Biology and Life Sciences

Abstract: The Mediterranean basin is higly affected by the spread of non-native species (alien spe-cies). Most non-native species originate from the Indo-Pacific domain, via the Suez Chan-nel, and a smaller number are of Atlantic origin and enter the Mediterranean through the Strait of Gibraltar. Many other NIS reach the Mediterranean through passive transport via ballastwater, the importation of fish and mollusc species for marine farming facilities, and also due to involuntary and/or voluntary releases by aquarium hobbists. Thanks to ongo-ing environmental monitoring and citizen science, most of these alien species have been recorded over the past 40 years. Molluscs are not exception; infact, thanks to their aestheti-cally pleasing shells, they are collected by ordinary peoples as well as professional re-searchers. It was precisely thanks to research projects aimed at NIS detection that the first record of the species Conus ebraeus Linnaeus 1758 was made for the Mediterranean basin. The first shell of this species was sampled from the coastal seabed of the Vendicari pro-tected natural area (southeastern Sicily) in the spring of 2023. In the following years, four more specimens of this species were found in the same area as the first discovery, while two more specimens of C. ebraeus were found at Portopalo di Capo Passero, in the extreme southeastern part of Sicily, a few kilometers from Vendicari. To date, a total of seven spe-cimens of C. ebraeus have been collected.

Abstract: Three-dimensional instrumented gait analysis (3D-IGA) is widely used to guide surgical decision-making in children with cerebral palsy (CP), but its interpretation is time-consuming and prone to inter-rater variability. We investigated whether a generative large language model (LLM) could consistently generate gait deviation findings and surgical procedure suggestions that align with expert judgement. Kinematic features for lower-limb joints across the gait cycle, stance, and swing were extracted from eight children with unilateral CP using the open-source GaitSharing Toolkit and a structured prompt, then submitted three times per patient to OpenAI's GPT-5.5 model. The model assessed 28 kinematic deviations and 12 surgical procedure groups using majority voting. One gait analyst rated the deviations, and two paediatric orthopaedic surgeons independently rated the procedures on a 0–2 ordinal scale, blinded to all clinical information beyond the kinematic curves and diagnosis. Agreement with the gait expert averaged 84.7% in the sagittal plane and was lowest at the knee (62.6%). Surgeons’ agreement with the LLM reached 83.9% and 73.5%, with the tibialis anterior procedure showing the lowest concordance. Inter-surgeon agreement was 79.2%. The LLM showed high self-consistency (>90% across runs). This work demonstrates the potential of generative LLMs as assistive tools in clinical gait analysis for deviation detection and future treatment planning.

Abstract: Environmental exposure to persistent and non-persistent endocrine-disrupting chemicals (EDCs), including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), dioxins, phthalates, and bisphenols, has been increasingly associated with elevated cardiovascular disease (CVD) risk. Emerging evidence suggests the importance of gene–environment interactions in modulating individual susceptibility to EDC-related cardiovascular effects. This review summarizes current knowledge by synthesizing the main classes of EDCs, evaluating the evidence linking them to cardiovascular outcomes, and highlighting how genetic variability may modulate EDC-induced cardiovascular risk. Across the studies analyzed, the most extensively investigated genetic polymorphisms involve pathways related to oxidative stress regulation, xenobiotic metabolism and detoxification, hormone signaling, and lipid homeostasis. Variants in antioxidant defense genes, such as CAT, eNOS, and PON1, have been associated with increased hypertension risk and vascular dysfunction following exposure to bisphenols and PAHs. Polymorphisms in GSTP1, CYP2C19, ABCB1, and MTHFR may influence susceptibility to cardiometabolic alterations and congenital heart defects, whereas variants in ESR2, FTO, LEPR, and INSIG2 have been linked to obesity, dyslipidemia, and hypertension associated with PFAS, PBDEs, and bisphenols. A deeper understanding of gene–environment interactions is essential to advance preventive cardiology and mitigate the cardiovascular impact of environmental pollutants.

