Abstract: Background: Autism spectrum disorder (ASD) is characterized by substantial biological and clinical heterogeneity that cannot be adequately explained by isolated biomarkers or single-system models. The Biological Burden Index (BBI) has been proposed as a hypothesis-generating multidimensional framework to organize convergent biological dysregulations that may contribute to interindividual variability in adaptive capacity, neurodevelopmental plasticity, and therapeutic responsiveness. Objective: This article examines how the BBI may be operationalized as a measurable, testable, and translational research construct rather than as a validated clinical instrument, providing a methodological foundation for future empirical investigation and precision stratification in autism. Methods and Conceptual Framework: Rather than representing a single biomarker, the BBI conceptualizes cumulative biological burden as an emergent multidomain property arising from the dynamic convergence of previously established physiological, molecular, immunological, metabolic, autonomic, and neurodevelopmental domains. Four complementary operational models are examined: (1) a weighted composite index, (2) a multidimensional burden profile, (3) a latent burden construct, and (4) a biological stratification framework for identifying clinically meaningful subgroups. Candidate biological domains, objective indicators, multimodal measurement layers, mathematical aggregation strategies, analytical approaches, and validation requirements are reviewed. Results and Translational Perspective: We argue that premature reduction of the BBI to a single summary score risks obscuring biologically meaningful heterogeneity, whereas multidimensional profile-based approaches provide a stronger foundation for early empirical validation, longitudinal characterization, biomarker integration, and precision stratification. Operationalization is presented as the critical methodological process through which the BBI can evolve from a conceptual framework into a scientifically usable research construct. Conclusions: By clarifying operational pathways, measurement architectures, and validation strategies, the BBI establishes a methodological foundation for future multimodal biomarker integration, translational autism research, and the progressive development of complementary precision frameworks addressing therapeutic engagement, intervention responsiveness, and human-supervised digital implementation while preserving the multidimensional complexity of biological burden.

Abstract: Transposable elements (TEs) constitute nearly half of the human genome and shape chromatin organization, gene regulation and genome evolution. We have large gaps in understanding their influence to physiology and pathology for now. In humans, the most active elements—LINE-1 (L1), Alu, and SVA retain some copies with the ability to evade epigenetic repression and mobilize via target-primed reverse transcription (TPRT), whereas copies become inactive through fragmentation, mutation, or nesting, a process where a TE segments integrates into another TE segment. TE activity contributes to genomic instability and has been implicated in aging, cancer, neurological disorders, chromatin organization, and epigenetic regulation. Studying TEs is challenging due to their repetitive and polymorphic nature. Recent advances in sequencing technologies, including short- and long-read platforms, combined with specialized bioinformatic pipelines, now allow more comprehensive characterization of TE insertions, deletions, expression, and epigenetic status. Computational approaches vary in sensitivity, specificity, and resource requirements, and their performance is influenced by sequencing modality, coverage, and the reference genome used. Assembly-based and read-based methods, as well as tools integrating methylation or single-cell data, provide complementary insights into TE biology. Here we review the biology of active human TE. Survey state of the art short and long-read pipelines for TE analysis. And highlight their applications in studies of aging cancer and other complex diseases. We also provide practical guidance for selecting appropriate sequencing strategies and tools for TE-focused projects, and discuss emerging approaches and open questions in the field.

Abstract: Foot-and-mouth disease (FMD) is one of the most infectious viral diseases of coven-hoofed animals. The crucial strategy for FMD control is the combination of animal quarantine and rapid onsite diagnostic assay capable of differential infected from vaccinated animals (DIVA). Herein, we have developed a lateral flow immunoassay to detect specific antibodies against FMDV non-structural protein (NSP), based on recombinant mu3ABC produced by E. coli as an antibody detector, so called mu3ABC strip test. Performance of mu3ABC strip test was examined using 566 field serum samples from cattle, pigs, and goats and compared with the commercial ELISA kit, resulting in the diagnostic sensitivity (DSn) and specificity (DSp) of 88.18% and 92.56%, respectively. Additionally, efficacies of the mu3ABC strip test and commercial ELISA were determined using 200 reference bovine sera (100 positives, 100 negatives) classified by the Regional Reference Laboratory for Foot and Mouth Disease in South East Asia (RRL). The result reveals that DSn and DSp of mu3ABC strip test were 78% and of 91%, respectively while the commercial ELISA kit had DSn of 69%and DSp of 100%. The developed mu3ABC strip tests are effective and can be used to differentiate the infected animals in parallel with the sero-surveillance ELISA test.

