Search Results (1,141)

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood–brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood–brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer’s disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components—including endothelial cells, pericytes, astrocytes, and tight junctions—contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer’s disease. Full article

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, disproportionately affecting older adults and is associated with high rates of mortality, functional dependence, and long-term cognitive decline. Aging profoundly alters the structure and function of the cerebral vasculature, predisposing the brain to both covert hemorrhage and the development of cerebral microbleeds (CMBs), small, often subclinical lesions that share common pathophysiological mechanisms with ICH. These mechanisms include endothelial dysfunction, impaired cerebral autoregulation, blood–brain barrier breakdown, vascular senescence, and chronic inflammation. Systemic factors such as age-related insulin-like growth factor 1 (IGF-1) deficiency further exacerbate microvascular vulnerability. CMBs and ICH represent distinct yet interconnected manifestations along a continuum of hemorrhagic small vessel disease, with growing recognition of their contribution to vascular cognitive impairment and dementia (VCID). Despite their increasing burden, older adults remain underrepresented in clinical trials, and few therapeutic approaches specifically target aging-related mechanisms. This review synthesizes current knowledge on the cellular, molecular, and systemic drivers of ICH and CMBs in aging, highlights diagnostic and therapeutic challenges, and outlines opportunities for age-sensitive prevention and individualized care strategies. Full article

Anecdotal reports have recently circulated suggesting that intramuscular injection of bacteriostatic saline (BS)—which contains benzyl alcohol (BnOH)—can reverse botulinum toxin type A (BoNTA)-induced brow ptosis. Given the well-established intracellular persistence of BoNTA’s light chain and its irreversible cleavage of SNAP-25, such rapid functional recovery challenges existing pharmacological understanding. This study employed high-resolution pharmacokinetic/pharmacodynamic (PK/PD) modelling using the AesthetiSim™ platform to systematically evaluate this hypothesis. A total of 30,000 virtual patients were randomized to receive BoNTA alone, BoNTA followed by BS injection, or BoNTA followed by normal saline (NS) at Day 7. The model incorporated BoNTA diffusion, internalization, SNAP-25 cleavage, neuromuscular output, and transient BS effects on membrane permeability and endosomal trafficking. Simulated recovery trajectories were tracked over 90 days. The primary outcome, time to 80% restoration of baseline frontalis muscle force (T₈₀), averaged 42.0 days in the BoNTA-only group and 35.5 days in the BS group (Δ = −6.5 days; p < 0.001). Only 13.9% of BS-treated patients reached the T₈₀ threshold by Day 30. Partial reactivation (T₃₀) occurred earlier with BS (21.8 ± 5.3 days vs. 27.3 ± 4.9 days), and the area under the effect curve (AUEC) was increased by 9.7%, reflecting higher overall muscle function over time. In molecular simulations, BnOH produced a minor rightward shift in the BoNTA–SNAP-25 dissociation curve, but receptor occupancy remained above 90% at therapeutic toxin concentrations, suggesting no meaningful impairment of binding affinity. A global Sobol sensitivity analysis demonstrated that the primary driver of recovery kinetics was intracellular LC degradation (49% of T₈₀ variance), while BS-modulated extracellular parameters collectively contributed less than 20%. These findings indicate that BS does not reverse the molecular action of BoNTA but may transiently influence recovery kinetics via non-receptor-mediated pathways such as increased membrane permeability or altered vesicular trafficking. The magnitude and variability of this effect do not support the notion of a true pharmacologic reversal. Instead, these results emphasize the need for mechanistic scrutiny when evaluating rapid-reversal claims, particularly those propagated through anecdotal or social media channels without supporting biological plausibility. Full article

