Search Results (19,623)

Background/Objectives: Therapeutic antibodies have become an important modality for cancer treatment; however, effective targeted antibody therapies for T-cell acute lymphoblastic leukemia (T-ALL) remain limited. CD99 is a promising therapeutic target due to its high expression in leukemic T cells and its capacity to transmit apoptotic signals. However, the efficacy of antibody-mediated apoptosis may depend on the CD99 region recognized by the antibody. This study compared the in vitro apoptotic activity of two chimeric anti-CD99 antibodies, ChAbMT99/1 and ChAbMT99/3, which recognize distinct regions of CD99 in T-ALL models. Methods: ChAbMT99/1 and ChAbMT99/3 were generated as human IgG1 antibodies. Antibody reactivity and binding site specificity were characterized using peptide-based ELISA. Binding to native CD99, apoptosis induction in two-dimensional (2D) Jurkat E6.1 and MOLT-4 suspension cultures and three-dimensional (3D) Jurkat E6.1-derived spheroid models, and cytotoxic effects on peripheral blood mononuclear cells (PBMCs) were assessed by flow cytometry. In vitro hematologic effects were assessed using hemagglutination and platelet aggregation assays. Results: ChAbMT99/1 and ChAbMT99/3 specifically recognized peptides corresponding to distinct CD99 regions, with peptide-binding EC₅₀ values of 0.813 and 0.819 μg/mL, respectively. Both antibodies exhibited binding reactivity to native CD99 on the tested cells. Functionally, both antibodies induced Annexin V/7-AAD-defined cell death in both 2D and 3D T-ALL models compared with controls in a crosslinking-dependent manner. In contrast, both antibodies induced low levels of cell death (<10%) in bulk PBMCs, with no visible hemagglutination or platelet aggregation observed in samples from five selected donors under the stated assay conditions. Conclusions: Both chimeric anti-CD99 antibodies demonstrated in vitro apoptotic activity against T-ALL models despite recognizing distinct regions of CD99. These findings provide a rationale for further investigation of their other mechanisms of action to support the future development of CD99-targeted antibody therapy for T-ALL. Full article

Malaysia intercepts and turns back Rohingya vessels in the Andaman Sea while party to neither the 1951 Refugee Convention, its 1967 Protocol, the Convention against Torture, nor the International Covenant on Civil and Political Rights, and the doctrinal literature on non-refoulement at sea, being largely European and Australasian, leaves this non-party setting under-examined. The article makes three contributions. First, through doctrinal analysis ordered under Article 38(1) of the Statute of the International Court of Justice, it establishes that the customary prohibition of refoulement binds Malaysia and that its return-to-torture core is best treated as peremptory, admitting no persistent-objector defence. Second, it shows that the prohibition reaches conduct at sea through effective-control jurisdiction and that the rescue duty under Article 98 of the United Nations Convention on the Law of the Sea reinforces rather than displaces it, because a place of safety read in good faith cannot be a place of persecution. Third, it develops good faith, through pacta sunt servanda, systemic integration, and the prohibition of abuse of rights, as an anti-evasion principle. Assessed against these standards, the provide-and-send-away pattern documented from 2015 to January 2025, on a route that remained in use into 2026, is irreconcilable with Malaysia’s obligations. Full article

Herein, a highly selective and sensitive fluorescent sensing system is developed for the accurate quantitative determination of γ-Hexachlorocyclohexane (γ-HCH, Lindane). With carboxyl-functionalized CdSe/ZnS core–shell quantum dots (QDs) as the substrate, 3-Aminophenylboronic acid (3-APBA) is covalently conjugated onto the quantum dot surface via an amidation reaction. Systematic characterizations are used to confirm the successful fabrication of the CdSe/ZnS-COOH@3-APBA fluorescent probe, which exhibits excellent luminescence properties and superior colloidal dispersion stability. Under optimal experimental conditions, an increased γ-HCH concentration induces gradual attenuation of the probe fluorescence intensity. A favorable linear correlation is achieved within 10–140 nM, and the limit of detection is 2.62 nM. Mechanistic studies reveal that γ-HCH binds to 3-APBA on the probe surface via halogen bonding to form non-fluorescent ground-state association complexes, thereby triggering static quenching of the probe. This method can effectively distinguish α-, β-, and δ-hexachlorocyclohexane isomers. With the merits of simple operation, high sensitivity, excellent stability, and strong anti-interference capability, it provides a new strategy for the rapid screening and accurate quantification of γ-HCH residues in environmental and food matrices. Full article

