Abstract: Foodborne diseases and food poisoning caused by bacterial pathogens is a significant global health as well as economic concern. While synthetic compounds are widely used as preservatives to ensure food safety, growing concerns regarding their potential health risks and the rise of antimicrobial resistance have driven the search for natural alternatives. Essential oils (EOs) and their individual bioactive constituents, known as essential oil components (EOCs), have emerged as promising, eco-friendly candidates for food preservation due to their robust broad-spectrum antibacterial properties. This review provides comprehensive mechanistic insights into how individual EOCs exert their antibacterial effects, detailing the disruption of bacterial cell membranes, inhibition of vital metabolic enzymes and ATP synthesis, modulation of virulence gene expression, and the prevention and eradication of biofilms. Furthermore, the review explores the practical applications and limitations of EOCs in food systems, addressing challenges such as chemical instability, toxicity at high doses, and adverse organoleptic effects. It also highlights advanced formulation strategies, such as micro/nano-encapsulation, nano-emulsions, and chemical derivatization, which significantly enhance EOC stability, bioavailability, and overall preservative efficacy. Ultimately, understanding the multifaceted mechanisms of individual EOCs paves the way for their optimized and sustainable use, ensuring global food safety.

Abstract: Antimicrobial resistance (AMR) is a silently escalating global crisis, presenting a specific challenge for the One Health approach. Landscapes can serve as reservoirs of AMR, while synurban wildlife may act as vectors of bidirectional exchange. However, these species can also be utilised as sentinels of landscape AMR load. Herbivorous avian bioindicators, such as the Common Wood Pigeon (Columba palumbus), continuously sample the landscape during foraging and drinking, providing unbiased data on the state of AMR. This study aimed to investigate the potential of this species for assessing the impact of landscape diversity on bacterial communities and their AMR patterns. Toward this objective, two landscape units of 4-km-diameter located at an upstream and a downstream section of a river, relative to a provincial town, were compared using 16 cloacal samples per site. Heterotrophic plate count techniques resulted in 60 isolates, of which 48 were identified, and 35 were tested for AMR using the VITEK 2 Compact system. Rényi diversity profiles of landscape compositions, bacterial communities, and AMR patterns revealed that higher landscape diversity was associated with lower bacterial but higher AMR pattern diversity. Additionally, the structure of more diverse bacterial communities shifted toward Gram-negative taxa. These findings support the hypothesis that culture-based methods using Common Wood Pigeons, complemented by Rényi diversity analysis and the determination of Gram-positive/Gram-negative ratios, provide valuable data on landscape health, even with small sample sizes.

Abstract: Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the NaV1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. Beyond its antagonistic action on AT1 receptor and agonistic activation of peroxisome proliferator-activator-γ, the direct stimulation of I_Na may also contribute to its modulation of AP firing in various excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation.

Abstract: Inadequate surface sanitization represents a significant risk to sterility assurance and regulatory compliance. Therefore an effective cleaning and disinfection programme is a critical component of contamination control strategies in pharmaceutical facilities manufacturing sterile medicinal products. This study aimed to standardize a carrier-based methodology for evaluating the efficacy of disinfectants against in-house environmental isolates recovered from a pharmaceutical industry facility. Nine representative strains (six bacteria and three fungi), selected based on historical environmental monitoring data (2012–2022), were characterized using matrix-assisted laser desorption/ionization - time-of-flight / mass spectrometry (MALDI-TOF MS) and molecular sequencing (16S rRNA or D2 LSU rDNA). Disinfectant efficacy was assessed on stainless-steel and low-density polyethylene surfaces using NF T 72-281:2014 with adaptations, testing alcohol 70%, sodium hypochlorite 0.5%, quaternary ammonium 0.05%, peracetic acid 0.5%, and accelerated hydrogen peroxide wipes. All agents demonstrated ≥5 log₁₀ reductions against vegetative bacteria and fungi on both surfaces. However, variable sporicidal performance was observed, particularly for one Bacillus cereus group strain (B1342/15), which showed limited reduction on stainless-steel. These findings highlight inter-strain variability and the greater tolerance of surface-associated spores. The study reinforces the importance of carrier-based testing using in-house isolates to ensure realistic validation of disinfectants and to strengthen microbiological risk management within pharmaceutical contamination control strategies.

