Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

Arthropod-borne flaviviruses represent human pathogens of global medical importance, against which no effective small molecule-based antiviral therapy is currently available. Arbidol (umifenovir) is a broad spectrum antiviral compound approved in Russia and China for prophylaxis and treatment of influenza. This compound showed activity against numerous DNA and RNA viruses. Its mode of action is based predominantly on the impairment of critical steps of virus-cell interaction. Here we demonstrate that arbidol possesses a micromolar inhibition activity (EC50 values ranging from 10.57 ± 0.74 to 19.16 ± 0.29 µM) in Vero cells infected with Zika virus, West Nile virus, and tick-borne encephalitis virus, three medically important representatives of arthropod-borne flaviviruses. Interestingly, no antiviral effect of arbidol is observed in porcine stable kidney cells (PS), human neuroblastoma cells (UKF-NB-6), human hepatoma cells (Huh-7 cells) indicating that the antiviral effect of arbidol is strongly cell-type dependent. Arbidol presents a significant increasing in cytotoxicity profiles when tested in various cell lines in the order: Huh-7 < HBCA < PS < UKF-NB-6 < Vero with CC50 values ranging from 18.69 ± 0.1 to 89.72 ± 0.19 µM. Antiviral activity and acceptable cytotoxicity profiles suggest that arbidol could be a promising candidate for further investigation as a potential therapeutic agent in treating flaviviral infections.

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.

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.

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.

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.

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.

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.

Duct-dependent lesions are classically divided into duct dependent pulmonary circulation which involves severe right sided obstructive lesions such as pulmonary atresia or critical stenosis, and duct dependent systemic circulation which is characterized by malformation of the left side of the heart, and whose severest spectrum is hypoplastic left heart syndrome. Dextro-transposition of the great arteries remains in gray zone between being included in some old classifications as a duct dependent pulmonary circulation lesion or a new category of duct-dependent or independent mixing lesion. We hypothesize that re-classifying duct dependent congenital defects into duct dependent perfusion and oxygenation offers a model to fit D-TGA into the same category of right sided obstructive lesions and reflects the clinical spectrum in a more comprehensive way.

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.

The cyclin-dependent kinase (Cdk) 1–cyclin B (CycB) complex plays critical roles in cell cycle regulation. Before Drosophila male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex in the nuclear pore complex. When this is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls cellular localization and activation of Cdk1. Cdk1–CycB continuously shuttled into and out of the nucleus in the prolonged G2 phase before meiosis. Overexpression of CycB, but not that with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in Nup62-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in Nup62-silenced cells, while Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nucleus of Nup62-silenced cells, suggesting the involvement of another suppression mechanism. Silencing of roughex rescued Cdk1 inhibition and initiated meiosis. Nuclear exports of Cdk1 ensured its escape from inhibition by cyclin-dependent kinase inhibitor. The complex reentered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1–CycB to initiate male meiosis.

The major goal of this work is to present a novel fractional temperature-dependent boundary element model (BEM) for solving thermoelastic wave propagation problems in smart nanomaterials. The computing performance of the suggested methodology was demonstrated by using stable communication avoiding S-step – generalized minimal residual method (SCAS-GMRES) to solve discretized linear BEM systems. The benefits of SCAS-GMRES are investigated and compared to those of other iterative techniques. The numerical results are graphed to demonstrate the influence of fractional, piezoelectric, and length scale characteristics on total force-stresses. These findings also demonstrate that the BEM methodology is practical, feasible, effective, and has superiority over domain methods. The results of the present paper help to develop the industrial uses of smart nanomaterials.

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.

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N=116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N=2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla &gt;14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

Time evolution operators of a strongly ionizing medium are calculated by a time-dependent unitary transformation (TDUT) method. The TDUT method has been employed in quantum mechanical system composed of discrete states. This method is especially helpful for solving molecular rotational dynamics in quasi-adiabatic regimes because the strict unitary nature of the propagation operator allows us to set the temporal step size large; a tight limitation on the temporal step size ($\delta t <<1$) can be circumvented by the strict unitary nature. On the other hand, in a strongly ionizing system where the Hamiltonian is not Hermitian, the same approach cannot be directly applied because it is demanding to define a set of field-dressed eigenstates. In this study, the TDUT method was applied to the ionizing regime using the Kramers-Henneberger frame, in which the strong-field-dressed discrete eigenstates are given by the field-free discrete eigenstates in a moving frame. Although the present work verifies the method for a one-dimensional atom as a prototype, the method can be applied to three-dimensional atoms, and molecules exposed to strong laser fields.

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.

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.

LuBO3 crystallizes in the calcite type (CaCO3) structure and is a widely applied inorganic host for luminescent materials and scintillators. Even though many scientific works have been published concerning the optical properties of rare earth doped LuBO3, so far, no study of the emission spectra as function of the excitation energy of such orthoborates has been conducted. Therefore, this work deals with the photoluminescence of RE doped LuBO3 with RE = Ce3+, Eu3+, Gd3+, or Tb3+, while an emphasize is laid on the energy dependence of these four luminescent compounds.

Unidirectional flow of a fluid with pressure-dependent viscosity through a porous structure is considered when the viscosity-pressure relationship is an exponential function of a pressure power function in order to investigate effects of the viscosity-pressure relation on the flow characteristics. The flow is governed by the generalized Brinkman’s equation with constant permeability, and a model flow domain of flow down an inclined porous channel is chosen for the sake of studying flow behaviour. Although the current work considers flow in a constant permeability porous structure, it does represent a first step in studying the more general, flow through a variable permeability porous channel. The arising governing equations are solved numerically using MATLAB and the flow is simulated to illustrate the effects of fluid properties as well as flow and medium parameters on the velocity profiles and shear stress.

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.

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

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.

Magneto-electrochemistry (MEC) is a unique paradigm in science, where electrochemical experiments are carried out as a function of an applied magnetic field, creating a new horizon of potential scientific and technological applications. Over the time, detailed understanding of this research domain was developed to identify and rationalize the possible effects exerted by a magnetic field on the various microscopic processes occurring in an electrochemical system, such as: electrolyte properties governed by charge-transfer process (electric conductivity, viscosity, and diffusivity), mass transfer, electrochemical kinetics and on the structure/quality of products formed either at the working electrode or in the electrochemical cell. Particularly, magnetic field controlled chiral architecture obtained from deposited metal, alloys and catalyst and their excellent enantio-recognition in experimental frame is highly appealing. Interestingly, Hall effect was also demonstrated in electrolytic medium via an impressive experimental technique which is being employed for further theoretical understanding in the field of magneto-electrochemical science. Later, a highly reproducible local temperature variation was observed in electrochemical electrolytes exposed to perpendicular magnetic and electric fields. However, until recent studies, none of the above mentioned reports considered the possibility of a spin-dependent related charge-transfer process. Recent experimental and theoretical studies reveal that electron’s transmission through chiral molecules is spin-selective and this effect has been referred to as chiral-induced spin-selectivity (CISS) effect. The CISS effect pave the way for the building up of a system characterized by a net magnetic moment exploiting the spin-filtering ability of chiral molecules. This interplay between chirality and magnetism may shed light on fundamental scientific aspects underlying the enantio-recognition and highly efficient electron-transfer that occurs in biological process.

Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcin-ogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron overloading-associated HCC development include the increased　reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treat-ment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapy and experience of novel treatment for HCC in thalassemia population were also reviewed in this article.

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.

Ionic channels are present in eucaryotic plasmatic and intracellular membranes. They coordinate and control several functions. One of the most diverse ionic channels family are the potassium (K) channels. Within this family are the ATP-dependent potassium channels (KATP), which belong to the potassium rectifier channel family. These channels were initially described in heart muscle, yet they are also present in different types of tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle. In ß-pancreatic cells, KATP are primarily responsible for maintaining membrane potential and for the depolarization mediated insulin release. KATP density/activity seems to be determinant in physiological the outcome, in pancreatic cells decrease of this density/activity may be related to Insulin resistance (IR). In extra pancreatic tissues KATP relation with IR is beginning to be explored. It is possible that in skeletal muscle, the KATP are involved in insulin dependent glucose recapture and that KATP activation leads to IR. In adipose tissue, KATP containing Kir6.2, could be related to increase in free fatty acids and insulin resistance, therefore, pathological processes leading to a prolonged adipocyte KATP inhibition might promote obesity related to insulin resistance. In central nervous system KATP activation can regulate peripheric glycemia and lead to brain IR which could be a much earlier manifestation of peripheral alterations that lead to the development of pathologies such as obesity and type 2 diabetes mellitus. In this review we aim to discuss the KATP channel characteristics, its relationship to known clinical disorders and the mechanisms and potential relations with peripheral and central insulin resistance.

A theoretical nonlocal thermoelastic model for studying the effects of the thermal conductivity variability on a rotating nanobeam has been described in the present article. The theory of thermal stress is employed using the Euler–Bernoulli beam model and generalized heat conduction with phase lags. It is believed that the thermal conductivity of the current model varies linearly according to temperature. Due to variable harmonic heat, the considered nanobeam excited and was subjected to a time-varying exponential decay load. Using the Laplace transform process, the analytical solutions for displacement, deflection, thermodynamic temperature and bending moment of rotating nanobeams are provided in final forms and a numerical example has been taken to address the problem. A comparison of the stated results was displayed and additionally, the influences of non-local parameters and varying load were analyzed and examined. We also investigate how the linear changes in the temperature of physical properties can influence both the static and dynamic responses to the rotating nanobeam.

Results are presented concerning the influence on the water splitting process of enantiopure tartaric acid present in bulk solution. Stainless steel and electrodeposited nickel are used as working electrode (WE) surface. The latter is obtained by electrodeposition on the two poles of a magnet. The influence and role played by the chiral compound in solution has been assessed by comparing the current values, in cyclic voltammetry (CV) experiments, recorded in the potential range at which oxygen evolution reaction (OER) occurs. In the case of tartaric acid and nickel WE a spin polarization of about 4 % is found. The use of the chiral environment (bulk solution) and ferromagnetic chiral Ni electrode allows for observing the OER at a more favourable potential: about 50 mV (i.e. a cathodic, less positive, shift of the potential at which the oxygen evolution is observed).

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 SARS–CoV-2 infection has caused both acute and chronic COVID–19 disease during the recent pandemic with emerging more transmissible SARS–CoV–2 Omicron variants (BQ1 and XBB1) that have increased demands for more effective immunogens and therapeutic approaches to protect the lives of numerous SARS–CoV-2 affected individuals and reduce overall disease burden that could be affected by concurrent other pathogens causing diseases. Following a worldwide campaign of mass vaccination, there is still a significant demand to quell the harmful effects of novel SARS–CoV–2 infections due to higher mutation rates within specific areas of the SARS–CoV-2 domain, leading to enhanced viral entry, especially within individuals with one or more significant comorbidities, and there is still a dilemma of how prevention of future pandemics will occur as within host animal mutations and cross species transfer naturally occurs. Concerns intersect at a specific point; a gained evolutionary ability of several viruses over the previous centuries to remain undetected during the first stages of infection by means of capping the 5' end of their DNA and RNA genes respectively. This may occur by reducing the rate of host Type I and Type III Interferons (IFN) cellular synthesis, that would usually occur and affect both apoptotic pathways, that facilitate viral replication and clearance, as well as immune cells, that process and present pathogenic antigen epitopes. Furthermore, although methods of vaccination exist, other methods in clinical development remain that could evoke an immune response in different cellular, serum or mucosal compartments being cellular, serum and mucosal that evoke differential antibody responses. Antibodies are classed as natural and synthetic. Natural antibodies are further classified into neutralizing and non-neutralizing, whilst synthetic antibodies are also further classified into monoclonal and polyclonal. As a result of single cell study transcriptome research, viruses do utilize an array of protein receptors for receptor-mediated cellular entry. This, therefore suggests that potential differential production of antibody immunoglobulins (Ig) within serum and mucosal areas remains affected by cytokines, adhesion molecules and chemokines that can be upregulated or downregulated upon host viral infection. Serum plasma antibodies can be multimeric that may not efficiently cross the nasal epithelium cell layer, therefore offering less protection against mucosal inflammation due to mucin proteins. On the other hand, antibodies produced by mucosal plasma cells at epithelial surfaces are known to provide effective immune responses in some viral infections. The existence of developments that stimulate mucosal immune responses has so far only been seen with influenza nasal immunogens. Nevertheless, scientists developed ways of immunization and early treatment worldwide 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. For example, the administration of human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can stimulate cellular activity to train the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Recently, it was discovered that specific plants secrete proteins that also stimulate the production of Type I Interferons. 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. Naturally-selected polymorphic viruses through genetic recombination pose challenges to traditional concepts of cellular and molecular immune system neutralization of these viruses during the first stages of cellular infection. It is until the scientific community realizes this potentially crucial aspect that we 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. Type I IFNs tend to be produced faster than Type III IFNs, and the first induce slightly more abundant pro-inflammatory signals than the latter, meaning that type III IFNs, if produced early, may further decrease the extent of excessive proinflammatory signals. Hence, we believe that nasal sprays containing a low dosage of Type I and Type III IFNs not only represent a relevant COVID-19 therapeutic, but also a potential unknown modulatory therapy of the future. Of note, it has been indicated that IFN I and / or III display significant immunizing and early therapeutic effects for other viral evoked diseases like Influenza (Influenza (A)H1N1), rabies (Rabies lyssavirus), measles (Measles virus), rubella (Rubivirus rubellae), Hepatitis B, HIV-induced AIDS, Ebola, Marburg, as well as bacterial diseases, such as lower respiratory tract infectious diseases induced by Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus, and a number of oncological diseases, like hepatic melanoma.

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.

