP in liver injury. FVP influences the liver, increasing the blood levels of the liver function parameters.
Assessment of the Risk of Exotic Zika Virus Strain Transmission by Aedes aegypti and Culex quinquefasciatus from Senegal Compared to a Native Strain
Authors: Gaye Alioune , Fall Cheikh , Faye Oumar , Dupont-Rouzeyrol Myrielle , Ndiaye El Hadji , Diallo Diawo , de Andrade Zanotto Paolo Marinho , Dia Ibrahima , Weaver Scott C. , Diallo Mawlouth
Published: February 2023

Zika virus (ZIKV) shows an enigmatic epidemiological profile in Africa. Despite its frequent detection in mosquitoes, few human cases have been reported. This could be due to the low infectious potential or low virulence of African ZIKV lineages. This study sought to assess the susceptibility of A. aegypti and C. quinquefasciatus to ZIKV strains from Senegal, Brazil, and New Caledonia. Vertical transmission was also investigated. Whole bodies, legs/wings and saliva samples were tested for ZIKV by real-time PCR to estimate infection, dissemination and transmission rates as well as the infection rate in the progeny of infected female A. aegypti. For A. aegypti, the Senegalese strain showed at 15 days post-exposure (dpe) a significantly higher infection rate (52.43%) than the Brazilian (10%) and New Caledonian (0%) strains. The Brazilian and Senegalese strains were disseminated but not detected in saliva. No A. aegypti offspring from females infected with Senegalese and Brazilian ZIKV strains tested positive. No infection was recorded for C. quinquefasciatus. We observed the incompetence of Senegalese A. aegypti to transmit ZIKV and the C. quinquefasciatus were completely refractory. The effect of freezing ZIKV had no significant impact on the vector competence of Aedes aegypti from Senegal, and vertical transmission was not reported in this study.
Beam Energy Dependence of the Linear and Mode-Coupled Flow Harmonics Using the a Multi-Phase Transport Model
Authors: Magdy Niseem
Published: February 2023

In the framework of the A Multi-Phase Transport (AMPT) model, the multi-particle azimuthal cumulant method is used to calculate the linear and mode-coupled contributions to the quadrangular flow harmonic (v4) and the mode-coupled response coefficient as functions of centrality in Au+Au collisions at sNN = 200, 39, 27 and 19.6 GeV. This study indicates that the linear and mode-coupled contributions to v4 are sensitive to beam energy change. Nevertheless, the correlations between different-order flow symmetry planes and the mode-coupled response coefficients show weak beam energy dependence. In addition, the presented results suggest that the experimental measurements that span a broad range of beam energies can be an additional constraint for the theoretical model calculations.
Curvature Dynamics in General Relativity
Authors: van Holten Jan W.
Published: February 2023

The equations of general relativity are recast in the form of a wave equation for the Weyl tensor. This allows reformulation of gravitational wave theory in terms of curvature waves, rather than metric waves. The existence of two transverse polarization states for curvature waves is proven and in the linearized approximation the quadrupole formula is rederived. A perturbative scheme to extend the linearized result to the non-linear regime is outlined.
SARS-CoV-2 S Glycoprotein Stabilization Strategies
Authors: Pedenko Borys , Sulbaran Guidenn , Guilligay Delphine , Effantin Gregory , Weissenhorn Winfried
Published: February 2023

The SARS-CoV-2 pandemic has again shown that structural biology plays an important role in understanding biological mechanisms and exploiting structural data for therapeutic interventions. Notably, previous work on SARS-related glycoproteins has paved the way for the rapid structural determination of the SARS-CoV-2 S glycoprotein, which is the main target for neutralizing antibodies. Therefore, all vaccine approaches aimed to employ S as an immunogen to induce neutralizing antibodies. Like all enveloped virus glycoproteins, SARS-CoV-2 S native prefusion trimers are in a metastable conformation, which primes the glycoprotein for the entry process via membrane fusion. S-mediated entry is associated with major conformational changes in S, which can expose many off-target epitopes that deviate vaccination approaches from the major aim of inducing neutralizing antibodies, which mainly target the native prefusion trimer conformation. Here, we review the viral glycoprotein stabilization methods developed prior to SARS-CoV-2, and applied to SARS-CoV-2 S, in order to stabilize S in the prefusion conformation. The importance of structure-based approaches is highlighted by the benefits of employing stabilized S trimers versus non-stabilized S in vaccines with respect to their protective efficacy.
Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection
Authors: Yang Tsai-Hsuan , Chan Chi , Yang Po-Jiun , Huang Yu-Han , Lee Mei-Hsuan
Published: February 2023