Abstract: Efficient irrigation management is critical for increasing water production and providing high-quality planting material in fruit tree nurseries. This study looked at how four different irrigation depths (0, 10, 20, and 30 mm each irrigation event) affected graft establishment, nursery survival rate, total water consumption, and irrigation water productivity in peach (Prunus persica (L.) Batsch). Field studies were carried out in a commercial nursery in northeastern Romania over two consecutive growth seasons, with two cultivars ('Redhaven' and 'Cresthaven') and four fertilization levels in a factorial design. Irrigation considerably increased graft take and the number of marketable nursery trees compared to rainfed circumstances. Moderate irrigation (20 mm per irrigation event) resulted in the highest nursery survival rate and water efficiency. Higher irrigation inputs increased total water use, but reduced irrigation water productivity. Regression analysis revealed nonlinear connections between water consumption and nursery performance, implying that productivity advantages drop with increasing irrigation levels. The findings suggest that moderate watering can boost nursery yield while conserving water. These findings offer practical recommendations for irrigation management in commercial peach nursery production systems.

Abstract: Visual field testing is critical in diagnosing and managing glaucoma, which affects over 80 million people worldwide, as well as other ocular diseases and stroke. Visual field test perimeters detect blind spots (scotomas) and map the boundaries of a patient’s visual field. Standard perimetry machines are accurate, but prohibitively expensive and inaccessible in low-resource settings, while traditionally accessible forms of perimetry are less reliable. Virtual reality (VR)- based perimetry systems offer a potential low-cost, accessible alternative. This study reviews the development, clinical potential, and accuracy of VR perimetry. Findings showed that VR-based perimetry systems were comparable to, and in some cases even more effective than, standard perimetry tests, but these results were not universal, suggesting that greater standardization of testing protocols is necessary.

Abstract: Background: Intraoperative radiotherapy with low-energy X-rays (IOXRT) is an increasingly utilized modality during breast conserving therapy (BCT). However, the molecular mechanisms by which it affects the postoperative microenvironment remain to be fully elucidated. Surgical wound fluid (WF) has been demonstrated to modulate cancer cell behavior; however, its metabolomic composition has not been previously characterized in the context of breast cancer. The objective of this study was to evaluate metabolic alterations in postoperative WF and to determine whether IOXRT induces distinct metabolic signatures compared with mastectomy (AMP).Methods: Postoperative WF was collected from 54 breast cancer patients (38 BCT IOXRT; 16 AMP) at two time points: day 1 (A) and day 5 (B) after surgery. The samples were then subjected to analysis using ¹H NMR spectroscopy, encompassing NOESY, CPMG, and JRES techniques. A total of 114 spectral signals were quantified, and 42 metabolites were identified. Multivariate analyses (PCA, PLS DA, OPLS DA) and Wilcoxon signed rank tests were applied to assess temporal and intergroup differences.Results: A clear metabolic separation between time points A and B was observed in both treatment groups. However, statistical analysis revealed no significant differences between BCT IOXRT and AMP. In BCT IOXRT, on the fifth day, WF exhibited a decline in branched chain amino acids, asparagine, lysine, methionine, and glutamate, concomitant with an increase in lactate and pyruvate. AMP-specific alterations encompassed a decrease in 2-oxoglutarate and hypoxanthine on the first day, along with an increase in glucose and creatinine on the fifth day. A decline in ketone bodies (3-hydroxybutyrate, acetoacetate, acetone) was observed in both groups.Conclusions: Postoperative WF demonstrates dynamic metabolic changes reflecting early wound healing processes and treatment-related effects. IOXRT has been found to be associated with enhanced glycolytic signatures and reduced amino acid levels, suggesting altered metabolic activity in the irradiated tumor bed. The metabolomic profiling of WF has the potential to offer a novel source of biomarkers, which could facilitate the assessment of treatment response and tumor microenvironment characteristics.

Abstract: The Neotropical genus Inga (Fabaceae) is a dominant component of tropical forests and plays important ecological and functional roles; however, its diversity patterns and environmental controls across Andean landscapes remain poorly documented under increasing deforestation pressure. This study quantified the diversity, distribution, and environmental determinants of Inga species in the Imbabura Province, northern Ecuador, by integrating field surveys along five elevational transects, herbarium records, and Geographic Information Systems (GIS)-based analyses of climatic and edaphic variables. We recorded 17 species, nearly tripling previous regional findings. Species richness and occurrence were strongly structured by altitude, temperature, and soil properties. Ten species showed narrow altitudinal range and limited thermal tolerance (<2 °C), indicating habitat specialization, whereas I. densiflora and I. insignis exhibited broader niche breadths and generalist behavior. Edaphically, most species were associated with sandy loam soils, particularly Mollisols and Inceptisols. These results indicate that environmental gradients and soil conditions act as primary filters shaping Inga assemblages in heterogeneous montane landscapes. The high level of specialization observed suggests elevated vulnerability to land-use change and highlights the need for habitat-specific conservation strategies in Andean forests.