Abstract: Gut microbiota–derived short-chain fatty acids (SCFAs) shape epithelial and immune homeostasis, yet systemic SCFA profiles may diverge from gut microbial composition due to absorption and host metabolism. We quantified fasting serum SCFAs in 36 surgically resected Colorectal Cancer (CRC) patients and 20 cancer-free controls using targeted high performance liquid chromatography-triple quadrupole mass spectrometry, and integrated these data with fecal and serum bacterial DNA profiles generated by 16S ribosomal RNA sequencing and functional inference. CRC was associated with a distinct circulating SCFA pattern: total SCFAs and acetate were increased, branched SCFAs were higher, and butyrate and valerate were lower relative to controls. Despite this clear systemic signature, associations between serum SCFAs and the relative abundance (RA) of putative SCFA-producing genera were sparse and inconsistent across CRC and control groups, both when considering fecal producers and serum-detected taxa. Interestingly, the total RA of SCFA-producing genera was higher in controls in feces but higher in CRC in serum, further supporting compartment-specific decoupling. Finally, several circulating SCFAs showed inverse associations with indicators of tumor progression within CRC. These results motivate integrative microbiota–metabolite studies and validation in larger cohorts to clarify how circulating SCFAs relate to gastrointestinal disease biology and immune regulation.

Abstract: Marine-derived Streptomyces have emerged as one of the most prolific microbial resources for structurally diverse and pharmacologically significant natural products. Adaptation to highly competitive marine ecological niches, including deep-sea sediments, hydrothermal vents, mangrove ecosystems, marine invertebrates, and saline habitats, has driven the evolution of specialized biosynthetic systems capable of generating chemically complex secondary metabolites. Recent advances in genome sequencing, bioinformatics, metabolomics, synthetic biology, and artificial intelligence-assisted discovery pipelines have significantly expanded understanding of cryptic biosynthetic gene clusters (BGCs) encoded within marine actinomycete genomes. These BGCs produce structurally diverse metabolites including polyketides, non-ribosomal peptides, ribosomally synthesized and post-translationally modified peptides (RiPPs), terpenoids, alkaloids, and hybrid metabolites with potent antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, and anticancer activities. Nevertheless, despite rapid technological progress, major translational limitations remain, including low cultivation efficiency, silent pathway expression, rediscovery of known compounds, metabolite yield instability, dereplication bottlenecks, and insufficient ecological interpretation. This critical review comprehensively discusses the biosynthetic diversity of marine Streptomyces-derived metabolites with emphasis on biosynthetic pathways, enzymatic tailoring reactions, genome mining strategies, metabolomics-guided discovery, synthetic biology approaches, and pharmaceutical applications. In addition, current limitations and future perspectives in marine natural product research are critically evaluated to highlight the transition from descriptive omics-driven exploration toward functionally validated and translationally relevant drug discovery.

Abstract: Myocardial infarction (MI) has become one of the leading causes of mortality worldwide, and the prevalence is anticipated to rise considerably in the coming years. Among non-surgical procedures, chemical drugs, including diuretics, vasodilators, calcium channel blockers, ꞵ blockers, angiotensin converting enzyme inhibitors, are now in use to treat MI progression. These drugs often cause side effects and do not focus on mitigating oxidative stress, which has been recently proven to contribute to MI advancement. Naturally occurring antioxidant compounds, on the other hand, are safe, effective due to their multiple molecular targets, and have the potential to be used as lead compounds for finding novel drugs to therapeutically manage MI. Some of them, namely quercetin, puerarin, α-lipoic acid, and curcumin, have already made their way up to clinical trials. To develop and formulate natural antioxidant compounds as drugs against MI, it is crucial to comprehend their underlying mechanisms of cardio-protective activities and structure-activity relationships. This comprehensive review sheds light on the contribution of oxidative stress in the pathogenesis and progression of Myocardial Infarction, and highlights the cardio-protective roles of 51 natural antioxidant compounds along with their mechanistic insights and structure-activity relationships.