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies.
Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention
Authors: Sehgal Ayushi , Mehta Sanya , Sahay Kritika , Martynova Ekaterina , Rizvanov Albert , Baranwal Manoj , Chandy Sara , Khaiboullina Svetlana , Kabwe Emmanuel , Davidyuk Yuriy
Published: February 2023

Hemorrhagic Fever with Renal Syndrome (HFRS) is the most frequently diagnosed zoonosis in Asia. This zoonotic infection is the result of exposure to the virus-contaminated aerosols. Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability. Several species of orthohantaviruses were identified as causing infection, where Hantaan, Puumala, and Seoul viruses are most common. Orthohantaviruses are endemic to several Asian countries, such as China, South Korea, and Japan. Along with those countries, HFRS tops the list of zoonotic infections in the Far Eastern Federal District of Russia. Recently, orthohantavirus circulation was demonstrated in small mammals in Thailand and India, where orthohantavirus was not believed to be endemic. In this review, we summarized the current data on orthohantaviruses in Asia. We gave the synopsis of the history and diversity of orthohantaviruses in Asia. We also described the clinical presentation and current understanding of the pathogenesis of orthohantavirus infection. Additionally, conventional and novel approaches for preventing and treating orthohantavirus infection are discussed.
The Host Non-Coding RNA Response to Alphavirus Infection
Authors: Behnia Mahgol , Bradfute Steven B.
Published: February 2023

Alphaviruses are important human and animal pathogens that can cause a range of debilitating symptoms and are found worldwide. These include arthralgic diseases caused by Old-World viruses and encephalitis induced by infection with New-World alphaviruses. Non-coding RNAs do not encode for proteins, but can modulate cellular response pathways in a myriad of ways. There are several classes of non-coding RNAs, some more well-studied than others. Much research has focused on the mRNA response to infection against alphaviruses, but analysis of non-coding RNA responses has been more limited until recently. This review covers what is known regarding host cell non-coding RNA responses in alphavirus infections and highlights gaps in the knowledge that future research should address.
Metagenomic Approach Reveals the Second Subtype of PRRSV-1 in a Pathogen Spectrum during a Clinical Outbreak with High Mortality in Western Siberia, Russia
Authors: Krasnikov Nikita , Yuzhakov Anton , Aliper Taras , Gulyukin Alexey
Published: February 2023

Porcine reproductive and respiratory syndrome virus (PRRSV) has a significant economic impact on pig farming worldwide by causing reproductive problems and affecting the respiratory systems of swine. In Eastern Europe, PRRSV-1 strains are characterized by high genetic variability, and pathogenicity differs among all known subtypes. This case study describes the detection of a wide pathogen spectrum, including the second subtype PRRSV-1, with a high mortality rate among nursery piglets (23.8%). This study was conducted at a farrow-to-finish farm in the Western Siberia region of Russia. Clinical symptoms included apathy, sneezing, and an elevation in body temperature, and during the autopsy, degenerative lesions in different tissues were observed. Moreover, 1.5 percent of the affected animals displayed clinical signs of the central nervous system and were characterized by polyserositis. Nasal swabs from diseased piglets and various tissue swabs from deceased animals were studied. For diagnostics, the nanopore sequencing method was applied. All the samples tested positive for PRRSV, and a more detailed analysis defined it as a second subtype of PRRSV-1. The results, along with the clinical picture, showed a complex disease etiology with the dominant role of PRRSV-1 and were informative about the high pathogenicity of the subtype in question under field conditions.
Definition of a New HLA B*52-Restricted Rev CTL Epitope Targeted by an HIV-1-Infected Controller
Authors: El Kenz Boutaina , Schmidt Katja G. , Ogungbemi-Alt Victoria K. , Bergmann Silke , Steininger Philipp , Korn Klaus , Spriewald Bernd , Harrer Ellen G. , Nganou-Makamdop Krystelle , Harrer Thomas
Published: February 2023