Abstract: Tea (Camellia sinensis), a widely consumed beverage, reduces oxidative stress and has antimicrobial properties due to its phytochemicals. Ethanolic extracts from Bangladeshi green tea were analyzed for phytochemicals, antioxidants, bioactive compounds, and antibacterial activity using in vitro and in silico methods. Qualitative screening detected alkaloids, phenolics, flavonoids, and tannins, with total phenolic content (TPC) at 35.95 ± 0.24 mg GAE/g and total flavonoid content (TFC) at 34.61 ± 1.53 mg QE/g. Antioxidant tests showed strong total antioxidant capacity (301.01 ± 14.32 mg AAE/g) and DPPH radical scavenging (IC50 2.70 μg/mL vs. ascorbic acid’s 3.75 μg/mL). HPLC identified gallic acid and vanillic acid as key compounds. Agar well diffusion assays revealed dose-dependent zones of inhibition against Staphylococcus aureus (12–22 mm) and Escherichia coli (10–20 mm) at concentrations of 25–200 mg/mL. In silico docking showed gallic and vanillic acids binding to S. aureus (PBP2a, SrtA) and E. coli (AmpC β-lactamase, GyrB) targets with affinities of -4.9 to -6.0 kcal/mol, stabilized by hydrogen bonds and π-interactions. ADME profiles indicated high gastrointestinal absorption, Lipinski compliance, and bioavailability (0.56–0.85). Toxicity predictions suggested minimal risks, mainly nephrotoxicity. PASS analysis predicted antibacterial, β-lactamase, and DNA gyrase inhibition activities. These findings underscore Bangladeshi green tea as a promising source of antioxidants and antibacterials for oxidative stress and infections.

Abstract: Reactive oxygen species are essential signalling molecules that regulate numerous aspects of skeletal muscle physiology. These effects are mediated through redox post-translational modifications on protein cysteine thiols, which influence the structure and function of redox-sensitive proteins. Mass spectrometry–based redox proteomic approaches have greatly advanced our ability to detect and characterise cysteine redox modifications, revealing a broad network of redox-sensitive proteins and pathways in skeletal muscle. Recent methodological developments enable quantification of the stoichiometry of reversible oxidative modifications at specific cysteine residues, providing critical insight into the extent and functional relevance of site-specific redox regulation. Redox proteomic approaches are being employed to improve our understanding of the specific redox protein modifications underlying physiological and pathophysiological processes in skeletal muscle. This review summarises current proteomic strategies for quantifying redox post-translational modifications and their application to study redox signalling in skeletal muscle. Emerging experimental approaches that offer the potential to study the specific roles of site-specific redox modifications in muscle physiology are also discussed. Collectively, these technologies present exciting opportunities to define the mechanistic roles of individual cysteine residues in muscle biology and help uncover new therapeutic avenues for conditions characterised by impaired redox homeostasis.

Abstract: The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated nuclear transcription factor belonging to the nuclear receptor superfamily. Although classically characterised as the master regulator of hepatic fatty acid oxidation (FAO) and lipid catabolism, accumulating evidence positions PPARα as an indispensable molecular conductor at the feto-maternal interface. Within the human placenta, PPARα is expressed in both cytotrophoblast and syncytiotrophoblast layers throughout gestation, where it governs mitochondrial and peroxisomal β-oxidation, orchestrates pro-resolution inflammatory signalling, modulates trophoblast differentiation and invasion, and participates in epigenetic programming of the developing fetus. Derangements of placental PPARα activity are increasingly identified in major obstetric complications, including preeclampsia, gestational diabetes mellitus, and intrauterine growth restriction, where aberrant lipid accumulation, heightened oxidative stress, and amplified pro-inflammatory cytokine signalling converge. This review synthesises current knowledge on the molecular biology and genomic targets of PPARα in the placenta, its integration with maternal metabolic adaptations of pregnancy, its role in nutrient sensing and fetal programming, and the consequences of its dysregulation in pregnancy pathology. We further discuss emerging therapeutic implications of PPARα modulation and outstanding questions in this rapidly evolving field.

