Search Results (11,895)

Background: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by autoimmune-driven inflammation in the central nervous system that damages axons and destroys myelin. It is difficult to diagnose multiple sclerosis due to its complexity, and different people may react differently to different treatments. While the exact cause of multiple sclerosis (MS) and the reasons for its increasing prevalence remain unclear, it is widely believed that a combination of genetic predisposition and environmental influences plays a significant role. Methods: Finding biomarkers for complicated diseases like multiple sclerosis (MS) is made more promising by the emergence of network and system biology technologies. Currently, using tools like Network Analyst to apply network-based gene expression profiling provides a novel approach to finding potential medication targets followed by molecular docking and MD Simulations. Results: There were 1200 genes found to be differentially expressed, with CD44 showing the highest degree score of 15, followed by CDC42 and SNAP25 genes, each with a degree score of 14. To explore the regulatory kinases involved in the protein–protein interaction network, we utilized the X2K online tool. The present study examines the binding interactions and the dynamic stability of four ligands (Obeticholic acid, Chlordiazepoxide, Dextromethorphan, and Hyaluronic acid) in the Hyaluronan binding site of the human CD44 receptor using molecular docking and molecular dynamics (MD) simulations. Docking studies demonstrated a significant docking score for Obeticholic acid (−6.3 kcal/mol), underscoring its medicinal potential. MD simulations conducted over a 100 ns period corroborated these results, revealing negligible structural aberrations (RMSD 1.3 Å) and consistent residue flexibility (RMSF 0.7 Å). Comparative examinations of RMSD, RMSF, Rg, and β-factor indicated that Obeticholic acid exhibited enhanced stability and compactness, establishing it as the most promising choice. Conclusions: This integrated method underscores the significance of dynamic validations for dependable drug design aimed at CD44 receptor-mediated pathways. Future experimental techniques are anticipated to further hone these findings, which further advance our understanding of putative biomarkers in multiple sclerosis (MS). Full article

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by bi-allelic deletions or pathogenic SMN1 variants. Early diagnosis through neonatal screening is essential for timely therapeutic intervention, significantly improving clinical outcomes. In August 2022, a pilot neonatal screening program for SMA was launched in Romania, aiming to assess feasibility and impact. Objectives are to present the preliminary results of the ongoing SMA neonatal screening pilot program in Romania, evaluating its effectiveness in early detection and referral for treatment. The program started in August 2022 with four maternity hospitals and has progressively expanded to 28 maternity hospitals nationwide. Dried blood spot samples from newborns were analyzed for SMN1 gene deletions using real-time PCR. Positive results were confirmed through genetic testing, and affected infants, along with their families, were referred for further medical evaluation and early therapeutic intervention. Approximately 60,000 newborns have been screened since the program’s inception, and 12 newborns tested positive for SMN1 deletions, resulting in an estimated incidence rate of 1 in 5125 live births. All confirmed cases were promptly referred for specialized care, with early access to disease-modifying therapies. The program has faced challenges in logistics, parental awareness, and equitable access to treatment, but its expansion from 4 to 28 maternities demonstrates increasing feasibility, suitability, and acceptance. Conclusions: The Romanian pilot neonatal screening program for SMA has successfully identified affected infants early, proving its feasibility and clinical impact. The ongoing expansion suggests a strong foundation for a future national program, which could significantly improve early SMA diagnosis and patient outcomes in Romania. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by various clinical manifestations, including significant neurovascular complications. This review aims to synthesize current knowledge regarding intracranial stenoses and associated vascular abnormalities in patients with NF1, emphasizing the differences between pediatric and adult populations. Methods: A narrative review was conducted, analyzing the existing literature on the epidemiology, clinical manifestations, and management of neurovascular issues related to NF1. Data were collected from a range of studies, including retrospective analyses and case series, focusing on the incidence and outcomes of intracranial vascular abnormalities. Results: The study found that intracranial vasculopathy affects between 0.4% and 6.4% of NF1 patients, with children experiencing higher rates of stenotic lesions. However, vascular issues in adults are less understood, with 3.5% of adult patients presenting vascular abnormalities. The review highlights a significant underdiagnosis of these conditions due to the lack of routine use of magnetic resonance angiography (MRA) in standard evaluations. The management of NF1-related vascular conditions, particularly in adults, remains poorly defined, particularly regarding the efficacy of antithrombotic therapies. Conclusions: The management of neurovascular complications in NF1 requires urgent attention, with a need for standardized screening protocols and further research to elucidate the natural history and optimal treatment strategies for these patients. Enhanced diagnostic practices, including routine neuroimaging, are essential to improve outcomes and reduce the risk of significant vascular events. Full article

