Search Results (4,219)

Alzheimer’s disease (AD) is characterized by cognitive decline and amyloid-β (Aβ)-related pathology. Non-rodent models that capture selected aspects of human AD remain limited. We established and characterized a human APP-driven, Aβ-related AD-like tree shrew model following AAV-mediated delivery of triple-mutant human amyloid precursor protein (hAPP-SLA) carrying the Swedish, Austrian, and London mutations by bilateral stereotaxic injection directed at CA1 coordinates. Adult tree shrews received bilateral AAV-hAPP-SLA injections directed at CA1 coordinates and were evaluated by bioluminescence imaging, behavioral testing, PCR, RT-qPCR, Western blotting, ELISA, and histopathology. Vector-associated reporter signals remained detectable for 6 months. The experimental group showed exogenous hAPP expression and reduced endogenous tsAPP expression, increased relative hippocampal Aβ₄₂ protein level, enhanced 4G8-reactive APP/Aβ-related signals, elevated total Aβ immunoreactivity, increased serum Aβ₄₂/Aβ₄₀ ratio, cytoarchitectural alterations, reduced Nissl staining, and Thioflavin S-reactive aggregate-associated signals. AT8 (Ser202/Thr205), GFAP, and Iba-1 immunoreactivity increased, whereas Synaptophysin and PSD-95 immunoreactivity was reduced. These changes were accompanied by reduced short-delay recognition-related performance and reduced social approach and social novelty preference. Aged tree shrews showed partly overlapping alterations. This model provides a non-rodent platform for studying human APP-driven Aβ-related pathology. Full article

Background: Posterior malleolar fractures are commonly assessed using two-dimensional measurements and morphology-based classification systems. However, ankle fracture morphology is inherently three-dimensional, and the reproducibility of CT-based volumetric segmentation for malleolar fracture fragments has not been sufficiently established. Objectives: This study aimed to evaluate the relationship between lateral and posterior malleolar fragment volumes in homogeneous supination–external rotation (SER)-type trimalleolar ankle fractures and to assess the intraobserver and interobserver reproducibility of a manual CT-based three-dimensional volumetric segmentation workflow. Methods: This retrospective musculoskeletal imaging study included 71 patients with SER-type trimalleolar ankle fractures who underwent preoperative computed tomography (CT). Posterior and lateral malleolar fracture fragments were segmented on thin-slice axial CT images using a standardized manual contour-based slice-by-slice workflow. Fragment volumes were calculated using dedicated volumetric imaging software. The association between lateral and posterior malleolar fragment volumes was assessed using Spearman correlation and multivariable linear regression analyses. Measurement reproducibility was evaluated using intraclass correlation coefficients for absolute agreement [ICC(A,1)] and Bland–Altman analyses. Results: The median lateral and posterior malleolar fragment volumes were 8.63 cm³ (interquartile range [IQR], 7.18–10.71) and 2.64 cm³ (IQR, 1.88–4.24), respectively. A weak but statistically significant positive correlation was observed between lateral and posterior malleolar fragment volumes (Spearman rho = 0.313, p = 0.008). In multivariable linear regression analysis, lateral malleolar fragment volume remained independently associated with posterior malleolar fragment volume after adjustment for age, sex, and body mass index (B = 0.316, standardized β = 0.39, p = 0.002). Intraobserver and interobserver reproducibility were excellent for all volumetric measurements, with ICC(A,1) values ranging from 0.996 to 0.999. Bland–Altman analyses demonstrated low mean bias and narrow limits of agreement across all comparisons. Geometric agreement was also excellent, with Dice similarity coefficient values ranging from 0.93 to 0.96 across intraobserver and interobserver segmentation comparisons. Full article