Abstract: Biological coherence arises from coordinated integration of redox chemistry, hydration dynamics, electromagnetic interactions, and bioenergetic flux. Although substantial progress has been made in characterizing these processes individually, current frameworks do not fully explain how distributed biochemical events achieve stable temporal coordination across scales. In thermally noisy, dissipative environments, energy alone cannot account for sustained biological organization. A missing element is the establishment and renewal of phase reference - the temporal alignment that enables spatially distributed processes to act in synchrony. Here we propose a physical mechanism for phase reference access and anchoring based on cyclic nanodomain dynamics at a nanoscale redox-photonic interface previously termed the Redox Photonic Coupling System (RPCS). This interface supports an additional functional modality - phase breathing - a process mediated by molecular nitrogen (N₂) through which cyclic nanodomain nucleation and collapse anchors and sustains phase reference in living systems. Nitrogen-mediated oscillatory boundary dynamics create transient coherence windows that permit local access to phase reference, enabling phase-aligned oxidative-reductive resolution and anchoring of phase onto redox-generated Photonic Activation Quanta (PAQs). Absorption of phase-conditioned PAQs by adjacent hydration shells enables generation and accumulation of centropy, defined as stored organizational capacity that supports coordinated biological work.This framework identifies phase breathing as a previously unrecognized mechanism sustaining biological coherence and assigns molecular nitrogen a structural organizational role beyond respiratory dilution. By integrating nanodomain mechanics, photonic phase conditioning, and redox dynamics within a single interface, it provides a mechanistic basis for how coherent biological function is generated and maintained.

Abstract: The Central Dogma has provided a foundational framework for biological information flow, yet it does not fully explain how living systems preserve stable identity, functional robustness, and recoverability under continuous molecular noise and environmental perturbation. Here, I propose the Central Homeostatic Principle (CHP) as a complementary first-principle framework that shifts the explanatory center from information execution alone to the physical constraint architecture that makes biological execution possible. The CHP posits that, in living cells, a central homeostatic state functions as a system-level coordinating layer that defines the feasible state space within which genetic and biochemical programs can operate.This framework is motivated by convergent evidence across mechanical confinement, electrophysiological coupling, membrane contact-site transduction, phase-state regulation, and non-genetic phenotypic heterogeneity, all of which indicate that global physical states can gate, reshape, or buffer molecular outcomes. Building from systemic prerequisites and material constraints, I further argue through an exclusionary first-principle analysis that lipid-organized boundary systems occupy a near-irreplaceable physical position in implementing this central homeostatic constraint in aqueous cellular life-not as exclusive causal authors, but as the dominant substrate of feasibility control.To render the theory scientifically actionable, this manuscript provides a formal articulation of CHP, a three-tier realization model, operational corollaries, and a rule typology that distinguishes stronger and weaker forms. It then derives a set of falsifiable hypotheses spanning temporal commitment dynamics, non-genetic resistance, aging-related resilience loss, state-engineering-based reprogramming, and evolutionary primacy in prebiotic systems. By reframing life as a problem of constrained state maintainability rather than information flow alone, the CHP offers a testable theoretical scaffold for integrating molecular biology, biophysics, systems biology, and translational state engineering.

Abstract: Biochar, a carbon-rich material traditionally used to improve soil health and as a feed additive, has recently attracted attention for its potential biological activity. This study investigated the effects of an aqueous biochar extract (BC-AE) on human intestinal epithelial cells (Caco-2), specifically examining its impact on cell viability and apoptosis. The metabolic activity of Caco-2 cells exposed to BC-AE was first evaluated using an MTS assay. A concentration of 3 mg/mL, which promoted Caco-2 metabolic activity, was selected for further testing at 24 and 72 hours. The effect of BC-AE on cell viability was assessed by epifluorescence microscopy (morphology) and flow cytometry (apoptosis profiling). The transcriptional response of cell viability-related genes (BAX, BAD, BCL-2, BCL-xL, MCL-1, P21, and P53) and microRNAs (miR-15b, miR-19, miR-21, miR-33a, miR-155, and miR-486) was analyzed by RT-qPCR. In parallel, selected proteins (BAD, BAX, BCL-2, and MCL-1) were examined by Western blotting. BC-AE decreased cell viability after 24 hours via late apoptosis, while 72-hour exposure increased necrosis without further viability loss. Both BAX and MCL-1 protein levels increased in Caco-2 cells after 72 hours of BC-AE treatment, and miR-15b and miR-21 were upregulated, suggesting the involvement of a regulatory mechanism controlling cell survival. The obtained findings highlight the importance of considering both concentration and exposure duration when assessing biochar bioactivity.

