Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p<0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p<0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

CRCMSS/pMMR contain a significantly increased fraction of TREM2+ macrophages (TAMs) and CD66+ neutrophils (TANs) together with decrease of CD4-CD8-CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of myeloid and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells display an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCMSS/pMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCMSS/pMMR.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The interferons (IFNs) were discovered in 1957, and recombinant IFN-β-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for MS in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN-β-1a phase 3 trial was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN-β-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN-β-1a is associated with an increased incidence of injection site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians’ ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and monitoring. MRI studies show that treatment with IFN-β-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN-β-1a, several high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events. For some subpopulations of patients, including pregnant women, the safety profile of IFN-β formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate therapeutic opportunities for IFN-β in the treatment of viral infections such as COVID-19.

Several vaccines against COVID -19 have been developed and licenced to enhance the immune response against SARS-CoV-2. Similarly, infection with SARS-CoV-2 before vaccination has been shown to provide significant protection against severe infection and hospitalisation. The aim of this study was to investigate the effect of three doses of Sinopharm vaccine and SARS-CoV-2 infection on the specific immune response in 103 volunteers, measuring neutralizing antibodies, anti-S1 IgG, anti-RBD IgM, anti-N IgM, anti-N IgG antibodies and interferon γ. Our results showed that the presence of cardiovascular diseases increased the level of anti-N-IgG antibodies, while endocrinological diseases decreased the level of neutralizing antibodies and anti-N-IgG antibodies, suggesting that these diseases alter the effect of vaccine immunity. In addition, there was a significant decrease in anti-S1 IgG levels 6 months and in anti-N IgG levels 18 months post-infection, while neutralizing antibody and interferon γ levels were constant at 3, 6 and 18 months post-infection. Therefore, our results confirm the importance of hybrid immunity as the strongest and most durable compared to exclusively natural or vaccine-induced immunity. Significant positive correlations were found between humoral and cellular immunity markers: neutralizing antibodies, anti-S1 IgG, anti-N IgG and interferon γ, indicating a unique coordinated response specific to COVID-19.

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.

Interferons were the original prototype cytokine system discovered in 20th-century research. As the name implies, they were originally thought to be synthesised and secreted between cells. Thanks to technological advances, the processes involved in protein secretion can be explained comparatively more clearly at both the genetic and biochemical levels. The discovery of interferon (IFN) occurred when genetic research was still in its infancy. Franklin and Wilkins discovered the structure and function of deoxyribonucleic acid (DNA) at the same time as Crick and Watson; however, Isaacs and Lindemann, two scientists, described the first IFN in 1957. Mutations can be caused by inherent genetic protein synthesis and during infection as well as within IFN regulation pathways affecting cell proliferation. This remains central to host cell IFN synthesis and effects through IFN protein receptor subunits defined by 6 protein domains. Type II IFN is key to immune cell function secreted by a variety of immune cells, mainly natural killer (NK) as well as T cells. Single–stranded and/or double–stranded RNA/DNA viruses, as well as bacterial infections (e.g., Escherichia coli) and fungal infections (e.g., Aspergillus), also affect IFN regulation. Pathogenic proteins utilise intra/extracellular proteins that sense foreign antigens like Toll–like Receptors (TLRs), affected by mutations within the human cellular IFN transduction pathways. Since the discovery of the third IFN type in 2003, when immune cell phenotypes were further characterised, questions remain about the immunological mechanisms contributing to the regulation of the innate and adaptive host immune system. Alterations in the synthesis of type I/II/III host IFNs can differentially and beneficially alter homeostatic cellular pathways in pathological disease, with type I IFN being synthesised in cancer as well as by homeostatic cells. Therefore, considered here are the overall IFN molecular, cell regulatory mechanisms in the context of immune cell research developments.

Interferon-gamma (IFN-γ) is an important cytokine in host defense against tuberculosis infection. In some cases, administration of IFN-γ during tuberculosis infection can promote faster cure. In the present work, we have shown that in a mouse model, human interferon-gamma, exhibits some anti-tuberculosis activity, especially in combination with isoniazid.

Catalytic hydrogenation of a biomass-derived molecule, levulinic acid (LA) to γ-valerolactone (GVL) has been getting a lot of attention from researchers across the globe recently. This is because GVL has been identified as one of the potential molecules for the replacement of fossil fuels. For instance, GVL can be catalytically converted into liquid alkenes in the molecular weight range close to that found in transportation fuels via a process that does not require an external hydrogen source. Noble and non-noble metals have been used as catalysts for the selective hydrogenation of LA to GVL. Of these, Ru has been reported to be the most active metal for this reaction. The type of metal supports and solvents has been proved to affect the activity, selectivity, and yields of GVL. Water has been identified as a potential, effective “green” solvent for the hydrogenation of LA to GVL. The use of different sources of H2 other than molecular hydrogen (such as formic acid) has also been explored. In a few instances, the product, GVL, is hydrogenated further to other useful products such as 1,4-pentanediol (PD) and methyl tetrahydrofuran (MTHF). This review selectively focuses on the potential of immobilized Ru catalysts as a potential superior catalyst for selective hydrogenation of LA to GVL.

The diamondback moth, Plutella xylostella (Linnaeus), is one of the notorious pests causing substantial loses to many cruciferous vegetables across the nations. We have got the result that 200Gy dosage irradiated 6-day male pupae of P. xylostella inducing F1 generation sterile. First, in our research, we detected Oxidase system and stress response mechanism of irradiated pupae, the results displayed that 200Gy irradiation significantly alters the antioxidant enzyme regulation in 6-day male pupae of P. xylostella. The level of SOD, CAT were increased significantly in contrast the level of POD and GST were decreased in 12-24h post-treatment. The heat shock proteins (Hsps) gene expression level was significant increasing, maximum > 2 folds up-regulation of genes were observed in peak. But they also had a trend of gradual recovery with development. Second, in order to explore the irradiated sterility further, we detected the testis LDH and ACP activity found that in male adults testis they increased significantly than control during its development. Thus the present research investigation highlights that the ⁶⁰Co-γ radiation treatments alters the physiological development of diamondback moth. The results showed that 200Gy dosage resulted stress damage to the body and reproductive system of the diamondback moth.

Mammalian species possess sophisticated innate immune mechanisms that collectively combat a wide array of viral pathogens. Among these, the well-characterized interferon (IFN) response has been extensively researched; however, the role of antiviral RNA interference (RNAi) in mammals is emerging as an area of significant interest. Previous research has noted that Dicer, an enzyme crucial for processing double-stranded RNA (dsRNA), exhibits reduced activity in vitro, and that the IFN response may overshadow or inhibit the antiviral functions of RNAi in mammalian cells. Consequently, the functional relevance of RNAi in antiviral defense within mammalian somatic cells remains an open question. The evolution of antiviral systems in human populations reflects their substantial advantages, paralleling the evolutionary pressure on genomes encoding such defense mechanisms. While the well-studied protein-guided immune responses in mammals are essential for survival in viral environments, small RNA-mediated antiviral systems, which utilize complementary base pairing to silence non self-genetic material, also play a crucial role. In mammals, evidence suggests that microRNAs (miRNAs) regulate genes integral to antiviral responses, and emerging data indicate that small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNAs (tRNAs) can directly target virus-derived nucleic acids. This review aims to highlight some of the recent progress in understanding mammalian antiviral RNAi mechanisms.

Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.

Survival following Ebola virus (EBOV) infection correlates with the ability to mount an early and robust interferon (IFN) response. The host IFN-induced proteins that contribute to controlling EBOV replication are not fully known. Among the top genes with the strongest early increases in expression after infection in vivo is IFN-induced HERC5. Using a transcription- and replication-competent VLP system, we showed that HERC5 inhibits EBOV virus-like particle (VLP) replication by depleting EBOV mRNAs. The HERC5 RCC1-like domain was necessary and sufficient for this inhibition and did not require zinc finger antiviral protein (ZAP). Moreover, we showed that EBOV (Zaire) glycoprotein (GP) but not Marburg virus GP antagonized HERC5 early during infection. Our data identifies a novel ‘protagonist-antagonistic’ relationship between HERC5 and GP in the early stages of EBOV infection that could be exploited for the development of novel antiviral therapeutics.

This study aimed to investigate the effect of potassium poly-γ-glutamate (PGA-K) on mice fed a high-fat diet consisting of 60% of total calories for a duration of 12 weeks. PGA-K administration reduced the increase in body weight, epididymal fat, and liver weight caused by a high-fat diet compared to the obese group. The triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, which are blood lipid indicators, were significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. The administration of PGA-K resulted in a significant inhibition of pro-inflammatory cytokines, including tumor necrosis factor α and interleukin 6. Moreover, the levels of leptin and insulin, which are insulin resistance indicators, significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. These results suggest that PGA-K exhibits a protective effect against obesity induced by a high-fat diet, underscoring its potential as a candidate for obesity treatment.

The adaptation of plants to biotic and abiotic stress depends on their abilities to sense their surroundings and to generate and transmit corresponding signals to different parts of their body that can evoke changes necessary for optimizing growth and defense. Light has been shown to be one of the key environmental factors that modulate the physiology of both plants and animals via the diverse photoreceptors found in them. Both plants and animals contain a large repertoire of intra- and intercellular signals molecules that include organic and inorganic. One such molecule is a neurotransmitter, γ-aminobutyric acid (GABA), a non-protein amino acid, that rapidly accumulates in plant tissues in response to biotic and abiotic stress and regulates plant growth. Lots of research has been done on GABA in plants for slightly more than half a century now: Its discovery in plant tissues was immediately followed by physiological and biochemical studies. Thereafter molecular-genetics era of cloning the genes encoding the GABA shunt enzymes and transporters, and recombinant expression and purification of the enzymes in vitro to elucidate their regulatory properties and substrate specificity was established. Recently the discovery of the first bona fide GABA target proteins in plants, the ALMTs suggest that GABA indeed could be one of the signaling molecules in plants. All this research did not address in detail the relationship between light and GABA. To better understand the role of GABA in relation to light we set up six light conditions to investigate the changes in the hypocotyl and root growth in Arabidopsis thaliana under different light conditions, including total light, total dark, light blocker, gradient light, shoot dark, shoot dark with blocker. We treated the seedlings with 3-MPA, a GABA inhibitor, using different concentrations grown under different light conditions between 24 to 96 h. Our results show that both the root and hypocotyl are modulated by GABA when grown under different light conditions. These results clearly suggest a link in the signaling pathway of GABA with photoreceptor signaling pathways.

Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues should modulate tumor immunity. We found that a transient histamine synthesis was induced in CD11b⁺Gr-1⁺splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when they were co-cultured with CT-26 cells. Significant levels of IFN-γ were produced under this co-culture condition. We explored the modulatory roles of histamine on IFN-γ production and found that several histamine receptor antagonists, such as pyrilamine, diphenhydramine, JNJ7777120, and thioperamide, could significantly suppress IFN-γ production. However, suppression of IFN-γ production by these antagonists was also found when splenocytes were derived from the Hdc^-/- BALB/c mice. Suppressive effects of these antagonists were found on IFN-γ production induced by concanavalin A or the combination of an anti-CD3 antibody and an anti-CD28 antibody in a histamine-independent manner. Murine splenocytes were found to express H₁ and H₂ receptors, but not H₃ and H₄ receptors. IFN-γ production in the Hh1r^-/- splenocytes induced by the combination of an anti-CD3 antibody and an anti-CD28 antibody was significantly suppressed by these antagonists. These findings suggest that pyrilamine, diphenhydramine, JNJ7777120, and thioperamide could suppress IFN-γ production in activated splenocytes in histamine-independent manner.

