Biology and Life Sciences

Abstract: Promising results in the regeneration of skin lesions have been demonstrated with the use of natural (organic) products, such as dermal dressings made of polysaccharides (chitosan complexed with xanthan), as they promote a hydrated and thermally insu-lating microenvironment, allowing gas exchange; and sources rich in growth factors such as autologous platelet-rich plasma (PRPa), which contains transforming growth factor beta (TGF-β), vascular endothelial (VEGF) and platelet-derived (PDGF), re-sponsible for stimulating the inflammatory cascade and healing. The aim of this study was to evaluate the action of a polymeric membrane (chitosan, xanthan and β-glycan) and PRPa on healing in vivo, used alone or in combination. For the tests, rabbits un-derwent a surgical procedure to induce the lesion and were distributed into a control group (GC), membrane group (GM), PRPa group (GPa) and membrane group associated with PRPa (GMPa), evaluated at moments M0, M7, M14, M21 and M28 (28 days). Wound color and exudation, presence of infection and inflammation, formation of granulation, scarring and necrotic tissue, morphological and morphometric analysis were evaluated. Statistical analyzes of the results were performed using the Software R® software, adopting a significance level of 5%. While statistical differences between treatments in healing time were not significant (p>0.05), all wounds achieved 100% retraction by M21. Notably, at M7, PRPa alone and in combination with the membrane contributed to higher wound retraction percentages (29.71% and 21.65%, respectively) compared to the control group (16.96%). These findings suggest that the complexed membrane, alone or combined with PRPa, fosters a humid environment, gas exchange, and antimicrobial activity crucial for healing, with PRPa further enhancing early wound retraction. It is concluded that the treatment of experimental surgical wounds with biodressings such as PRPa alone or associated with a complexed membrane of chitosan, xanthan, and β-glycan significantly contributes to wound retraction, in addition to offering a propitious and indispensable environment for the healing cascade, such as a humid environment, gas exchange, and antibacterial action. Future studies should consider a larger number of animals per group, histological evaluation for global tissue assess-ment, and collagen quantification.

Abstract: Objectives: This prospective, open‑label, non‑randomized study evaluated a specific combination of cystine, B vitamins, and minerals (Pantovigar^® vegan) in 34 women (aged 30-75 years) with diffuse hair loss (Modified Savin Score 1–3) for improvements in hair condition and product acceptance and safety following up to 6 months of intake of one test product capsule three times daily. Methods: Hair condition was assessed using phototrichogram analysis, and participants completed a product acceptance questionnaire. Blood nutrient levels associated with hair loss were measured at baseline, and at 3 and 6 months. Results: From baseline to 6 months, a significant increase of 2.35% in the rate of anagen (p = 0.012) and a decrease of 2.35% in the rate of telogen (p = 0.012) hairs resulted in an increase of 2.37% in the ratio of anagen/telogen hair rate (p = 0.013), reflecting a proportionate increase in the number of terminal hairs in the anagen phase. Most participants agreed with positive questionnaire hair condition statements. Increased levels of B vitamins, ferritin, and hematocrit did not exceed established tolerable upper limits, and no serious undesired effects were reported. Conclusion: The study results suggested that the specific nutrient combination of cystine, B vitamins, and minerals in the test product is beneficial to hair condition, is well‑accepted, and safe for use in the management of diffuse hair loss in women. Clinical Trial Registration: [https://clinicaltrials.gov/study/NCT05943860]; identifier [NCT05943860]; date of registration: June 21, 2023; retrospectively registered.

Abstract: Background/ Objectives: Burn care remains a major clinical challenge, as they require effective wound management to promote healing, reduce pain, and prevent complications. This study aimed to describe the use of a polylactic acid membrane in patients with burns of different depths and to assess wound healing outcomes. Methods: A descriptive case series was conducted including six patients with burn injuries treated with a polylactic acid (PLA) membrane (Suprathel®) at a specialized burn unit. The study was performed according to CARE guidelines. Clinical assessment included burn depth evaluation, pain measurement using the Visual Analog Scale, and scar assessment using the Vancouver Scar Scale. The application of the PLA membrane and its clinical performance during the healing process was described. Results: Complete wound closure was achieved in all cases by re-epithelialization as the PLA adhered, integrated and became transparent, clearly visualizing the progression of healing. Time to re-epithelialization ranged from 14 to 35 days, and final Vancouver Scar Scale scores ranged from 1 to 3 points. No major wound-related complications or local infections were documented during the clinical follow-up period. Conclusions: The use of a PLA membrane in burn management represents a promising advance in wound care, as it was associated with wound closure and pain reduction in this case series, with potential benefits for the optimization of nursing clinical practice.