Tourism is a key driver of Portugal’s economy, with the WTTC projecting it to contribute EUR 56.4 billion (21.1% of GDP) by 2033. However, the sector has proven highly vulnerable to external shocks, such as the 2008 financial crisis, Brexit, and the pandemic, which have disrupted demand patterns and exposed structural weaknesses. It is essential to understand these impacts at a regional level in order to design more resilient and sustainable tourism strategies. This study examines how major crises have shaped tourism in Portugal’s NUTS II regions, focusing particularly on overnight stays, and assesses the implications for sustainable development and regional policy. Quarterly data from the National Statistics Institute (INE) covering 2004/2024 are used. We apply ARIMA and SARIMA models to account for seasonality and autocorrelation, and evaluate the accuracy of our forecasts using Mean Absolute Percentage Error (MAPE) and Theil’s U statistics. Structural breaks are considered to capture the effects of crises. The findings show that crises have significantly altered tourism patterns, with a shift towards less crowded and more remote destinations. This reflects vulnerabilities and opportunities for sustainability-oriented tourism. The study offers policymakers actionable guidance by aligning its results with the United Nations Sustainable Development Goals (SDGs), particularly those related to economic resilience (SDG 8), innovation and infrastructure (SDG 9), and partnerships for sustainable governance (SDG 17). This work is original in combining long-term regional data with robust forecasting techniques to provide innovative insights for scientific research and practical policy planning. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Invasive species can alter community composition and ecosystem functioning. In the subtidal rocky shores of Arraial do Cabo Bay, southeastern Brazil, the invasive coral Tubastraea spp. has established populations, raising concerns about long-term impacts on native benthic communities. This study investigates temporal shifts in β-diversity across 44 fixed plots containing Tubastraea spp., monitored over 383 days. Underwater photographic surveys and multivariate analyses identified nine distinct benthic community types, each forming mosaic structures of sessile organisms. Temporal β-diversity analyses revealed that only the group characterized by Tubastraea, crustose calcareous algae and the zoantharian Palythoa caribaeorum showed significant differences between species gains and losses over time, suggesting temporal-scale dependency. Key contributors to community dissimilarity included P. caribaeorum, crustose calcareous algae, turf, the sponge genus Darwinella, and Tubastraea. This study highlights the importance of considering both spatial and temporal heterogeneity when assessing the ecological impact of marine invasive species. Our findings underscore the need for multi-scale monitoring to fully understand the dynamics of tropical subtidal ecosystems under biological invasion. While numerous studies report a correlation between Tubastraea abundance and shifts in ecological diversity, this relationship may be weak, as critical drivers such as the complexity of community organization are rarely accounted for. Full article

Background/Objective: Clinical statistics show that bacterial infection is a major driver of implant failure. To enhance antibacterial performance, some metallic elements, such as silver (Ag), zinc (Zn), and copper (Cu), are commonly used to modify the titanium surface. Despite the promising antibacterial performance of Ag, concerns persist regarding dose-dependent cytotoxicity, systemic accumulation, and potential effects on local bone metabolism. This review aimed to investigate the effects of incorporating or coating titanium (Ti) implant surfaces with Ag on bone formation around implants. Methods: A search was undertaken using three main databases (PubMed, Web of Science, and Scopus). The search was limited to studies published within the last 20 years that involved animal experiments using endosseous implants coated with or incorporating Ag. Meta-analyses were performed for bone-to-implant contact (BIC), bone formation (BA), and bone volume (BV/TV) around the implant in control and test groups. The compared groups were subjected to similar implant surface treatments aside from the presence of silver in the test group. Results: Sixteen studies met the inclusion criteria in this study and were included. The analysis of BIC values revealed a statistically significant overall effect in favor of silver-coated implants (Z = 2.01, p = 0.04), along with 95% confidence intervals (CIs). The BA analysis found no significant difference between silver-coated and control implants (Z = 1.09, p = 0.28). The BV/TV analysis also showed no statistically significant overall difference (Z = 0.35, p = 0.73). Conclusions: In animal models, silver-coated Ti implants improve bone–implant contact without altering peri-implant bone volume metrics. Full article

This study investigated the mechanism of hydroxysafflor yellow A (HSYA) on senescent human umbilical cord mesenchymal stem cells (hUC-MSCs) through transcriptome sequencing. HSYA treatment identified 2377 differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that these DEGs were primarily enriched in cell adhesion regulation and the extracellular matrix (ECM)–receptor interaction pathway. Gene Set Enrichment Analysis (GSEA) and protein–protein interaction (PPI) network analysis corroborated the central role of ECM–receptor interaction signaling, and Key Driver Analysis (KDA) revealed 10 core regulatory genes (e.g., ID1, SMAD3, TGFB3). SA-β-gal staining showed that HSYA significantly reduced senescence-associated β-galactosidase activity. Flow cytometry showed no significant changes in cell cycle distribution. Western blot analysis indicated that HSYA treatment reduced the protein expression level of p16 without significantly altering p53 levels. Furthermore, HSYA significantly attenuated intracellular reactive oxygen species (ROS) accumulation. qPCR validation demonstrated that HSYA significantly upregulated ID1, GDF5, SMAD3, and TGFB3 while downregulating BMP4, TGFB2, and CCN2. These findings indicate that HSYA modulates genes associated with the ECM–receptor interaction pathway, potentially contributing to improved ECM homeostasis in senescent hUC-MSCs. Full article