In this investigation magnetic γ-Al2O3 ceramic nanocomposite particles bearing epoxide functionality are prepared following a multistep process. The ultimate nanocomposite particles are named as γ-Al2O3/Fe3O4/SiO2/poly(glycidyl methacrylate (PGMA). The surface property is evaluated by carrying out the adsorption study of Remazol navy (RN), a model reactive azo dye, on both γ-Al2O3/Fe3O4/SiO2 and γ-Al2O3/Fe3O4/SiO2/PGMA nanocomposite particles. The adsorption is carried out at the point of zero charge (PZC) to neutralize the effect of particle surface charge. The adsorption rate is very fast, reached equilibrium (qe) value within five min. Due to mesoporous structure of silica layer γ-Al2O3/Fe3O4/SiO2 nanocomposite particles possessed relatively higher specific surface area and magnitude of adsorption is dependent on the total specific surface area. The introduction of epoxide functionality favored high adsorption capacity in mass per unit surface area. The adsorption process strictly followed Langmuir model. Thermodynamic equilibrium parameters implied that irrespective of surface functionality the adsorption process is spontaneous and exothermic. Pseudo-second-order rate kinetic model is more appropriate to explain the adsorption kinetics.

We have drawn a few interesting conclusions while studying reaction products of Ph₂Si(OH)₂ with Al(ⁱBu)₃ and tetraisobutylalumoxane. In the first place, this is the production (at Ph₂Si(OH)₂ and Al(ⁱBu)₃ equimolar ratio) of oligomer siloxyalumoxane structure with alternating four- and six-member rings, as well as isobutyl and phenyl groups migration between aluminum and silicon due to the formation of intramolecular four-member cyclic complex [Ph₂(OH)SiO]Al(ⁱBu)₂ → [(ⁱBu)Ph(OH)SiO]Al(ⁱBu)Ph. Ph₂Si(OH)₂ interaction with Al(ⁱBu)₃ not only starts from intramolecular complex production, but the chain is terminated for the same reason, which in the case of Ph₂Si(OH)₂ reaction with tetraisobutylalumoxane results in failure of obtaining high-polymer siloxyalumoxane compounds. When Al(ⁱBu)₃ interacts with α- and γ-diols, no oligomer compounds are produced. Al(ⁱBu)₃ reaction with α, γ-diols results in monomer compounds that are likely to have cyclic structure. Notably at Al(ⁱBu)₃ interaction with α-diol only double excess of Al(ⁱBu)₃ allows full replacement of hydrogen in α-diol hydroxyl groups by aluminum alkyl residue with 1,3-bis(diisobutylalumoxymethyl)-1,1,3,3-tetramethyldisiloxane production. At equimolar ratio of initial reagents the second isobutyl radical at Al does not interact with the second hydroxyl group of α-diol, apparently due to the steric hindrance and 1-(diisobutylalumoxymethyl)-3-(hydroxymethyl)-1,1,3,3-tetramethyl-disiloxane is produced. Al(ⁱBu)₃ reactions with γ-diol also result in monomer compounds but the presence of a chain consisting of three СН₂-groups between Si and hydroxyl group facilitates interaction between the second hydroxyl group of γ-diol and the second isobutyl radical Al(ⁱBu)₃. Tetraisobutylalumoxane reaction with α- and γ-diols results in oligomer compounds.

Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are 6 species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD disease pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically-contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post treatment. To assess the interferon stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ were evaluated. Secreted ISGs blocked recombinant VSV expressing EBOV GP (rVSV/EBOV GP) infection, but failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction of the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach.

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases like metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex, which affects Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most HS reported cases do not follow a simple genetic pattern. In this article, we performed a whole-exome sequencing (WES) on a cohort of 100 individuals with HS and we provide a comprehensive review of the variants known to be described or associated with HS, referencing 91 of them in the γ-secretase and 78 in other genes involved in the Notch pathway, keratinization, or immune response. From this new genetic analysis, we add ten new variants to these catalogs.

This study concentrates on assessing the insecticidal attributes of γ-Al2O3 nanoparticles derived from remnants of Mentha pulegium, which include essential oil, ethanolic extract, and plant waste. The synthesis of γ-Al2O3 nanoparticles was executed via a direct sol-gel procedure, affirming the crystal structure through extensive physicochemical analyses such as UV-VIS, XRD, FTIR, and SEM. The evaluation of insecticidal activity in vitro was conducted against Xylosandrus crassiusculus, a pest that infests carob wood, utilizing strains from diverse forests in the Khenifra region, situated in the Moroccan Middle Atlas. The lethal doses 50 ranged from 40 mg/g to 68 mg/g, indicating moderate effectiveness compared to the commercial insecticide Permethrin. The optimization of the conditions for the efficiency of γ-Al2O3 nanoparticles was determined by experimental plans, revealing that time, humidity, and temperature were influential factors in the lethal dose 50 of these nanomaterials. Moreover, this study encompasses the establishment of correlations through Principal Component Analysis (PCA) and Ascending Hierarchical Classification (AHC) among various geographic, biological, and physical data, amalgamating geographic altitude, γ-Al2O3 nanoparticle insecticide parameters, as well as the attributes of mechanical tests conducted on carob wood affected by insects. The correlation highlights a close connection between the effectiveness of the insecticide, mountain altitude, and the mechanical parameters that were examined. Ultimately, these nanoparticles demonstrate promising potential as alternative insecticides, thus opening encouraging prospects for safeguarding against carob wood pests.

Emerging evidence demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human research aims to investigate therapeutic effects of daily GO tea consumption on the improvement of blood pressure, relaxation-related brain waves and quality of life (QOL) during a period of 28 consecutive days. Total polyphenols, major catechins and free amino acids were analyzed via HPLC assay. Changes of heart rate, blood pressure, α-brain wave (index of relaxation) and eight-item QOL score were investigated on day 0, 7, 14, 21 and 28, respectively. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, daily drinking GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p < 0.05, respectively). For participants with pre-hypertension, GO tea could effectively reduce heart rate, systolic and diastolic blood pressure on day 28 (p < 0.05). At the end of the study, incremental changes in alpha-brain wave and QOL scores were also demonstrated (p < 0.05, respectively). This study recommended that GO tea might potentially serve as a natural source of alternative therapy to benefit blood pressure, stress-relief and QOL.

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.

Background Cytomegalovirus (CMV) is a major pathogen that cause remarkable rate of morbidity and mortality, especially in immunocompromised patients. It is important to find risk factors associated with CMV viremia. We studied the differences in CMV seropositivity in relation to liver function biomarkers in male and female Saudi population in an attempt to understand the variation in the CMV seroprevalence with sex and find the risk factor to develop liver dysfunction or hepatocellular carcinoma. Material and subjects: The CMV- IgG and IgM were screened in serum samples of 150 non- A-G hepatities patients with elevation of liver profiles (ALT, AST, ALP and GGT) and categorized as males and females. Samples were collected from different general hospitals and polyclinic in KSA from March 2014 to June 2015. A correlation between CMV seropositivity measured with both antibodies and liver enzymes were tested. Receiver operating characteristics (ROC) analysis and multiple regressions were done for the obtained data. Results: Our study shows that females had much higher IgG and IgM compared to age-matching males. A significant correlation between both antibodies and liver enzymes (AST, ALT) was recorded. Less significant correlation of both IgG and IgM with GGT was also observed. Receiver operating characteristics (ROC) analysis revealed that both IgG and IgM can be used as excellent predictive markers for CMV infection as both recorded 100% specificity and sensitivity together with area under the curve of 1 in males and females. Multiple regression analysis ascertain the correlation between both antibodies as dependent variables and liver enzymes as independent variables with ALT being the most affected enzyme with CMV seropositivity especially in females. Conclusion:he data discussed above This study shows that CMV is capable of initiating and accelerating liver dysfunction in both sexes. The high seroprevalence in females at reproductive age is especially important as they can transmit the virus to their developing fetus. Prevention of CMV infection in young girls 11-14 years old, through counseling on hygiene or possible future vaccination, may lead to a decrease of congenital CMV infections with the concomitant risk of developing liver dysfunction or hepatocellular carcinoma. Keywords: Cytomegalovirus, Alanine transaminase, Aspartate transaminase Alkaline phosphatase, γ-Glutamyltranspeptidase, liver function.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.

As more cases of COVID-19 are studied and treated world-wide, it had become apparent that lethal and most severe cases of pneumonia are due to an out-of-control inflammatory response to the SARS-CoV2 virus. I explored the putative causes of this specific feature through a detailed genomic comparison with the closest SARS-CoV-2 relatives isolated from bats, as well as previous coronavirus strains responsible for the previous epidemics (SARS-CoV, and MERS-CoV). The high variability region of the nsp3 protein was confirmed to exhibit the most variations between closest strains. It was then studied in the context of physiological and molecular data available in the literature. A number of convergent findings point out de-mono-ADP-ribosylation (de-MARylation) of STAT1 by the SARS-CoV-2 nsp3 as a likely cause of the cytokine storm observed in the most severe cases of COVID-19. This may suggest new therapeutic approaches and an assay to predict the virulence of naturally circulating SARS-like animal coronaviruses.

1) Background: The Aicardi-Goutières syndrome (AGS) is a rare congenital disease which courses with severe psychomotor delay in neurodevelopment. We studied a 3-years and 4-months old child with very important growth and weight affectation, microcephaly and loss of his developmental skills from 16-months of age, in which previous metabolic and genetic studies discarded any abnormality. Therefore diagnosis was cerebral palsy of unknown etiology. He presented spastic paraparesia, poor fine motricity, cognitive impairment and absence of oral communication. One year after discharge, a de novo mutation was detected in a single nucleotide in the gene IFIH1: c.2317G>C, being then diagnosed of AGS. 2) Methods: Blood analysis showed very low IGF-1 and slightly elevated liver transaminases. Treatment consisted in GH (0.04 mg/kg/day), melatonin (20 mg/day, and after 3-months 50 mg/day), and daily intense neurorehabilitation (5 days/week). Tests for evaluating childhood developmental milestones (GMFM-88, BDIST and the WeeFim test) were carried out every 3-months. 3) Results: The equivalent age at admission (10-months) increased to 24-months at discharge. There were clear improvements in spasticity, fine motor function, swallowing, cognition and autonomy as well as in communication, growth and weight. 4) Conclusion: Most likely melatonin blocked or decreased the interferon signature, allowing GH and neurorehabiltation to act on neurodevelopment.

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

Zoon balanitis (ZB) is a mild and chronic inflammatory dermatosis that mostly affects uncircumcised men of middle and old age. The etiology of this disease remains unknown. Moreover, some authors have questioned the presence of this type of balanitis. Our study aimed to assess the expression of proinflammatory cytokines in ZB and demonstrate the presence of a characteristic expression pattern, different from that reported in the literature for penile lichen sclerosus(LS) and penile cancer. Skin biopsies from four foreskins affected by Zoon’s balanitis with surrounding morphologically unchanged skin and 13 from nonlesional foreskins (healthy control adult males undergoing circumcision) were obtained. RNA was extracted from each biopsy, followed by quantitative assessment of the gene expression of interleukin 1-A(IL-1A), interleukin 1-B(IL-1B),interleukin 1 receptor antagonist(IL-1RN),interleukin 6(IL-6), transforming growth factor β1(TGF-β1), and interferon-gamma(INF-γ). The decreased level of IL-1A mRNA was observed in Zoon’s balanitis in both inflamed and healthy skin compared to control samples. There were no statistically significant differences in other investigated cytokines gene expression between Zoon’s balanitis and the control group. In conclusion, the expression of proinflammatory cytokines was not related to the course of zoon balanitis. Moreover, in the case of IL-1A, we observed the suppression of the immune response.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

Glutamate decarboxylase (L-glutamate-1-carboxylase, GAD; EC 4.1.1.15) is a pyridoxal 5-phosphate-dependent enzyme, which catalyzes the irreversible α-decarboxylation of L-glutamic acid to γ-aminobutyric acid (GABA) and CO2. The enzyme is widely distributed in eukaryotes as well as prokaryotes, where it – together with its reaction product GABA - fulfils very different physiological functions. The occurrence of gad genes encoding GAD has been shown for many microorganisms, and GABA-producing lactic acid bacteria (LAB) have been a focus of research during recent years. A wide range of traditional foods produced by fermentation based on LAB offer the potential of providing new functional food products enriched with GABA that may offer certain health-benefits. Different GAD enzymes and genes from several strains of LAB have been isolated and characterized recently. GABA-producing LAB, biochemical properties of their GAD enzymes, and possible applications are reviewed here.