Abstract: This study examined the wood properties, i.e. anatomical characteristics, chemical composition, physical and mechanical properties of seven-year-old plantation-grown B. microphyllum harvested from a research plot at the Forest Research Institute Malaysia. Microscopic analysis revealed diffuse-porous wood with very large solitary vessels, aliform to confluent parenchyma, medium-sized rays, and non-septate fibres. Fibre morphology showed a Runkel ratio below 1.0 and a slenderness ratio of 41.9, indicating favourable fibre flexibility and bonding potential. The absence of tyloses and silica suggests good treatability and machinability. Chemical analysis showed high holocellulose content (79.5–81.9%), α-cellulose (~44%), moderate lignin (22.6–23.9%), and low extractives (0.9–2.1%), indicating a substantial carbohydrate fraction with minimal non-structural compounds. Preliminary phytochemical screening detected flavonoids, tannins/polyphenols, and triterpenes/steroids as dominant constituents, supporting its traditional medicinal relevance. The wood density ranged from 441.4 to 606.8 kg m⁻³ (mean: 524.1 kg m⁻³), classifying the timber as light to moderately heavy. Shrinkage at 15% moisture content was 2.2% (tangential), 1.2% (radial), and 0.6% (longitudinal), giving a tangential-to-radial ratio of 1.6 and indicating moderate dimensional stability. Despite being harvested at only seven years of age, B. microphyllum exhibited mechanical properties comparable to or superior to several commonly planted fast-growing species, such as Eucalyptus nitens, rubberwood (Hevea brasiliensis), and batai (Paraserianthes falcataria). In particular, the bending and shear strengths were considerably higher than those reported for some older plantation timbers. These findings suggest that B. microphyllum has strong potential as a fast-growing plantation timber with favourable strength characteristics and other promising properties, making it a suitable candidate for structural and value-added wood applications.

Abstract: Rel/SpoT family enzymes participate in controlling the cellular levels of the alarmone (p)ppGpp, thereby activating the stringent response and promoting survival under stress conditions. These proteins contain an N-terminal catalytic domain and a C-terminal regulatory domain. They catalyze both the synthesis of ppGpp/pppGpp from ATP and GDP/GTP and their hydrolysis to GDP/GTP and pyrophosphate. Here, we report the crystal structure of the N-terminal domain of Rel from Streptococcus equisimilis (Rel_Seq385) in complex with pppGpp at 3.2 Å resolution. The asymmetric unit contains a dimer with asymmetric ligation, in which pppGpp occupies only the synthetase site in one monomer, whereas it is observed in both the hydrolase and synthetase sites in the other. Molecular dynamics simulations supported this binding arrangement for the monomer with both sites occupied and revealed additional probable transient binding sites that may contribute to alarmone binding.