Background: Antimitotic agents are very successful antitumor therapies, but lack tumor selectivity, causing toxicity. Antitumor alkylphospholipids (APLs) selectively accumulate in tumor cells but display low potencies. Hypothesis: Incorporating APL moieties onto antimitotic N-trimethoxyphenyl naphthalene sulfonamides (TMNS) might afford SMDCs with the potency of antimitotics and the tumor selectivity of APLs. Methods: 24 new TMNSs with spacers of different lengths (4 to 9 atoms) and nature (alkanes or ethers) on the sulfonamide nitrogen and capped with phosphorus-containing groups such as diethylphosphonates, phosphonic acids, and hydrogenophosphonate esters of aminoalcohols (diethylaminopropanol, choline, or dimethylaminoethanol) were designed and synthesized. Their antiproliferative effects against several cancer cell lines and their cotreatment with verapamil to assess whether they are substrates of MDR pumps were evaluated. The mechanism of action was studied: cell cycle effects, apoptosis induction, and immunofluorescence microscopy. Computational studies considered binding to tubulin and pharmacokinetics. Results: Diethyl phosphonates and phosphonic acids are antiproliferative in the micromolar to submicromolar range. P-gp inhibitor verapamil renders inactive compounds active, suggesting that efflux, not binding, removes activity. Mechanistic studies agree with an antimitotic action. Proposed binding to tubulin is similar to TMNS, with the phospholipid-like substituent projecting towards the interdimer space. Conclusions: Hybridization of TMNSs with potentially tumor–targeting APLs yields microtubule-disrupting antitumor compounds. However, the modifications assayed turn the compounds into substrates of MDR. These compounds are a proof of concept of the strategy that might succeed if future modifications avoid MDR and might target the compounds towards cancer cells. Full article

Nonylphenol (NP) is a chemical compound belonging to the class of alkylphenols (APs), known for its widespread environmental distribution and endocrine-disrupting properties. It is commonly used in the production of detergents, pesticides, and plastic materials and, owing to these properties, it can accumulate in both aquatic and terrestrial ecosystems. As a xenoestrogenic compound, NP can bind steroid receptors, including estrogen receptors (ERs), thereby activating ER-dependent pathways. In this work, we investigated the effects of NP alone and in combination with the endogenous hormones 17β-oestradiol (E2) and/or testosterone (T) on a human non-tumoral prostate cell line (PNT1A). Cell viability and migration assays, together with analysis of ER expression and localization, were carried out to assess the xenoestrogenic activity of NP, particularly in the presence of E2 and T. Our results showed that NP retained its endocrine-disrupting features in the mixtures, positively affecting cell viability, except for the NP+E2 mixture, in which cell viability did not significantly differ from control, suggesting an antagonistic interaction between NP and E2. The mixtures also interfered with steroid receptor dynamics, affecting receptor expression and delaying receptor localization and activation kinetics. Moreover, all mixtures negatively affected cell migration compared with treatment with endogenous hormones alone. In conclusion, our results demonstrate that NP retains its xenoestrogenic behavior in mixture, inducing a significant alteration in prostate cell homeostasis. Full article

Signalling between the ER and mitochondria regulates a number of key cellular functions that are damaged in frontotemporal dementia and related amyotrophic lateral sclerosis (FTD/ALS). This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER–mitochondria “tethering” proteins. A number of studies have shown that mutant genes which cause familial FTD/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3β. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER–mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER–mitochondria Ca²⁺ delivery. We also show that these effects involve inhibition of the kinase GSK3β, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer’s disease, also stimulates VAPB-PTPIP51 binding via GSK3β inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER–mitochondria signalling in FTD/ALS. Full article

Accessible molecular diagnostics is fundamental to effective healthcare. While most current point-of-care devices detect only the presence of a molecular biomarker(s), biomarker quantification can be equally important for decision-making on disease treatment and containment. Here, we present a diagnostic platform that enables the equipment-free quantification of molecular biomarkers with the simplicity of a binary (yes/no) readout. This capability is achieved by integrating a stoichiometric quantitative approach with widely available and easy-to-use lateral flow dipsticks. To implement the approach, we engineer negative cooperativity into target–probe binding interactions for oligonucleotide targets as a model system. The resulting threshold-based semi-quantitative assay with lateral flow dipsticks quantifies targets in the low-nanomolar range and operates reliably in complex biological backgrounds. A key advantage of this platform is its potential adaptability to new and emerging targets: repurposing will require only reagent redesign, without the need for additional fabrication. Full article