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5–20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development. Full article

Cephalotaxus hainanensis, a valuable medicinal and endangered conifer, requires scientific conservation and precision management to ensure the sustainable utilization of its genetic and ecological resources. Nitrogen (N) is a key nutrient that regulates plant growth and metabolism; rapid and accurate nitrogen diagnosis is vital for optimizing fertilization, reducing nutrient losses, and promoting healthy plant development. This study employed a combined approach integrating stepwise regression, correlation analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify leaf color features strongly correlated with leaf nitrogen content (LNC). A support vector regression (SVR) model, suitable for small-sample datasets, was then employed to accurately estimate LNC across canopy layers. Nine color variables were found to be highly associated with LNC, among which the Green Minus Blue index (GMB) consistently appeared across all correlation methods, demonstrating strong robustness and generality. Color features effectively reflected LNC variations among nitrogen treatments—especially between N1 and N4—and across canopy layers, with the most pronounced contrasts observed between upper and lower leaves. The Spearman-based SVR model revealed that the middle canopy maintained the highest and most stable LNC. However, the lower leaves were most sensitive to nitrogen deficiency, while the upper leaves were more sensitive to nitrogen excess. Comprehensive analysis identified N2 as the optimal nitrogen treatment, representing a balanced nutrient state. Overall, this study confirms the reliability of color features for LNC estimation and highlights the importance of vertical canopy LNC distribution in nitrogen diagnostics, providing a theoretical and methodological foundation for color-based nitrogen diagnosis and precision nutrient management in evergreen conifers. Full article

Flag leaf angle (FLA) in rice (Oryza sativa L.) is one of the important traits affecting F₁ seed production by mechanization. Here, we report the map-based cloning and functional characterization of the FLA1 (FLAG-LEAF-ANGLE 1) gene, which resides at a major-effect quantitative trait locus (QTL). Through cell morphological observations and exogenous hormone treatment assays, we demonstrate that gibberellin (GA) modulates rice FLA by altering both the number of cell layers and cell length. Combining genetic and molecular biological analyses with genetic complementation and gene overexpression assays, we elucidated and validated the biological function of FLA1. In addition, we found that FLA1 is constitutively expressed and encodes a protein localized to both the cell membrane and nucleus. Via RT-qPCR assays, we further demonstrated that the FLA1^fla-R allele from the rice accession fla-R enhances GA biosynthesis by upregulating the expression of CLA1 and GA20ox2. Furthermore, yeast two-hybrid assays revealed that auxin-repressed protein 1 (ARP1) interacts with FLA1, suggesting a potential role of this interaction in the modulation of rice FLA. Collectively, our results demonstrate that optimizing rice FLA via molecular manipulation of FLA1 can resolve the problem of flag leaf shearing during F₁ hybrid rice seed production without compromising F₁ hybrid seed yield, thereby facilitating mechanized F₁ hybrid rice seed production. Full article

Background: Childhood cancers account for approximately 1–2% of all malignancies worldwide, with hematologic cancers representing about 35–40% of pediatric cases. Improved survival has brought increased recognition of both acute and long-term therapy-related complications, including secondary malignant neoplasms (SMNs). Survivors of pediatric hematologic malignancies face a lifelong risk of secondary malignant neoplasms (SMNs), which remain among the most severe late effects of therapy. Methods: We conducted a PRISMA 2020–aligned systematic review of cohort and registry studies evaluating SMNs after childhood hematologic cancers. Databases searched included PubMed, Embase, Web of Science, Scopus, and Cochrane Library. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Newcastle–Ottawa Scale; disagreements were resolved by a third reviewer. Results: Forty-three studies (>70,000 survivors, median follow-up 5–30+ years) were included. Standardized incidence ratios (SIRs) for secondary malignant neoplasms compared to the general population ranged from 2.0 to 6.0, with absolute excess risks (AERs) of approximately 10–40 per 10,000 person-years. Therapy-related acute myeloid leukemia occurred within 5–10 years, while solid secondary malignant neoplasms (breast, thyroid, central nervous system, sarcomas) emerged after 10–25 years. The highest risks for developing secondary malignant neoplasms were observed among female survivors of Hodgkin lymphoma treated with chest and neck radiotherapy, particularly during adolescence, and among hematopoietic stem cell transplant recipients exposed to total body irradiation or chronic graft-versus-host disease. Conclusions: SMNs are predictable late effects requiring lifelong, exposure-anchored surveillance. Precision survivorship—integrating treatment exposures, transplant conditioning, and genetic predisposition—should guide future screening strategies. Full article