Abstract: Sleep disorders affect a substantial proportion of hospitalized patients yet remain among the most systematically underdiagnosed conditions in acute care medicine, with up to 80% of moderate-to-severe cases carrying no formal diagnosis at the time of admission. At the same time, frailty—a state of heightened physiological vulnerability arising from cumulative multi-system biological decline—is present in 40–80% of inpatients and shares deep, bidirectional neurobiological pathways with sleep pathology through shared mechanisms of circadian dysregulation, hypothalamic-pituitary-adrenal axis activation, and chronic low-grade inflammation. Despite this convergence, no study has integrated validated, administratively computable frailty phenotyping with a machine learning framework specifically designed to predict inpatient sleep disorder diagnosis at the point of hospital admission. To address this gap, we developed and evaluated a suite of five binary classification models—XGBoost, Random Forest, LightGBM, CatBoost, and Decision Tree—using 9,682 balanced hospitalization episodes from the MIMIC-IV (version 2.2) database. The predictor set comprised 23 admission-time structured features across three domains: frailty and comorbidity burden, including the Hospital Frailty Risk Score (HFRS) derived from ICD-10 codes, the Elixhauser comorbidity index, prior admission history, and six binary disease flags (obesity, hypertension, type 2 diabetes, heart failure, COPD, and depression/anxiety); physiological and laboratory biomarkers from the first 24 hours of care, including minimum SpO₂, heart rate variability, hemoglobin, creatinine, albumin, and arterial blood gas parameters; and sociodemographic and administrative variables encompassing age, sex, ethnicity, insurance type, and admission acuity. Two binary outcomes were modeled independently: any sleep disorder diagnosis (ICD-10: G47.x) and insomnia specifically (ICD-10: G47.00). Model performance was assessed through five-fold stratified cross-validation and bootstrap confidence intervals (n = 1,000 iterations), with predictor importance quantified using SHapley Additive exPlanations (SHAP). XGBoost achieved the strongest aggregate performance across all evaluation metrics, attaining an area under the receiver operating characteristic curve (AUC) of 0.871 (95% CI: 0.856–0.887), accuracy of 79.6%, F1-score of 0.820, and sensitivity of 94.9%, correctly identifying 903 of 952 true positive cases in the held-out test set; all gradient boosting frameworks substantially outperformed the Decision Tree baseline (AUC 0.836). SHAP analysis identified the HFRS and Elixhauser index as the two dominant predictors, followed by depression/anxiety, obesity, hypertension, and minimum SpO₂—a pattern that is mechanistically consistent with established pathophysiological literature on frailty-associated sleep pathology. The well-calibrated probability outputs of the XGBoost model make it directly suitable for integration into clinical decision support systems, offering a deployable, interpretable screening tool for inpatient sleep disorder identification that requires no dedicated instrumentation beyond routine admission data.

Abstract: For the first time, a race survey of Puccinia graminis f. sp. tritici (Pgt) population was conducted on Triticum durum in the Altai region of Western Siberia, Russia. A total of 34 single pustule isolates with different virulence phenotypes were identified on durum wheat (Triticum durum) in 2025 and compared with Pgt from bread wheat (Triticum aestivum). The UPGMA-based clustering separated Pgt isolates into two distinct groups, suggesting the host-driven differentiation that was further proven using tools of population genetics. The pathogen isolates from durum showed a wider range of virulence complexity, higher variability, and greater average singularity. Virulence frequencies of Pgt on T. durum and T. aestivum differed markedly for Sr6, Sr7b, Sr9e, Sr17+13 and several other genes, while Sr24 and Sr31 remained effective independently of the pathogen origin. Two races, PKCSF and NFMSF, were detected on both the hosts, indicating a shared pathogen gene pool between bread and durum wheat. Even assuming host-specific divergence of Pgt in the Altai region, there is a need in deployment of the same resistance genes into both T. aestivum and T. durum cultivars to prevent an outbreak of stem rust in an event of favorable conditions for inoculum exchange between crops.

Abstract: Periodontal disease (PD) affects a large proportion of adults and is increasingly associated with systemic inflammation and neurodegenerative risk. However, current therapies have limited efficacy in disrupting biofilms and modulating systemic responses. In this pilot study, we evaluated nanoparticles (NPs) of epigallocatechin-3-gallate-palmitate (EGCG-palmitate or EC16), a lipid-soluble derivative of epigallocatechin-3-gallate (EGCG), generated using Facilitated Self-Assembling Technology (FAST). FAST is a green nanotechnology that enables spontaneous formation of stable nanoparticles without surfactants or carrier materials. We hypothesized that EC16 NPs could inhibit periodontal pathogens and modulate neuroinflammatory responses. Antimicrobial activity was assessed in vitro, and potential therapeutic effects were evaluated in a ligature + pathogen-induced periodontitis mouse model. EC16 NPs inhibited the growth of Porphyromonas gingivalis. Oral administration of EC16 NPs (0.02% w/v) at a dose equivalent to 16-20 mg/kg significantly reduced Porphyromonas gingivalis abundance and decreased alveolar bone loss by approximately 50% compared with controls. Importantly, biodistribution analysis using Cy5-labeled EC16 NPs demonstrated detectable signals in mouse brain tissue following oral gavage, indicating EC16 NPs can cross the blood–brain barrier. In addition, EC16 NP treatment was associated with increased regulatory T cell (Treg) populations in cervical lymph nodes and reduced expression of inflammatory (IL-1β) and senescence-related markers (p16, p53) in brain tissue. This represents, to our knowledge, the first evidence that an orally administered EGCG derivative in nanoparticle form reaches the central nervous system and induces biological responses. These findings demonstrate that EC16 nanoparticles possess dual local and systemic activity and support further investigation of FAST-enabled nanoformulations as a novel therapeutic strategy for periodontal disease and inflammation-related brain conditions.