The analysis of T-cell responses in HIV-1-infected controllers may contribute to a better understanding of the protective components of the immune system. Here, we analyzed the HIV-1-specific T-cell response in a 59-year-old HIV-1-infected controller, infected for at least seven years, who presented with low viral loads ranging from <20 copies/mL to 200 copies/mL and normal CD4 counts of >800 cells/µL. In γ-IFN-ELISpot assays using freshly isolated PBMCs, he displayed a very strong polyclonal T-cell response to eight epitopes in Gag, Nef and Rev; with the dominant responses directed against the HLA-B*57-epitope AISPRTLNAW and against a so-far-unknown epitope within Rev. Further analyses using peptide-stimulated T-cell lines in γ-IFN-ELISpot assays delineated the peptide RQRQIRSI (Rev-RI8) as a newly defined HLA-B*52-restricted epitope located within a functionally important region of Rev. Peptide-stimulation assays in 15 HLA-B*52-positive HIV-1-infected subjects, including the controller, demonstrated recognition of the Rev-RI8 epitope in 6/15 subjects. CD4 counts before the start of antiviral therapy were significantly higher in subjects with recognition of the Rev-RI8 epitope. Targeting of the Rev-RI8 epitope in Rev by CTL could contribute to the positive association of HLA-B*52 with a more favorable course of HIV-1-infection.
Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases
Authors: Hajjo Rima , Sabbah Dima A. , Abusara Osama H. , Kharmah Reham , Bardaweel Sanaa
Published: February 2023

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.
From Capillary Electrophoresis to Deep Sequencing: An Improved HIV-1 Drug Resistance Assessment Solution Using In Vitro Diagnostic (IVD) Assays and Software
Authors: Mohamed Sofiane , Boulmé Ronan , Sayada Chalom
Published: February 2023

Background: Drug-resistance mutations were mostly detected using capillary electrophoresis sequencing, which does not detect minor variants with a frequency below 20%. Next-Generation Sequencing (NGS) can now detect additional mutations which can be useful for HIV-1 drug resistance interpretation. The objective of this study was to evaluate the performances of CE-IVD assays for HIV-1 drug-resistance assessment both for target-specific and whole-genome sequencing, using standardized end-to-end solution platforms. Methods: A total of 301 clinical samples were prepared, extracted, and amplified for the three HIV-1 genomic targets, Protease (PR), Reverse Transcriptase (RT), and Integrase (INT), using the CE-IVD DeepChek® Assays; and then 19 clinical samples, using the CE-IVD DeepChek® HIV Whole Genome Assay, were sequenced on the NGS iSeq100 and MiSeq (Illumina, San Diego, CA, USA). Sequences were compared to those obtained by capillary electrophoresis. Quality control for Molecular Diagnostics (QCMD) samples was added to validate the clinical accuracy of these in vitro diagnostics (IVDs). Nineteen clinical samples were then tested with the same sample collection, handling, and measurement procedure for evaluating the use of NGS for whole-genome HIV-1. Sequencing analyzer outputs were submitted to a downstream CE-IVD standalone software tailored for HIV-1 analysis and interpretation. Results: The limits of range detection were 1000 to 106 cp/mL for the HIV-1 target-specific sequencing. The median coverage per sample for the three amplicons (PR/RT and INT) was 13,237 reads. High analytical reproducibility and repeatability were evidenced by a positive percent agreement of 100%. Duplicated samples in two distinct NGS runs were 100% homologous. NGS detected all the mutations found by capillary electrophoresis and identified additional resistance variants. A perfect accuracy score with the QCMD panel detection of drug-resistance mutations was obtained. Conclusions: This study is the first evaluation of the DeepChek® Assays for targets specific (PR/RT and INT) and whole genome. A cutoff of 3% allowed for a better characterization of the viral population by identifying additional resistance mutations and improving the HIV-1 drug-resistance interpretation. The use of whole-genome sequencing is an additional and complementary tool to detect mutations in newly infected untreated patients and heavily experienced patients, both with higher HIV-1 viral-load profiles, to offer new insight and treatment strategies, especially using the new HIV-1 capsid/maturation inhibitors and to assess the potential clinical impact of mutations in the HIV-1 genome outside of the usual HIV-1 targets (RT/PR and INT).
The Role of NS1 Protein in the Diagnosis of Flavivirus Infections
Authors: Fisher Ron , Lustig Yaniv , Sklan Ella H. , Schwartz Eli
Published: February 2023