Among the non-classical platinum complexes, Pt(IV) prodrugs are most promising as versatile scaffolds for structural modification and fine tuning of their activation-by-reduction mechanism of action and the resulting anticancer activity. Herein, four new asymmetrically disubstituted pyrenebutyrate complexes of Pt(IV) (2–5) were synthesized and thoroughly studied. In this series, the second axial ligand was derived from dicarboxylic acids of different length—4 and 5 C-atoms, or replacement of the C-atom in the middle with either O- or S-atom. The structural effects on reduction kinetics, lipophilicity and cellular internalization of the complexes were monitored by NMR, HPLC, fluorescence and ICP-MS measurements. Their cytotoxicity was tested on a panel of cancer cell lines and mechanistic insights were obtained from proteome analysis and microscope imaging. The data indicate that all complexes, especially complex 3, represent a promising class of Pt(IV) prodrugs, exhibiting significantly higher cytotoxic activity than cisplatin in all tested models, including a cisplatin-resistant line. This was explained with a stronger and more integrated apoptotic response than cisplatin: pronounced Bax upregulation (3.6-fold), maximal cleaved caspase-3 (4-fold), activation of both intrinsic and extrinsic pathways, and effective p53 Ser15/Ser46 phosphorylation. The consistent rank order of potency (3 > 4 > 5 ≈ 2 ≫ cisplatin) suggests that subtle ligand modifications can substantially enhance efficacy, possibly by improving cellular uptake or altering DNA binding. Full article

Urine pH is an important biomarker related to metabolic status and urinary system health, but reliable SERS quantification in real urine remains limited by matrix interference, heterogeneous hotspot distribution, and the narrow response range of single pH-responsive molecules. Here, we report a core–gap–shell Au@1,4-BDT@Au@4-MBA/MPY nanoprobe for ratiometric SERS detection of urine pH. 1,4-BDT was confined within the gap between the gold core and shell as an internal standard, while 4-MBA and 4-MPY were co-assembled on the outer gold shell to provide complementary protonation/deprotonation responses. The internal standard-corrected ratio I₁₀₀₄/I₁₄₀₀/I₇₃₁ reduced signal fluctuation and enabled segmented linear fitting over pH = 1.0–7.0 and pH = 7.0–10.0, with coefficients of determination of 0.98806 and 0.99989, respectively. The sensing platform also maintained stable ratiometric responses under different interference conditions. In real urine samples from five volunteers, SERS-predicted pH values agreed well with commercial pH meter measurements, with relative accuracies of 98.71–101.9% and RSD values below 2.1%. This confined internal standard and dual-molecule ratiometric strategy provides a feasible approach for urine pH sensing in complex biofluid matrices. Full article

Seven indigenous strains of Bradyrhizobium japonicum subsp. saratovii isolated from soybean nodules (Glycine max (L.) Merr.) grown in the arid Lower Volga region of Russia were investigated. A complete set of the major symbiotic genes was detected in all strains. Single synonymous nucleotide substitutions were identified in nifH and nifD, whereas a missense mutation, Ser149Phe, was found in the nifK gene of strain II-2. Homology modelling showed that this substitution did not cause any noticeable rearrangement of the overall structure of the nitrogenase β-subunit, although it was located near the conserved Cys152 residue. The nodB and nodC genes were completely conserved; the nodC sequence corresponded to symbiovar glycinearum. Structural disruptions in the nap operon were detected in strains II-2 and III-2, which was consistent with the absence of nitrate-reducing activity. Comparison of the genomic data with the inoculation results showed that the most effective strain, II-2, combined strong growth-promoting and yield-enhancing effects with the presence of a complete set of symbiotic genes and disruption of napA. These findings indicate that the integration of genomic analysis with phenotypic assessment improves the accuracy of selecting promising indigenous Bradyrhizobium strains for soybean inoculation. Full article