Abstract: ME/CFS patients suffer from manifestations of disturbed connective tissue including ligament laxity, hypermobility, craniocervical instability, and orthostatic intolerance due to connective tissue weakness of large vessels, while muscular capillaries show basement membrane thickening. Mast cell overactivity may destabilize connective tissue through chymase and tryptase, activating collagen-degrading metalloproteinases, while cytokines enhance expression. Hypoxia and ROS-mediated inhibition of prolyl hydroxylases impairs crosslinking of newly formed collagen and reduces hypoxia-inducible factor (HIF)-1α degradation. Chronic HIF-1α elevation, in turn, can worsen connective tissue stability by unfavorably altering its composition as recently shown in tendinopathies. ME/CFS associated skeletal muscle dysfunction affecting neck muscles cannot compensate for ligament laxity to stabilize cervical spine but aggravates instability. In skeletal muscle capillaries, elevated HIF-1α may promote extracellular matrix overproduction and basement membrane thickening, impairing capillary perfusion and diffusion, and glycolytic metabolism. The sensitivity of HIF-2α to ROS-mediated degradation may impair angiogenic maturation; the imbalance between HIF-2 α and HIF-1α may permit sustained HIF-1α–driven extracellular matrix production and reduce capillary density. Overall, there seems to be a bidirectional relationship between connective tissue disorders and ME/CFS, whereby connective tissue disorders may predispose individuals to ME/CFS, and ME/CFS, in turn, may exacerbate the underlying connective tissue pathology.

Abstract: Intensive agricultural practices based on continuous monocropping and prolonged bare-soil fallows have contributed to soil degradation and loss of biological functioning. Replacing fallows with cover crops (CC) is a promising strategy to restore soil quality, yet their legacy effects on rhizosphere fungal communities remain poorly understood. This study evaluated the legacy effects of Urochloa (syn. Brachiaria) brizantha cover cropping on rhizosphere fungal communities, as well as soil physicochemical and biological properties, in a degraded common bean system. A field experiment with a randomized complete block design included: bare fallow (BM), one (B1) or two (B2) CC cycles before bean, a perennial pasture (PB), and a pristine soil reference (PS). High-throughput sequencing showed that Urochloa-based treatments significantly shifted fungal community composition compared to BM, increasing saprotrophic and beneficial taxa (e.g., Mortierella, Penicillium, Coprinellus) and reducing potential pathogens such as Fusarium. These changes were associated with higher soil organic carbon, aggregate stability, microbial biomass, and enzyme activities, especially in B2 and PB. Indicator taxa identified by LEfSe were linked to organic matter decomposition and nutrient cycling. Multivariate analyses revealed strong associations between fungal community structure and soil properties. Overall, U. brizantha cover cropping induced measurable legacy effects, promoting soil biological recovery even after short-term implementation.

Abstract: The Alliance of Bioversity International and CIAT curates the world’s largest cassava (Manihot esculenta Crantz) germplasm collection, held at its Future Seeds genebank in Cali, Colombia. Since first collection expeditions in 1969, a primary focus was to assemble and conserve the diversity from the crop’s center of origin in the American tropics. Later additions expanded representation from Asia and Africa as secondary centers of diversity. The collection consists mainly of landraces (about 5000 accessions), bred lines from CIAT (375) and from partner institutions (253), and related wild Manihot (377 accessions from 23 species or subspecies). Secure conservation, first as a field collection and then in a slow-growth in vitro system, gave priority to pathogen testing and methods to assure successful clonal propagation over many generations. Cryopreservation research is ongoing to achieve additional security and efficiency. CIAT extensively characterized accessions through morphological, biochemical and molecular criteria. As a core goal, the collection has been a foundation for genetic improvement of the crop globally. The paper provides perspectives on the future management and use of the collection in the context of the recently established Future Seeds genebank facilities at CIAT, and new tools and technologies that support more effective conservation, evaluation and use.