Alternariol (AOH) is a mycotoxin produced mainly by Alternaria alternata on fruits including tomatoes and strawberries as well as cereal grains including wheat and soybeans. In this study, we isolated Rhodotorula taiwanensis (R. taiwanensis) P1 from a pear and investigated the effects of incubation time and temperature on AOH reduction rates and the mechanism involved in AOH detoxification by the yeast strain. The yeast strain showed a 76.10% AOH reduction rate from the initial level (1 μg/mL) at 30 °C after 48 h of incubation. The yeast cell-free filtrate from the yeast culture did not increase the AOH reduction rate relative to the control without cell-free filtrate after 48 h. In addition, the AOH reduction rate by heat-inactivated yeast cells (74.57%) was similar to that by viable yeast cells (76.33%). The AOH detoxification test using the yeast cell wall fraction showed that AOH binds to its cell walls and that approximately 1/3 of the AOH bound onto the cell walls was extracted from them. These data strongly suggest that the AOH detoxification by the yeast strain was not due to degradation by either intracellular enzymes or extracellular enzymes of the yeast culture but was due to binding to yeast cell walls. The use of spheroplasts, in which cell walls are deficient, confirmed that AOH detoxification occurred by binding onto the cell walls of R. taiwanensis. Our data demonstrated that R. taiwanensis P1 was able to remove AOH by adsorption onto its cell walls. These results could help in the development of potential strategies to effectively mitigate AOH contamination of food. Full article

Chronic allograft dysfunction, driven by interstitial fibrosis and tubular atrophy, remains a major cause of long-term renal allograft loss. Everolimus (EVR), a mammalian target of rapamycin (mTOR) inhibitor, may reduce fibrosis through antifibrotic effects and calcineurin inhibitor minimization. This study aimed to evaluate the impact of EVR-involving immunosuppression on renal allograft fibrosis and to identify predictors of fibrotic progression. A total of 104 living-donor kidney transplant recipients transplanted between 2011 and 2017 were retrospectively analyzed (EVR, n = 61; non-EVR, n = 43). Interstitial fibrosis was quantified in protocol biopsies using digital image analysis. Phosphorylation of the mTOR-signaling proteins p70 ribosomal S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1 was assessed using a semiquantitative immunoreactive score. Multivariable regression analyses identified independent predictors of fibrotic progression. Cytomegalovirus infection was less frequent in the EVR group, whereas acute rejection, graft function, and graft survival were comparable between groups. At 1-year posttransplantation, interstitial fibrosis was significantly lower in the EVR group. EVR significantly suppressed p-4EBP1 phosphorylation and effectively modulated the mTOR-signaling pathway. Multivariable analysis identified the absence of EVR therapy as an independent predictor of accelerated fibrosis. EVR-involving immunosuppression attenuated renal interstitial fibrosis, likely through suppression of mTOR-signaling. Full article

Fe^II-doped zinc ferrite nanocrystals (Fe^II_xZn_1-xFe^III₂O₄) were prepared via a sol–gel approach in the presence of polyvinyl alcohol as a stabilizer and assessed for their capability to eliminate crystal violet (CV) dye from water-based solutions. The structural and surface characteristics of the prepared materials were examined by XRD, HRTEM, FESEM, ATR–FTIR, XPS, UV–visible spectrophotometer and BET analyses. XRD patterns confirmed the formation of a cubic spinel ferrite structure (Fd-3m), indicating successful incorporation of Fe^II into the ZnFe₂O₄ lattice. ATR–FTIR spectra showed characteristic metal–oxygen vibrations at the tetrahedral and octahedral sites. XPS analysis confirmed the coexistence of Fe^II and Fe^III species, which may promote interfacial charge transfer and redox reactions. HRTEM and FESEM images showed particle agglomeration and grain growth after calcination at 700 °C. Fe^II_0.2Zn_0.8Fe^III₂O₄ exhibited the highest photocatalytic performance, achieving 97.2% degradation of CV under optimized conditions. The effects of contact time, catalyst dosage, initial dye concentration, and pH were systematically studied. The maximum removal efficiency was obtained at pH 10 using 0.075 g catalyst for 20 mg L⁻¹ CV solution within 40 min. Freundlich isotherm models exhibited the strongest correlation (R² = 0.918), pointing to multilayer adsorption occurring across a non-uniform nanoparticle surface. The Dubinin–Radushkevich analysis returned an adsorption energy of 3.01 kJ mol⁻¹, implying that physical forces predominantly control the adsorption mechanism. Kinetic investigations revealed a two-stage CV uptake pathway: fast initial binding at exterior surface sites, succeeded by a slower migration of dye molecules into the internal pores of the adsorbent. Full article