Anti-diabetic effects of Glycine soja seed extract (GS) on Type 2 diabetes mellitus mouse model and human hepatocytes induced insulin resistance were investigated. 3 weeks old db/db mice were divided into 5 groups (n = 6) including two control groups and 3 GS treated groups with different doses. Oral administration of GS for 6 weeks to diabetic db/db mice reduced blood glucose level significantly in a dose dependent manner by 44.7% (300 mg/kg/day), 30.9% (150 mg/kg/day) and 21.1% (75 mg/kg/day). GS treatment also lowered significantly plasma level of HbA1c, insulin, IGF-1 and leptin, and increased that of adiponectin. GS treatment activated AMPK, and down-regulated GLUT2 in liver tissues of mice while up-regulated GLUT4 in muscle tissues of mice. In in vitro study with insulin resistance induced human hepatocyte, GS treatment increased glucose uptake and increased the activities of Akt and PPAR-γ in response to insulin. Treatment of GS appears to reduce blood glucose level by regulating energy metabolism positively through various metabolic pathways and reducing insulin resistance in Type 2 diabetes mellitus.

Anti-diabetic effects of Glycine soja seed extract (GS) on Type 2 diabetes mellitus mouse model and human hepatocytes induced insulin resistance were investigated. 3 weeks old db/db mice were divided into 5 groups (n = 6) including two control groups and 3 GS treated groups with different doses. Oral administration of GS for 6 weeks to diabetic db/db mice reduced blood glucose level significantly in a dose dependent manner by 44.7% (300 mg/kg/day), 30.9% (150 mg/kg/day) and 21.1% (75 mg/kg/day). GS treatment also lowered significantly plasma level of HbA1c, insulin, IGF-1 and leptin, and increased that of adiponectin. GS treatment activated AMPK, and down-regulated GLUT2 in liver tissues of mice while up-regulated GLUT4 in muscle tissues of mice. In in vitro study with insulin resistance induced human hepatocyte, GS treatment increased glucose uptake and increased the activities of Akt and PPAR-γ in response to insulin. Treatment of GS appears to reduce blood glucose level by regulating energy metabolism positively through various metabolic pathways and reducing insulin resistance in Type 2 diabetes mellitus.

Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of pro-inflammatory and immune-regulatory cytokines and cytokine-induced stimulation of indoleamine-2,3-dioxygenase (IDO). There is also some evidence that anti-inflammatory drugs may have a clinical efficacy in MDD.The aim of this study is to examine the clinical effects of an eight-week combinatorial treatment of ketoprofen (a nonsteroidal anti-inflammatory drug) combined or not with sertraline, on serum levels of IDO, interferon (IFN)-γ, interleukin (IL)-4 and transforming growth factor (TGF)-β1 in association with changes in the Beck-Depression Inventory-II (BDI-II). The study included 140 MDD patients and 40 normal controls. The pre-treatment serum levels of IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients compared with the control group. Treatment with sertraline with or without ketoprofen significantly reduced the increased baseline production of all 4 biomarkers to levels which were similar as those of normal controls. Ketoprofen add-on had a significantly greater effect on IDO and BDI-II as compared with placebo. The reductions in IDO, IL-4 and TGF-β1 during treatment were significantly associated with those in the BDI-II.In conclusion, the clinical efficacy of both sertraline + ketoprofen may be ascribed at least in part to attenuated IDO levels and immune-inflammatory responses in MDD. Moreover, add-on treatment with ketoprofen may augment the efficacy of sertraline by attenuating IDO. However, these treatments may also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) immune subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD, while enhancing the compensatory immune-regulatory system (CIRS).

Interferon-gamma release assays (IGRAs) gained attention for diagnosing latent tuberculosis infection (LTBI) due to their higher specificity compared to the tuberculin skin test (TST). However, IGRA performance varied across different populations. This study evaluated the diagnostic performance of three IGRA assays (TBF-FIA, TBF-ELISA, and QFT-Plus) in Ghana, comparing them among individuals exposed and unexposed to MTB infection. Conducted in TB clinics across three regions, this prospective and cross-sectional study included healthy individuals with no known TB exposure (unexposed group) and patients with confirmed active TB (exposed group). Blood samples were tested using all three assays per manufacturers’ guidelines. The TBF-ELISA showed 3.4% higher sensitivity, but 4.6% lower specificity compared to QFT-Plus. The TBF-FIA had a sensitivity of 78.5%-87.3% and a specificity of 82.9%-90.0%. These findings indicated that while the three IGRA assays offered similar diagnostic accuracy, variations in specificity and limited data on point-of-care assays like TBF-FIA required further investigation.

This study investigated the influence of single nucleotide polymorphisms (SNPs) in genes asso-ciated with the interferon pathway (IFNAR2 rs2236757), antiviral response (OAS1 rs10774671, OAS3 rs10735079), and viral entry (ACE2 rs2074192) on COVID-19 severity and their association with non-alcoholic fatty liver disease (MAFLD). We did not observe a significant association between the investigated SNPs and COVID-19 severity. While the IFNAR2 rs2236757 A allele correlated with higher creatinine levels upon admission and the G allele with lower band neu-trophils upon discharge, these findings require further investigation. The distribution of OAS gene polymorphisms (rs10774671, rs10735079 did not differ between MAFLD and non-MAFLD patients. Our study population's distribution of ACE2 rs2074192 genotypes and alleles differed from the European reference population. Overall, our findings suggest that these specific SNPs may not be major contributors to COVID-19 severity in our patient population, highlighting the potential role of other genetic factors and environmental influences.

A Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by a complex interplay of genetic, molecular, and cellular factors. It is considered a multifactorial disorder influenced by genetic susceptibility, environmental triggers, and dysregulated immune responses. Understanding the molecular and cellular mechanisms driving SLE pathogenesis has been instrumental in developing targeted therapies to manage the disease and improve patient outcomes. In this essay, we will delve into the intricate molecular and cellular processes underlying SLE and examine the key lessons learned from human therapies.

The evolutionary conserved STING-cGAS pathway represents one of the most important cytosolic DNA sensing systems that is activated in response to viral invasion and/or damaged integrity of the nuclear envelope. The key outcome of this pathway is the production of IFN, which subsequently stimulates hundreds of genes. In oncology, the situation is a complex one since this pathway may serve either anti- or pro-oncogenic roles in a context-dependent fashion. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as from ruptured micronuclei, it results in the production of interferon which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression. In these cells, the pathway initiates a non-canonical nuclear factor κB transcriptional response, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in conjunction with cancer progression and development of new treatment modalities.

A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between either the tick or mosquito vector to small mammals (e.g. rodents, skunks) and reptiles to non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continue to be reported. In addition to in humans, viral persistence can also be established in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines in culture. Although a considerable amount of research has focused on the potential roles of defective virus particles, autophagy and/or apoptosis induced evasion of the immune response, the precise mechanism of flavivirus has yet to be elucidated. In this review, we present findings that aid in further understanding of how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in viral persistence, the development of relevant animal models of viral persistence, and investigating the host responses that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral–host relationships in wildlife animals and could be used to elucidate the mechanisms for the establishment of viral persistence in these animals.

As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanisms of SARS-CoV-2, the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS. Interferons have shown to play a crucial role in the defense against coronavirus diseases. CoV can impede the interferon induction in humans. Moreover, STAT1, a key protein in the interferon-mediated immune response, is antagonized by the virus. This could explain the increased response threshold of immune cells to IFNs during CoV infections. A vivid correlation between the innate immune response threshold and the fatality rates in COVID-19 can be found. Differences in the dynamics of the interferon-related innate immune responses in children, adults, and elderly may explain the reported fatality rates. The increased mortality rates in the elderly can be explained by the higher threshold of interferon-mediated immune responses. Earlier induction of interferons in children and their less developed immune system could contribute to their near to zero fatality rate. Administration of interferon-inducing agents, such as poly (ICLC), could reduce the mortality of SARS at the very early stages of the disease. Interferon-γ combination with an interferon-I might induce synergistic effects and maximize the benefits. However, in-depth research is needed to validate it and determine the optimum dosage and timing to prevent unwanted results. Such interventions can act as a double-edged sword and aid the imbalance of the immune reactions, which may occur at the later stages of the disease. With the advancement of the disease and the virus overload, the responses would shift toward immnopathogenic over-reactions and probably cytokine storm. Moderating the activity of the immune system and supportive care in such conditions might be the optimum approach.

The structural stability of γ-boron is investigated using Raman spectra under high pressures up to 126 GPa at ambient temperature. The pressure dependence of all the Raman-active modes of the γ-boron is reported. We also observe amusing changes within the B3g and B1g Raman-active vibrational modes, which results in the phenomenon of merging first and then separating of the Raman peaks. In addition to the Raman measurements, the changes in crystal structure and force constants are calculated to reasonably explain the discrepancy between the two Raman modes in response to pressure. The results of the continuous shifts for all Raman modes with increasing pressure indicate that γ-boron remains stable below this pressure value, with no changes in either symmetry or structure.

PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we showed that cell lines vary based on their antioxidation potential at basal conditions. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein-coding transcripts, and 4.2k non-coding RNAs relative to control cells treated with non-specific siRNAs. Among the coding genes, ~200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with regulation of type 1 interferons (IFN) and induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated by non-specific siRNAs that were used as a negative control. Beyond the antiviral response, 114 genes were specific to KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) were associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that KD of DJ-1 diminish its protective potency against oxidative stress, rendering the cells labile and responsive to dsRNA signal by activation of a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its crucial role in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 is highly expressed in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of DJ-1 levels may reduce cancer cell viability and enhance the efficacy of cancer treatments.