Laryngeal squamous carcinoma is a major type of head and neck cancer. Despite a wide range of treatment options, it remains a challenge to identify which ones are the most effective for which groups of patients. One solution is to analyse selected biomarkers. In this paper, biomarkers are divided into distinctive groups according to the molecular pathways analysed or specific molecules within the cell or in tissue fluids. The paper provides a description of these groups, including genetic and apoptosis-associated factors, factors regulating angiogenesis, cell structure regulators, immune factors in the form of programmed cell death ligand (PD-L1), hormone receptors, molecules involved in growth factor pathways, and cell cycle regulators. Representative examples are discussed for each of these groups, indicating their potential usefulness in staging, assessing tumour aggressiveness, and making a prognosis. Full article

Background/Objectives: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, most commonly arising in the choroid. Its development is associated with phenotypic characteristics, ultraviolet radiation, and germline or somatic genetic alterations. Despite progress in diagnostics and local therapies, UM remains characterized by high metastatic risk and poor overall prognosis. This review aimed to summarize current knowledge on epidemiology, clinical features, genetic background, prognostic factors, and therapeutic approaches in metastatic UM. Methods: A structured literature review was conducted to evaluate epidemiological trends, genetic alterations, prognostic markers, clinical presentation, and therapeutic strategies. The results of different systemic treatments were analyzed, with special attention to liver-directed interventions and emerging systemic therapies. Results: The incidence of UM in Europe increases with latitude, ranging from two per million in the southern regions to more than eight per million in the North. The median age at diagnosis is 62 years, and most cases are detected incidentally during ophthalmological examinations due to nonspecific symptoms. Some genetic alterations serve as important prognostic indicators. Local treatment consists of globe-preserving procedures, including radiation therapy, surgery, laser therapy, or enucleation, with failure rates between 6.15% and 20.8%. Up to 70% of patients develop distant metastases, predominantly in the liver. Metastatic UM (mUM) carries a poor prognosis, with overall survival ranging from 3 to 30 months. Liver-directed therapies, particularly surgical resection, provide the most favorable outcomes. Systemic therapies demonstrate limited efficacy; however, tebentafusp has shown an overall survival benefit in HLA-A*02:01 (human leukocyte antigen A*02:01)-positive patients. Conclusions: UM is a rare but aggressive malignancy with limited treatment options once metastatic. Liver-directed strategies remain the mainstay of management, while novel systemic approaches, including tebentafusp, represent promising advances. Further research is required to improve survival and expand therapeutic opportunities. Full article

Kidney organoids, as three-dimensional microstructures derived from human pluripotent stem cells or adult stem cells, precisely simulate the cellular heterogeneity, spatial conformation, and some physiological functions of human kidney units in vitro. Kidney organoids are three-dimensional microstructures derived from human pluripotent stem cells (hPSCs). They precisely simulate the cellular heterogeneity, spatial conformation, and key physiological functions of human kidney units in vitro. This technology, by replicating the interaction network between the glomerulus and renal tubules, provides an unprecedented window for observing the dynamic development and pathological processes of human kidneys. This technology replicates the interaction network between the glomerulus and renal tubules. It thereby provides an unprecedented window into human kidney development and disease. Based on the strong similarity between organoids and native organs, as well as the human genetic information they carry, both iPSC-derived and patient-specific organoids have demonstrated significant value in kidney disease modeling, drug toxicity testing, and the development of regenerative treatment strategies. This review systematically elucidates the key advancements in the field of kidney organoids, including optimized strategies for stem cell-directed differentiation, innovations in culture systems driven by biomaterials engineering, technological breakthroughs in disease model construction, and applications of organoids in drug screening platforms and regenerative medicine. Additionally, it analyzes translational challenges such as the lack of vascularization, insufficient functional maturity, and obstacles in standardized production. These insights will deepen the understanding of kidney pathological mechanisms and propel organoid technology towards substantial clinical therapeutic applications. This review summarizes how convergent technologies in stem cell biology and bioengineering aim to bridge this functional gap. We examine the use of advanced organoids in disease modeling and drug discovery. We also highlight their current limitations. Our focus is on the core translational bottlenecks: vascularization, long-term maturation, and scalable production. Overcoming these hurdles is essential to transform kidney organoids from a research tool into a platform for precision medicine and regenerative therapy. Full article

