Search Results (19,196)

Antimicrobial peptides (AMPs) are a primary defense against pathogens. Here, we examined the interaction of two BP100 analogs, R²R⁵-BP100 (where Arg substitutes Lys 2 and 5) and R²R⁵-BP100-A-NH-C₁₆ (where an Ala and a C₁₆ hydrocarbon chain are added to the R²R⁵-BP100 C-terminus), with membrane models. Large unilamellar vesicles (LUVs) and giant unilamellar vesicles (GUVs) were prepared with the major lipids in Gram-positive (GP) and Gram-negative (GN) bacteria, as well as red blood cells (RBCs). Fluorescence data, dynamic light scattering (DLS), and zeta potential measurements revealed that upon achieving electroneutrality through peptide binding, vesicle aggregation occurred. Circular dichroism (CD) spectra corroborated these observations, and upon vesicle binding, the peptides acquired α-helical conformation. The peptide concentration, producing a 50% release of carboxyfluorescein (C₅₀) from LUVs, was similar for GP-LUVs. With GN and RBC-LUVs, C₅₀ decreased in the following order: BP100 > R²R⁵-BP100 > R²R⁵BP100-A-NH-C₁₆. Optical microscopy of GP-, GN-, and RBC-GUVs revealed the rupture or bursting of the two former membranes, consistent with a carpet mechanism of action. Using GUVs, we confirmed RBC aggregation by BP100 and R²R⁵-BP100. We determined the minimal inhibitory concentrations (MICs) of peptides for a GN bacterium (Escherichia coli (E. coli)) and two GP bacteria (two strains of Staphylococcus aureus (S. aureus) and one strain of Bacillus subtilis (B. subtilis)). The MICs for S. aureus were strain-dependent. These results demonstrate that Lys/Arg replacement can improve the parent peptide’s antimicrobial activity while increasing hydrophobicity renders the peptide less effective and more hemolytic. Full article

Background/Objectives: Axial spondyloarthritis (axSpA) is a chronic immune-mediated inflammatory disorder affecting the spine and sacroiliac joints, with variable clinical expression. This study assessed serum levels of inflammatory (TNF-α, IL-17A) and metabolic (leptin, adiponectin) biomarkers and their associations with disease activity, inflammation, structural damage, and comorbidities. Methods: This prospective cross-sectional study assessed 89 axSpA patients using clinical, laboratory, and radiological evaluations. Disease activity was measured using ASDAS-CRP and BASDAI scores. Radiographic damage was quantified using the Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Serum concentrations of TNF-α, IL-17A, leptin, and adiponectin were quantified by enzyme-linked immunosorbent assay (ELISA). Clinical and imaging correlations were analyzed. Results: Serum leptin levels correlated significantly with higher disease activity scores, inflammatory markers (CRP, ESR), radiographic progression (syndesmophyte formation, mSASSS), and arterial hypertension. Adiponectin levels were inversely associated with disease activity, structural damage, and arterial hypertension, suggesting anti-inflammatory, bone- and cardio-protective properties. TNF-α levels showed an association with inflammatory markers and were higher in patients with peripheral enthesitis. IL-17A levels were weakly correlated with disease activity and structural severity and were significantly lower in patients with a history of anterior uveitis. Conclusions: Leptin and adiponectin may serve as complementary biomarkers in axSpA, reflecting both inflammatory burden and structural damage. While TNF-α and IL-17A remain key therapeutic targets, their correlation with structural changes appears limited. Biomarker profiling could support personalized disease monitoring. Longitudinal studies are needed to validate prognostic implications. Full article