Surface-enhanced Raman spectroscopy (SERS) has emerged as a highly promising analytical technique for disease diagnostics due to its exceptional sensitivity, molecular specificity, and ability to detect a broad range of biomarkers in complex biological matrices. This review provides a comprehensive overview of gold- and silver-nanoparticle-based SERS platforms for plasma disease diagnostics, covering advances in plasmonic nanostructures, biological sample analysis, biomarker detection, and AI-driven spectral data processing. Particular emphasis is placed on the application of SERS to clinically relevant biofluids, especially plasma, where the technique has demonstrated considerable potential for detecting diseases such as cancer, inflammatory disorders, and neurological conditions. The review also critically examines the major challenges currently limiting the clinical translation of SERS technologies. These include variability associated with substrate fabrication, matrix-induced signal fluctuations, limited interlaboratory reproducibility, and the lack of standardized protocols for spectral preprocessing and data analysis. Strategies proposed to address these issues are discussed, including comprehensive post-synthesis substrate characterization, optimization of biological sample preparation, advanced spectral preprocessing workflows, and the integration of machine learning and artificial intelligence algorithms to improve diagnostic robustness and reproducibility. Collectively, the advances summarized in this review indicate that SERS-based diagnostic technologies are rapidly progressing beyond proof-of-concept studies toward clinically applicable systems. Continued interdisciplinary collaboration and standardization efforts will be essential to bridge the remaining gap between experimental SERS methodologies and routine clinical implementation. Full article

The escalating crisis of herbicide-resistant weeds threatens global wheat production. While key mutations are well-documented in weeds, the principles governing their interactions in wheat remain largely unknown. Here, we first developed a novel wheat germplasm carrying the acetolactate synthase (TaALS) Ser-627-Asn (S627N) mutation via ethyl methanesulfonate (EMS) mutagenesis. We then employed a computational design strategy to explore its synergy with the prevalent Trp-548-Leu (W548L) mutation—a combination not yet reported in nature. Integrated molecular dynamics (MD) simulations and free energy landscape analysis revealed that the in silico W548L/S627N double mutant triggers synergistic global destabilization of the herbicide–enzyme complex. Binding affinity progressively weakened from wild-type (−25.54 ± 2.05 kcal/mol) to the double mutant (−18.13 ± 2.76 kcal/mol), driven by a polarity inversion at the Arg-347 anchor. Comparative transcriptomic profiling of the S627N germplasm confirmed the absence of deleterious metabolic feedback in the branched-chain amino acid biosynthesis pathway. This work exemplifies a paradigm shift from mimicking natural variation to predictive crop design via multiplex gene editing. Full article

In this study, a new series of (E)-4-((2-(2-(4-amino-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetyl)hydrazono)methyl)phenyl 4-halogenobenzenesulfonates (3a–3d), where 3a = F, 3b = Cl, 3c = Br, and 3d = I, were successfully synthesized via a straightforward synthetic route. The structures of the obtained compounds were fully characterized and confirmed by spectroscopic techniques, including FT-IR, ¹H NMR, and ¹³C NMR, as well as LC-MS/MS analysis. 1,2,4-triazole-based hydrazone derivatives (3a–3d) were investigated using IR and NMR spectroscopy and DFT calculations. Intermolecular interactions, HOMO-LUMO, dipole moment, polarization, first-order hyperpolarizability, and molecular electrostatic potential studies on the molecules were examined. The HOMO and LUMO energy gap study supports the charge transfer probability in the molecules. These were conducted to investigate the reactivity and stability of heterocyclic molecules in bioactivity analysis. Electron density mapping within the molecular electrostatic potential plot and electrostatic potential representation within the iso-surface plot evaluated the concept of charge distribution in the molecule as nucleophilic reactions and electrophilic regions. The predicted nonlinear optical (NLO) properties of the molecules are much greater than those of urea. The results obtained from these investigations collectively provide evidence that the molecules possess nonlinear optical applications. Novel triazole–hydrazone-functionalized aryl sulfonate derivatives (3a–3d) were evaluated for their anticancer potential against a panel of brain and non-brain cancer cell lines. Compound 3b exhibited the most favorable overall biological profile, displaying potent activity against SH-SY5Y neuroblastoma (GI = 7.59 μM) and U87MG glioblastoma cells (GI = 13.85 μM), together with the lowest toxicity toward normal FL fibroblasts (GI = 62.02 μM). Compounds 3c and 3d demonstrated remarkable potency against IDHmut-U87 glioma cells (GI = 3.87 and 3.27 μM, respectively), although their selectivity toward cancer cells was limited. DNA degradation studies revealed substantial fragmentation, particularly in C6 and SH-SY5Y cells, while migration assays indicated reduced cellular motility. Molecular docking studies identified compound 3b as the strongest PI3Kα binder, supporting a possible. In addition, the antimicrobial activities of compounds 3a–3d were evaluated against selected Gram-positive and Gram-negative bacteria as well as Candida species using the broth microdilution method. The compounds exhibited measurable antimicrobial effects with MIC values ranging from 156 to 625 µg/mL, showing moderate growth inhibition against the tested microorganisms. Although the observed activity was lower than that of the reference antimicrobial agents, the results indicate that these triazole–hydrazone derivatives possess a detectable level of antimicrobial activity and provide a basis for further structural optimization. Collectively, the results suggest that compound 3b represents the most promising lead structure due to its balanced combination of potency, selectivity, and predicted target engagement. Molecular docking was performed to evaluate the binding potential of newly synthesized triazole derivatives (3a–3d) against PI3Kα. The docking protocol was validated by re-docking alpelisib, yielding an RMSD of 0.64 Å. Among the tested compounds, 3b showed the most favorable binding energy (−9.94 kcal/mol) and estimated Ki value (52.13 nM), consistent with its superior in vitro activity. Its interactions with key PI3Kα residues, including Val851, Ser854, Met922, and Asp933, support a stable binding mode within the ATP-binding pocket. In silico ADME and toxicity analyses suggested acceptable drug-likeness characteristics, absence of major hepatotoxic, mutagenic, and carcinogenic liabilities, and moderate predicted acute toxicity profiles. These findings suggest that 3b is the most promising derivative for further validation. Full article