Extravillous trophoblast (EVT) differentiation is essential for placental development and successful pregnancy, yet the molecular mechanisms regulating this process remain incompletely understood. CREB-binding protein (CREBBP) and E1A-binding protein p300 (EP300) are closely related lysine acetyltransferases that function as transcriptional co-activators. Previous studies reported that EP300 depletion impairs EVT differentiation whereas CREBBP depletion has little or no effect. We found that CREBBP mRNA expression was approximately one-third of EP300 expression in trophoblast stem cells (TSCs) and differentiated trophoblast lineages. To investigate whether differential CREBBP and EP300 expression explains this asymmetry in EVT differentiation initiation, we combined siRNA-mediated knockdown, CRISPR-generated CREBBP-deficient TSCs, pharmacological inhibition, and lentiviral Crebbp overexpression during EVT differentiation. While CREBBP depletion alone produced minimal phenotypic effects, CREBBP-deficient cells displayed increased sensitivity to the CREBBP/EP300 inhibitor A-485, with inhibitory effects appearing at lower A-485 concentrations in cells with reduced CREBBP level. Moreover, increased CREBBP expression partially rescued the EP300-depletion phenotype, including EVT-like morphology and selected differentiation marker expression. Together, these findings demonstrate that CREBBP contributes to EVT differentiation, but its role is obscured by its lower endogenous expression. We propose that the combined contributions of CREBBP and EP300, rather than EP300-specific activity alone, influence human trophoblast differentiation efficiency. Full article

Although the Pacific oyster (Crassostrea gigas) is a premium marine protein source, its neuroprotective peptidome remains largely uncharacterized. This study established an integrated in silico and in vitro pipeline to discover acetylcholinesterase (AChE)-targeting peptides with cellular AChE-regulating and neuroprotective peptides from simulated gastrointestinal digests of oyster. Peptidomic profiling identified 18,292 sequences, which were filtered down to seven candidates predicted to have favorable blood–brain barrier (BBB) permeability and to be non-toxic and non-allergenic (VPYPR, VPVHF, HHTF, PVHF, GPKPW, HWF, and KYW) via multi-step virtual screening. In cellular assays, simulated H₂O₂ injury (500 μM) reduced PC12 cell viability to 47.53 ± 4.53%. Compared with the model group, pretreatment with the three most potent candidates—HHTF, VPYPR, and VPVHF (200 μM)—significantly rescued injured cells, restoring cell viability to 88.31 ± 7.83%, 85.12 ± 3.35%, and 82.00 ± 3.47%, respectively (p < 0.05). These peptides effectively fortified cellular antioxidant defenses by increasing glutathione (GSH) levels to 24.24, 30.11, and 26.83 nmol/mg protein (from 20.22 nmol/mg protein in the model group) and superoxide dismutase (SOD) activity to 151.41, 153.97, and 151.96 U/mg protein (from 119.33 U/mg protein), while suppressing malondialdehyde (MDA) accumulation to 0.088, 0.064, and 0.086 nmol/mg protein (from 0.193 nmol/mg protein). Crucially, the peptides alleviated cholinergic dysfunction by normalizing the H₂O₂-induced elevation of intracellular AChE activity (11.39 nmol/min/mg protein) down to 7.02, 6.22, and 7.14 nmol/min/mg protein, respectively. Specifically, VPYPR (200 μM) restored AChE activity to a level (6.22 nmol/min/mg protein) that was not significantly different from that in the normal control group (p > 0.05). Molecular dynamics (MD) simulations (100 ns) and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations identified VPYPR as the leading candidate with a remarkably low binding free energy of −49.74 ± 3.58 kcal/mol. This study demonstrates that oyster gastrointestinal digests are valuable reservoirs of multi-target neuroprotective ingredients and provides an efficient strategy for marine bioactive peptide discovery. Full article