Dental implant components are typically fabricated using subtractive manufacturing, often involving metal materials that can be costly, inefficient, and time-consuming. This study explores the use of additive manufacturing (AM) with zirconia for dental implant overdenture bars, focusing on mechanical performance, stress distribution, and fit. Solid and lattice-structured bars were designed in Fusion 360 and produced using LithaCon 210 3Y-TZP zirconia (Lithoz GmbH, Vienna, Austria) on a CeraFab 8500 printer. Post-processing included cleaning, debinding, and sintering. A 3D-printed denture was also fabricated to evaluate fit. Thermography and optical imaging were used to assess adaptation. Custom fixtures were developed for flexural testing, and fracture loads were recorded to calculate stress distribution using finite element analysis (ANSYS R2025). The FEA model assumed isotropic, homogeneous, linear-elastic material behavior. Bars were torqued to 15 Ncm on implant analogs. The average fracture loads were 1.2240 kN (solid, n = 12) and 1.1132 kN (lattice, n = 5), with corresponding stress values of 147 MPa and 143 MPa, respectively. No statistically significant difference was observed (p = 0.578; α = 0.05). The fracture occurred near high-stress regions at fixture support points. All bars demonstrated a clinically acceptable fit on the model; however, further validation and clinical evaluation are still needed. Additively manufactured zirconia bars, including lattice structures, show promise as alternatives to conventional superstructures, potentially offering reduced material use and faster production without compromising mechanical performance. Full article

Anticoagulant rodenticides (ARs) are highly effective, but can be of environmental concern due to primary and secondary non-target exposure, with the latter possible being relevant to domestic cats. Therefore, liver residues of ARs and an alternative rodenticide, α-chloralose, were systematically monitored in domestic cats for the first time in the current study. In 2021 and 2022, the carcasses of 99 cats were collected in Slovenia and liver residues were measured by using solid supported liquid–liquid extraction and LC-MS/MS. The results show that 65% of cats carried at least one rodenticide. The second-generation ARs brodifacoum and bromadiolone were most prevalent and found in 53.5 and 25.3% of the samples, respectively. Of first-generation ARs, coumatetralyl was the most prevalent (21.2% of cats). More compounds were detected at high human population density, low farm density and in rural versus intermediate landscapes, but no effect was found for livestock density. Similar trends were found for the presence of brodifacoum, bromadiolone and all rodenticides combined. Farm density was negatively correlated with brodifacoum liver concentration. Individual factors (cat age, sex, outdoor activity) did not matter. The results indicate that a reasonably populated rural landscape, and not the rural or intermediate environment as such, is the main driver of cat exposure to ARs. The risk quotient (RQ) of worst-case acute brodifacoum poisoning was 1506. In summary, a potential environmental problem is globally highlighted for cats that is probably related to secondary exposure to ARs, with a pattern different to that seen in wild predators. Cats are an appropriate sentinel species for assessing rodenticide exposure and endangerment in the environment. Full article

End-of-life (EoL) continuous glass fibre-reinforced polyamide 6 composites (cGF/PA6) are commonly recycled by shredding and milling, followed by injection moulding, often resulting in lower mechanical properties of second-generation products, primarily due to fibre length reduction. This study investigates the thermomechanical reprocessing of cGF/PA6 laminates via compression moulding, aiming to retain maximum mechanical performance by preserving the fibre length. Two types of 2/2 twill glass fibre-reinforced anionically polymerised polyamide 6 laminates (cGF/APA6), with either a reactive sizing agent (RS) or a non-reactive sizing agent (nRS), were reprocessed at two different temperatures, i.e., at 180 °C (between the glass transition temperature (Tg) and the melting temperature (Tm) of PA6) and 230 °C (above the melting temperature (Tm) of PA6). The influence of reprocessing on matrix crystallinity, thermomechanical properties, microstructure, and flexural performance was investigated. The results revealed that reprocessing at both temperatures led to an improvement in matrix crystallinity, retention of the desirable α-crystalline phases, and an elevated T_g (glass transition temperature) in both reprocessed laminates. Additionally, reprocessing at 180 °C maintained the flexural performance in both, whereas reprocessing at 230 °C led to nearly 20% improvement in flexural strength for the RS laminate. The microstructural analysis of the failed flexural specimens showed matrix-coated fibre surfaces, highlighting retained fibre–matrix adhesion. Overall, the results offer insights into the potential of compression moulding as a viable alternative for recycling cGF/APA6 laminates. Full article