In response to China’s drive to bring newly cultivated land into production, this study evaluated how combined organic fertilizer and microbial inoculants affect soil quality, bacterial community structure, and maize yield. Four treatments were evaluated: FC (chemical fertilizer only), T50 (50% organic fertilizer + 50% chemical fertilizer), T50M (T50 plus microbial inoculant), and CK (no fertilizer). T50M significantly increased yield compared to FC and CK (p < 0.05), achieving the highest yield of 6995.73 kg ha⁻¹. This was 20.09% greater than FC. Community composition analyses showed that soil in newly cultivated land was dominated by Blastocatellia, Vicinamibacteria, and Alphaproteobacteria, together accounting for over 35.7% of total bacterial abundance. Redundancy analysis at the class level explained 55.7% of variance; soil organic matter (SOM) and available potassium positively correlated with Alphaproteobacteria and Bacteroidia, while available phosphorus and nitrate nitrogen aligned with Actinobacteria and Bacilli. Path analysis indicated that SOM and total nitrogen were the strongest positive drivers of yield. Actinobacteria and Acidobacteriae also showed direct positive effects, whereas Verrucomicrobiae had a negative effect. These results demonstrate that integrated organic–microbial amendments can enhance soil fertility and alter microbial diversity toward taxa that can improve maize productivity. Full article

Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy and typically has a favorable prognosis. However, a subset of patients experience aggressive disease, recurrence, or treatment resistance, underscoring the need for more precise diagnostic and therapeutic strategies. Advances in molecular profiling have improved the management of thyroid cancer by enabling risk-adapted treatment and targeted interventions. This narrative review offers a clinically focused synthesis of the current role of molecular diagnostics and personalized therapeutics in DTC. We examine key genetic alterations and their diagnostic, prognostic, and therapeutic implications, and discuss how molecular markers enhance traditional risk stratification systems, informing surgical decisions, radioactive iodine (RAI) use, and surveillance. The growing role of targeted therapies, such as tyrosine kinase inhibitors and agents against specific oncogenic drivers, is reviewed, particularly for RAI-refractory DTC. We also address real-world challenges in implementing precision medicine, including access, cost, and standardization. Future directions, such as liquid biopsy, artificial intelligence, and multi-omic integration, are explored as tools to achieve fully personalized care. This review aims to bridge the gap between molecular discovery and clinical application, offering practical insights for endocrinologists, surgeons, oncologists, and multidisciplinary teams managing DTC. Full article

Saline–alkali soils in arid regions are increasingly recognized as critical yet underrepresented components of the global carbon cycle. However, their CO₂ flux dynamics under warming remain poorly understood. In this study, we conducted controlled growth-chamber experiments using typical saline–alkali soils from the Taklamakan Desert, where temperature, soil moisture, and atmospheric CO₂ concentrations were systematically manipulated. We quantified how warming reshaped moisture–temperature interactions regulating soil CO₂ fluxes. The results revealed a pronounced diurnal variation pattern, characterized by daytime CO₂ release and nighttime uptake. Temperature was identified as the dominant driver (R² > 0.93, p < 0.001), whereas soil moisture primarily modulated flux intensity; at 0.8 cm³ cm⁻³, fluxes declined by up to 61% compared with the baseline. Warming enhanced the temperature–moisture synergy (−43%, p < 0.01) and simultaneously reduced baseline fluxes (−56%, p < 0.01). These shifts fundamentally altered the regulation of CO₂ flux dynamics. Our findings highlight the necessity of integrating salt dynamics and carbonate equilibria into multiphase reactive transport models to improve regional carbon sink assessments. Ultimately, this study refines estimates of the contribution of saline–alkali soils to the global “missing carbon sink” (~1.7 Pg C a⁻¹) and emphasizes their overlooked role in the Earth’s carbon budget under a warming climate. Full article

In tropical regions, the establishment of large-scale exotic plantations has addressed the demand for timber resources but has also disrupted the structural stability of native vegetation and altered soil nutrient cycling, thereby impairing ecosystem functions. Identifying effective restoration strategies for these plantations is crucial for sustainable forest management and ecological security. This study examined Acacia mangium Willd., Cunninghamia lanceolata (Lamb.) Hook., and Pinus caribaea Morelet. plantations in Hainan Tropical Rainforest National Park under three treatments: plantation control, girdling, and natural secondary forest. Vegetation surveys and soil analyses were conducted to explore the relationships between community structure, soil physicochemical properties, and enzyme activities. Diversity indices, Pearson correlations, and redundancy analysis were used to assess plant–soil relationships. The results showed that girdling significantly accelerated succession in C. lanceolata and P. caribaea plantations, increased species diversity, and enhanced the dominance of native species. Shrub-layer diversity indices (H_shrub, D_shrub, E_shrub) were the main drivers of soil properties and enzyme activities, while tree-layer effects were weaker. Girdling regulated soil nutrients and biological activity primarily via changes in community structure. These findings highlight the importance of optimizing shrub-layer structure and enhancing diversity for tropical plantation restoration. Combining forest type conversion with moderate interventions can promote coordinated plant–soil development over time. Full article