Abstract: Bestrophin-1 (BEST1) was first linked to retinal disease, yet in the central nervous system BEST1 has been assigned a distinct functional scope spanning transmitter permeation, circuit set point control, and injury responses. In this mini-review, current evidence is examined for BEST1 as a neurotransmitter-gated anion channel, with emphasis placed on structural and biophysical studies that have clarified gating, pore behavior, and ligand-dependent tuning. The long-running dispute over CNS localization is critically revisited, because broad conclusions have often rested on antibodies lacking stringent validation. Astrocytic BEST1 is then considered in the setting of tonic inhibition, where regulated GABA flux has been linked to sensory coding, network excitability, and behavior across circuits. Its contribution to ischemic pathology is also assessed, with attention given to the timing-dependent shift from acute injury mechanisms to post-stroke recovery windows. Finally, emerging evidence for BEST1 in microglia and neurons is weighed cautiously and framed as a tractable agenda for direct testing. A more rigorous BEST1 field is argued to depend on cell-type-resolved genetics, validated localization pipelines, and temporally precise intervention studies.

Abstract: Medicinal plants grown outside their native forest habitat may produce phytochemical profiles that differ from wild-harvested material, yet the ecological mechanisms underlying these differences remain poorly synthesized across disciplines. This review proposes that the forest understory functions as a multi-signal elicitation system in which canopy light filtering, arbuscular mycorrhizal fungi (AMF), and above-ground biotic interactions collectively shape secondary metabolite profiles. AMF-mediated induced systemic resistance and above-ground biotic interactions operate through confirmed jasmonate-mediated pathways. Sunfleck-driven reactive oxygen species signaling is hypothesized but untested, and the red-to-far-red ratio modulated phytochrome B pathway characterized in Arabidopsis remains unconfirmed in shade-tolerant species. Using three saponin-rich herbs (Panax vietnamensis, P. ginseng/P. quinquefolius, and Paris polyphylla) as case studies, we formalize this as a testable chemical terroir hypothesis with three falsifiable predictions. We also translate it into an ecological co-cultivation design principle with three production levels and a two-step operational framework, and identify priority experiments, analytical methods, and implementation challenges needed for validation. These contributions bridge forest ecology and medicinal plant science while identifying critical evidence gaps requiring resolution before field implementation.

Abstract: Sweet potato (Ipomoea batatas L.) is a key food security crop in the developing world. Its production is, however, constrained by low-quality, virus-infected planting material derived from conventional vegetative propagation. In this study, we developed an efficient and reproducible in vitro micropropagation protocol for the orange-fleshed sweet potato cv. ‘Kulfo’. Nodal and apical shoot explants were cultured on Murashige and Skoog (MS) medium containing different combinations of 6-benzylaminopurine (BAP), naphthalene acetic acid (NAA), and gibberellic acid (GA₃) for shoot initiation and multiplication, and indole-3-butyric acid (IBA) and NAA for rooting. The maximum shoot regeneration was achieved (62% from nodal and 59% from apical explants) on MS medium supplemented with 0.5 mg L⁻¹ BAP and 0.1 mg L⁻¹ GA₃. MS medium supplemented with 1.0 mg L⁻¹ BAP and 0.1 mg L⁻¹ NAA produced a mean of 7.2 shoots per explant per subculture with vigorous growth during the shoot multiplication stage. Half-strength MS medium supplemented with 0.1 mg L⁻¹ IBA and 0.1 mg L⁻¹ NAA was the best rooting medium. The acclimatized plantlets from the optimal treatment showed a 98.2% survival rate in the greenhouse. The optimized cultivar-specific protocol provides a reliable system for the mass production of high-quality, orange-fleshed sweet potato planting material to support food security, genetic improvement, and germplasm conservation.

Abstract: Mineral waters represent unique limnological ecosystems with stable physicochemical conditions and specialised microbial communities adapted to extreme environments. Bulgarian mineral waters remain comparatively underexplored despite their considerable ecological and biotechnological significance. This review analyses current knowledge on the diversity, ecological functions, and biotechnological potential of microbial communities from Bulgarian mineral springs. A comprehensive literature survey covers studies published between 1990 and 2026. The study integrates hydrogeological, limnological, microbiological, and biotechnological data and encompasses both culture-dependent methods and molecular approaches. The available evidence demonstrates that microbial communities in Bulgarian mineral waters include diverse bacteria, archaea, cyanobacteria, microalgae that adapt to broad thermal and geochemical gradients. These microorganisms actively participate in element cycles, form complex biofilms, and show numerous physiological adaptations to oligotrophic and extreme conditions. Many taxa produce thermostable enzymes, antimicrobial compounds, exopolysaccharides with potential applications in medicine, industrial biotechnology, environmental remediation, and cosmeceutical technologies. The review identifies significant research gaps and emphasises the importance of integrated multi-omics approaches for future exploration of Bulgarian mineral water ecosystems.