In arid regions, water scarcity and soil potassium destruction are major constraints on the sustainable development of the jujube industry. In this regard, the use of crop models can compensate for time-consuming and costly field trials to screen for better irrigation regimes, but their predictive accuracy is often compromised by parameter uncertainty. To address this issue, we utilized data from a three-year (2022–2024) field trial (with irrigation at 50%, 75%, and 100% of evapotranspiration and potassium applications of 120, 180, and 240 kg/ha) to simulate the growth process of jujube trees in arid regions using the WOFOST model. In this study, parameter sensitivity analyses were conducted to determine that photosynthetic capacity maximization (A_max), the potassium nutrition index (K_status), the water stress factor (SWF), the water–potassium photosynthetic coefficient of synergy (α), and potassium partitioning weight coefficients (β_i) were the important parameters affecting the simulated growth process of the crop. Path analysis using segmented structural equations also showed that water stress factor (SWF) and potassium nutrition index (K_status) indirectly controlled yield by significantly affecting photosynthesis (path coefficients: 0.72 and 0.75, respectively). The ability of the crop model to simulate the growth process and yield of jujube trees was improved by the introduction of water and potassium parameters (R² = 0.94–0.96, NRMSE = 4.1–12.2%). The subsequent multi-objective optimization of yield and crop water productivity of dates under different combinations of water and potassium treatments under a bi-objective optimization model based on the NSGA-II algorithm showed that the optimal strategy was irrigation at 80% ET_c combined with 300 kg/ha of potassium application. This management model ensures yield and maximizes crop water use efficiency (CWP), thus providing a scientific and efficient irrigation and fertilization regime for jujube trees in arid zones. Full article

Runt-related transcription factor-2 (RUNX2) is an integral player in osteogenesis and is highly expressed in osteosarcoma. Emerging evidence suggests that aberrant RUNX2 expression is a key factor in osteosarcoma oncogenesis. Patients with advanced stages of osteosarcoma overexpressing RUNX2 are more likely to have high tumour grades, metastasis, and lower overall or progression-free survival rates. Thus, RUNX2 is considered a potential candidate for targeted therapy of osteosarcoma. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor involved in the regulation of cellular reprogramming in response to hypoxia. Overexpression of HIF-1α decreases overall survival, disease-free survival, and chemotherapy response and promotes tumour stage and metastasis. Hence, our review focused on highlighting the intricate network between RUNX2 and HIF-1α, which support each other or may work synergistically to develop resistance to therapy and osteosarcoma progression. An in-depth understanding of these two important tumour progression markers is required. Therefore, this review focuses on the role of RUNX2 and HIF-1α in the alteration of the tumour microenvironment, which further promotes angiogenesis, metastasis, and resistance to therapy in osteosarcoma. Full article

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

Although the allocation of biomass among floral organs reflects critical trade-offs in plant reproductive strategies, the scaling relationships governing biomass allocations remain poorly resolved, particularly in flowers. Here, we report the fresh mass scaling allocation patterns among four floral organs (i.e., sepals, petals, stamens, and carpels), and the two subtending structural components (i.e., the pedicel and receptacle) of 497 flowers of the hypogynous Rosa chinensis var. minima (miniature rose) using reduced major axis protocols. The two-parameter Weibull probability density function was also applied to characterize the distributions of floral organ mass, and revealed skewed tendencies in all six measured traits. The results show that the numerical values of the scaling exponents (α) for all pairwise power-law relationships significantly exceeded unity (α > 1), indicating disproportionate investments in larger floral structures with increasing overall flower size. Specifically, the scaling exponent of corolla fresh mass vs. calyx fresh mass was α = 1.131 (95% confidence interval [CI]: 1.086, 1.175), indicating that petal investment outpaces sepal investment as flower size increases. Reproductive organs also exhibited significant disproportionate investments (i.e., allometry): the collective carpel (gynoecium) fresh mass scaled allometrically with respect to the collective stamen (androecium) mass (α = 1.062, CI: 1.028, 1.098). Subtending axial structures (pedicel and receptacle) also had hyperallometric patterns, with pedicel mass scaling at α = 1.167 (CI: 1.106, 1.235) with respect to receptacle mass. Likewise, the combined fresh mass of all four foliar homologues (sepals, petals, androecium, and gynoecium) scaled disproportionately with respect to the biomass of the two subtending axial structures (α = 1.169, CI: 1.126, 1.214), indicating a prioritized resource allocation to reproductive and display organs. These findings are in accord with hypotheses positing that floral display traits, such as corolla size, primarily enhance pollen export by attracting pollinators, while maintaining fruit setting success through coordinated investment in gynoecium development. The consistent hyperallometry across all organ pairwise comparisons underscores the role of developmental integration in shaping floral architecture in Rosaceae, as predicted by scaling theory. By integrating morphometric and scaling analyses, this study proposes a tractable methodology for investigating floral resource allocation in monomorphic-flowering species and provides empirical evidence consistent with the adaptive patterns of floral traits within this ecologically and horticulturally significant lineage. Full article