If a subject learns about the properties of an alternative under a high state of food deprivation, it will prefer this alternative over a similar one in a later choice test, although the subject is currently under a relative state of satiety. In this experiment, we probe this effect in a delay-discounting task, where the reward of the experienced alternative is progressively delayed. Eight male Wistar rats were trained to respond to an alternative under a high state of deprivation and eight rats under a relative state of satiety. After 20 sessions, their weight was recalibrated to a state of relative satiety. Then, they were exposed to a delay-discounting task where the long-larger alternative was the one used during training. The group that experienced the alternative under a higher level of food deprivation preferred more this alternative, and its preference stayed across time. On the contrary, the group that experienced the alternative under a lower level of food deprivation systematically preferred the small-shorter alternative. Our results support that the reinforcement value may be sensitive to the organism's state at the moment an alternative is experienced for the first time.

The epithelial cell adhesion molecule (EpCAM) is a stem cell and carcinoma antigen, which mediates cellular adhesion and proliferative signaling by the proteolytic cleavage. In contrast to low expression in normal epithelium, EpCAM is frequently overexpressed in various carcinomas, which correlates with poor prognosis. Therefore, EpCAM has been considered as a promising target for tumor diagnosis and therapy. Using the Cell-Based Immunization and Screening (CBIS) method, we previously established an anti‐EpCAM monoclonal antibody (EpMab-37; mouse IgG1, kappa). In this study, we investigated the antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), and an antitumor activity by a defucosylated mouse IgG2a-type of EpMab-37 (EpMab-37-mG2a-f) against an EpCAM‐expressing breast cancer cell line (BT-474). EpMab-37-mG2a-f recognized BT-474 cells with a moderate binding-affinity [a dissociation constant (KD): 2.9x10-8 M] by flow cytometry. EpMab-37-mG2a-f exhibited ADCC and CDC for BT-474 cells by murine splenocytes and complements, respectively. Furthermore, administration of EpMab-37-mG2a-f significantly suppressed the BT-474 xenograft tumor development compared with the control mouse IgG. These results indicated that EpMab-37-mG2a-f exerts antitumor activities against the BT-474 xenograft, and could provide valuable therapeutic regimen for the breast cancers.

Background: Dengue is the most common arthropod-borne sickness worldwide, impacting at least 50 million people each year. The dengue virus has four primary serotypes. Infection with one serotype confers homotypic immunity but not heterologous immunity, and secondary infections may be more severe. Although blood transfusions and organ donations have also been observed, the Aedes aegypti mosquito is the primary vector for the transmission of dengue. Infection causes a continuum of clinical illness, from asymptomatic infection to dengue fever, DHF, and dengue shock syndrome (DSS).Aim: To assess the presence of anti DENV IgG and anti DENV IgM antibodies specific to the four dengue serotypes in blood donor service donors and the importance of pre-donation screening in routine blood collection procedures.Method: 3 mL of peripheral venous blood from 507 blood donors was collected in tubes with BD vacutainer gel tube for serum separation after epidemiological records were reviewed. After that, serum was separated and tests were performed by SD Bioline Dengue Duo. Participants in the study completed a social and epidemiological questionnaire that contained information such as age, gender, and dengue diagnosis.Result: Out of the 507 blood samples that were taken, 473 (93.3%) came from male blood donors, while the remaining 34 (6.7%) belonged to female blood donors. The ratio of males to females is 13.91 to 1. The age range is 18–60 years, and the mean and standard deviation are both 27.7 and 6.5. 183 of the 507 samples produced anti DENV IgG positivity, while 324 did not. The ratio of positive to negative was 1.25:2.Conclusion: According to the findings of this study, quantitative methods for determining the presence of anti-dengue antibodies or detecting the dengue virus in blood donors in endemic areas should be devised in order to ensure the quality of blood transfusions.

The recent advances in Human-Computer Interaction and Artificial Intelligence have significantly increased the importance of identifying human emotions from different sensory cues. Hence, understanding the underlying relationships between emotions and sensory cues have become a subject of study in many fields including Acoustics, Psychology, Psychiatry, Neuroscience and Biochemistry. This work is a preliminary step towards investigating cues for human emotion on a fundamental level by aiming to establish relationships between tonal frequencies of sound and emotions. For that, an online perception test is conducted, in which participants are asked to rate the perceived emotions corresponding to each tone. The results show that a crossover point for four primary emotions lies in the frequency range of 417–440 Hz, thus consolidating the hypothesis that the frequency range of 432–440 Hz is neutral from human emotion perspective. It is also observed that the frequency dependant relationships between emotion pairs Happy—Sad, and Anger—Calm are approximately mirrored symmetric in nature.

ccJE+Advax is an inactivated cell culture Japanese encephalitis (JE) vaccine formulated with Advax™, a novel polysaccharide adjuvant based on delta inulin. This vaccine has previously shown promise in murine and equine studies and the current study sought to better understand its mechanism of action and assess the feasibility of single dose vaccine protection. Mice immunised with ccJE-Advax had higher serum neutralisation titres than those immunised with ccJE alone or with alum adjuvant. ccJE+Advax induced extraordinarily broad cross-neutralising antibodies against multiple flaviviruses including West Nile virus (WNV), Murray Valley Encephalitis Virus (MVEV), St Louis Encephalitis virus (SLE) and Dengue-1 and -2 viruses. Notably, the DENV-2 cross-neutralising antibodies from ccJE+Advax immunised mice uniquely had no DENV-2 antibody dependent enhancement (ADE) activity, by contrast to high ADE activity seen with DENV-1 cross-reactive antibodies induced by mbJE or ccJE alone or with alum adjuvant. JEV-stimulated splenocytes from ccJE+Advax immunised mice showed increased IL-17 and IFN-γ production, consistent with a mixed Th1 and Th17 response, whereas ccJE-alum was associated with production of mainly Th2 cytokines. There is an ongoing lack of human vaccines against particular flaviviruses, including WNV, SLE and MVEV. Given its ability to provide single-dose JEV protection as well as to induce broadly neutralising antibodies free of ADE activity, ccJE+Advax vaccine could be highly useful in all situations where rapid protection is desirable but ADE needs to be avoided, e.g. during a local outbreak or for use in travellers or the military requiring rapid travel to JEV endemic regions.

Understanding the detailed timing of crop phenology and their variability enhances grain yield and quality by providing precise scheduling of irrigation, fertilization, and crop protection mechanisms. Advances in information and communication technology (ICT) provide a unique opportunity to develop agriculture-related tools that enhance wall-to-wall upscaling of data outputs from point-location data to wide-area spatial scales. Because of the heterogeneity of the worldwide agro-ecological zones where crops are cultivated, it is unproductive to perform plant phenology research without providing means to upscale results to landscape-level while safeguarding field-scale relevance. This paper presents an advanced, reproducible, and open-source software for plant phenology prediction and mapping (PPMaP) that inputs data obtained from multi-location field experiments to derive models for any crop variety. This information can then be applied consecutively at a localized grid within a spatial framework to produce plant phenology predictions at the landscape level. This software supports the development of process-oriented and temperature-driven plant phenology models by intuitively and interactively leading the user through a step-by-step progression to the production of spatial maps for any region of interest. Maize (Zea mays L.) was used to demonstrate the robustness, versatility, and high computing efficiency of the resulting modeling outputs of the PPMaP. The framework is implemented in R, providing a flexible and easy‐to‐use GUI interface. Since this allows appropriate scaling to the larger spatial domain, the software can effectively be used to determine the spatially explicit length of growing period (LGP) of any variety.

Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.

Background and Research Highlights: Despite all the concerns and initiatives, natural resources like forests, as well as biodiversity are decreasing at an alarming rate worldwide. Conservation is considered as one of the major tools to prevent such loss and rapid degradation. Evidence around the world shows the adverse effects of conservation laws and policies on indigenous peoples and other local communities. Objectives: This study was conducted in one of the forest-dependent communities situated in Sundarban (world’s largest mangrove forest) to understand the impact of conservation laws and policies on their livelihood. Materials and Methods: A qualitative methodology was designed to collect data, using focus group discussions and case study with community people, and individual interviews with the personnel from NGOs and relevant government departments. Findings: Strict conservation policies and restrictions in accessing forest resources made lives and livelihoods of the local community insecure and unstable, thus putting the community in a vulnerable situation. The had to leave their traditional mode of income and look for alternative livelihood options. Almost no evidence was found in relation to upkeeping their rights in conservation activities. Prohibited movement, provision of punishment for entering into the forest without proper permission and struggles in everyday life were some of the highlighted issues. They had no participation in conservation activities, management of alternative livelihood options, and even they were not sensitized before putting restrictions. Although they had a history of emotional and physical attachment with the forest, existing activities did not consider these issues. In addition, corruption and abuse of power by law enforcement agencies towards the local community intensified the sufferings. Conclusion: This study argues that the realization of human rights in conservation activities and the sensitization of the implementing stakeholders are prerequisites for ensuring the sustainability of both biodiversity and the affected people.

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.

In this study, we investigated, for the first time, the effects of the spatially varying effective mass, asymmetry parameter, and well width on the electronic and optical properties of the quantum well which has an improved Rosen-Morse potential. Calculations are made within the framework of the effective mass and parabolic band approximations. We have used the diagonalization method by choosing a wave function based on the trigonometric orthonormal functions to find eigenvalues and eigenfunctions of the electron confined within the improved Rosen-Morse potential. Our results show that the position-dependence mass, asymmetry, and confinement parameters cause significant changes in the electronic and optical properties of the structure we focus on since these effects create a significant increase in electron energies and a blue shift in the absorption spectrum. The increase in energy levels enables the development of optoelectronic devices that can operate at wider wavelengths and absorb higher energy photons. This offers potential advancements in fields such as optical communication, imaging technology, and solar cells.

In this article, we delve into the intricate behavior of electronic mechanisms underlying NMR magnetic shieldings, σ, in molecules containing heavy atoms such as cadmium, platinum, and mercury. Specifically, we explore PtXn^{−2} (X = F, Cl, Br, I; n = 4, 6) and XCl2 Te2 Y2 H6 (X = Cd, Hg; Y = N, P) molecular systems. It is known that the leading electronic mechanisms responsible for the relativistic effects on σ are well characterized by the linear response with elimination of small components model (LRESC). In this study, we present results obtained from the innovative LRESC-Loc model, which offers the same outcomes as the LRESC model but employs localized molecular orbitals (LMOs) instead of canonical MOs. These LMOs provide a chemist’s representation of atomic core, lone pairs, and bonds. The whole set of electronic mechanisms responsible of the relativistic effects can be expressed in terms of both non-ligand-dependent and ligand-dependent contributions. We elucidate the electronic origins of trends and behaviors exhibited by these di- verse mechanisms in the aforementioned molecular systems. In PtX4^{−2} molecules, the predominant relativistic mechanism is the well-established one-body spin-orbit (σ^SO(1) ) mechanism, while the paramagnetic mass-velocity (σ^Mv ) and Darwin (σ^Dw ) contributing mechanisms also demand con- sideration. However, in PtX6−2 molecules, the σ Mv+ Dw contribution surpasses that of the SO(1) mechanism, thus influencing the overall ligand-dependent contributions. As for complexes con- taining Cd and Hg, the ligand-dependent contributions exhibit similar magnitudes when nitrogen is substituted with phosphorus. The only discrepancy arises from the σ^SO(1) contribution, which changes sign between the two molecules due to the contribution of bond orbitals between the metal and tellurium atoms.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that not only messenger RNAs but also other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long non-coding RNAs-associated ceRNA networks. Here, we identify an extended-ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of four hormone-dependent (HD) cancers, i.e., prostate, breast, colorectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across four HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding shared molecular pathogenesis in a group of related diseases.

River valley bottoms have hydrological, geomorphological, and ecological importance and are buffers for protecting the river from upland nutrient loading coming from agriculture and other sources. They are relatively flat, low-lying areas of the terrain that are adjacent to the river and bound by increasing slopes at the transition to the uplands. These areas have under natural conditions, a groundwater table close to the soil surface. The objective of this paper is to present a stepwise GIS approach for the delineation of river valley bottom within drainage basins and use it to perform a national delineation. We developed a tool that applies a concept called cost distance accumulation with spatial data inputs consisting a river network and slope derived from a digital elevation model. We then used wetlands adjacent to rivers as a guide finding the river valley bottom boundary from the cost distance accumulation. We present results from our tool for the whole country of Denmark carrying out a validation within three selected areas. The results reveal that the tool visually performs well and delineates both confined and unconfined river valleys within the same drainage basin. We use the most common forms of wetlands (meadow and marsh) in Denmark's river valleys known as Groundwater Dependent Ecosystems (GDE) to validate our river valley bottom delineated areas. Our delineation picks about half to two-thirds of these GDE. However, we expected this since farmers have reclaimed Denmark's low-lying areas during the last 200 years before the first map of GDE was created. Our tool can be used as a management tool, since it can delineate an area that has been the focus of management actions to protect waterways from upland nutrient pollution.

Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children.Aim of the study: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children.Methods: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1β and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning.Results: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance.Conclusions: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT.

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.

The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the “Central Dogma of Molecular Biology”, has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNA-dependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesisfound to occur, in mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained with multiple mRNA species in several mammalian systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundanceof a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer’s disease. The aim of the present article is to systematize the current knowledge and understanding of this pathway. The outlined framework introduces unexpected features of the mRNA amplification such as its ability to generate polypeptides non-contiguously encoded in the genome, its second Tier, a physiologically occurring intracellular polymerase chain reaction, iPCR, a Two-Tier Paradox and RNA Dark Matter. RNA-dependent mRNA amplification represents a new mode of genomic protein-encoding information transfer in mammalian cells. Its potential physiological impact is substantial, it appears relevant to multiple pathologies and its understanding opens new venues of therapeutic interference, it suggests powerful novel bioengineering approaches and its further rigorous investigations are highly warranted.