Abstract: Precision nutrition is the personalization of dietary recommendations based on characteristics such as genetics, the microbiome, lifestyle, environment, and baseline metabolic state. One potential basis for the development of guidelines is the characterization of gene-diet interactions. In this narrative review, we evaluate the published literature reporting associations between salivary amylase gene copy number and metabolic health. The salivary amylase enzyme facilitates starch digestion and is encoded by AMY1, a gene copy number (CN) variant. Humans have 2–20 copies, and AMY1 CN has been associated with metabolic health conditions such as obesity and insulin resistance. Studies of these associations have conflicting findings. The objectives of this review are to assess the findings from studies testing associations between AMY1 CN and adiposity, glucose metabolism, and gut microbiome composition; to explore possible mechanisms underlying the effects on metabolic health; and to identify knowledge gaps requiring additional research. To identify relevant articles, we searched PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and Centre for Agricultural and Biosciences International for articles focused on AMY1 CN and one or more of the following: body mass index, glucose metabolism, and the microbiome. Key findings are that AMY1 CN has a positive association with postprandial glucose response and that a high AMY1 CN is protective against insulin resistance. AMY1 CN alone does not appear to be an accurate predictor of adiposity, and the relationship is likely convoluted by habitual starch intake, genetic background, and lifestyle factors. Future studies are required to determine how AMY1 CN could be used as a biomarker or to inform precision nutrition protocols to achieve metabolic health outcomes.

Abstract: Background/Objectives: Oral candidiasis is an infection of the oral cavity caused by Candida albicans. Mucoadhesive buccal films could adhere to the buccal mucosa for prolonged periods, improving the therapeutic outcomes of patients with oral candidiasis. This study aimed to develop and evaluate the properties of fluconazole containing sodium alginate/methylcellulose-based buccal films for potential treatment of oral candidiasis. Methods: Drug-polymer compatibility was investigated using FT-IR spectrophotometry. Three optimised fluconazole films (F1 to F3) containing 1-1.6% sodium alginate and methylcellulose (1.6%) were formulated using the solvent casting method. Their physicomechanical properties were characterised using standard protocols. Drug content and in vitro drug release profiles were evaluated using UV-visible spectroscopy; in vitro / ex vivo mucoadhesion studies were conducted using the shaking water bath technique, and their antifungal activity against Candida albicans was evaluated using the agar ditch method. Results: FT-IR data analysis revealed that sodium alginate, methyl cellulose and fluconazole were compatible in the films. The films were off-white, smooth, peelable, thin, with satisfactory pH values, folding endurance, drug content, excellent zones of inhibition against Candida albicans (40 mm), controlled drug release profile (3.6-4.1 mg/cm2 after 6 h), and they displayed Korsmeyer-Peppas drug release kinetics. Film F3 containing 1.6% sodium alginate and 1.6% of methylcellulose exhibited superior swelling index (70±1%), tensile strength (0.68±0.04 MPa) and in vitro/ex vivo mucoadhesion time (5.5±0.3 h; 2.3±0.3 h) relative to other studied films. Conclusions: The sodium alginate content of the films influenced their tensile and muco-adhesive properties. Film F3 was the most promising formulations, for potential treatment of oral candidiasis.

Abstract: Background: The therapeutic effect of neurodynamic mobilization (NM) of the median nerve in mild to moderate carpal tunnel syndrome (CTS) remains inconclusive based on subjective reports and nerve conduction studies. Sonographic measurement of cross-sectional area (CSA) of the median nerve provides an objective method to evaluate treatment outcomes. Objective: To compare the effect of carpal bones and flexor retinaculum mobilization (CBFRM) vs. NM using various subjective outcome measures and a single objective measure: sonographic measurement of the median nerve CSA. Methods: Fifty-one individuals with mild to moderate CTS were randomly assigned to three groups:(1) CBFRM (n=17) (2) NM (n= 17) and (3) a control group awaiting surgery (n=17). Outcomes were assessed pre and post intervention and consisted of included median nerve CSA, pain severity rating using a visual analogue scale (VAS) and functional status using the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire. Pain improvement was also evaluated using the Pain Relief Scale (PRS). The intervention consisted of eight sessions over four weeks. Results: Both NM and CBFRB interventions significantly reduced pain and improved function compared with the control group. While both groups showed reduced median nerve CSA, post-hoc analysis revealed that this reduction was primarily driven by the NM group, with the CBFRB group not differing significantly from either condition. Conclusions: NM appears to be an effective conservative intervention for patients with mild to moderate CTS, demonstrating meaningful clinical and functional improvements. In addition, sonographic assessment of median nerve CSA may serve as a valuable complementary objective measure for evaluating treatment response and monitoring clinical status.