Chronic infection with the hepatitis B virus (HBV) results in over 1 million deaths annually. Although currently licensed treatments, including pegylated interferon-α and nucleoside/nucleotide analogs, can inhibit viral replication, they rarely eradicate covalently closed circular DNA (cccDNA) reservoirs. Moreover, vaccination does not offer therapeutic benefit to already infected individuals or non-responders. Consequently, chronic infection is maintained by the persistence of cccDNA in infected hepatocytes. For this reason, novel therapeutic strategies that permanently inactivate cccDNA are a priority. Obligate heterodimeric transcription activator-like effector nucleases (TALENs) provide the precise gene-editing needed to disable cccDNA. To develop this strategy using a therapeutically relevant approach, TALEN-encoding mRNA targeting viral core and surface genes was synthesized using in vitro transcription with co-transcriptional capping. TALENs reduced hepatitis B surface antigen (HBsAg) by 80% in a liver-derived mammalian cell culture model of infection. In a stringent HBV transgenic murine model, a single dose of hepatotropic lipid nanoparticle-encapsulated TALEN mRNA lowered HBsAg by 63% and reduced viral particle equivalents by more than 99%, without evidence of toxicity. A surveyor assay demonstrated mean in vivo HBV DNA mutation rates of approximately 16% and 15% for Core and Surface TALENs, respectively. This study presents the first evidence of the therapeutic potential of TALEN-encoding mRNA to inactivate HBV replication permanently. Full article

Parkinson’s disease (PD) is a progressive, multisystemic α-synucleinopathy, recognized as the second most prevalent neurodegenerative disorder globally. Its neuropathology is characterized by the degeneration of dopaminergic neurons, particularly in the substantia nigra pars compacta (SNpc), and the intraneuronal accumulation of α-synuclein-forming Lewy bodies. Oxidative stress is a key contributor to PD pathogenesis. Thioredoxin-interacting protein (TXNIP) is a crucial regulator of cellular redox balance, inhibiting the antioxidant function of thioredoxin. This pilot study aimed to investigate the protein expression and localization of TXNIP in the SNpc of PD patients compared to healthy controls. We performed immunohistochemical analyses on 12 post-mortem human brain sections (formalin-fixed, paraffin-embedded) from six subjects with PD and six healthy controls. The study was performed on PD subjects with Braak stage 6. Our findings revealed that in control samples, TXNIP protein was distinctly and closely associated with neuromelanin (NM) pigment within the cytoplasm of SNpc dopaminergic neurons. Conversely, in PD samples, there was a markedly weak cytoplasmic expression of TXNIP, and critically, this association with NM pigment was absent. Furthermore, PD samples exhibited a significant reduction in both dopaminergic neurons and NM content, consistent with advanced disease. These findings, which mirror previous transcriptomic data showing TXNIP gene under-expression in the same subjects, suggest that altered TXNIP expression and localization in SNpc dopaminergic neurons are features of late-stage PD, potentially reflecting neuronal dysfunction and loss. Full article