Abstract: Aging is accompanied by a progressive decline in olfactory function, which affects a large proportion of older adults and has substantial consequences for nutrition, safety, and overall quality of life. Increasing evidence indicates that sex-dependent differences in olfactory processing become more pronounced with advancing age, particularly in late life. However, the cellular basis beyond the peripheral level by which aging and sex interact to influence neuronal and synaptic functions in central structures remains poorly understood. To bridge this gap, we compared behavioral outcomes, intrinsic and synaptic properties of the olfactory bulb (OB) output neurons mitral cells (MCs) that receive direct sensory input from odor receptor neurons and integrate olfactory information to most higher order brain regions, in male and female C57BL/6J mice of three ages spanning the natural lifespan. Consistent with human studies and the key role of mitral cells in transforming input to output in the OB, our behavioral tests showed that both aging and sex significantly influenced odor detection performance, which declined with age, particularly in females while locomotor activity remained preserved. At the cellular level, our whole-cell patch-clamp recordings in OB slices demonstrated that MCs in male mice across the lifespan exhibit a gradual decline in excitability and synaptic strength with age, while female mice maintain stable function until advanced age, when marked alterations emerge. This study provides the first physiological evidence of the joint influence of aging and sex on the functional operation of the OB at the cellular and synaptic levels. Considering olfactory impairment as the earliest and most sensitive indicator of the age-dependent and sex-biased neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, our findings provide functional insights not only into normal aging-induced olfactory deficits but also into the future development of early biomarkers and intervention strategies for these neurodegenerative disorders.

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline and the accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles. Beyond genetic and proteostatic mechanisms, a growing body of work has revived infection- and dysbiosis-based models of AD, including the antimicrobial protection hypothesis in which Aβ participates in innate immune defense. Here, we reanalyzed ribosomal-depleted (Ribo Zero) RNA-seq data from dorsolateral prefrontal cortex (DLPFC) samples from the Mount Sinai Brain Bank cohort (GSE53697) to screen for non-human transcripts. Reads underwent quality control and adapter trimming, taxonomic classification with Kraken2, Bayesian re-estimation with Bracken, and differential abundance testing with edgeR. Across 17 samples (9 advanced AD; 8 controls), we detected low-biomass microbial signals with a disease-associated shift. Acinetobacter radioresistens was enriched in the AD group (FDR = 0.018), whereas several taxa were relatively enriched in controls (including Lactobacillus iners; FDR = 0.051). In silico analysis of an A. radioresistens biofilm-associated protein homolog identified multiple amyloidogenic hexapeptides and surface-exposed regions in an AlphaFold2 structural model, consistent with a hypothetical cross-seeding capacity. Given the technical challenges of brain microbiome inference from post-mortem RNA-seq (contamination, low microbial biomass, and host background), these findings should be interpreted as hypothesis-generating and warrant orthogonal validation.

Abstract: Neural decoding has demonstrated that population activity contains behaviorally relevant information, yet predictive accuracy alone does not constitute mechanistic explanation. Decoding models establish statistical mappings between neural responses and task variables but leave the underlying computational processes underdetermined. We argue that neural computation is more appropriately framed within a dynamical state-space perspective, in which population activity reflects the evolution of latent states governed by structured transition operators. Across empirical and theoretical work, neural trajectories increasingly appear as low-dimensional, nonlinear flows shaped by recurrent circuit structure and contextual inputs. This shift reframes the central scientific objective: not merely extracting representations, but learning the evolution operator that governs state transitions. However, even accurate reconstruction of latent dynamics does not guarantee mechanistic validity. Observational data typically constrain only an equivalence class of admissible operators, rendering the inferred dynamics structurally non-identifiable. We therefore propose that causal neural dynamics must be defined through perturbation and experimental design. By introducing directional constraints on state transitions, targeted interventions collapse equivalence classes and enable identification of operators that remain valid under manipulation. In this framework, evolution operators are treated as falsifiable hypotheses whose mechanistic status depends on predictive stability under perturbation. This perspective recasts neural modeling as the search for perturbation-validated dynamical laws governing population activity, moving the field from decoding-based description toward causal dynamical explanation.