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 essay, I revisit Neural Networks (NNs) through the lens of evolutionary dynamics. From the two most important features of NNs, I recover the two most general equations of evolutionary dynamics. These two equations may thus serve as a connection between NNs and a body of knowledge that has been built over multiple centuries and has found application across a vast range of disciplines. This connection may therefore also help explain why NNs with the two features in question are applicable across a much broader range of domains than initially envisioned.

Chromium poisoning strongly influences the performance of solid oxide fuel cell (SOFC) stacks. A three-dimensional, time-dependent, computational fluid dynamics model of a single channel of a F10 SOFC stack in Forschungszentrum Jülich GmbH is developed to investigate chromium poisoning for different stack designs, temperatures and absolute air humidities. The model takes into account both chemical and electrochemical mechanisms of chromium poisoning and is able to predict the spatial distribution of SrCrO4 and Cr2O3. The voltage degradation over 100 kh can be simulated quantitatively. According to the simulation results, chromium poisoning is almost eliminated by the application of the protective coating fabricated by the atmospheric plasma-spraying (APS) technology. Besides, with the help of the APS protective coating, operating a SOFC stack with less dehumidified air at 650 oC is possible according to the simulation.

Many studies on magnetorheological fluid (MRF) have been carried out over last three decades several salient advantages such as fast phase change, easy control of the yield stress and so forth. Especially, several review articles of MRF technology have been reported for last two decades summarizing the development of MRFs and their applications. As specific examples, the review articles including the optimization of the particles and carrier liquid to achieve minimum off-state viscosity and maximum yield stress at on-state, the formulation of many constitutive models in-cluding Casson model and Herschel-Bulkley (H-B) model, the sedimentation enhancement using additives and nanosized particles, many types of dampers for automotive suspension and civil structures, medical and rehabilitation devices, MRF polishing technology, the methods of mag-netic circuit design, and the synthesis of various controllers have been published. More recently, the effect of the temperature and thermal conductivity on the properties of MRFs and application systems are actively being investigated by several works. However, there is no review article on this issue so far despite of that the thermal problem is one of crucial factors to be seriously con-sidered for the development of advanced MRFs and commercial products of application systems. In this work, studies on the thermal conductivity and temperature in MRFs themselves and tem-perature-dependent application systems are reviewed, respectively, and principal results are summarized emphasizing on the followings: how to reduce the temperature effect on the field-dependent properties of MRFs and how to design application system to minimize the thermal effect. It is noted here that the review summary is organized in a chronological format using tables.

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.

In this paper, we examine the mathematical and physical consistencies of the three primary couple stress theories: original Mindlin-Tiersten-Koiter couple stress theory (MTK-CST), modified couple stress theory (M-CST) and consistent couple stress theory (C-CST). As has been known for many years, MTK-CST suffers from some fundamental inconsistencies, such as the indeterminacy of the couple-stress tensor. Therefore, despite the fact that MTK-CST has a fundamental position in the evolution of size-dependent continuum mechanics, it is not a reliable theory within continuum mechanics, for example, in developing new size-dependent multi-physics formulations. We also observe that M-CST not only inherits all inconsistences from the original MTK-CST, but also suffers from new additional inconsistencies, such as the introduction of a new non-physical governing equation. These inconsistencies refute the claim of those who state that the couple-stress tensor may be chosen symmetric. Therefore, the apparent success of MTK-CST and M-CST in describing a size-effect for some problems, such as two-dimensional plate and beam bending, is not enough to justify these theories as suitable for general cases. In fact, the symmetric couple-stresses in M-CST create torsional or anticlastic deformation, not bending. On the other hand, C-CST, with a skew-symmetric couple-stress tensor, is the consistent continuum mechanics suitable for solving different size-dependent solid, fluid and multi-physics problems.

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.

A difficult open problem that has never been fully resolved in the literature to date is the behaviour of the (TDCDP) third approximation. As a giant step towards modern control theory, this cutting-edge paper will advance control theory and other relevant inter-disciplinary subjects. Because control theory is important in industry and engineering, this study will be especially beneficial to anyone working in these disciplines who wish to understand more about recent advances in control theory settings. In contrast, the wealth of applications of Fokker Planck Kolmogorov (FPK) equations numerous disciplines As a result, the study instantly gains more taste and credibility. At the end of the paper, there are several challenging open problems, some concluding remarks, and recommendations for further investigation.

Neuronal timing is critical for many brain functions such as perception and learning. At the level of the chemical synapse, the synaptic delay is determined by the presynaptic release probability (Pr) and the waveform of the presynaptic action potential (AP). Depolarization-induced analogue-digital facilitation (d-ADF) is a form of context-dependent synaptic facilitation that is induced by constant depolarization of the presynaptic neuron and is mediated by voltage inactivation of presynaptic Kv1 channels. Whether synaptic delay is modulated during d-ADF remains unclear. We show here that despite Pr is elevated during d-ADF at L5-L5 synapses, the synaptic delay is surprisingly unchanged, suggesting that both Pr- and AP-dependent changes in synaptic delay compensate for each other. We conclude that in contrast with other short- or long-term modulation of presynaptic release, timing is not affected during d-ADF because of the opposite interaction of Pr- and AP-dependent modulations of synaptic delay.

An exposition is undertaken to reveal the significant impact of the time-dependent root parameter, on the stability of Pointwise Stationary Fluid Flow Approximation (PSFFA) model of the non-stationary queueing system. This opens new grounds to stability analysis of non-stationary queueing systems. Potential PSFFA applications of IoT are highlighted.

Drought stress imposes substantial constraints on the growth and production of wheat (Triticum aestivum L.), a globally important cereal crop that is essential for food security. To mitigate these adverse effects, researchers are intensifying their efforts to comprehend how different genotypes respond to drought stress, aiding in the development of sustainable breeding and management strategies. This review summarized past and recent research on genotype-dependent responses of wheat to drought stress, encompassing morphological, physiological, biochemical, molecular, genetic, and epigenetic reactions in plants. Screening of drought-affected features at early developmental stages can provide valuable insights into the adult growth stages that are closely linked to plant productivity. The review underscores the importance of identifying key traits associated with drought resistance, and the potential of leveraging wheat diversity to select cultivars with desirable agronomic characteristics. It also highlights recent advancements in investigating Bulgarian wheat genotypes with varying levels of drought tolerance, specifically in detecting essential features contributing to drought tolerance. Cultivating drought-resistant wheat genotypes and understanding stress stability determinants could markedly contribute to enhancing wheat production and ensuring stable yields under changing climate conditions.

The dynamic response of a Bell-and-Bloom magnetometer to a parallel (to the bias field) time-dependent field is modelled beyond the commonly assumed quasi-static regime. The results unveil features that are related to the parametric nature of the considered system. It is shown that a for low-amplitude time-dependent field different operating conditions are possible and that, beside the commonly reported low-pass-filter behaviour, a band-pass response emerges. Moreover, we numerically show that for larger field amplitude the system, due to its parametric nature, has a kind of ``non-linear'' response.