Emerging paradigms in interferon (IFN) biology suggest a dynamic INF induced interactome that extends through broader Interferon Stimulated Gene (ISG)- induction, which implicates interferon- ISG coordinated cross-talk with mRNA processing, post-translational modification and metabolic processes that underlie pathological (viral, autoimmune and tumor biology) and physiological (stem cell regenerative pathways) processes. INF immune responses can also be triggered by endogenous host-derived molecules that are generated in response to cellular stress or hemostasis imbalance to establish tissue repair and regeneration in first place, however, overactivation or lack of countermeasures can result in host tissue damage. The proteases are integral to viral and tumor pathology, and importantly serine proteases TMPRSS2 and trypsin have been identified as important molecular determinants underlying COVID-19 pathology, and emergence of coronaviruses cultured in vitro, respectively. We propose that pathogen associated proteases can act as novel stress-inducers to facilitate viral- competent immunomodulation. We term it as Protease Induced Transcriptomic/ epi-Transcriptomic Reshaping (PITTR) of host cells to counter cellular stress. We present a novel experimental model and our preliminary findings of trypsin- primed Caco-2 cells (CPT) that result in translational halt comparable to cells grown under serum-starvation conditions (CSS). CPT at escalating trypsin concentration (CPT- EC) induce upregulation of selective proteins that majorly map to ribosomal, RNA transport, and spliceosome ribonucleoproteins (RNPs). The inclusion of proinflammatory IL1-b to CPT (CPT- IL) resulted in global overexpression of proteins comparable to Caco-2 cells cultured in growth-factor rich serum conditions (CFBS), indicating a likely de-repression of trypsin- induced translational halt. Caco-2 cells display abortive interferon proteome under differential trypsin conditions (CPT, CPT-EC and CPT-IL), which is marked by complete lack of INF generation despite induction of intermediate ISGs, suggestive of protease (trypsin)- dependent regulation of INF response. Viruses regulate the proteome of stress granules (SGs) that are induced to cope transient translational halt as a central adaptive response to pathogen induced cellular stress. The integral components of SGs include non-translating mRNA, ribonucleoproteins (RNPs) and RNA binding proteins (RBPs), which together form biological condensates through a biophysical process involving weak electrostatic interactions through intrinsically disordered regions in RBPs resulting in liquid- liquid phase separation. We compared the CPT- EC proteome to the Mammalian Stress Granules Proteome (MSGP) database to explore potential RBPs that could possibly regulate INF response (and could act as potential anti-viral targets). Notably, differentially upregulated RNPs and potential RBPs from ISG family including ADAR and PRKRA, and RNA helicases implicated in viral pathogenesis were found to be upregulated in the CPT- EC proteome further strengthening the role of proteases (trypsin) in regulating INF pathways independent of the pathogen. We propose that the supplementation of viable SARS-CoV-2 viral loads to trypsin- primed host cells could recapitulate an infectious disease model, which may closely phenocopy pathogen- driven inflammation and signaling events. Based on the global downregulation of seven SERPINS (serine protease inhibitors) linked to thromboinflammation in our LCMS profiling data, we support the candidature of serine protease inhibitors for protease mediated viral pathologies. COVID-19 is increasingly linked to coagulopathy and resemblance to Neutrophil Extracellular Trap (NET) related thromboinflammatory features; SERPIN A1AT (alpha 1 antitrypsin) being a potent neutrophil- elastase inhibitor and a negative regulator of coagulation complement pathway may be a promising candidate for establishing hemostasis rebalancing in COVID-19 pathology.

Previous studies have demonstrated that cold pools play a pivotal role in the initiation and organization of convection, yet their influence on the evolution of GFs remains inadequately understood. A destructive wind event associated with a rearward gust front (RGF, 8 grade gale appeared after passing GF) and a prior gust front (PGF, 10 grade gale appeared before passing GF) over the north coast of China on 10 June 2016 was analyzed. Using multiple observation data as well as the four-dimensional Variational Doppler Radar Data Assimilation System (VDRAS), we found that the intensity of the GFs increased with increasing cold pool strength, depth and propagation speed. Two schematic models were proposed to explain the discrepancy between GFs and associated cold pools. The depth and intensity of the cold pool in RGF are found to be relatively shallower and weaker, leading to a correspondingly reduced strength in both outflow and convergence. In contrast, the enhanced vertical shear and boundary northeaster inflow of PGF generate intensified and more organized downdrafts, resulting in a deeper cold pool, robust outflow, and convergence. These findings offer novel insights into the diversity of GFs and associated cold pools.

Graphyne is a material that has unique mechanical properties, but little is known about how these properties change when the material has holes. In this work, the effect of hole geometry, considering circular, triangle, and rhombus hole configurations, on the mechanical nonlinear response of γ-graphyne structures is studied. Graphyne, graphdiyne, graphyne-3, and graphyne-4 structures are under investigation. An efficient nonlinear finite element analysis (FEA) method is adequately implemented under large deformations for this purpose. The study varied the size and shape of the holes to understand how these changes affect the nanostructure's mechanical response. The results indicate that the hole geometry significantly impacts the mechanical nonlinear response of γ-graphyne structures. The holes' size and shape affect the structures' elastic behavior, deformation, and strength. The findings can be used to optimize the design of γ-graphyne structures for specific mechanical applications. The study highlights the importance of considering the hole geometries in the design and fabrication of these materials.

The effect of γ-ray irradiation on surface plasmon resonance (SPR) sensing capability of refractive index (n = 1.418–1.448) of the silica glass optical fiber comprised of germano-silicate glass cladding embedded with Au nano-particles (NPs) was investigated. As the γ-ray irradiation increased from 1 hour to 3 hours with the dose rate of 1,190 Gy/h, the morphology of the Au NPs and the SPR spectrum were found to change. The average diameter of Au NPs increased with the aspect ratio from 1 to 2 and the nano-particles became grown to the clusters. The SPR peak wavelength shifted towards longer wavelength with the increase of total dose of γ-ray irradiation regardless of the corresponding refractive indices. The SPR sensitivities (wavelength/refractive index unit, nm/RIU) also increased from 407 nm/RIU to 3,553 nm/RIU, 1,483 nm/RIU, and 2,335 nm/RIU after the γ-ray irradiation at the total dose of 1,190 Gy, 2,380 Gy, and 3,570 Gy, respectively.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Newcastle disease (ND) is a highly contagious and usually causes severe illness that affects Aves all over the world, including domestic poultry. Depending on the virus's virulence, it can impact the nervous, respiratory, and digestive systems and causes up to 100% mortality. The chIFITM genes are activated in response to viral infection. The current study was conducted to quantify the mRNA of chIFITM genes in vitro in response to ND viral infection. It also examined its ability to inhibit ND virus replication in Chicken Embryo Fibroblast (CEF) cells of Aseel and Kadaknath breeds. Results from the study showed that the expression of all chIFITM genes was significantly upregulated throughout the period in the infected CEF cells of both breeds compared to uninfected CEF cells. In CEF cells of the Kadaknath breed, elevated levels of expression of the chIFITM3 gene dramatically reduced the ND viral growth and the viral load was 60% lower than in CEF cells of the Aseel breed. The expression level of the chIFITMs in Kadaknath ranged from 2.39 to 11.68 log2 folds higher than that of control CEFs, and was consistently (p<0.01) higher than Aseel CEFs. Similar to this, IFN-γ gene expresses strongly quickly and peaks at 13.9 log2 fold at 48 hpi. The result suggests that the Kadaknath chicken breed may have a higher level of disease tolerance compared to the Aseel chicken.

Type III interferon (IFN-λs) exhibit potent antiviral activity and immunomodulatory effects in specific cells. Nucleotide fragements of bovine ifn-λ (boifn-λ) gene was synthetized after codon optimization. The boifn-λ gene was then amplified by splicing by overlap extension PCR (SOE PCR), resulting in serendipitous acquisition of the mutated boIFN-λ3V18M. Recombinant plasmids pPICZαA-boIFN-λ3/λ3V18M were constructed and the corresponding proteins were expressed in Pichia pastoris with high-level extracellular soluble form. Dominant expression strains of boIFN-λ3/λ3V18M were selected by Western blot and ELISA, cultured on a large scale, and the recombinant proteins purified by ammonium sulphate precipitation and ion exchange chromatography, yielding 1.5g/L and 0.3 g/L, with 85% and 92% purity, respectively. The antiviral activities of boIFN-λ3/λ3V18M exceeded 106 U/mg, were neutralized with IFN-λ3 polyclonal antibodies, were susceptible to trypsin, and retained stability within defined pH and temperature ranges. Furthermore, boIFN-λ3/λ3V18M exerted antiproliferative effects on MDBK cells without cytotoxicity at 104 U/mL. Overall, boIFN-λ3 and boIFN-λ3V18M did not differ substantially in biological activity, except for reduced glycosylation of the latter. Development of boIFN-λ3 and comparative evaluation with the mutant provide theoretical insights into antiviral mechanisms of boIFN-λs and provide material for therapeutic development.

The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2023, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease via the double methylation of the 5' end of eukaryotic DNA or RNA-based viral genomes, the 7-MeGpppA2’-O-Me cap, and its double methylation capping process is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16) and by N7-Methyltransferase (N7-MTase/NSP14), respectively. Moreover, it was discovered that polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), and consequently, detection of Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) alike. NSP1 also silences important interferon-encoding genes (INGs) and interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Another important viral NSP is NSP14, as it plays two functional roles that are independent of each other; to produce new viral genetic material for the purpose of maintaining the validity of the viral genome as well, and not just transfer a methyl group to the 5’ end of the viral genome. Other viral NSPs share a role with NSP1, 10, 14 and 16 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases.

The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to Old World mammarenavirus, these viruses are not able to completely suppress the innate immune response, and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their non-pathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor-protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to prevent the effect of PKR on viral protein translation and its viral titer is inhibited when PKR is pre-stimulated via IFN-I. Here, we provide first evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. IMPORTANCE: The mechanisms for innate immune evasion are key for emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses such as JUNV or MACV trigger a weaker IFN response than non-pathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. In this study, we found that TCRV protein expression and viral propagation are inhibited from early times after infection, and when externally activated, PKR inhibits TCRV viral progeny production. Our present findings further characterize the innate immune response in absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection.

DDX3 is an ATP-dependent RNA helicase involved in multiple cellular activities, including RNA metabolism and innate immunity. DDX3 is known to assist the replication of some viruses while restricting some others through direct interaction with the viral proteins. However, the role of DDX3 in the replication of the hepatitis E virus (HEV) is unknown. In this study, DDX3 is shown to interact with the HEV capsid protein and provide an indispensable role in HEV replication. The DDX3 C-terminal domain was demonstrated to interact with the capsid protein, which was previously demonstrated to inhibit the production of type I interferons. Knockdown of DDX3 compromised the capsid protein-mediated blockage of interferon induction. Notably, DDX3 silencing led to a significant reduction in HEV replication. Also, the ATPase activity of DDX3 is required for the HEV replication as an ATPase-null mutant DDX3 failed to rescue the viral replication in the DDX3-silenced cells. These results demonstrate a pro-viral role of DDX3 in HEV replication, providing further insights into the virus-cell interactions.

Indoor dusts are collectively formed from anthropogenic and atmospheric activities. Particle matter 10 (PM10) is inhalable and causes significant inflammation by interaction with the pulmonary epithelial barrier. The mediators involved in bronchial epithelial cells response to dust are remined unknown. The air-liquid interface of our lung on chip model was exposed to indoor dust collected from highly polluted houses in Delhi, India. The media were collected after 4 days and cytokine levels were measured. We found that the concentration of IFN, IFNγ, Interleukin-6 (IL-6), IL1b, TNFa, and Granulocyte monocyte colony stimulating factor (GM-CSF) were significantly increased after exposure to indoor dust. IFN type I pathways were a major response from dust exposure. Further investigation is needed to determine the mechanism of action and targets of dust in bronchial epithelial cells.

High circulating concentrations of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are significantly associated with the risk of obesity and type 2 diabetes (T2D). We aimed at evaluating the impact of glycemic control and bariatric surgery on circulating concentrations of TMAO and its microbiota-dependent intermediate, γ-butyrobetaine (γBB), in newly diagnosed T2D patients and morbidly obese subjects. An additional experiment was carried out in eight male C57BL/6J mice fed a Western-type diet for twelve weeks. The strategy for glycemic control in the T2D patients significantly improved the HbA1c concentrations without producing changes in the estimated glomerular filtration rate. However, the plasma TMAO and γBB concentrations were significantly increased following the glycemic control in T2D patients. Bariatric surgery was very effective in reducing weight in obese subjects. Nevertheless, the surgery reduced plasma γBB concentrations without affecting TMAO concentrations and the estimated glomerular filtration rate. Neither diet-induced obesity nor insulin resistance were associated with circulating TMAO and γBB concentrations in mice. Our findings do not support that glycemic control or bariatric surgery improve the circulating concentrations of TMAO in newly diagnosed T2D and morbidly obese patients. The contribution of antidiabetic drugs to gut microbiota composition could explain TMAO elevations in treated T2D subjects.