Abstract: Osteoporosis (OP) is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, but no effective clinical therapies exist. To address this unmet need, we employed a computational pipeline drug repositioning method based on single-cell data and Mendelian randomization analysis to screen potential candidate drugs for the treatment of osteoporosis. Quinidine was identified as a potential therapeutic agent for osteoporosis. Mendelian Randomization analysis indicated a causal relationship between Quinidine's drug target SCN5A and osteoporosis. Larval zebrafish experiments confirmed that Quinidine can ameliorate the Dexamethasone-induced osteoporosis model and promote cranial bone mineralization. qPCR showed that Quinidine can promote osteoblast-related gene expression and inhibit osteoclast-related genes expression. This study systematically revealed Quinidine as a potential drug in the prevention and treatment of osteoporosis through an integrated strategy of single-cell drug repositioning, genetic causal inference, and animal model validation.

Abstract: Despite the global crisis of mangrove deforestation, certain sediment-dominated estuaries exhibit remarkable morphodynamic resilience. This study investigates the spatiotemporal trajectory of the Ujung Pangkah estuary (1995–2025) to quantify natural progradation against anthropogenic pressures. Utilizing Google Earth Engine (GEE), Landsat archives, and a Random Forest classifier enhanced with advanced spectral indices (NDVI, mNDWI, EVI, MVI), we rigorously mapped the estuarine landscape. Accuracy assessment using independent historical validation yielded an exceptional overall accuracy of 97.30% for 2025. The change dynamics analysis revealed an explosive natural recovery. While the ecosystem suffered a gross historical loss of 574.02 ha primarily due to aquaculture conversion, this was vastly offset by a massive seaward gain of 1,245.15 ha on accreted mudflats. The total mangrove extent expanded from 613.88 ha in 1995 to 1,285.01 ha in 2025. Non-parametric statistical evaluation confirmed a highly significant, continuous median expansion rate of 27.65 ha/year. Crucially, hydrodynamic driver analysis using a red-band proxy for Total Suspended Solids (TSS) empirically validated that this progradation is intrinsically sediment-driven, fueled by the hyper-concentrated monsoonal discharge of the Bengawan Solo River. Safeguarding these dynamic frontiers requires urgent policy frameworks to legally protect newly accreted estuarine zones from future land-use conversion.

Abstract: We propose a novel approach to the problem of interconnecting the probabilistic formalisms of classical and quantum physics, focusing on its most challenging aspect: the classical probabilistic generation of entangled states. We show that the statistics encoded in the density operators of composite quantum systems correspond to fourth-order classical statistics. Specifically, to generate a density operator, one must consider the covariance of a random covariance operator. We term this framework the Double Covariance Model (DCM). This double covariance possesses a non-trivial internal structure that arises from the interplay between two distinct time scales, combining temporal and statistical covariances. In this article, we exploit a well-known property of Gaussian processes: the second-order moment determines the moments of higher orders, specifically the fourth-order moment. This Gaussian reduction simplifies the DCM by reducing it to second-order statistics. Utilizing (circular) Gaussian processes simplifies and generalizes the DCM construction for entangled states, rendering it mathematically rigorous. Furthermore, it clarifies the classical probabilistic meaning of concurrence, a foundational quantitative measure of entanglement.

Abstract: The authors examined the psychophysiological effects before and after the treatment with the aim of clarifying the effects on the mind and body of continuous treatment on the head (hereinafter referred to as head-therapy). As a result, psychologically, negative emotions such as fatigue, stress awareness, depression, and anxiety decreased significantly immediately after the treatment, and positive emotions such as a feeling of clarity of mind, concentration, and exhilaration were significantly increased. Thirty minutes after the treatment, these positive emotions were even higher. Physiologically, immediately after the head-therapy, the parasympathetic nervous system activity was significantly higher than before the treatment. On the other hand, no noticeable changes were observed in central nervous system activity. Furthermore, 30 minutes after the head-therapy, the parasympathetic nervous system activity dominant state seen immediately after the treatment was maintained. It was suggested that the central nervous system activity, which did not show significant changes immediately after the treatment, was more active than before the head-therapy.