Abstract: The sterility of injection pharmaceutical preparation is the most crucial requirement to achieve, as it is injected directly to human body, either intravenously, intramuscularly, or other injection routes and once drug is injected, it moves to other parts of the body through blood flow follows the rules of drug distribution and will have direct contact to all tissues and organ [1]. Theoretically, in order to prevent contamination of microbial by inhibiting the proliferation process, especially in multiple dose of injection drugs, in the final formulation of the drug may need special addition of suitable preservative agent in the preparation [2]. The first step to perform this experimental study was by preparing the sterile pharmaceutical preparation, Diphenhydramine Hydrochloride injection at Sterile Pharmaceutical Preparation Laboratory, of Universitas Muhammadiyah Malang, Indonesia. Once the injection drug was ready, the second step conducted sterility test. The most common method used for sterility test in injection drugs is named direct inoculation. It was conducted by preparing sample from diluted solution of the injection drug, and the concentration was divided into five groups of sample 1:1, 1:2, 1:3, 1:4, 1:5, and undiluted sample (with three times replications) has determined certain level of inactivation of benzyl alcohol as its preservative agent, that was undiluted sample in Thioglycolate medium and 1:1 in Casamino medium. The indicator of bacterial growth in the study was Bacillus subtilis for Thioglycolate medium on range of temperature 30°-35 °C, and Candida albicans as an indicator of fungal growth in Casamino medium on range of temperature 20°-25 °C, both of Thioglycolate and Casamino medium were observed for 14 days. Inactivation of preservative agent and sterility test were performed under LAFC condition and it required some controls of LAFC environment to ensure that experiment was conducted under optimum condition and to avoid false positive result. According to those results of our study, the sterility test has indicated that our Diphenhydramine Hydrochloride injection was sterile after over a period of 14 days of observation.

Abstract: Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and remains therapeutically challenging owing to its marked inter- and intratumoral heterogeneity, diverse etiologies, and high rates of drug resistance. This review aims to summarize the current knowledge on the complexity of HCC and to evaluate emerging therapeutic strategies, with a particular focus on targeting the RNA-binding protein HuR as a novel approach to overcome treatment limitations. Methods: A narrative review was conducted of peer-reviewed publications focusing on HCC pathogenesis, tumor heterogeneity, resistance mechanisms, and therapeutic developments. Emphasis was placed on studies investigating the molecular drivers of HCC, tumor microenvironment interactions, and novel treatment strategies. Results: HCC progression is driven by complex interactions between genetic, epigenetic, and environmental factors, resulting in significant variability in treatment response. Tumor heterogeneity, cancer stem cell populations, and an immunosuppressive tumor microenvironment contribute to resistance to conventional therapies, including multikinase inhibitors and immune checkpoint inhibitors. Emerging strategies targeting these mechanisms, such as combination immunotherapies, metabolic targeting, and epigenetic modulation, show promise, but remain limited by incomplete efficacy. HuR is a central post-transcriptional regulator that stabilizes mRNAs encoding oncogenic and pro-survival factors. Preclinical studies have demonstrated that the pharmacological inhibition of HuR disrupts tumor-promoting pathways and enhances therapeutic sensitivity. Conclusions: The complexity of HCC necessitates multifaceted precision-based therapeutic approaches. Targeting HuR is a promising strategy for addressing tumor heterogeneity and drug resistance. Continued integration of molecular profiling, advanced technologies, and rational combination therapies is critical for translating these advances into improved clinical outcomes.