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Its hallmarks are extracellular amyloid-beta (Aβ) plaques and intracellular hyperphosphorylated tau forming neurofibrillary tangles, leading to synaptic dysfunction and neuronal loss. Despite extensive research, the mechanisms driving these proteinopathies and the contribution of genetic, molecular, and environmental factors remain unclear. Objective: This review summarizes the molecular mechanisms underlying AD and the factors influencing its onset and progression. Methods: A narrative review of peer-reviewed studies from PubMed, Scopus, and Web of Science was conducted. Relevant articles on neuropathology, molecular pathways, genetic susceptibility, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metabolic and lifestyle risk factors were analyzed. Results: AD is marked by Aβ accumulation and tau pathology, causing synaptic and neuronal loss. Key mechanisms include abnormal amyloid precursor protein processing, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and calcium dysregulation. Genetic variants (APP, PSEN1, PSEN2, APOE ε4) increase risk, while aging, cardiovascular disease, diabetes, and lifestyle factors further influence disease onset and progression. Conclusion: AD arises from complex interactions among molecular and environmental factors. Understanding these pathways is essential for developing preventive strategies and effective therapies, with personalized approaches offering future promise.

Abstract: The biosphere is undergoing an unprecedented transformation driven by global warming, habitat loss, and resource depletion, threatening biodiversity through widespread species extinctions and population declines. Although conservation and restoration remain essential, the risk of irreversible tipping points demands new strategies. Synthetic biology offers one such approach: engineering existing ecosystems by modifying functional traits of resident communities to enhance resilience and prevent abrupt shifts. Despite and because of public concern, advances in biosafety and control have been achieved, mainly on a cellular scale. However, after decades of bioremediation efforts, a central question emerges: not only can interventions be perfectly controlled, but also whether they can persist and sustain ecological function. Meeting this challenge requires a paradigm shift in design philosophy, from classical to emergent engineering, embracing adaptation, feedback, and multiscale complexity as the foundation of ecosystem design.

Abstract: The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2023, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease via the double methylation of the 5' end of eukaryotic DNA or RNA-based viral genomes, the 7-MeGpppA2’-O-Me cap, and its double methylation capping process is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16) and by N7-Methyltransferase (N7-MTase/NSP14), respectively. Moreover, it was discovered that polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), and consequently, detection of Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) alike. NSP1 also silences important interferon-encoding genes (INGs) and interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Another important viral NSP is NSP14, as it plays two functional roles that are independent of each other; to produce new viral genetic material for the purpose of maintaining the validity of the viral genome as well, and not just transfer a methyl group to the 5’ end of the viral genome. Other viral NSPs share a role with NSP1, 10, 14 and 16 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. With regards to efforts to delay the onset of malignant diseases, approaches of chrono-biological oncotherapies that include a combination of Type I and Type III Interferon-based “immune re-awakening” and low-dose SSRI or SNRI approaches, could display meaningful extents of efficacy, at least in effective delays in the onset of malignant diseases. Such overall approaches could also be considerably effective in efforts to delay and/or even prevent a number of acquired immunodeficiencies (i.e. HIV-1-induced AIDS) and diverse forms of malignant cancer, potentially helping to notably decrease the overall burden of disease worldwide in the long run. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases. Microbial agents could undergo loss-of-function research upon genes responsible for inducing clinical illness whilst keeping genes responsible for microbial reproduction and transmission at least generally as functional, CRISPR-Cas9 genome editing to have genes encoding proteins suppressive of the host interferon system eliminated prior to human genes encoding Pattern Recognition Receptor activator or agonist proteins, such as outer membrane proteins of Neisseria meningitidis, as well as Type I, Type III and possibly even Type IV Interferons and various ISGs inserted into the microbial genome. Importantly, the present study is theoretical and conceptual in nature and does not advocate for any practical steps or deployment into any real-world context. Such an approach is imagined as a potential prophylactic and early therapeutic method based upon the model of editing genes of harmless bacteria to transform such them into “producers” and “distributors” of human insulin, and could turn several microbial agents into clinically harmless, transmissible “factories” for various key elements of the host interferon system, potentially placing such microbes into a reverse evolutionary path that would be deemed as “natural de-selection”, visibly reducing the average burden of disease and metabolic stresses, which in turn could gradually increase average human and animal lifespans worldwide.