Abstract: Background: Piezo1 is a mechanosensitive Ca²⁺-permeable ion channel that plays a crucial role in the Ca²⁺ signaling processes of human red blood cells (RBCs). Ca²⁺ influx through Piezo1 controls the activity of various molecules that are crucial for RBC physiology and pathophysiology, including Ca²⁺-activated K⁺ channels of intermediate conductance (KCa3.1, or Gardos channels), ANO6 lipid scramblases and pannexins-1 (Panx1). Erythropoiesis, the differentiation of erythropoietic stem cells in the bone marrow to myeloid progenitor cells and then to mature (RBCs, is traditionally studied using different blood cell lines as models. Among them, K562 cells, a human chronic myeloid leukemia cell line, are multipotent progenitors of hematopoietic cells that can be differentiated along the erythroid lineage, thus making these cells an invaluable model for studying human erythropoiesis. As K562 is an immortalized cell line obtained from a specific donor, the putative differences in the relevant pathways between K562 cells and human RBCs should be identified and taken into account. Here, we aimed to reveal and compare the functional interactions between Ca²⁺ influx through Piezo1 and Gardos channel, ANO6 and Panx1 activities in K562 cells and RBCs. Methods: Database analysis was performed to confirm the expression of genes of interest and putative mutations in K562 cells. Mutations were confirmed using Sanger sequencing. Piezo1 activity in the plasma membrane was stimulated by a selective Piezo1 agonist, Yoda1. KCa3.1 activation was detected using light microscopy and single-channel patch-clamp analysis. PS exposure was detected by AnV fluorescent staining. Presence of Panx1 was shown using RT-PCR, Western Blot and immunofluorescence. K562 differentiation was induced by cytarabine-hemin treatment and confirmed by a benzidine test. Panx1 activation was probed using dye uptake assay and whole-cell patch-clamp recordings. Results: We found that, similar to RBCs, both Piezo1-KCa3.1 and Piezo1-ANO6 functional links are present in K562 cells, whereas the Piezo1-Panx1 axis is not functional because Panx1 cannot be activated by Ca²⁺ in this cell line. Conclusions: Thus, the physiologically relevant pathways associated with Ca²⁺-induced Panx1 activity in K562 cells may significantly differ from those that are functional in human RBCs.

Abstract: Chronic non-communicable conditions – type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), metabolic obesity syndrome (MOS), polycystic ovary syndrome (PCOS), colorectal and extra-intestinal cancers, systemic autoimmune disease, and dermatologic and gynecologic disorders linked to gut dysbiosis – share a prolonged asymptomatic phase during which conventional screening is invasive, insensitive, or resource-intensive. This review synthesizes 2021-2025 literature on fecal microbiome-based artificial intelligence (AI) diagnostics across these conditions. We surveyed machine learning classifiers trained on 16S rRNA and shotgun metagenomic data, extracting reported discriminative performance, validated microbial and short-chain fatty acid (SCFA) biomarkers, and cross-cohort reproducibility. Reported classifiers achieve areas under the curve (AUC) typically between 0.79 and 0.93 across disease domains (e.g., 0.792 for autoimmune disease subtyping, 0.82-0.90 for colorectal cancer, 0.93 for PCOS subtyping), with dietary data integration and SCFA quantification further improving discrimination. We propose a multimodal deep learning architecture – combining a microbiome transformer encoder, dietary embedding module, host feature multilayer perceptron, phylogenetic graph neural network, and cross-attention fusion layer – coupled with explainable AI (SHAP, attention heatmaps, microbial risk scores) for clinical interpretability. We conclude that fecal microbiome-based multimodal AI is a technically mature but clinically unvalidated candidate for population-scale pre-symptomatic screening, pending prospective, harmonized cross-cohort trials.