Depression and osteoporosis frequently co-occur, presenting a significant and increasing clinical challenge, especially among older adults. Growing research highlights the bone–brain axis, a complex bidirectional communication network connecting the skeletal and central nervous systems, as a central mechanism linking these conditions. This review comprehensively examines the current knowledge of the molecular and cellular pathways within this axis that contribute to depression–osteoporosis interactions. It details how depression promotes bone loss through sustained hypothalamic–pituitary–adrenal axis activation, sympathetic nervous system overactivity, and chronic low-grade inflammation. This review also explores how bone-derived factors, including osteocalcin, lipocalin 2, and extracellular vesicles, cross the blood–brain barrier to influence brain function by regulating hippocampal neurogenesis, serotonin signaling, and neuroinflammation. This bidirectional communication is modulated by circadian rhythms and genetic factors. Understanding these pathways offers critical insights into the shared pathophysiology and reveals promising therapeutic targets. Interventions such as neuromodulation, customized exercise programs, and novel treatments focusing on bone-derived signals show potential for simultaneously addressing both mood disorders and bone health deterioration. This review emphasizes the need for an integrated system-based approach in clinical care that moves beyond traditional specialty-focused treatment to improve overall health outcomes, particularly for vulnerable elderly individuals. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy, for which predicting clinical outcomes remains challenging. Although immune-checkpoint pathways are known to influence tumor biology, the impact of their germline variants on DLBCL susceptibility and prognosis has not been fully elucidated. Methods: Variants in PD-L1 gene CD274 (rs4143815, rs822336), and miR-155 gene MIR155HG (rs767649, rs1893650), assessed by TaqMan assays in 99 DLBCL patients and 113 age- and sex-matched healthy controls, were associated with clinicopathological features, treatment response, overall survival (OS), relapse-free survival (RFS), and disease susceptibility. Results: The PD-L1 variant rs822336 was significantly associated with relapse status (p = 0.005) and RFS (p = 0.008), with the wild-type GG genotype showing the poorest RFS that remained independent in the multivariate Cox analysis (HR = 2.387, p = 0.003). Conversely, rs4143815 showed a nominal association with treatment resistance (p = 0.026), while patients carrying the GG genotype had worse OS (p = 0.006). In susceptibility analyses, miR-155 variant rs767649 showed a nominal association with DLBCL risk, with the rare AA genotype showing an increased risk of DLBCL (OR = 5.234, p = 0.045), which did not remain significant after Bonferroni correction. Conclusions: In a hypothesis-generating manner, these findings suggest that PD-L1 genetic variants may predominantly influence disease progression and outcomes, while miR-155 variation may contribute to DLBCL susceptibility. These findings highlight germline immunogenetic variants as stable, treatment-independent markers that may inform future studies on risk stratification and prognosis in DLBCL. Full article

Increases in global temperatures, due to the climate change, are generating stress in most plant species. We hypothesize that young plants of Opuntia spp. adjust their Crassulacean acid metabolism (CAM) to the increase in nighttime temperature, allowing them to continue growing. The study was carried out in a greenhouse and laboratory of the Colegio de Postgraduados, Montecillo, Mexico. Three-month-old greenhouse-grown plants remained in a control environment with an average day/night temperature of 19.1/12.3 °C or were maintained in a chamber with increased nighttime temperatures averaging 19.1/18.9 °C day/night for 70 days. The experimental design was completely randomized with two treatments (control and high nighttime temperatures). After 70 days of high nighttime temperatures (HNT), at dawn (end of CAM phase I), plants had a 45% decrease in glucose (2.9 to 1.5 mg/100 mg dry tissue; dt) concentration and doubled and tripled fructose (0.43 to 0.95 mg/100 mg dt) and sucrose (0.47 to 0.09 mg/100 mg dt) concentrations. Glucose consumption may be related to the plant’s metabolic energy expenditure to overcome stress. The significant increase in fructose and sucrose is explainable by their function as signaling molecules among others. In contrast, photosynthetic efficiency, i.e., increased compared to the control, but the difference of acidity (end of phase I less phase III), the concentration of starch (1 mg/100 mg dt), free amino acids and soluble protein (1.2 mg/100 mg dt), wet and dry matter, stem height (60 cm) and width of the stem at dawn were not significantly affected. The adjustments in C and N metabolism and the non-significant effect on growth promoted by 70 HNT days may be related to adjustments in enzyme activities without changes in protein concentration. Young Opuntia spp. plants adjust their metabolism in response to increased nighttime temperatures, allowing them to maintain growth similar to that of the control. The results confirm the great potential of using the Opuntia genus in agriculture and genetic improvement in the face of the challenges posed by climatic change. Full article