We have tested the performance of spectroscopic single-crystal Chemical Vapor-Deposited (sCVD) diamond detectors with radioactive sources and with a pulsed deuterium-tritium neutron generator. The tests demonstrate that the detectors could provide good timing and spectroscopic information at high neutron fluxes. The spectroscopic information can be obtained at a 14 MeV neutron rate as high as 10¹⁰ n/cm²/s, despite some limitations associated with pulse character of the used neutron generator. Monte-Carlo simulations were performed in order to achieve better understanding of neutron interaction with the detector material. Possible applications for the use of the detectors at Soreq Applied Research Accelerator Facility (SARAF) are considered. The detectors could be used as reliable neutron rate monitors in the vicinity of a strong accelerator-based source of energetic neutrons. The detectors could also be utilized as time-of-flight tagging counters in nuclear physics experiments under condition of high neutron fluxes during short beam pulses. In particular, measurement of the ¹²C(n,n′)3α cross-section is discussed. Full article

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

TYC 622-742-1 and TYC 1193-1918-1 are evolved metal-poor (MP) high-speed stars with r-enhanced characteristics discovered in the Milky Way (MW) halo. The study of these halo stars is important for clarification of and knowledge about their origin. We employ the abundance decomposition method to fit the observed abundances of 25 elements in TYC 622-742-1 and 24 elements in TYC 1193-1918-1, representing the largest number of elements fitted in the current observed dataset. We analyze the astrophysical formation sites of both sample stars by calculating their abundance ratios and component ratios. The calculation results suggest that both stars originated in a gas cloud that was contaminated by the ejecta of primary and main r-process materials such as those from a neutron star merger (NSM), which enriched their heavy neutron-capture elements (HNCEs), and the material from the massive stars ($M\ge 10M_{\odot }$), which enriched their primary light, iron-group, and lighter neutron-capture elements (LNCEs). This implies that TYC 622-742-1 and TYC 1193-1918-1 are the main r-process-enhanced stars with strong primary-process contributions. We find that the component coefficients of the sample stars closely resemble those of metal-poor Galactic populations, indicating a probable origin within the MW. Furthermore, the $\alpha$-enhanced abundance patterns and orbital trajectories suggest that both stars likely formed in the Galactic disk, possibly within a globular cluster (GC), and were subsequently ejected into the halo through dynamical processes. Full article

Circadian rhythms are intrinsic 24 h cycles that regulate metabolic processes across multiple tissues, with skeletal muscle emerging as a central node in this temporal network. Muscle clocks govern gene expression, fuel utilisation, mitochondrial function, and insulin sensitivity, thereby maintaining systemic energy homeostasis. However, circadian misalignment, whether due to behavioural disruption, nutrient excess, or metabolic disease, impairs these rhythms and contributes to insulin resistance, and the development of obesity, and type 2 diabetes mellitus. Notably, the muscle clock remains responsive to non-photic cues, particularly exercise, which can reset and amplify circadian rhythms even in metabolically impaired states. This work synthesises multi-level evidence from rodent models, human trials, and in vitro studies to elucidate the role of skeletal muscle clocks in circadian metabolic health. It explores how exercise entrains the muscle clock via molecular pathways involving AMPK, SIRT1, and PGC-1α, and highlights the time-of-day dependency of these effects. Emerging data demonstrate that optimally timed exercise enhances glucose uptake, mitochondrial biogenesis, and circadian gene expression more effectively than time-agnostic training, especially in individuals with metabolic dysfunction. Finally, findings are integrated from multi-omic approaches that have uncovered dynamic, time-dependent molecular signatures that underpin circadian regulation and its disruption in obesity. These technologies are uncovering biomarkers and signalling nodes that may inform personalised, temporally targeted interventions. By combining mechanistic insights with translational implications, this review positions skeletal muscle clocks as both regulators and therapeutic targets in metabolic disease. It offers a conceptual framework for chrono-exercise strategies and highlights the promise of multi-omics in developing precision chrono-medicine approaches aimed at restoring circadian alignment and improving metabolic health outcomes. Full article