Abstract: Enzyme replacement therapy (ERT) for central nervous system symptoms and newborn screening (NBS) are available in Japan for patients with mucopolysaccharidosis type II (MPS II). The participants were individuals referred to our facility through NBS who were suspected of having neuronopathic MPS II. We reviewed the clinical course of patients who received intracerebroventricular (ICV)-ERT, idursulfase beta (Hunterase®), followed by hematopoietic stem cell transplantation (HSCT) using umbilical cord blood. Longitudinal measurements of heparan sulfate (HS) in the cerebrospinal fluid (CSF) were performed as a therapeutic biomarker, and developmental age was evaluated. Three patients diagnosed and treated with ICV-ERT received cord blood transplantation (CBT). All patients achieved successful engraftment with no severe complications except for one patient with sinusoidal obstruction syndrome. The HS in the CSF showed a temporary increase during the ERT discontinuation period owing to CBT and a subsequent reduction after the resumption of ICV-ERT. The patients exhibited age-appropriate development. The pattern of change in HS suggests the importance of continuing ICV-ERT even after HSCT. The combination of ICV-ERT and CBT may yield promising outcomes in patients with neuronopathic MPS II and underscores the importance of early intervention through NBS.

Abstract: Production of a biodegradable, environmentally friendly polymer film material, composed of potato starch (PS), xanthan gum (XG), and plasticizers: glycerin, sorbitol, and citric acid, was carried out. The effect of these components on the structural and biopolymer composite mechanical properties, including elasticity and tensile strength, was investigated. The addition of XG significantly reduces the hardness for the film forming materials, thereby lowering the difficulty of gelatinization. It was demonstrated that increasing the plasticizers mass during composite blend preparation improved elasticity but reduced the mechanical strength of the films. It is assumed that these additives in the biopolymer disrupted hydrogen bonds and other intermolecular contacts between starch and gum macro chains. Glycerol influences the elasticity of the bioplastic, while sorbitol influences its strength. Taking various factors into account, the optimal combined concentration of glycerol, sorbitol and citric acid was determined in composite during film preparation. Based on the results of the new polymeric films’ flexibility study, it was concluded that they could be used as a replacement for traditional, non-biodegradable polymeric materials. At the optimal concentration of components, the strength of polymer films is 1.6 MPa, and the relative elongation is 45%.

Abstract: Generally, cancer is responsible for nearly every sixth death worldwide. Early cancer revelation can provide successful and low-cost treatment of cancer, enhancing survival rates of cancer patients. This explains the key importance of development of novel highly sensitive systems for revelation of cancers in humans. Ribonucleic acids (RNAs) of several different types (microRNAs, circular RNAs, and small nucleolar RNAs) represent promising cancer biomarkers. At the same time, nanoribbon biosensors allow one to detect cancer-associated RNAs at ultra-low concentrations. Here we focus at experimental results on the detection of cancer-associated RNAs in human plasma with our nanoribbon biosensor, demonstrating promising capabilities of this nanotechnology-based device as a base of highly efficient diagnostic screening platform for early diagnosis of cancers in humans.

Abstract: Sequence information can specify molecular components, but specification is not equivalent to cellular state realization. A gene product contributes to living function only when the cell occupies a physical state in which gradients persist, compartments remain intact, diffusion and phase organization remain compatible with execution, and perturbations can be recovered without loss of viability. This gap defines a state-realization problem: what physical architecture constrains the feasible state space within which molecular programs can be executed, stabilized, reversed, or transformed? From this problem, I derive a set of substrate requirements: self-bounded aqueous interfaces, selective permeability, electrochemical asymmetry, tunable continuous physical variables, cross-scale coupling, recursive interaction with protein and information-memory systems, and measurable recovery dynamics. Lipid-organized boundary systems satisfy these requirements in an exceptionally integrated way in modern aqueous cellular life. I therefore propose the Central Homeorhetic Principle (CHP): cellular identity, robustness, and fate transitions are constrained by a distributed homeorhetic state architecture, with lipid-organized boundary systems occupying a privileged but nonexclusive substrate position. CHP is not a rejection of the Central Dogma, nor a claim that lipids alone determine phenotype. It is a complementary constraint framework that asks how molecular information becomes physically executable and dynamically sustainable. The proposed mechanism is a distributed constraint-sensing-enactment loop in which boundary-state variables are sensed, evaluated through thresholds, converted into regulatory responses, and recursively remodeled by execution and memory systems. The framework yields testable predictions concerning temporal precedence of boundary-state shifts, threshold-like fate transitions, recovery kinetics, state degeneracy, protocell persistence, and state-trajectory restoration. It is falsifiable if boundary-state variables consistently follow rather than precede commitment, fail to alter fate thresholds under controlled perturbation, or add no predictive power beyond molecular profiles.