Intermediate band solar cells require in-gap electronic states that remain sufficiently extended to sustain collective electronic coupling and facilitate carrier motion. We investigate how structural disorder affects an intermediate band formed by coupled colloidal quantum dots embedded in a perovskite-like matrix. The system is represented by a single-orbital tight-binding Hamiltonian on a dilated face-centered-cubic lattice containing 4000 quantum dots, with system sizes between 1372 and 5324 in the finite-size analysis. Radius dispersion modifies on-site energies and hopping amplitudes, whereas positional disorder acts mainly through variations in interdot separation. Eigenstate extension is quantified using the normalized participation ratio. To distinguish spectral broadening from the loss of useful extended states, we also evaluate the mean participation of a contiguous threshold-defined spectral core, its relative energy width, and their product as a combined robustness descriptor. For the adopted baseline parameter set, degradation is energy selective: states near the spectral edges lose participation before states near the band center. At equal nominal amplitudes, radius disorder produces a stronger response than positional disorder, although the two amplitudes do not represent equal realized variances. A positional-disorder amplitude of 0.05 retains approximately 86% of the ordered-reference value of the combined descriptor, whereas a radius-disorder amplitude of 0.05 reduces it to about 22%; when both amplitudes are 0.05, about 14% remains. The model displays a comparatively robust regime near ${\sigma }_R=0.02$, a model-dependent crossover around ${\sigma }_R=0.03$–$0.04$, and strong degradation at larger values. Finite-size results are consistent with near-extensive scaling of the effective core participation number over the simulated sizes, but do not establish a thermodynamic mobility edge. These findings identify quantum-dot size uniformity as the more restrictive model control variable for preserving an extended intermediate-band core. Full article

The effects of equimolar La/Ce co-doping (0–0.4 wt.% of each element) on the microstructure, mechanical properties, and electrical conductivity of the Al-0.5Fe (8176) conductor alloy were investigated in the as-cast, cold-drawn, and annealed (300 °C, 2 h) states. La/Ce additions refine the as-cast eutectic cells and modify the detrimental Al₁₃Fe₄ intermetallic from coarse plate-like to fine spheroidal particles. At 0.3 wt.% La + 0.3 wt.% Ce (0.3LC), the annealed wire reaches a peak elongation of 16.7% (+42.7% relative to the rare-earth-free alloy), while its electrical conductivity rises from 59.87 to 61.81% IACS. The conductivity increase is explained by a solute-scavenging mechanism: La and Ce bind Fe and Si impurities into stable Al-RE intermetallics, reducing solute-induced electron scattering in the α-Al matrix. At the same time, thermally stable Al-RE dispersoids pin subgrain boundaries during annealing, retard recrystallization, and preserve the fine-grained structure that benefits ductility. Both effects originate from the same RE addition. This coupled scavenging–pinning pathway breaks the usual trade-off between conductivity and ductility and defines an optimal composition range for high-performance Al-Fe conductor alloys. Full article

Monoclonal antibodies (mAbs) are widely used as therapeutic molecules for the treatment of serious diseases, primarily cancer. The market for mAbs is one of the fastest-growing segments of the biopharmaceuticals industry. Purification is a crucial stage in the production of mAbs. While staphylococcal protein A (SpA) affinity chromatography remains the gold standard in industrial mAb purification, its limitations—low alkaline stability and insufficient binding capacity of SpA, as well as the need for harsh acidic elution conditions—have driven extensive efforts for novel progressive affinity ligands. This review focuses on the development and performance of bacterial protein-based affinity resins for the purification of class G immunoglobulins (IgGs), including conventional proteins A and G, the promising protein L, and the more recently discovered protein M (from M. genitalium), each offering unique specificities for different antibody fragments and species. Hybrid ligands combining domains from multiple bacterial proteins are also discussed, along with next-generation synthetic alternatives such as affibodies, affimers, nanobodies, etc., as well as peptide-based or mixed-mode ligands. The key finding is that the reliable and time-tested resins like those based on protein A continue to dominate the market, although future trends also point toward smaller, more stable, and cost-effective synthetic ligands for specific applications. Full article