Rivers, vital for life and civilizations, face severe threats from human activities such as hydropower development, with heavy metal pollution emerging as a critical concern due to altered biogeochemical cycles. Understanding how river damming affects heavy metal transport processes and developing targeted remediation strategies are essential for safeguarding the health of river-reservoir ecosystems and enabling the sustainable utilization of hydropower resources. Therefore, this review first summarizes the global hydropower development, details how damming disrupts hydrology, environments, and ecosystems, and analyzes heavy metal distribution and transport in reservoir water, suspended sediments, and riverbed sediments. It reveals that river damming promotes heavy metal adsorption onto suspended particles, deposition in riverbed sediments, and re-release during reservoir regulation, and anthropogenic activities are a primary driver of significant pollution in key reservoirs worldwide. Additionally, we further evaluate in situ (e.g., stabilizing agents, sediment capping, and phytoremediation) and ex situ (e.g., dredging, chemical washing, electrochemical separation, and ultrasonic extraction) remediation techniques, highlighting the challenges of phytoremediation in deep, stratified reservoir environments. Moreover, solidification/stabilization emerges as a promising in situ strategy, emphasizing the need for specific approaches to balance pollution control with hydropower functionality in dammed river systems. Full article

This review catalogs candidate LUAD driver genes and their roles, recent discoveries, and therapeutic avenues. Beyond experimental repurposing, we evaluate modern computational methods and how they complement bench work. We conclude by appraising recent LUAD repurposing studies through a computational lens, emphasizing practical integration into translational research. Highlights: Overview of drug repurposing methods: We provide a list of six experimental and a brief taxonomy of eight computational drug repurposing method families. Recent insights into LUAD driver genes: We present a curated panel of LUAD drivers mapped to pathways, with alteration types, functions, and therapeutic implications. LUAD-focused computational repurposing studies: We provide a synthesis of recent LUAD studies presenting clear method families, highlighting exemplar pipelines, prioritized candidate drugs, and datasets. Full article

Background: The ESR2 gene encodes Estrogen Receptor-β1 (ERβ1), a putative tumor suppressor in hormone-dependent malignancies. Although ERβ biology has been studied extensively at the expression level, the functional impact of nonsynonymous SNPs (nsSNPs) and untranslated-region (UTR) variants in ESR2 remains underexplored. Methods: We retrieved variants from Ensembl and performed an integrative in silico assessment using PredictSNP, I-Mutant, MUpro, HOPE, MutPred2, and CScape for pathogenicity, oncogenicity and structural stability; STRING/KEGG/GO for pathway context; RegulomeDB and polymiRTS for regulatory effects; and cBioPortal for pan-cancer clinical outcomes (breast (BRCA), endometrial (UCEC), and ovarian (OV)). We evaluated effects of nsSNPs on ERβ1 stability, ligand-binding/DNA-binding domains, co-factor recruitment, and post-transcriptional regulation. Results: Across tools, 93 missense nsSNPs were consistently predicted to be deleterious. Notably, several variants were found to destabilize ERβ1, particularly within the ligand-binding domains (LBD) and DNA-binding domains (DBD). Putative oncogenic drivers R198P and D154N showed high CScape scores and very low population frequencies, consistent with pathogenicity. Several substitutions were predicted to impair coactivator binding and disrupt interactions with key transcriptional partners, including JUN, NCOA1, and SP1. At the post-transcriptional level, rs139004885 was predicted to disrupt miRNA binding, while 3′UTR rs4986938 showed strong regulatory potential and comparatively high population frequency; by contrast, most other identified SNPs were rare. Clinically, pan-cancer survival analyses indicated worse overall survival (OS) in BRCA for ESR2-Altered cases (HR ≈ 2.25; q < 0.001), but better OS in UCEC (HR ≈ 0.24; q ≈ 0.014) and OV (HR ≈ 0.29; q < 0.001), highlighting a tumor-type-specific association. Conclusions: This integrative analysis prioritizes high-impact ESR2 variants that likely impair ERβ1 structure and shows context-dependent clinical effects. Despite their generally low frequency (except for rs4986938), prospective validation linking variant class to ERβ expression and survival outcomes is needed to support biomarker development and therapeutic applications. Full article