Nonstructural protein 1 (NS1) is a glycoprotein among the flavivirus genus. It is found in both membrane-associated and soluble secreted forms, has an essential role in viral replication, and modulates the host immune response. NS1 is secreted from infected cells within hours after viral infection, and thus immunodetection of NS1 can be used for early serum diagnosis of dengue fever infections instead of real-time (RT)-PCR. This method is fast, simple, and affordable, and its availability could provide an easy point-of-care testing solution for developing countries. Early studies show that detecting NS1 in cerebrospinal fluid (CSF) samples is possible and can improve the surveillance of patients with dengue-associated neurological diseases. NS1 can be detected postmortem in tissue specimens. It can also be identified using noninvasive methods in urine, saliva, and dried blood spots, extending the availability and effective detection period. Recently, an enzyme-linked immunosorbent assay (ELISA) assay for detecting antibodies directed against Zika virus NS1 has been developed and used for diagnosing Zika infection. This NS1-based assay was significantly more specific than envelope protein-based assays, suggesting that similar assays might be more specific for other flaviviruses as well. This review summarizes the knowledge on flaviviruses’ NS1′s potential role in antigen and antibody diagnosis.
The Interplay among Glucocorticoid Therapy, Platelet-Activating Factor and Endocannabinoid Release Influences the Inflammatory Response to COVID-19
Authors: de Carvalho Jonatan C. S. , da Silva-Neto Pedro V. , Toro Diana M. , Fuzo Carlos A. , Nardini Viviani , Pimentel Vinícius E. , Pérez Malena M. , Fraga-Silva Thais F. C. , Oliveira Camilla N. S. , Degiovani Augusto M. , Ostini Fátima M. , Feitosa Marley R. , Parra Rogerio S. , da Rocha José J. R. , Feres Omar , Vilar Fernando C. , Gaspar Gilberto G. , Santos Isabel K. F. M. , Fernandes Ana P. M. , Maruyama Sandra R. , Russo Elisa M. S. , Bonato Vânia L. D. , Cardoso Cristina R. B. , Dias-Baruffi Marcelo , Faccioli Lúcia H. , Sorgi Carlos A. ,   on behalf of the ImmunoCovid Study Group
Published: February 2023

COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course.
Antagonisms of ASFV towards Host Defense Mechanisms: Knowledge Gaps in Viral Immune Evasion and Pathogenesis
Authors: Yu Liangzheng , Zhu Zhenbang , Deng Junhua , Tian Kegong , Li Xiangdong
Published: February 2023

African swine fever (ASF) causes high morbidity and mortality of both domestic pigs and wild boars and severely impacts the swine industry worldwide. ASF virus (ASFV), the etiologic agent of ASF epidemics, mainly infects myeloid cells in swine mononuclear phagocyte system (MPS), including blood-circulating monocytes, tissue-resident macrophages, and dendritic cells (DCs). Since their significant roles in bridging host innate and adaptive immunity, these cells provide ASFV with favorable targets to manipulate and block their antiviral activities, leading to immune escape and immunosuppression. To date, vaccines are still being regarded as the most promising measure to prevent and control ASF outbreaks. However, ASF vaccine development is delayed and limited by existing knowledge gaps in viral immune evasion, pathogenesis, etc. Recent studies have revealed that ASFV can employ diverse strategies to interrupt the host defense mechanisms via abundant self-encoded proteins. Thus, this review mainly focuses on the antagonisms of ASFV-encoded proteins towards IFN-I production, IFN-induced antiviral response, NLRP3 inflammasome activation, and GSDMD-mediated pyroptosis. Additionally, we also make a brief discussion concerning the potential challenges in future development of ASF vaccine.
Whole-Genome Analysis of Influenza A(H3N2) and B/Victoria Viruses Detected in Myanmar during the COVID-19 Pandemic in 2021
Authors: Chon Irina , Saito Reiko , Kyaw Yadanar , Aye Moe Myat , Setk Swe , Phyu Wint Wint , Wagatsuma Keita , Li Jiaming , Sun Yuyang , Otoguro Teruhime , Win Su Mon Kyaw , Yoshioka Sayaka , Win Nay Chi , Ja Lasham Di , Tin Htay Htay , Watanabe Hisami
Published: February 2023