Abstract: Hepatitis B virus (HBV) remains highly endemic in sub-Saharan Africa, where perinatal and early childhood transmission contribute substantially to chronic infection. Although routine infant vaccination is widely implemented, birth-dose coverage remains inconsistent in many settings. This study carried out in strict compliance with ethical rules, evaluated serological markers of HBV exposure and vaccine-induced immunity among fully vaccinated infants in Cameroon. It was a cross sectional study involving 9 to 15 months old hepatitis B fully vaccinated and HIV negative infants living in the towns of Douala and Yaoundé. Infants born to mothers known to be HBsAg-positive were excluded. Serum samples were tested for HBV serological markers, using lateral flow immunochromatography [1] techniques and indirect elisa [2,3]. Whereas 84.85% (56/66) of theses infants achieved seroprotective anti-HBs levels, 16.67% (11/66) was Anti-HBc seropositive. Overall, 63.64% of these anti-HBc seropositive infants were significantly less likely to demonstrate seroprotection compared with anti-HBc seronegative infants (adjusted OR 30.3; 95% CI 5.58–164.75). These results that highlights the association between anti-HBc positivity and reduced seroprotection, warrants further investigation, including molecular testing to distinguish passive maternal antibody transfer from occult or resolved infection. Strengthening perinatal HBV prevention strategies remains critical to achieving elimination targets.

Abstract: A static carrier construction for the low-energy, zero-momentum fine-structure constant is formulated within Recursive Interval Geometry (RIG). The carrier hierarchy is fixed before numerical evaluation by four requirements: discrete minimal closure, space-filling compatibility, boundary recursion, and nonzero boundary-state recursion. Each free boundary variable has two states, active or silent. The link has two freely variable endpoints, the triangle has three freely variable edges, and the octahedron has eight triangular faces with one whole-shell closing relation, leaving seven freely variable faces. Thus \( b_1=2 \), \( b_2=3 \), and \( b_3=7 \), and exclusion of the all-silent state gives \( D_1=3 \), \( D_2=7 \), and \( D_3=127 \). Adding the three level counts gives the skeleton \( N_{\mathrm{sk}}=137 \), while choosing one state from every level gives the joint boundary-state resolution \( \Omega=D_1D_2D_3=2667 \). The localized base ring organizes this recursive arithmetic skeleton; the exact physical state is its continuous geometric readout in the real metric completion of the depth-one principal/structural space. The structural sector is built from three dimension-filtered terms in this continuous readout. Pairing-sphere geometry gives an exact null locus for the oriented link readout; the centre-preserving antipodal branch supplies the phase holonomy \( \pi \) and a two-endpoint support loss \( -2 \). The octet-truss completion locks the pairing circle to four face-centred-cubic phases and gives a tetrahedral transmission-sharing contribution \( 127/2 \). Of the connector's four faces, one is occupied by attachment to the central octahedron and the closed-shell condition removes one further outward contribution, leaving the transmission coefficient \( 2/4=1/2 \). The geometric coefficients belong to the real readout, while \( \mathbb Z[\Omega^{-1}] \) carries the recursive arithmetic skeleton. The completed RIG norm defines the model output \( \alpha^{-1}_{\textrm{RIG}} \), and the electromagnetic interface postulate identifies it with the Thomson-limit inverse fine-structure constant. With the carrier and bridge rules fixed, this gives \( \alpha^{-1}_{\textrm{RIG}}=\sqrt{137^2+\left(\pi-\frac{2}{2667}+\frac{137+127/2}{2667^2}\right)^2}=137.035999176253\cdots \) The difference from the CODATA 2022 value is \( 5.45\times10^{-3} \) ppb. The construction addresses the static zero-momentum baseline, while QED supplies finite-momentum dynamics. The norm-to-coupling identification enters as a foundational interface postulate. Conditional on it, carrier, pairing, and closure geometry fix the \( \pi \), \( -2 \), and \( 127/2 \) terms without continuously fitted coefficients.

Abstract: The endocannabinoid system (ECS) has been extensively mapped at the level of receptors, ligands, enzymes, and signaling pathways, forming a detailed component inventory of a major homeostatic network. However, prevailing ECS models largely omit the nutritional substrates required to sustain ligand synthesis, membrane composition, signaling capacity, and regenerative function, leaving the system operationally incomplete from a systems-biology perspective. This Hypothesis identifies this gap by integrating evidence from nutritional biochemistry, lipid metabolism, and regenerative physiology, and argues that inclusion of dietary inputs is necessary to advance toward a nutritionally complete model of the ECS. By reframing the ECS as a metabolically sustained regulatory network rather than a purely signaling system, this framework has implications for understanding resilience, regeneration, and system failure under chronic stress, nutritional insufficiency, and environmental disruption. This synthesis is intended as a hypothesis-generating foundation to guide future experimental and clinical investigation.