Arterivirus can establish persistent infection in animals such as equids, pigs, nonhuman primates, rodents, and possums. Some Arterivirus can even cause overt and severe diseases such as Equine Arteritis in horses and Porcine Reproductive and Respiratory Syndrome in pigs, leading to huge economic losses. Arterivirus have evolved viral proteins to antagonize the host cell’s innate immune responses by inhibiting type I interferon (IFN) signaling, assisting viral evasion and persistent infection. So far, the role of the Arterivirus glycoprotein 5 (GP5) protein in IFN signaling inhibition remains unclear. Here, we investigated the inhibitory activity of 47 Arterivirus GP5 proteins derived from various hosts. We demonstrated that all GP5 proteins showed conserved activity for antagonizing TIR-domain-containing adapter protein inducing interferon-β (TRIF)-mediated IFN- signaling through TRIF degradation. In addition, Arterivirus GP5 proteins showed conserved inhibitory activity against IFN-β signaling, induced by either pig or human TRIF. Furthermore, certain Arterivirus GP5 proteins could inhibit the induction of IFN-stimulated genes. These findings highlight the role of Arterivirus GP5 proteins in supporting persistent infection.

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the non-structural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and in particular the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. By contrast, MetPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent as MetPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

Keywords: Porcine reproductive and respiratory syndrome virus, baculovirus surface display vectors, neutralizing antibody, IFN-γ, IL-4.

Microbial immune escape represents the primary cause of induced pathogenesis in humans, and it represents a pivotal method used by viral agents to increase their load and suppress key mechanisms of the innate and adaptive immune system. This phenomenon represents the primary factor that led to the onset of the 1918-1920 A(H1N1) Influenza and 2020-2022 COVID-19 pandemics, and it possibly played a major role in the onset of the AIDS pandemic as well. Moreover, repeated incidents of immune evasion could be associated with higher rates of cellular aging (Jackson et al., 2017), most likely due to the consequent increased demands of energy consumption. Highly developed viral immune evasion ultimately indicates the high inner intelligence of human immunity due to reflective and imitative characteristics of reactions that are produced against initial actions. Ribonucleic acid-based viral genomes contain open reading frames, which consist of genes producing sixteen non-structural proteins. Such proteins play a considerable role in desensitizing first-line immunity during cellular infection, and non-structural proteins 1, 10 and 16 have the strongest effects against a healthy expression rate of Type I and Type III Interferon-encoding genes. Type I Interferons consist of IFN-alpha, -beta, -delta, -epsilon, -omega, -tau and -zeta, whilst Type III Interferons consist of IFN-lambda1, -lambda2 and -lambda3, and they act as stimulators of intracellular signalling cascades that in turn lead to the activation and expression of interferon-stimulated genes (Brown et al., 2022). The earlier the interferon-stimulated genes are activated, the lower the extent of pro-inflammatory mediation and overall, the more effective the antiviral immune response will be, given the exponential nature of the viral load increase. Non-structural protein 16 methylates the 5’ cap of the virus, making the pathogen-associated molecular patterns less recognisable by pattern-recognition receptors, and it requires activation by bonding with non-structural protein 10. It is preserved in the S-Adenosyl-L-Methionine pocket of the SARS-CoV-2 genome. Non-structural protein 1 (NS1) directly cleaves the host cell mRNA producing Type I and possibly Type III Interferons, thereby preventing a translation process of the immune proteins. NS1 has recently been found to often be packaged into exosomes once secreted by the viral genome in the cytosol, meaning that exocytosis and paracrine signalling to neighbouring cells before their actual infection is possible. As a result, NS1 is highly capable of silencing the first-line immune responses of uninfected neighbouring cells as well, thereby highlighting the need to adjust the focus of therapeutics and vaccinology toward first-line immunity and further indicating its foundational importance in the support for the development of precise and balanced defenses against microbial agents of concern (EL SAFADI et al., 2022).

Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogramme the tumour microenvironment. However, the antitumour immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumour potential in vitro in a model of 3D spheroids and in vivo in immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived IFN-g stimulated bone marrow macrophages to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoural administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumour growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intra-tumoural lymphoid cells isolated from tumours after SFV/IFNg treatment revealed an increase in CD4+ and CD8+ and a decrease in T-reg (CD4+/CD25+/FoxP3+) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38 and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumour T-cell response and inhibits myeloid cell infiltration in treated tumours.

Rift valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes an important disease in ruminants, with great economic losses. The infection can be also transmitted to humans; therefore it is considered a major threat to both human and animal health. In a previous work, we described a novel RVFV variant selected in cell culture in the presence of the antiviral agent favipiravir that was highly attenuated in vivo. This variant displayed 24 amino acid substitutions in different viral proteins when compared to its parental viral strain, two of them located in the NSs protein that is known to be the major virulence factor of RVFV. By means of a reverse genetics system, in this work we have analyzed the effect that one of these substitutions, P82L, has in viral attenuation in vivo. Rescued viruses carrying this single amino acid change were clearly attenuated in BALB/c mice while their growth in an IFN-competent cell line as well as the production of IFN-β did not seem to be affected. However, the pattern of nuclear NSs accumulation was modified in cells infected with the mutant viruses. These results unveil a new RVFV virulence marker highlighting the multiple ways of NSs protein to modulate viral infectivity.

Previously, we demonstrated that IR triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9, and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

The effects of heating rate before solution treatment and cooling rate after solution treatment on the morphological distribution and evolution of precipitation phase of nickel-based single crystal superalloy were studied. The dissolution, precipitation and growth of precipitation phase and matrix phase during heat treatment were analyzed by means of high power scanning electron microscopy. The results show that the morphology of precipitated phase has nothing to do with the distribution of precipitated phase and the heating rate in the heating process, but the cooling rate in the cooling process affects the shape, size and distribution of precipitated phase. The faster the cooling rate, the smaller the precipitated phase is, the more irregular the shape is, the smaller the equivalent edge length is, and the smaller the channel width of matrix phase is.

1) Background: Recently, illegal abuse of γ-hydroxybutyric acid (GHB) has increased in drug-facilitated crimes, but determination of GHB exposure and intoxication is difficult due to rapid metabolism of GHB. Its biochemical mechanism has not been completely investigated. And metabolomic study by polyamine profile and pattern analyses was not performed in rat urinefollowing intraperitoneal injection with GHB. 2) Methods: Polyamine profiling analysis by gas chromatography-mass spectrometry combined with star pattern recognition analysis was performed in this study. Multivariate statistical analysis was used to evaluate discrimination between control and GHB administration groups. 3) Results: Six polyamines were determined in control, single and multiple GHB administration groups. Star pattern showed distorted hexagonal shapes with characteristic and readily distinguishable patterns for each group. N¹-Acetylspermine (p < 0.001), putrescine (p <0.006), N¹-acetylspermidine (p <0.009), and spermine (p < 0.027) were significantly increased in single administration group but were significantly lower in the multiple administration group than in the control group. N¹-Acetylspermine was the main polyamine for discrimination between control, single and multiple administration groups. Spermine showed similar levels in single and multiple administration groups. 4) Conclusions: The polyamine metabolic pattern was monitored in GHB administration groups. N¹-Acetylspermine and spermine were evaluated as potential biomarkers of GHB exposure and addiction.

Orthohepadnavirus causes chronic hepatitis in a broad range of mammals, including primates, cats, woodchucks, and bats. Hepatitis B virus (HBV) X protein inhibits type-I interferon (IFN) signaling, promoting HBV escape from the innate immune system to establish persistent infection. However, whether X proteins of Orthohepadnavirus viruses in the other species have similar inhibitory activity remains unknown. Here, we investigated the anti-IFN activity of 17 Orthohepadnavirus X proteins derived from various hosts. We observed conserved activity of Orthohepadnavirus X proteins in inhibiting TIR-domain-containing adaptor protein inducing IFN-β (TRIF)-mediated IFN-β signaling pathway through TRIF degradation. X proteins from domestic cat hepadnavirus (DCH), a novel member of Orthohepadnavirus, inhibited mitochondrial antiviral signaling protein (MAVS)-mediated IFNβ signaling pathway comparable with HBV X. These results indicate that inhibition of IFN signaling is conserved in Orthohepadnavirus X proteins.

In this work, we explore the intrinsic disorder status of the three members of the synuclein family of proteins - α-, β-, and γ-synucleins. We also analyzed the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members to find potential effects of pathological mutations. Furthermore, we conducted a comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluated their levels of intrinsic disorder using a set of commonly used bioinformatics tools. Next, we conducted a detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members using various web-based disorder analysis and prediction tools, such as RIDAO, D2P2 and FuzDrop. We identify that the interactome of human α-synuclein has relatively higher levels of intrinsic disorder, as compared to the interactomes of human β- and γ- synucleins. These observations highlight the critical importance of intrinsic disorder of human α-synuclein and its interactors in neuronal processes as compared to other proteins of the synuclein family.

Introduction: Tuberculosis (TB) is one of the most prevalent respiratory diseases in the world. In 2020 there were at least 9.9 million new infections, with 1.5 million deaths. Approximately 10% of people infected with Mycobacterium tuberculosis (LTBI) develop the disease during the first 2 to 5 years after infection. Currently in South America, the diagnosis of LTBI continues to be per-formed through the Mantoux tuberculin skin test (TST). Objective: The objective of our study was to compare the sensitivity of a new immunofluorescence IGRA test against a widely available IGRA kit on the market. Material and method: Close contact to infectious patients with TB, or HIV patients or immunocompromised for another cause were recruited. Two interferon gamma release assay (IGRA) diagnostic kits were used and compared with TST. Results: 76 patients were recruited. 93.42% were Chilean nationality, 98.68% of the patients did not have immunosuppres-sion. The sensitivity of the new technique was 88.89% and specificity 92.50% in the study popula-tion compared to the IGRA previously used. In the subgroup older than 36 years, the sensitivity was 95.65% and the specificity 89.47%. Conclusion: IGRA techniques are a new resource in clini-cal laboratories to be able to make an accurate diagnosis in LTBI in the region of the Americas. In our population, the greatest benefit of this new IGRA would be observed in people over 36 years of age, where the sensitivity of the technique was like that of the currently available test.

Bats are reservoirs of many pathogenic viruses including the lyssaviruses rabies virus (RABV) and Australian bat lyssavirus (ABLV). Lyssavirus strains are closely associated with particular host reservoir species, with evidence of specific adaptation. Associated phenotypic changes remain poorly understood but are likely to involve P protein, a key mediator of the intracellular virus-host interface. Here, we examine the phenotype of P protein of ABLV, which circulates as two defined lineages associated with frugivorous and insectivorous bats, providing the opportunity compare proteins of viruses adapted to divergent bat species. We report that key functions of P protein in interferon/STAT1 antagonism and the capacity of P protein to undergo nuclear trafficking differ between lineages. Molecular mapping indicates that these differences are functionally distinct, and appear to involve modulatory effects on regulatory regions or structural impact, rather than changes to defined interaction sequences. This results in partial but significant phenotypic divergence, consistent with ‘fine-tuning’ to host biology, and with potentially distinct properties in the virus-host interface between bat families that represent key zoonotic reservoirs.