Salicylic acid (SA) is an important signaling molecule that regulates plant primary and secondary metabolites accumulation. Although SA has been shown to promote folate accumulation, the underlying mechanism remains unclear. In this study, the effect of SA on folate biosynthesis in spinach (Spinacia oleracea L.) and its regulatory mechanisms were investigated. Physiological and metabolomic analyses showed that foliar SA application increased the contents of folate, soluble protein, and soluble sugar and the abundance of 5-methyltetrahydrofolate, p-aminobenzoate (pABA), and Trp, while the abundance of Ser decreased. The expression of aminodeoxychorismate synthase (ADCS) and alkaline phosphatase (ALP) genes in the folate biosynthesis pathway was upregulated, while the expression of five genes in the folate interconversion pathway and two genes in the Phe/Tyr synthesis pathway was downregulated. Fifty-one transcription factors (TFs) showed expression patterns correlated with those of ADCS and ALP and were predicted to bind to their promoter regions. SA upregulated many hormone genes, and 12 of these correlated strongly with both ADCS and ALP. Moreover, transgenic Arabidopsis lines overexpressing SoADCS constitutively displayed higher folate content in leaves. Taken together, our results suggested that SA may promote folate accumulation by enhancing folate precursor supply, and several candidate TFs and hormone-related genes that may be involved in the regulation of this pathway warrant further study. Full article

Background: The phylogenetic placement of the rheophilic glyptosternoid catfish Chimarrichthys kishinouyei within Sisoridae remains insufficiently resolved because mitogenome-derived phylogenetic evidence has been unavailable. Methods: We sequenced, assembled, and annotated the complete mitogenome of C. kishinouyei and reconstructed its mitochondrial phylogenetic relationships using 13 protein-coding genes and two rRNA genes. Results: The mitogenome was a circular molecule of 16,718 bp and contained 37 typical mitochondrial genes, including 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a control region. The genome showed an A + T bias, with an A + T content of 57.27%. Most tRNAs formed typical cloverleaf structures, whereas tRNA-Ser(GCU) lacked a typical DHU arm. Codon usage was biased, and all 13 protein-coding genes had Ka/Ks ratios below 1, consistent with predominant purifying selection. Phylogenetic analyses placed C. kishinouyei within the glyptosternoid lineage and recovered a strongly supported sister relationship with Pareuchiloglanis sichuanensis rather than direct clustering with Euchiloglanis davidi. Conclusions: Phylogenetic analyses based on 13 protein-coding genes and two rRNA genes support the placement of C. kishinouyei within glyptosternoid Sisoridae and indicate that relationships among Chimarrichthys, Pareuchiloglanis, and Euchiloglanis require further testing with broader integrative evidence. Full article