Natural gas hydrate has gained significant attention in recent years. To safely and sustainably exploit the natural gas from gas hydrate-bearing sediments, it is crucial to understand the long-term mechanical characteristics of the hydrate reservoir. In this study, the influence of hydrate and fine particles on the strain rate dependence of hydrate-bearing sediments under plane strain conditions has been studied. The experimental results show that the strain rate dependency of the mechanical properties of hydrate-bearing sediments is positively correlated with hydrate saturation instead of the morphology of hydrate in sediments. The residual strength of hydrate-bearing sediments is primarily controlled by the hydrate saturation and is independent of the strain rate. Changes in hydrate saturation, and fines content, can affect the relationship between the strain rate and shear band angle. Finally, the local volumetric expansion effect of hydrate-bearing sediments without fines content is more significant and shows a strong strain rate dependence characteristic. Overall, this study provides valuable insights into the long-term mechanical characteristics of hydrate reservoirs. These insights can contribute to the development of a constitutive model of hydrate-bearing sediments with time-dependence in the future, and which is meaningful to the exploitation of natural gas hydrate.

Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of TMZ and cholesterol lowering medications (statins) is currently under investigation in in vivo and clinical trials. In our current investigation, we have used a triple combination therapy of TMZ, Simvastatin (Simva), and Acetylshikonin (ASH) and investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used viability, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. Our results showed that TMZ/Simva/ASH combination therapy significantly induced more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage (increase of ROS, decrease of MMP) and induced caspase-3/7 activation in both GBM cell lines. Compared to all single treatments and the TMZ/Simva treatment, TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment was due to partial inhibition of autophagy flux (accumulation of LC3β-II and decrease in p62 degradation) in GBM cells. Our investigation also showed that TMZ/Simva/ASH-induced cell death was depended on autophagy flux as further inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially depends on an increase of Bax expression in GBM cells. Our current investigation might open new avenues for more effective treatment of GBM but further investigations are required for better identification of the mechanisms.

Human metapneumovirus is one of major causes of common cold among children, especially infants. Its key enzyme is RNA-dependent RNA-polymerase, which performs both replication and transcription, including capping and cap methylation. The goal of the work is to find possible inhibitors of RNA-dependent RNA-polymerase across the active compounds of Rosaceae plants. The candidates were selected by molecular docking to cap-transferring domain of RNA-polymerase (PDB ID: 4UCZ) in Autodock VINA. Among all the substances tested by docking, ellagic acid derivatives showed the most promising results (affinity values below -10 kcal/mol). Hence, they could be treated as possible candidate drugs against metapneumoviral infection after experimental examination. The main advantage of using these substances should be their low toxicity, which is quite uncommon for selective RNA polymerase inhibitors used in clinical practice. Occurrence of ellagic acid derivatives among the plants from Rosaceae family like raspberry could explain their effect during common cold.

The lateral pressure generated by liquefied soil on pile is a critical parameter in the analysis of soil-pile interaction in liquefaction-susceptible sites. Previous studies have shown that liquefied sand behaves like a non-Newton fluid, and its effect on piles has rate-dependent properties. In this study, a simplified pseudo-static method for liquefiable soil-pile interaction analysis is proposed by treating the liquefied soil as a thixotropic fluid, which considers the rate-dependent behavior. The viscous shear force generated by the relative movement between the viscous fluid (whose viscosity coefficient varies with excess pore pressure and shear strain rate) and the pile was assumed to be the lateral load on the pile. The results from the simplified analysis show that the distribution of bending moment is in good agreement with experiments data. Besides, the effects of various parameters, including relative density, thickness ratio of non-liquefiable layer to liquefiable layer, and frequency of input ground motion, on the pile-soil rate-dependent interaction were discussed in detail.

In this paper, we address the energy eigenvalues of two-dimensional Dirac oscillator perturbed by dynamical noncommutative space. We derived the relativistic Hamiltonian of Dirac oscillator in dynamical noncommutative space ($\tau$-space), in which the space-space Heisenberg–like commutation relations and noncommutative parameter are position-dependent. Then used this Hamiltonian to calculate the first-order correction to the eigenvalues and eigenvectors, based on the second quantization and using the perturbation theory. It is shown that the energy shift depends on the dynamical noncommutative parameter $\tau$. Knowing that with a set of two-dimensional Bopp-shift transformation, we mapped the noncommutative problem to the standard commutative one.

Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

In recent years, the photophysical properties of crystalline metal-organic frameworks (MOFs) have become increasingly relevant for their potential application in light-emitting devices, photovoltaics, nonlinear optics and sensing. The availability of high-quality experimental data for such systems makes them ideally suited for a validation of quantum mechanical simulations, aiming at an in-depth atomistic understanding of photophysical phenomena. Here we present a computational DFT study of the absorption and emission characteristics of a Zn-based surface-anchored metal-organic framework (Zn-SURMOF-2) containing anthracenedibenzoic acid (ADB) as linker. Combining band-structure and cluster-based simulations on ADB chromophores in various conformations and aggregation states, we are able to provide a detailed explanation of the experimentally observed photophysical properties of Zn-ADB SURMOF-2: The unexpected (weak) red-shift of the absorption maxima upon incorporating ADB chromophores into SURMOF-2 can be explained by a combination of excitonic coupling effects with conformational changes of the chromophores already in their ground state. As far as the unusually large red-shift of the emission of Zn-ADB SURMOF-2 is concerned, based on our simulations, we attribute it to a modification of the exciton coupling compared to conventional H-aggregates, which results from a relative slip of the centers of neighboring chromophores upon incorporation in Zn-ADB SURMOF-2.

The vast majority of antibodies generated against a virus will be non-neutralising1. However, this does not denote an absence of protective capacity. Yet, within the field there is typically a large focus on antibodies capable of directly blocking infection (neutralising antibodies, nAbs) of either specific viral strains or multiple viral strains (broadly-neutralising antibodies, bnAbs). More recently, a focus on non-neutralising antibodies (nnAbs), or neutralisation-independent effects of nAbs, has emerged. These can have additive effects on protection or in some cases, be a major correlate of protection. As their name suggests, nnAbs do not directly neutralise infection but instead, through their Fc domains, may mediate interaction with other immune effectors to induce clearance of viral particles or virally infected cells. nnAbs may also interrupt viral replication within infected cells. Developing technologies of antibody modification and functionalisation may lead to innovative biologics that harness the activities of nnAbs for antiviral prophylaxis and therapeutics. In this review, we discuss specific examples of nnAb actions in viral infections where they have known importance. We also discuss the potential detrimental effects of such responses. Finally, we explore new technologies for nnAb functionalisation to increase efficacy or introduce favourable characteristics for their therapeutic applications.

This article deals with a finite-source stock-dependent stochastic inventory system with heterogeneous servers and retrial facility. The system can store up to S number of items, and the lifetime of each item follows an exponential distribution. The primary customers arrive in a finite waiting hall from a finite source and get service from the multi-channel (c-heterogeneous servers). The customer’s arrival rate depends on the present stock level. Those customers who arrive while the waiting hall is full enter into the finite orbit. Also, customers in the waiting hall can become impatient and enter the orbit. The (s,Q) ordering policy is adopted for the replenishment of stocks. In the steady state, the joint probability distribution of a number of items in the inventory, busy servers, customers in the waiting hall, and orbit is computed. The comparative numerical analysis of heterogeneous and homogeneous servers on the expected total cost, the average number of customers in the waiting hall and orbit, the fraction of successful retrial rate, and the average impatient customer rate are also carried out.