Abstract: Mangrove wetlands are important coastal ecosystems and are increasingly vulnerable to heavy metal contamination. The accumulation of heavy metals in man-grove ecosystems is well studied; however, studies on the seasonal variations of heavy metals in mangrove wetlands are scarce. This study investigated heavy metal (Cd, Cr, Cu, As, Pb, and Zn) accumulation in surface sediments of six typical mangrove wet-lands (DZG, QLH, XCP, SYR, SBW, and XY) in Hainan Island, China, during wet and dry seasons. In addition, potential ecological concerns and relationships between sedimentary physicochemical parameters and metal accumulation were assessed. The findings demonstrated significant spatial differences in heavy metal accumulation, with higher concentrations in the northern localities and lower concentrations in the southern areas. There were notable seasonal fluctuations in heavy metal concentrations, with higher levels in the dry season. Risk assessment models exhibited that Cadmium (Cd) and Arsenic (As) were the principal contaminants of concern in most research sites with moderate levels of contamination and posed at least moderate ecological concerns in both wet and dry seasons. The overall ecological risk index indicated a moderate risk to the environment, especially in the dry season. The principal component analysis (PCA) and correlation analysis results indicated that the physicochemical properties of sediments, mainly total organic carbon (TOC), total phosphorus (TP), total nitrogen (TN), and salinity, had significant effects on the heavy metals accumulation in the mangrove sediments. The present study helps raise awareness of seasonal fluctuations in heavy metal pollutants and provides strategies for the prevention and monitoring of metal pollution in mangrove wetlands.

Abstract:

Caryocar coriaceum Wittm. (Caryocaraceae) is a native Brazilian species predominantly distributed in Cerrado areas and transitional regions with the Caatinga in Northeastern Brazil, whose fruits exhibit significant nutritional, technological, and biofunctional potential. This review systematizes and critically analyzes the available scientific evidence regarding the fixed oil extracted from its fruits, addressing extraction methods, chemical composition, physicochemical parameters, nutritional value, technological applications, and the main bioactivities described in experimental models. Chromatographic and bromatological studies demonstrate that the oil presents a lipid profile characterized by the predominance of monounsaturated and saturated fatty acids, especially oleic acid and palmitic acid, in addition to the presence of carotenoids, phenolic compounds, and other bioactive lipophilic constituents. Available preclinical evidence indicates antioxidants, anti-inflammatory, wound-healing, gastroprotective, respiratory, anticonvulsant, and microbial resistance-modulating properties, suggesting potential applications in the food, pharmaceutical, cosmetic, and biotechnological fields. From the perspective of Food Science, the oil demonstrates characteristics compatible with lipid matrices of functional interest, although aspects related to oxidative stability, compositional standardization, sensory acceptability, and industrial scale-up remain insufficiently explored. Additionally, important limitations persist regarding the scarcity of systematic toxicological studies, the absence of clinical trials in humans, and the limited elucidation of the molecular mechanisms involved in the observed bioactivities. Thus, although C. coriaceum presents promising biotechnological potential, the advancement of its translational application will depend on multidisciplinary approaches capable of integrating chemical standardization, toxicological safety, and applied technological development.