An influenza circulation was observed in Myanmar between October and November in 2021. Patients with symptoms of influenza-like illness were screened using rapid diagnostic test (RDT) kits, and 147/414 (35.5%) upper respiratory tract specimens presented positive results. All RDT-positive samples were screened by a commercial multiplex real-time polymerase chain reaction (RT-PCR) assay, and 30 samples positive for influenza A(H3N2) or B underwent further typing/subtyping for cycle threshold (Ct) value determination based on cycling probe RT-PCR. The majority of subtyped samples (n = 13) were influenza A(H3N2), while only three were B/Victoria. Clinical samples with low Ct values obtained by RT-PCR were used for whole-genome sequencing via next-generation sequencing technology. All collected viruses were distinct from the Southern Hemisphere vaccine strains of the corresponding season but matched with vaccines of the following season. Influenza A(H3N2) strains from Myanmar belonged to clade 2a.3 and shared the highest genetic proximity with Bahraini strains. B/Victoria viruses belonged to clade V1A.3a.2 and were genetically similar to Bangladeshi strains. This study highlights the importance of performing influenza virus surveillance with genetic characterization of the influenza virus in Myanmar, to contribute to global influenza surveillance during the COVID-19 pandemic.
Epitope Coverage of Anti-SARS-CoV-2 Nucleocapsid IgA and IgG Antibodies Correlates with Protection against Re-Infection by New Variants in Subsequent Waves of the COVID-19 Pandemic
Authors: Mullins Michelle O. , Smith Muneerah , Maboreke Hazel , Nel Andrew J. M. , Ntusi Ntobeko A. B. , Burgers Wendy A. , Blackburn Jonathan M.
Published: February 2023

The COVID-19 pandemic continues to affect individuals across the globe, with some individuals experiencing more severe disease than others. The relatively high frequency of re-infections and breakthrough infections observed with SARS-CoV-2 highlights the importance of extending our understanding of immunity to COVID-19. Here, we aim to shed light on the importance of antibody titres and epitope utilization in protection from re-infection. Health care workers are highly exposed to SARS-CoV-2 and are therefore also more likely to become re-infected. We utilized quantitative, multi-antigen, multi-epitope SARS-CoV-2 protein microarrays to measure IgG and IgA titres against various domains of the nucleocapsid and spike proteins. Potential re-infections in a large, diverse health care worker cohort (N = 300) during the second wave of the pandemic were identified by assessing the IgG anti-N titres before and after the second wave. We assessed epitope coverage and antibody titres between the ‘single infection’ and ‘re-infection’ groups. Clear differences were observed in the breadth of the anti-N response before the second wave, with the epitope coverage for both IgG (p = 0.019) and IgA (p = 0.015) being significantly increased in those who did not become re-infected compared to those who did. Additionally, the IgG anti-N (p = 0.004) and anti-S titres (p = 0.018) were significantly higher in those not re-infected. These results highlight the importance of the breadth of elicited antibody epitope coverage following natural infection in protection from re-infection and disease in the COVID-19 pandemic.
Dynamics of Early Establishment of SARS-CoV-2 VOC Omicron Lineages in Minas Gerais, Brazil
Authors: de Menezes Mariane Talon , Moreira Filipe Romero Rebello , Whittaker Charles , Santos Franciele Martins , Queiroz Daniel Costa , Geddes Victor , Fonseca Paula Luize Camargos , de Jesus Jaqueline Góes , Mendes-Oliveira Franciane , Reis-Souza Valquíria , Santos Bibiana , Zauli Danielle Alves Gomes , de Lima Aline Brito , de Brito Mendonça Cristiane , Alvim Luige Biciati , do Prado Silva Joice , Malta Frederico Scott Varella , de Souza Ferreira Alessandro Clayton , Faria Nuno R. , Sabino Ester Cerdeira , Aguiar Renato Santana
Published: February 2023