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evi-dence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets – ATR, CHK1, PARP and their inhibitors.

Two-dimensional (2D) materials show advantages as surface enhanced Raman scattering (SERS) substrate over traditional noble metals, such as chemically inert flat surface and uniform SERS signals. However, due to the low density of free electrons of 2D materials, the enhancement mechanism is mainly restricted to chemical enhancement instead of electromagnetic enhancement, resulting a relatively low enhancement factor. In this work, we reported a sensitive 2D SERS substrate based on chemical vapor deposited MoN nanosheets with electromagnetic enhanced mechanism. The maximum enhancement factor can be 3×105 with a limit of detected concentration of 4×10-8 M, which is comparable to those noble metal SERS substrates without hot spots. The MoN nanosheets show strong surface plasmon resonance in the visible range as evidenced by the UV-vis absorption spectroscopy and first principle calculation. The MoN nanosheets SERS substrates exhibit excellent Raman signal uniformity within the nanosheets. Meanwhile, Distinct thickness dependent sensitivity was observed in the MoN nanosheets, higher sensitivity can be achieved by decreasing the thickness of the nanosheets. Furthermore, the MoN nanosheets SERS substrate also show high thermal stability, which can be annealed in air for more than 300℃ and maintain its SERS activity. The high stability of MoN nanosheets allows it to be reused for 20 cycles without obvious signal decay. The high sensitivity, stability, reusability and Raman signal uniformity, makes MoN nanosheets an ideal 2D SERS substrate for practical applications.

Creep is a fundamental property naturally exists in some types of rock, which is significant for the long-term stability of roadways during the mining process. In this paper, the long-term strength of coal and rock were obtained via laboratory experiments, and a Cvisc elasto-viscoplastic model was adopted and introduced in FLAC3D, based on the 3101 transport roadway in Hongqinghe Coal Mine, to investigate the influence of creep on the stability of deep-high stress roadway. The test results show that the long-term strength of 3-1 coal and sandy mudstone, respectively, is 18.65 MPa, 39.95 MPa. The plastic zone, the deformation, and the damage of roadway surrounding rock behave an obvious increase after being excavated for 720d as the creep model was chosen. The plastic zone failure with models shear-p (1090.7 m3), shear-n (381.7 m3), tension-n (98.4 m3), and tension-p (30.8 m3), the damage value has an obvious increment of increased 21.2% (0.053), the deformation increases in the order is two-sidewalls (1978 mm), roof (907 mm), floor (101 mm). The creep of the roadway can be divided into three stages: the accelerating stage, the decaying stage, and the stable stage. The creep speed of each stage is greatly affected by the presence or absence of anchor spray support: the creep speed of the bare roadway roof, roadway side, and floor stability, respectively, is 1.01, 1.02, and 0.12 mm/d; After anchor spray support, the creep velocity, correspondingly, decreased to 0.69, 0.37, and 0.12 mm/d, and the amount of surrounding rock damage decreased from 0.302 to 0.243. This indicates that the anchor spray support can significantly reduce the creep effect of the roadway. The Cvisc creep model was verified reliable and can provide guidance for deep high-stress coal roadway support.

Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) lymphocytes eliminates cells infected with viruses. Antiviral ADCC requires three components: 1) antibody; 2) effector lymphocytes with the Fc-IgG receptor CD16A; and 3) viral proteins in infected cell membranes. Fc-afucosylated antibodies bind with greater affinity to CD16A than fucosylated antibodies; individuals’ variation in afucosylation contributes to differences in ADCC. Current assays for afucosylated antibodies involve expensive methods. We report an improved bioassay for antibodies that support ADCC which encompasses afucosylation. This assay utilizes externalization of CD107a by NK-92-CD16A cells after antibody recognition. We used anti-CD20 monoclonal antibodies, GA101 WT or glycoengineered (GE), 10% or ~50% afucosylated, and CD20-positive Raji target cells. CD107a increased detection 7-fold compared to flow cytometry to detect Raji-bound antibodies. WT and GE antibody effective concentrations (EC50s) for CD107a externalization differed by 20-fold, with afucosylated GA101-GE more detectable. The EC50s for CD107a-externalization vs. 51Cr cell death were similar for NK-92 CD16A and blood NK cells. Notably, the %CD107a-positive cells negatively correlated with dead Raji cells and was nearly undetectable at high NK:Raji ratios required for cytotoxicity. This bioassay is very sensitive and adaptable to assess anti-viral antibodies but unsuitable as a surrogate assay to monitor cell death after ADCC.

Potential dependent special relativity and Gauss's law for the electric field have been used for gravity by assuming vacuum energy to be generated when the energy is a minimum useful expression for vacuum energy has been found. This expression shows that elementary particles are generated by gravity vacuum filling their hollow balls; using Schrödinger equation for spherically symmetric particles vacuum energy is quantized. Treating mass as vibrating spheres thus solving Schrödinger, coordinate harmonic oscillator energy relation has been found.

Regression models are mostly used in all fields of sciences for modelling the relationship between a dependent variable and independent variable(s). The least square method is often used to estimate the parameters in a linear model because it is the best linear unbiased estimator. These estimates can only be reliable if the assumption of normality is satisfied. In some cases the dependent variable might be bimodal and shows a non-linear relationship with the independent variable(s). In this case, a non-linear model should be used. In non-linear model, the standard errors are often obtained by linearizing the nonlinear function around the parameter, assuming central limit theorem. After the linearization, the least square parameter estimates are obtained. It should be noted that the error of the non-linear model is different from that of the transformed linear model. Thus, there is a need to transform back to the original non-linear model. In this note, a novel non-linear function was developed into a non-linear regression model, called Normal-Power model. The least square method was used to estimate the parameter of the transformed model. Its usefulness in regression model was demonstrated using real data of Nigeria Economy-Tourism model.

Dengue fever is a viral mosquito-borne infection, a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called Antibody-Dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: i) primary dengue infection, ii) secondary dengue infection with the same (homologous) dengue virus and iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production, and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights on the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.

Background: Clinical cases reports with snake accidents show that venom bite induces increased oxidative stress including several markers of lipid peroxidation and other oxidative stress marker in plasma. Methods: The main findings of this work were performed with BthTx-II on paw edema of animals treated with the toxin and biochemical measurement of COX-2, PGE2, MDA and the effects of peroxiredoxin inhibitors on edema and myotoxicity were also evaluated. Results: The results show that edema and myotoxocity induced by PLA2 (BthTx-II) induces a strong mobilization of arachidonic acid and an increase in cellular oxidative stress as measured by increased malondialdehydo (MDA) concentration and protein carbonylation. Thus, these findings establish the strong link between oxidative stress, arachidonic acid mobilization and that these events may explain the presence of oxidative stress markers in snake-bitten patients. Experiments performed with animals previously treated with commercially purchased inhibitors showed enzymes such as thioredoxin (TXN), thioredoxin reductase (TXNRD) and other glutathione (GSH)-related antioxidant defenses could play an essential role controlling and defining the end of edema on the late phase of PLA2 BthTx-II-induced process. Conclusion. This study showed that thioate-dependent antioxidant enzymes play an important role in resolving the edema induced by BthTx-II.