Abstract: In the current paper, pulmonary emphysema is hypothesized to emerge from a nonlinear breakdown of cooperation across two tightly coupled systems: the extracellular matrix (ECM) crosslink network and the cellular populations responsible for its maintenance. To formalize this concept, we construct a game-theoretic model that unifies the mechanical failure, inflammatory changes, and percolation-driven tissue collapse that are recognized features of the disease. At the ECM level, elastin and collagen crosslinks are modeled as players in an iterated Prisoner's Dilemma, where cooperation corresponds to maintaining structural integrity, and defection corresponds to rupture under mechanical stress. At the cellular level, fibroblasts, macrophages, and neutrophils engage in a parallel strategic game in which repair reflects cooperative activity, and protease- or oxidant-producing phenotypes are indicative of defection. These parallel games are coupled through bidirectional payoff modulation, generating a dynamical system with bistability, tipping points, and runaway positive feedback. As the fraction of intact crosslinks falls below a critical percolation threshold, global network connectivity collapses and lung function drops precipitously. This framework explains the characteristic features of pulmonary emphysema, including spatial heterogeneity, abrupt acceleration, and irreversibility as emergent properties of coupled cooperation–defection dynamics, and identifies new leverage points for stabilizing cooperation and preventing catastrophic network failure in early disease. In support of this hypothesis, we present previously published studies from our laboratory involving measurements of elastin-specific desmosine crosslinks in human postmortem emphysematous lungs showing a marked increase in tissue crosslink density at the early stage of the disease, and accelerating loss of these crosslinks as airspace enlargement progresses, consistent with initial cooperation followed by defection. This conceptual framework is then applied to the poorly understood lung disease, Combined Pulmonary Fibrosis and Emphysema, to provide a potential mechanism for its pathogenesis.

Abstract: Acidic cannabinoids (e.g., THCA, CBDA) are the dominant phytoconstituents in Cannabis sativa L. and serve as precursors to neutral forms (THC, CBD) via decarboxylation. This is the third work in an integrated series exploring how dietary cannabis inputs interact with Endocannabinoid System (ECS) pathways. This paper examines the role of physiological environments — stomach acidity, blood pH, and hepatic metabolism — in determining the fate, bioavailability, and independent pharmacological activity of ingested acidic cannabinoids. Integrating organic chemistry and pharmacokinetics, the study finds that gastric decarboxylation of acidic cannabinoids is negligible: the reaction's activation energy barrier is largely insurmountable at physiological temperature, and gastric acidity plays no direct catalytic role in overcoming it. Upon absorption, systemic blood pH (7.35–7.45) further stabilizes acidic cannabinoids, which exist almost entirely (>99%) as non-reactive carboxylate anions. Hepatic first-pass metabolism preserves this pattern: acidic cannabinoids are predominantly conjugated intact via UGT1A9, in contrast to neutral THC, which undergoes CYP-mediated oxidation to its own active and inactive metabolites; CBD's position between these two pathways remains unresolved in the literature. The gut microbiome acts as a secondary modulator via β-glucuronidase-mediated deconjugation, potentially enabling enterohepatic recirculation and extending systemic exposure, though this mechanism remains an inference by analogy for cannabinoids specifically rather than a directly demonstrated finding. Beyond their role as precursors, THCA and CBDA act directly on distinct molecular targets independent of any conversion to their neutral forms: CBDA through selective COX-2 inhibition and 5-HT1A receptor potentiation, and THCA through potent PPARγ agonism and weak partial TRPA1 activation. Direct detection of THCA in oral fluid following cannabis use corroborates delivery of the intact acidic form to peripheral tissues. Taken together, these findings indicate that ingested acidic cannabinoids reach systemic circulation and target tissues largely unconverted. Their therapeutic relevance is therefore shaped primarily by their own direct pharmacological activity and by metabolic and microbial processing, rather than by thermal decarboxylation to THC or CBD — a transformation the body's physiological conditions do not provide.