Brazil is one of the nations most affected by Coronavirus disease 2019 (COVID-19). The introduction and establishment of new virus variants can be related to an increase in cases and fatalities. The emergence of Omicron, the most modified SARS-CoV-2 variant, caused alarm for the public health of Brazil. In this study, we examined the effects of the Omicron introduction in Minas Gerais (MG), the second-most populous state of Brazil. A total of 430 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) samples from November 2021 to June 2022 from Belo Horizonte (BH) city were sequenced. These newly sequenced genomes comprise 72% of all previously available SARS-CoV-2 genomes for the city. Evolutionary analysis of novel viral genomes reveals that a great diversity of Omicron sublineages have circulated in BH, a pattern in-keeping with observations across Brazil more generally. Bayesian phylogeographic reconstructions indicate that this diversity is a product of a large number of international and national importations. As observed previously, São Paulo state is shown as a significant hub for viral spread throughout the country, contributing to around 70% of all viral Omicron introductions detected in MG.
Neutralization Effect of Sera against Delta and Omicron in Patients Recovering from COVID-19 and Inactivated Vaccine Recipients
Authors: Zhu Yajuan , Zhong Qianhong , Ma Zhanzhong , Liu Shuang , Lan Yunhua , Peng Bo , Zhang Xiaomin , Shi Xiaolu , Qu Jing , Wu Zhilong , Zhao Zhimeng , Zhang Xilin , Zhang Dingmei
Published: February 2023

This study aims to analyze the serum neutralization capacity against Delta and Omicron variants in three clusters of individuals, including those who had recovered from COVID-19 and those who had received two and three doses of inactivated vaccine. Pseudovirus neutralization tests were performed on serum samples. The neutralizing titers between different groups were compared using the Wilcoxon’s signed-rank test. Among the two-dose vaccinees, the neutralization titers of the Omicron variant were reduced by approximately 3.1-fold compared to the wild-type virus (p < 0.05). Meanwhile, among the three-dose vaccinees, the neutralization titers for Delta and Omicron variants were 3.5-fold (p < 0.05) and 5.0-fold (p < 0.05) lower, respectively, as compared to the wild-type virus. In addition, among the recovering patients, the neutralization titers for Delta and Omicron variants were 3.9-fold (p < 0.05) and 29.1-fold (p < 0.05) lower, respectively, as compared to the wild-type virus. Overall, only 12.0% (11/92) of participants showed neutralizing titers against Omicron above the detection limit. The ability to neutralize wild-type pseudovirus was significantly boosted in three-dose vaccinees as compared to two-dose vaccinees. Sera from recovered patients showed greater neutralizing titers for the wild-type and Delta pseudoviruses than the two- and three-dose inactivated vaccine groups. The present study revealed a loss of neutralizing activity against the Omicron variant in almost all samples. Moreover, the immunization effect obtained through natural infection is more robust than that from the active immunization method of vaccination.
Acute Macular Neuroretinopathy and Paracentral Acute Middle Maculopathy during SARS-CoV-2 Infection and Vaccination
Authors: Dutta Majumder Parthopratim , Agarwal Aniruddha
Published: February 2023

Purpose: To review the demographic and clinical profile of patients developing acute macular neuroretinopathy (AMN) or paracentral acute middle maculopathy (PAMM) after receiving coronavirus disease-2019 (COVID-19) vaccination or infection. Methods: In this review article, the published literature was searched to determine cases developing either AMN or PAMM after COVID-19 vaccinations or infections. Data, including demographic profile, presenting features, symptoms, diagnosis, and clinical outcomes, were extracted from the selected publications. These parameters were compared between the two groups, i.e., patients developing AMN/PAMM either after vaccination or infection. Results: After the literature review, 57 patients developing either AMN (n = 40), PAMM (n = 14), or both (n = 3) after COVID-19 infection (n = 29) or vaccination (n = 28) were included (mean age: 34.9 ± 14.4 years; n = 38; 66.7% females). In 24.6% patients, the diagnosis of COVID-19 infection was preceded by the development of ocular disease. There were no significant differences in the age or gender between the patients developing AMN or PAMM after vaccination or infection (p > 0.13). Among the vaccination group, the highest number of patients developing AMN/PAMM were after the Oxford-AstraZeneca (n = 12; 42.9%). Patients with vaccination had a significantly early onset of AMN/PAMM compared to those with infection (11.5 ± 17.6 days versus 37.8 ± 43.6 days; p = 0.001). Conclusions: Both AMN and PAMM are reported to be associated with COVID-19 infections and in persons receiving vaccination against COVID-19. While COVID-19 infections and vaccinations may have a contributory role, other risk factors such as oral contraceptive pills may also play a role in the development of the disease.