Background: Cutaneous squamous cell carcinoma (cSCC) is commonly regarded as a sporadic malignancy primarily driven by ultraviolet exposure. However, the occurrence of multiple, aggressive tumors at a relatively young age suggests the presence of underlying genetic susceptibility. The role of germline variants affecting extracellular matrix organization, pigmentation pathways, and tumor metabolism in aggressive cSCC remains incompletely understood. Case Presentation: We describe a 53-year-old patient with a long-standing history of multiple aggressive cutaneous squamous cell carcinomas involving the scalp and facial regions, characterized by recurrent and multifocal disease. A comprehensive diagnostic approach was undertaken, including histopathological examination, fluorescence confocal microscopy, high-frequency cutaneous ultrasound, and genetic analysis using whole-exome sequencing (WES). Results: Histopathology confirmed high-risk features consistent with aggressive cSCC. Cutaneous ultrasound and fluorescence confocal microscopy provided complementary, non-invasive insights into tumor depth, architecture, and invasive patterns. Whole-exome sequencing identified a heterozygous truncating variant in COL6A3 (NM_004369.4:c.5645C>A, p.Ser1882Ter), classified as likely pathogenic according to ACMG criteria. Additionally, two heterozygous variants of uncertain significance were detected in TYR (NM_000372.5:c.1569C>A, p.Ser523Arg) and FH (NM_000143.4:c.1237-5_1237-4insTCTCCCTCCCTC). Although individually inconclusive, the combined germline genetic background may have contributed to the patient’s aggressive and multifocal cutaneous phenotype. Discussion: This case report supports a potential role of extracellular matrix remodeling, pigmentation-related susceptibility, and metabolic dysregulation in cutaneous carcinogenesis and tumor aggressiveness. This case illustrates how integrating WES with advanced non-invasive imaging techniques can enhance the understanding of biologically aggressive cSCC. Conclusions: This report highlights a unique case of multifocal aggressive cSCC characterized by a distinct germline genetic profile identified by WES and multimodal imaging assessment. Comprehensive molecular and imaging evaluation may be beneficial in selected patients with atypical or aggressive cutaneous squamous cell carcinoma, with implications for personalized surveillance and management. Full article

Optical Benes networks are effective switching architectures for high-capacity communication systems. However, conventional routing algorithms primarily emphasize connectivity while often overlooking path quality, which often results in severe transmission loss along worst-case paths. To address this limitation, we propose an intelligent routing framework that integrates a feature extraction module with the K-Nearest Neighbors (KNN) algorithm. The proposed method guides path selection more effectively and avoids worst-case routing scenarios through effective preprocessing and feature extraction from routing tables. A 30 Gbps PAM4 transmission system is simulated to evaluate the proposed approach. For performance comparison, conventional routing methods, as well as Support Vector Machine (SVM), and Convolutional Neural Network (CNN) routing methods are considered. The results reflect significant improvements in routing accuracy (from 55% to 72.85%) with KNN, which significantly outperforming the CNN (52.23%) and SVM (51.06%) approaches while achieving the lowest computational cost of all tested methods (0.1–1 ms per iteration). Furthermore, the proposed approach reduces the power penalties, enhances the Extinction Ratio (EXT), and lowers the Symbol Error Rate (SER). Analysis using eye diagrams confirms superior signal integrity at lower received power levels. These findings demonstrate that the feature-enhanced KNN routing algorithm is an efficient and intelligent solution that not only ensures connectivity but also optimizes path quality, paving the way for scalable, high-speed optical Benes networks. Full article