Abstract: Background: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are established strategies for women carrying pathogenic or likely pathogenic (P/LP) variants in high-risk cancer susceptibility genes. However, real-world uptake remains variable and is influenced by clinical, demographic, and psychosocial factors. This study evaluated adherence to guideline-recommended surgical risk-reduction strategies following positive genetic testing. Materials and Methods: We conducted a retrospective observational study of 13,069 women who underwent hereditary cancer testing using a multigene next-generation sequencing panel between 2020 and 2025. Among them, 1,255 carriers of P/LP variants in genes with established recommendations for RRM and/or RRSO were identified. Physician-reported questionnaires were available for 203 individuals and captured data on counseling, acceptance, and implementation of risk-reducing surgery. Genes were grouped according to NCCN guideline recommendations: (i) BRCA1/2; (ii) PALB2, PTEN, TP53; and (iii) BRIP1, RAD51C, RAD51D. Results: Of the 203 women, 83% had a personal history of cancer. Overall, 83.7% were offered at least one risk-reducing intervention, with 64.9% accepting. RRM was more frequently discussed in higher breast cancer–risk genes, while RRSO discussion varied by gene group; these differences were statistically significant. Acceptance rates were moderate for RRM but consistently high for RRSO across groups. Younger age and advanced-stage disease were key factors limiting uptake or discussion, and 22 patients postponed surgery despite initial agreement. Conclusions: In this real-world cohort, physician counseling largely aligned with gene-specific guidelines, and acceptance of risk-reducing surgery was high once discussed, particularly for RRSO. However, uptake was influenced by age, disease stage, and clinical context. These findings highlight the importance of early genetic testing and multidisciplinary counseling to optimize timely decision-making and improve adherence to preventive strategies.

Abstract: Male infertility is estimated to affect over 30 million men around the world, with a prevalence of 2.5% - 12%. Plants, including Aframomum melegueta, are valued for their nutritive and medicinal properties, particularly on the reproductive system, due to bioactive compounds. This study examined the effects of Aframomum melegueta aqueous seed extract (AMASE) on male reproductive parameters Twenty-five adult male Sprague-Dawley rats (150-190 g) were randomly assigned to five groups (n=5). AMASE was orally administered at doses of 115, 230, 345, and 460 mg/kg daily for 21 days alongside a naïve control group. Blood and reproductive organs were collected post-treatment for hormonal, histological, and sperm quality assessments. Data were analyzed using ANOVA with Dunnett’s post hoc test comparing the various treatments to the naïve control group. Treatment with 345 mg/kg AMASE significantly increased prostate gland weight (p=0.038). Sperm concentration significantly increased in all treated groups, with 345 and 460 mg/kg showing the most pronounced effects (p < 0.0001), while sperm morphology improved significantly at 345 mg/kg (p = 0.0013). Testosterone levels exhibited a biphasic response, with a significant increase at 115 mg/kg (p = 0.0009) and a decline at 460 mg/kg. Histological analysis confirmed preserved testicular structure at 115 and 230 mg/kg, enhanced spermatogenesis at 345 mg/kg, and alterations at 460 mg/kg. Although AMASE exhibited selective activity improving sperm concentration and morphology without affecting motility or viability, it demonstrated promising potential as a fertility-enhancing agent.

Abstract: Background: Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 up-regulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor and sartan) on parietal remodeling comparing them with a miR-632 inhibitor in an ex vivo TGFβ –induced model of MFS TAA. Methods and Results: Gene expression and western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvediol compromised losartan’s efficacy, highlighting the need for careful therapeutic selection. miR-632 inhibitor was the most effective strategy in this ex vivo setting, although further preclinical validation is needed to confirm its therapeutic potential in vivo. Conclusions: Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug while suggesting miR-632 as a promising future target to stabilize the aortic wall and delay surgery.

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: 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.