FeIFeI Fe2(S2C3H6)(CO)6(µ-CO) (1a-CO) and its FeIFeII cationic species (2a+-CO) are the simplest model of the CO-inhibited [FeFe] hydrogenase active site, which is known to undergo CO photolysis within a temperature- dependent process whose products and mechanism are still a matter of debate. Using Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) computations, the ground state and low-lying excited state potential energy surfaces (PESs) of 1a-CO and 2a+-CO have been explored aimed at elucidating the dynamics of the CO photolysis yielding Fe2(S2C3H6)(CO)6 (1a) and Fe2(S2C3H6)(CO)6+ (2a+), two simple models of the catalytic site of the enzyme. Two main results came out from these investigations. First, a-CO and 2a+-CO are both bound with respect to any CO dissociation with lowest free energy barriers around 10 kcal mol-1, suggesting that at least 2a+-CO might be synthetized. Second, focusing on the cationic form, we found at least two clear excited state channels along the PESs of 2a+-CO that are unbound with respect to equatorial CO dissociation.

Real-time evolution of the electron densities under excitations in La₂CuO₄ was calculated by the time-dependent density functional theory (TDDFT). The author found, for the first time, under excitations, the electron cloud of Cu²⁺ changes obviously and the characteristic frequencies are 83 meV and 36 meV, respectively, for two different modes. The results are unexpected and close to that of lattice vibrations. The results show that the electron cloud of Cu²⁺ (just like the lattice) can be the electron-pairing medium in high temperature copper oxide superconductors.

Prompt removal of misfolded membrane proteins and misassembled membrane protein complexes is essential for membrane homeostasis. However, the elimination of these toxic proteins from the hydrophobic membrane environment has high energetic barriers. Transmembrane FtsH is the only known ATP-dependent protease responsible for this task, unlike other well-studied soluble ATP-dependent proteases. The mechanisms by which FtsH recognizes, unfolds, translocates, and proteolyzes its substrates remain unclear. Here, we report the crystal structures of the Thermotoga maritima FtsH periplasmic domain (PD) in an associative trimeric state at a 1.5-1.95 Å resolution. We also describe the pH-dependent oligomerization states of the isolated PD using dynamic light scattering. These observations help us understand how FtsH recognizes membrane-anchored misfolded proteins.

As the natural resources are getting exhausted, the concept of sustainable development of region has received increasing attentions, especially for resource-dependent cities. In this paper an innovative method that emergy analysis and IPAT (Human Impact Population Affluence Technology) model were combined in order to analyze the quantitative relationship of economic growth and energy consumption and further to evaluate its overall sustainability level. Taiyuan, a traditional, resource-dependent city in China, is selected as the case study region. The main results show that total emergy of Taiyuan increased from 9.023× 1023 sej in 2007 to 9.116× 1023sej in 2014, with 38% reduction on non-renewable emergy and 125% growth on imported emergy. Regional emergy money ratio (RMB) was reduced by 48% from 5.31× 1013sej/$ in 2007 to 2.74× 1013sej/$ in 2014, indicating that the increasing speed of consuming resources and energy was faster than the increase of GDP, and that Taiyuan’s money purchasing power declined. The lower emergy sustainability index (ESI) indicates that Taiyuan was explored and produced large quantities of mineral resources, which puts more stress on the environment as a consequence, and that this is not sustainable in the long run. The IPAT analysis demonstrates that Taiyuan sticks to the efforts of energy conservation and environmental protection, in order to promote regional sustainable development, it is necessary to take an integrated effort. Policy insights suggest that resourceful regions should improve include energy and resource efficiency, optimizing energy and resourceful structure.

We consider a Cauchy problem for differential equations in a Hilbert space $X$. The problem is stated in a time interval $I$, which can be finite or infinite. Weuse a fixed point argument for history-dependent operators to prove the unique solvability of the problem. Then, we state and prove convergence criteria for both a general fixed point problem and thecorresponding Cauchy problem. These criteria provide necessary and sufficient conditions on a sequence $\{u_n\}$ which guarantee its convergence to the solution of the corresponding problem, in the space of both continuous and continuously differentiable functions. We then specify our results in the study of a particular differential equation governed by two nonlinear operators. Finally, we provide an application in viscoelasticity and give a mechanical interpretation of the corresponding convergence result.

From the first isolation of the cystovirus bacteriophage Φ6 from Pseudomonas syringae 50 years ago, we have progressed to a better understanding of the structure and transformations of the many parts of the virion. The three-layered virion encapsulating the tripartite double stranded RNA (dsRNA) genome, breaches the cell envelope on infection, generates its own transcripts, and coopts the bacterial machinery to produce its proteins. The generation of new virions starts with a procapsid with a contracted shape, followed by packaging single stranded RNA segments with concurrent expansion of the capsid, and finally replication to reconstitute the dsRNA genome. The outer two layers are then added, and the fully formed virions released by cell lysis. Most of the procapsid structure composed of the proteins P1, P2, P4 and P7 is now known, as well as its transformations to the mature, packaged nucleocapsid. The outer two layers are less well studied. One additional study investigated the binding of the host protein YajQ to the infecting nucleocapsid, where it enhances the transcription of the large RNA segment that codes for the capsid proteins. Finally, we relate the structural aspects of bacteriophage Φ6 top those of other dsRNA viruses, noting the similarities and differences.

The integrated stress response is a signaling network comprised of four branches, each of which senses different cellular stressors, converging on the phosphorylation of eIF2α to depress global translation and initiate recovery. One of these branches is composed of GCN2, which senses cellular amino acid insufficiency and participates in the maintenance of amino acid homeostasis. Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is provoked by inhibiting an additional target. In this light, we screened a combination of drugs to identify biologically active compounds which synergize with the GCN2 inhibitor TAP20. First, a panel of 25 compounds was assayed in six cancer cell lines for drug sensitivity. Each compound was then combined with TAP20 at concentrations below their IC50, and the impact on cell growth was assessed. Selected strongly synergistic combinations were further characterised using synergy analyses and matrix-dependent invasion assays. Inhibitors of proteostasis, of the MEK-ERK pathway and pan-CDK inhibitors flavopiridol and seliciclib were found to potently synergize with TAP20 in two of the tested cell lines. Among their common CDK targets is CDK7, which was selectively targeted with THZ-1 and found to synergize with TAP20. Finally, these combinations were found to be partially synergistic when assessed using matrix-dependent invasion assays. However, we found that TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC50. We conclude that GCN2 can be targeted for treating cancers by polytherapy or even monotherapy.