Objectives: An ideal cardiotoxicity inhibitor targeting the angiotensin (Ang) II type 1 (AT₁) receptor would be a β-arrestin-biased orthostatic ligand, which inhibits the G protein pathway and activates the β-arrestin pathway. Therefore, this study examined seven Ang II mimetic peptides (MP1–7), Ang A and TRV027 as potential β-arrestin-biased AT₁ receptor ligands to prevent doxorubicin (Dox)-induced cardiotoxicity. Methods: Competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) 1/2 activation were performed using COS7 cells. Changes in phosphorylated Akt (Ser473), c-Jun N-terminal kinase (JNK) (Thr183/Tyr185), Bad (Ser112), Bcl-2 (Ser70), p53 (Ser46), active caspase-8 (Asp384) and active caspase-9 (Asp315) in cell lysates were measured using AT₁ receptor-transfected H9C2 cells. Results: Binding assays showed Ang II and Ang A had the highest affinity, with MP2 and MP7 similar to TRV027. IP production was strong for Ang II and Ang A, minimal for MP1 and MP7, and no stimulation for MP2 and TRV027. Ang II and Ang A significantly activated ERK1/2 in this cell system. MP2 and MP7 in addition to TRV027 also significantly activated ERK1/2, whereas MP1 did not activate it. Dox-activated JNK and Bad, while Ang A, TRV027, MP2, and MP7 inhibited JNK activation without affecting Bad or Akt. Conclusions: MP2, which is a candidate biased ligand for the AT₁ receptor and has similar amino acid sequence to TRV027, along with TRV027, attenuated Dox-induced JNK activation while avoiding excessive G protein-mediated activation. Interestingly, MP7, which showed minimal G protein-mediated activation with β-arrestin-mediated ERK activation, also attenuated Dox-induced JNK activation, a marker of pro-apoptotic stress signaling. Full article

High homocysteine levels are a key risk factor for cognitive impairment, a major public health concern in aging societies. Although betaine is known to reduce Hcy levels, its effects on hyperhomocysteinemia (hHcy)-induced cognitive impairment and the underlying mechanisms remain unclear. Here, we established an hHcy-induced cognitive impairment mouse model by feeding mice a high-methionine diet for 8 weeks, followed by betaine supplementation for 14 days. Betaine treatment attenuated hHcy-induced cognitive impairment. This improvement was accompanied by alleviation of neuropathological alterations and enhancement of antioxidant capacity. Notably, betaine suppressed reactive oxygen species (ROS) accumulation, neuronal apoptosis, and Tau hyperphosphorylation at Ser396 and Thr231 in both mouse hippocampus and HT-22 cells. Mechanistically, betaine-induced activation of the PI3K/AKT/GSK-3β pathway was effectively blocked by the PI3K inhibitor LY294002. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) alone phenocopied this activation, suggesting that ROS functions as an upstream regulator of this signaling cascade. Collectively, our data demonstrate that betaine attenuates hHcy-induced cognitive impairment by suppressing oxidative stress-driven apoptosis and Tau pathology through modulation of the PI3K/AKT/GSK-3β signaling pathway. These findings suggest that betaine may hold promise for further preclinical and clinical studies, although long-term efficacy and safety evaluations remain necessary. Full article

This review systematically summarizes the inherent characteristics and application superiorities of various nanomaterials, including metallic nanomaterials, metal oxides, carbon-based materials, metal–organic frameworks (MOFs), and quantum dots (QDs). State-of-the-art research progress is elaborated on the applications of these nanomaterials in multiple analytical techniques, such as surface-enhanced Raman spectroscopy (SERS), fluorescence spectroscopy, infrared spectroscopy, ultraviolet-visible spectroscopy, and electrochemistry. Furthermore, their pivotal functions in signal amplification, specific molecular recognition, and rapid analyte enrichment are thoroughly discussed. Additionally, this paper analyzes the prevailing challenges, including material heterogeneity, potential biosafety risks, poor anti-interference capacity against complex matrices, and the absence of unified industrial standardization. Future development directions are also proposed, involving green synthesis strategies, precise functional modification, portable intelligent detection, and simultaneous multi-component detection. This work aims to provide a reliable reference for further fundamental research and industrial translation of nanomaterials in the rapid and high-precision detection of pesticide residues. Full article