Terpenes are high-value chemicals which can be produced by engineered cyanobacteria from sustainable resources, solar energy, water and CO2. We previously reported that the euryhaline unicellular cyanobacteria Synechocystis PCC 6803 (S.6803) and Synechococcus PCC 7002 (S.7002) produce farnesene and limonene, respectively, more efficiently than other terpenes. In the present study, we attempted at enhancing farnesene production in S.6803 and limonene production in S.7002. Practically, we tested the influence of key cyanobacterial enzymes acting in carbon fixation (RubisCO, PRK, CcmK3 and CcmK4), utilization (CrtE, CrtR and CruF) and storage (PhaA and PhaB) on terpene production in S.6803, and we compared some of the findings with the data obtained in S.7002. We report that the overproduction of RubisCO from S.7002 and PRK from Cyanothece PCC 7425 increased farnesene production in S.6803, but not limonene production in S.7002. The overexpression of the crtE genes (synthesis or terpene precursors) from S.6803 or S.7002 did not increased farnesene production in S.6803. In contrast, the overexpression of the crtE gene from S.6803, but not S.7002, increased farnesene production in S.7002, emphasizing the physiological difference between these two model cyanobacteria. Furthermore, the deletion of the crtR and cruF genes (carotenoid synthesis) and phaAB genes (carbon storage) did not increase the production of farnesene in S.6803. Finally, as a containment strategy of genetically modified (GMO) strains of S.6803 we report that the deletion of the ccmK3K4 genes (carboxysome for CO2 fixation) did not affect the production of limonene but decreased the production of farnesene in S.6803.

Sirtuins, especially SIRT1, play a significant role in the regulation of inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-aging and longevity-promoting enzymes. Sirtuin-regulated processes seem to take part in most prevalent placental pathologies, such as preeclampsia. Furthermore, more and more research studies indicate that SIRT1 may prevent pre-eclampsia development, or at least alleviate its manifestations. Having taken this into consideration, we have made a review of recent studies on the role of sirtuins, especially SIRT1, in the regulation of processes determining normal or abnormal development and functioning of the placenta.

Nicastrin (NICT) is a transmembrane protein physically associated with the polytypical aspartyl protease presenilin that plays a vital role in the correct localization and stabilization of presenilin to the membrane-bound γ-secretase complex. This complex is involved in the regulation of a wide range of cellular events including cell signaling and the regulation of endocytosed membrane proteins for their trafficking and protein processing. Mehtods: In Trypanosoma cruzi, the causal agent of the Chagas disease, an NICT-like protein (Tc/NICT) was identified with a short C-terminus orthologous to the human protein, a large ectodomain (ECD) with numerous glycosylation sites and a single core transmembrane domain containing a putative TM-domain (457GSVGA461) important for the γ-secretase complex activity. Results: Using the Spot-synthesis strategy with Chagasic patient sera, five extracellular epitopes were identified and synthetic forms were used to generate rabbit anti-Tc/NICT polyclonal serum that recognized a ~72-kDa molecule in immunoblots of T. cruzi epimastigote extracts. Confocal microscopy suggests that Tc/NICT is localized in the flagellar pocket, which is consistent with data from our previous studies with a T. cruzi presenilin-like protein. Phylogenetically, Tc/NICT was localized within a subgroup with the T. rangeli protein that are clearly detached from the other Trypanosomatidae such as T. brucei. These results, together with a comparative analysis of the selected peptide sequence regions between the T. cruzi and mammalian proteins suggest a divergence from the human NICT that might be relevant to Chagas disease pathology. As a whole, our data show that an NICT-like protein is expressed in the infective and replicative stages of T. cruzi and may be considered further evidence for a γ-secretase complex in trypanosomatids.

Maternal infectious disease may pose considerable challenges to the fetal health due to the distribution of important elements of the sanguine and lymphatic system from the mother via the umbilical cord. The mother and the fetus have a degree of interdependence that is similar to the one between the eukaryotic cell and the mitochondrion, particularly during the first half term of the pregnancy, which explains the increased appetite of the expecting mother during the first stages of the fetal development. There is a solid bridge between the adaptive immune system and the encephalon that was only discovered a few decades ago. As a result, scientists may still be in the introductory stages of research, and there might be a significant and profound degree of association between the immune system and a healthy neurological development. There is a significant link between the onset of significant maternal infectious disease and the onset of neurodevelopmental disease in the fetus, and virtually all immune cells play major roles in the promotion and inhibition of neurogenesis alike. Likewise, there is a probability that maternal infectious diseases during pregnancy represent a risk factor of fetal neurodevelopmental disease, as a pressurised development of the adaptive immune memory could result in a pressurised or inhibited neurological development, which both can result in a delayed development of certain sub-regions of the brain. For example, the fetus may display poorer social abilities and sharp analytical skills later in life, which is an important sign of neurodevelopmental disease. A pressurised development of the adaptive immune memory could not require the development of a significant form of disease, but rather just a sharp rate of immune preparation against several important pathogenic agents during the introductory stages of life, when the encephalon experiences the sharpest increase rate in development. The problem per se is not the process of immunisation, but a much sharper process of immunisation over the first stages of life in case of an exposure to one dangerous pathogen or more numerous kinds of pathogens and antigens that normally cause moderate disease morbidity. The more dangerous the microbe is, the sharper the development of the adaptive immune memory will be, and the same happens in the case of an increased number of infectious microbes and antigens that infected the cells of the mothers and the fetuses in cause, and this may, in the majority of the situations, still be the case even if the pathogens are already significantly weakened or lifeless, given that the gain of adaptive immune memory alone constitutes an important factor of neurogenesis and an increased rate of neurological development, and that the infant will become almost or fully protected against the pathogens in cause, despite not having had experienced the disease beforehand. In this case, neurodevelopmental delays are possibly not caused by an impaired neurogenesis, but by an excessive one, whilst maternal infection-associated neurodevelopmental delays may be caused by an impaired neurogenesis. Nevertheless, the aetiology of immunity-related neurodevelopmental delays may be more complex in nature and implicate a chronological and spatial sequence of induced excedentary and deficitary rates of neurogenesis, hence reflecting the incredibly complex nature and various forms of neurodevelopmental disease. It is important to mention that a single dose of infant immunisation brings significantly lower risks of adverse neurological events than the onset of a significant maternal infectious disease during pregnancy. The objective of paediatric neuro-immunological studies may be to improve the understanding of the association between a healthy immune developmental rate and a balanced ratio of the developmental rates of important brain regions and sub-regions.

The most common liver disorder nowadays is non-alcoholic fatty liver disease(NAFLD) and it is a progressive disease that rises in severity from steatosis to nonalcoholic steatohepatitis(NASH), fibrosis and cirrhosis to increase risk of developing hepatocellular carcinoma. It is a cause of great concern as there is an estimated seventy million Americans who are currently affected by NAFLD, and this is expected to only increase because of its association with obesity and diabetes and also a lack of therapies to keep its development and progression in check. In this particular study we performed a gene set enrichment analysis(GSEA) of differentially expressed genes in a green tea against methionine-choline deficient diet in high-fat patients in the development of non-alcoholic fatty liver disease(NAFLD). The downregulated genes were used to perform an enrichment analysis and in the ARCHS4 TFs Coexpression database the most significant gene was found to be KLF5_human_tf_ARCHS4_coexpression. In the ARCHS4 Kinases Coexpression pathway database STYK1_human_kinase_ARCHS4 Coexpression was found to be the most significant gene. And finally for the upregulated genes a similar enrichment analysis was performed and in the humancy database γ-linolenate biosynthesis_Homo sapiens_PWY-6000 gene was discovered to be the most significant one. This study has used bioinformatics tools and the Enrichr software to perform a comparative analysis of differentially expressed gene sets for high-fat patients having a diet consisting of green tea against a methionine-choline deficient diet. Green tea is known to contain several antioxidants and polyphenols which provide protection against many liver diseases such as non-alcoholic fatty liver disease(NAFLD). The present study simply tries to build awareness of this to the general public and allow them to learn more about certain diets which have protective effects against liver diseases. Hopefully by implementing these in their daily lifestyles the public can gain some form of protection against these types of liver disorders.

Despite huge effort has been devoted to the design of the initiators and reaction conditions, it remains challenging to synthesize high molecular weight polypeptides with conventional solution phase synthesis. In this work, surface-initiated vapor deposition polymerization (SI-VDP) was utilized to graft synthetic polypeptides poly (γ-benzyl L-glutamate) (PBLG) from polystyrene (PS) resin beads by ring-opening polymerization of N-carboxyanhydrides (NCAs). It was demonstrated for the first time that high molecular weight bulk PBLG (> 500,000) could be readily obtained within one hour via solvent-free synthetic method which paves the way for the synthesis of copolypeptides with high molecular weight.

Currently, SARS-CoV-2 infection which is the causative agent for COVID-19 disease is a worldwide pandemic with more than 100 million global cases and more than 2.0 million deaths (as of January, 2021). While several vaccines for prevention of COVID-19 have already been registered by the regulatory authorities, the problem is that the substitution rate of this virus is estimated to be one change per 2 weeks, thus mutations could arise that threaten the efficacy of vaccines. Unfortunately, there is no current evidence from random clinical trials to recommend any specific post-exposure treatment for patients with suspected or confirmed COVID-19 disease. Here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated harmless viruses might interact in patients infected with pathogenic virus. During SIT, the patient benefits from superinfection with an apathogenic double-stranded RNA (dsRNA) virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). The safety of orally administered acid-resistant IBDV strain R903/78 reverse engineered viral drug candidate was demonstrated in 10 stage IV cancer patients who exhausted all conventional therapy. Following repeated oral administration of the virus up to 10⁹ infectious units (IU)/ dose, only mild flu-like side effects were reported in some patients. Proof-of-principle efficacy was demonstrated in an early COVID-19 patient who was successfully treated with 3x10⁶ IU of an attenuated IBDV vaccine. A small scale dose-finding Phase I safety study is proposed.

We report the characterization of phenotype, genotype, and functional parameters such as CD4+ T cell, viral load, HIV-1 genotype, class I HLA genotype, CCR5 polymorphism, and IFN-γ producing cells from a cohort of 37 people living with HIV-1 (PLWH) (viremic controllers, were compared those on antiretroviral therapy (ART) from two sites in São Paulo, Brazil. Half the PLWH (51.4%) were classified as viremic controllers (Controller group - CG), compared to 48.6% were on ART. As expected, controllers showed baseline higher levels of CD4+ T cells and nadir compared to those under ART, confirming the ability of HIV-1 controllers to preserve these cells even in the absence of ART. IFN-γ-producing cells showed greater magnitude to the HIV peptides Gag in controllers (p<0.03). Our results demonstrated that HLA protective alleles are associated with strong production of IFN-γ to Gag, Nef and RT epitopes in people living with HIV controllers.