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a major cause of bloodstream infections and poses serious challenges to clinical management because treatment options are limited. This study aimed to characterize antimicrobial resistance, virulence-associated features, and molecular epidemiology of CRKP bloodstream isolates using integrated phenotypic and genomic approaches. A total of 74 non-duplicate CRKP isolates were collected from bloodstream infections at three tertiary-care hospitals in Riyadh, Saudi Arabia, between 2022 and 2024. All isolates showed classical Klebsiella pneumoniae phenotypic characteristics, including intrinsic resistance to natural and aminopenicillins, and were classified as either multidrug-resistant (MDR) or extensively drug-resistant (XDR). Resistance to imipenem was universal, and resistance to other β-lactams and fluoroquinolones was high. Carbapenemase genes were detected in 96.0% of isolates using the GeneXpert^® Carba-R assay, with bla_OXA-48-like and bla_NDM being most common. Whole-genome sequencing demonstrated predominance of Ambler class D carbapenemases, particularly bla_OXA-232, with additional contributions from bla_NDM-1 and bla_NDM-5. Co-occurrence of carbapenemase genes was observed in a subset of isolates. Virulence analysis showed that 37.8% of isolates exhibited a hypermucoviscous phenotype, and more than half carried at least one virulence-associated determinant linked to capsule regulation or iron acquisition. In contrast, most isolates showed weak or no biofilm-forming capacity. Multilocus sequence typing revealed substantial genetic diversity but clear dominance of high-risk lineages, particularly ST147 and the emerging ST2096, both closely associated with bla_OXA-232 and bla_OXA-48-like genes. Capsular and O-antigen analysis showed a non-random distribution dominated by KL64 and O1/O2. Phylogenetic analysis was consistent with clonal expansion and suggested intra-hospital spread, with the intensive care unit serving as a key reservoir and dissemination to other wards. In conclusion, CRKP bloodstream infections in this setting are largely associated with a limited number of epidemic clones that combine extensive antimicrobial resistance with virulence-associated traits. These findings support the need for ongoing genome-based surveillance, strengthened infection control measures, and antimicrobial stewardship to limit the spread of high-risk K. pneumoniae lineages in healthcare settings. Full article

Background/Objectives: Cystic fibrosis (CF) is a genetic condition with an increasing life expectancy in recent years. As a result, addressing psychosocial aspects in this population has become an increasingly important concern. This mixed-methods systematic review aimed to update the current knowledge on the psychosocial aspects of living with CF in adults. Methods: Following PRISMA guidelines, a literature search was conducted in November 2024 across several databases, including Scopus, ScienceDirect, Academic Search Complete, MEDLINE, Supplemental Index, Complementary Index, APA PsycInfo, Business Source Complete, SciELO, and the Directory of Open Access Journals via EBSCO. Results: Of the 701 articles retrieved, 24 were analyzed, including a total of 2023 participants (mean age: 31.2 years; 57.2% female). Quantitative findings identified optimistic coping as the most frequent strategy associated with improved survival. High social support and gratitude emerged as key factors for treatment adherence and quality of life, while depression remained the primary mental health concern. Qualitatively, the findings highlighted concerns with adult life transitions and financial stressors. Participants described experiences of social stigma and embarrassment linked to chronic symptoms, often leading to selective disclosure to avoid discrimination. Conclusions: This review confirms that psychosocial factors are central to the adult CF experience, shifting the focus beyond biological survival and highlighting areas that require clinical intervention. As life expectancy increases, clinical care must evolve to incorporate interventions that address these factors to improve mental health and overall quality of life (QoL), ensuring that patients are supported through the unique challenges of extended adulthood. Full article