Abstract: Computer-aided simulation and data-driven analysis provide an effective technical basis for optimizing the spatial organization of mechanical, electrical, and plumbing systems in large-scale commercial complexes. To reduce construction clashes, repeated rework, and investment losses caused by high-density MEP layouts, a BIM-based spatial topology and stochastic optimization model is developed. The model integrates BIM data parsing, component coding, topology construction, bounding-box screening, precise distance calculation, conflict-intensity evaluation, and Monte Carlo simulation. Conflict-type severity, impact range, and rework probability are normalized, and their coefficients are estimated by constrained non-negative regression rather than subjective assignment. Safety clearances are determined from design codes, equipment maintenance manuals, installation tolerances, and project coordination requirements. The stochastic model specifies Beta-Bernoulli, lognormal, and triangular distributions for conflict occurrence, construction and rework losses, and operation and maintenance losses, respectively, and performs 50,000 simulation iterations. A 420,000 m² commercial complex in Shenzhen is used for validation. Compared with the original scheme, the integrated optimization scheme reduced pipeline density from 7.82 m/m² to 6.44 m/m², total conflict nodes from 186 to 109, and the conflict intensity index from 5.85 to 3.41. The average conflict occurrence probability decreased from 55.2% to 33.8%, the rework cost ratio declined from 9.6% to 4.1%, the comprehensive investment cost index decreased by 10.7%, and the unit-area investment return index increased by 12.6%. The results demonstrate that the proposed model can support reproducible MEP spatial optimization and quantitative investment-risk control.

Abstract: Background: The domain of microencapsulation technology is considered to be at the level of an advanced scientific discipline that includes the fields of materials science, pharmaceutical technology, and food technology in the formulation of very specific matrices of polymeric or lipid nature. Method: In this review, a comprehensive analysis of sixteen different techniques of microparticles preparation has been presented: Solvent Evaporation, Solvent Extraction, Coacervation, Spray Drying, Spray Congealing, Ionic Gelation, Interfacial Polymerization, Air Suspension, Pan Coating, In-situ Polymerization, Supercritical Fluid Technology, Electrospraying, Microfluidics, Sol-Gel Process, Hot Melt Encapsulation, and Salting Out. Each technique has been explained by describing the basic physical and chemical phenomena that govern the process of microparticles formation. Results: The review has been presented with a critical analysis of the operating parameters, along with the core and shell material, as well as the applications of the technique, which are of interest in the field of pharmaceuticals, cosmetics, food, and medicine. Conclusion: The types of drugs that are best suited for the particular technique, as per their physical and chemical properties, i.e., solubility in water, lipid solubility, acid–base properties, as well as their thermoreactive properties, have been discussed in the review. The possibility of scaling up the technique from the laboratory scale to the industrial scale has been evaluated by searching the patent database, as well as the grant status of the patents, presented in the review. The prospective industrial applications of the technique, as well as the current limitations that restrict the scaling up of the laboratory-scale protocol, have been discussed in the review.

Abstract: Background:Mixed methods reviews are increasingly used to address complex healthcare and social research questions; however, their methodological diversity has led to fragmentation in terminology, design, and execution. This lack of clarity presents challenges for both methodological choice and reproducibility.Aim:To systematically map and critically examine the range of mixed methods review approaches, with a focus on their methodological characteristics, integration processes, and operational guidance.Methods:A scoping review was conducted to identify methodological papers and applied examples of mixed methods reviews. To be included, studies had to primarily identify instructional content on how to undertake a mixed methods review, including information on integration or synthesis of data. Data were extracted on review type, synthesis processes, integration mechanisms, data transformation, and use of frameworks or guidance tools. Findings were analysed using an extraction map which provided the basis for synthesis of information.Results:Ninety-two methodological contributions were identified. A wide range of review types were identified, including realist, meta-narrative, mixed methods systematic, integrative, framework, rapid, scoping and QCA-informed approaches. Mixed methods systematic reviews and framework synthesis approaches were the most identified approaches. Despite this diversity, four dominant integration mechanisms emerged: narrative, comparative, mapping-based, and mixed-evidence integration. Operational clarity varied substantially, with theory-driven and structured approaches (e.g., realist synthesis, QCA) demonstrating clearer procedural guidance than integrative and rapid approaches. Iterative processes and theoretical engagement were key differentiators between descriptive and explanatory review outputs.Conclusion:Mixed methods review approaches are characterised by both methodological richness and conceptual fragmentation. Greater emphasis is needed on standardising reporting, clarifying integration and transformation processes, and aligning methodological choices with review purpose. This review provides a structured framework to support methodological decision-making and enhance transparency in mixed methods evidence synthesis.