Abstract: Mechanistic models in radiobiology have proliferated across FLASH ultra-high dose-rate radiotherapy, spatially fractionated radiation therapy (SFRT), and stereotactic body radiotherapy (SBRT), yet the field has not converged on unified mechanistic explanations despite decades of model development. We propose that this proliferation partly reflects a structural property of the model-observation pairing itself: clinically accessible measurements may be insufficient to uniquely recover the parameters governing the underlying biological dynamics. Using generating-series structural identifiability analysis, we examine four representative models spanning the temporal, spatial, magnitude, and adaptive-state dimensions of radiobiological response: the Pratx-Kapp radiolytic oxygen depletion model (FLASH), the McMahon kinetic-bystander model (SFRT), the LQ-L extension (SBRT), and the Gupta phenotypic-plasticity model of adaptive resistance. The Pratx-Kapp and McMahon models exhibit intrinsic non-identifiability under conventional surviving-fraction observation, while the LQ-L and Gupta models exhibit observation-dependent identifiability conditional on dose-range coverage and marker-panel richness. These findings suggest that increasing radiobiological complexity progressively exposes the limitations of fixed-parameter mechanistic descriptions under partial observability. As a constructive response, we propose, as a hypothesis, that adaptive latent-state inference frameworks operating over a coupled multi-layer organizational state may provide a complementary operational paradigm for radiobiology under uncertainty.

Abstract: The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) threatens the efficacy of this last-line antibiotic. The GraSR two component system is frequently mutated in VISA strains. Here, we demonstrate that the GraS(T136I) point mutation, identified in the clinical VISA isolate XN108, is a key determinant of reduced vancomycin susceptibility. Introducing this mutation into the susceptible strain Newman increased the vancomycin MIC from 1.5 to 4 mg/L, while its reversion in XN108 decreased the MIC from 12 to 8 mg/L. The mutation conferred common phenotypes, including thickened cell wall, decreased autolysis, and reduced cell surface negative charge via upregulation of the dltABCD operon and mprF. Notably, GraS(T136I) mutation also upregulated virulence genes (efb, hlb, sbi, hld) and enhanced hemolytic activity. Interestingly, despite this hypervirulence profile, the mutant showed impaired long term survival within macrophages. Our study reveals that a single GraSR mutation can co-regulate vancomycin resistance and virulence, offering new insights into the adaptation of S. aureus to antibiotic pressure.

Abstract: Background: Chronic low back pain (CLBP) is the leading cause of years lived with disability globally, affecting over 600 million individuals. Intervertebral disc degeneration (IVDD) is a principal structural contributor, yet conventional treatments, including pharmacotherapy, physical therapy, and surgical intervention, do not reverse the underlying degenerative pathology. Regenerative medicine has introduced a spectrum of biological therapies, ranging from cell-based mesenchymal stromal cells (MSCs) transplantation to cell-free modalities, including platelet-rich plasma (PRP), platelet lysate, MSC-derived extracellular vesicles (EVs), and MSC-derived secretomes. However, these approaches have largely been studied in isolation, without a unified framework to compare their respective advantages and limitations in CLBP secondary to IVDD. Accordingly, this narrative review aims to provide an integrated and comparative evaluation of these regenerative strategies within a single translational and clinical context. Methods: For this narrative review, PubMed, Scopus, and Web of Science were searched from January 2000 to January 2026 using terms combining regenerative modalities with intervertebral disc degeneration, and chronic low back pain. Randomized controlled trials (RCTs), prospective cohort studies, systematic reviews, and preclinical studies with translational relevance were included. Results: Intradiscal MSC therapy has demonstrated safety across multiple phase I–III trials, but two recent landmark RCTs (RESPINE and the Mesoblast phase III trial) failed to meet primary efficacy endpoints, highlighting the gap between preclinical promise and clinical outcomes. PRP has the largest clinical evidence base, with level II evidence supporting short- to medium-term pain relief for discogenic pain, although standardization remains a critical barrier. Platelet lysate, MSC-derived EVs, and MSC-derived secretomes show compelling preclinical data, including extracellular matrix restoration, anti-inflammatory modulation, and attenuation of nucleus pulposus cell apoptosis, but remain at early translational stages for spinal applications, with no completed RCTs. The hostile disc microenvironment (avascular, hypoxic, acidic, and nutrient-poor) poses unique challenges for all regenerative modalities, differing fundamentally from other musculoskeletal applications. Conclusions: The studies included in this narrative review suggest that no single regenerative modality has yet shown consistent and unequivocal efficacy for CLBP secondary to IVDD across clinical trials. Cell-free approaches offer manufacturing, scalability, and safety advantages over cell-based therapies, but lack clinical validation. Future progress requires standardized preparation protocols, disc-specific delivery systems, patient phenotyping strategies, and rigorously designed comparative clinical trials. This narrative review provides a framework for researchers and clinicians to evaluate these therapies in context rather than isolation.