The Influenza A Virus (IAV) represents an enveloped, positive-sense and single-stranded RNA-based virus that infects mammals mainly via the respiratory system, although other bodily systems are also infected and undergo various extents of inflammatory pathogenesis. There are two well-known strains of IAV that cause life-threatening disease in mammals; H1N1 and H5N1, and the first strain caused the 1918 IAV H1N1 pandemic that claimed between 30 and 50 million human lives. Due to the significant ability of IAV to evade important immune recognition, the virus was observed to favour the onset of secondary microbial infections (i.e. bacterial or fungal), as the overall performance of the immune system became transiently weakened during the viral infection. During the IAV H1N1 pandemic, many patients died as a result of bacterial pneumonia, as pathogenic bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, gained a wider opportunity to colonise and infect vital areas of the lower respiratory tract, and such a phenomenon led to the excessive, prophylactic usage of antibiotics due to the increased levels of panic, which in turn favoured the natural selection of bacteria with genes that became resistant to such antibiotics. Antibiotics might be required for usage solely when bacteria are known to be colonising vital areas of the human body, and this aspect is tricky, as microbial colonisation as such is asymptomatic and screening is consequently rare. Recently, new variants of the avian IAV H5N1 strain were transmitted from live, infected birds to mammals, including humans in some isolated cases, and given that there have already been several zoonotic spillover events overall since the beginning of 2023, we are rapidly approaching the time when a zoonotic spillover into humans will mark the first epidemic outbreak of the avian flu in humans. A lethality rate of approximately 60% was projected by the World Health Organization, as the virus was shown to favour the development of life-threatening hyper-inflammatory responses at the levels of alveolar tissues constituted by Type II pneumocytes. There are hints that novel variants of H5N1 are capable of infecting the intestinal layer, as recently, two dolphins died as a result of ingesting infected birds within the area of the British Isles. IAV is known to suppress the production and transmission of Type I Interferons by expressing various non-structural proteins (NSPs), such as NSP1, which was found to be also packaged into exosomes and transmitted to neighbouring uninfected cells, thereby preventing them from responding to the virus in the first place. Additionally, it was determined that NSP1 induces the apoptosis of the cells it is produced in and the neighbouring ones it enters via induced paracrine signalling, and such an aspect may only emphasise upon the critical role that early innate immune stimulation plays in preventing the development of severe respiratory illness afterward, given the context of increased viral ability of suppressing the production of first-line and second-line signals. A more pronounced rate of innate immune evasion would probably be observed in H5N1 IAV infection than in the infection caused by recent variants of H1N1 IAV. The H5N1 strain of IAV was also found to secrete a higher concentration of NSP1 than SARS-CoV-2, indicating the existence of an association to the greater mortality rate of H5N1 IAV infection. A direct, prophylactic stimulation of the interferon system using a reduced oral or nasal dosage of recombinant anti-inflammatory and anti-viral interferon glycoproteins may represent the most viable approach to prevent an emergence of a life-threatening H5N1 IAV pandemic. A similar non-invasive approach could be developed for a Marburg Virus (MARV) and a Nipah Virus (NiV) infection of humans, as risks of the emergence of a Marburg epidemic and also of a Nipah epidemic may be substantial at this stage as well. Clinical testing of clinical approaches as such could be of critical importance at the moment. Animals could also benefit from related clinical approaches. Somatic natural and adaptive lymphocytes treated with IFN I and III could also constitute a substantial approach of immunisation and heavily favour an indefinite shift in the evolutionary battle between the host organism and microbes of public health concern, as IFN I and III could improve the immunity of T-lymphocytes against HIV infection and even improve the performance of the mentioned types of immune cells during other types of infections. Likewise, a combination of all intellectual and clinical efforts implicating a shift of scientific and medical focus toward natural immunity in vaccine-related research could be a wise method in making the best efforts to prevent or alleviate the effects of a possible future pandemic, given the highly significant and diverse abilities of microbial “intelligence” to effectively hijack the natural immune system, many times causing severe implications upon the quality of the overall immune response against such microbes.

Bioactive lipids are involved in cellular signalling events with links to human disease. Many of these are involved in inflammation under normal and pathological conditions. Despite being attractive molecules from a pharmacological point of view, detection and quantification of lipids has been a major challenge. Here, we have optimised a liquid chromatography dynamic multiple reaction monitoring targeted mass spectrometry (LC-dMRM-MS) approach to profile eicosanoids and fatty acids in biological samples. In particular, by applying this analytic workflow to study a cellular model of Chronic Myeloid Leukaemia (CML), we found that intra- and extra-cellular 2-Arachidonoylglycerol (2-AG), intracellular Arachidonic Acid (AA), and extracellular Prostaglandin F_2α (PGF_2α), 5-Hydroxyeicosatetraenoic acid (5-HETE), Palmitic acid (PA, C16:0) and Stearic acid (SA, C18:0) were altered in response to immunomodulation by type I Interferon (IFN-I), a currently approved treatment for CML. Our observations indicate changes in eicosanoid and fatty acid metabolism with potential relevance in the context of cancer inflammation and CML.

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-Covid-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of Mannose Receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of Covid-19 pathology and immunity to SARS-CoV-2.

To further understand the role of phosphorylation in ISGF3- and STAT2/IRF9-mediated constitutive and long-term IFN-I-stimulated transcriptional responses, we performed RNA-Seq and ChIP-Seq, in combination with phosphorylation inhibition and anti-viral experiments. First, we identified a group of ISRE-containing ISGs that were commonly regulated in IFNα treated WT and STAT1-KO cells. Thus, in 2fTGH and Huh7.5 WT cells IFNα-inducible transcription and anti-viral activity relied on the recruitment of the ISGF3 components STAT1, STAT2 and IRF9 in a phosphorylation- and time-dependent manner. Likewise, in ST2-U3C and Huh-STAT1KO cells lacking STAT1, ISG expression correlated with DNA-binding of phosphorylated STAT2/IRF9. This pointed to a dominant role of classical ISGF3 and STAT2/IRF9, and not U-ISGF3 or U-STAT2/IRF9, in the regulation of early and prolonged ISG expression and viral protection, in WT and STAT1-KO cells. In addition, comparative experiments in U3C (STAT1-KO) cells overexpressing all ISGF3 components (ST1-ST2-IRF9-U3C), revealed a threshold-dependent role of U-ISFG3, and potentially U-STAT2/IRF9, in the regulation of constitutive and possibly long-term IFNα-treated ISG expression and anti-viral activity.

The vaccine industry has undoubtedly contributed massively in the medical world, with hundreds of millions of lives saved as a result of the successful development of prophylactic and therapeutic vaccines against various infectious and oncological diseases. Simultaneously, there has been an ongoing evolutionary battle between polymorphic microbes and the human immune system, and various microbes have developed counter-responses against the human host immune system, by creating diverse “holes” of vulnerability in the innate immune system. Such mechanisms may have resulted due to the lower prophylactic and therapeutic focus upon sharpening the innate immune lines as directly as necessary. The overall objective of vaccine-development should be the sharpening of all immune departments that are targeted by various microbial agents for the purpose of transient innate immune suppression and the distribution of the microbial count/load at a systemic level. Likewise, it could be viable for the clinical research community to start focusing upon filling in the “gaps” of vulnerability that are now present in the pathways responsible for the proper natural immune activation and proportionate signalling toward the adaptive immune system. Perhaps, through such a process, the “road” toward the adaptive immune system, which is “old” and filled with “holes”, could be gradually transformed into a perfectly uniform “highway”, with all the required signals transmitted robustly from the innate to the adaptive immune system, before microbes manage to translate the various pathogenic proteins that transiently prevent such transmission altogether, until it becomes too late for the immune response to possibly develop in a proportionate and non-harmful manner to the organism. The potential “missing piece of puzzle” in vaccine-based clinical research could involve training of the human organism to develop immune memory without the host organism reaching a threshold of clinical disease onset even if viruses translate proteins that silence the host interferon system and make it unable to trace produced toxins whilst not directly causing clinical pathophysiology. Whilst it is realistically almost impossible to train the human immune system to develop responses and memory against viral proteins that do not directly cause immunopathology, there could be a set of clinical approaches involving a stimulation for more robust activation of the host interferon system, with an example of such stimuli being the same principal elements of the interferon system. Another example of pharmaceutical approaches would involve the development of drug-like components to target such viral proteins, though they would be more costly and consequently more restricted in usage; due to the fact that viruses are obligate intracellular, particle-based parasites and can only synthesise their proteins inside host cells. Such a scenario would be possible, given that it is almost impossible for human evolutionary growth to eventually stall and not risk experiencing a decrease as a result. Simultaneously, it is important for human society to bind by the principles of maintaining a healthy and nature-friendly lifestyle, given the philosophical quote of “We are what we eat.” The overall objective should be the facilitation of human and animal immune evolution over viral and bacterial molecular self-camouflaging from all possible directions, as a sharper human and animal evolutionary growth resulting from such actions could “cost” the sharper evolutionary growth of microbes as such, given that evolutionary patterns are based upon the models observed in Physics, in Newton’s Third Law of Motion, as well as in the First Law of Thermodynamics, which concerns the Conservation of Energy.

It has recently been discovered that mere cell contact by human cytomegalovirus (CMV) particles leads to profound modulation of cellular gene expression. Reduced monocyte human leukocyte antigen (HLA-DR) expression is a novel biomarker of severity and outcome in many diseases. Modulation of CD14 protein by CMV was shown in vitro, but little is known about the phenomenon in vivo (during active cytomegalovirus disease). Therefore, we investigated monocyte CD14 and HLA-DR expression in CMV infected patients in relation to logarithmic phase of infectious process. Samples from patients with active CMV replication (exponential growth of CMV viremia) were tested. After CD45/SSC gating monocyte CD14 and HLA-DR expression were determined by double-color flow-cytometry. Significant monocytosis and poor correlation between CMV replication and CD14+HLA-DR(-) cells prompted CD14 investigation. During logarithmic phase of CMV infection increased count and percentage of CD14low monocytes were observed which correlated with viral replication in several clinical situations except when there was a rapid recovery without relapse. Furthermore, most of CD14low monocytes are HLA-DR+. The increase of CD14low monocytes is also observed under the influence of high dose of glucocorticoids (20 mg of dexamethasone). The reduction in CD14 induced by CMV and dexamethasone indicates that the monocyte balance is disturbed between the classical and non-classical phenotype. A high percentage of CD14lowHLA-DR+ probably gives rise to adaptive and a decrease of innate immune response. In light of the logarithmic increase of viral load (with exponent between 3,23 and 5,77), high monocytosis above 1200 / µl is a hallmark of CMV replication.

Group-B enteroviruses (EV-B) are ubiquitous naked single-stranded positive RNA viral pathogens that are responsible for common acute or persistent human infections. Their genome is composed in the 5'end by a non-coding region, which is crucial for the initiation of the viral replication and translation processes. RNA domain-I secondary structures can interact with viral or cellular proteins to form viral ribonucleoprotein (RNP) complexes regulating viral genomic replication, whereas RNA domains-II to -VII (IRES) are known to interact with cellular ribosomal subunits to initiate the viral translation process. Natural 5’ terminally deleted viral forms lacking some genomic RNA domain-I secondary structures have been described in EV-B induced murine or human infections. Recent in vitro studies have evidenced that the loss of some viral RNP complexes in the RNA domain-I can modulate the viral replication and infectivity levels in EV-B infections. Moreover, the disruption of secondary structures of RNA domain-I could impair viral RNA sensing by RIG-I or MDA5 receptors, a way to overcome antiviral innate immune response. Overall, natural 5′ terminally deleted viral genomes resulting in the loss of various structures in the RNA domain-I could be major key players of host-cell interactions driving the development of acute or persistent EV-B infections.

Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory response is of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 hours. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results &amp; conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in ROS homeostasis. Low and high concentrations of AFDs have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both a “prooxidant” and “antioxidant” effect, but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.

Maternal-derived immunity is a critical component for survival and success of offspring in pigs to protect from circulating pathogens like Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). The purpose of this study was to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (TRT 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2- and 4-wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α+ B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In lungs, CD8 T cells were the primary and CD4 T cells the secondary IFN-γ producers including a novel subset of porcine CD8α-CCR7- CD4 T cells, potentially terminally differentiated CD4 TEMRA cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets; and it introduces two novel immune cell subsets in pigs – IFN-γ producing CD21α+ B cells and CD8α-CCR7- CD4 T cells.