Abstract: Over a finite prime shell \(\mathbb F_p\), \(p=4\kappa+1\), the roles of \(\pi\) and \(e\) are exact residues: the half-period \(\pi=2\kappa\), and the exponential marker \(e=g^{\lambda(i)}\). We determine the exact relation between these carriers and the classical values. Each classical value is the horizon readout of a chain of framed rationals \(n!/!n\) for \(e\); the Wallis, arcsin and Machin chains for \(\pi\); at IEEE-754 double precision the constants are the readouts of \(18!/!18\) and the Machin partial \(M_{10}\). Inside the shell the same chains carry exact residue lines that the readout deletes: the line of \(e\) is antiperiodic and terminates on Kurepa's left factorial, universal existence being equivalent to Kurepa's hypothesis; the line of $\pi$ is legible exactly up to the angular address of -1 and terminates on the calibration face \(\pi^{-1}\equiv-2\). Angularly the constants are dual: \(\chi(-1)=e^{i\pi}\) holds exactly in every shell, while radian calibration of \(e\) is impossible in every shell and abundant across shells. \(\pi\) is structural, \(e\) statistical; transcendence belongs to the external completion, never to the shell element. All exact claims are machine-verified in integer and rational arithmetic.

Abstract: Background and Objectives: Melatonin is traditionally recognized as a central regulator of circadian rhythms, but it is also a pleiotropic molecule with antioxidant, anti-inflammatory, mitochondrial-protective and immunomodulatory properties. These mechanisms are biologically relevant to degenerative, inflammatory and traumatic disorders of the musculoskeletal system. Materials and Methods: This narrative review summarizes evidence from PubMed/MEDLINE, Scopus and Web of Science regarding the role of melatonin in bone metabolism, cartilage homeostasis, osteoarthritis, muscle injury, tendon and ligament healing, spine disorders, sports medicine and musculoskeletal rehabilitation. Preclinical studies, translational investigations, clinical trials, systematic reviews and relevant mechanistic papers were considered. Results: Experimental evidence suggests that melatonin promotes osteoblast differentiation, limits osteoclastogenesis, protects chondrocytes from oxidative stress and apoptosis, modulates nuclear factor kappa B and nuclear factor erythroid 2-related factor 2 signaling, supports mitochondrial homeostasis and may influence autophagy, mitophagy and ferroptosis. These effects have potential implications for osteoporosis, fracture healing, osteoarthritis, tendinopathy, intervertebral disc degeneration and recovery after strenuous exercise. Clinical evidence remains promising but insufficient to define standardized orthopedic indications. Conclusions: Melatonin is a biologically plausible adjunct in musculoskeletal medicine, particularly where oxidative stress, low-grade inflammation and mitochondrial dysfunction contribute to disease progression. Well-designed randomized controlled trials are required to determine indications, timing, dose, route of administration and clinically meaningful outcomes.

Abstract: Residential courtyards in Saharan cities face extreme summer thermal conditions that render them physiologically unusable for much of the day, yet their performance under standardized promotional-housing morphologies remains poorly documented. This study characterizes the summer environmental quality of a representative R+3 courtyard in Laghouat, Algeria (Köppen BWk), combining in situ measurements at five contrasting stations with ENVI-met simulation across six output maps. All five stations remained in the EXTREME physiological-stress category (PET = 51.1–52.3°C), with a peak thermal sur-plus of +4.87 to +5.97°C and minimum relative humidity of 9.26–10.35%. Sky view factor correlated strongly with thermal amplitude (r = 0.936) and shading with both humidity (r = 0.977) and comfort (PET, r = −0.887); given the small sample (n = 5), these associations are indicative rather than conclusive. A central finding is a vegetation paradox: the vege-tated, unshaded station recorded the highest thermal surplus and lowest humidity, con-sistent with stomatal closure under extreme aridity (VPD ≈7 kPa), while a shaded, vege-tated station performed best—indicating that shading, not vegetation per se, is the prima-ry regulator of courtyard microclimate here. ENVI-met simulation corroborates a 9.5°C surface-temperature differential between bare asphalt and shaded vegetated ground, in-forming bioclimatic redesign of Saharan promotional housing.