“All diseases originate in the gut.” Hippocrates (400 BC) A healthy gut microbiome via the gut-brain-axis (GBA) elevates heart rate variability (HRV), a general measure of health and well-being. A dysbiotic gut microbiome, low in biodiversity and butyrate producers, alters tryptophan metabolism with release of proinflammatory cytokines, predominantly TNF-α, IL-6, and IL-1β. These also characterize chronic inflammation, oxidative stress, and a multitude of diseases, all exhibiting low HRV. Gut dysbiosis upregulates IFN-γ and with it IDO (indoleamine 2,3 dioxygenase). Tryptophan pivots from serotonin synthesis to that of IDO induced kynurenine, increasing the kynurenine to tryptophan ratio (KTR). An elevated KTR is positively linked to neurodegenerative and autoimmune diseases and negatively linked to HRV. Elevated IDO activity is not only enzymatic but also an intracellular signal transducer potentiated by TGF-β. This cytokine is the primary determinant of the TME. Also proposed is the gut-lung dysbiosis concept and consequent degradation of ACE2 (richest in lungs and gut). Leaky gut induced autoantibodies related to G-protein coupled receptors (GPCRs) in combination with increased Ang II further potentiate oxidative stress. Aldosterone and paroxysmal orthostatic tachycardia syndrome (POTS) paradoxes are highlighted in the context of GPCR and gut dysbiosis, and the role of Candida is explored. The triple play of a prebiotic (d-mannose), probiotic (bifidobacteria and lactobacilli), and postbiotic (butyrate) might improve intestinal barrier integrity, oppose entry of GPCR antigens, suppress the inflammatory cytokine triad, balance IFN-γ and TGF-β, suppress oxidative stress, depress KTR, elevate HRV, and extend lifespan and its quality.

This study addresses the enhancement of material efficiency and reduction of brittleness in timber-to-concrete adhesive connections for beam-type timber and timber-concrete composite panels. The research explores the potential benefits of adding longitudinal timber ribs to Cross-Laminated Timber (CLT) beam-type panels. Three groups of flexure-tested specimens were analysed: (1) timber panels (1400 mm × 400 mm) with two 100 mm thick CLT panels and two 60 mm thick CLT panels reinforced with 150x80 mm timber ribs; (2) eight specimens (600 mm × 100 mm × 150 mm) with CLT members (600 mm × 100 mm × 100 mm) connected to a 50 mm concrete layer using granite chips and Sikadur-31 (AB) epoxy adhesive; (3) six CLT panels (1400 mm × 400 mm × 50 mm) bonded to a 50 mm concrete layer, with two panels containing polypropylene microfibers and two panels incorporating polyethene dowels for mechanical connection. Specimens were subjected to three-point bending tests and analysed using the transformed section method, γ-method, and finite element method with ANSYS 2023R2 software. Results indicated a 53% increase in load-carrying capacity for ribbed CLT panels with no additional material consumption, a 24.8%-41.1% increase for CLT panels strengthened with a concrete layer, and improved ductility and prevention of disintegration in timber-concrete composites with polypropylene microfibers.

Previously we discovered that among 15 DNA-binding plant secondary metabolites (PSMs) possessing anticancer activity, 11 compounds cause depletion of the linker histones H1.2 and/or H1.4 from chromatin fraction. Chromatin remodeling or multiH1 knocking-down is known to promote the upregulation of repetitive elements, ultimately triggering an interferon response. Herein, using HeLa cells and applying fluorescent reporter assay with flow cytometry and quantitave RT-PCR, we found that among PSMs depleting linker histones, 8 compounds significantly activate type I interferon signaling pathway. Out of these compounds resveratrol, berberine, genistein, delphinidin, naringenin and curcumin also caused LINE1 expression detected by quantitate RT-PCR and by immunefluorescent staining analysis of ORF1 LINE1 and γ-H2AX. Fisetin and quercetin, which also induced linker histone depletion, significantly activated only type I interferon signaling, but not LINE1 expression. Curcumin, sanguinarine and kaempferol, causing depletion of the linker histone H1.4 more intensively respectively to H1.2, activate interferon signaling less intensively without any changes of LINE1 expression. For 4 PSMs, which did not cause linker histone depletion, we did not observe effects of interest. Thus, we have shown for the first time that activation of type I interferon signaling accompanies chromatin remodeling caused by PSMs, and LINE1 expression often impacts this activation.

The development of nucleic acid sequencing technology and the unprecedented availability of metadata has evidenced that 45% of human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically needed. Aberrant regulation of TEs, and of human retroviral endogenous sequences (HERVs) in particular, associates with several neurologic and autoimmune diseases, including the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) frequently comorbid with fibromyalgia (FM). However, no study has yet addressed whether abnormal expression of these sequences correlates with FM. The work presented here shows, for the first time, that in fact HERVs of the H, K and W types are overexpressed in the cells of the immune system of FM patients with or without comorbid ME/CFS. The patients with increased HERV expression (N=14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. In support of our proposal that TE activation is a contributor to FM, we find that the tRNA pools are decreased in comparison to matched healthy participants (N=14). The findings reported here could explain the flu-like symptoms FM patients present with in the absence of concomitant infections. Future work towards identifying specific genomic loci differentially affected in FM and ME/CFS is granted.

Type I (IFN-α/β) and Type III (IFN-λ) interferon-inducible myxovirus resistance (Mx) proteins have long been recognized to inhibit a broad spectrum of RNA- and DNA-containing viruses (1-5). Mx proteins are dynamin-family GTPases of size 60-70 kDa (1-3) with different subcellular localization and antiviral activities. In the last 5 years there has been a paradigm shift in our understanding of the structures formed by human and murine Mx proteins in the cytoplasm and nucleus. We now recognize that the major human MxA protein forms structures in the cytoplasm and the major murine Mx1 forms structure in the nucleus which comprise liquid-liquid phase separated (LLPS) biomolecular condensates [membraneless organelles (MLOs)] with a gel-like internal consistency. The second human Mx protein, MxB, which had been previously observed to associate with the cytoplasmic face of nuclear pores, was also recently confirmed to represent cytoplasmic biomolecular condensates. Our overall focus now is to understand the formation, dynamics and antiviral function of biomolecular condensates of different Mx proteins in the cytoplasm and nucleus in cells of different species. We highlight the metastability and rapidly reversible hypotonicity sensing properties of MxA condensates in human cells, especially as applicable to environmental stress inflicted on the oral mucosa.

The oral mucosa represents a defense between the external environment and the rest of the body and encompasses several antimicrobial and antiviral mechanisms. Oral mucosal cells are constantly bathed in hypotonic saliva (normally one-third tonicity compared to plasma) and are repeatedly exposed to environmental stresses of tonicity, temperature and pH by the drinks we imbibe (e.g. hypotonic: water, tea, coffee; hypertonic: assorted fruit juices, red wines), as well as of diverse microbial and viral flora. In the mouth, the broad-spectrum antiviral mediator MxA (a dynamin-family large GTPase) is constitutively expressed in healthy periodontal tissues, and also induced by Type III interferons (e.g. IFN-λ1). Endogenously induced human MxA and exogenously expressed human GFP-MxA formed membraneless biomolecular condensates in the cytoplasm of oral carcinoma cells (OECM1 cell line). These condensates likely represent storage granules in equilibrium with antivirally active dispersed MxA. Remarkably, cytoplasmic MxA condensates were exquisitely sensitive sensors of hypotonicity – the condensates in oral epithelium disassembled within 1-2 min of exposure of cells to saliva-like one-third hypotonicity, and spontaneously reassembled in the next 4-7 min. OECM1 cells preloaded with calcein-AM (a reporter of cytosolic “macromolecular crowding”) confirmed unquenching and then requenching of calcein fluorescence during this process. Hypertonicity had little effect on MxA condensates. The spontaneous reassembly of GFP-MxA condensates in oral epithelial cells even under continuous saliva-like hypotonicity was slowed by the protein phosphatase inhibitor cyclosporin A (CsA) and by the K-channel blocker tetraethylammonium chloride (TEA) suggestive of the involvement of the volume-sensitive WNK kinase-protein phosphatase (PTP)-K-Cl cotransporter (KCC) pathway in the regulated volume decrease (RVD) during condensate reassembly in oral cells. Thus, physiologically, hypotonic drinks (water, tea, coffee) trigger a rapid deployment of antiviral MxA throughout the cytoplasm of oral epithelial cells, with subsequent salvage of MxA back into storage granules/condensates.

Despite being a rare disease worldwide, rabies has the highest morbidity and mortality rates, with nearly all symptomatic cases leading to coma and death. Rabies represents an infectious disease caused by the Rabies virus (RABV), which is part of the Lyssavirus group and the Rhabdoviridae family, and it mainly spreads through the bite and scratch of an infected mammal, but particularly of wild animals, such as bats, foxes, wolves and racoons, and of domestic animals, such as dogs and cats, in rabies-prone areas of the world. Airborne transmission has been deemed as extremely rare, and no clinical case as such has been recorded worldwide yet, except in the enclosed environment, such as research laboratories and caves where infected bats are present. Domestic mammals, such as dogs and ferrets, represent other important reservoirs of disease transmission, and the human cases of Asia and Africa amount approximately 95% of all human cases worldwide. Infected animals most commonly start transmitting the virus once the first symptoms have occurred, and if they experience disease aggravation and death within 10 days, a case of rabies is registered, more easily if the incidence occurred in the urban area and then, any person or animal that had been potentially exposed are strongly recommended to receive the inoculation. It is rare for asymptomatic mammals to transmit the illness. Most First-World and several Second-World countries have recently been declared dog rabies-free by the World Health Organization. The disease can only be treated prophylactically, with three doses of a vaccine containing an inactivated form of RABV, or with five doses of the vaccine and two doses of anti-RABV immunoglobulins within 28 days if the patient is believed to have been exposed to the virus beforehand. It has been projected that, once the viral load reaches elements of the central nervous system, prophylactic approaches are no longer effective, even if symptoms have not begun yet, and this highlights the urgent trait of the medical condition, strongly recommending exposed people to receive the prophylactic doses immediately after the potential exposure to the virus. The pathogen first infects the bodily fluids, before reaching the peripheral nervous system, from where it will gradually move toward the spinal cord or the encephalon, at a speed of movement ranging from 1 to 40 cm per day. It was also found, in extremely rare circumstances, to infect the nasopharyngeal cavity and the lungs. The primary cause of a successful, gradual advance of the viral load toward the point of clinical no-return for the patient - the CNS - is a complex mechanism of induced innate immune evasion, with the interferon system being heavily targeted and silenced by RABV proteins. The ‘Milwaukee’ protocol is locally believed to decrease the mortality rate of the clinical illness to approximately 80%, although significantly more research is required in this sense. First-line immune evasion represents the central mechanism developed by viruses during their evolutionary process to gain control over human immunity, so it could be the development and adjustment of a counter-offensive to this evolutionary operating system that could address the core elements of the problem. Human recombinant Type I and Type III Interferons were found to be significant vaccine adjuvants and to considerably delay the clinical onset of the disease. Despite their central role in natural immunity-based prophylaxis, vaccine support and, in often cases, vaccination per se, a local administration of IFNs as such may not be enough to tackle the core problem of the endemic disease, and a specific and systemic treatment of potential host cells with IFN I and III, as well as IFN-stimulating proteins, may constitute a major research requirement in the coming years of disease investigation, as the inoculation efforts with the inactivated virus and immunoglobulin administration continue. The administration of a relatively low dosage of somatic Natural Killer cells, gamma-interferon and perhaps, of somatic helper CD4+ and somatic cytotoxic CD8+ T-lymphocytes treated with alpha-, beta- and lambda-interferon could be merged with the administration of a similar dosage of alpha-, beta- and lambda-interferon during the efforts to develop an effective and less costly prophylactic vaccine against rabies. A combination of a nasal substance containing a low dosage of IFN I and III with a reduced concentration of neutralized RABV copies, and/or with a low dose of anti-RABV IgA antibodies, could also be tested for humans for the purposes of pre- and post-exposure prophylaxis.

Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.